Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response.
Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.


Early emergence in a butterfly causally linked to anthropogenic warming.
There is strong correlative evidence that human-induced climate warming is contributing to changes in the timing of natural events. Firm attribution, however, requires cause-and-effect links between observed climate change and altered phenology, together with statistical confidence that observed regional climate change is anthropogenic. We provide evidence for phenological shifts in the butterfly Heteronympha merope in response to regional warming in the southeast Australian city of Melbourne. The mean emergence date for H. merope has shifted -1.5 days per decade over a 65-year period with a concurrent increase in local air temperatures of approximately 0.16°C per decade. We used a physiologically based model of climatic influences on development, together with statistical analyses of climate data and global climate model projections, to attribute the response of H. merope to anthropogenic warming. Such mechanistic analyses of phenological responses to climate improve our ability to forecast future climate change impacts on biodiversity.


Pseudomonas aeruginosa resistance patterns and clinical outcomes in hospitalized exacerbations of COPD.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) due to Pseudomonas aeruginosa (PA) are associated with worse outcomes. PA antibiotic resistance is important to determine treatment and may influence clinical outcomes. The aim was to study clinical characteristics and outcomes in patients with AECOPD associated with PA based on their antibiotic resistance. This was a prospective observational study including all patients with AECOPD and positive PA sputum culture admitted in a respiratory ward in a tertiary hospital in Barcelona during 2013-2014. PA was defined as resistant (PA-R) when the antibiogram showed ≥1 resistance. Four hundred one patients with AECOPD were evaluated. Of them, 54 (13%) had a positive PA sputum culture. Eighty-two per cent were men, median age was 77 (SD 7) years old and FEV1 was less than 36% (SD 17) of predicted value. PA-R was isolated in 35 patients (66%), and PA-sensitive (PA-S) was isolated in 18 (34%) patients. No differences were found in demographics, lung function and comorbidities among groups. PA-R patients were more likely exposed to prior oral corticosteroids (77% vs 44%, P = 0.03) and antibiotics (77% vs 31%, P = 0.01), respectively. AECOPD patients associated with PA-S were more likely to die at 30 days (odds ratio 13.53, 95% confidence interval: 1.14-69.56, P = 0.03) and 90 days (odds ratio 7.09, 95% confidence interval: 1.33-37.89, P = 0.02), respectively. Pseudomonas aeruginosa-resistant affects patients with severe AECOPD and previous use of corticosteroids and antibiotics. The presence of PA-S is associated with higher mortality. These results may suggest increased virulence in PA-S strains causing acute infections.


X-ray crystallographic snapshots of reaction intermediates in the G117H mutant of human butyrylcholinesterase, a nerve agent target engineered into a catalytic bioscavenger.
OPs (organophosphylates) exert their acute toxicity through inhibition of acetylcholinesterase, by phosphylation of the catalytic serine residue. Engineering of human butyrylcholinesterase, by substitution of a histidine residue for the glycine residue at position 117, led to the creation of OP hydrolase activity. However, the lack of structural information and poor understanding of the hydrolytic mechanism of the G117H mutant has hampered further improvements in the catalytic activity. We have solved the crystallographic structure of the G117H mutant with a variety of ligands in its active site. A sulfate anion bound to the active site suggested the positioning for an OP prior to phosphylation. A fluoride anion was found in the active site when NaF was added to the crystallization buffer. In the fluoride complex, the imidazole ring from the His117 residue was substantially shifted, adopting a relaxed conformation probably close to that of the unliganded mutant enzyme. Additional X-ray structures were obtained from the transient covalent adducts formed upon reaction of the G117H mutant with the OPs echothiophate and VX [ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl](methyl)phosphinate]. The position of the His117 residue shifted in response to the introduction of these adducts, overlaying the phosphylserine residue. These structural data suggest that the dephosphylation mechanism involves either a substantial conformational change of the His117 residue or an adjacent nucleophilic substitution by water.


"At the foot of a very long ladder": discussing the end of life with older people and informal caregivers.
International policy advocates the development of approaches to raise public awareness about end-of-life-care issues, so that when people face a final illness, they may better articulate their needs for care. This article reports findings from one approach of engaging older members of the general public and informal caregivers in discussions about end-of-life care. To increase understanding of the concerns many older people have around end-of-life issues and provide advice and information to address these. Listening events were delivered across the United Kingdom using principles of focus group conduct to facilitate discussions among older people, informal caregivers, and representatives from community groups (n=74) in four workshops. Participants discussed their feelings, experiences, and concerns about the end of life, guided by the booklet Planning for Choice in End-of-Life Care, which was piloted in an earlier study. After framework analysis, three themes arose: communicating about end-of-life issues, factors that influence individuals' concerns about death and dying, and advance care planning. The heterogeneity of stories told not only illustrates how people's responses and needs at the end of life vary greatly but also reveals shared reactions, experiences, and some confusion. The stories also demonstrate people's willingness to engage with concerns associated with the end of life and their conviction that this is an important area of community action and development. Further community-based solutions to questions of quality of death need to be found, encouraged by programs of public education.


3D nanochannel electroporation for high-throughput cell transfection with high uniformity and dosage control.
Of great interest to modern medicine and biomedical research is the ability to inject individual target cells with the desired genes or drug molecules. Some advances in cell electroporation allow for high throughput, high cell viability, or excellent dosage control, yet no platform is available for the combination of all three. In an effort to solve this problem, here we show a "3D nano-channel electroporation (NEP) chip" on a silicon platform designed to meet these three criteria. This NEP chip can simultaneously deliver the desired molecules into 40,000 cells per cm(2) on the top surface of the device. Each 650 nm pore aligns to a cell and can be used to deliver extremely small biological elements to very large plasmids (>10 kbp). When compared to conventional bulk electroporation (BEP), the NEP chip shows a 20 fold improvement in dosage control and uniformity, while still maintaining high cell viability (>90%) even in cells such as cardiac cells which are characteristically difficult to transfect. This high-throughput 3D NEP system provides an innovative and medically valuable platform with uniform and reliable cellular transfection, allowing for a steady supply of healthy, engineered cells.


Nontuberculous mycobacterial disease mortality in the United States, 1999-2010: a population-based comparative study.
Environmental nontuberculous mycobacteria (NTM) are ubiquitous organisms with which humans commonly interact. The epidemiologic characteristics of NTM diseases including mortality rate and its associated factors remain largely unknown. In this study, we explored the geographical area of exposure and mortality and comorbid conditions of affected persons to determine environment, host, and host-pathogen interactive factors. We analyzed mortality related to nontuberculous mycobacterial infections from 1999 through 2010 by examining multiple-cause-of-death data from the National Center for Health Statistics. Among those who died with these diseases, we analyzed age-adjusted mortality rates, trends, associations with demographic variables, and comorbid conditions and correlated this information with similar data for tuberculosis-related mortality during the same time. From 1999 through 2010, nontuberculous mycobacterial disease was reported as an immediate cause of death in 2,990 people in the United States with a combined overall mean age-adjusted mortality rate of 0.1 per 100,000 person-years. A significant increase in the number of NTM related deaths was seen from 1999 through 2010 (R(2) = 0.72, p<0.0001), but it was not significant after adjustment for age. Persons aged 55 years and older, women, those living in Hawaii and Louisiana, and those of non-Hispanic, white ethnicity had higher mortality rates. Compared to tuberculosis-related mortality, chronic obstructive pulmonary disease, bronchiectasis, HIV, interstitial lung diseases, and tobacco use were significantly more common in persons with nontuberculous mycobacteria-related deaths. Nontuberculous mycobacteria-related death numbers are rising and are unevenly distributed. The strong association of nontuberculous mycobacterial disease with age suggests that its prevalence will increase as the United States population ages.


Emergency Department Deaths in a Nigerian University Hospital: Deaths Too Many.
We reviewed the demographic pattern and distribution of deaths in the emergency department (ED) of the University College Hospital (UCH) in order to identify gaps in the standard of care, thereby providing evidence for intervention and enhanced research in acute care. After obtaining institutional ethics approval, we retrospectively studied all deaths in the ED of UCH from January 1 to December 31, 2011. Data were retrieved from the ED's electronic register. During the 12-month period, a total of 10 728 patients attended the emergency centre and 647 deaths occurred, giving a mortality rate of 6.0%. Male deaths constituted 62% of all deaths. The mean age at death was 44.5 ± 19.1 (range 5 months-92) years. The age group with the highest proportional mortality was 60-69 years (11.4%). Out of all deaths, 295 (45.6%) had alterations of consciousness. Medicine was the specialty with the most deaths (56%), followed by surgery (40%) and lastly, obstetrics and gynaecology (4%). Of the 190 patients that died from trauma, 153 (80.5%) had injury severity score ≥ 15. Most deaths (75.4%) occurred within 24 hours of arrival and the 12-hour night shift had 322 (50%) of the mortalities. Autopsies were carried out in 36 (5.6%) of the 647 deaths. Of the 36 autopsies, 24 (66.7%) were deaths due to medical causes. Mortalities within 24 hours of presentation at the ED of UCH remain high. This calls for an efficient pre-hospital care, well-organized emergency transport system, new guidelines, establishment of protocols and regular audit.


