Differential temporal and spatial progerin expression during closure of the ductus arteriosus in neonates.
Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure.


SU-E-I-46: Quantitative Effects of Clinical Practice on the Efficiency of CT Tube Current Modulation for Radiation Dose Reduction.
CT tube current modulation (TCM) represents one of the most important and efficient methods for radiation dose reduction and has been well accepted. However, the possible influence of clinical practice is likely to be ignored although venders may provide clinical protocols and instructions. This study is designed to further investigate the quantitative effects of clinical operation, including radiograph direction and patient positioning, on the efficiency of TCM by measuring patient radiation dose and image quality. An anthromorphologic chest phantom was scanned in a Sensation 40 and a lightSpeed 16 CT scanner, respectively, using routine chest protocols with TCM. We first investigated the effects of radiograph direction. Anterior-posterior (AP), lateral, and posterior-anterior (PA) directions were chosen. CTDIvol and dose-length-product (DLP) were recorded for analyses. Our second experiment studied the influence of patient position. First the phantom was positioned at the iso-center then scanned with AP direction. CTDIvols and DLPs were recorded as reference. Then the phantom was moved out of iso-center, up or down 2 and 4 cm respectively then scanned. CTDIvols and DLPs were recorded for comparison. For each setting, image noise was measured. CTDIvol increases approximately 20% for PA direction, compared to AP or lateral direction which generates similar CTDIvol and DLP with TCM. Image noise for the PA direction is less than those for the AP or lateral directions. CTDIvol increases approximately 9% for LightSpeed 16 and 13% for Sensation 40 when the phantom was moved up 4 cm, while CTDIvol decreases approximately 5% for LightSpeed 16 and 8% for Sensation 40 when the phantom was moved down 4 cm. Our quantitative study can direct clinical practice to improve the efficiency of CT tube current modulation and reduce patient radiation dose.


Intrarater test-retest reliability of static and dynamic stability indexes measurement using the Biodex Stability System during unilateral stance.
The measurements of postural balance often involve measurement error, which affects the analysis and interpretation of the outcomes. In most of the existing clinical rehabilitation research, the ability to produce reliable measures is a prerequisite for an accurate assessment of an intervention after a period of time. Although clinical balance assessment has been performed in previous study, none has determined the intrarater test-retest reliability of static and dynamic stability indexes during dominant single stance. In this study, one rater examined 20 healthy university students (female=12, male=8) in two sessions separated by 7 day intervals. Three stability indexes--the overall stability index (OSI), anterior/posterior stability index (APSI), and medial/ lateral stability index (MLSI) in static and dynamic conditions--were measured during single dominant stance. Intraclass correlation coefficient (ICC), standard error measurement (SEM) and 95% confidence interval (95% CI) were calculated. Test-retest ICCs for OSI, APSI, and MLSI were 0.85, 0.78, and 0.84 during static condition and were 0.77, 0.77, and 0.65 during dynamic condition, respectively. We concluded that the postural stability assessment using Biodex stability system demonstrates good-to-excellent test-retest reliability over a 1 week time interval.


Differences in the mode of phagocytosis of bacteria between macrophages and testicular Sertoli cells.
Sertoli cells, the sole somatic cell type in the seminiferous epithelium, play an essential role in spermatogenesis and spermiogenesis by nursing germ cells for their survival and differentiation as well as physically inhibiting the entrance of harmful substances into the seminiferous tubules. Sertoli cells possess the characteristics of immune cells; they express pattern recognition receptors, secrete antimicrobial proteins, and engulf dead or dying cells. In this study, we determined the mechanism by which Sertoli cells engulf and kill bacteria compared to that of macrophages. When the primary cultured Sertoli cells of rats were incubated with Staphylococcus aureus, they produced the mRNA of neutrophil protein 3, an antimicrobial peptide of the α-defensin family, but not superoxide or nitric oxide, in contrast to mouse peritoneal macrophages. Sertoli cells effectively phagocytosed S. aureus in a manner that was accompanied by cytoskeleton rearrangement and dependent on phosphatidylinositol 3-kinase. Engulfed bacteria appeared to stay alive in Sertoli cells, while they were rapidly killed in macrophages. These results collectively suggest that Sertoli cells eliminate bacteria that have invaded the seminiferous epithelium without evoking inflammation, unlike macrophages.


Genetic Basis of Emerging Vancomycin, Linezolid, and Daptomycin Heteroresistance in a Case of Persistent Enterococcus faecium Bacteremia.
Whole-genome sequencing was used to examine a persistent Enterococcus faecium bacteremia that acquired heteroresistance to three antibiotics in response to prolonged multidrug therapy. A comparison of the complete genomes before and after each change revealed the emergence of known resistance determinants for vancomycin and linezolid and suggested that a novel mutation in fabF, encoding a fatty acid synthase, was responsible for daptomycin nonsusceptibility. Plasmid recombination contributed to the progressive loss of vancomycin resistance after withdrawal of the drug.


The impact of vitamin D in breast cancer: genomics, pathways, metabolism.
Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.


Competition-induced starvation drives large-scale population cycles in Antarctic krill.
Antarctic krill (Euphausia superba) - one of the most abundant animal species on Earth - exhibits a 5-6 year population cycle, with oscillations in biomass exceeding one order of magnitude. Previous studies have postulated that the krill cycle is induced by periodic climatological factors, but these postulated drivers neither show consistent agreement, nor are they supported by quantitative models. Here, using data analysis complemented with modeling of krill ontogeny and population dynamics, we identify intraspecific competition for food as the main driver of the krill cycle, while external climatological factors possibly modulate its phase and synchronization over large scales. Our model indicates that the cycle amplitude increases with reduction of krill loss rates. Thus, a decline of apex predators is likely to increase the oscillation amplitude, potentially destabilizing the marine food web with drastic consequences for the entire Antarctic ecosystem.


Tannerella forsythia and Pseudomonas aeruginosa in subgingival bacterial samples from parous women.
Information on the subgingival microbiota in parous women is limited. The present study assessed 74 bacterial species at periodontal sites. Subgingival bacterial plaque was collected from women > or =6 months after delivery. Bacteria were assessed by the checkerboard DNA-DNA hybridization method. Gingivitis was defined as > or =20% of sites with bleeding on probing (BOP), and periodontitis was defined as radiographic evidence of bone loss and probing depths > or =5.0 mm. A total of 197 women (mean age: 29.4 +/- 6.8 years; range: 18 to 46 years) were included in the study. Gingivitis was identified in 82 of 138 subjects without evidence of periodontitis (59.4%). Periodontitis was found in 59 women (32%). Higher bacterial levels in subjects with gingivitis compared to those without evidence of gingivitis were observed for Actinomyces neuii, Bifidobacterium bifidum, Corynebacterium pseudogenitalis, Porphyromonas endodontalis, Prevotella bivia, and Pseudomonas aeruginosa (P <0.001 for each). Higher bacterial levels in subjects with periodontitis compared to those without periodontitis (BOP not accounted for) were found for 32 of 79 species (P <0.001) including Lactobacillus iners, Haemophilus influenzae, Porphyromonas gingivalis, Tannerella forsythia (previously T. forsythensis), Prevotella bivia, P. aeruginosa, and Staphylococcus aureus. Binary univariate logistic regression analysis identified that P. aeruginosa (P <0.001) and T. forsythia (P <0.05) were independently predictive of periodontal status. The odds ratio of having P. aeruginosa at levels > or =1 x 10(5) in the sample and periodontitis was 3.1 (95% confidence interval: 1.6 to 5.9; P <0.001). In addition to P. gingivalis and T. forsythia, a diverse microbiota, including P. aeruginosa, P. endodontalis, P. bivia, and S. aureus, can be found in subgingival plaque samples from women of child-bearing age with periodontitis.


Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016.
Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.


Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.
Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.


Fish antiviral tripartite motif (TRIM) proteins.
Tripartite motif (TRIM) family or RBCC proteins comprises characteristic zinc-binding domains (a RING (R), a B-box type 1 (B1) and a B-box type 2 (B2)) and coiled-coil (CC) domain followed by a C-terminus variable domain. There are about 80 different TRIM proteins in human, but more than 200 in zebrafish with several large gene expansions (ftr >70 genes; btr >30 genes; trim35 > 30 genes). Repertoires of trim genes in fish are variable across fishes, but they have been remarkably diversified independently in a number of species. In mammals, TRIM proteins are involved in antiviral immunity through an astonishing diversity of mechanisms, from direct viral restriction to modulation of immune signaling and more recently autophagy. In fish, the antiviral role of TRIM proteins remains poorly understood. In zebrafish, fish specific TRIMs so called fintrims show a signature of positive selection in the C terminus SPRY domain, reminding features of mammalian antiviral trims such as TRIM5. Expression studies show that a number of trim genes, including many fintrims, can be induced during viral infections, and may play a role in antiviral defence. Some of them trigger antiviral activity in vitro against DNA and RNA viruses, such as FTR83 that also up-regulates the expression of type I IFN in zebrafish larvae. The tissue distribution of TRIM expression suggests that they may be involved in the regionalization of antiviral immunity, providing a particular protection to sensitive areas exposed to invading pathogens.


