Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion.
The metabolic pathway of protein N-glycosylation influences intercellular adhesion by affecting the composition and cytoskeletal association of E-cadherin protein complexes, or adherens junctions (AJs). In sparse cells, E-cadherin is modified extensively with complex N-glycans and forms nascent AJs, while in dense cultures, hypoglycosylated E-cadherin drives the assembly of mature AJs with increased levels of γ- and α-catenins. N-glycosylation of E-cadherin is controlled by the DPAGT1 gene, a key regulator of the N-glycosylation pathway. DPAGT1 is a target of the canonical Wnt signaling pathway, with both β- and γ-catenins binding to Tcf at its promoter. We now report that DPAGT1 senses cell density through canonical Wnt signaling. In dense cells, depletion of β-catenin from the DPAGT1 promoter correlated with downregulation of its cellular abundance, while loss of nuclear γ-catenin reflected its greater recruitment to AJs. DPAGT1 itself affected canonical Wnt signaling, with forced changes in its expression resulting in corresponding changes in transcriptionally active β-catenin and canonical Wnt activity. Remarkably, a 2.4-fold increase in the DPAGT1 mRNA level resulted in increased N-glycosylation and reduced membrane localization of E-cadherin, coincident with dramatic changes in cell morphology. Lastly, we present evidence that N-glycosylation status of E-cadherin controls its antagonism of canonical Wnt signaling. Transfection of hypoglycosylated E-cadherin mutant, V13, but not fully N-glycosylated E-cadherin, into sparse cells inhibited canonical Wnt activity by depleting nuclear β- and γ-catenins. Collectively, our studies show that cells coordinate DPAGT1 expression and protein N-glycosylation with canonical Wnt signaling and E-cadherin adhesion via positive and negative feedback mechanisms.


Reduction of the geomagnetic field delays Arabidopsis thaliana flowering time through downregulation of flowering-related genes.
Variations in magnetic field (MF) intensity are known to induce plant morphological and gene expression changes. In Arabidopsis thaliana Col-0, near-null magnetic field (NNMF, i.e., <100 nT MF) causes a delay in the transition to flowering, but the expression of genes involved in this response has been poorly studied. Here, we showed a time-course quantitative analysis of the expression of both leaf (including clock genes, photoperiod pathway, GA20ox, SVP, and vernalization pathway) and floral meristem (including GA2ox, SOC1, AGL24, LFY, AP1, FD, and FLC) genes involved in the transition to flowering in A. thaliana under NNMF. NNMF induced a delayed flowering time and a significant reduction of leaf area index and flowering stem length, with respect to controls under geomagnetic field. Generation experiments (F1 - and F2 -NNMF) showed retention of flowering delay. The quantitative expression (qPCR) of some A. thaliana genes expressed in leaves and floral meristem was studied during transition to flowering. In leaves and flowering meristem, NNMF caused an early downregulation of clock, photoperiod, gibberellin, and vernalization pathways and a later downregulation of TSF, AP1, and FLC. In the floral meristem, the downregulation of AP1, AGL24, FT, and FLC in early phases of floral development was accompanied by a downregulation of the gibberellin pathway. The progressive upregulation of AGL24 and AP1 was also correlated to the delayed flowering by NNMF. The flowering delay is associated with the strong downregulation of FT, FLC, and GA20ox in the floral meristem and FT, TSF, FLC, and GA20ox in leaves. Bioelectromagnetics. 39:361-374, 2018. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.


Low Consultation Rate of General Population with Atrial Fibrillation.
In order to prevent ischemic stroke, it is important to identify and treat patients with atrial fibrillation (AF) who do not consult a doctor in a medical institution. The aim of this study was to determine the consultation rate at medical institutions for patients with AF in group medical examinations conducted in a city in western Japan. Of 6101 examinees of group medical examinations (40 years of age or older) conducted in Ibara City, Okayama Prefecture, Japan, from 2012 to 2014, 4338 participants (71.1%) who were evaluated by electrocardiogram (ECG) gave written informed consent and responded to surveys in the form of questionnaires through a personal interview conducted by nurses were included in the Ibara-AF study. A cumulative total of 82 subjects were diagnosed as having AF by ECG (prevalence of AF = 1.89%), and 51 individuals had AF during the three-year period.15 (29.4%) of the 51 patients with AF did not regularly visit medical institutions. Among them, 46.7% (n = 7) and 53.3% (n = 8) of the patients were symptomatic and asymptomatic, respectively, and 73.3% of the patients had a CHADS2 score of more than one point. There were no significant differences in patients' characteristics between regular and non-regular visit groups. In conclusion, about one-third of the patients with AF did not regularly see a doctor in a medical institution and most of them had a CHADS2 score of more than one point in a Japanese rural area. Educating the public about the risks of AF is required.


A comparison of two time-domain analysis procedures in the determination of .VO(2) kinetics by pseudorandom binary sequence exercise testing.
The purpose of this study was to apply and compare two time-domain analysis procedures in the determination of oxygen uptake (.VO(2)) kinetics in response to a pseudorandom binary sequence (PRBS) exercise test. PRBS exercise tests have typically been analysed in the frequency domain. However, the complex interpretation of frequency responses may have limited the application of this procedure in both sporting and clinical contexts, where a single time measurement would facilitate subject comparison. The relative potential of both a mean response time (MRT) and a peak cross-correlation time (PCCT) was investigated. This study was divided into two parts: a test-retest reliability study (part A), in which 10 healthy male subjects completed two identical PRBS exercise tests, and a comparison of the .VO(2) kinetics of 12 elite endurance runners (ER) and 12 elite sprinters (SR; part B). In part A, 95% limits of agreement were calculated for comparison between MRT and PCCT. The results of part A showed no significant difference between test and retest as assessed by MRT [mean (SD) 42.2 (4.2) s and 43.8 (6.9) s] or by PCCT [21.8 (3.7) s and 22.7 (4.5) s]. Measurement error (%) was lower for MRT in comparison with PCCT (16% and 25%, respectively). In part B of the study, the .VO(2) kinetics of ER were significantly faster than those of SR, as assessed by MRT [33.4 (3.4) s and 39.9 (7.1) s, respectively; P<0.01] and PCCT [20.9 (3.8) s and 24.8 (4.5) s; P<0.05]. It is possible that either analysis procedure could provide a single test measurement of .VO(2) kinetics; however, the greater reliability of the MRT data suggests that this method has more potential for development in the assessment of .VO(2) kinetics by PRBS exercise testing.


Reduction of catheter-associated sepsis in parenteral nutrition using low-dose intravenous heparin.
To assess whether adding low-dose heparin to the infusate of patients receiving parenteral nutrition reduced the incidence of septic complications related to the central venous catheter, 80 consecutive patients requiring intravenous feeding were studied. Half of these patients received heparin 1 unit/ml of infusate, while in the remaining 40 (controls) an equal volume of physiological saline was added to the infusate. Strict criteria for the management of the indwelling CVC were observed. The catheter tips were cultured after removal: only one was infected in the heparin group compared with nine in the control group. This significant reduction may have been due to the heparin preventing a fibrin sleeve from forming around the catheter tip. It is recommended that, as well as observing the usual aseptic precautions in managing the cannula, 500 units of heparin are added to each 500 ml of fluid infused to reduce the incidence of catheter-associated sepsis.


Newly developed techniques to study and diagnose acute renal failure.
Progress in treating human acute renal failure (ARF) is dependent on developing techniques that allow for the rapid diagnosis, quantification of injury, further understanding of the pathophysiology, and the effects of therapy. Therefore, four techniques that will facilitate this progress are described and illustrated by four different investigative teams. Techniques to measure rapid changes in GFR are available for rapid diagnosis and quantification of ARF in humans. State-of-the-art magnetic resonance imaging (MRI) presently allows for enhanced resolution of regional renal blood flow and functional evaluations in patients. Furthermore, new probes and techniques for MRI that allow for identification and quantitation of inflammation, applicable to human ARF, are being developed and tested in animal models. Finally, two-photon microscopy will allow for four-dimensional cellular and subcellular studies in animal models of ARF providing rapid insights into pathophysiology and the therapeutic effects of a variety of promising agents. Further development and utilization of these techniques, especially in concert with genetic, proteomic, and molecular approaches, will allow for needed insights into the pathophysiology and therapy in human ARF.


Asymmetry of the acetylcholine channel revealed by quaternary anesthetics.
Tissue-cultured rat myoballs were examined electrophysiologically with a suction pipette, which was used for voltage clamping and internal perfusion. The lidocaine derivative QX-314 caused a time- and membrane potentia-dependent block of acetylcholine-induced current only when applied from the extracellular membrane surface. The same compounds caused a use-dependent block of the sodium channel only from the intracellular membrane surface. These experiments demonstrate a fundamental asymmetry of the acetylcholine receptor-channel complex.


Use of intermittent presumptive treatment and insecticide treated bed nets by pregnant women in four Kenyan districts.
The roll back malaria (RBM) movement promotes the use of insecticide-treated bednets (ITNs) and intermittent presumptive treatment (IPT) of malaria infection as preventive measures against the adverse effects of malaria among pregnant women in Africa. To determine the use of these preventive measures we undertook a community-based survey of recently pregnant women randomly selected from communities in four districts of Kenya in December 2001. Of the 1814 women surveyed, only 5% had slept under an ITN. More than half of the 13% of women using a bednet (treated or untreated) had bought their nets from shops or markets. Women from rural areas used bednets less than urban women (11% vs. 27%; P < 0.001), and 41% of the bednets used by rural women had been obtained free of charge from a research project in Bondo or a nationwide UNICEF donation through antenatal clinics (ANCs). Despite 96% of ANC providers being aware of IPT with sulphadoxine-pyrimethamine (SP), only 5% of women interviewed had received two or more doses of SP as a presumptive treatment. The coverage of pregnant women with at least one dose of IPT with SP was 14%, though a similar percentage also had received at least a single dose as a curative treatment. The coverage of nationally recommended strategies to prevent malaria during pregnancy during 2001 was low across the diverse malaria ecology of Kenya. Rapid expansion of access to these services is required to meet international and national targets by the year 2005. The scaling up of malaria prevention programmes through ANC services should be possible with 74% of women visiting ANCs at least twice in all four districts. Issues of commodity supply and service costs to clients will be the greatest impediments to reaching RBM targets.


