Predictive Factors for Functional Outcomes After Intravenous Thrombolytic Therapy in Acute Ischemic Stroke.
The objective of our study is to detect the patient group that will most benefit from intravenous (IV) thrombolytic therapy by showing predictive factors of good functional outcomes. The present study covers 88 patients who were admitted to our clinic within the first 4.5 hours from the onset of stroke symptoms, diagnosed with acute ischemic stroke and who received IV thrombolytic therapy between May 2014 and June 2017 as a result of a retrospective analysis of a database prospectively collected. The patients with a score of ≤2 on modified Rankin scale within 3 months were accepted as good functional outcome and those with a score of >2 were accepted as poor functional outcome. As a result, within the period of 3 months posttreatment, good functional outcomes were obtained in 45 (51.1%) patients and poor functional outcomes were obtained in 43 (48.9%) patients. In comparisons, cardioembolic stroke group was statistically significantly higher in the good functional outcome group (P = .03). Pretreatment National Institute of Health Stroke Scale (NIHSS) scores (P < .001), presence of proximal hyperintense middle cerebral artery sign in noncontrast computed brain tomography (P = .03), and being aged ≥80 and older (P = .04) were markedly higher in the group with poor functional outcomes. In conclusion, our study demonstrated that cardioembolic strokes may have an impact on good functional outcomes and being aged 80 and older, presence of proximal HMCAS in computed brain tomography, and pretreatment NIHSS scores may have an impact on poor functional outcomes.


Progressive reduction of auditory evoked gamma in first episode schizophrenia but not clinical high risk individuals.
The early auditory-evoked gamma band response (EAGBR) may serve as an index of the integrity of fast recurrent inhibition or synaptic connectivity in the auditory cortex, where abnormalities in individuals with schizophrenia have been consistently found. The EAGBR has been rarely investigated in first episode schizophrenia patients (FESZ) and individuals at clinical high risk (CHR) for schizophrenia, and never been compared directly between these populations nor evaluated longitudinally. Here we examined the EAGBR in FESZ, CHR, and matched healthy controls (HC) at baseline and 1-year follow-up assessments to determine whether the EAGBR was affected in these clinical groups, and whether any EAGBR abnormalities changed over time. The electroencephalogram was recorded with a dense electrode array while subjects (18 FESZ, 18 CHR, and 40 HC) performed an auditory oddball task. Event-related spectral measures (phase locking factor [PLF] and evoked power) were computed on Morlet-wavelet-transformed single epochs from the standard trials. At baseline, EAGBR PLF and evoked power did not differ between groups. FESZ showed progressive reductions of PLF and evoked power from baseline to follow-up, and deficits in PLF at follow-up compared to HC. EAGBR peak frequency also increased at temporal sites in FESZ from baseline to follow-up. Longitudinal effects on the EAGBR were not found in CHR or HC, nor did these groups differ at follow-up. In conclusion, we detected neurophysiological changes of auditory cortex function in FESZ during a one-year period, which were not observed in CHR. These findings are discussed within the context of neurodevelopmental models of schizophrenia.


"Sex ratio" meiotic drive in Drosophila testacea.
We document the occurrence of "sex ratio" meiotic drive in natural populations of Drosophila testacea. "Sex ratio" males sire greater than 95% female offspring. Genetic analysis reveals that this effect is due to a meiotically driven X chromosome, as in other species of Drosophila in which "sex ratio" has been found. In contrast to other drosophilids, the "sex ratio" and standard chromosomes of D. testacea do not differ in gene arrangement, implying that the effect may be due to a single genetic factor in this species. In all likelihood, the "sex ratio" condition has evolved independently in D. testacea and in the Drosophila obscura species group, as the loci responsible for the effect occur on different chromosomal elements. An important ecological consequence of "sex ratio" is that natural populations of D. testacea exhibit a strong female bias. Because D. testacea mates, oviposits, and feeds as adults and larvae on mushrooms, this species provides an excellent opportunity to study the selective factors in nature that prevent "sex ratio" chromosomes from increasing to fixation and causing the extinction of the species.


Centralisation of radical cystectomies for bladder cancer in England, a decade on from the 'Improving Outcomes Guidance': the case for super centralisation.
To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re-intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the 'Improving Outcomes Guidance' (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high-output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation. RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30-day, 90-day, and 1-year all-cause postoperative mortality; median LoS; complication and re-intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers' annual case volume and mortality. In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30-day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30-day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1-year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re- intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977-0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988-0.993), and significantly reduced rates of re-intervention. Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re-intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.


Human Ribonuclease 6 has a Protective Role During Experimental Urinary Tract Infection.
Mounting evidence suggests that antimicrobial peptides and proteins (AMPs) belonging to the RNase A superfamily have a critical role in defending the bladder and kidney from bacterial infection. RNase 6 has been identified as a potent, leukocyte-derived AMP, but its impact on urinary tract infection (UTI) in vivo has not been demonstrated. To test the functional role of human RNase 6, we generated RNASE6 transgenic mice and studied their susceptibility to experimental UTI. In addition, we generated bone marrow derived macrophages to study the impact of RNase 6 on antimicrobial activity within a cellular context. When subjected to experimental UTI, RNASE6 transgenic mice developed reduced UPEC burden, mucosal injury, and inflammation compared to non-transgenic controls. Monocytes and macrophages were the predominant cellular sources of RNase 6 during UTI, and RNASE6 transgenic macrophages were more proficient at intracellular UPEC killing than non-transgenic controls. Altogether, our findings indicate a protective role for human RNase 6 during experimental UTI.


Atypical age-dependent effects of autism on white matter microstructure in children of 2-7 years.
Atypical age-dependent changes of white matter (WM) microstructure play a central role in abnormal brain maturation of the children with autism spectrum disorder (ASD), but their early manifestations have not been systematically characterized. The entire brain core WM voxels were surveyed to detect differences in WM microstructural development between 31 children with ASD of 2-7 years and 19 age-matched children with typical development (TD), using measurements of fractional anisotropy (FA) and radial diffusivity (RD) from diffusion tensor imaging (DTI). The anatomical locations, distribution, and extent of the core WM voxels with atypical age-dependent changes in a specific tract or tract group were delineated and evaluated by integrating the skeletonized WM with a digital atlas. Exclusively, unidirectional FA increases and RD decreases in widespread WM tracts were revealed in children with ASD before 4 years, with bi-directional changes found for children with ASD of 2-7 years. Compared to progressive development that raised FA and lowered RD during 2-7 years in the TD group, flattened curves of WM maturation were found in multiple major WM tracts of all five tract groups, particularly associational and limbic tracts, in the ASD group with trend lines of ASD and TD crossed around 4 years. We found atypical age-dependent changes of FA and RD widely and heterogeneously distributed in WM tracts of children with ASD. The early higher WM microstructural integrity before 4 years reflects abnormal neural patterning, connectivity, and pruning that may contribute to aberrant behavioral and cognitive development in ASD. Hum Brain Mapp 37:819-832, 2016. © 2015 Wiley Periodicals, Inc.


Parasitism of Hoplolaimus galeatus on Diploid and Polyploid St. Augustine grasses.
'Floratam' and 'FX-313' St. Augusfinegrasses (Stenotaphrum secundatum) were compared in a time-course experiment for host suitability and susceptibility to the lance nematode, Hoplolaimus galeatus. Nematode densities were determined in the soil and acid-fuchsin stained roots 42, 84, 126, 168, and 210 days after pots containing 230 cm(3) of autoclaved native Margate fine sand/pot were infested with 104 +/- 9 nematodes and maintained at 25 +/- 2 C in the laboratory. 'FX-313' was a more suitable host for H. galeatus. Numbers of H. galeatus reached a maximum at 210 days after inoculation, with 5,550 and 4,120 nematodes (adults plus juveniles)/pot for 'FX-313' and 'Floratam,' respectively. Root and shoot dry weights of both grasses were not affected by H. galeatus throughout the experiment. Three polyploid, 2n = 30 to 32 ('Floratam,' 'FX-10,' and 'Bitterblue') and three diploid, 2n = 18 ('FX-313,' 'Florida Common,' and 'Seville') S. secundatum genotypes were inoculated with H. galeatus (99 +/- 9/pot) and compared with uninoculated controls 210 days after inoculation. St. Augustinegrass genotypes differed as hosts of H. galeatus. 'FX-313' and 'Florida Common' represented the high and low extremes, respectively, for nematode reproduction (9,750 and 5,490 nematodes/pot or 4,239 and 2,387 nematodes/100 cm(3) of soil). However, differences in root and shoot growth were not detected 210 days after inoculation with H. galeatus.


Cost-effective but clinically inappropriate: new NICE intervention thresholds in osteoporosis (Technology Appraisal 464).
To comment on the latest technology appraisal of the National Institute for Clinical Excellence (NICE) in osteoporosis. Review of NICE Technology Appraisal (TA464) on bisphosphonate use in osteoporosis. The NICE appraisal on bisphosphonate use in osteoporosis indicates that treatment with oral bisphosphonates may be instituted at a FRAX 10-year probability of major osteoporotic fracture above 1%. Implementation would mean that all women aged 50 years or older are deemed eligible for treatment, a position that would increase the burden of rare long-term side effects across the population. Cost-effectiveness thresholds for low-cost interventions should not be used to set intervention thresholds but rather to validate the implementation of clinically driven intervention thresholds.