Deletion of chromosome 11q predicts response to anthracycline-based chemotherapy in early breast cancer.
Despite the recent consensus on the eligibility of adjuvant systemic therapy in patients with lymph node-negative breast cancer (NNBC) based on clinicopathologic criteria, specific biological markers are needed to predict sensitivity to the different available therapeutic options. We examined the feasibility of developing a genomic predictor of chemotherapy response and recurrence risk in 185 patients with NNBC using assembled arrays containing 2,460 bacterial artificial chromosome clones for scanning the genome for DNA copy number changes. After surgery, 90 patients received anthracycline-based chemotherapy, whereas 95 did not. Tamoxifen was administered to patients with hormone receptor-positive tumors. The association of genomic and clinicopathologic data and outcome was computed using Cox proportional hazard models and multiple testing adjustment procedures. Analysis of NNBC genomes revealed a common genomic signature. Specific DNA copy number aberrations were associated with hormonal receptor status, but not with other clinicopathologic variables. In patients treated with chemotherapy, none of the genomic changes were significantly correlated with recurrence. In patients not receiving chemotherapy, deletion of eight bacterial artificial chromosome clones clustered to chromosome 11q was independently associated with relapse (disease-free survival at 10 years+/-SE, 40%+/-14% versus 86%+/-6%; P<0.0001). The 54 patients with deletion of 11q (29%) did not present more aggressive clinicopathologic features than those without 11q loss. The adverse influence of 11q deletion on clinical outcome was confirmed in an independent validation series of 88 patients with NNBC. Our data suggests that patients with NNBC with the 11q deletion might benefit from anthracycline-based chemotherapy despite other clinical, pathologic, or genetic features. However, these initial findings should be evaluated in randomized clinical trials.


Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress.
As an essential nutrient and a potential toxin, iron poses an exquisite regulatory problem in biology and medicine. At the cellular level, the basic molecular framework for the regulation of iron uptake, storage, and utilization has been defined. Two cytoplasmic RNA-binding proteins, iron-regulatory protein-1 (IRP-1) and IRP-2, respond to changes in cellular iron availability and coordinate the expression of mRNAs that harbor IRP-binding sites, iron-responsive elements (IREs). Nitric oxide (NO) and oxidative stress in the form of H2O2 also signal to IRPs and thereby influence cellular iron metabolism. The recent discovery of two IRE-regulated mRNAs encoding enzymes of the mitochondrial citric acid cycle may represent the beginnings of elucidating regulatory coupling between iron and energy metabolism. In addition to providing insights into the regulation of iron metabolism and its connections with other cellular pathways, the IRE/IRP system has emerged as a prime example for the understanding of translational regulation and mRNA stability control. Finally, IRP-1 has highlighted an unexpected role for iron sulfur clusters as post-translational regulatory switches.


Is There Evidence that Runners can Benefit from Wearing Compression Clothing?
Runners at various levels of performance and specializing in different events (from 800 m to marathons) wear compression socks, sleeves, shorts, and/or tights in attempt to improve their performance and facilitate recovery. Recently, a number of publications reporting contradictory results with regard to the influence of compression garments in this context have appeared. To assess original research on the effects of compression clothing (socks, calf sleeves, shorts, and tights) on running performance and recovery. A computerized research of the electronic databases PubMed, MEDLINE, SPORTDiscus, and Web of Science was performed in September of 2015, and the relevant articles published in peer-reviewed journals were thus identified rated using the Physiotherapy Evidence Database (PEDro) Scale. Studies examining effects on physiological, psychological, and/or biomechanical parameters during or after running were included, and means and measures of variability for the outcome employed to calculate Hedges'g effect size and associated 95 % confidence intervals for comparison of experimental (compression) and control (non-compression) trials. Compression garments exerted no statistically significant mean effects on running performance (times for a (half) marathon, 15-km trail running, 5- and 10-km runs, and 400-m sprint), maximal and submaximal oxygen uptake, blood lactate concentrations, blood gas kinetics, cardiac parameters (including heart rate, cardiac output, cardiac index, and stroke volume), body and perceived temperature, or the performance of strength-related tasks after running. Small positive effect sizes were calculated for the time to exhaustion (in incremental or step tests), running economy (including biomechanical variables), clearance of blood lactate, perceived exertion, maximal voluntary isometric contraction and peak leg muscle power immediately after running, and markers of muscle damage and inflammation. The body core temperature was moderately affected by compression, while the effect size values for post-exercise leg soreness and the delay in onset of muscle fatigue indicated large positive effects. Our present findings suggest that by wearing compression clothing, runners may improve variables related to endurance performance (i.e., time to exhaustion) slightly, due to improvements in running economy, biomechanical variables, perception, and muscle temperature. They should also benefit from reduced muscle pain, damage, and inflammation.


Liver transplantation for hilar cholangiocarcinoma--a single-centre experience.
Cholangiocarcinoma is an infrequent malignancy, often unresectable at the time of diagnosis. Liver transplantation may offer a chance for cure, but results in the past have been disappointing, prompting transplant centres to adopt multimodal treatment protocols and extreme patient selection. This study was designed to evaluate the outcome of patients with irresectable hilar cholangiocarcinoma undergoing liver transplantation in order to determine criteria for patient selection. We reviewed our prospective cancer registry for patients with hilar cholangiocarcinoma treated by transplantation since 1997. Data were evaluated regarding tumour location, stage, overall survival, recurrence rates and prognostic factors. Liver transplantation with lymphadenectomy was realised in 16 patients with hilar cholangiocarcinoma. Seven patients received a living donor graft. Lymph node metastases were found in eight patients with a median of 13 harvested nodes and had a statistically significant negative impact on overall survival irrespective of tumour size. Only one patient underwent neoadjuvant brachytherapy and developed fatal septic complications; 3- and 5-year survival rates were 63 and 50 % in lymph node-negative patients without neoadjuvant treatment. Acceptable survival rates can be achieved by transplantation for hilar cholangiocarcinoma with lymph node metastases as the only exclusion criterion. We recommend staging laparotomy with lymphadenectomy along the common hepatic artery prior to liver transplantation.


Voltage- and transmitter-gated currents of all-amacrine cells in a slice preparation of the rat retina.
All-amacrine cells are crucial interneurons in the rod pathway of the mammalian retina. They receive input synapses from rod bipolar cells and make electrical output synapses into the ON-pathway and glycinergic chemical synapses into the OFF-pathway. Whole-cell currents from more than 50 voltage-clamped All-amacrine cells were recorded in a slice preparation of the rat retina. The recorded cells were identified by intracellular staining with Lucifer yellow. Spike-like potentials could be elicited upon depolarization by current injection. A voltage-activated, fast, TTX-sensitive, inward Na+ current was identified. A prominent outward K+ current could be suppressed by tetraethylammonium. GABA as well as glycine activated Cl- channels, which could be blocked by bicuculline and strychnine, respectively. Four agonists of excitatory amino acid receptors--kainate (KA), AMPA, 2-amino-4-phosphonobutyrate (APB), and NMDA--were tested. Inward currents at holding potentials of VH = -70 mV were found by application of KA and AMPA but not by application of APB and NMDA. These currents could be blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). ACh did not evoke any current responses.


Effect of nicotine on in vitro maturation of bovine oocytes.
The putative effect of nicotine on maturation and the chromosomal complement of bovine oocytes were investigated in the present study. Cumulus-enclosed oocytes were incubated in maturation medium with 0, 0.5, 1.0, 2.5, 5.0, and 10.0 mmol concentrations of nicotine. The results indicated that: (1) nicotine affected cumulus cell expansion in a dose-dependent manner and the perivitelline space failed to form when concentrations were equal to or greater than 5.0 mmol; (2) oocytes treated with 0.5 and 1.0 mmol nicotine concentrations resulted in maturation rates (83.3% and 85.9%, respectively) which was similar to the control (86.2%), whereas treatment with 2.5 and 5.0 mmol concentrations significantly decreased maturation rates to 70.2% and 26.7%, respectively; (3) nicotine at or over 2.5 mmol caused extremely irregular meiotic spindles and interrupted microfilament organization; (4) chromosomal analyses of oocytes with PB1 showed that oocytes derived from 0.5 and 1.0 mmol nicotine groups had haploid complements similar to the control (87-90%), but when the concentrations were increased to 2.5 and 5.0 mmol the haploid state was significantly reduced to around 70%; (5) oocytes at GVBD (germinal vesicle breakdown) and metaphase I stages were less affected by nicotine at 5.0 and 10.0 mmol concentrations than GV-stage oocytes; (6) maturation rates of the short-term nicotine-treated oocytes could be improved when subsequently incubated in normal maturation medium. Prolonged culture of nicotine-pretreated oocytes resulted in self-activation and some oocytes formed 1 or 2 pronuclei. In conclusion, nicotine affects bovine oocyte cumulus cell expansion, maturation rate, and chromosomal complement in a dose-dependent and an oocyte-stage-dependent manner.