Genetic and Functional Analyses of Virulence Potential of an Escherichia coli O157:H7 Strain Isolated From Super-Shedder Cattle.
Shiga toxin (Stx)-producing Escherichia coli (STEC) O157:H7 is an enteric pathogen that causes life-threatening disease in humans, with cattle being major natural reservoirs. A group of STEC O157:H7 with a dramatic combination of high virulence potentials and super-shedder bovine origin have been isolated. Here, an STEC O157:H7 isolate, JEONG-1266, was analyzed by comparative genomics, stx genotyping, and phenotypic analyses. The phylogenetic typing and whole-genome comparison consistently showed that JEONG-1266 is genetically close to EC4115 (one of 2006 Spinach outbreak isolates) and SS17 (an isolate from super-shedder cattle) strains, all of which belong to lineage I/II and Clade 8. Both lineage I/II and Clade 8 are known to be mostly associated with clinical strains with high virulence and severe clinical symptoms. Further, JEONG-1266, like EC4115 and SS17, harbors stx2a/stx2c genes, and carries Stx-encoding prophages, specifically the φstx2a-γ subtype. Possession of the φstx2a-γ subtype of Stx-encoding prophages and production of Stx2a have been shown to be a key signature associated with hypervirulent STEC O157:H7 strains. In silico virulence typing elucidated JEONG-1266, EC4115, and SS17 shared a highly conserved profile of key virulence genes at the nucleotide sequence level. Consistently, phenotypic data showed that JEONG-1266 expressed a high level of Stx2 toxins and had the full capacity of adhesion in vitro. Taken together, our study suggests that JEONG-1266 may represent an emerging STEC O157:H7 group, which are hypervirulent strains that originate from super-shedders, that can be a threat to food safety and public health.


Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells.
Phosphorylation of ion channels plays an important role in the regulation of cardiac function, but signaling mechanisms controlling dephosphorylation are not well understood. We have tested the hypothesis that p(21)-activated kinase-1 (Pak1), a serine-threonine protein kinase regulated by Ras-related small G proteins, regulates sinoatrial node (SAN) ion channel activity through a mechanism involving protein phosphatase 2A. We report a novel role of Pak1-mediated signaling in attenuating isoproterenol-induced enhancement of L-type Ca(2+) current (I(CaL)) and delayed rectifier potassium current (I(K)) in guinea pig SAN pacemaker cells. We demonstrate that in guinea pig SAN: (1) there is abundant expression of endogenous Pak1 in pacemaker cells; (2) expression of constitutively active Pak1 depresses isoproterenol-induced upregulation of I(CaL) and I(K); (3) inhibition of protein phosphatase 2A increases the enhancement of I(K) and I(CaL) by isoproterenol in Ad-Pak1-infected cells; (4) protein phosphatase 2A coimmunoprecipitates with endogenous Pak1 in SAN tissue; and (5) expression of constitutively active Pak1 suppresses the chronotropic action of isoproterenol on pacemaker activity of intact SAN preparations. In conclusion, our data demonstrate that a Pak1 signaling pathway exists in cardiac pacemaker cells and that this novel pathway plays a role in the regulation of ion channel activity.


Age-dependent changes in the proteome following complete spinal cord transection in a postnatal South American opossum (Monodelphis domestica).
Recovery from severe spinal injury in adults is limited, compared to immature animals who demonstrate some capacity for repair. Using laboratory opossums (Monodelphis domestica), the aim was to compare proteomic responses to injury at two ages: one when there is axonal growth across the lesion and substantial behavioural recovery and one when no axonal growth occurs. Anaesthetized pups at postnatal day (P) 7 or P28 were subjected to complete transection of the spinal cord at thoracic level T10. Cords were collected 1 or 7 days after injury and from age-matched controls. Proteins were separated based on isoelectric point and subunit molecular weight; those whose expression levels changed following injury were identified by densitometry and analysed by mass spectrometry. Fifty-six unique proteins were identified as differentially regulated in response to spinal transection at both ages combined. More than 50% were cytoplasmic and 70% belonged to families of proteins with characteristic binding properties. Proteins were assigned to groups by biological function including regulation (40%), metabolism (26%), inflammation (19%) and structure (15%). More changes were detected at one than seven days after injury at both ages. Seven identified proteins: 14-3-3 epsilon, 14-3-3 gamma, cofilin, alpha enolase, heart fatty acid binding protein (FABP3), brain fatty acid binding protein (FABP7) and ubiquitin demonstrated age-related differential expression and were analysed by qRT-PCR. Changes in mRNA levels for FABP3 at P7+1day and ubiquitin at P28+1day were statistically significant. Immunocytochemical staining showed differences in ubiquitin localization in younger compared to older cords and an increase in oligodendrocyte and neuroglia immunostaining following injury at P28. Western blot analysis supported proteomic results for ubiquitin and 14-3-3 proteins. Data obtained at the two ages demonstrated changes in response to injury, compared to controls, that were different for different functional protein classes. Some may provide targets for novel drug or gene therapies.


The demographics of patients affected by surgical disease in district hospitals in two sub-Saharan African countries: a retrospective descriptive analysis.
There is a growing awareness of the importance of surgical disease within global health. We hypothesised that surgical disease in low income countries predominantly affects young adults and may therefore have a significant economic impact. We retrospectively reviewed all surgical admission data from two rural government district hospitals in two different sub-Saharan African countries over a 6-month period. We analysed all surgical admissions with respect to patient demographics (age and gender), diagnosis, and procedure performed. Surgical admissions accounted for 12.9 and 19.8 % of all hospital admissions in Malawi and Sierra Leone respectively. 18.5 and 6.2 % of all hospital patients required a surgical procedure in Malawi and Sierra Leone respectively, with the low number in Sierra Leone accounted for in that many of the obstetric admissions were referred to a nearby Medicins Sans Frontiers (MSF) hospital for treatment. 17.9 and 10.5 % of surgical admissions were under the age of 16 in Malawi and Sierra Leone respectively, with 16-35 year olds accounting for 57.3 % of surgical admissions in Sierra Leone and 53.5 % in Malawi. Men accounted for 53.7 and 46.0 % of surgical admissions in Sierra Leone and Malawi respectively. An unexpected finding was the high level of patients who absconded from hospital in Sierra Leone after diagnosis but before treatment. This involved 11.8 % of all surgical patients, including 38 % with a bowel obstruction, 39 % with peritonitis and 20 % with ectopic pregnancy. Most people affected by disease requiring surgery are young adults and this may have significant economic implications.


Atlantic DIP: high prevalence of abnormal glucose tolerance post partum is reduced by breast-feeding in women with prior gestational diabetes mellitus.
Gestational diabetes (GDM) is associated with adverse fetal and maternal outcomes, and identifies women at risk of future type 2 diabetes mellitus (T2DM). Breast-feeding may improve post partum maternal glucose tolerance. Our objective was to identify the prevalence of post partum dysglycemia after GDM, to delineate associated factors and to examine the effect of lactation on post partum glucose tolerance. We compared post partum 75 g oral glucose tolerance test (OGTT) results from 300 women with GDM and 220 controls with normal gestational glucose tolerance (NGT) in five regional centers. Breast-feeding data was collected at time of OGTT. Methods Post partum OGTT results were classified as normal (fasting plasma glucose (FPG) <5.6 mmol/l, 2 h <7.8 mmol/l) and abnormal (impaired fasting glucose (IFG), FPG 5.6-6.9 mmol/l; impaired glucose tolerance (IGT), 2 h glucose 7.8-11 mmol/l; IFG+IGT; T2DM, FPG ≥7 mmol/l±2 h glucose ≥11.1 mmol/l). Binary logistic regression was used to identify factors predictive of persistent hyperglycemia. Five hundred and twenty women were tested; six (2.7%) with NGT in pregnancy had post partum dysglycemia compared with 57 (19%) with GDM in index pregnancy (P<0.001). Non-European ethnicity (odds ratio (OR) 3.40; 95% confidence interval (CI) 1.45-8.02, P=0.005), family history of T2DM (OR 2.14; 95% CI 1.06-4.32, P=0.034), and gestational insulin use (OR 2.62; 95% CI 1.17-5.87, P=0.019) were associated with persistent dysglycemia. The prevalence of persistent hyperglycemia was significantly lower in women who breast-fed vs bottle-fed post partum (8.2 vs 18.4%, P<0.001). Non-European ethnicity, gestational insulin use, family history of T2DM, and elevated body mass index were associated with persistent dysglycemia after GDM. Breast-feeding may confer beneficial metabolic effects after GDM and should be encouraged.


Cortex functional connectivity as a neurophysiological correlate of hypnosis: an EEG case study.
Cortex functional connectivity associated with hypnosis was investigated in a single highly hypnotizable subject in a normal baseline condition and under neutral hypnosis during two sessions separated by a year. After the hypnotic induction, but without further suggestions as compared to the baseline condition, all studied parameters of local and remote functional connectivity were significantly changed. The significant differences between hypnosis and the baseline condition were observable (to different extent) in five studied independent frequency bands (delta, theta, alpha, beta, and gamma). The results were consistent and stable after 1 year. Based on these findings we conclude that alteration in functional connectivity of the brain may be regarded as a neuronal correlate of hypnosis (at least in very highly hypnotizable subjects) in which separate cognitive modules and subsystems may be temporarily incapable of communicating with each other normally.


Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys.
The D2 dopamine (DA) receptor agonist, quinpirole, was characterized in young adult monkeys, young reserpine-treated monkeys and aged monkeys to assess the contribution of DA to age-related loss of prefrontal cortical (PFC) cognitive function. Monkeys were tested on a delayed response memory task that depends on the PFC, and a fine motor task that taps the functions of the motor cortex. In young adult monkeys, low quinpirole doses impaired performance of the PFC and fine motor tasks, while higher doses improved memory performance and induced dyskinesias and "hallucinatory-like" behaviors. The pattern of the quinpirole response in reserpine-treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors, while the improvement in delayed response performance, dyskinesias and "hallucinatory-like" behaviors resulted from actions at postsynaptic receptors. In aged monkeys, low doses of quinpirole continued to impair fine motor performance, but lost their ability to impair delayed response performance. The magnitude of cognitive improvement and the incidence of "hallucinatory-like" behaviors were also reduced in the aged animals, suggesting some loss of postsynaptic D2 receptor function. The pattern of results is consistent with the greater loss of DA from the PFC than from motor areas in aged monkey brain (Goldman-Rakic and Brown, 1981; Wenk et al., 1989), and indicates that DA depletion contributes significantly to age-related cognitive decline.


Skull fractures in children: a population study.
To provide information about children with a skull fracture in the Edinburgh area, since head injury is the single most important traumatic cause of death in children over 1 year of age. During the period January 1983 to December 1989, all children in the Edinburgh area under 13 years of age who sustained a skull fracture were identified. Details of the children who died primarily from a head injury, and the total number of children who were admitted to hospital with a head injury not associated with a skull fracture, were also documented. Data were obtained from the General Register Office for Scotland, Edinburgh Fiscal Office records, and Lothian Health Board records. Data on cause of injury and clinical condition were obtained. 3498 children under 13 years of age were admitted to hospital after sustaining a head injury and 27 died primarily as a result of their injuries; 409 children had a skull fracture and 76 of this group had cranial CT scans. Nineteen of the CT scans performed were on children who had been admitted to hospital in a coma, and all had abnormal scan findings. In addition all children with intracerebral haematomas/haemorrhages had been admitted in a coma. Road traffic accidents accounted for the greatest number of deaths (84%), associated injuries, and overall morbidity. To reduce the incidence of head injuries, and the associated morbidity and mortality, the following are required: identify at risk groups; promote accident prevention; publicise the findings and guidelines concerning childhood head injuries; ensure that all children with head injuries have appropriate investigations and begin treatment as early as possible; establish clinical audit; and set up regional rehabilitation teams.


Estimation of the spatial coherence outer scale relevant to long baseline interferometry and imaging in optical astronomy.
A technique is proposed allowing estimation of the spatial coherence outer scale, from simultaneous measurements of Fried's parameter ro and of the variance of angle-of-arrival fluctuations. This optical parameter must be differentiated from the classical geophysical parameter called the outer scale of turbulence; its knowledge is important for long baseline interferometry and imaging in optical astronomy.


Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties.
Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading to a different in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs. Recent evidence suggests extracellular vesicles (EVs) as another route of cellular communication. These EVs may be utilized for future therapeutics. In this article, the authors compared ultrafiltration with size-exclusion liquid chromatography (UF-LC) and ultra-centrifugation (UC) for EV recovery.


Evaluation of the newly established acne severity classification among Japanese and Korean dermatologists.
Recently, we established an acne severity classification that is based on scientific evidence. Our classification allows three different methods for grading, which include general impression of consulted dermatologist, photograph-based estimation by independent experts, and grading by lesion counting. In our classification, we proposed standard photographs for the estimation of general severity to adjust the basis of judgments. In this study, we evaluated the validity of our classification. We made questionnaires of acne severity using acne patients' photographs, which were selected from the collection of representative photographs of our classification. Participants answered these questionnaires before and after our presentations about our classification of acne severity. We identified the conformity rate with our consensus decision. The results revealed that average conformity rates were raised from 67.0% to 88.9% among Japanese dermatologists and from 68.0% to 79.8% among Korean ones. These data show the adequacy of both our grading system itself and its presentation. We believe our classification will be one of the most effective and reasonable grading systems to classify acne severity.


[Results of active surveillance of acute flaccid paralysis in the Central African Republic and Chad from 1995 to 2000].
The threefold purpose of this report is to describe the epidemiology of acute flaccid paralysis (AFP), to determine the impact of the National Immunization Days (NID), and evaluate the quality of active surveillance in the Central African Republic (CAR) and Chad. The data in this study was obtained from the Enterovirus Division of the Pastear Institute in Bangui (National WHO Inter-country Reference Laboratory for the CAR and Chad and Regional Poliovirus Reference Laboratory in Africa). An increase in the number of AFP cases was observed in the CAR between 1995 and 2000 and in Chad between 1997 and 2000, mainly as a result of enhancement of the surveillance system. The goals set by the WHO in terms of the proportion of AFP cases with 2 specimens collected within 14 days of onset of paralysis and the number of cases with 60-day follow-up have not been reached in either country. The presence of 2 strains of wild poliovirus (types 1 and 3) and several genotypes (West African 13 and West African 7 for type 1 and Central African and Nigeria-P3 for type 3) not only show that Central Africa is still a significant reservoir for poliovirus transmission but also raise serious doubts about the quality of the NID organized over the last 3 years. The priority of the next NID round must be to reach unimmunized children who have been missed by routine immunization coverage.


Disconnection of intracortical synaptic linkages disrupts synchronization of a slow oscillation.
The intracortical synaptic linkages underlying the synchronization of a recently described slow (< 1 Hz) oscillation (Steriade et al., 1993b,c) were investigated in anesthetized cats by means of multisite extra- and intracellular recordings, including dual impalements, from rostral and caudal sites in the association cortical suprasylvian and marginal gyri, before and after reversible lidocaine inactivation or transections in the middle suprasylvian gyrus. Stimulus-evoked responses revealed that the rostral and caudal suprasylvian foci are reciprocally connected, with a preference for posterior-to-anterior responses. Lidocaine infusion between the stimulating and recording sites disrupted the intracortical synaptic linkage, while leaving unaffected the responses at the sites close to the stimulating electrodes. The high coherence between slowly oscillating field potentials and intracellular activities recorded from anterior and posterior suprasylvian foci was lost after reversible inactivation or transections in the middle suprasylvian gyrus, whereas the synchrony between adjacent foci within the anterior or posterior areas was preserved. Two to four hours after inactivation or transection the synchrony between all channels was totally or partially recovered. We introduced the synchrony coefficient (SyCo) and calculated the SyCo for closely located and distant sites. Lidocaine infusion or transection did not affect the SyCo between leads placed on the same site, but significantly (60%) decreased the SyCo between channels separated by the functionally inactivated or transected sector. Our results demonstrate that pathways within or beneath the suprasylvian gyrus sustain the synchronization of the slow oscillation between cortical sites. As the loss of long-range coherence was not permanent, intergyral paths and/or corticothalamocortical loops may exert compensatory functions after the disconnection of intrasuprasylvian synaptic linkages.


Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex.
Bipolar disorder has been associated with anatomical as well as functional abnormalities in a brain network that mediates normal and impaired emotion regulation. Previous brain imaging studies have highlighted the subgenual cingulate (SC) and the amygdalo-hippocampal (AH) complex as core regions of this network. Thus we investigated white matter (WM) fiber tracts between the SC and the AH region, the uncinate fasciculus, as well as between two control regions (pons and cerebellum), using diffusion tensor imaging tractography in 16 euthymic bipolar patients (BP) and 16 sex-, age- and handedness-matched controls. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the reconstructed fiber bundle and the number of virtual reconstructed fibers were compared between groups. The tractography results revealed a significantly increased number of reconstructed fibers between the left SC and left AH in BP as compared to healthy controls. FA and ADC of the reconstructed fiber tract did not differ significantly between the groups. Furthermore, no significant group differences were observed neither for reconstructed fiber tracts between the right SC and right AH nor between the control regions. The present results suggest an altered WM pathway between the left SC and AH region and thus extend previous findings of anatomical and functional modifications in these structures in BP.


Total counts of marine bacteria include a large fraction of non-nucleoid-containing bacteria (ghosts).
Counts of heterotrophic bacteria in marine waters are usually in the order of 5 x 10(sup5) to 3 x 10(sup6) bacteria ml(sup-1). These numbers are derived from unspecific fluorescent staining techniques (J. E. Hobbie, R. J. Daley, and S. Jasper, Appl. Environ. Microbiol. 33:1225-1228, 1977; K. G. Porter and Y. S. Feig, Limnol. Oceanogr. 25:943-948, 1980) and are subsequently defined as total counts of bacteria. In samples from the Baltic Sea, the North Sea (Skagerrak), and the northeastern Mediterranean Sea, we found that only a minor fraction (2 to 32%) of total counts can be scored as bacteria with nucleoids. Lack of DNA no doubt means inactive cells; therefore, a much lower number of bacteria that grow at rates higher than those previously estimated must be responsible for the measured bacterial production in these seas. The remaining bacterium-sized and/or -shaped particles included in total counts may be cell residues of virus-lysed bacteria (ghosts) or remains of protozoan grazing.