ATAD control goals through the analysis of process variables and evaluation of quality, production and cost.
The aim of this paper is to establish and quantify different operational goals and control strategies in autothermal thermophilic aerobic digestion (ATAD). This technology appears as an alternative to conventional sludge digestion systems. During the batch-mode reaction, high temperatures promote sludge stabilization and pasteurization. The digester temperature is usually the only online, robust, measurable variable. The average temperature can be regulated by manipulating both the air injection and the sludge retention time. An improved performance of diverse biochemical variables can be achieved through proper manipulation of these inputs. However, a better quality of treated sludge usually implies major operating costs or a lower production rate. Thus, quality, production and cost indices are defined to quantify the outcomes of the treatment. Based on these, tradeoff control strategies are proposed and illustrated through some examples. This paper's results are relevant to guide plant operators, to design automatic control systems and to compare or evaluate the control performance on ATAD systems.


[Mental problems of victims and caregivers after critical incidents].
Critical incidents often challenge the structures of a community to their upper limits. Therefore not only victims and their relatives, but often the whole community or region have to deal with disaster consequences, which have to be psychologically processed and fostering mental reactions, often far from normal experience. Meanwhile different rescue and security specialists are exposed to high pressure to perform and mental stress. In modern disaster deployments also specialists in psychological early interventions and caregivers are integrated, which are as well not immune to stress. Despite the chaotic initial position in the aftermath of disaster, a great deal of scientific evidence concerning acute stress reactions and possible long-term mental health consequences has been gathered. But chaos also holds hidden, often poorly measurable and therefore scientifically not comparable aspects, which might nevertheless be useful for understanding of and coping with psychological trauma. Therefore this article addresses not just scientific, evidence based medical and psychological aspects of traumatization but focuses especially on less measurable experiences from defined disasters.


Continuous requirement for pp60-Src and phospho-paxillin during fibronectin matrix assembly by transformed cells.
Fibronectin (FN) matrix assembly is an integrin-mediated process that is regulated by both the extracellular environment and intracellular signaling pathways. The activity of Src-family kinases is important for initiation of FN assembly by normal fibroblasts. Here we report that in HT1080 fibrosarcoma cells, Src kinase activity is required not only for the assembly of FN matrix but also for the maintenance of FN matrix fibrils at the cell surface. Dexamethasone-induced FN fibril formation by these cells was completely blocked for at least 24 h when Src-family kinase activity was inhibited by either PP1 or SU6656. Inhibition of Src after significant matrix had already been assembled, resulted in an increased rate of loss of detergent-insoluble FN. Binding of activation-dependent integrin antibodies reveals a role for Src in maintaining integrin activity. The requirement for Src kinase activity appears to depend, in part, on phosphorylation of paxillin at tyrosine 118 (Y118). Phospho-paxillin co-localized with FN fibrils, and overexpression of GFP-paxillin but not of GFP-paxillinY118F enhanced cell-mediated assembly of FN. Our results indicate that Src maintains FN matrix at the cell surface through its effect on integrin activity and paxillin phosphorylation.


Devolution and its effects on health workforce and commodities management - early implementation experiences in Kilifi County, Kenya.
Decentralisation is argued to promote community participation, accountability, technical efficiency, and equity in the management of resources, and has been a recurring theme in health system reforms for several decades. In 2010, Kenya passed a new constitution that introduced 47 semi-autonomous county governments, with substantial transfer of responsibility for health service delivery from the central government to these counties. Focusing on two key elements of the health system, Human Resources for Health (HRH) and Essential Medicines and Medical Supplies (EMMS) management, we analysed the early implementation experiences of this major governance reform at county level. We employed a qualitative case study design, focusing on Kilifi County, and adapted the decision space framework developed by Bossert et al., to guide our inquiry and analysis. Data were collected through document reviews, key informant interviews, and participant and non-participant observations between December 2012 and December 2014. As with other county level functions, HRH and EMMS management functions were rapidly transferred to counties before appropriate county-level structures and adequate capacity to undertake these functions were in place. For HRH, this led to major disruptions in staff salary payments, political interference with HRH management functions and confusion over HRH management roles. There was also lack of clarity over specific roles and responsibilities at county and national government, and of key players at each level. Subsequently health worker strikes and mass resignations were witnessed. With EMMS, significant delays in procurement led to long stock-outs of essential drugs in health facilities. However, when the county finally managed to procure drugs, health facilities reported a better order fill-rate compared to the period prior to devolution. The devolved government system in Kenya has significantly increased county level decision-space for HRH and EMMS management functions. However, harnessing the full potential benefits of this increased autonomy requires targeted interventions to clarify the roles and responsibilities of different actors at all levels of the new system, and to build capacity of the counties to undertake certain specific HRH and EMMS management tasks. Capacity considerations should always be central when designing health sector decentralisation policies.


Stress type dependence of expression and cytoplasmic-nuclear partitioning of glucocorticoid receptor, hsp90 and hsp70 in Wistar rat brain.
Chronic exposure to stress is associated with different behavioral and neurological syndromes including impaired excitability of nerve cells in hippocampus (HIPPO) and prefrontal cortex (PFC), regions of the brain that are important for adaptation. The successful adaptation to stress involves negative feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis provided by the glucocorticoid receptor (GR), which is a steroid-dependent transcription factor found in a heterocomplex with heat shock proteins Hsp90 and Hsp70. In Wistar rats, chronic social isolation leads to a significant decrease in serum corticosterone (CORT), probably due to alterations in the GR signaling pathway. We exploited this type of stress, alone or in combination with acute immobilization, to define changes in the expression level and compartmental distribution of GR, Hsp90 and Hsp70 in HIPPO and PFC. The results indicated that in acute and combined stress, when CORT was increased, GR was translocated to the nucleus in both brain structures. Under chronic stress, when CORT was below the control level, GR was retained in the cytoplasm of PFC, and evenly distributed between compartments in HIPPO. Simultaneously, heat shock proteins partitioning in HIPPO seemed to be mainly stress type-independent, while that of PFC was dependent on stress type. Thus, the stress type-specific responses of GR and heat shock proteins were mainly detected in PFC rather than in HIPPO of Wistar rats. The observed alterations in protein expression and cytoplasmic-nuclear partitioning of the GR, Hsp90 and Hsp70 proteins may be related to maladaptive response of the HPA axis under chronic stress.


Relevance of polymeric matrix enzymes during biofilm formation.
Extracellular polymeric substances (EPS) contribute to biofilm stability and adhesion properties. The EPS matrix might also be a site for free extracellular enzyme activity; however, little is known about participation of enzyme activity in EPS during biofilm formation. In this study, we analyzed the activities of beta-glucosidase, leu-aminopeptidase, and beta-glucosaminidase during the colonization of artificial substrata (glass tiles) in a stream distinguishing enzyme activity in EPS matrix (matrix-enzymes) and total biofilm extracellular enzyme activity. The 1-h incubation of a biofilm suspension and cation-exchange resin followed by centrifugation seems appropriate to extract the matrix fraction (supernatant) and measure matrix enzymes (including free and linked to EPS) in freshwater biofilms, although there is a methodological limitation for using a biofilm suspension instead of an undisrupted biofilm. Total biofilm activities and matrix-enzyme activities showed similar capabilities to decompose organic matter compounds, with a greater capacity for peptide decomposition (leu-aminopeptidase) than for polysaccharides (beta-glucosidase), and a low decomposition of chitin and peptidoglycan (beta-glucosaminidase). Matrix-enzyme activity increased with colonization time, but more slowly than that of total enzyme activity. At the beginning of the colonization experiment (days 1-4) matrix enzymes accounted for 65-81% of total biofilm enzyme activity. Higher proportion of polysaccharides in EPS versus total biofilm, and higher matrix-enzyme activities per microgram of polysaccharides in the EPS were measured during the first 1-3 days of biofilm formation, indicating a high rate of enzyme release into the matrix during this period. Relative contribution of matrix-enzyme activities decreased as biofilm matures, but was maintained at 13-37% of total enzyme activity at the 42- to 49-day-old biofilm. These enzymes, retained and conserved in the EPS, may contribute to community metabolism. When analyzing extracellular enzymes in biofilms, the contribution of matrix enzymes must be considered, especially for young biofilms.


Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction.
Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this betaAR dysfunction was explored in transgenic mice overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6 versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels. Functional coupling of both betaAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these mice showed decreased formation of the active high-affinity conformation (R(H) = 29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C), only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V adenylyl cyclase was decreased approximately 45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq) mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by in vivo G(q) signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased G(alphaq) signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered.


Cantú syndrome is caused by mutations in ABCC9.
Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.