Hereditary angioedema: Safety of long-term stanozolol therapy.
Attenuated androgens control attacks of hereditary angioedema. Short-term studies of such patients treated at our institution with attenuated androgens demonstrated no adverse effects. However, the side-effect frequencies in patients receiving long-term treatment are relatively less well characterized. To assess the frequencies of various side effects of the attenuated androgen stanozolol in a population of patients with hereditary angioedema treated for 20 to 40 years. Data on side effects in patients who continued stanozolol therapy since 1987 were obtained by means of questionnaire. Patients were evaluated by physical examination; biochemical assays of hepatic function, serum lipids, and prostate specific antigen; and liver ultrasound. The minimal initial effective dosage of stanozolol was 0.5 to 2.0 mg daily, although most patients achieved symptomatic control and decreased the dose and frequency as the frequency of attacks decreased. Treatment-related symptoms developed in 10 of 21 patients. No interruption in stanozolol therapy was required because symptoms subsided with a reduction in the stanozolol dosage. Adverse side effects included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays revealed no persistent abnormalities. Liver ultrasounds in 8 patients revealed 3 abnormalities deemed unrelated to therapy. Five patients had a reduced high-density lipoprotein, and 2 patients had elevated triglycerides. Stanozolol is a safe and effective drug for the long-term management of hereditary angioedema. Stanozolol may be used in the long-term treatment of patients with hereditary angioedema provided such patients are closely supervised with routine clinical, biochemical, and radiologic assessments.


Hydrogel based cartilaginous tissue regeneration: recent insights and technologies.
Hydrogels have been extensively employed as an attractive biomaterial to address numerous existing challenges in the fields of regenerative medicine and research because of their unique properties such as the capability to encapsulate cells, high water content, ease of modification, low toxicity, injectability, in situ spatial fit and biocompatibility. These inherent properties have created many opportunities for hydrogels as a scaffold or a cell/drug carrier in tissue regeneration, especially in the field of cartilaginous tissue such as articular cartilage and intervertebral discs. A concise overview of the anatomy/physiology of these cartilaginous tissues and their pathophysiology, epidemiology and existing clinical treatments will be briefly described. This review article will discuss the current state-of-the-art of various polymers and developing strategies that are explored in establishing different technologies for cartilaginous tissue regeneration. In particular, an innovative approach to generate scaffold-free cartilaginous tissue via a transient hydrogel scaffolding system for disease modeling to pre-clinical trials will be examined. Following that, the article reviews numerous hydrogel-based medical implants used in clinical treatment of osteoarthritis and degenerated discs. Last but not least, the challenges and future directions of hydrogel based medical implants in the regeneration of cartilaginous tissue are also discussed.


Comparison of cefazolin versus oxacillin for treatment of complicated bacteremia caused by methicillin-susceptible Staphylococcus aureus.
Contrary to prior case reports that described occasional clinical failures with cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infections, recent studies have demonstrated no difference in outcomes between cefazolin and antistaphylococcal penicillins for the treatment of MSSA bacteremia. While promising, these studies described low frequencies of high-inoculum infections, such as endocarditis. This retrospective study compares clinical outcomes of cefazolin versus oxacillin for complicated MSSA bacteremia at two tertiary care hospitals between January 2008 and June 2012. Fifty-nine patients treated with cefazolin and 34 patients treated with oxacillin were included. Osteoarticular (41%) and endovascular (20%) sources were the predominant sites of infection. The rates of clinical cure at the end of therapy were similar between cefazolin and oxacillin (95% versus 88%; P=0.25), but overall failure at 90 days was higher in the oxacillin arm (47% versus 24%; P=0.04). Failures were more likely to have received surgical interventions (63% versus 40%; P=0.05) and to have an osteoarticular source (57% versus 33%; P=0.04). Failures also had a longer duration of bacteremia (7 versus 3 days; P=0.0002), which was the only predictor of failure. Antibiotic selection was not predictive of failure. Rates of adverse drug events were higher in the oxacillin arm (30% versus 3%; P=0.0006), and oxacillin was more frequently discontinued due to adverse drug events (21% versus 3%; P=0.01). Cefazolin appears similar to oxacillin for the treatment of complicated MSSA bacteremia but with significantly improved safety. The higher rates of failure with oxacillin may have been confounded by other patient factors and warrant further investigation.


Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review.
To systematically review the literature and present data on the safety and efficacy of induced moderate hypothermia combined with ICP monitoring in critically ill patients with acute liver failure. We conducted a retrospective observational search of MEDLINE database using both OVID and PubMed with the following MeSH terms, "Hypothermia, Induced," "Brain Edema," "Intracranial Hypertension" (ICH), "Liver failure, Acute" and "Liver Failure, Fulminant." We limited our search to case series involving at least three human subjects and all other clinical trials. Baseline ICP, cerebral perfusion pressure (CPP) and cerebral blood flow (CBF) as well as the response of these variables to hypothermia were recorded when available. Additional clinical and demographic data were also recorded. Five case series were identified. Pre-existing coagulopathy from liver failure was reversed by various modalities in all studies prior to insertion of ICP monitors. Induction of moderate hypothermia combined with ICP monitoring consistently improved ICP, CPP and CBF in four trials; one trial demonstrated the feasibility and effectiveness of moderate induced hypothermia as part of a protocolized strategy for the management of ICH. Limited data exist concerning the safety and efficacy of moderate hypothermia and ICP monitoring for the treatment of ICH in acute liver failure. The available evidence shows that induction of moderate hypothermia in this clinical setting is feasible and possibly efficacious. Well-designed prospective clinical trials are warranted in this challenging context, given the potential of providing a bridge to liver transplantation or even clinical recovery.


Regulation of p53 expression by thymidylate synthase.
Previous studies showed that thymidylate synthase (TS), as an RNA binding protein, regulates its own synthesis by impairing the translation of TS mRNA. In this report, we present evidence that p53 expression is affected in a similar manner by TS. For these studies, we used a TS-depleted human colon cancer HCT-C cell that had been transfected with either the human TS cDNA or the Escherichia coli TS gene. The level of p53 protein in transfected cells overexpressing human TS was significantly reduced when compared with its corresponding parent HCT-C cells. This suppression of p53 expression was the direct result of decreased translational efficiency of p53 mRNA. Similar results were obtained upon transfection of HCT-C cells with pcDNA 3.1 (+) containing the E. coli TS gene. These findings provide evidence that TS, from diverse species, specifically regulates p53 expression at the translational level. In addition, TS-overexpressing cells with suppressed levels of p53 are significantly impaired in their ability to arrest in G1 phase in response to exposure to a DNA-damaging agent such as gamma-irradiation. These studies provide support for the in vivo biological relevance of the interaction between TS and p53 mRNA and identify a molecular pathway for controlling p53 expression.


The economic value of childhood varicella vaccination in France and Germany.
To determine the economic impact of childhood varicella vaccination in France and Germany. A common methodology based on the use of a varicella transmission model was used for the two countries. Cost data (2002 per thousand) were derived from two previous studies. The analysis focused on a routine vaccination program for which three different coverage rates (CRs) were considered (90%, 70%, and 45%). Catch-up strategies were also analyzed. A societal perspective including both direct and indirect costs and a third-party payer perspective were considered (Social Security in France and Sickness Funds in Germany). A routine vaccination program has a clear positive impact on varicella-related morbidity in both countries. With a 90% CR, the number of varicella-related deaths was reduced by 87% in Germany and by 84% in France. In addition, with a CR of 90%, routine varicella vaccination induces savings in both countries from both societal (Germany 61%, France 60%) and third-party payer perspectives (Germany 51%, France 6.7%). For lower CRs, routine vaccination remains cost saving from a third-party payer perspective in Germany but not in France, where it is nevertheless cost-effective (cost per life-year gained of 6521 per thousand in the base case with a 45% CR). Considering the impact of vaccination on varicella morbidity and costs, a routine varicella vaccination program appears to be cost saving in Germany and France from both a societal and a third-party payer perspective. For France, routine varicella vaccination remains cost-effective in worst cases when a third-party payer perspective is adopted. Catch-up programs provide additional savings.