Serum Levels of Metabolites Produced by Intestinal Microbes and Lipid Moieties Independently Associated With Acute-on-Chronic Liver Failure and Death in Patients With Cirrhosis.
Inpatients with cirrhosis have high rates of acute-on-chronic failure (ACLF) development and high mortality within 30 days of admission to the hospital. Better biomarkers are needed to predict these outcomes. We performed metabolomic analyses of serum samples from patients with cirrhosis at multiple centers to determine whether metabolite profiles might identify patients at high risk for ACLF and death. We performed metabolomic analyses, using liquid chromatography, of serum samples collected at time of admission to 12 North American tertiary hepatology centers from 602 patients in the North American Consortium for the Study of End-Stage Liver Disease sites from 2015 through 2017 (mean age, 56 years; 61% men; mean model for end-stage liver disease score, 19.5). We performed analysis of covariance, adjusted for model for end-stage liver disease at time of hospital admission, serum levels of albumin and sodium, and white blood cell count, to identify metabolites that differed between patients who did vs did not develop ACLF and patients who did vs did not die during hospitalization and within 30 days. We performed random forest analysis to identify specific metabolite(s) that were associated with outcomes and area under the curve (AUC) analyses to analyze them in context of clinical parameters. We analyzed microbiomes of stool samples collected from 133 patients collected at the same time and examined associations with serum metabolites. Of the 602 patients analyzed, 88 developed ACLF (15%), 43 died in the hospital (7%), and 72 died within 30 days (12%). Increased levels of compounds of microbial origin (aromatic compounds, secondary or sulfated bile acids, and benzoate) and estrogen metabolites, as well as decreased levels of phospholipids, were associated with development of ACLF, inpatient, and 30-day mortality and were also associated with fecal microbiomes. Random forest analysis and logistic regression showed that levels of specific microbially produced metabolites identified patients who developed ACLF with an AUC of 0.84 (95% confidence interval [CI] 0.78-0.88; P = .001), patients who died while in the hospital with an AUC of 0.81 (95% CI 0.74-0.85; P = .002), and patients who died within 30 days with an AUC of 0.77 (95% CI 0.73-0.81; P = .02). The metabolites were significantly additive to clinical parameters for predicting these outcomes. Metabolites associated with outcomes were also correlated with microbiomes of stool samples. In an analysis of serum metabolites and fecal microbiomes of patients hospitalized with cirrhosis at multiple centers, we associated metabolites of microbial origin and lipid moieties with development of ACLF and death as an inpatient or within 30 days, after controlling for clinical features.


Mentoring programs for physicians in academic medicine: a systematic review.
Mentoring is vital to professional development in the field of medicine, influencing career choice and faculty retention; thus, the authors reviewed mentoring programs for physicians and aimed to identify key components that contribute to these programs' success. The authors searched the MEDLINE, EMBASE, and Scopus databases for articles from January 2000 through May 2011 that described mentoring programs for practicing physicians. The authors reviewed 16 articles, describing 18 programs, extracting program objectives, components, and outcomes. They synthesized findings to determine key elements of successful programs. All of the programs described in the articles focused on academic physicians. The authors identified seven mentoring models: dyad, peer, facilitated peer, speed, functional, group, and distance. The dyad model was most common. The authors identified seven potential components of a formal mentoring program: mentor preparation, planning committees, mentor-mentee contracts, mentor-mentee pairing, mentoring activities, formal curricula, and program funding. Of these, the formation of mentor-mentee pairs received the most attention in published reports. Mentees favored choosing their own mentors; mentors and mentees alike valued protected time. One barrier to program development was limited resources. Written agreements were important to set limits and encourage accountability to the mentoring relationship. Program evaluation was primarily subjective, using locally developed surveys. No programs reported long-term results. The authors identified key program elements that could contribute to successful physician mentoring. Future research might further clarify the use of these elements and employ standardized evaluation methods to determine the long-term effects of mentoring.


Bleeding caused by portal hypertension.
Variceal bleeding is one of the dreaded complications of portal hypertension. Patients who have suspected or proven cirrhosis should undergo diagnostic upper endoscopy to detect medium and large gastro-esophageal varices. Patients with medium and large gastro-esophageal varices should be treated with non-selective beta-blockers (propranolol or nadolol), and these agents should be titrated to a heart rate of 55 beats per minute or adverse effects. If there are contraindications to or if patients are intolerant to beta-blockers, it is appropriate to consider prophylactic banding therapy for individuals with medium-to-large esophageal varices. When patients who have cirrhosis present with GI bleeding, they should be resuscitated and receive octreotide or other vasoactive agents. Endoscopy should be performed promptly to diagnose the source of bleeding and to provide endoscopic therapy (preferably banding). The currently available treatment for acute variceal bleeding provides hemostasis in most patients. These patients, however, are at significant risk for rebleeding unless secondary prophylaxis is provided. Although various pharmacological, endoscopic, radiological, and surgical options are available, combined pharmacological and endoscopic therapy is the most common form of secondary prophylaxis. TIPS is a radiologically placed portasystemic shunt, and if placed in suitable patients, it can provide effective treatment for patients with variceal bleeding that is refractory to medical and endoscopic therapy.


Oncolytic virotherapy for hematological malignancies.
Hematological malignancies such as leukemias, lymphomas, multiple myeloma (MM), and the myelodysplastic syndromes (MDSs) primarily affect adults and are difficult to treat. For high-risk disease, hematopoietic stem cell transplant (HCT) can be used. However, in the setting of autologous HCT, relapse due to contamination of the autograft with cancer cells remains a major challenge. Ex vivo manipulations of the autograft to purge cancer cells using chemotherapies and toxins have been attempted. Because these past strategies lack specificity for malignant cells and often impair the normal hematopoietic stem and progenitor cells, prior efforts to ex vivo purge autografts have resulted in prolonged cytopenias and graft failure. The ideal ex vivo purging agent would selectively target the contaminating cancer cells while spare normal stem and progenitor cells and would be applied quickly without toxicities to the recipient. One agent which meets these criteria is oncolytic viruses. This paper details experimental progress with reovirus, myxoma virus, measles virus, vesicular stomatitis virus, coxsackievirus, and vaccinia virus as well as requirements for translation of these results to the clinic.


Role of Effector-Sensitivity Gene Interactions and Durability of Quantitative Resistance to Septoria Nodorum Blotch in Eastern U.S. Wheat.
Important advances have been made in understanding the relationship of necrotrophic effectors (NE) and host sensitivity (Snn) genes in the Parastagonospora nodorum-wheat pathosystem. Yet much remains to be learned about the role of these interactions in determining wheat resistance levels in the field, and there is mixed evidence on whether breeding programs have selected against Snn genes due to their role in conferring susceptibility. SNB occurs ubiquitously in the U.S. Atlantic seaboard, and the environment is especially well suited to field studies of resistance to natural P. nodorum populations, as there are no other important wheat leaf blights. Insights into the nature of SNB resistance have been gleaned from multi-year data on phenotypes and markers in cultivars representative of the region's germplasm. In this perspective article, we review the evidence that in this eastern region of the U.S., wheat cultivars have durable quantitative SNB resistance and Snn-NE interactions are of limited importance. This conclusion is discussed in light of the relevant available information from other parts of the world.


What Is the Role of Pyridinium in Pyridine-Catalyzed CO2 Reduction on p-GaP Photocathodes?
Experimental evidence suggests that pyridinium plays an important role in photocatalytic CO2 reduction on p-GaP photoelectrodes. Pyridinium reduction to pyridinyl has been previously proposed as an essential mechanistic step for this reaction. However, theoretical calculations suggest that this step is not feasible in solution. Here, cluster models and accurate periodic boundary condition calculations are used to determine whether such a reduction step could occur by transfer of photoexcited electrons from the p-GaP photocathode and whether this transfer could be catalyzed by pyridinium adsorption on the p-GaP surface. It is found that both the transfer of photoexcited electrons to pyridinium and pyridinium adsorption are not energetically favored, thus making very unlikely pyridinium reduction to the pyridinyl radical and the proposed mechanisms requiring this reduction step. Given this conclusion, an alternative and energetically viable pathway for pyridinium reduction on p-GaP photoelectrodes is proposed. This pathway leads to the formation of adsorbed species that could react to form adsorbed dihydropyridine, which was proposed previously to play the role of the active catalyst in this system.


Intra-axiom redundancies in SNOMED CT.
Intra-axiom redundancies are elements of concept definitions that are redundant as they are entailed by other elements of the concept definition. While such redundancies are harmless from a logical point of view, they make concept definitions hard to maintain, and they might lead to content-related problems when concepts evolve. The objective of this study is to develop a fully automated method to detect intra-axiom redundancies in OWL 2 EL and apply it to SNOMED Clinical Terms (SNOMED CT). We developed a software program in which we implemented, adapted and extended readily existing rules for redundancy elimination. With this, we analysed occurence of redundancy in 11 releases of SNOMED CT (January 2009 to January 2014). We used the ELK reasoner to classify SNOMED CT, and Pellet for explanation of equivalence. We analysed the completeness and soundness of the results by an in-depth examination of the identified redundant elements in the July 2012 release of SNOMED CT. To determine if concepts with redundant elements lead to maintenance issues, we analysed a small sample of solved redundancies. Analyses showed that the amount of redundantly defined concepts in SNOMED CT is consistently around 35,000. In the July 2012 version of SNOMED CT, 35,010 (12%) of the 296,433 concepts contained redundant elements in their definitions. The results of applying our method are sound and complete with respect to our evaluation. Analysis of solved redundancies suggests that redundancies in concept definitions lead to inadequate maintenance of SNOMED CT. Our analysis revealed that redundant elements are continuously introduced and removed, and that redundant elements may be overlooked when concept definitions are corrected. Applying our redundancy detection method to remove intra-axiom redundancies from the stated form of SNOMED CT and to point knowledge modellers to newly introduced redundancies can support creating and maintaining a redundancy-free version of SNOMED CT.