Rise of community-onset urinary tract infection caused by extended-spectrum β-lactamase-producing Escherichia coli in children.
Urinary tract infection (UTI) caused by resistant bacteria is becoming more prevalent. Few studies are available regarding community-onset UTIs caused by extended-spectrum β-lactamase (ESBL)-producing bacteria in children. During a 5-year period, hospitalized children with community-onset UTI caused by ESBL-producing Escherichia coli (case) and those with non-ESBL-producing E. coli (control) were identified. Patients with long-term care facility stay within the preceding month and those with urine cultures obtained >72 hours after admission were excluded. Clinical features and risk factors associated with the occurrence of ESBL-producing E. coli UTI were reviewed. The prevalence of UTI due to ESBL-producing E. coli increased slightly from 0.59% in 2002 to 0.96% in 2006. A total of 104 cases and 208 controls were included for comparison. The ciprofloxacin resistance of the ESBL-producing E. coli increased significantly in this period (p = 0.006). Pre-existing neurological diseases (p < 0.001), use of antibiotics in the past 3 months (p < 0.001), and recent hospitalization within 1 month (p < 0.001) were found to be potential risk factors. Moreover, previous exposure to third-generation cephalosporins (p < 0.001) and aminoglycosides (p < 0.001) was associated with the selection of ESBL-producing E. coli. Children with ESBL-producing E. coli UTIs had a longer hospital stay (p = 0.031) than those without. ESBL-producing E. coli gradually became coresistant to other broad-spectrum antibiotics, notably ciprofloxacin. UTIs caused by such resistant organisms led to a longer hospital stay and more antibiotic use. Reinforcement of infection control measures, especially hand washing in childcare settings and antibiotic stewardship, is critical to reduce the spread of ESBL-producing E. coli.


To the point: reviews in medical education--the Objective Structured Clinical Examination.
This article, the eighth in the To the Point Series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee, discusses the effectiveness of the Objective Structured Clinical Examination (OSCE) for assessment of learners' knowledge, skills, and behaviors. The OSCE has also been used for the appraisal of residents and physicians undergoing licensure examinations; herein we focus on its application to undergraduate medical education. We review evidence for best practices and recommendations on effective use of the OSCE and requirements for and challenges to its implementation, including creative ways to design an OSCE program with a limited budget. We discuss its role in providing formative and summative feedback and describe learner performance on the OSCE as the OSCE relates to subsequent testing, including US Medical Licensing Examination step 1. A representative case with assessment used at the authors' medical schools is included.


Pancreatectomy in multiple endocrine neoplasia type 1-related gastrinomas and pancreatic endocrine neoplasias.
The aim of this study was to evaluate the results of pancreatic resection in pancreatic endocrine neoplasias (PENs) in patients affected by multiple endocrine neoplasia type 1 (MEN1) syndrome. Since these tumors often show an indolent course, the role of diagnostic procedures and type of surgical approach are controversial. Experience with new diagnostic approaches and more aggressive surgery is still limited. Sixteen MEN1 patients were referred to our Surgical Unit (1992-2003) and were operated on for the indications of hypergastrinism, hypoglycemia, and/or pancreatic endocrine neoplasias larger than 1 cm. Zollinger-Ellison syndrome (ZES) was present in 13 patients, 2 of whom experienced a recurrence after previous surgery. Preoperative tumor localization was carried out using ultrasonography (US), computed tomography (CT), endoscopic ultrasonography (EUS), somatostatin receptor scintigraphy (SSRS), or selective arterial secretin injection (SASI). Rapid intraoperative gastrin measurement (IGM) was carried out in 8 patients, and 1 patient also underwent an intraoperative secretin provocative test. Either pancreatoduodenectomy (PD) or total pancreatectomy (TP) or distal pancreatectomy was performed. There was no postoperative mortality; 37% complications included pancreatic (27%) and biliary (6%) fistulas, abdominal collection (6%), and acute pancreatitis (6%). EUS and SSRS were the most sensitive preoperative imaging techniques. At follow-up, 10 of 13 hypergastrinemic patients (77%) are currently eugastrinemic with negative secretin provocative test, while 3 are showing a recurrence of the disease. All patients affected by insulinoma were cured. MEN1 tumors should be considered surgically curable diseases. IGM may be of value in the assessment of surgical cure. Our experience suggests that PD is superior to less radical surgical approaches in providing cure with limited morbidity in MEN1 gastrinomas and pancreatic neoplasias.


Multi-functionalized herringbone carbon nanofiber for anodes of lithium ion batteries.
Herringbone carbon nanofibers (HCNFs) are prepared for use as anode materials in lithium-ion batteries (LIBs). HCNFs are prepared using a Ni-Fe catalyst and subsequently multi-functionalized with oxygen using the Hummers' method, and then with both oxygen and nitrogen-containing 2-ureido-4[1H]pyrimidinone (UHP) moieties, which endow the HCNFs with the ability to form quadruple hydrogen bonds (QHBs). The as-prepared HCNFs are, on average, 13 μm in length and 100 nm in diameter, with a highly graphitic structure. The oxidized HCNFs (Ox-HCNFs) obtained by Hummers' method are partially exfoliated, having double-bladed saw-like structures that extend in the direction of the graphite planes. QHBs are formed between the HCNFs after functionalization with the UHP moieties. The final surface-modified HCNFs (N-Ox-HCNFs) have more electrochemical sites, shorter Li+ diffusion lengths, and additional electron pathways compared with the as-prepared HCNF and Ox-HCNF. The introduction of oxygen- and nitrogen-containing functional groups improves the performance of LIBs: a high charge capacity of 763 mA h g-1 at 0.1 A g-1, excellent rate capability (a capacity of 402 mA h g-1 at 3 A g-1), and near 100% capacity retention after 300 cycles are reported.


Hyperinflation with intrinsic PEEP and respiratory muscle blood flow.
Increased end-expiratory lung volume and intrinsic positive end-expiratory pressure (PEEP) are common in obstructive lung disease, especially during exacerbations or exercise. This loads the respiratory muscles and may also stress the circulatory system, causing a reduction or redistribution of cardiac output. We measured the blood flow to respiratory muscles and systemic organs using colored microspheres in 10 spontaneously breathing anesthetized tracheotomized dogs. Flows during baseline breathing (BL) were compared with those during hyperinflation (HI) induced by a mechanical analogue of airway closure and with those during an inspiratory resistive load (IR) that produced an equivalent increase in inspiratory work and time-integrated transdiaphragmatic pressure. Cardiac output was unchanged during IR (3.19 +/- 0.27 l/min at BL, 3.09 +/- 0.34 l/min during IR) but was reduced during HI (2.14 +/- 0.29 l/min; P < 0.01). Among the organs studied, flow was unaltered by IR but decreased to the liver and pancreas and increased to the brain during HI. For the respiratory muscles, flow to the diaphragm increased during IR. However, despite a 1.9-fold increase in inspiratory work per minute and a 2.5-fold increase in integrated transdiaphragmatic pressure during HI, blood flow to the diaphragm was unchanged and flow to the scalenes and sternomastoid fell. The only respiratory muscle to which flow increased during HI was the transversus abdominis, an expiratory muscle. We conclude that the circulatory effects of hyperinflation in this model impair inspiratory muscle perfusion and speculate that this may contribute to respiratory muscle dysfunction in hyperinflated states.


12-Month-Olds Produce Others' Intended but Unfulfilled Acts.
Following Meltzoff's (1995) behavioral reenactment paradigm, this study investigated the ability of 12-month-olds (N = 44) to reproduce a model's attempted-but-failed actions on objects. Testing was conducted using a novel set of objects designed to enable young infants to readily identify the potential outcome of the model's actions. Infants who saw an adult's attempted-but-failed actions now produced her intended outcomes at an equivalent rate to infants who saw the model's completed acts, and significantly more so than infants who either observed an adult manipulating the test apparatus using nontarget actions or who did not see any actions demonstrated on the test apparatus. This result shows that, contrary to previous studies, 12-month-olds can produce the intended but unconsummated acts of others.


Identification of a linear epitope recognized by a monoclonal antibody directed to the heterogeneous nucleoriboprotein A2.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by progressive joint destruction and disability. Classical autoantibodies of RA are rheumatoid factors and citrulline antibodies. Patients positive for these autoantibodies are usually associated with a progressive disease course. A subgroup of RA patients does not express citrulline antibodies, instead are approximately 35% of these anti-citrulline-negative patients reported to express autoantibodies to the heterogeneous nucleoriboprotein A2, a ribonucleoprotein involved in RNA transport and processing also referred to as RA33. In the absence of citrulline antibodies, RA33 antibodies have been suggested to be associated with a milder disease course. In this study we screened the reactivity of a monoclonal antibody to RA33-derived peptides by modified enzyme-linked immunosorbent assays (ELISA). Terminally truncated resin-bound peptides were applied for determination of the functional epitope necessary for antibody recognition. In addition, screening of substituted peptides by modified ELISA identified amino acids necessary for antibody reactivity. A potential epitope was identified in the region 71-79 (PHSIDGRVV), where the amino acids Ser, Ile and Asp were found to be essential for antibody reactivity. These amino acids were found to contribute to the antibody-antigen interface through side-chain interactions, possibly in combination with a positively charged amino acid in position 77. Moreover, the amino acids in the N-terminal end (Pro and His) were found to contribute to the interface through backbone contributions. No notable reactivity was found with RA-positive patient sera, thus screening of RA33 antibodies does not seem to be a supplementary for the diagnosis of RA.