Born to Cry: A Genetic Dissection of Infant Vocalization.
Infant vocalizations are one of the most fundamental and innate forms of behavior throughout avian and mammalian orders. They have a critical role in motivating parental care and contribute significantly to fitness and reproductive success. Dysregulation of these vocalizations has been reported to predict risk of central nervous system pathologies such as hypoxia, meningitis, or autism spectrum disorder. Here, we have used the expanded BXD family of mice, and a diallel cross between DBA/2J and C57BL/6J parental strains, to begin the process of genetically dissecting the numerous facets of infant vocalizations. We calculate heritability, estimate the role of parent-of-origin effects, and identify novel quantitative trait loci (QTLs) that control ultrasonic vocalizations (USVs) on postnatal days 7, 8, and 9; a stage that closely matches human infants at birth. Heritability estimates for the number and frequency of calls are low, suggesting that these traits are under high selective pressure. In contrast, duration and amplitude of calls have higher heritabilities, indicating lower selection, or their importance for kin recognition. We find suggestive evidence that amplitude of infant calls is dependent on the maternal genotype, independent of shared genetic variants. Finally, we identify two loci on Chrs 2 and 14 influencing call frequency, and a third locus on Chr 8 influencing the amplitude of vocalizations. All three loci contain strong candidate genes that merit further analysis. Understanding the genetic control of infant vocalizations is not just important for understanding the evolution of parent-offspring interactions, but also in understanding the earliest innate behaviors, the development of parent-offspring relations, and the early identification of behavioral abnormalities.


Draft Genome Sequence of Streptomyces sp. Strain RFCAC02, Isolated from the Gut Microflora of the Pacific Chub Mackerel Scomber japonicus peruanus.
A new strain of Streptomyces sp., strain RFCAC02, was isolated from the gut of the Pacific chub mackerel Scomber japonicus peruanus This strain produces a variety of secondary metabolites. Further bioinformatic analysis revealed the presence of biosynthetic gene clusters putatively coding for compounds related to the polycyclic tetramate macrolactams (PTMs).


Effect of a physician assistant as triage liaison provider on patient throughput in an academic emergency department.
Overcapacity issues plague emergency departments (EDs). Studies suggest that triage liaison providers (TLPs) may shorten patient length of stay (LOS) and reduce the proportion of patients who leave without being seen (LWBS), but these results are not universal. Previous studies used physicians as TLPs. We evaluated whether a physician assistant (PA), acting as a TLP, would shorten LOS and decrease LWBS rates. The authors used an observational cohort controlled before-and-after study design with predefined outcome measures, comparing 8 pilot days to 8 control days. The TLP evaluated all Emergency Severity Index (ESI) level 3, 4, and 5 patients, excluding pediatric and behavioral health patients. A total of 353 patients were included on pilot days and 371 on control days. LOS was shorter on pilot days than control days (median [interquartile range {IQR}] = 229 [168 to 303] minutes vs. 270 [187 to 372] minutes, p < 0.001). Waiting room times were similar between pilot and control days (median [IQR] = 69 [20 to 119] minutes vs. 70 [19 to 137] minutes, p = 0.408), but treatment room times were shorter (median [IQR] = 151 [92 to 223] minutes vs. 187 [110 to 254] minutes, p < 0.001). Finally, a lower proportion of patients LWBS on pilot days (1.4% vs. 9.7%, p < 0.001). The addition of a PA as a TLP was associated with a 41-minute decrease in median total LOS and a lower proportion of patients who LWBS. The decrease in total LOS is likely attributable to the addition of the TLP, with patients having shorter duration in treatment rooms on pilot days compared to control days.


Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms.
Increasing obesity is a major global health concern while at the same time iron-deficiency anemia remains common worldwide. Although these two conditions represent opposite ends of the spectrum of over- and under-nutrition, they appear to be linked: overweight individuals are at higher risk of iron deficiency than normal-weight individuals. Potential explanations for this association include dilutional hypoferremia, poor dietary iron intake, increased iron requirements, and/or impaired iron absorption in obese individuals. Recent evidence suggests obesity-related inflammation may play a central role through its regulation of hepcidin. Hepcidin levels are higher in obese individuals and are linked to subclinical inflammation; this may reduce iron absorption and blunt the effects of iron fortification. Thus, low iron status in overweight individuals may result from a combination of nutritional (reduced absorption) and functional (increased sequestration) iron deficiency. In this review, we focus on subclinical inflammation in obesity, and its effect on hepcidin levels, as the most plausible explanation for the link between iron deficiency and obesity.


Bone marrow involvement in pediatric malignancies: a comparison study of Positron emission tomographycomputed tomography and bone marrow biopsy.
The comparison of Positron emission tomography- computed tomography (PETCT) and bone marrow biopsy (BMB) modalities in detecting bone marrow disease is an up to date research topic. In this study, we aimed to compare the results of PET-CT and BMB procedures in detecting bone marrow involvement in pediatric malignancies. At the time of diagnosis, PET-CT imaging and BMB performed patients` data were evaluated, retrospectively. Malign diagnoses were Hodgkin's lymphoma in 23 (30.7%), non-Hodgkin's lymphoma in 20 (26.7%), neuroblastoma in 11 (14.7%), Ewing sarcoma in 10 (13.7%), Langerhans cell histiocytosis in 6 (8%), and rhabdomyosarcoma in 5 (6.6%) patients. Bone marrow involvement was detected in 39 (52%) of 75 patients. Bone marrow involvement was identified by both PET-CT and BMB in 18 (46.1%) patients, by only PET-CT in 12 (30.7%) patients, by only BMB in 9 (23%) patients. The sensitivity of PET-CT was 66%, specificity was 75%, positive predictive value was 60%, and negative predictive value was 80%. Sensitivity, spesificity, positive and negative predictive values of PETCT were different in before mentioned malignancy groups. PET-CT may not have high sensitivity and specificity to identify bone marrow involvement for each type of cancer. The approach of using bone marrow biopsy and PET-CT as complementary modalities seems reliable.


Acute cardiopulmonary effects of subarachnoid hemorrhage in monkeys.
Twenty-eight cynomolgus monkeys had an autologous subarachnoid blood clot placed in the basal cisternae via craniectomy. Twenty-three monkeys survived clot placement and five animals died within 24 h. An additional eight monkeys underwent sham procedures and six acted as anesthetic controls. Cardiopulmonary indices were measured before clot placement and 30 to 60 min thereafter, to determine if certain changes had prognostic value for immediate outcome. In the 24-h survivors, heart rate and arteriovenous oxygen content difference increased significantly (p less than .05 and .01, respectively), while stroke index (SI) (p less than .01), mean pulmonary artery pressure (p less than .001), pulmonary artery wedge pressure (p less than .001), and central venous pressure (p less than .05) fell. In the 24-h nonsurvivors, cardiac index (CI) (p less than .05) and SI (p less than .01) fell to an even greater extent than in the survivors. There was a significant (p less than .05) difference between the two groups for CI and SI. There were no significant differences in the sham-operated animals. In six control monkeys, neither heart rate nor CI significantly increased throughout 5 h of anesthesia.


Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins.
Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP- and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity to modulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.


Infection of T84 cells with enteropathogenic Escherichia coli alters barrier and transport functions.
The effect of enteropathogenic Escherichia coli (EPEC) infection on electrophysiology of T84 cell monolayers was examined. After 18 h of infection with EPEC (E2348), transepithelial electrical resistance was decreased (30 +/- 5% of uninfected values) compared with monolayers infected with a nonpathogenic E. coli strain (104 +/- 13%). Resistance of monolayers infected with EPEC mutant strain CVD206, deficient in attaching and effacing lesion formation, was partially reduced (66 +/- 10%). In addition, permeability of EPEC-infected T84 monolayers increased compared with uninfected cells. Associated with these changes was an altered distribution of the tight junction protein, ZO-1. Taken together, these findings suggest that the barrier defect induced by EPEC was at the level of the tight junction. Adenosine 3'5'-cyclic monophosphate-stimulated chloride secretion was also diminished in EPEC-infected cells, whereas Ca2+ -dependent chloride secretion was not different from uninfected cells. These findings indicate that EPEC infection alters intestinal epithelial barrier and transport functions. Furthermore, these results provide a possible mechanism for EPEC-induced diarrheal disease.


Dynamic cerebral autoregulation and tissue oxygenation in amnestic mild cognitive impairment.
Vascular disease and dysfunction are associated with the higher risk of Alzheimer's disease hypothetically due to cerebral hypoperfusion. Brain perfusion is protected by cerebral autoregulation, which, under normal conditions, maintains a constant cerebral blood flow and brain tissue oxygenation. To determine whether dynamic regulation of cerebral blood flow and tissue oxygenation is impaired in patients with amnestic mild cognitive impairment (aMCI). Twenty-seven patients with aMCI and 15 control subjects with normal cognitive function underwent the measurements of cerebral hemodynamics, brain MR imaging, and neurocognitive assessment. Dynamic regulation of cerebral blood flow and tissue oxygenation were assessed by transfer function analysis of changes in mean blood pressure (MBP), normalized cerebral blood flow velocity (CBFV%), and cerebral tissue oxygenation index (TOI) at baseline and during a sit-stand maneuver. Patients with aMCI demonstrated lower cognitive performance in memory and executive function, accompanied by smaller entorhinal cortex volumes. At baseline, cerebral TOI was lower in patients with aMCI than in control subjects. Lower cerebral TOI was also correlated with lower cognitive performance in memory and executive function in all subjects. Transfer function gain and phase between MBP and CBFV% and between CBFV% and cerebral TOI were not different between the groups. Within aMCI patients, greater oscillations of cerebral TOI and higher transfer function gain between cerebral TOI and CBFV% were associated with the lower scores on delayed recall. Dynamic regulation of cerebral tissue oxygenation is associated with neurocognitive dysfunction in aMCI patients.