Home treatment for mental health problems: a systematic review.
This review investigates the effectiveness of 'home treatment' for mental health problems in terms of hospitalisation and cost-effectiveness. For the purposes of this review, 'home treatment' is defined as a service that enables the patient to be treated outside hospital as far as possible and remain in their usual place of residence. METHODS - SYSTEMATIC LITERATURE SEARCH: 'Home treatment' excluded studies focused on day, residential and foster care. The review was based on Cochrane methodology, but non-randomised studies were included if they compared two services; these were only analysed if they provided evidence of the groups' baseline clinical comparability. METHODS - REVIEW OF ECONOMIC EVALUATIONS: Economic evaluations among the studies found were reviewed against established criteria. METHODS - IDENTIFICATION OF SERVICE COMPONENTS: A three-round Delphi exercise ascertained the degree of consensus among expert psychiatrists concerning the important components of community-based services that enable them to treat patients outside hospital. The identified components were used to construct the follow-up questionnaire. METHODS - FOLLOW-UP OF AUTHORS: As a supplement to the information available in the papers, authors of all the studies were followed up for data on service components, sustainability of programmes and service utilisation. METHODS - DATA ANALYSIS: The outcome measure was mean days in hospital per patient per month over the follow-up period. (1) Comparative analysis - compared experimental to control services. It analysed all studies with available data, divided into 'inpatient-control' and 'community-control' studies, and tested for associations between service components and difference in hospital days. (2) Experimental services analysis - analysed only experimental service data and tested for associations between service components and hospital days. RESULTS - SYSTEMATIC LITERATURE SEARCH: A total of 91 studies were found, conducted over a 30-year period. The majority (87) focused on people with psychotic disorders. RESULTS - REVIEW OF ECONOMIC EVALUATIONS: Only 22 studies included economic evaluations. They provided little conclusive evidence about cost-effectiveness because of problems with the heterogeneity of services, sample size, outcome measures and quality of analysis. RESULTS - DELPHI EXERCISE: In all, 16 items were rated as 'essential', falling into six categories: home environment; skill-mix; psychiatrist involvement; service management; caseload size; and health/social care integration. There was consensus that caseloads under 25 and flexible working hours over 7 days were important, but little support for caseloads under 15 or for 24-hour services, and consensus that home visiting was essential, but not on teams being 'explicitly dedicated' to home treatment. RESULTS - RESPONSE TO FOLLOW-UP: A total of 60% of authors responded, supplying data on service components and hospital days in most cases. Other service utilisation data were far less readily available. RESULTS - SERVICE CHARACTERISATION AND CLASSIFICATION: The services were homogeneous in terms of 'home treatment function' but fairly heterogeneous in terms of other components. There was some evidence for a group of services that were multidisciplinary, had psychiatrists as integrated team members, had smaller caseloads, visited patients at home regularly and took responsibility for both health and social care. This was not a cohesive group, however. RESULTS - SUSTAINABILITY OF SERVICES: The sustainability of home treatment services was modest: less than half the services whose authors responded were still identifiable. Services were more likely to be operational if the study had found them to reduce hospitalisation significantly. RESULTS - META-ANALYSIS: Meta-analysis with heterogeneous studies is problematic. The evidence base for the effectiveness of services identifiable as 'home treatment' was not strong. Within the 'inpatient-control' study group, the mean reduction in hospitalisation was 5 days per patient per month (for 1-year studies only). No statistical significance could be measured for this result. For 'community-control' studies, the reduction in hospitalisation was negligible. Moreover, the heterogeneity of control services, the wide range of outcome measures and the limited availability of data might have confounded the analysis. Regularly visiting at home and dual responsibility for health and social care were associated with reduced hospitalisation. Evidence for other components was inconclusive. Few conclusions could be drawn from the analysis of service utilisation data. RESULTS - LOCATION: Studies were predominately from the USA and UK, more of them being from the USA. North American studies found a reduction in hospitalisation of 1 day per patient per month more than European studies. North American and European services differed on some service components, but this was unlikely to account for this finding, particularly as no difference was found in their experimental service results. CONCLUSIONS - STATE OF RESEARCH: There is a clear need for further studies, particularly in the UK. The benefit of home treatment over admission in terms of days in hospital was clear, but over other community-based alternatives was inconclusive. CONCLUSIONS - NON-RANDOMISED STUDIES: Difficulties in systematically searching for non-randomised studies may have contributed to the smaller number of such studies found (35, compared with 56 randomised controlled trials). This imbalance was compounded by a relatively poor response rate from non-randomised controlled trial authors. Including them in the analysis had little effect. CONCLUSIONS - LIMITATIONS OF THIS REVIEW: A broad area was reviewed in order to avoid the problem of analysing by service label. While reviews of narrower areas may risk implying a homogeneity of the services that is unwarranted, the current strategy has the drawback that the studies cover a range of heterogeneous services. The poor definition of control services, however, is ubiquitous in this field, however reviewed areas are defined. Inclusion of mean data for which no standard deviations were available was problematic in that it prevented measuring the significance of the main findings. The lack of availability of this data, however, is an important finding, demonstrating the difficulty in seeking certainty in this area. Only days in hospital and cost-effectiveness were analysed here. The range and lack of uniformity of measures used in this field made meta-analysis of other outcomes impossible. It should be noted, however, that the findings pertain to these aspects alone. The Delphi exercise reported here was limited in being conducted only with psychiatrists, rather than a multidisciplinary panel. Its findings were used as a framework for the follow-up and analysis. Their possible bias should be borne in mind when considering them as findings in themselves. CONCLUSIONS - IMPLICATIONS FOR CLINICIANS: The evidence base for home treatment compared with other community-based services is not strong, although it does show that home treatment reduces days spent in hospital compared with inpatient treatment. There is evidence that visiting patients at home regularly and taking responsibility for both health and social care each reduce days in hospital. CONCLUSIONS - IMPLICATIONS FOR CONSUMERS: Services that visit patients at home regularly and those that take responsibility for both health and social care are likely to reduce time spent in hospital. Psychiatrists surveyed in this review also considered support for carers to be essential. The evidence from this review, however, was that few services currently have protocols for meeting carers' needs. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH AND COMMISSIONERS: A centrally coordinated research strategy, with attention to study design, is recommended. Studies should include economic evaluations that report health and social service utilisation. Service components should be collected and reported for both experimental and control services. Studies should be designed with adequate power and longer durations of follow-up and use comparable outcome measures to facilitate meta-analysis. Research protocols should be adhered to throughout the studies. It may be advisable that independent researchers conduct studies in future. It is no longer recommended that home treatment be tested against inpatient care, or that small, localised studies replicate existing, more highly powered studies.


Treatment outcome of female agoraphobics 3-9 years after exposure in vivo: a comparison with healthy controls.
It is well documented that most agoraphobics, with or without panic disorder, respond to exposure in vivo. But only little data compared their anxiety levels at follow-up (FU) with those of healthy controls. Forty-two female agoraphobics with or without panic disorder participated in FUs 3-9 years after exposure in vivo. Agoraphobic symptoms were compared to data of 42 healthy controls, who were matched according to gender, age, marital and occupational status. Remission criteria were defined from agoraphobia scores of the controls. A total of 17 (40%) of the patients had no further agoraphobic symptoms at all. A total of 15 (36%) patients still had mild-to-moderate agoraphobic symptoms at FU. A total of 10 (24%) were non-responders and suffered from severe agoraphobia at FU. The percentage of treated patients with complete remission is much higher than previously reported. However, the majority still suffer from mild or severe agoraphobic symptoms and could possibly benefit from additional interventions.


Bone metabolism markers in sports medicine.
Bone mass can be viewed as the net product of two counteracting metabolic processes, bone formation and bone resorption, which allow the skeleton to carry out its principal functions: mechanical support of the body, calcium dynamic deposition and haemopoiesis. Besides radiological methods, several blood and urinary molecules have been identified as markers of bone metabolic activity for estimating the rates and direction of the biological activities governing bone turnover. The advantages for the use of bone metabolism markers are that they are potentially less dangerous than radiological determinations, are more sensitive to changes in bone metabolism than radiological methods and are easily collected and analysed. The disadvantages are that they have high biological variability. Physical exercise is a known source of bone turnover and is recommended for preventing osteoporosis and bone metabolism problems. There are numerous experiments on bone metabolism markers after acute exercise, but not after long-term training and during or after a whole competition season. Moreover, few studies on bone metabolism markers have evaluated their performance in elite and top-level athletes, who have a higher bone turnover than sedentary individuals. Despite discrepant results among studies, most have shown that short exercise is insufficient for modifying serum concentrations of bone metabolism markers. Marker variations are more evident after several hours or days after exercise, bone formation markers are more sensitive than bone resorption markers, and stimulation of osteoblast and/or osteoclast functions is exercise dependent but the response is not immediate. The response depends on the type of exercise; the markers seem to be less sensitive to resistance exercise and the intensity of exercise is not discriminate. Comparisons between trained subjects and untrained controls have demonstrated the influence of exercise on bone turnover. During training, carboxy-terminal collagen cross-links (CTx), a bone resorption marker, was shown to be less sensitive than amino-terminal cross-linking telopeptide of type I collagen (NTx) and urinary pyridinolines, which were sensitive to anaerobic exercise. Whereas, the bone formation markers, bone alkaline phosphatase (BAP) and osteocalcin (OC) changed after 1 month and 2 months of an exercise programme, respectively. After 2 months, while BAP normalized, it was found to be sensitive to aerobic exercise and OC was found to be sensitive to anaerobic exercise. After prolonged training and competition, bone formation markers are found to change in sedentary subjects enrolled in a physical activity programme. Professional athletes show changes in bone formation markers depending on programme intensity, whereas bone resorption appears to stabilize. Crucial for long-term training, are the characteristics of exercise (e.g. weight-bearing, impact).