Gene by environment interactions for production traits in Australian dairy cattle.
Dairy farming is carried out under a wide range of production environments, including large variations in the level of feeding. Although reranking of dairy sires based on the level of feeding of their daughters has been reported, detecting the genetic mutations that cause this genotype by environment interaction has not been previously attempted. In our experiment to find genetic markers for such mutations, we selected 388 Holstein bulls from the Australian dairy bull population and genotyped them for 9,919 single nucleotide polymorphism (SNP) markers. Production data, consisting of first-lactation test-day records for milk yield, fat yield, protein yield, protein percentage, and fat percentage, from the daughters of the genotyped bulls were used to estimate the effect of each SNP, which was modeled as a regression on herd mean test-day yield, where herd mean test-day yield is a descriptor of the environment. Data were analyzed with 4 models; in 2 models, daughter records were analyzed directly, with and without taking sire relationships into account. With the other 2 models, sire reaction norms for each trait were calculated and marker effects on the sire reaction norms were estimated with and without taking sire relationships into account. The results showed that using daughter records directly and accounting for sire relationships was necessary to obtain high power and to limit the number of false positives. With this approach, SNP with significant effects were found for all traits. Log transformation of the data did not affect the power of gene detection. The significant markers were categorized according to their joint effects on production and environmental sensitivity. Potential gene candidates and application of the markers is discussed. About one-third of the significant markers affect intercept and slope in opposite directions, and some of these facilitate marker-assisted selection for robustness.


Human erythrocyte myosin: identification and purification.
Human erythrocytes contain an Mr 200,000 polypeptide that cross-reacts specifically with affinity-purified antibodies to the Mr 200,000 heavy chain of human platelet myosin. Immunofluorescence staining of formaldehyde-fixed erythrocytes demonstrated that the immunoreactive myosin polypeptide is present in all cells and is localized in a punctate pattern throughout the cell. Between 20-40% of the immunoreactive myosin polypeptide remained associated with the membranes after hemolysis and preparation of ghosts, suggesting that it may be bound to the membrane cytoskeleton as well as being present in the cytosol. The immunoreactive myosin polypeptide was purified from the hemolysate to approximately 85% purity by DEAE-cellulose chromatography followed by gel filtration on Sephacryl S-400. The purified protein is an authentic vertebrate myosin with two globular heads at the end of a rod-like tail approximately 150-nm long, as visualized by rotary shadowing of individual molecules, and with two light chains (Mr 25,000 and 19,500) in association with the Mr 200,000 heavy chain. Peptide maps of the Mr 200,000 heavy chains of erythrocyte and platelet myosin were seen to be nearly identical, but the proteins are distinct since the platelet myosin light chains migrate differently on SDS gels (Mr 20,000 and 17,000). The erythrocyte myosin formed bipolar filaments 0.3-0.4-micron long at physiological salt concentrations and exhibited a characteristic pattern of myosin ATPase activities with EDTA, Ca++, and Mg++-ATPase activities in 0.5 M KCl of 0.38, 0.48, and less than 0.01 mumol/min per mg. The Mg++-ATPase activity of erythrocyte myosin in 0.06 M KCl (less than 0.01 mumol/min per mg) was not stimulated by the addition of rabbit muscle F-actin. The erythrocyte myosin was present in about 6,000 copies per cell, in a ratio of 80 actin monomers for every myosin molecule, which is an amount comparable to actin/myosin ratios in other nonmuscle cells. The erythrocyte myosin could function together with tropomyosin on the erythrocyte membrane (Fowler, V.M., and V. Bennett, 1984, J. Biol. Chem., 259:5978-5989) in an actomyosin contractile apparatus responsible for ATP-dependent changes in erythrocyte shape.


If she is not a victim, does that mean she was not traumatized? Evaluation of predictors of PTSD symptomatology among college rape victims.
The issue of whether individuals can be traumatized by the experience of rape if they do not label the experience a victimization remains controversial. Indeed, there are conflicting findings with regard to the extent to which such unacknowledged victims experience posttraumatic symptoms. The goal of the current study was to evaluate acknowledgment status as a predictor of posttraumatic stress disorder symptomatology using structural equation modeling among a sample of 346 college rape victims. Results showed that whereas acknowledged victims reported more symptoms of posttraumatic stress disorder, acknowledgment status did not add to the prediction of posttraumatic stress disorder symptoms in a model including assault violence and other important predictors of these symptoms.


Harnessing Wheat Fhb1 for Fusarium Resistance.
Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is an economically devastating disease of wheat worldwide. Fhb1, a widely used genetic source of FHB resistance, originated in East Asia. The recent cloning of Fhb1 opens a new avenue to improve FHB resistance in wheat and potentially other crops.


Immunohistochemical investigations of cathepsin D activity in the structures of cholesteatoma.
Cathepsin D decomposes cytoplasmic proteins, cell organelles, collagen, elastase and proteoglycans. It takes part in angiogenesis and activates osteoclasts, and is thought to play a major role in the destruction of bone tissue by cholesteatoma. The aim of the present study was to evaluate the activity of cathepsin D in the structures of cholesteatoma. Cholesteatomas were collected from 16 patients operated on for chronic inflammation of the middle ear. Specimens were fixed in formalin at pH 7.2, after which parrafin slices were made. Cathepsin D was assayed with a Dako set. Keratin was measured by the Kreyberg method. Normal skin from behind the ear was taken from the patients during the same operation. The samples included a stratified, desquamative epithelium (matrix), a streak containing connective tissue (perimatrix), and a mass of keratin debris. Cathepsin D demonstrates high activity in perimatrix cells adjacent to bone tissue, while it occurs in trace amounts in the matrix. A highly positive reaction was observed within keratin, which was present in the superficial layer of the epithelium. Pseudocathepsin located in desquamative epithelial cells demonstrated a high positive reaction. There were trace amounts of cathepsin D within the dermis. In the control group (the skin samples), there were trace amounts of cathepsin D within the corneous layer of the epithelium. Cathepsin D places a major role in bone tissue destruction due to cholesteatoma.


Tanshinone IIA inhibits angiotensin II-induced cell proliferation in rat cardiac fibroblasts.
Tanshinone IIA extracted from danshen, a popular medicinal herb used in traditional Chinese medicine, exhibits cardio-protective effects. However, the mechanism of its cardioprotective effect is not well established. The aims of this study were to examine whether tanshinone IIA may alter angiotensin II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Cultured rat cardiac fibroblasts were pre-treated with tanshinone IIA and stimulated with Ang II, cell proliferation and endothelin-1 (ET-1) expression were examined. The effect of tanshinone IIA on Ang II-induced reactive oxygen species (ROS) formation, and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effect of tanshinone IIA on nitric oxide (NO) production, and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. The increased cell proliferation and ET-1 expression by Ang II (100 nM) were partially inhibited by tanshinone IIA. Tanshinone IIA also inhibited Ang II-increased ROS formation, and ERK phosphorylation. In addition, tanshinone IIA was found to increase the NO generation, and eNOS phosphorylation. N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of tanshinone IIA on Ang II-induced cell proliferation. The results suggest that tanshinone IIA prevents cardiac fibroblast proliferation by interfering with the generation of ROS and involves the activation of the eNOS-NO pathway.


Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells.
The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment.


GPCRs, G-proteins, effectors and their interactions: human-gpDB, a database employing visualization tools and data integration techniques.
G-protein coupled receptors (GPCRs) are a major family of membrane receptors in eukaryotic cells. They play a crucial role in the communication of a cell with the environment. Ligands bind to GPCRs on the outside of the cell, activating them by causing a conformational change, and allowing them to bind to G-proteins. Through their interaction with G-proteins, several effector molecules are activated leading to many kinds of cellular and physiological responses. The great importance of GPCRs and their corresponding signal transduction pathways is indicated by the fact that they take part in many diverse disease processes and that a large part of efforts towards drug development today is focused on them. We present Human-gpDB, a database which currently holds information about 713 human GPCRs, 36 human G-proteins and 99 human effectors. The collection of information about the interactions between these molecules was done manually and the current version of Human-gpDB holds information for about 1663 connections between GPCRs and G-proteins and 1618 connections between G-proteins and effectors. Major advantages of Human-gpDB are the integration of several external data sources and the support of advanced visualization techniques. Human-gpDB is a simple, yet a powerful tool for researchers in the life sciences field as it integrates an up-to-date, carefully curated collection of human GPCRs, G-proteins, effectors and their interactions. The database may be a reference guide for medical and pharmaceutical research, especially in the areas of understanding human diseases and chemical and drug discovery. Database URLs: http://schneider.embl.de/human_gpdb; http://bioinformatics.biol.uoa.gr/human_gpdb/


The use of PHC clinic-based women's groups for financial empowerment in a rural area.
The article is based on a four-year project during which Primary Health Care (PHC) nurses worked with women's groups in their areas. The aim of the study was to explore the involvement of PHC nurses in economic empowerment, both in terms of health promotion and in terms of the PHC approach. In particular the objectives were to establish whether nurses could lead economic empowerment groups, whether such groups could establish adequate external links and become financially viable. Eleven groups were used as case studies, and a cross-case analysis was done in terms of the three objectives. It was found that between the women and the nurses, adequate leadership existed for the groups to function well. Very limited external linkages were established, notwithstanding efforts in this regard. Nine out of 11 groups contributed to financial welfare of their members after 18 months, but a range of problems with regard to financial viability are identified.


Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus.
Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor. Clinical findings point to a rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity. Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. In conclusion, our findings suggest that the increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.


Analysis of gene profiles involved in the enhancement of all-trans retinoic acid-induced HL-60 cell differentiation by sesquiterpene lactones identifies asparagine synthetase as a novel target for differentiation-inducing therapy.
All-trans retinoic acid (ATRA) is one of the most useful drugs in the treatment for acute promyelocytic leukemia (APL), but its adverse effects, which include drug resistance and hypercalcemia are obstacles to achieving complete remission. Our previous study showed that some sesquiterpene lactones (STLs), i.e., helenalin (HE) and parthenolide (PA) but not sclareolide (SC), enhance ATRA-induced differentiation of HL-60 APL cells with no unexpected effects, but the precise mechanism on underlying this synergism is not yet fully understood. In this study, we investigated the distinctive transcriptional profile of cells treated with effective STL compounds, which were identified by comparing the profile with that of cells treated with SC. Genome-wide approaches using cDNA microarrays showed that co-treatment with the differentiation-enhancing STLs HE and PA maximized the transcriptional variation regulated by the suboptimal concentration of ATRA in HL-60 cells. Of the genes of interest, asparagine synthetase was remarkably downregulated by ATRA co-treated with either HE or PA, but not with SC. In an additional analysis for the role of asparagine synthetase, ATRA-mediated HL-60 cell differentiation was enhanced when asparagine in the culture media was depleted by an addition of L-asparaginase, indicating that downregulation of asparagine synthetase gene expression may be involved in the enhanced cell differentiation by STL compounds. These results provide useful insight into differentiation-inducing therapy in the treatment of leukemia.


Efficient algorithm for nonconvex minimization and its application to PM regularization.
In image processing, nonconvex regularization has the ability to smooth homogeneous regions and sharpen edges but leads to challenging computation. We propose some iterative schemes to minimize the energy function with nonconvex edge-preserving potential. The schemes are derived from the duality-based algorithm proposed by Bermúdez and Moreno and the fixed point iteration. The convergence is proved for the convex energy function with nonconvex potential and the linear convergence rate is given. Applying the proposed schemes to Perona and Malik's nonconvex regularization, we present some efficient algorithms based on our schemes, and show the approximate convergence behavior for nonconvex energy function. Experimental results are presented, which show the efficiency of our algorithms, including better denoised performance of nonconvex regularization, faster convergence speed, higher calculation precision, lower calculation cost under the same number of iterations, and less implementation time under the same peak signal noise ratio level.


Advocacy for Increased International Efforts for Antimicrobial Stewardship Actions in Low-and Middle-Income Countries on Behalf of Alliance for the Prudent Use of Antimicrobials (APUA), Under the Auspices of the International Society of Antimicrobial Chemotherapy (ISAC).
Antimicrobial stewardship (AMS) is a set of coordinated strategies to improve the use of antimicrobials, to enhance patient outcomes, reduce antimicrobial resistance, and decrease unnecessary costs. The pioneer years of AMS were restricted to high-income countries (HIC), where overconsumption of antibiotics was associated with emergence of multidrug-resistant (MDR) bacteria. AMS in low- and middle-income countries (LMIC) is also necessary. However, programs effective in HIC may not perform as well in LMIC, because (i) While decreased consumption of antibiotics may be an appropriate target in overconsuming HIC, this may be dangerous in LMIC, where many patients die from the lack of access to antibiotics; (ii) although AMS programs in HIC can be designed and monitored through laboratory surveillance of resistance, surveillance programs are not available in many LMIC; (iii) the heterogeneity of health care systems implies that AMS programs must be carefully contextualized. Despite the need to individually tailor AMS programs in LMIC, international collaborations remain highly valuable, through the dissemination of high-quality documents and educational material, that may be shared, adapted where needed, and adopted worldwide. This process, facilitated by modern communication tools, combines many benefits, including: (i) saving time, a precious dimension for health care workers, by avoiding the duplication of similar works in different settings; (ii) taking advantage of colleagues skills, and initiatives, through open access to the work performed in other parts of the world; (iii) sharing experiences, so that we all learn from each others' successes and failures.


Color-Coded Prefilled Medication Syringes Decrease Time to Delivery and Dosing Error in Simulated Emergency Department Pediatric Resuscitations.
The Institute of Medicine has called on the US health care system to identify and reduce medical errors. Unfortunately, medication dosing errors remain commonplace and may result in potentially life-threatening outcomes, particularly for pediatric patients when dosing requires weight-based calculations. Novel medication delivery systems that may reduce dosing errors resonate with national health care priorities. Our goal was to evaluate novel, prefilled medication syringes labeled with color-coded volumes corresponding to the weight-based dosing of the Broselow Tape, compared with conventional medication administration, in simulated pediatric emergency department (ED) resuscitation scenarios. We performed a prospective, block-randomized, crossover study in which 10 emergency physician and nurse teams managed 2 simulated pediatric arrest scenarios in situ, using either prefilled, color-coded syringes (intervention) or conventional drug administration methods (control). The ED resuscitation room and the intravenous medication port were video recorded during the simulations. Data were extracted from video review by blinded, independent reviewers. Median time to delivery of all doses for the conventional and color-coded delivery groups was 47 seconds (95% confidence interval [CI] 40 to 53 seconds) and 19 seconds (95% CI 18 to 20 seconds), respectively (difference=27 seconds; 95% CI 21 to 33 seconds). With the conventional method, 118 doses were administered, with 20 critical dosing errors (17%); with the color-coded method, 123 doses were administered, with 0 critical dosing errors (difference=17%; 95% CI 4% to 30%). A novel color-coded, prefilled syringe decreased time to medication administration and significantly reduced critical dosing errors by emergency physician and nurse teams during simulated pediatric ED resuscitations.


FES for abnormal movement of upper limb during walking in post-stroke subjects.
Hemiplegia can cause accidental falls, as the patients place their arms in front of their chests or next to the hips when they walk. This is due to limitations in the ability to swing their arms during walking. This study proposes a functional electrical stimulator approach in order to improve the foot drop and abnormal movement of the upper limbs during walking. The goal of this study is to verify the feasibility of improving the foot drop and arm swing problems of hemiplegic patients using electrical stimulators in a clinical trial. The present study utilizes a functional electrical stimulator found on the market. The stimulator is controlling the gait and arm swing of the patient while the patient is walking. It can help him or her restore regular gait cycles and arm swings. The FES device can also train the patient to walk safely and regain control of his or her arm swing. After the four-week training, the subjects had to walk 10 meters without the FES system. The step length, step time, and joint goniograms were recorded in order to determine whether there was any improvement. After the four-week training was concluded, the three post-stroke patients showed an improvement in arm swing angle when walking. The improvement was found to be 7.16% in the first patient, 43.06% in the second, and 54.66% in the third. These results are all statistically significant. The t-test had a p-value 0.012 (p< 0.05), which demonstrated that the method used in the present study had the potential to significantly improve the arm swing of post-stroke patients. The present study showed that a traditional foot drop functional electrical stimulator providing stimulation also to the patient's upper limbs, while being triggered by a foot switch under his or her heel, can help the patient to swing the arms and reduce the foot drop. The method has significant effect on traditional foot drop therapy. The subjects' high degree of acceptance and willingness to commit to long-term use showed that the method is indeed worthy of further research.


Endoscopy in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto IBD Group of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition.
Endoscopy is a central tool for the evaluation and management of inflammatory bowel disease (IBD). In the last few decades, gastrointestinal (GI) endoscopy has undergone significant technological developments including availability of pediatric-size equipment, enabling comprehensive investigation of the GI tract in children. Simultaneously, professional organization of GI experts have developed guidelines and training programs in pediatric GI endoscopy. This prompted the Porto Group on Pediatric IBD of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition to develop updated guidelines on the role of GI endoscopy in pediatric IBD, specifically taking into considerations of recent advances in the diagnosis, disease stratification, and novel therapeutic targets in these patients.


Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy.
Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset Parkinson's disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy. While this pathway is generally accepted to occur upon chemical uncoupling of mitochondria, the (patho-) physiologic relevance has been questioned. However, few studies have indicated that PINK1 and Parkin are also activated upon accumulation of misfolded proteins in the mitochondrial lumen upon overexpression of ΔOTC (Ornithine transcarbamylase). Here, we used the mitochondrial targeted HSP90 inhibitor Gamitrinib-triphenylphosphonium (G-TPP), an anti-cancer agent, to chemically interfere with mitochondrial protein folding. G-TPP treatment induced PINK1 accumulation, ubiquitin phosphorylation at Ser65, Parkin activation and its recruitment to mitochondria was specific for mitochondrial HSP90 inhibition and largely independent of mitochondrial membrane depolarization. Mitophagy induction was observed by monitoring autophagy receptor recruitment and the mitoKeima reporter. Importantly, mitophagy was not only induced in cancer cells but also in primary human fibroblasts and thereof converted neurons. G-TPP treatment might represent a novel strategy to study PINK1 and Parkin-mediated mitochondrial quality control using a more physiologically relevant stress.


Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide.
The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofloxacin (OR = 2.08; 95% CI: 1.23-3.52). In conclusion, exposure to all studied anti-infective agents were associated with subsequent severe hypoglycemia. Using cephalexin as the reference, drug-drug interactions were evident with ciprofloxacin (in glyburide users only), clarithromycin, co-trimoxazole, fluconazole, and levofloxacin.


Thrombolytic therapy in acute stroke.
To report the safety and efficacy of local, direct, intra-arterial and intravenous fibrinolysis treatment in selected cases of clinically symptomatic patients with acute occlusion of the intracranial cerebral arteries and dural sinuses. Patients with acute progressive neurological deterioration, in spite of systemic anticoagulation and/or antiplatelet medications, presenting with occlusion of a major intracranial cerebral artery or dural sinus were tested. From a transfemoral approach through a guiding catheter, a 2.5F microcatheter was guided directly into the intracranial cerebral circulation and embedded within the clot. Infusion of urokinase was then performed directly into the thrombus until lysis was attained. In 36 total patients, 27 cases were treated for an acute arterial occlusion in 45 vascular territories. Clinically, there was neurological improvement in 18 (66.7%) cases. Complications directly related to therapy included symptomatic intracranial hemorrhage in three cases (11.1%), which included 1 case (3.7%) of vessel perforation. In 8 (29.6%) patients, there was no evidence of clinical improvement, and in long-term follow-up there were 9 (33.3%) patient deaths. Nine patients were treated for an intracerebral dural sinus thrombosis in ten vascular territories by local urokinase infusion. In 7 (77.8%) cases, there was angiographic evidence of clot lysis and clinical improvement of the patient's neurological condition. Minor complications including infection and noncerebral sites of bleeding occurred in 3 (33.3%) patients, requiring adjustment in urokinase infusion therapy. Local, direct intra-arterial or intravenous infusion of thrombolytic drugs for treatment of stroke patients may improve overall patient morbidity and mortality related to acute thromboembolic disease in the central nervous system. Further clinical studies are warranted to evaluate this form of therapy.


Punching above its weight: life cycle energy accounting and environmental assessment of vanadium microalloying in reinforcement bar steel.
Steel-reinforced concrete is ubiquitously used in construction across the world. The United Nations estimates that the worldwide energy consumption of buildings accounts for 30-40% of global energy production, underlining the importance of the judicious selection of construction materials. Much effort has focused on the use of high-strength low-alloy steels in reinforcement bars whose economy of materials use is predicated upon improved yield strengths in comparison to low-carbon steels. While microalloying is known to allow for reduced steel consumption, a sustainability analysis in terms of embodied energy and CO2 has not thus far been performed. Here we calculate the impact of supplanting lower grade reinforcement bars with higher strength vanadium microalloyed steels on embodied energy and carbon footprint. We find that the increased strength of vanadium microalloyed steel translates into substantial material savings over mild steel, thereby reducing the total global fossil carbon footprint by as much as 0.385%. A more granular analysis pegs savings for China and the European Union at 1.01 and 0.19%, respectively, of their respective emissions. Our cradle-to-gate analysis provides an accounting of the role of microalloying in reducing the carbon footprint of the steel and construction industries and highlights the underappreciated role of alloying elements.


The distribution of cellular retinoic acid-binding protein I (CRABPI) and cellular retinol-binding protein I (CRBPI) during molar tooth development and eruption in the rat.
The distribution of cellular retinoic acid-binding protein (CRABPI) and cellular retinol binding protein (CRBPI) was studied in a series of prenatal and early postnatal rats, covering the main stages of development and eruption of the molar teeth. CRABPI positive cells were found in the mesenchymal cells of the dental follicle from the cap stage and in the dental papilla from the early bell stage. In the dental papilla, CRABPI positive cells were situated adjacent to the enamel organ in the cervical loop region and in the subodontoblastic region. Newly formed odontoblasts were CRABPI positive for a short period of time. The enamel organ was CRBPI and CRABPI negative, except for the presence of CRABPI positive cells in the internal enamel epithelium over the tip of cusps and in parts of the stratum intermedium. During root formation, CRABPI positive cells were found in the developing periodontal ligament, in the dental papilla adjacent to the epithelial root sheath and in the subodontoblastic zone. During crown formation, CRBPI positive cells were mainly localized to the mesenchymal cells of the dental papilla during the cap stage of crown development. The periosteum of the developing mandible contained CRABPI positive cells while some osteoclasts appeared to show a weak but positive reaction to CRBPI. The findings were considered in terms of the possible significance of retinoid-binding proteins during tooth and bone development.


Life-Long AAV-Mediated CRISPR Genome Editing in Dystrophic Heart Improves Cardiomyopathy without Causing Serious Lesions in mdx Mice.
Previous studies from others and us have demonstrated that CRISPR genome editing could offer a promising therapeutic strategy to restore dystrophin expression and function in the skeletal muscle and heart of Duchenne muscular dystrophy (DMD) mouse models. However, the long-term efficacy and safety of CRISPR genome-editing therapy for DMD has not been well established. We packaged both SaCas9 and guide RNA (gRNA) together into one AAVrh.74 vector, injected two such vectors (targeting intron 20 and intron 23, respectively) into mdx pups at day 3 and evaluated the mice at 19 months. We found that AAVrh.74-mediated life-long CRISPR genome editing in mdx mice restored dystrophin expression and improved cardiac function without inducing serious adverse effects. PCR analysis and targeted deep sequencing showed that the DSBs were mainly repaired by the precise ligation of the two cut sites. Serological and histological examination of major vital organs did not reveal any signs of tumor development or other deleterious defects arising from CRISPR genome editing. These results support that in vivo CRISPR genome editing could be developed as a safe therapeutic treatment for DMD and potentially other diseases.


Risk factors predicting subsequent falls and osteoporotic fractures at 4 years after distal radius fracture-a prospective cohort study.
In a prospective cohort of 113 patients followed 4 years after distal radius fracture (DRF), 24% of patients experienced a subsequent fall and 19% experienced a subsequent fracture. People with poor balance, greater fracture-specific pain/disability, low bone density, and prior falls had nearly a three times higher risk of subsequent falls. To determine the extent to which modifiable risk factors alone or in combination with bone mineral density (BMD) and non-modifiable risk factors predict subsequent falls and osteoporotic (OP) fractures after distal radius fracture (DRF). We assessed a cohort of patients (n = 191; mean age = 62 ± 8 years; female = 88%) shortly after DRF (baseline) and again at 4 years to identify subsequent falls or OP fractures. Baseline predictors included age, sex, prior falls, and modifiable risk factors such as balance, muscle strength, physical activity, fear of falling, BMD, fracture-specific pain/disability, and general health status. Univariate, multivariate, and stepwise logistic regression analyses were conducted to compute odds ratio (OR) with 95% CI to determine the extent of association between the risk factors and outcomes. Among the 113 patients, who completed 4-year follow-up, 24% reported ≥ 1 subsequent fall and 19% reported ≥ 1 subsequent fracture. Significant predictors of subsequent falls included poor balance (OR = 3.3), low total hip BMD (OR = 3.3), high patient-rated wrist evaluation (PRWE) score (OR = 3.0), and prior falls (OR = 3.4). When adjusted for BMD, age, and sex; only prior falls (OR = 4.1) remained a significant independent predictor of future falls. None of the modifiable or non-modifiable risk factors were significantly associated with subsequent fractures. Prior falls (≥ 2) is an independent predictor of subsequent falls in patients with DRF. In clinical practice, screening of patients for prior falls, balance, fracture-specific pain/disability, and BMD may identify those who might be at risk of subsequent falls after their first DRF.


The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline.
Possession of an Apolipoprotein E (APOE) e4 allele is an established risk factor for Alzheimer's disease, whereas the less commonly studied e2 variant is premised to offer some protection. This research explores the purported deleterious-protective dichotomy of APOE variants on attentional control in mid-adulthood. Sixty-six volunteers, aged 45-55 years, completed 3 tasks that provided complementary measures of attentional control: prospective memory, sustained attention, and inhibition. Performance was compared between e2 carriers, e4 carriers, and e3 homozygotes (the population norm). Carriers of the e4 allele showed subtle disadvantages, compared with the e3 group, in accuracy of Stroop task and prospective memory performance. Contrary to expectations, e2 carriers showed performance disadvantages in sustained attention. The finding of detrimental effects in attentional control for both e4 and e2 complicates the current model that proposes opposing effects of these variants on later-life cognition. Future research is needed to understand how cognitive differences develop with increasing age, and the physiological mechanisms that underpin these changes.