Fractionation and quantification of calcium-dependent proteinase activity from small tissue samples.
Almost all mammalian tissues contain a cytoplasmic Ca2+-dependent proteolytic system consisting of two different proteinases (CDP I and CDP II) and an endogenous inhibitor specific for these proteinases. It was difficult to determine the relative activities of CDP I and CDP II directly and accurately without extensive purification, requiring relatively large amounts of tissue. We developed a simple technique based on Reactive Red-agarose affinity chromatography for quantitatively measuring CDP II activities in small (less than 100 mg) tissue samples. This technique is rapid, sensitive and highly reproducible. CDP II activities can be quantified in numerous tissue samples in a single day. Using this method, we analysed the components of the CDP system in various rat tissues and demonstrated quantitative differences in CDP II activities as well as relative differences in the amounts of CDP-inhibitor activity among the various tissues. This technique should prove useful in the efforts to define the currently unknown physiological function(s) of the Ca2+-dependent proteolytic system by allowing comparison of CDP activities in tissues under diverse conditions of protein metabolism.


Compression for venous leg ulcers.
Up to one percent of people in industrialised countries will suffer from a leg ulcer at some time. The majority of these leg ulcers are due to problems in the veins, resulting in an accumulation of blood in the legs. Leg ulcers arising from venous problems are called venous (or varicose or stasis) ulcers. The main treatment is the application of a firm compression garment (bandage or stocking) in order to aid venous return. There is a large number of compression garments available and it was unclear whether they are effective in treating venous ulcers and, if so, which method of compression is the most effective. To undertake a systematic review of all randomised controlled trials (RCTs) evaluating the effects on venous ulcer healing of compression bandages and stockings.Specific questions addressed by the review are:1. Does the application of compression bandages or stockings aid venous ulcer healing? 2. Which compression bandage or stocking system is the most effective? For this second update we searched: the Cochrane Wounds Group Specialised Register (31 May 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 5, 2012); Ovid MEDLINE (1950 to May Week 4 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 30 May 2012); Ovid EMBASE (1980 to 2012 Week 21); and EBSCO CINAHL (1982 to 30 May 2012). No date or language restrictions were applied. RCTs recruiting people with venous leg ulceration that evaluated any type of compression bandage system or compression stockings were eligible for inclusion. Eligible comparators included no compression (e.g. primary dressing alone, non-compressive bandage) or an alternative type of compression. RCTs had to report an objective measure of ulcer healing in order to be included (primary outcome for the review). SECONDARY OUTCOMES of the review included ulcer recurrence, costs, quality of life, pain, adverse events and withdrawals. There was no restriction on date, language or publication status of RCTs. Details of eligible studies were extracted and summarised using a data extraction table. Data extraction was performed by one review author and verified independently by a second review author. Forty-eight RCTs reporting 59 comparisons were included (4321 participants in total). Most RCTs were small, and most were at unclear or high risk of bias. Duration of follow-up varied across RCTs. Risk ratio (RR) and other estimates are shown below where RCTs were pooled; otherwise findings refer to a single RCT.There was evidence from eight RCTs (unpooled) that healing outcomes (including time to healing) are better when patients receive compression compared with no compression.Single-component compression bandage systems are less effective than multi-component compression for complete healing at six months (one large RCT).A two-component system containing an elastic bandage healed more ulcers at one year than one without an elastic component (one small RCT).Three-component systems containing an elastic component healed more ulcers than those without elastic at three to four months (two RCTs pooled), RR 1.83 (95% CI 1.26 to 2.67), but another RCT showed no difference between groups at six months.An individual patient data meta-analysis of five RCTs suggested significantly faster healing with the four-layer bandage (4LB) than the short stretch bandage (SSB): median days to healing estimated at 90 and 99 respectively; hazard ratio 1.31 (95% CI 1.09 to 1.58).High-compression stockings are associated with better healing outcomes than SSB at two to four months: RR 1.62 (95% CI 1.26 to 2.10), estimate from four pooled RCTs.One RCT suggested better healing outcomes at 16 months with the addition of a tubular device plus single elastic bandage to a base system of gauze and crepe bandages when compared with two added elastic bandages. Another RCT had three arms; when one or two elastic bandages were added to a base three-component system that included an outer tubular layer, healing outcomes were better at six months for the two groups receiving elastic bandages.There is currently no evidence of a statistically significant difference for the following comparisons:⋅alternative single-component compression bandages (two RCTs, unpooled);⋅two-component bandages compared with the 4LB at three months (three RCTs pooled);⋅alternative versions of the 4LB for complete healing at times up to and including six months (three RCTs, unpooled);⋅4LB compared with paste bandage for complete healing at three months (two RCTs, pooled), six months or one year (one RCT for each time point);⋅adjustable compression boots compared with paste bandages for the outcome of change in ulcer area at three months (one small RCT);⋅adjustable compression boots compared with the 4LB with respect to complete healing at three months (one small RCT);⋅single-layer compression stocking compared with paste bandages for outcome of complete healing at four months (one small RCT) and 18 months (another small RCT);⋅low compression stocking compared with SSB for complete healing at three and six months (one small RCT);⋅compression stockings compared with a two-component bandage system and the 4LB for the outcome of complete healing at three months (one small, three-armed RCT); and,⋅tubular compression compared with SSB (one small RCT) for complete healing at three months. 4LB was more cost-effective than SSB. It was not possible to draw firm conclusions regarding other secondary outcomes including recurrence, adverse events and health-related quality of life. Compression increases ulcer healing rates compared with no compression. Multi-component systems are more effective than single-component systems. Multi-component systems containing an elastic bandage appear to be more effective than those composed mainly of inelastic constituents. Two-component bandage systems appear to perform as well as the 4LB. Patients receiving the 4LB heal faster than those allocated the SSB. More patients heal on high-compression stocking systems than with the SSB. Further data are required before the difference between high-compression stockings and the 4LB can be established.


Bet-hedging and epigenetic inheritance in bacterial cell development.
Upon nutritional limitation, the bacterium Bacillus subtilis has the capability to enter the irreversible process of sporulation. This developmental process is bistable, and only a subpopulation of cells actually differentiates into endospores. Why a cell decides to sporulate or not to do so is poorly understood. Here, through the use of time-lapse microscopy, we follow the growth, division, and differentiation of individual cells to identify elements of cell history and ancestry that could affect this decision process. These analyses show that during microcolony development, B. subtilis uses a bet-hedging strategy whereby some cells sporulate while others use alternative metabolites to continue growth, providing the latter subpopulation with a reproductive advantage. We demonstrate that B. subtilis is subject to aging. Nevertheless, the age of the cell plays no role in the decision of its fate. However, the physiological state of the cell's ancestor (more than two generations removed) does affect the outcome of cellular differentiation. We show that this epigenetic inheritance is based on positive feedback within the sporulation phosphorelay. The extended intergenerational "memory" caused by this autostimulatory network may be important for the development of multicellular structures such as fruiting bodies and biofilms.


Natural course of behavioral addictions: a 5-year longitudinal study.
Resolving the theoretical controversy on the labeling of an increasing number of excessive behaviors as behavioral addictions may also be facilitated by more empirical data on these behavioral problems. For instance, an essential issue to the classification of psychiatric disorders is information on their natural course. However, longitudinal research on the chronic vs. episodic nature of behavioral addictions is scarce. The aim of the present study, therefore, was to provide data on prevalence, substance use comorbidity, and five-year trajectories of six excessive behaviors-namely exercising, sexual behavior, shopping, online chatting, video gaming, and eating. Analyses were based on the data of the Quinte Longitudinal Study, where a cohort of 4,121 adults from Ontario, Canada was followed for 5 years (2006 to 2011). The response rate was 21.3%, while retention rate was 93.9%. To assess the occurrence of each problem behavior, a single self-diagnostic question asked people whether their over-involvement in the behavior had caused significant problems for them in the past 12 months. To assess the severity of each problem behavior reported, the Behavioral Addiction Measure was administered. A mixed design ANOVA was used to investigate symptom trajectories over time for each problem behavior and whether these symptom trajectories varied as a function of sex. The large majority of people reported having problematic over-involvement for just one of these behaviors and just in a single time period. A main effect of time was found for each problem behavior, indicating a moderately strong decrease in symptom severity across time. The time x sex interaction was insignificant in each model indicating that the decreasing trend is similar for males and females. The data also showed that help seeking was very low in the case of excessive sexual behavior, shopping, online chatting, and video gaming but substantially more prevalent in the case of excessive eating and exercising. The present results indicate that self-identified excessive exercising, sexual behavior, shopping, online chatting, video gaming, and/or eating tend to be fairly transient for most people. This aspect of the results is inconsistent with conceptualizations of addictions as progressive in nature, unless treated.