Global rise in human infectious disease outbreaks.
To characterize the change in frequency of infectious disease outbreaks over time worldwide, we encoded and analysed a novel 33-year dataset (1980-2013) of 12,102 outbreaks of 215 human infectious diseases, comprising more than 44 million cases occuring in 219 nations. We merged these records with ecological characteristics of the causal pathogens to examine global temporal trends in the total number of outbreaks, disease richness (number of unique diseases), disease diversity (richness and outbreak evenness) and per capita cases. Bacteria, viruses, zoonotic diseases (originating in animals) and those caused by pathogens transmitted by vector hosts were responsible for the majority of outbreaks in our dataset. After controlling for disease surveillance, communications, geography and host availability, we find the total number and diversity of outbreaks, and richness of causal diseases increased significantly since 1980 (p < 0.0001). When we incorporate Internet usage into the model to control for biased reporting of outbreaks (starting 1990), the overall number of outbreaks and disease richness still increase significantly with time (p < 0.0001), but per capita cases decrease significantly ( p = 0.005). Temporal trends in outbreaks differ based on the causal pathogen's taxonomy, host requirements and transmission mode. We discuss our preliminary findings in the context of global disease emergence and surveillance.


A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity.
This trial studied the biodistribution, pharmacology, toxicity, immunogenicity, and biologic characteristics of a trace-labeled, anti-CD33, humanized monoclonal antibody M195 (Hu-M195) in patients with relapsed and refractory myeloid leukemia. Hu-M195 is a computer-modeled, "complementarity-determining region-grafted," IgG1, humanized version of M195. M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia (acute myelogenous leukemia and chronic myelogenous leukemia) cells, but not normal stem cells. 131I-murine-M195 has already shown significant ability to cytoreduce patients with relapsed or refractory myeloid leukemias. Hu-M195 has higher avidity than the original mouse monoclonal antibody and, unlike murine M195, has the capability to mediate antibody-dependent cellular cytotoxicity against leukemia targets. Thirteen patients with relapsed or refractory myelogenous leukemia were treated with Hu-M195 at 4 levels of 0.5, 1.0, 3.0, and 10.0 mg/m2 in a phase I trial. Patients received a total of 6 doses per patient over 18 days. Two patients were retreated for a total of 12 doses. The first dose of Hu-M195 was trace-labeled with 131I to allow detailed pharmacokinetic and biodistribution studies by serial sampling of blood, radioimmunoassays of cells, and whole-body gamma-camera imaging. Cumulative total doses of up to 216 mg of Hu-M195 were administered safely. Reversible fever and rigors were observed after infusion at the highest dose levels. The entire bone marrow was specifically and clearly imaged within hours after infusion, with optimal biodistribution occurring at the 3 mg/m2 level. Adsorption of Hu-M195 onto targets in vivo was demonstrated by flow cytometry; near saturation of available sites occurred at the 3 mg/m2 dose level. Plasma and whole body half lives were 38 and 51 hours, respectively, which may reflect continual replenishment of target sites on new leukemia cells. 131I-Hu-M195 was rapidly internalized into the target cells in vivo within 1 hour. Human antihuman antibody responses were not observed. In conclusion, Hu-M195 can be administered safely in multiple doses, without significant toxicity or any evidence of immunogenicity, and can localize rapidly and efficiently to the bone marrow in patients with myeloid leukemias. Additional phase II trials with this agent alone or in combination with cytokines or isotopes are warranted at the optimal biologic dose.


Hypercholesterolemia is associated with the apolipoprotein C-III (APOC3) genotype in children receiving HAART: an eight-year retrospective study.
Polymorphisms in apolipoprotein genes have shown to be predictors of plasma lipid levels in adult cohorts receiving highly active antiretroviral therapy (HAART). Our objective was to confirm the association between the APOC3 genotype and plasma lipid levels in an HIV-1-infected pediatric cohort exposed to HAART. A total of 130 HIV-1-infected children/adolescents that attended a reference center in Argentina were selected for an 8-year longitudinal study with retrospective data collection. Longitudinal measurements of plasma triglycerides, total cholesterol, HDL-C and LDL-C were analyzed under linear or generalized linear mixed models. The contribution of the APOC3 genotype at sites -482, -455 and 3238 to plasma lipid levels prediction was tested after adjusting for potential confounders. Four major APOC3 haplotypes were observed for sites -482/-455/3238, with estimated frequencies of 0.60 (C/T/C), 0.14 (T/C/C), 0.11 (C/C/C), and 0.11 (T/C/G). The APOC3 genotype showed a significant effect only for the prediction of total cholesterol levels (p<0.0001). However, the magnitude of the differences observed was dependent on the drug combination (p = 0.0007) and the drug exposure duration at the time of the plasma lipid measurement (p = 0.0002). A lower risk of hypercholesterolemia was predicted for double and triple heterozygous individuals, mainly at the first few months after the initiation of Ritonavir-boosted protease inhibitor-based regimens. We report for the first time a significant contribution of the genotype to total cholesterol levels in a pediatric cohort under HAART. The genetic determination of APOC3 might have an impact on a large portion of HIV-1-infected children at the time of choosing the treatment regimens or on the counter-measures against the adverse effects of drugs.


Statistical review of US macronutrient consumption data, 1965-2011: Americans have been following dietary guidelines, coincident with the rise in obesity.
For almost 50 y, the US National Health and Nutrition Examination Survey (NHANES) has measured the caloric consumption, and body heights and weights of Americans. The aim of this study was to determine, based on that data, how macronutrient consumption patterns and the weight and body mass index in the US adult population have evolved since the 1960s. We conducted the first comprehensive analysis of the NHANES data, documenting how macronutrient consumption patterns and the weight and body mass index in the US adult population have evolved since the 1960s. Americans in general have been following the nutrition advice that the American Heart Association and the US Departments of Agriculture and Health and Human Services have been issuing for more than 40 y: Consumption of fats has dropped from 45% to 34% with a corresponding increase in carbohydrate consumption from 39% to 51% of total caloric intake. In addition, from 1971 to 2011, average weight and body mass index have increased dramatically, with the percentage of overweight or obese Americans increasing from 42% in 1971 to 66% in 2011. Since 1971, the shift in macronutrient share from fat to carbohydrate is primarily due to an increase in absolute consumption of carbohydrate as opposed to a change in total fat consumption. General adherence to recommendations to reduce fat consumption has coincided with a substantial increase in obesity.


Steps Toward Creating A Therapeutic Community for Inpatients Suffering from Chronic Ulcers: Lessons from Allada Buruli Ulcer Treatment Hospital in Benin.
Reducing social distance between hospital staff and patients and establishing clear lines of communication is a major challenge when providing in-patient care for people afflicted by Buruli ulcer (BU) and chronic ulcers. Research on hospitals as therapeutic communities is virtually non-existent in Africa and is currently being called for by medical anthropologists working in the field of health service and policy planning. This paper describes a pioneering attempt to establish a therapeutic community for patients suffering from BU and other chronic ulcers requiring long term hospital care in Benin. A six-month pilot project was undertaken with the objectives of establishing a therapeutic community and evaluating its impact on practitioner and patient relations. The project was designed and implemented by a team of social scientists working in concert with the current and previous director of a hospital serving patients suffering from advanced stage BU and other chronic ulcers. Qualitative research initially investigated patients' understanding of their illness and its treatment, identified questions patients had about their hospitalization, and ascertained their level of social support. Newly designed question-answer health education sessions were developed. Following these hospital wide education sessions, open forums were held each week to provide an opportunity for patients and hospital staff to express concerns and render sources of discontent transparent. Patient group representatives then met with hospital staff to problem solve issues in a non-confrontational manner. Psychosocial support for individual patients was provided in a second intervention which took the form of drop-in counseling sessions with social scientists trained to serve as therapy facilitators and culture brokers. Interviews with patients revealed that most patients had very little information about the identity of their illness and the duration of their treatment. This knowledge gap surprised clinic staff members, who assumed someone had provided this information. Individual counseling and weekly education sessions corrected this information gap and reduced patient concerns about their treatment and the status of their healing process. This led to positive changes in staff-patient interactions. There was widespread consensus among both patients and staff that the quality of communication had increased significantly. Open forums providing an opportunity for patients and staff to air grievances were likewise popular and patient representative meetings resulted in productive problem solving supported by the hospital administration. Some systemic problems, however, remained persistent challenges. Patients with ulcers unrelated to BU questioned why BU patients were receiving preferential treatment, given special medicines, and charged less for their care. The idea of subsidized treatment for one disease and not another was hard to justify, especially given that BU is not contagious. This pilot project illustrates the basic principles necessary for transforming long term residential hospitals into therapeutic communities. Although the focus of this case study was patients suffering from chronic ulcers, the model presented is relevant for other types of patients with cultural adaptation.