Mechanisms of Resistance to Mitogen-Activated Protein Kinase Pathway Inhibition in BRAF-Mutant Melanoma.
Anticancer drug resistance remains a crucial impediment to the care of many patients with cancer. Although the exact mechanisms of resistance may differ for each therapy, common mechanisms of resistance predominate, including drug inactivation or modification, mutation of the target protein, reduced drug accumulation, or bypass of target inhibition. With the discovery and use of targeted therapies (such as small-molecule kinase inhibitors), resistance has received renewed attention-especially in light of the dramatic responses that may emerge from such therapeutics in particular genetic or molecular contexts. Recently, the mitogen-activated protein kinase (MAPK) pathway has become exemplary in this regard, since it is activated in many different cancers. Drugs targeting RAF and MAPK kinase (MEK) are currently in clinical trials for the treatment of several types of cancer. Vemurafenib, a selective RAF kinase inhibitor recently approved for the treatment of BRAF(V600E) melanoma, shows strong efficacy initially; however, the development of resistance is nearly ubiquitous. In vitro testing and analysis of patient samples have uncovered several mechanisms of resistance to RAF inhibition. Surprisingly, mutations in the drug-binding pocket have not thus far been observed; however, other alterations at the level of RAF, as well as downstream activation of MEK and bypass of MEK/extracellular signal-regulated kinase (ERK) signaling altogether, confer resistance to vemurafenib. Looking forward, combined RAF and MEK inhibitor treatments may improve efficacy-yet we must anticipate mechanisms of resistance to this combination as well. Therefore, understanding and/or determining the mechanism of resistance are paramount to effective cancer treatment.


Night time aircraft noise exposure and children's cognitive performance.
Chronic aircraft noise exposure in children is associated with impairment of reading and long-term memory. Most studies have not differentiated between day or nighttime noise exposure. It has been hypothesized that sleep disturbance might mediate the association of aircraft noise exposure and cognitive impairment in children. This study involves secondary analysis of data from the Munich Study and the UK Road Traffic and Aircraft Noise Exposure and Children's Cognition and Health (RANCH) Study sample to test this. In the Munich study, 330 children were assessed on cognitive measures in three measurement waves a year apart, before and after the switchover of airports. Self-reports of sleep quality were analyzed across airports, aircraft noise exposure and measurement wave to test whether changes in nighttime noise exposure had any effect on reported sleep quality, and whether this showed the same pattern as for changes in cognitive performance. For the UK sample of the RANCH study, night noise contour information was linked to the children's home and related to sleep disturbance and cognitive performance. In the Munich study, analysis of sleep quality questions showed no consistent interactions between airport, noise, and measurement wave, suggesting that poor sleep quality does not mediate the association between noise exposure and cognition. Daytime and nighttime aircraft noise exposure was highly correlated in the RANCH study. Although night noise exposure was significantly associated with impaired reading and recognition memory, once home night noise exposure was centered on daytime school noise exposure, night noise had no additional effect to daytime noise exposure. These analyses took advantage of secondary data available from two studies of aircraft noise and cognition. They were not initially designed to examine sleep disturbance and cognition, and thus, there are methodological limitations which make it less than ideal in giving definitive answers to these questions. In conclusion, results from both studies suggest that night aircraft noise exposure does not appear to add any cognitive performance decrement to the cognitive decrement induced by daytime aircraft noise alone. We suggest that the school should be the main focus of attention for protection of children against the effects of aircraft noise on school performance.


Comparison of subject-reported allergy versus skin test results in a common cold trial.
Few studies have examined the relationship between subject-reported allergy and results of allergy skin testing in large unselected or unbiased cohorts. The objective of this study was to compare the results of self-reported allergy via verbal questioning with the results of allergy skin testing by the puncture method in 237 healthy adult subjects enrolled in a common cold study. On enrollment, all subjects were verbally asked if they had a history of allergy and then underwent puncture skin testing to 19 relevant aeroallergens, as well as appropriate positive and negative controls. A skin test was considered positive if its wheal diameter was at least 3 mm larger than that obtained with the negative control. Forty-eight (20%) subjects reported a history of allergy and 124 (52%) subjects had at least one positive skin test response. A history of allergy was reported in 40 (32%) of the skin test-positive subjects and 8 (7%) of the skin test-negative subjects. At least one positive skin test response was found in 40 (83%) of those subjects reporting a history of allergy and 84 (44%) of those subjects denying a history of allergy. These data indicate that there is a relatively poor correlation between self-reported history of allergy and skin test results in subjects enrolled in a common cold study. These results have implications in both clinical practice and research settings.


Air bubble-induced light-scattering effect on image quality in 193 nm immersion lithography.
As an emerging technique, water immersion lithography, offers the capability of reducing critical dimensions by increasing the numerical aperture that is due to the higher refractive indices of immersion liquids than that of air. However, in the process of forming a water fluid layer between the resist and the lens surfaces, air bubbles are often created because of the high surface tension of water. The presence of air bubbles in the immersion layer will degrade the image quality because of the inhomogeneity-induced light scattering in the optical path. Analysis by geometrical optics indicates that the total reflection of light causes the enhancement of scattering in the region in which the scattering angle is less than the critical scattering angle, which is 92 deg at 193 nm. Based on Mie theory, numerical evaluation of scattering that is due to air bubbles, polystyrene spheres, and poly(methyl methacrylate) spheres was conducted for TE, TM, or unpolarized incident light. Comparison of the scattering patterns shows that the polystyrene spheres and air bubbles resemble each other with respect to scattering properties. In this paper, polystyrene spheres are used to mimic air bubbles in studies of lithographic imaging of bubbles in immersion water. In an interferometric lithography system, the distance beyond which bubbles will not print can be estimated by direct counting of defect sites.


Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy.
Clostridioides difficile infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across C. difficile underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 C. difficile genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, and pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of C. difficile specifically and taxonomy of the Peptostreptococcaceae in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of C. difficile and close relatives. Beyond the taxonomic ramifications, this work may impact the diagnosis of CDI.


Measuring facial expressions by computer image analysis.
Facial expressions provide an important behavioral measure for the study of emotion, cognitive processes, and social interaction. The Facial Action Coding System (Ekman & Friesen, 1978) is an objective method for quantifying facial movement in terms of component actions. We applied computer image analysis to the problem of automatically detecting facial actions in sequences of images. Three approaches were compared: holistic spatial analysis, explicit measurement of features such as wrinkles, and estimation of motion flow fields. The three methods were combined in a hybrid system that classified six upper facial actions with 91% accuracy. The hybrid system outperformed human nonexperts on this task and performed as well as highly trained experts. An automated system would make facial expression measurement more widely accessible as a research tool in behavioral science and investigations of the neural substrates of emotion.


Evaluation of Genotypic and Phenotypic Methods to Detect Carbapenemase Production in Gram-Negative Bacilli.
Carbapenemase-producing gram-negative bacteria (CP-GNB) are an urgent and expanding public health threat. Rapid and accurate identification of these organisms facilitates infection prevention efforts in healthcare facilities. The objective of our study was to evaluate methods to detect and identify CP-GNB. We examined 189 carbapenem-resistant GNB(CR-GNB), including Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii complex, using 3 different methods: 2 methods to screen isolates of GNB for carbapenemase production [the carbapenem inactivation method (CIM) and 2 chromogenic agars] and a molecular method (Cepheid GeneXpert Carba-R) to identify the mechanism of carbapenem resistance and the associated resistance genes (blaKPC, blaNDM, blaIMP, blaOXA-48-like, and blaVIM). The CIM was a simple and inexpensive phenotypic screen to differentiate between CR-GNB and CP-GNB, with improved analytical performance characteristics and inter-reader correlation compared to the modified Hodge test. Both chromogenic agars evaluated (HardyCHROM CRE and chromID CARBA) were able to support growth of most of the organisms tested, including isolates possessing the blaOXA-48-like gene. However, these media had a low analytical specificity for carbapenemase production, with breakthrough of CR-GNB that did not produce a carbapenemase. The Xpert Carba-R assay was rapid and easy to perform, and demonstrated 100% positive and negative agreement for characterization of genetic determinants of carbapenem resistance. Screening by CIM followed by the Xpert Carba-R PCR is an accurate method for detecting and characterizing CP-GNB, including Enterobacteriaceae, P. aeruginosa, and A. baumannii complex.


Course of Cation Absorption by Plant Tissue.
The absorption of rubidium by excised barley roots from solutions containing calcium was a strictly linear function of time for 1 hour and was temperature-sensitive throughout; there was no evidence of an initial nonmetabolic exchange phase of uptake. The rubidium absorbed reached concentrations many times the external concentration without any slackening of the rate of absorption-evidence for a high degree of irreversibility of the overall absorption process. This is discussed in terms of the "enzyme-kinetic" model of ion transport by carriers.