Potential role of zinc supplementation in prophylaxis and treatment of COVID-19.
Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents the largest current health challenge for the society. At the moment, the therapeutic strategies to deal with this disease are only supportive. It is well known that zinc (Zn) possesses a variety of direct and indirect antiviral properties, which are realized through different mechanisms. Administration of Zn supplement has a potential to enhance antiviral immunity, both innate and humoral, and to restore depleted immune cell function or to improve normal immune cell function, in particular in immunocompromised or elderly patients. Zn may also act in a synergistic manner when co-administered with the standard antiviral therapy, as was demonstrated in patients with hepatitis C, HIV, and SARS-CoV-1. Effectiveness of Zn against a number of viral species is mainly realized through the physical processes, such as virus attachment, infection, and uncoating. Zn may also protect or stabilize the cell membrane which could contribute to blocking of the virus entry into the cell. On the other hand, it was demonstrated that Zn may inhibit viral replication by alteration of the proteolytic processing of replicase polyproteins and RNA-dependent RNA polymerase (RdRp) in rhinoviruses, HCV, and influenza virus, and diminish the RNA-synthesizing activity of nidoviruses, for which SARS-CoV-2 belongs. Therefore, it may be hypothesized that Zn supplementation may be of potential benefit for prophylaxis and treatment of COVID-19.


Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation.
In the randomized, controlled study Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotic supplementation reduced the incidence of atopic dermatitis (AD) in the offspring. In the current study, we hypothesized that the effect was mediated by a shift in the T helper (Th) cells in the children. To examine whether Th cell proportions were affected by maternal probiotic supplementation and thus could mediate the preventive effect of probiotics on AD. A total of 415 pregnant women were randomized to ingest a combination of Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12) and Lactobacillus acidophilus La-5 (La-5) or placebo, and their offspring were assessed for AD during the first 2 years of life. Peripheral blood collected at 3 months of age was analysed for regulatory T cells (n=140) and Th subsets (n=77) including Th1, Th2, Th9, Th17 and Th22. The proportion of Th22 cells was reduced in children in the probiotic group compared to the placebo group (median 0.038% vs 0.064%, P=.009). The difference between the probiotic and placebo groups was also observed in the children who did not develop AD during the 2-year follow-up. The proportion of Th22 cells was increased in children who developed AD compared to the children who did not develop AD (0.090% vs 0.044%, P<.001). Mediation analysis indicated that the preventive effect of probiotics was partially mediated through the reduction in Th22 cells. Perinatal maternal probiotic supplementation with a combination of LGG, Bb-12 and La-5 reduced the proportion of Th22 cells in 3-month-old children. This may partially explain the preventive effect of probiotics on AD.


The Impact of Dietary Protein or Amino Acid Supplementation on Muscle Mass and Strength in Elderly People: Individual Participant Data and Meta-Analysis of RCT's.
Increasing protein or amino acid intake has been promoted as a promising strategy to increase muscle mass and strength in elderly people, however, long-term intervention studies show inconsistent findings. Therefore, we aim to determine the impact of protein or amino acid supplementation compared to placebo on muscle mass and strength in older adults by combining the results from published trials in a meta-analysis and pooled individual participant data analysis. We searched Medline and Cochrane databases and performed a meta-analysis on eight available trials on the effect of protein or amino acid supplementation on muscle mass and strength in older adults. Furthermore, we pooled individual data of six of these randomized double-blind placebo-controlled trials. The main outcomes were change in lean body mass and change in muscle strength for both the meta-analysis and the pooled analysis. The meta-analysis of eight studies (n=557) showed no significant positive effects of protein or amino acid supplementation on lean body mass (mean difference: 0.014 kg: 95% CI -0.152; 0.18), leg press strength (mean difference: 2.26 kg: 95% CI -0.56; 5.08), leg extension strength (mean difference: 0.75 kg: 95% CI: -1.96, 3.47) or handgrip strength (mean difference: -0.002 kg: 95% CI -0.182; 0.179). Likewise, the pooled analysis showed no significant difference between protein and placebo treatment on lean body mass (n=412: p=0.78), leg press strength (n=121: p=0.50), leg extension strength (n=121: p=0.16) and handgrip strength (n=318: p=0.37). There is currently no evidence to suggest that protein or amino acid supplementation without concomitant nutritional or exercise interventions increases muscle mass or strength in predominantly healthy elderly people.


Clinical outcomes and surgeon assessment after implantation of a new diffractive multifocal toric intraocular lens.
To evaluate the clinical outcome in eyes with significant corneal astigmatism after cataract surgery with implantation of a new diffractive multifocal toric intraocular lens (IOL). Prospective, non-randomised multicentre clinical study including 57 eyes of 38 consecutive patients with an age between 37 and 84 years that underwent cataract surgery with implantation of the toric multifocal IOL Tecnis ZMT (Abbott Medical Optics, Santa Ana, California, USA). Changes in uncorrected and corrected logMAR distance, intermediate and near visual acuity ((uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA) uncorrected near visual acuity (UNVA), corrected distance visual acuity (CDVA), corrected near visual acuity) and manifest refraction were evaluated during a 2-4 month follow-up. Additionally, patients were asked about photic phenomena and spectacle dependence. The surgeons subjectively assessed various aspects of the surgery. A significant improvement in CDVA was observed postoperatively (p<0.01), with a significant reduction in manifest cylinder (p<0.01). Mean postoperative binocular UDVA and UNVA were 0.04±0.10 and 0.06±0.12, respectively. Monocular UDVA and UNVA was 0.20 or better in 85.4% and 87.0% of eyes, respectively. Mean binocular logMAR UIVA was 0.21±0.20. Only 10.5% of patients required postoperative correction for near or intermediate distance. The incidence of moderate to severe photic phenomena was limited. Surgeons defined the IOL implantation in most cases as easy or very easy, with a satisfaction rate with the procedure of 84%. The implantation of the multifocal toric IOL is a safe procedure that provides a very good visual rehabilitation in eyes with corneal astigmatism.


New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets.
Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.


Expressed sequence tags from the Yukon ecotype of Thellungiella reveal that gene expression in response to cold, drought and salinity shows little overlap.
Thellungiella salsuginea (also known as T. halophila) is a close relative of Arabidopsis that is very tolerant of drought, freezing, and salinity and may be an appropriate model to identify the molecular mechanisms underlying abiotic stress tolerance in plants. We produced 6578 ESTs, which represented 3628 unique genes (unigenes), from cDNA libraries of cold-, drought-, and salinity-stressed plants from the Yukon ecotype of Thellungiella. Among the unigenes, 94.1% encoded products that were most similar in amino acid sequence to Arabidopsis and 1.5% had no match with a member of the family Brassicaceae. Unigenes from the cold library were more similar to Arabidopsis sequences than either drought- or salinity-induced sequences, indicating that latter responses may be more divergent between Thellungiella and Arabidopsis. Analysis of gene ontology using the best matched Arabidopsis locus showed that the Thellungiella unigenes represented all biological processes and all cellular components, with the highest number of sequences attributed to the chloroplast and mitochondria. Only 140 of the unigenes were found in all three abiotic stress cDNA libraries. Of these common unigenes, 70% have no known function, which demonstrates that Thellungiella can be a rich resource of genetic information about environmental responses. Some of the ESTs in this collection have low sequence similarity with those in Genbank suggesting that they may encode functions that may contribute to Thellungiella's high degree of stress tolerance when compared with Arabidopsis. Moreover, Thellungiella is a closer relative of agriculturally important Brassica spp. than Arabidopsis, which may prove valuable in transferring information to crop improvement programs.


Demonstration of different contractile mechanisms for angiotensin II and des-Asp1-angiotensin II in rabbit aortic strips.
Evidence of selective inhibition, differences in dose-response relationships, and cross-tachyphylaxis studies suggest that separate receptors and/or mechanisms may be involved in responses to angiotensin (Ang), [Sar1]Ang II, and Ang III (= des-Asp1-Ang II). The extracellular Ca2+ requirement for contractile responses induced by angiotensin peptides and norepinephrine was determined in rabbit aortic strips. Responses to K+ and [Sar1]Ang II were attenuated markedly by treatment with SKF-525A, verapamil, or Ca2+-free buffer. The response to Ang II was not impaired by verapamil, was blocked partially by SKF-525A, and was reduced markedly in Ca2+-free medium. Norepinephrine- and Ang III-induced contractions were not dependent on extracellular Ca2+. K+, Ang II, and [Sar1]Ang II required extracellular Ca2+ to induce contraction of the rabbit aorta. The data indicate that Ang III may have a mechanism of action that differs from that of [Sar1]Ang II and Ang II.


