Meta-Modal Information Flow: A Method for Capturing Multimodal Modular Disconnectivity in Schizophrenia.
Multimodal measurements of the same phenomena provide complementary information and highlight different perspectives, albeit each with their own limitations. A focus on a single modality may lead to incorrect inferences, which is especially important when a studied phenomenon is a disease. In this paper, we introduce a method that takes advantage of multimodal data in addressing the hypotheses of disconnectivity and dysfunction within schizophrenia (SZ). We start with estimating and visualizing links within and among extracted multimodal data features using a Gaussian graphical model (GGM). We then propose a modularity-based method that can be applied to the GGM to identify links that are associated with mental illness across a multimodal data set. Through simulation and real data, we show our approach reveals important information about disease-related network disruptions that are missed with a focus on a single modality. We use functional MRI (fMRI), diffusion MRI (dMRI), and structural MRI (sMRI) to compute the fractional amplitude of low frequency fluctuations (fALFF), fractional anisotropy (FA), and gray matter (GM) concentration maps. These three modalities are analyzed using our modularity method. Our results show missing links that are only captured by the cross-modal information that may play an important role in disconnectivity between the components. We identified multimodal (fALFF, FA and GM) disconnectivity in the default mode network area in patients with SZ, which would not have been detectable in a single modality. The proposed approach provides an important new tool for capturing information that is distributed among multiple imaging modalities.


Non-evidence-based variables affecting physicians' test-ordering tendencies: a systematic review.
The concept of evidence-based medicine (EBM) was introduced in 1992. Incorporation of EBM into physicians' practices, however, has been slow. Testordering tendencies are still based on variables that are not necessarily evidence-based. The literature was reviewed to identify the non-EBM variables that affect physicians' practices of test ordering. Studies of interest were limited to original research on the determinants of physicians' test-ordering tendencies. The search strategy included queries in MEDLINE (1992-2006), Web of Science (1993-2006), EMBASE (1992-2006), and PsycINFO (1992-2006); checking of reference lists; hand searching relevant journals; and personal communication with experts. Two independent reviewers abstracted information on the design, quality, and limitations of the study. Review articles, letters, and editorials were excluded from analysis. 104 original studies reporting on the variables affecting test ordering were identified. Of these, 53 studies assessing physician variables affecting test ordering were identified. Some of the recognisable physician factors included age, sex, degree of specialisation, geographic location and practice setting, individual belief systems, experience, knowledge, fear of malpractice litigation, physician regret, financial incentives, awareness of costs of tests ordered, and provision of written feedback by peers or employers. Despite considerable advances in our understanding of EBM and its application to patient care, several non-EBM physician variables influence physicians' test-ordering characteristics. Ongoing effort is needed to identify the modifiable non-EBM determinants of physicians' test ordering and to use appropriate tools and techniques to encourage evidence-based behaviours for test ordering.


[The transfusion medicine program in Cuba].
Cuba's Transfusion Medicine Program (TMP) is a subsystem of the country's National Health System. The TMP's objective is to ensure hemotherapy with blood that is safe and sufficient for all the individuals who need it. The TMP subsystem is made up of the National Commission on Transfusion Medicine, the Institute of Hematology and Immunology, 37 clinical services, 44 blood banks, 120 collection centers, 19 mobile units, and 37 blood certification laboratories. Additional facilities include a laboratory for plasma separation, a laboratory that produces leukocyte interferon and transfer factor, and two laboratories that produce reagents for blood classification and blood diagnosis symptoms. In Cuba, blood donation is voluntary. Since 1997 approximately 5% of the population per year has donated blood, thus meeting the goal recommended by the Pan American Health Organization of one voluntary blood donation annually for every 20 persons. During 2002, 563,204 blood donations were received, and there were 445,898 transfusions of blood or blood components. All donations are individually screened for HIV 1 and 2, hepatitis B, hepatitis C, and syphilis, thus meeting the country's current regulations. In 2002 these screening measures led to discarding, respectively, 0.12%, 0.60%, 0.71%, and 1.8% of the blood donations. Although the prevalence of human T-cell lymphotropic virus I and II in Cuba is very low, this test will soon be added to the screening process.