Youth Attitudes to Domestic and Family Violence: A Scoping Review of Young People's Attitudes and Perceptions in Australia.
Domestic and family violence (DFV) has been described as a "national emergency" in Australia, with a suite of policies and interventions introduced over the past decade to better support women and their children. Within these frameworks, young people have been identified as agents of change for primary prevention; however, little is known about their attitudes and knowledge of DFV. This scoping review thus sought to establish the attitudes and knowledge of DFV held by young people (under 25 years old) in Australia. Nine international databases were searched, yielding 11 studies that met the inclusion criteria. The studies were quantitative, qualitative, and mixed methods in design, with the findings demonstrating that young Australians have good knowledge about DFV. However, the review also indicates problematic areas around young people's understanding of the harms of DFV with many continuing to hold victim-blaming attitudes. In addition, much of the existing research is survey-based in nature, there is no strong uniformity across the studies, nor is there an engaged approach to research design. Moreover, the current measures used in research are not sufficient to gauge where young people gain knowledge about DFV, nor do they explain under what conditions attitudes change or what are the medium- and long-term effects of DFV prevention work. We therefore contend that future research ought to be interdisciplinary and intersectional in nature and collaborate with a range of young people in order to understand their full potential as agents of social change and primary prevention.


Dairy food intake is positively associated with cardiovascular health: findings from Observation of Cardiovascular Risk Factors in Luxembourg study.
Conflicting findings have been reported about dairy food consumption and risk for cardiovascular disease. Furthermore, few studies have examined dairy food intake in relation to cardiovascular health and the incorporation of lifestyle factors such as diet and physical activity. This study examined whether dairy food consumption was associated with cardiovascular health, recently defined by the American Heart Association. Data were analyzed from 1352 participants from the Observation of Cardiovascular Risk Factors in Luxembourg survey. A validated food frequency questionnaire was used to measure intakes of milk, yogurt, cheese, dairy desserts, ice cream, and butter. Seven cardiovascular health metrics were assessed: smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose. A total cardiovascular health score (CHS) was determined by summing the total number of health metrics at ideal levels. It was hypothesized that greater dairy food consumption (both low fat and whole fat) would be associated with better global cardiovascular health, as indicated by a higher CHS. Total dairy food intake was positively associated with the CHS. Higher intakes of whole fat milk, yogurt, and cheese were associated with better cardiovascular health. Even when controlling for demographic and dietary variables, those who consumed at least 5 servings per week of these dairy products had a significantly higher CHS than those who consumed these products less frequently. Higher total whole fat dairy food intake was also associated with other positive health behaviors, including being a nonsmoker, consuming the suggested dietary intakes of recommended foods, and having a normal body mass index. Increased dairy food consumption was associated with better cardiovascular health.


Von Willebrand factor, angiodysplasia and angiogenesis.
The large multimeric glycoprotein Von Willebrand factor (VWF) is best known for its role in haemostasis; however in recent years other functions of VWF have been identified, indicating that this protein is involved in multiple vascular processes. We recently described a new role for VWF in controlling angiogenesis, which may have significant clinical implications for patients with Von Willebrand disease (VWD), a genetic or acquired condition caused by the deficiency or dysfunction of VWF. VWD can be associated with angiodysplasia, a condition of degenerative blood vessels often present in the gastrointestinal tract, linked to dysregulated angiogenesis. Angiodysplasia can cause severe intractable bleeding, often refractory to conventional VWD treatments. In this review we summarise the evidence showing that VWF controls angiogenesis, and review the angiogenic pathways which have been implicated in this process. We discuss the possible mechanisms though which VWF regulates angiopoietin-2 (Ang-2) and integrin αvβ3, leading to signalling through vascular endothelial growth factor receptor-2 (VEGFR2), one of the most potent activators of angiogenesis. We also review the evidence that links VWF with angiodysplasia, and how the newly identified function of VWF in controlling angiogenesis may pave the way for the development of novel therapies for the treatment of angiodysplasia in congenital VWD and in acquired conditions such as Heyde syndrome.


A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics.
The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.


Effects of chronic gamma irradiation: a multigenerational study using Caenorhabditis elegans.
The effects of chronic exposure to (137)Cs gamma radiation (dose rate ranging from 6.6 to 42.7 mGy h(-1)) on growth and reproductive ability were carried out over three generations of Caenorhabditis elegans (F0, F1, and F2). Exposure began at the egg stage for the first generation and was stopped at the end of laying of third-generation eggs (F2). At the same time, the two subsequent generations from parental exposure were returned to the control conditions (F1' and F2'). There was no radiation-induced significant effect on growth, hatchability, and cumulative number of larvae within generations. Moreover, no significant differences were found in growth parameters (hatching length, maximal length, and a constant related to growth rate) among the generations. However, a decrease in the cumulative number of larvae across exposed generations was observed between F0 and F2 at the highest dose rate (238.8 ± 15.4 and 171.2 ± 13.1 number of larvae per individual, respectively). Besides, the F1' generation was found to lay significantly fewer eggs than the F1 generation for tested dose rates 6.6, 8.1, 19.4, and 28.1 mGy h(-1). Our results confirmed that reproduction (here, cumulative number of larvae) is the most sensitive endpoint affected by chronic exposure to ionizing radiation. The results obtained revealed transgenerational effects from parental exposure in the second generation, and the second non-exposed generation was indeed more affected than the second exposed generation.


Thinning of large mammalian cells for cryo-TEM characterization by cryo-FIB milling.
Focused ion beam milling at cryogenic temperatures (cryo-FIB) is a valuable tool that can be used to thin vitreous biological specimens for subsequent imaging and analysis by cryo-transmission electron microscopy (cryo-TEM) in a frozen-hydrated state. This technique offers the potential benefit of eliminating the mechanical artefacts that are typically found with cryo-ultramicrotomy. However, due to the additional complexity in transferring samples in and out of the FIB, contamination and devitrification of the amorphous ice is commonly encountered. To address these problems, we have designed a sample cryo-shuttle that directly and specifically accepts Polara TEM cartridges to simplify the transfer process between FIB and TEM. We optimized several parameters in the cryo-FIB and cryo-TEM processes using the quality of the samples' ice as an indicator and demonstrated high-quality milling with large mammalian cells. By comparing the results from HeLa cells to those from Escherichia coli cells, we discuss some of the artefacts and challenges we have encountered using this technique.


Effects of Obstructive Sleep Apnea in Children as a Result of Adenoid and/or Adenotonsillar Hypertrophy on Maternal Psychologic Status.
The authors aimed to evaluate the effects of obstructive sleep apnea in children as a result of adenoid and/or adenotonsillar hypertrophy on maternal psychologic status. The study sample comprised the mothers of 66 children aged 3 to 15 years (mean age: 7.55 ± 2.94 years) who were scheduled to undergo curette adenoidectomy or adenotonsillectomy because of airway obstruction. The mothers completed the 14-item Hospital Anxiety and Depression Scale (HADS), 20-item State-Trait Anxiety Inventory-1 (STAI-1), and 20-item State-Trait Anxiety Inventory-2 (STAI-2) questionnaires before the operation and 10 days afterwards. Mothers who were under psychiatric treatment or declined to fill the questionnaires were excluded from the study. The results obtained postoperatively by day 10, when all the children had considerable improvement in their breathing, were analyzed as control data. The mean postoperative HAD-A and HAD-D scores of the mothers were significantly lower than the mean preoperative scores (P < 0.001). Mothers' mean STAI-1 and STAI-2 scores were also significantly lower postoperatively (P < 0.001). Pediatric adenoidectomy or adenotonsillectomy to relieve airway obstruction has a beneficial effect not only on the health of pediatric patients but also on the psychologic status of their mothers.


Voltage dependence of beta-adrenergic modulation of conduction in the canine Purkinje fiber.
Although recent voltage-clamp and microelectrode studies have demonstrated beta-adrenergic modulation of Na+ current (INa) the modulation of conduction by catecholamines and the voltage dependence of that process have not been elucidated. To determine whether voltage-dependent modulation of conduction occurs in the presence of a beta-adrenergic agonist, the effect of 1 mumol/L isoproterenol on impulse propagation in canine Purkinje fibers was examined by using a dual-microelectrode technique. At physiological membrane potentials ([K+]o 5.4 mmol/L), isoproterenol increased squared conduction velocity [theta 2, 0.39 +/- 0.25 (m/s)2 (mean +/- SD)] from 3.46 +/- 0.86 to 3.85 +/- 0.98 (m/s)2 (P < .011), an 11% change, without altering the maximum first derivative of the upslope of phase 0 of the action potential (Vmax, 641 +/- 50 versus 657 +/- 47 V/s, P = NS). At transmembrane potential of -65 mV, produced by 12 mmol/L [K+]o titration, theta 2 declined 79% to 0.73 +/- 0.44 (m/s)2 as Vmax decreased 85% to 95 +/- 43 V/s (P < .02). The addition of isoproterenol further decreased theta 2 to 0.49 +/- 0.33 (m/s)2 (P = .02) in parallel with a further decline in Vmax to 51 +/- 25 V/s (P < .05). Isoproterenol produced a 3-mV hyperpolarizing shift of apparent Na+ channel availability curves generated from both theta 2 and Vmax, used as indexes of the fast inward INa, without changing the slopes of the relation. The relation between normalized theta 2 and Vmax over a range of depolarized potentials was linear and was not appreciably altered by isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)