The Nexus between Bovine Tuberculosis and Fasciolosis Infections in Cattle of the Kafue Basin Ecosystem in Zambia: Implications on Abattoir Surveillance.
Bovine tuberculosis (bTB) and fasciolosis are important but neglected diseases that result in chronic infections in cattle. However, in Zambia, these diseases are mainly diagnosed at abattoirs during routine meat inspection. Albeit the coinfection status, these diseases have been reported as nothing more than normal separate findings without an explanatory phenomena. Forthwith, we formulated this study to assess the possible association of the two diseases in a known high prevalence area on the Kafue basin ecosystem. Of the 1,680 animals screened, 600 (35.7%; 95% CI 33.4%-38%) and 124 (7.4%; 95% CI 6.1%-8.6%) had fasciolosis and tuberculous lesions; respectively, whilst 72 had both fasciola and tuberculous lesions representing 12% (95% CI 9.4%-14.6%) and 58.1% (95% CI; 49.3%-66.7%) of the total positives for fasciola and tuberculosis, respectively. Jaundice was seen in 304 animals, 18.1% (95% CI; 16.3%-19.9%) and was significantly correlated to fasciolosis (r = 0.59, P < 0.0001). A significant association (χ(2) = 76.2, df = 1, and P < 0.0001) was found between fasciolosis and tuberculous lesions. Simple logistic regression intimated fasciolosis as a strong predictor for tuberculous lesions with animals that had fasciola being five times more likely to have tuberculous lesions (odds ratio = 4.8, 95% CI: 3.3-7.0). This study indicates that transmission and spatial risk factors of communicable and noncommunicable diseases such as bTB and fasciolosis can be correlated in an ecosystem such as the Kafue flats.


Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV.
Cells infected with the human immunodeficiency virus (HIV) show decreased expression of the 58-kilodalton T4 (CD4) antigen on their surface. In this study, the effect of HIV infection on the synthesis of T4 messenger RNA (mRNA) and protein products was evaluated in T-cell lines. Metabolically labeled lysates from the T4+ cell line Sup-T1 were immunoprecipitated with monoclonal antibodies to T4. Compared with uninfected cells, HIV-infected Sup-T1 cells showed decreased amounts of T4 that coprecipitated with both the 120-kilodalton viral envelope and the 150-kilodalton envelope precursor molecules. In four of five HIV-producing T-cell lines studied, the steady-state levels of T4 mRNA were also reduced. Thus, the decreased T4 antigen on HIV-infected cells is due to at least three factors: reduced steady-state levels of T4-specific mRNA, reduced amounts of immunoprecipitable T4 antigen, and the complexing of available T4 antigen with viral envelope gene products. The data suggested that the T4 protein produced after infection may be complexed with viral envelope gene products within infected cells. Retroviral envelope-receptor complexes may thus participate in a general mechanism by which receptors for retroviruses are down-modulated and alterations in cellular function develop after infection.


Cervical human papillomavirus infection and squamous intraepithelial lesions in rural Gambia, West Africa: viral sequence analysis and epidemiology.
The development of effective strategies against cervical cancer in Africa requires accurate type specific data on human papillomavirus (HPV) prevalence, including determination of DNA sequences in order to maximise local vaccine efficacy. We have investigated cervical HPV infection and squamous intraepithelial lesions (SIL) in an unselected cohort of 1061 women in a rural Gambian community. Squamous intraepithelial lesions was diagnosed using cytology and histology, HPV was typed by PCR-ELISA of DNA extracts, which were also DNA sequenced. The prevalence of cervical HPV infection was 13% and SIL were observed in 7% of subjects. Human papillomavirus-16 was most prevalent and most strongly associated with SIL. Also common were HPV-18, -33, -58 and, notably, -35. Human papillomavirus DNA sequencing revealed HPV-16 samples to be exclusively African type 1 (Af1). Subjects of the Wolof ethnic group had a lower prevalence of HPV infection while subjects aged 25-44 years had a higher prevalence of cervical precancer than older or younger subjects. This first report of HPV prevalence in an unselected, unscreened rural population confirms high rates of SIL and HPV infection in West Africa. This study has implications for the vaccination of Gambian and other African populations in the prevention of cervical cancer.


Reproducing American Sign Language sentences: cognitive scaffolding in working memory.
The American Sign Language Sentence Reproduction Test (ASL-SRT) requires the precise reproduction of a series of ASL sentences increasing in complexity and length. Error analyses of such tasks provides insight into working memory and scaffolding processes. Data was collected from three groups expected to differ in fluency: deaf children, deaf adults and hearing adults, all users of ASL. Quantitative (correct/incorrect recall) and qualitative error analyses were performed. Percent correct on the reproduction task supports its sensitivity to fluency as test performance clearly differed across the three groups studied. A linguistic analysis of errors further documented differing strategies and bias across groups. Subjects' recall projected the affordance and constraints of deep linguistic representations to differing degrees, with subjects resorting to alternate processing strategies when they failed to recall the sentence correctly. A qualitative error analysis allows us to capture generalizations about the relationship between error pattern and the cognitive scaffolding, which governs the sentence reproduction process. Highly fluent signers and less-fluent signers share common chokepoints on particular words in sentences. However, they diverge in heuristic strategy. Fluent signers, when they make an error, tend to preserve semantic details while altering morpho-syntactic domains. They produce syntactically correct sentences with equivalent meaning to the to-be-reproduced one, but these are not verbatim reproductions of the original sentence. In contrast, less-fluent signers tend to use a more linear strategy, preserving lexical status and word ordering while omitting local inflections, and occasionally resorting to visuo-motoric imitation. Thus, whereas fluent signers readily use top-down scaffolding in their working memory, less fluent signers fail to do so. Implications for current models of working memory across spoken and signed modalities are considered.


Earlier snowmelt may lead to late season declines in plant productivity and carbon sequestration in Arctic tundra ecosystems.
Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO2 later in the season.


The Pain & Policy Studies Group international program.
The purpose and activities of the Pain & Policy Studies Group (PPSG) at the University of Wisconsin are discussed, especially in its role as the World Health Organization Collaborating Center for Policy and Communications in Cancer Care. Issues relating to the need for balanced opioid policy, the International Narcotics Control Board, opioid availability, overly restrictive national laws and regulations, and specific examples of improvements that have resulted from work of the PPSG are described.


Temporal tree representation for similarity computation between medical patients.
The aim of this study is to compute similarities between patient records in an electronic health record (EHR). This is an important problem because the availability of effective methods for the computation of patient similarity would allow for assistance with and automation of tasks such as patients stratification, medical prognosis and cohort selection, and for unlocking the potential of medical analytics methods for healthcare intelligence. However, health data in EHRs presents many challenges that make the automatic computation of patient similarity difficult; these include: temporal aspects, multivariate, heterogeneous and irregular data, and data sparsity. We propose a new method for EHR data representation called Temporal Tree: a temporal hierarchical representation which, based on temporal co-occurrence, preserves the compound information found at different levels in health data. In addition, this representation is augmented using the doc2vec embedding technique which here is exploited for patient similarity computation. We empirically investigate our proposed method, along with several state-of-the-art benchmarks, on a dataset of real world Intensive Care Unit (ICU) EHRs, for the task of identifying patients with a specific target diagnosis. Our empirical results show that the Temporal Trees representation is significantly better than other traditional and state-of-the-art methods for representing patients and computing their similarities. Temporal trees capture the temporal relationships between medical, hierarchical data: this enables to effectively model the rich information provided within EHRs and thus the identification of similar patients.