Effectiveness of new vibration delivery system on pain associated with injection of local anesthesia in children.
Pain is highly subjective and it is neurologically proven that stimulation of larger diameter fibers - e.g., using appropriate coldness, warmth, rubbing, pressure or vibration - can close the neural "gate" so that the central perception of itch and pain is reduced. This fact is based upon "gate control" theory of Melzack and Wall. The present study was carried out to investigate the effects of vibration stimuli on pain experienced during local anesthetic injections. Thirty patients aged 6-12 years old of both the genders with Frankel's behavior rating scale as positive and definitely positive requiring bilateral local anesthesia injections for dental treatment were included in the split-mouth cross over design. Universal pain assessment tool was used to assess the pain with and without vibration during the administration of local anesthesia and the results obtained were tabulated and statistically analyzed. Local anesthetic administration with vibration resulted in significantly less pain (P = 0.001) compared to the injections without the use of vibe. The results suggest that vibration can be used as an effective method to decrease pain during dental local anesthetic administration.


A comparison of cardiometabolic risk factors in households in rural Uganda with and without a resident with type 2 diabetes, 2012-2013.
Few studies have examined the health consequences of living in a household with a person who has been diagnosed with type 2 diabetes (T2D). We assessed the association of sharing a household with a person with diagnosed T2D and risk factors for cardio-metabolic diseases in Uganda, a low-income country. Ninety households with 437 residents in southwestern Uganda were studied from December 2012 through March 2013. Forty-five of the households had a member with diagnosed T2D (hereafter "diabetic household"), and 45 households had no member with diagnosed T2D (hereafter "nondiabetic household"). We compared glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), hypertension, anthropometry, aerobic capacity, physical activity, nutrition, smoking, and diabetes-related knowledge of people without diagnosed T2D living in diabetic and nondiabetic households. People living in diabetic households had a significantly higher level of diabetes-related knowledge, lower levels of FPG (5.6 mmol/L vs 6.0 mmol/L), and fewer smoked (1.3% vs 12.9%) than residents of nondiabetic households. HbA1c was significantly lower in people aged 30 years or younger (5.2% vs 5.4%) and in males (5.2% vs 5.4%) living in diabetic households compared to residents of nondiabetic households. No differences were found between the 2 types of households in overweight and obesity, upper-arm fat area, intake of staple foods or cooking oil, or physical activity. Sharing a household with a person with T2D may have unexpected benefits on the risk factor profile for cardio-metabolic diseases, probably because of improved health behaviors and a closer connection with the health care system. Thus, future studies should consider the household for interventions targeting primary and secondary prevention of T2D.


Asymmetric aerobic oxidation of alpha-hydroxy acid derivatives by C4-symmetric, vanadate-centered, tetrakisvanadyl(V) clusters derived from N-salicylidene-alpha-aminocarboxylates.
A series of chiral vanadyl(V) methoxides bearing 3-t-butyl-5-substituted N-salicylene-L-valinate and L-t-leucinate as chiral auxiliaries has been prepared. In all cases except the 3,5-di-t-butyl analogue, they exist as monomers both in solution and in the single crystal state. In the case of the 3,5-di-t-butyl analogue, the architectural nature of the vanadyl(V) complex highly depends on the base used during the complex formation event. A pentanuclear C4-symmetric complex was formed when potassium salts were employed instead of the corresponding sodium salts. A central vanadate(V) unit serves to grip four identical chiral monomeric vanadyl(V) units together, by which a potassium ion sits on top of the four flanking units through carbonyl coordinations and serves to hold the whole cluster by cooperation with the central vanadate(V) unit. In comparison with the corresponding monomeric vanadyl(V) methoxide complex, the cluster complex was utilized to facilitate the asymmetric aerobic oxidations of various racemic alpha-hydroxyesters, -amides, and -thioesters with excellent selectivity factors (krel 40 to >500).


Computational assignment of redox states to Coulomb blockade diamonds.
With the advent of molecular transistors, electrochemistry can now be studied at the single-molecule level. Experimentally, the redox chemistry of the molecule manifests itself as features in the observed Coulomb blockade diamonds. We present a simple theoretical method for explicit construction of the Coulomb blockade diamonds of a molecule. A combined quantum mechanical/molecular mechanical method is invoked to calculate redox energies and polarizabilities of the molecules, including the screening effect of the metal leads. This direct approach circumvents the need for explicit modelling of the gate electrode. From the calculated parameters the Coulomb blockade diamonds are constructed using simple theory. We offer a theoretical tool for assignment of Coulomb blockade diamonds to specific redox states in particular, and a study of chemical details in the diamonds in general. With the ongoing experimental developments in molecular transistor experiments, our tool could find use in molecular electronics, electrochemistry, and electrocatalysis.


The role of epidemiology in determining if a simple short fall can cause fatal head injury in an infant: a subject review and reflection.
This article is a subject review summarizing and interpreting the existing knowledge on the question "Can a simple short fall cause fatal head injury in an infant?" It also reflects on the challenges of undertaking a review in the contentious area of pediatric forensic pathology. The authors identified and considered 1055 publications for inclusion. Using explicit selection criteria 27 publications were included in the subject review. The literature suggests that it is rare, but possible, for fatal head injury to occur from a simple short fall. Large population studies of childhood injuries indicate that severe head injury from a short fall is extremely rare. This is counter pointed by a single documented case report that demonstrates it can happen. The question of whether it is a credible claim in a particular case is inextricable from the circumstances of that case.To strengthen the evidence based on fatal potential of simple short falls in infants, future studies addressing this question would ideally be prospective in design and include the key elements of: (1) a large sample size, (2) clearly defined comparison groups, (3) clear and verifiable criteria for causation, (4) specified fall height, (5) specified fall type: vertical free fall or the presence of additional forces, (6) composition of contact surface, and (7) nature of contact point: concentrated to one point or onto a flat surface.We believe subject reviews for forensic pathology require a specific approach because the application of information differs between clinical and courtroom settings.


Acute pancreatitis with pseudocyst formation in a patient with polyarteritis nodosa.
Polyarteritis nodosa (PAN) is a term that includes patients with necrotizing inflammation of medium sized arteries, and excludes those with microscopic vessel involvement. Its manifestations are protean and include constitutional symptoms such as fever, malaise, weight loss, myalgia, peripheral neuropathy, rash, and gut and renal involvement. Although gastrointestinal manifestations have been noted in up to a third of patients with PAN, clinical presentation with pancreatic involvement has been reported only rarely. We describe a patient with PAN who developed acute pancreatitis with pseudocyst formation as well as infarcts in the spleen and liver.


The WHO-5 Well-Being Index: a systematic review of the literature.
The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well-being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields.


Pharmacologic management of cancer pain.
Cancer remains the second most common cause of death in the United States despite advances in prevention, early detection, and newer treatment protocols. Pain continues to be the most feared complication of this diagnosis. Numerous studies have shown that when the World Health Organization treatment guidelines are followed, 90% of patients are pain-free. Although evidence is convincing that opioids are effective in the treatment of patients with cancer pain, reluctance to use them continues. Barriers to opioid use are multifactorial, but with education of healthcare providers and patients, treatment to manage pain will be more effective.


Opa1 Reduces Hypoxia-Induced Cardiomyocyte Death by Improving Mitochondrial Quality Control.
Mitochondrial dysfunction contributes to cardiovascular disorders, especially post-infarction cardiac injury, through incompletely characterized mechanisms. Among the latter, increasing evidence points to alterations in mitochondrial quality control, a range of adaptive responses regulating mitochondrial morphology and function. Optic atrophy 1 (Opa1) is a mitochondrial inner membrane GTPase known to promote mitochondrial fusion. In this study, hypoxia-mediated cardiomyocyte damage was induced to mimic post-infarction cardiac injury in vitro. Loss- and gain-of-function assays were then performed to evaluate the impact of Opa1 expression on mitochondrial quality control and cardiomyocyte survival and function. Hypoxic stress reduced cardiomyocyte viability, impaired contractile/relaxation functions, and augmented the synthesis of pro-inflammatory mediators. These effects were exacerbated by Opa1 knockdown, and significantly attenuated by Opa1 overexpression. Mitochondrial quality control was disturbed by hypoxia, as reflected by multiple mitochondrial deficits; i.e., increased fission, defective fusion, impaired mitophagy, decreased biogenesis, increased oxidative stress, and blunted respiration. By contrast, overexpression of Opa1 normalized mitochondrial quality control and sustained cardiomyocyte function. We also found that ERK, AMPK, and YAP signaling can regulate Opa1 expression. These results identify Opa1 as a novel regulator of mitochondrial quality control and highlight a key role for Opa1 in protecting cardiomyocytes against post-infarction cardiac injury.


Pancreas transplantation: the Nebraska experience.
In summary, we believe that combined PKT can be performed safely and effectively in the absence of uremia, thereby providing the potential for arresting the progression of diabetic complications prior to the development of ESRD. Furthermore, performing solitary PTx prior to the need for a kidney transplant can be accomplished with morbidity and results comparable to PKT. Rehabilitation potential tends to favor patients undergoing either solitary PTx or preemptive PKT. In selected IDDM patients without end-stage diabetic nephropathy, we believe that solitary PTx or PKT are effective treatment options and need not be considered as preemptive, especially in view of increasing waiting times and the variable progressive nature of diabetic complications. As results continue to improve, solitary PTx may offer a potential solution to the growing number of IDDM patients awaiting kidney transplantation in the United States. Ultimately, the role of solitary PTx in the treatment of IDDM will be determined by long-term studies documenting the prevention or arrest of secondary diabetic complications. In the short-term, improvement in quality of life and rehabilitation potential makes preemptive PKT or solitary PTx important therapeutic alternatives for consideration.