Feasibility and effect of home-based therapy programmes for children with cerebral palsy: a protocol for a systematic review.
Given the promising advantages of upper extremity home-based programmes in children with cerebral palsy (CP), a systematic review of the available literature on this topic is warranted. The purpose of the systematic review described in this protocol is to investigate currently available home-based occupational therapy and physiotherapy programmes regarding both their feasibility and effect. This protocol describes a systematic review, developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015. Studies will be included in which primary data are collected, participants are children aged <18 years with any type of CP and the intervention of interest is a home-based occupational therapy or physiotherapy intervention. Comparators of interest are: no therapy, care as usual, centre-based occupational therapy or physiotherapy, an alternative home-based programme and a medical intervention. Studies will be included that report either on feasibility (ie, acceptability, demand, implementation, practicality, adaptation, expansion or integration) or on efficacy/effectiveness (ie, child-related upper extremity outcomes within all International Classification of Functioning, Disability and Health levels or parent-related/caregiver-related outcomes on the psychological and social domain). Relevant studies will be identified by searching the databases MEDLINE, EMBASE, CINAHL, PsycINFO, PEDro, OTSeeker and CPCI-S as well as the trial registers ICTRP and CENTRAL, the reference lists of included records and by circulating a bibliography of the included records to authors of included studies. There will be no restrictions on language or year of publication. The search strategy consists of terms related to the population and intervention. Data will be extracted in duplicate using a digital data extraction form. The proposed study does not involve collection of primary data. Accordingly, no ethical approval is required. The authors will disseminate the findings of this systematic review through publication in a peer-reviewed journal and conference presentation(s). CRD42016043743; pre-results.


Chronic widespread bodily pain is increased among individuals with history of fracture: findings from UK Biobank.
In this cross-sectional analysis of the UK Biobank cohort, a history of fracture was associated with increased risk of current widespread chronic pain. We aimed to test the hypothesis that a history of fracture is associated with reporting chronic widespread bodily pain (CWBP), using baseline data from the UK Biobank cohort, comprising 502,656 people aged 40-69 years. The case definition of current chronic widespread bodily pain was based on a response of 'yes' to the question 'do you have pain all over the body?' and 'yes' to 'and have you experienced pain all over the body for more than 3 months?' Multivariable Poisson regression with robust standard errors was used to test the relationship between fracture (occurring within 5 years prior to the baseline interview, and recorded by self-report) at the spine, hip, upper limb or lower limb and CWBP, adjusting for confounders. Of 501,733 participants (mean age 56.5 years), 7130 individuals reported CWBP and 23,177 had a history of fracture affecting the upper limb, lower limb, spine and/or hip. Individuals with prior fracture were significantly more likely to report CWBP than those without. After adjustment for potential risk factors (age, gender, demographic, lifestyle and socioeconomic, and psychological), risk ratios were attenuated but remained statistically significant with a more than doubling of risk for CWBP with spine fractures in men (risk ratio (RR) 2.67, 95% confidence interval (CI) 1.66-4.31; p < 0.001) and women (RR 2.13, 95% CI 1.35-3.37, p = 0.001) and with hip fractures in women (RR 2.19, 95% CI 1.33-3.59; p = 0.002). In this cross-sectional analysis, previous fracture is associated with an increased likelihood of chronic widespread bodily pain, particularly with hip fractures in women, and spine fractures in both sexes. If replicated, these findings may help inform the identification of those most at risk of chronic widespread pain post-fracture, allowing preventative measures to be targeted.


Effects of an ergonomic training program on workers with video display units.
This study evaluated the effect of an ergonomic training program on workstation changes and on the prevalence of musculoskeletal disorders among video display unit (VDU) users at a large university. A pretest-posttest design with a reference group was used with random allocation of administrative and geographic units. In each group, the measurements involved direct observation of the workstations, a self-administered questionnaire, and a physical examination. The measurements were performed 2 weeks before and 6 months after the training in parallel in both groups. The study population was composed of 627 workers (81% of those eligible). The prevalence of all 3 of the postural stressors evaluated decreased in the experimental group after the training. In the reference group, 2 of the 3 stressors decreased in frequency but to a less extent. Some of these beneficial changes were more frequent in workers under 40 years of age. The prevalence of musculoskeletal disorders decreased among the workers under 40 years of age in the experimental group, from 29% to 13% determined by questionnaire and from 19% to 3% determined by physical examination. In other groups, there was no significant change in the prevalence of musculoskeletal disorders. Improvements in postural stressors occurred more frequently in the experimental group, and these beneficial changes tended to be more frequent in workers under 40 years of age. Improvements in musculoskeletal disorders occurred in the experimental group among the workers under 40 years of age.


Myopia predicts better outcome in persistent hyperplastic primary vitreous.
Persistent hyperplastic primary vitreous (PHPV) is a congenital disorder that presents with a spectrum of ocular anomalies, including cataracts, microphthalmia, and hyaloid vessel remnants. Severe visual loss due to secondary glaucoma and retinal detachment is common. This report evaluates the visual outcome of a variant of PHPV with myopia not associated with glaucoma. The records of 23 consecutive patients with the diagnosis of PHPV (all unilateral) from October 1992 to August 1995 were reviewed. All but three patients had a cataract extraction procedure and all underwent amblyopia therapy. Eyes with a phakic myopic refractive error (Rx) or aphakic refractive correction < or = 8.5 diopters (D) in the immediate postoperative period were designated as myopic. Six patients were in the myopic group (Group 1) and 17 in were the nonmyopic group (Group 2). The mean age of diagnosis was 21.1 months in Group 1 versus 2.0 months in Group 2, with a comparable follow-up period of 36 months. The mean preoperative Rx of Group 1 was -7.78 D. The mean aphakic Rx of Group 2 was +18.29 D. Average axial length measurement determined by echography was 22.46 mm in Group 1 and 14.03 mm in Group 2. The mean corneal diameter was 11.3 mm in Group 1 vs 8.9 mm in Group 2. In Group 2, seven eyes developed retinal detachment and four developed glaucoma. These complications did not develop in Group 1 during the follow-up period. Overall functional visual acuity was better in Group 1, with a median visual acuity at final follow up of 20/160, as compared with light perception for Group 2. PHPV eyes with myopia were not detected as early as the typical PHPV eyes, primarily because of less media opacification and near-normal corneal diameters. These eyes showed a more favorable visual outcome as they were less likely to develop typical PHPV-related postoperative complications. Myopic PHPV eyes may require a different management approach.


Asymmetrical cortical processing of radial expansion/contraction in infants and adults.
We report asymmetrical cortical responses (steady-state visual evoked potentials) to radial expansion and contraction in human infants and adults. Forty-four infants (22 3-month-olds and 22 4-month-olds) and nine adults viewed dynamic dot patterns which cyclically (2.1 Hz) alternate between radial expansion (or contraction) and random directional motion. The first harmonic (F1) response in the steady-state VEP response must arise from mechanisms sensitive to the global radial motion structure. We compared F1 amplitudes between expansion-random and contraction-random motion alternations. F1 amplitudes for contraction were significantly larger than those for expansion for the older infants and adults but not for the younger infants. These results suggest that the human cortical motion mechanisms have asymmetrical sensitivity for radial expansion vs. contraction, which develops at around 4 months of age. The relation between development of sensitivity to radial motion and cortical motion mechanisms is discussed.


Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-binding proteins that interact with the translation machinery.
Trypanosoma brucei and related pathogens transcribe most genes as polycistronic arrays that are subsequently processed into monocistronic mRNAs. Expression is frequently regulated post-transcriptionally by cis-acting elements in the untranslated regions (UTRs). GPEET and EP procyclins are the major surface proteins of procyclic (insect midgut) forms of T. brucei. Three regulatory elements common to the 3' UTRs of both mRNAs regulate mRNA turnover and translation. The glycerol-responsive element (GRE) is unique to the GPEET 3' UTR and regulates its expression independently from EP. A synthetic RNA encompassing the GRE showed robust sequence-specific interactions with cytoplasmic proteins in electromobility shift assays. This, combined with column chromatography, led to the identification of 3 Alba-domain proteins. RNAi against Alba3 caused a growth phenotype and reduced the levels of Alba1 and Alba2 proteins, indicative of interactions between family members. Tandem-affinity purification and co-immunoprecipitation verified these interactions and also identified Alba4 in sub-stoichiometric amounts. Alba proteins are cytoplasmic and are recruited to starvation granules together with poly(A) RNA. Concomitant depletion of all four Alba proteins by RNAi specifically reduced translation of a reporter transcript flanked by the GPEET 3' UTR. Pulldown of tagged Alba proteins confirmed interactions with poly(A) binding proteins, ribosomal protein P0 and, in the case of Alba3, the cap-binding protein eIF4E4. In addition, Alba2 and Alba3 partially cosediment with polyribosomes in sucrose gradients. Alba-domain proteins seem to have exhibited great functional plasticity in the course of evolution. First identified as DNA-binding proteins in Archaea, then in association with nuclear RNase MRP/P in yeast and mammalian cells, they were recently described as components of a translationally silent complex containing stage-regulated mRNAs in Plasmodium. Our results are also consistent with stage-specific regulation of translation in trypanosomes, but most likely in the context of initiation.