An optically transparent thin-layer electrochemical cell for the study of vibrational circular dichroism of chiral redox-active molecules.
An optically transparent thin-layer electrochemical (OTTLE) cell with a locally extended optical path has been developed in order to perform vibrational circular dichroism (VCD) spectroscopy on chiral molecules prepared in specific oxidation states by means of electrochemical reduction or oxidation. The new design of the electrochemical cell successfully addresses the technical challenges involved in achieving sufficient infrared absorption. The VCD-OTTLE cell proves to be a valuable tool for the investigation of chiral redox-active molecules.


Building a genomic framework for prospective MRSA surveillance in the United Kingdom and the Republic of Ireland.
The correct interpretation of microbial sequencing data applied to surveillance and outbreak investigation depends on accessible genomic databases to provide vital genetic context. Our aim was to construct and describe a United Kingdom MRSA database containing over 1000 methicillin-resistant Staphylococcus aureus (MRSA) genomes drawn from England, Northern Ireland, Wales, Scotland, and the Republic of Ireland over a decade. We sequenced 1013 MRSA submitted to the British Society for Antimicrobial Chemotherapy by 46 laboratories between 2001 and 2010. Each isolate was assigned to a regional healthcare referral network in England and was otherwise grouped based on country of origin. Phylogenetic reconstructions were used to contextualize MRSA outbreak investigations and to detect the spread of resistance. The majority of isolates (n = 783, 77%) belonged to CC22, which contains the dominant United Kingdom epidemic clone (EMRSA-15). There was marked geographic structuring of EMRSA-15, consistent with widespread dissemination prior to the sampling decade followed by local diversification. The addition of MRSA genomes from two outbreaks and one pseudo-outbreak demonstrated the certainty with which outbreaks could be confirmed or refuted. We identified local and regional differences in antibiotic resistance profiles, with examples of local expansion, as well as widespread circulation of mobile genetic elements across the bacterial population. We have generated a resource for the future surveillance and outbreak investigation of MRSA in the United Kingdom and Ireland and have shown the value of this during outbreak investigation and tracking of antimicrobial resistance.


Intratumor pharmacokinetics, flow resistance, and metabolism during gemcitabine infusion in ex vivo perfused human small cell lung cancer.
The relationship between tumor physiology and the pharmacokinetics of 2',2' difluorodeoxycytidine [gemcitabine (dFdC)] in ex vivo perfused human small cell lung cancer was examined. Two small cell lung cancer sublines, 54A and 54B, with known in vivo sensitivity to dFdC, were grown as tissue-isolated tumors in athymic mice and perfused ex vivo with or without 20-40 micrometer dFdC. Arteriovenous differences in gases, pH, and metabolites were determined before and during drug infusion. The geometric flow resistance (FR) of individual tumors was calculated, and dFdC and its inactive metabolite 2',2' difluorodeoxyuridine were determined by high-performance liquid chromatography of consecutive samples from the output line. Both tumors had prominent lactate production concurrent with a significant O2 consumption. The arteriovenous pH drop was approximately 0.3 in both tumor lines. Significant metabolic differences between 54A and 54B tumors were found that elucidated previously described differences further. Pharmacokinetic analysis showed that the initial tumor uptake of dFdC was flow limited, and a significant inverse correlation between the geometric FR and initial drug uptake was found. The rate constant for recovery of the drug in the tumor outflow was greater in 54B tumors (P < 0.05), and the geometric FR was greater in 54A tumors (P < 0.01). The drug conversion rate was independent of physiological parameters. Attempts to modify the delivery of dFdC should be directed at the tumor blood flow distribution. More generally, our experimental model provides useful new insight into metabolism and intratumor pharmacokinetics of chemotherapeutic agents in solid tumors.


Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms.
Positive symptoms arise after lesions of the nervous system. They include neurogenic pain, tinnitus, abnormal movements, epilepsy and certain neuropsychiatric disorders. Stereotactic medial thalamotomies were performed on 104 patients with chronic therapy-resistant positive symptoms. Peroperative recordings of 2012 single units revealed an overwhelming unresponsiveness (99%) to sensory stimuli or motor activation. Among these unresponsive cells, 45.1% presented a rhythmic or random bursting activity. Rhythmic bursting activities had an average interburst interval of 263 +/- 46 ms corresponding to a frequency of 3.8 +/- 0.7 Hz. Frequency variations among the different symptoms were not statistically different. Intraburst characteristics such as the highest frequency encountered in the burst (480 +/- 80 Hz) or the mean frequency of the burst (206 +/- 44 Hz) were also similar in all patients. All bursts, rhythmic or random, fulfilled the extracellular criteria of low-threshold calcium spike (LTS) bursts. After medial thalamotomy and depending on the symptom, 43-67% of the patients reached a 50-100% relief, with sparing of all neurological functions. On the basis of these electrophysiological and clinical results, we propose a unified concept for all positive symptoms centred on a self-perpetuating thalamic cell membrane hyperpolarization, similar to the one seen in slow-wave sleep.


The hippocampal formation in schizophrenia.
The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in "runaway" CA3-mediated pattern completion could result in cognitive "mistakes," generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.


Risk, significance and biomedicalisation of a new population: older women's experience of osteoporosis screening.
This article explores the illness experience associated with being diagnosed at risk of a long term chronic condition and discusses the implications of an emergent form of predictive medicine. We report on findings from a study involving 30 older women between the ages of 73-85 years of age recently screened for osteoporosis and informed that they are at a higher than average risk of breaking a bone in the next 10 years, but not formally diagnosed with osteoporosis. Data were gathered by the Adherence to Osteoporosis Medicine (ATOM) study using in-depth interviews with women in their own homes in Norfolk & Suffolk, UK in 2009-2010. We analyse and discuss the significance participants give to their new fracture risk status and consider the practical, physical and existential consequences of this 'diagnosis'. The findings are discussed under three broad themes: Predictive technology, meaning and the risk-of-illness experience; knowledge, understanding and the embodiment of fracture risk status; and, social implications of biomedicine for an ageing population. We argue that screening for osteoporosis and assessment of fracture risk can be understood as a process of biomedicalisation of ageing and bone health. This article offers insight into the meaning of risk status as an illness experience for older women. We conclude by discussing how biomedicalisation of a new population through diagnosis of fracture risk status has significance and consequence at both the individual and the societal level expanding the population of older women labelled at risk and increasing demand for biomedical tests and prescribed medication for the prevention of disease.


Ultra-Widefield Retinal Imaging for Analyzing the Association Between Types of Pathological Myopia and Posterior Staphyloma.
High myopia may develop to pathologic myopia, which brings severe visual impairment; however, the etiology is not fully understood. We, therefore, investigated the relationship between the presence of posterior staphyloma and posterior ocular disorders by assessing the patients with high myopia. A retrospective study was performed for the patients, who have more than 26 mm of the axial length and of whom fundus photography was taken with an ultra-widefield retinal imaging system. The objectives were 138 cases encompassing 229 eyes. In 138 cases, 91 were bilateral and 47 were unilateral. The averages ± SD of axial length of bilateral and unilateral were 28.8 ± 2.2 mm, 27.3 ± 1.2 mm, respectively, showing statistically significant difference. The number of eyes with and without posterior staphyloma were 107 (46.7%) and 122 (53.3%), respectively. Retinal detachment and retinal breaks are more observed in cases without posterior staphyloma (p = 0.017). Myopic choroidal neovascularization (mCNV) (p = 0.002), chorioretinal atrophy (p < 0.001), retinoschisis (p < 0.001), and optic neuropathy (p = 0.038) are more often seen in cases with posterior staphyloma. In conclusion, the prevalence rates of myopic choroidal neovascularization, retinal choroidal atrophy, and optic neuropathy were significantly higher with posterior staphyloma. The rate of periocular disorders such as retinal detachment was significantly higher without posterior staphyloma. These results indicate associations between types of pathological myopia and presence or absence of posterior staphyloma analyzed by ultra-widefield retinal imaging.


Finding partners: emerging protein interaction technologies applied to signaling networks.
Signal transduction pathways play essential roles in cell differentiation, proliferation, and survival. Their precise regulation is achieved through specific protein-protein interactions that mediate the assembly of protein complexes in response to different signals. Disturbances of the normal protein-protein interactions within signaling pathways can lead to many diseases, including cancer. In this review, Stagljar aims to highlight the emerging protein interaction technologies that are advancing the field of signal transduction. These approaches include stable isotope labeling by amino acids in cell culture, SH2 profiling, target-assisted iterative screening, and the split-ubiquitin membrane yeast two-hybrid system. Although still at an early stage, these technologies show promise as useful methods for the characterization of novel components of various signal transduction pathways.