Depth-of-interaction measurement in a single-layer crystal array with a single-ended readout using digital silicon photomultiplier.
We present the first experimental evaluation of a depth-of-interaction (DOI) positron emission tomography (PET) detector using a digital silicon photomultiplier (dSiPM). To measure DOI information from a mono-layer array of scintillation crystals with a single-ended readout, our group has previously proposed and developed a new method based on light spread using triangular reflectors. Since this method relies on measurement of the light distribution, dSiPM, which has a fully digital interface, has several merits for our DOI measurement. The DOI PET detector comprised of a dSiPM sensor (DPC-3200-22-44) coupled with a 14 × 14 array of 2 mm × 2 mm × 20 mm unpolished LGSO crystals. All crystals were covered with triangular reflectors. To obtain a good performance of the DOI PET detector, several parameters of detector were selected as a preliminary experiment. Detector performance was evaluated with the selected parameters and the optimal experimental setup, and a DOI measurement was conducted by irradiating the crystal block at five DOI positions spaced at intervals of 4 mm. Maximum-likelihood estimation was employed for DOI positioning and the optimal DOI estimation scheme was also investigated in this study. As a result, the DOI PET detector showed clear crystal identification. The energy resolution (full-width at half-maximum (FWHM)) averaged over all depths was 10.21% ± 0.15% at 511 keV, and time resolution averaged over all depths was 1198.61 ± 39.70 ps FWHM. The average DOI positioning accuracy for all depths was 74.22% ± 6.77%, which equates to DOI resolution of 4.67 mm. Energy and DOI resolutions were uniform over all crystal positions except for the back parts of the array. Furthermore, additional simulation studies were conducted to verify the results of our DOI measurement method that is combined with dSiPM technology. In conclusion, our continuous DOI PET detector coupled with dSiPM is a promising PET/MRI detector with DOI-encoding capability.


Genomic Evidence for Local Adaptation of Hunter-Gatherers to the African Rainforest.
African rainforests support exceptionally high biodiversity and host the world's largest number of active hunter-gatherers [1-3]. The genetic history of African rainforest hunter-gatherers and neighboring farmers is characterized by an ancient divergence more than 100,000 years ago, together with recent population collapses and expansions, respectively [4-12]. While the demographic past of rainforest hunter-gatherers has been deeply characterized, important aspects of their history of genetic adaptation remain unclear. Here, we investigated how these groups have adapted-through classic selective sweeps, polygenic adaptation, and selection since admixture-to the challenging rainforest environments. To do so, we analyzed a combined dataset of 566 high-coverage exomes, including 266 newly generated exomes, from 14 populations of rainforest hunter-gatherers and farmers, together with 40 newly generated, low-coverage genomes. We find evidence for a strong, shared selective sweep among all hunter-gatherer groups in the regulatory region of TRPS1-primarily involved in morphological traits. We detect strong signals of polygenic adaptation for height and life history traits such as reproductive age; however, the latter appear to result from pervasive pleiotropy of height-associated genes. Furthermore, polygenic adaptation signals for functions related to responses of mast cells to allergens and microbes, the IL-2 signaling pathway, and host interactions with viruses support a history of pathogen-driven selection in the rainforest. Finally, we find that genes involved in heart and bone development and immune responses are enriched in both selection signals and local hunter-gatherer ancestry in admixed populations, suggesting that selection has maintained adaptive variation in the face of recent gene flow from farmers.


Development of a lethal, closed-abdomen, arterial hemorrhage model in noncoagulopathic swine.
Prehospital treatment for noncompressible abdominal bleeding, particularly due to large vascular injury, represents a significant unmet medical need on the battlefield and in civilian trauma. To date, few large animal models are available to assess new therapeutic interventions and hemostatic agents for prehospital hemorrhage control. We developed a novel, lethal, closed-abdomen injury model in noncoagulopathic swine by strategic placement of a cutting wire around the external iliac artery. The wire was externalized, such that percutaneous distraction would result in vessel transection leading to severe uncontrolled abdominal hemorrhage. Resuscitation boluses were administered at 5 and 12 min. We demonstrated 86% mortality (12/14 animals) at 60 min, with a median survival time of 32 min. The injury resulted in rapid and massive hypotension and exsanguinating blood loss. The noncoagulopathic animal model incorporated clinically significant resuscitation and ventilation protocols based on best evidenced-based prehospital practices. A new injury model is presented that enables screening of prehospital interventions designed to control noncompressible arterial hemorrhage.


Prognostic value of newborn hearing screening in patients with myelomeningocele.
Brainstem dysfunction occurs in a minority of patients with myelomeningocele (MMC), most of whom have Chiari Type II malformation. Some surgeons advocate early identification of these patients for craniocervical decompression to avoid significant mortality. The auditory brainstem response has been found to be abnormal in most children with MMC. The present study examines whether failure of routine newborn hearing screening (NHS) predicts brainstem dysfunction in MMC patients. The charts of 40 newborns with MMC and 50 newborns without MMC who stayed in the neonatal intensive care unit were reviewed. Results of NHS, brainstem symptoms, birth demographics, and surgical history were retrospectively examined. Differences in the presence and onset of brainstem symptoms by NHS result were assessed. Failure of NHS was more common among newborns with MMC who developed brainstem symptoms (31%, 4 of 13 patients) than among newborns without MMC (0%, 0 of 50 patients; p = 0.001). Among the 40 newborns with MMC, brainstem symptoms were more common in those who failed NHS (80%, 4 of 5 patients) than in those who passed (26%, 9 of 35 patients; p = 0.031). Respiratory symptom onset occurred later in patients who failed NHS (median 16 months) than among those who passed (median 0 months; p = 0.022). The positive and negative predictive values of NHS for brainstem dysfunction in MMC were 0.80 and 0.74, respectively. Results of NHS may help predict future brainstem dysfunction in patients with MMC and may be useful to incorporate into prognostic assessment and surgical decision making.


Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
Fluid accumulation is associated with adverse outcomes in critically ill patients. Here, we sought to determine if fluid accumulation is associated with mortality and non-recovery of kidney function in critically ill adults with acute kidney injury. Fluid overload was defined as more than a 10% increase in body weight relative to baseline, measured in 618 patients enrolled in a prospective multicenter observational study. Patients with fluid overload experienced significantly higher mortality within 60 days of enrollment. Among dialyzed patients, survivors had significantly lower fluid accumulation when dialysis was initiated compared to non-survivors after adjustments for dialysis modality and severity score. The adjusted odds ratio for death associated with fluid overload at dialysis initiation was 2.07. In non-dialyzed patients, survivors had significantly less fluid accumulation at the peak of their serum creatinine. Fluid overload at the time of diagnosis of acute kidney injury was not associated with recovery of kidney function. However, patients with fluid overload when their serum creatinine reached its peak were significantly less likely to recover kidney function. Our study shows that in patients with acute kidney injury, fluid overload was independently associated with mortality. Whether the fluid overload was the result of a more severe renal failure or it contributed to its cause will require clinical trials in which the role of fluid administration to such patients is directly tested.


The Prognostic Impact of Lymph Node Involvement in Large Scale Operable Node-Positive Esophageal Squamous Cell Carcinoma Patients: A 10-Year Experience.
Lymph node (LN)-related factors including the number of LN regions involved, the LN ratio (LNR), and the number of metastatic LNs are strong prognostic indicators for esophageal squamous cell carcinoma (ESCC) patients. Accurately staging LN involvement may improve the stratification of patients and guide the management of patients. A total of 688 potentially resectable patients who had regional LN metastases were enrolled in this retrospective study. ESCC involving a single region was associated with better outcomes than that involving multiple regions (P < 0.001 for both PFS and OS). An increased number of metastatic LNs was significantly associated with reduced PFS and OS based on univariate analysis (P < 0.001). PFS and OS were significantly higher in patients with a lower cancer-involved LNR, with 5-year OS rates of 9.7% and 31.4% for patients with a lower and higher cancer-involved LNR, respectively. Based on multivariate analysis, patients with N1 LN involvement experienced longer survival than patients with N2 LN involvement (HR: 1.37; 95% CI: 1.12-1.68) or N3 LN involvement (HR: 1.96; 95% CI: 1.52-2.53). Higher LNR resulted in longer OS than lower LNR based on multivariate analysis (HR: 1.45; 95% CI: 1.15-1.84; P = 0.002). Our study has shown that not only the number of metastatic LNs but also the number of involved LN regions predicts outcomes after definitive surgery among Chinese patients with N-positive ESCC. LNR might serve as a powerful indicator that should be included in TNM staging for EC patients.


Menagerie: A text-mining tool to support animal-human translation in neurodegeneration research.
Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases.


Plasma levels of fluphenazine in patients receiving fluphenazine decanoate. Relationship to clinical response.
The levels of fluphenazine and fluphenazine sulphoxide in schizophrenic patients who were randomly assigned to receive either 5 mg or 25 mg of fluphenazine decanoate every two weeks were monitored. Patients treated with 25 mg of fluphenazine decanoate required three months to reach a steady-state plasma level, indicating that those patients who are being converted from oral to depot fluphenazine should continue to receive oral supplementation during the first three months of treatment with fluphenazine decanoate. Plasma levels of fluphenazine sulphoxide were lower than levels of fluphenazine. At six and nine months following randomisation, there was a statistically significant relationship between lower fluphenazine plasma levels and an increased risk of psychotic exacerbations. A relatively weak relationship was found between fluphenazine plasma levels and akinesia, but non-significant relationships between fluphenazine levels and other neurological side-effects including akathisia, retardation, and tardive dyskinesia. Monitoring the plasma levels may be helpful to clinicians who are attempting to treat stabilised patients with the lowest effective dose of fluphenazine decanoate.