Neuro tissue engineering of glial nerve guides and the impact of different cell types.
The aim of neuro tissue engineering is to imitate biological features in order to enhance regeneration. Following lesions of peripheral nerves, Schwann cells (SCs) reorganize to form longitudinal bands of Büngner (boB) which function as guides for regrowing axons. In order to imitate boB in synthetic implants designed to bridge nerve lesions, we developed resorbable, semipermeable nerve guide conduits with microstructured internal polymer filaments. We utilized a novel microcell chip and identified three extracellular matrix components conducive for coating non-permissive polymer surfaces. In order to maximize SC alignment, seven different microtopographies were investigated via the silicon chip technology. Special longitudinal microgrooves directed SC orientation and growing axons of dorsal root ganglia (DRG), thus achieving stereotropism. When these results were applied to microgrooved polymer filaments inside nerve guide conduits, we observed highly oriented axon growth without meandering. Since scar-forming fibroblasts could potentially interfere with axonal regrowth, triple cultures with fibroblasts, SC and DRG were conducted. Fibroblasts positioned on the outer nanopore containing conduit wall, did not hamper neuronal and glial differentiation inside the tube. In summary, for more rapid regrowth, functional boB can be induced by guided microtissue engineering. By considering both the negative and positive effects of cell interactions, a more rational design of nerve implants becomes feasible.


Alveolar macrophages regulate neutrophil recruitment in endotoxin-induced lung injury.
Alveolar macrophages play an important role during the development of acute inflammatory lung injury. In the present study, in vivo alveolar macrophage depletion was performed by intratracheal application of dichloromethylene diphosphonate-liposomes in order to study the role of these effector cells in the early endotoxin-induced lung injury. Lipopolysaccharide was applied intratracheally and the inflammatory reaction was assessed 4 hours later. Neutrophil accumulation and expression of inflammatory mediators were determined. To further analyze in vivo observations, in vitro experiments with alveolar epithelial cells and alveolar macrophages were performed. A 320% increase of polymorphonuclear leukocytes in bronchoalveolar lavage fluid was observed in macrophage-depleted compared to macrophage-competent lipopolysaccharide-animals. This neutrophil recruitment was also confirmed in the interstitial space. Monocyte chemoattractant protein-1 concentration in bronchoalveolar lavage fluid was significantly increased in the absence of alveolar macrophages. This phenomenon was underlined by in vitro experiments with alveolar epithelial cells and alveolar macrophages. Neutralizing monocyte chemoattractant protein-1 in the airways diminished neutrophil accumulation. These data suggest that alveolar macrophages play an important role in early endotoxin-induced lung injury. They prevent neutrophil influx by controlling monocyte chemoattractant protein-1 production through alveolar epithelial cells. Alveolar macrophages might therefore possess robust anti-inflammatory effects.


Hospital revenue cycle management and payer mix: do Medicare and Medicaid undermine hospitals' ability to generate and collect patient care revenue?
The continuing efforts of government payers to contain hospital costs have raised concerns among hospital managers that serving publicly insured patients may undermine their ability to manage the revenue cycle successfully. This study uses financial information from two sources-Medicare cost reports for all US hospitals for 2002 to 2007 and audited financial statements for all bond-issuing, not-for-profit hospitals for 2000 to 2006 to examine the relationship between hospitals' shares of Medicare and Medicaid patients and the amount of patient care revenue they generate as well as the speed with which they collect their revenue. Hospital-level fixed effects regression analysis finds that hospitals with higher Medicare and Medicaid payer mix collect somewhat higher average patient care revenues than hospitals with more privately insured and self-pay patients. Hospitals with more Medicare patients also collect on this revenue faster; serving more Medicaid patients is not associated with the speed of patient revenue collection. For hospital managers, these findings may represent good news. They suggest that, despite increases in the number of publicly insured patients served, managers have frequently been able to generate adequate amounts of patient revenue and collect it in a timely fashion.


A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters.
The downward directed exit of the swan neck catheter may decrease the risk of exit-site infection (ESI). The percentage of migrations of the swan neck catheter seems to be less than the conventional Tenckhoff catheter and the swan neck catheter is more expensive and cannot be manipulated by guidewire technique if tip migration occurs. In this study, the conventional Tenckhoff catheter was used. The straight tunnel was converted to an arcuate one using the triple incision method, resulting in a downward directed exit. The arcuate tunnel was created by passing the catheter through an additional incision located between the paramedian incision and the exit site. We compared the infective and mechanical complications of the Tenckhoff catheter with a downward exit, implanted using the triple incision method, with the swan neck catheter. 101 new peritoneal dialysis patients were prospectively randomized to receive either the Tenckhoff catheter with a downward exit, implanted using the triple incision method, or the swan neck catheter. Each patient was followed up for 24 months. 50 patients were in the triple incision method group (TIMG) and 51 were in the swan neck catheter group (SNCG). Over a mean period of 18.9 +/- 8.0 months of follow-up, ESI occurred in 35 patients (70%) in TIMG and 37 patients (72.5%) in SNCG (p = 0.83). The ESI rates were 0.71 and 1.0 episodes/catheter-year in TIMG and SNCG respectively (p = 0.21). The peritonitis rates were similar in the 2 groups (0.64 episodes/year in TIMG and 0.68 episodes/year in SNCG, p = 0.47). More patients in TIMG had tip migration [15 patients (30%) in TIMG vs 10 patients (19.6%) in SNCG] but the difference was not statistically significant. Repositioning of the catheter by guidewire manipulation was successful in patients in TIMG but not in SNCG. Overall catheter survival at 12 and 24 months was 95% and 83% in TIMG and 93% and 79% in SNCG respectively (p = 0.72). By using the conventional Tenckhoff catheter with a downward exit created using the triple incision method, high catheter survival rates with infective and mechanical complication rates similar to those of the swan neck catheter can be achieved. The triple incision method has the additional advantages of lower cost and the catheter can be manipulated by guidewire technique if tip migration occurs.


Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.
Coenzyme Q10 (CoQ10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ10 biosynthesis (COQ genes) cause primary CoQ10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ10 ], CoQ10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4ed -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687-1703.


Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
Obesity is reported to be associated with erosive esophagitis (EE). However, the temporal association of obesity and abdominal obesity with EE is unclear. We conducted this study to investigate the temporal association of obesity, especially abdominal obesity with EE. Among 1,182 subjects who underwent health screening examinations including upper endoscopy in both 2003 and 2006, a total 1,029 subjects with a normal esophagogastric junction on upper endoscopy in 2003 were enrolled. All subjects completed questionnaires and anthropometric measurements were obtained twice by trained personnels. The patients with newly developed EE were compared to the subjects without newly developed EE. Among 1,029 subjects, 42 (4.1%) were newly diagnosed with EE and 82 (8.0%) with hiatal hernia. The mean body mass index (BMI) in both examinations was significantly different between the two groups based on the development of erosive esophagitis (p<0.05 in both examinations). The mean waist circumference (WC) in both examinations was also significantly different between the two groups (p<0.01 in both examinations). The multivariate analysis demonstrated that EE was not associated with the BMI in 2003 and the increase of BMI; however, it was associated with the WC in 2003 (Odds ratio, 7.21; 95% CI, 1.78 to 29.19; >90 cm vs <80 cm). Our study showed that abdominal circumference is an independent risk factor for EE, demonstrating a temporal relationship between abdominal obesity and EE.


Photostability and photodegradation pathways of distinctive pesticides.
Transformation of pesticides in the environment is a highly complex process affected by different factors. Biological and physical-chemical factors may play a role in the degradation to variable extent. Photodecomposition might be regarded as one of the most crucial factors affecting the fate of pesticides. Therefore, our study focused on revealing specific details of the photolytic degradation of pesticides. The toxicity of the examined pesticides is well known; however, little information is available regarding their natural degradation processes. More detailed examinations are required to reveal the exact mechanism of the pesticide decomposition and the biological impacts of the degradates. Significance of this study is enhanced by the fact that decomposition of pesticides may result in the formation of toxic degradation products. The photolytic degradation of frequently applied pesticides (e.g., acetochlor, simazine, chlorpyrifos, and carbendazim) with different chemical structures was investigated. An immersible ultraviolet light source was applied to induce photodegradation. The degradation processes were followed by thin-layer chromatography and gas chromatography/mass spectrometry techniques. Electron ionization mass spectrometry was used to identify the degradation species. Detailed mechanisms of photolytic transformation were established by identification of each degradate. The photolytic degradation of pesticides of distinctive chemical character exhibited markedly different photodecomposition mechanisms. At least four degradation species were detected and identified in each case. Loss of alkyl, chloro, and hydroxyl groups as well as cleavage of alkyloxy, amide, amino-alkyl, and ester bonds might be regarded as typical decomposition patterns. Deamination and ring opening might be observed at the last stages of decomposition.