Experimental mummification-In the tracks of the ancient Egyptians.
Understanding natural and artificial postmortem alterations in different tissues of the human body is essential for bioarchaeology, paleogenetics, physical anthropology, forensic medicine, and many related disciplines. With this study, we tried to gain a better understanding of tissue alterations associated with the artificial mummification techniques of ancient Egypt, in particular for mummified visceral organs. We used several entire porcine organs and organ sections (liver, lung, stomach, ileum, and colon), which provided a close approximation to human organs. First, we dehydrated the specimens in artificial natron, before applying natural ointments, according to the ancient literary sources and recent publications. We periodically monitored the temperature, pH value, and weight of the specimens, in addition to radiodensity and volumetric measurements by clinical computed tomography and sampling for histological, bacteriological, and molecular analyses. After seven weeks, mummification was seen completed in all specimens. We observed a considerable loss of weight and volume, as well as similar courses in the decay of tissue architecture but varying levels of DNA degradation. Bacteriologically we did not detect any of the initially identified taxa in the samples by the end of the mummification process, nor any fungi. This feasibility study established an experimental protocol for future experiments modeling ancient Egyptian mummification of visceral organs using human specimens. Understanding desiccation and mummification processes in non-pathological tissues of specific visceral organs may help to identify and interpret disease-specific alterations in mummified tissues in ancient Egyptian canopic jars and organ packages contained in whole mummies.


Preclinical efficacy testing in middle-aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact.
Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500 mg/kg or 50 mg/kg) or saline alone (1 mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1 h and 24 h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood-brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50 mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials.


Under-reporting of socioeconomic status of patients in stroke trials: adherence to CONSORT principles.
The 2001 Revised Consolidated Standards of Reporting of Trials (CONSORT) statement requires reporting of Randomized Controlled Trials (RCTs) to include participants' baseline demographics. This enables comparison of intervention and control groups on potential confounding variables as well as assessment of study generalizability. Socioeconomic status (SES) is associated with access to care and outcomes (mortality, functional outcome, recurrent stroke, and hospital readmission) poststroke. We aimed to document the reporting of baseline SES in reports of RCTs of stroke and transient ischemic attack. Measures of SES were extracted from studies reporting trials of stroke or transient ischemic attack published in 12 major journals in the disciplines of general medicine, general neurology, cerebrovascular disease, and rehabilitation subsequent to revised CONSORT. Percentages of studies reporting SES measures were calculated. Differences in reporting between journal categories, and temporal trends in reporting, were tested. Only 12% of studies reported any SES measure. Journal categories did not differ in rate of SES reporting. SES reporting did not increase over time. Improving reporting of SES could enhance clinicians' ability to evaluate RCT findings and apply them to their patients.


CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation.
CD28 is the quintessential costimulatory molecule expressed on CD4(+) and CD8(+) T cells. During chronic infections and the normal aging process, CD28 expression is lost, compromising the functional activity of T cells. CD28 loss is promoted by replicative stress, particularly in the presence of tumor necrosis factor-alpha, owing to an inoperative CD28 initiator element. It is currently unknown whether CD28 loss is irreversible. The present study examined cytokines for their ability to reinduce CD28 expression. CD4(+)CD28(null) T cells constitutively expressed interleukin-12 (IL-12) alpha and beta receptors, which were functional and allowed for the up-regulation of the signal transducer and activator of transcription-4 (STAT-4)-dependent gene CD161. Costimulation of the T-cell and IL-12 receptors induced the transcription of CD28 in approximately 50% of CD4(+)CD28(null) T-cell clones and lines. IL-12 by itself did not restore CD28 expression. Up-regulation of CD28 after IL-12 exposure correlated with the reassembly of the CD28-initiator protein complex. The re-expressed CD28 was functional and restored the ability of CD4(+)CD28(null) T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4(+) T cells.


The Professional Association's Perspective on Nursing Informatics and Competencies in the US.
The American Nurses Association (ANA) recognized nursing informatics as a nursing specialty in 1992, developed the first scope and standards of nursing informatics practice in the mid-1990s, and remains the custodian and steward of each document revision. Over the past two decades, the definition of nursing informatics, scope of practice statement, and framework of the standards of practice have evolved to now include a collection of competencies for the informatics nurse and informatics nurse specialist. The American Nurses Credentialing Center (ANCC), an ANA subsidiary, created and maintains a nursing informatics certification program that offers a board certification credential to qualified applicants, including international nurse colleagues. Such a certification program is intended to assess and publicly recognize competence of the informatics nurse.


Volumetric in vivo imaging of microvascular perfusion within the intact cochlea in mice using ultra-high sensitive optical microangiography.
Studying the inner ear microvascular dynamics is extremely important to understand the cochlear function and to further advance the diagnosis, prevention, and treatment of many otologic disorders. However, there is currently no effective imaging tool available that is able to access the blood flow within the intact cochlea. In this paper, we report the use of an ultrahigh sensitive optical micro-angiography (UHS-OMAG) imaging system to image 3-D microvascular perfusion within the intact cochlea in living mice. The UHS-OMAG image system used in this study is based on spectral domain optical coherence tomography, which uses a broadband light source centered at 1300 nm with an imaging rate of 47[Formula: see text] 000 A-scans/s, capable of acquiring high-resolution B scans at 300 frames/s. The technique is sensitive enough to image very slow blood flow velocities, such as those found in capillary networks. The 3-D imaging acquisition time for a whole cochlea is ∼ 4.1 s. We demonstrate that volumetric reconstruction of microvascular flow obtained by UHS-OMAG provides a comprehensive perfusion map of several regions of the cochlea, including the otic capsule, the stria vascularis of the apical and middle turns and the radiating arterioles that emanate from the modiolus.


Observation of angle-modulated switch between enhancement and suppression of nonlinear optical processes.
We simultaneously investigate the four-wave mixing and the fluorescence signals via two cascade electromagnetically induced transparency (EIT) systems in atomic rubidium vapor. By manipulating the deflection angle between the probe beam and certain coupling beams, the dark state can extraordinarily switch to bright state, induced by the angle-modulation on the dressing effect. Besides, in the fluorescence signal, the peak of two-photon fluorescence due to classical emission and the dip of single-photon fluorescence due to dressing effect are distinguished, both in separate spectral curves and in the global profile of spectrum. Meanwhile, we observe and analyze the similarities and discrepancies between the two ground-state hyperfine levels F = 2 and F = 3 of Rb 85 for the first time.


Benzene degradation in a denitrifying biofilm reactor: activity and microbial community composition.
Benzene is an aromatic compound and harmful for the environment. Biodegradation of benzene can reduce the toxicological risk after accidental or controlled release of this chemical in the environment. In this study, we further characterized an anaerobic continuous biofilm culture grown for more than 14 years on benzene with nitrate as electron acceptor. We determined steady state degradation rates, microbial community composition dynamics in the biofilm, and the initial anaerobic benzene degradation reactions. Benzene was degraded at a rate of 0.15 μmol/mg protein/day and a first-order rate constant of 3.04/day which was fourfold higher than rates reported previously. Bacteria belonging to the Peptococcaceae were found to play an important role in this anaerobic benzene-degrading biofilm culture, but also members of the Anaerolineaceae were predicted to be involved in benzene degradation or benzene metabolite degradation based on Illumina MiSeq analysis of 16S ribosomal RNA genes. Biomass retention in the reactor using a filtration finger resulted in reduction of benzene degradation capacity. Detection of the benzene carboxylase encoding gene, abcA, and benzoic acid in the culture vessel indicated that benzene degradation proceeds through an initial carboxylation step.


Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10.
The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by extracts from other enteropathogens and requires a heat-sensitive H. pylori component and the DC-intrinsic production of IL-10. The basic leucine zipper ATF-like 3 (BATF3)-dependent CD103(+)CD11b(-) dendritic cell lineage is enriched in the lungs of protected mice and strictly required for protection. Two H. pylori persistence determinants, the γ-glutamyl-transpeptidase GGT and the vacuolating cytotoxin VacA, are required and sufficient for asthma protection and can be administered in purified form to prevent asthma. In conclusion, we provide preclinical evidence for the concept that the immunomodulatory properties of H. pylori can be exploited for tolerization strategies aiming to prevent allergen-induced asthma.


CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression.
The normal epithelial cell-specific-1 (NES1)/kallikrein 10 gene is expressed in normal mammary epithelial cells, but its expression is dramatically decreased in breast cancer cell lines. Now, we have cloned and characterized the active promoter region of NES1. Using a luciferase reporter system, we demonstrate that most tumor cell lines are able to support full or partial transcription from the NES1 promoter, suggesting a role for promoter-independent cis-acting mechanisms of loss of NES1 expression. We show that hypermethylation of the NES1 gene represents one such mechanism. Using methylation-specific PCR and sequence analysis of sodium bisulfite-treated genomic DNA, we demonstrate a strong correlation between exon 3 hypermethylation and loss of NES1 mRNA expression in a panel of breast cancer cell lines and in primary tumors. Treatment of NES1-nonexpressing cells with a demethylating agent led to reexpression of NES1, suggesting an important role of hypermethylation in the loss of NES1 expression. We suggest that hypermethylation is responsible for tumor-specific loss of NES1 gene expression. Our results also suggest that hypermethylation of the NES1 gene may serve as a potential marker for breast cancer.


Characterization of bioactive cell penetrating peptides from human cytochrome c: protein mimicry and the development of a novel apoptogenic agent.
Cell penetrating peptides (CPPs) with intrinsic biological activities offer a novel strategy for the modulation of intracellular events. QSAR analysis identified CPPs within human cytochrome c. Two such sequences, Cyt c(77-101) and Cyt c(86-101), induced tumor cell apoptosis, thus mimicking the role of Cyt c as a key regulator of programmed cell death. Quantitative analyses confirmed that Cyt c(77-101) is an extremely efficient CPP. Thus, Cyt c(77-101) was selected for modification to incorporate target-specific peptidyl motifs. Chimeric N-terminal extension with a target mimetic of FG nucleoporins significantly enhanced the apoptogenic potency of Cyt c(77-101) to a concentration readily achievable in vivo. Moreover, this construct, Nup153-Cyt c, facilitates the dramatic redistribution of nuclear pore complex proteins and thus propounds the nuclear pore complex as a novel target for the therapeutic induction of apoptosis.


Field collection of rectal samples for sexually transmitted infection diagnostics among men who have sex with men.
Rectal sexually transmitted infections (STIs) are common in men at risk for urethral infections with these pathogens, particularly men who have sex with men (MSM). However, for those individuals not regularly seen by a clinician, screening for rectal STI is not currently a widespread option. Qualitative data and samples (i.e. self-obtained rectal specimens) were collected from 75 MSM in a variety of venues. Upon completion of the rectal self-sampling, each participant completed a brief interview regarding their overall experience with the process. Participants reported an overall high level of acceptability and comfort-level involved with self-sampling for rectal STI. Of the majority of men who agreed to provide a rectal self-sample, all reported that they would provide a sample again in the future. However, many men also appreciated the interaction with a health-care provider that a clinical setting offered. In conclusion, self-sampling is a feasible and acceptable option when offered to MSM in a range of community-based venues. Further research is needed to determine which combinations of STI testing and treatment methods (including self-sampling) are most appropriate for diverse groups of men.


Susceptibility to Yersinia pestis experimental infection in wild Rattus rattus, reservoir of plague in Madagascar.
In Madagascar, the black rat, Rattus rattus, is the main reservoir of plague (Yersinia pestis infection), a disease still responsible for hundreds of cases each year in this country. This study used experimental plague challenge to assess susceptibility in wild-caught rats to better understand how R. rattus can act as a plague reservoir. An important difference in plague resistance between rat populations from the plague focus (central highlands) and those from the plague-free zone (low altitude area) was confirmed to be a widespread phenomenon. In rats from the plague focus, we observed that sex influenced plague susceptibility, with males slightly more resistant than females. Other individual factors investigated (weight and habitat of sampling) did not affect plague resistance. When infected at high bacterial dose (more than 10⁵ bacteria injected), rats from the plague focus died mainly within 3-5 days and produced specific antibodies, whereas after low-dose infection (< 5,000 bacteria), delayed mortality was observed and surviving seronegative rats were not uncommon. These results concerning plague resistance level and the course of infection in the black rat would contribute to a better understanding of plague circulation in Madagascar.


The induction of anterior and posterior neural genes in Xenopus laevis.
We have investigated the interactions between mesoderm and ectoderm that result in the formation of a regionally differentiated nervous system in Xenopus embryos. We have used genes expressed at different positions along the neural tube as regional markers of neural induction in both whole, and in experimentally manipulated embryos. By comparing transcription from the anterior marker, XIF3, with that from the posterior marker, X1Hbox6, and the general neural marker XIF6, we have shown that the normal induction process requires interactions between ectoderm and mesoderm that persist through gastrulation into the late neurula stages. We have found that competence of the ectoderm to respond to induction is lost at the same early neurula stage for all three marker genes. Using rhodamine dextran-labelled mesoderm, we have established that the duration of contact between ectoderm and mesoderm required for gene activation in conjugates is the same for each of the markers. We have, however, identified regions of the mesoderm that can induce different combinations of neural marker gene expression. The anterior mesoderm induces expression of the anterior marker, XIF3, and the later migrating posterior mesoderm induces the ectoderm overlying it to express the posterior marker X1Hbox6. It has been proposed that neural inducing signals reach the ectoderm by two different routes: from mesoderm lying directly beneath the ectoderm or along the plane of the ectoderm. We have assessed the contribution of each route in respect of our three neural markers and find that a signal passing directly from mesoderm to ectoderm fully accounts for neural gene expression. We were unable to detect an inducing signal that passes along the plane of the ectoderm.


Network and Systems Medicine: Position Paper of the European Collaboration on Science and Technology Action on Open Multiscale Systems Medicine.
Introduction: Network and systems medicine has rapidly evolved over the past decade, thanks to computational and integrative tools, which stem in part from systems biology. However, major challenges and hurdles are still present regarding validation and translation into clinical application and decision making for precision medicine. Methods: In this context, the Collaboration on Science and Technology Action on Open Multiscale Systems Medicine (OpenMultiMed) reviewed the available advanced technologies for multidimensional data generation and integration in an open-science approach as well as key clinical applications of network and systems medicine and the main issues and opportunities for the future. Results: The development of multi-omic approaches as well as new digital tools provides a unique opportunity to explore complex biological systems and networks at different scales. Moreover, the application of findable, applicable, interoperable, and reusable principles and the adoption of standards increases data availability and sharing for multiscale integration and interpretation. These innovations have led to the first clinical applications of network and systems medicine, particularly in the field of personalized therapy and drug dosing. Enlarging network and systems medicine application would now imply to increase patient engagement and health care providers as well as to educate the novel generations of medical doctors and biomedical researchers to shift the current organ- and symptom-based medical concepts toward network- and systems-based ones for more precise diagnoses, interventions, and ideally prevention. Conclusion: In this dynamic setting, the health care system will also have to evolve, if not revolutionize, in terms of organization and management.


Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity.
Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic iNKT cell activators in the design of immunotherapeutic agents.


Perception of affective and linguistic prosody: an ALE meta-analysis of neuroimaging studies.
Prosody refers to the melodic and rhythmic aspects of speech. Two forms of prosody are typically distinguished: 'affective prosody' refers to the expression of emotion in speech, whereas 'linguistic prosody' relates to the intonation of sentences, including the specification of focus within sentences and stress within polysyllabic words. While these two processes are united by their use of vocal pitch modulation, they are functionally distinct. In order to examine the localization and lateralization of speech prosody in the brain, we performed two voxel-based meta-analyses of neuroimaging studies of the perception of affective and linguistic prosody. There was substantial sharing of brain activations between analyses, particularly in right-hemisphere auditory areas. However, a major point of divergence was observed in the inferior frontal gyrus: affective prosody was more likely to activate Brodmann area 47, while linguistic prosody was more likely to activate the ventral part of area 44.


The future of HIV vasculopathy when our patients are on antiretroviral therapy.
South Africa was one of the last countries in Africa to be affected by the HIV epidemic, but currently has one of the highest prevalences in the world. Antiretroviral therapy (ART) was recently introduced in South Africa, and as of December 2007 antiretroviral treatment coverage in this country was about 25% (UNAIDS, 2008). There is a well-documented relationship between vascular disease and HIV infection. This HIV vasculopathy may manifest as arterial aneurysms, occlusive disease or complications of hypercoagulability. The question to be asked is 'What is the future of HIV vasculopathy when our patients are on antiretroviral therapy?'