Court intervention to address the mental health needs of mentally ill offenders.
The authors examined the outcomes of mental health consultation provided to a municipal court and the court's resulting interventions for mentally ill persons who committed minor crimes. One aim of the consultation program was to avoid criminalization of mentally ill people who committed minor offenses. Clinical and forensic records of 96 persons charged with misdemeanors and referred to a clinical psychologist court consultant for evaluation were studied. Determination of good versus poor outcome during a one-year follow-up period was based on clients' status during the year after the court's disposition. Poor outcome was defined as the occurrence of one or more of four events during the follow-up year: psychiatric hospitalization, arrest, significant physical violence against persons, and homelessness. Fifty-six defendants (58 percent) were mandated to receive judicially monitored mental health treatment, as recommended by the psychologist court consultant, and 33 of them (59 percent) had a good one-year outcome. The relationship was statistically significant. Nonclinicians in the criminal justice system should have psychiatric assistance in making appropriate dispositions for mentally ill persons. If the judge is considering mental health treatment as a condition for eliminating or reducing punishment, then, to the extent justified by the law and the nature of the offense, the judge should both mandate and monitor the treatment on an ongoing basis.


Loss of function of Colgalt1 disrupts collagen post-translational modification and causes musculoskeletal defects.
In a screen for organogenesis defects in N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we discovered a line carrying a mutation in Colgalt1 [collagen beta(1-O)galactosyltransferase type 1], which is required for proper galactosylation of hydroxylysine residues in a number of collagens. Colgalt1 mutant embryos have not been previously characterized; here, we show that they exhibit skeletal and muscular defects. Analysis of mutant-derived embryonic fibroblasts reveals that COLGALT1 acts on collagen IV and VI, and, while collagen VI appears stable and its secretion is not affected, collagen IV accumulates inside of cells and within the extracellular matrix, possibly due to instability and increased degradation. We also generated mutant zebrafish that do not express the duplicated orthologs of mammalian Colgalt1 The double-homozygote mutants have muscle defects; they are viable through the larvae stage but do not survive to 10 days post-fertilization. We hypothesize that the Colgalt1 mutant could serve as a model of a human connective tissue disorder and/or congenital muscular dystrophy or myopathy.


Associations between patterns of emerging sexual behavior and young adult reproductive health.
Identifying young adult outcomes associated with adolescent sexual behavior, including patterns of first oral, vaginal and anal sex, is critical to promoting healthy sexual development. Associations between patterns of emerging sexual behavior, defined using latent class analysis, and young adult sexual and reproductive health were examined among 9,441 respondents to Waves 1 (1994-1995), 3 (2001-2002) and 4 (2008) of the National Longitudinal Study of Adolescent Health. Logistic regression analyses examined associations between class membership and young adult outcomes, and tested for interactions by race and ethnicity. Compared with respondents who initiated vaginal sex first and reported other sexual behaviors within two years, those who initiated oral and vaginal sex during the same year had similar odds of having had an STD diagnosis ever or in the last year, of having had concurrent sexual partnerships in the last year and of having exchanged sex for money. However, respondents who postponed sexual activity had reduced odds of each outcome (odds ratios, 0.2-0.4); those who initiated vaginal sex and reported only one type of sexual behavior had reduced odds of reporting STD diagnoses and concurrent partnerships (0.4-0.6). Respondents who reported early initiation of sexual activity combined with anal sex experience during adolescence had elevated odds of having had concurrent partnerships (1.6). The data suggest racial and ethnic disparities even when patterns of emerging sexual behavior were the same. Patterns of early sexual behavior considered high-risk may not predict poor sexual and reproductive health in young adulthood.


Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis.
Axon outgrowth during development and neurotransmitter release depends on exocytotic mechanisms, although what protein machinery is common to or differentiates these processes remains unclear. Here we show that the neural t-SNARE (target-membrane-associated-soluble N-ethylmaleimide fusion protein attachment protein (SNAP) receptor) SNAP-25 is not required for nerve growth or stimulus-independent neurotransmitter release, but is essential for evoked synaptic transmission at neuromuscular junctions and central synapses. These results demonstrate that the development of neurotransmission requires the recruitment of a specialized SNARE core complex to meet the demands of regulated exocytosis.


Predicted Risks of Cardiovascular Disease Following Chemotherapy and Radiotherapy in the UK NCRI RAPID Trial of Positron Emission Tomography-Directed Therapy for Early-Stage Hodgkin Lymphoma.
The contemporary management of early-stage Hodgkin lymphoma (ES-HL) involves balancing the risk of late adverse effects of radiotherapy against the increased risk of relapse if radiotherapy is omitted. This study provides information on the risk of radiation-related cardiovascular disease to help personalize the delivery of radiotherapy in ES-HL. We predicted 30-year absolute cardiovascular risk from chemotherapy and involved field radiotherapy in patients who were positron emission tomography (PET)-negative following three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy within a UK randomized trial of PET-directed therapy for ES-HL. Cardiac and carotid radiation doses and chemotherapy exposure were combined with established dose-response relationships and population-based mortality and incidence rates. Average mean heart dose was 4.0 Gy (range 0.1-24.0 Gy) and average bilateral common carotid artery dose was 21.5 Gy (range 0.6-38.1 Gy), based on individualized cardiovascular dosimetry for 144 PET-negative patients receiving involved field radiotherapy. The average predicted 30-year radiation-related absolute excess overall cardiovascular mortality was 0.56% (range 0.01%-6.79%; < 0.5% in 67% of patients and > 1% in 15%), whereas average predicted 30-year excess incidence was 6.24% (range 0.31%-31.09%; < 5% in 58% of patients and > 10% in 24%). For cardiac disease, the average predicted 30-year radiation-related absolute excess mortality was 0.42% (0.79% with mediastinal involvement and 0.05% without) and for stroke, it was 0.14%. Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk. Individual assessment of cardiovascular and other risks before treatment would allow personalized decision making about radiotherapy in ES-HL.


Coarse-grained event tree analysis for quantifying Hodgkin-Huxley neuronal network dynamics.
We present an event tree analysis of studying the dynamics of the Hodgkin-Huxley (HH) neuronal networks. Our study relies on a coarse-grained projection to event trees and to the event chains that comprise these trees by using a statistical collection of spatial-temporal sequences of relevant physiological observables (such as sequences of spiking multiple neurons). This projection can retain information about network dynamics that covers multiple features, swiftly and robustly. We demonstrate that for even small differences in inputs, some dynamical regimes of HH networks contain sufficiently higher order statistics as reflected in event chains within the event tree analysis. Therefore, this analysis is effective in discriminating small differences in inputs. Moreover, we use event trees to analyze the results computed from an efficient library-based numerical method proposed in our previous work, where a pre-computed high resolution data library of typical neuronal trajectories during the interval of an action potential (spike) allows us to avoid resolving the spikes in detail. In this way, we can evolve the HH networks using time steps one order of magnitude larger than the typical time steps used for resolving the trajectories without the library, while achieving comparable statistical accuracy in terms of average firing rate and power spectra of voltage traces. Our numerical simulation results show that the library method is efficient in the sense that the results generated by using this numerical method with much larger time steps contain sufficiently high order statistical structure of firing events that are similar to the ones obtained using a regular HH solver. We use our event tree analysis to demonstrate these statistical similarities.


Spectroscopic, steady-state kinetic, and mechanistic characterization of the radical SAM enzyme QueE, which catalyzes a complex cyclization reaction in the biosynthesis of 7-deazapurines.
7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes the complex heterocyclic radical-mediated conversion of 6-carboxy-5,6,7,8-tetrahydropterin (CPH(4)) to CDG in the third step of the biosynthetic pathway to all 7-deazapurines. Here we present a detailed characterization of QueE from Bacillus subtilis to delineate the mechanism of conversion of CPH(4) to CDG. QueE is a member of the radical S-adenosyl-l-methionine (SAM) superfamily, all of which use a bound [4Fe-4S](+) cluster to catalyze the reductive cleavage of the SAM cofactor to generate methionine and a 5'-deoxyadenosyl radical (5'-dAdo(•)), which initiates enzymatic transformations requiring hydrogen atom abstraction. The ultraviolet-visible, electron paramagnetic resonance, and Mössbauer spectroscopic features of the homodimeric QueE point to the presence of a single [4Fe-4S] cluster per monomer. Steady-state kinetic experiments indicate a K(m) of 20 ± 7 μM for CPH(4) and a k(cat) of 5.4 ± 1.2 min(-1) for the overall transformation. The kinetically determined K(app) for SAM is 45 ± 1 μM. QueE is also magnesium-dependent and exhibits a K(app) for the divalent metal ion of 0.21 ± 0.03 mM. The SAM cofactor supports multiple turnovers, indicating that it is regenerated at the end of each catalytic cycle. The mechanism of rearrangement of QueE was probed with CPH(4) isotopologs containing deuterium at C-6 or the two prochiral positions at C-7. These studies implicate 5'-dAdo(•) as the initiator of the ring contraction reaction catalyzed by QueE by abstraction of the H atom from C-6 of CPH(4).


Saliva activated transmission (SAT) of Thogoto virus: relationship with vector potential of different haematophagous arthropods.
Tick saliva (or salivary gland extract) potentiates the transmission of Thogoto (THO) virus to uninfected ticks feeding on a non-viraemic guinea-pig. This phenomenon has been named saliva activated transmission (SAT). To investigate the potential of different haematophagous arthropods to mediate SAT, guinea-pigs were infested with uninfected R.appendiculatus Neumann nymphs and inoculated with THO virus and salivary gland extract (SGE) derived from a range of ixodid (metastriate and prostriate) or argasid ticks, or mosquitoes; control guinea-pigs were inoculated with virus alone. Enhancement of THO virus transmission was observed only when SGE was derived from metastriate ticks. Comparison with the vector potential of these various arthropod species revealed that enhancement of THO virus transmission was specific for ticks which were competent vectors of the virus. The data indicate a correlation between vector competence and the ability of haematophagous arthropods to mediate SAT of THO virus.