Sudden Infant Death Syndrome: review of implicated genetic factors.
Genetic studies in Sudden Infant Death Syndrome (SIDS) have been motivated by clinical, epidemiological, and/or neuropathological observations in SIDS victims, with subsequent pursuit of candidate genes in five categories: (1) genes for ion channel proteins based on electrocardiographic evidence of prolonged QT intervals in SIDS victims, (2) gene for serotonin transporter based on decreased serotonergic receptor binding in brainstems of SIDS victims, (3) genes pertinent to the early embryology of the autonomic nervous system (ANS) (and with a link to the 5-HT system) based on reports of ANS dysregulation in SIDS victims, (4) genes for nicotine metabolizing enzymes based on evidence of cigarette smoking as a modifiable risk factor for SIDS, and (5) genes regulating inflammation, energy production, hypoglycemia, and thermal regulation based on reports of postnatal infection, low birth weight, and/or overheating in SIDS victims. Evidence for each of these classes of candidate genes is reviewed in detail. As this review indicates, a number of genetically controlled pathways appear to be involved in at least some cases of SIDS. Given the diversity of results to date, genetic studies support the clinical impression that SIDS is heterogeneous with more than one entity and with more than one possible genetic etiology. Future studies should consider expanded phenotypic features that might help clarify the heterogeneity and improve the predictive value of the identified genetic factors. Such features should be evaluated to the extent possible in both SIDS victims and their family members. With 2,162 infants dying from SIDS in 2003 in the U.S. alone, and improved but still imperfect parent and caretaker compliance with known modifiable risk factors for SIDS, it behooves clinicians, researchers, and parents to combine efforts to reach a common goal. The message of the "Back to Sleep" campaign needs to be re-introduced/re-engineered to reach families and caretakers of all ethnic groups. Clinicians and researchers need to gently inform new SIDS parents about the opportunity to contribute tissue to the NICHD-funded University of Maryland Brain and Tissue Bank. By expanding the network of clinicians, scientists, and families working together, and by combined efforts in a collaborative multi-center study of candidate genes and/or genomics, the discovery of the genetic profile of the infant at risk for SIDS can ultimately be determined.


The effects of exercise on vascular endothelial function in type 2 diabetes: a systematic review and meta-analysis.
Vascular endothelial dysfunction induced by hyperglycemia and elevated insulin resistance is a potent risk factor for cardiovascular disease and likely contributes to multiple chronic disease complications associated with aging. The aim of this study was to systematically review and quantify the effects of exercise on endothelial function (EF) in type 2 diabetes (T2D). Five electronic databases were searched (until June 2017) for studies that met the following criteria: (i) randomized controlled trials; (ii) T2D aged ≥ 18 years; (iii) measured EF by brachial artery flow-mediated dilation (FMD); (iv) structured and supervised exercise intervention for ≥ 8 weeks. Thirteen cohorts, selected from eight studies (306 patients, average age 59 years), met the inclusion criteria. Exercise training significantly increased FMD (mean ES = 0.41, 95% CI 0.21-0.62, P < 0.001). Low to moderate intensity subgroups and aerobic exercise (AE) subgroups significantly increased FMD more than moderate to high intensity subgroups and combined AE and resistance exercise subgroups respectively (P < 0.01, P < 0.05). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments reported that quality of evidence for all outcomes was moderate except shear rate showing low. Egger's test showed no significant publication bias for all outcomes. Our results suggest that in patients with T2D, lower intensity exercise has physiological meaningful effects on EF, in support of the emerging concept that the lower efforts of exercise are not necessarily less cardioprotective than higher intensity training.


Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells.
Polymorphonuclear leukocytes (PMN) traverse an endothelial cell (EC) barrier by crawling between neighboring EC. Whether EC regulate the integrity of their intercellular adhesive and junctional contacts in response to chemotaxing PMN is unresolved. EC respond to the binding of soluble mediators such as histamine by increasing their cytosolic free calcium concentration ([Ca++]i) (Rotrosen, D., and J.I. Gallin. 1986. J. Cell Biol. 103:2379-2387) and undergoing shape changes (Majno, G., S. M. Shea, and M. Leventhal. 1969. J. Cell Biol. 42:617-672). Substances such as leukotriene C4 (LTC4) and thrombin, which increased the permeability of EC monolayers to ions, as measured by the electrical resistance of the monolayers, transiently increased EC [Ca++]i. To determine whether chemotaxing PMN cause similar changes in EC [Ca++]i, human umbilical vein endothelial cells (HUVEC) maintained as monolayers were loaded with fura-2. [Ca++]i was measured in single EC during PMN adhesion to and migration across these monolayers. PMN-EC adhesion and transendothelial PMN migration in response to formyl-methionyl-leucyl-phenylalanine (fMLP) as well as to interleukin 1 (IL-1) treated EC induced a transient increase in EC [Ca++]i which temporally corresponded with the time course of PMN-EC interactions. When EC [Ca++]i was clamped at resting levels with a cell permeant calcium buffer, PMN migration across EC monolayers and PMN induced changes in EC monolayer permeability were inhibited. However, clamping of EC [Ca++]i did not inhibit PMN-EC adhesion. These studies provide evidence that EC respond to stimulated PMN by increasing their [Ca++]i and that this increase in [Ca++]i causes an increase in EC monolayer permeability. Such [Ca++]i increases are required for PMN transit across an EC barrier. We suggest EC [Ca++]i regulates transendothelial migration of PMN by participating in a signal cascade which stimulates EC to open their intercellular junctions to allow transendothelial passage of leukocytes.


Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin in DBA2/J Mice.
Thalidomide's reported ability to inhibit angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. This study explored thalidomide's antitumorigenic potential when administered alone and in combination with cisplatin to DBA2/J mice whose tumors were induced by murine erythroleukemic cells. Thalidomide treatment alone produced no significant inhibitory effect on tumor development and metastasis. Mice that received both drugs had significantly lower incidences of both primary and secondary tumors as compared to the untreated control group. Cisplatin, administered alone or in combination with thalidomide, led to a significant delay in tumor formation and a longer life span than was recorded in untreated mice. However, the combination treatment results were not significantly different from those of cisplatin treatment used as a single agent. In in vitro cell multiplication studies using murine erythroleukemic and murine endothelial cells, thalidomide failed to inhibit cell proliferation. However, cisplatin treatment with or without thalidomide, significantly inhibited the multiplication of both cell lines in a dose dependent manner. Thalidomide does not appear to be a beneficial adjuvant to cisplatin treatment.


Neural effects of mindfulness-based interventions on patients with major depressive disorder: A systematic review.
Growing evidence has suggested that mindfulness-based interventions (MBIs) could have beneficial effects on the acute phase of depression and on the prevention of depressive relapse or recurrence. Despite growing clinical interest, the effects of MBIs on brain functioning in patients with MDD remain unclear. The aim of this systematic review was to assess the changes in brain functioning associated with MBIs in patients with MDD. A systematic search was conducted, and of the 56 articles found, 8 were eligible. MBIs have modulatory effects on several brain regions implicated in the pathophysiology of MDD, such as the prefrontal cortex, the basal ganglia, the anterior and posterior cingulate cortices, and the parietal cortex. These regions have been implicated in self-awareness, attention and emotion regulation. Some of these findings were consistent with the effects of MBIs observed in healthy subjects and patients with other psychiatric disorders, especially enhanced activity in the frontal and subcortical regions related to the improved somatosensory awareness. Further studies are needed to elucidate the mechanisms of MBIs in MDD.


Shunt implantations and peritoneal catheters: Do not cut beyond 20 cm.
Ventriculoperitoneal shunts are supplied with long peritoneal catheters, most commonly between 80 and 120 cm long. ISO/DIS 7197/2006([15]) shunt manufacturing procedures include peritoneal catheter as an integrate of the total resistance. Cutting pieces of peritoneal catheters upon shunt implantation or revision is a common procedure. We evaluated five shunts assembled with different total pressure resistances and variable peritoneal catheter lengths in order to clarify the changes that occurred in the hydrodynamic profile when peritoneal catheters were cut upon shunt implantation or shunt revision. Originally, all shunts performed within the operational range. Shunt 1 performed in a lower pressure range at 200 mm cut off peritoneal catheter and as a low-pressure shunt with -300 mm cut off. Shunt 2 was manufactured to run at the higher border pressure range, and it went out of specification with a 300 mm cut off. Shunt 3 was manufactured to run close to the lower border pressure range, and at 100 mm cutoff, it was already borderline in a lower resistive category. Other shunts also responded similarly. The limit to maintain a shunt in its original pressure settings was 20 cm peritoneal catheter cutting length. By cutting longer pieces of peritoneal catheter, one would submit patients to a less-resistive regimen than intended and his reasoning will be compromised. The pediatric population is more prone to suffer from the consequences of cutting catheters. Shunt manufacturers should consider adopting peritoneal catheters according to the age (height) of the patient.


Transferrin microheterogeneity in fetal blood.
To investigate the distribution of microheterogeneous subfractions of transferrin in fetal blood and the influence of highly sialylated transferrins on fetal growth. Serum transferrin concentrations were determined by a standard turbidimetric assay. Microheterogeneous transferrin subfractions were assessed by crossed immunoisoelectric focusing. In normal term infants, total serum transferrin concentrations and percent distribution of highly sialylated transferrins (> or = 5-sialo-transferrins) were markedly lower; the percent distributions of hyposialylated transferrins (0- and 1-sialo-transferrins) were apparently higher than those in non-pregnant and pregnant women. There was no significant positive correlation between the serum concentrations of total transferrin or highly sialylated transferrins in infants' blood and birth weights (r = 0.187, p = 0.582; r = 0.374, p = 0.257, respectively). The transferrin microheterogeneity pattern shifted towards reduced glycosylation and sialylation in addition to a decrease in total transferrin concentration in fetal blood compared to that of non-pregnant and pregnant women. The concentrations of serum total transferrin and the highly sialylated transferrins in fetal blood, if higher than a certain level, did not seem to have any influence on normal fetal growth.


Discovery of a low order drug-cell response surface for applications in personalized medicine.
The cell is a complex system involving numerous components, which may often interact in a non-linear dynamic manner. Diseases at the cellular level are thus likely to involve multiple cellular constituents and pathways. As some drugs, or drug combinations, may act synergistically on these multiple pathways, they might be more effective than the respective single target agents. Optimizing a drug mixture for a given disease in a particular patient is particularly challenging due to both the difficulty in the selection of the drug mixture components to start out with, and the all-important doses of these drugs to be applied. For n concentrations of m drugs, in principle, n(m) combinations will have to be tested. As this may lead to a costly and time-consuming investigation for each individual patient, we have developed a Feedback System Control (FSC) technique which can rapidly select the optimal drug-dose combination from the often millions of possible combinations. By testing this FSC technique in a number of experimental systems representing different disease states, we found that the response of cells to multiple drugs is well described by a low order, rather smooth, drug-mixture-input/drug-effect-output multidimensional surface. The main consequences of this are that optimal drug combinations can be found in a surprisingly small number of tests, and that translation from in vitro to in vivo is simplified. This points to the possibility of personalized optimal drug mixtures in the near future. This unexpectedly simple input-output relationship may also lead to a simple solution for handling the issue of human diversity in cancer therapeutics.


Altered Resting State Effective Connectivity of Anterior Insula in Depression.
Depression has been associated with changes in both functional and effective connectivity of large scale brain networks, including the default mode network, executive network, and salience network. However, studies of effective connectivity by means of spectral dynamic causal modeling (spDCM) are still rare and the interaction between the different resting state networks has not been investigated in detail. Thus, we aimed at exploring differences in effective connectivity among eight right hemisphere brain areas-anterior insula, inferior frontal gyrus, middle frontal gyrus (MFG), frontal eye field, anterior cingulate cortex, superior parietal lobe, amygdala, and hippocampus, between a group of healthy controls (N = 20) and medicated depressed patients (N = 20). We found that patients not only had significantly reduced strength of the connection from the anterior insula to the MFG (i.e., dorsolateral prefrontal cortex) but also a significant connection between the amygdala and the anterior insula. Moreover, depression severity correlated with connectivity of the hippocampal node. In conclusion, the results from this resting state spDCM study support and enrich previous data on the role of the right anterior insula in the pathophysiology of depression. Furthermore, our findings add to the growing evidence of an association between depression severity and disturbances of the hippocampal function in terms of impaired connectivity with other brain regions.


"Kankasha" in Kassala: A prospective observational cohort study of the clinical characteristics, epidemiology, genetic origin, and chronic impact of the 2018 epidemic of Chikungunya virus infection in Kassala, Sudan.
The public health impact of Chikungunya virus (CHIKV) is often underestimated. Usually considered a mild condition of short duration, recent outbreaks have reported greater incidence of severe illness, fatality, and longer-term disability. In 2018/19, Eastern Sudan experienced the largest epidemic of CHIKV in Africa to date, affecting an estimated 487,600 people. Known locally as Kankasha, this study examines clinical characteristics, risk factors, and phylogenetics of the epidemic in Kassala City. A prospective cohort of 102 adults and 40 children presenting with chikungunya-like illness were enrolled at Kassala Teaching Hospital in October 2018. Clinical information, socio-demographic data, and sera samples were analysed to confirm diagnosis, characterise illness, and identify viral strain. CHIKV infection was confirmed by real-time reverse transcription-PCR in 84.5% (120/142) of participants. Nine (7.5%) CHIKV-positive participants had concurrent Dengue virus (DENV) infection; 34/118 participants (28.8%) had a positive Rapid Diagnostic Test for Plasmodium falciparum; six (5.0%) had haemorrhagic symptoms including two children with life-threatening bleeding. One CHIKV-positive participant died with acute renal injury. Age was not associated with severity of illness although CHIKV-infected participants were younger (p = 0.003). Two to four months post-illness, 63% of adults available for follow-up (30) were still experiencing arthralgia in one or more joints, and 11% remained moderately disabled on Rapid3 assessment. Phylogenetic analysis showed all CHIKV sequences from this study belonged to a single clade within the Indian Ocean Lineage (IOL) of the East/Central/South African (ECSA) genotype. History of contact with an infected person was the only factor associated with infection (p = 0.01), and likely related to being in the same vector environment. Vulnerability to CHIKV remains in Kassala and elsewhere in Sudan due to widespread Aedes aegypti presence and mosquito-fostering household water storage methods. This study highlights the importance of increasing awareness of the severity and impact of CHIKV outbreaks, and the need for urgent actions to reduce transmission risk in households.


21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia.
U74006F is a member of a new family of steroid drugs called 21-aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity. We investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present.


Concussion advocacy and legislation: a neurological surgeon's view from the epicenter.
Traumatic brain injury is the leading cause of death and disability in the world for adolescents according to the World Health Organization. Sports-related concussion is a small but perhaps one of the most preventable causes of that morbidity. Legislation to protect student athletes is one of the ways in which we can advocate for safety in sports. This paper reviews the legislative history of the first concussion law passed to protect youth athletes: Washington State's Zackery Lystedt Law. This history is viewed from the point of view of one of the participants in the efforts to pass laws in all 50 states. The key provisions of the Zackery Lystedt Law include (1) education for parents, athletes, and coaches; (2) immediate removal from play during a game or practice, after a suspected concussion with no return to play until (3); (3) written clearance by a concussion expert for return to play; and (4) uniformity of rules for all schools who use public land. Last, the nature of this legislative process, which included attorneys, legislators, and physicians, demonstrated that effective collaboration of local, state, and national leaders can address a critical public health challenge such as concussion affecting student athletes.


Repeat gamma knife radiosurgery for trigeminal neuralgia.
Trigeminal neuralgia (TN) may recur after treatment by gamma knife stereotactic radiosurgery (GKSR). To evaluate management outcomes in patients who underwent repeat GKSR for TN. The authors reviewed their experience with repeat GKSR in 119 patients with recurrent TN. The median patient age was 74 years (range, 34-96 years). The median interval between procedures was 26 months. The median target dose for repeat GKSR was 70 Gy (range, 50-90 Gy) and the median cumulative dose was 145 Gy (range, 120-170 Gy). The median follow-up was 48 months (range, 6-187 months) after repeat GKSR. After repeat GKSR, 87% of patients achieved initial pain relief (Barrow Neurological Institute pain score I-IIIb). Pain relief was maintained in 87.8% at 1 year, 69.8% at 3 years, and 44.2% at 5 years. Facial sensory dysfunction occurred in 21% of patients within 18 months after GKSR. Longer pain relief was observed in patients who had recurrent pain in a reduced pain distribution of the face compared with the pain distribution at the time of their initial GKSR, and in those who developed additional trigeminal sensory loss after a repeat procedure. A cumulative edge of brainstem dose ≥ 44 Gy was more likely to be associated with the development of sensory loss. Repeat GKSR provides a similar rate of pain relief as the first procedure. The best responses were observed in patients who had good pain control after the first procedure and those who developed new sensory dysfunction in the affected trigeminal distribution.


Clustering gene expression time series data using an infinite Gaussian process mixture model.
Transcriptome-wide time series expression profiling is used to characterize the cellular response to environmental perturbations. The first step to analyzing transcriptional response data is often to cluster genes with similar responses. Here, we present a nonparametric model-based method, Dirichlet process Gaussian process mixture model (DPGP), which jointly models data clusters with a Dirichlet process and temporal dependencies with Gaussian processes. We demonstrate the accuracy of DPGP in comparison to state-of-the-art approaches using hundreds of simulated data sets. To further test our method, we apply DPGP to published microarray data from a microbial model organism exposed to stress and to novel RNA-seq data from a human cell line exposed to the glucocorticoid dexamethasone. We validate our clusters by examining local transcription factor binding and histone modifications. Our results demonstrate that jointly modeling cluster number and temporal dependencies can reveal shared regulatory mechanisms. DPGP software is freely available online at https://github.com/PrincetonUniversity/DP_GP_cluster.


System for high-speed time-resolved holography of transient events.
A configuration for sequential holographic recording based on a new system for obtaining a train of spatially separated light pulses at frequencies ranging from 6 to 35 MHz has been developed. The multipulse system uses a high-energy Q-switched Nd:YAG laser as a light source and incorporates a phase-front-preserving optical delay line and a specially graded beam splitter to produce as many as ten spatially separated light pulses of nearly equal energy. The temporal spacing between successive output pulses may be varied discretely in increments of 28.3 ns from 28.3 to 169.8 ns. The system is currently used for high-speed time-resolved holography of dynamic events with lifetimes between 100 ns and 1.5 micros. Other applications include using the system either as a single point or sequential-array source for laser generation of ultrasound.