Stationary bumps in networks of spiking neurons.
We examine the existence and stability of spatially localized "bumps" of neuronal activity in a network of spiking neurons. Bumps have been proposed in mechanisms of visual orientation tuning, the rat head direction system, and working memory. We show that a bump solution can exist in a spiking network provided the neurons fire asynchronously within the bump. We consider a parameter regime where the bump solution is bistable with an all-off state and can be initiated with a transient excitatory stimulus. We show that the activity profile matches that of a corresponding population rate model. The bump in a spiking network can lose stability through partial synchronization to either a traveling wave or the all-off state. This can occur if the synaptic timescale is too fast through a dynamical effect or if a transient excitatory pulse is applied to the network. A bump can thus be activated and deactivated with excitatory inputs that may have physiological relevance.


Succinate dehydrogenase and other respiratory pathways in thylakoid membranes of Synechocystis sp. strain PCC 6803: capacity comparisons and physiological function.
Respiration in cyanobacterial thylakoid membranes is interwoven with photosynthetic processes. We have constructed a range of mutants that are impaired in several combinations of respiratory and photosynthetic electron transport complexes and have examined the relative effects on the redox state of the plastoquinone (PQ) pool by using a quinone electrode. Succinate dehydrogenase has a major effect on the PQ redox poise, as mutants lacking this enzyme showed a much more oxidized PQ pool. Mutants lacking type I and II NAD(P)H dehydrogenases also had more oxidized PQ pools. However, in the mutant lacking type I NADPH dehydrogenase, succinate was essentially absent and effective respiratory electron donation to the PQ pool could be established after addition of 1 mM succinate. Therefore, lack of the type I NADPH dehydrogenase had an indirect effect on the PQ pool redox state. The electron donation capacity of succinate dehydrogenase was found to be an order of magnitude larger than that of type I and II NAD(P)H dehydrogenases. The reason for the oxidized PQ pool upon inactivation of type II NADH dehydrogenase may be related to the facts that the NAD pool in the cell is much smaller than that of NADP and that the NAD pool is fully reduced in the mutant without type II NADH dehydrogenase, thus causing regulatory inhibition. The results indicate that succinate dehydrogenase is the main respiratory electron transfer pathway into the PQ pool and that type I and II NAD(P)H dehydrogenases regulate the reduction level of NADP and NAD, which, in turn, affects respiratory electron flow through succinate dehydrogenase.


Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.
Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ΔΔCt method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.


Validation of the Instagram Addiction Scale in Greek Youth.
Instagram is one of the fastest growing social networking platforms. A body of evidence suggests that Instagram problematic use and addiction have negative effects on the psychological well-being of young people. The Instagram Addiction Scale, a self-report tool assessing Instagram problematic use and addiction, has been developed recently. The aim of the present study was to validate the Instagram Addiction Scale in the Greek language and to assess its psychometric properties. An online and on-print self-report survey was conducted among Greek youth, aged between 18 and 24 years. The survey included the Instagram Addiction Scale, the Rosenberg Self-esteem Scale, the Perceived Stress Scale, and the Big Five Inventory. A total of 967 respondents participated in the study. The analysis suggested that the Greek version of the Instagram Addiction Scale has good psychometric properties. The principal component factor analysis for construct validity generated two subscales as the original instrument: social effect and impulsion. Internal consistency for the two subscales and the scale's total score was satisfactory, with Cronbach's α at 0.76, 0.85 and 0.88, respectively. Correlation analyses revealed positive associations between the perceived stress scale and social effect, and the Instagram Addiction Scale's total score (p<0.0001 and p=0.002 respectively). This is the first study validating the Instagram Addiction Scale in Greek youth, which can be used by researchers and practitioners for the evaluation of youth problematic use of Instagram.


Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats.
Intrauterine growth retardation (IUGR) is associated with reduced lung function during infancy and perhaps throughout adulthood. The retinoic acid (RA) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. On Gestation Day 18, either uteroplacental insufficiency was induced through bilateral uterine vessel ligation (IUGR group) or sham surgery (control group) was performed. Lung tissues from the offspring were examined through Western blotting, immunohistochemistry, and morphometry on Postnatal Day 3 and Postnatal Day 7. Compared with control rats, the IUGR rats exhibited significantly lower body weights on Postnatal Day 3 and Postnatal Day 7 and significantly lower lung weights on Postnatal Day 3. Uteroplacental insufficiency significantly increased RA receptor (RAR)-β protein expression on Postnatal Day 3. The expression of RAR-α, RAR-γ, cellular RA-binding protein-1, and cellular RA-binding protein-2 between the control and IUGR rats was comparable on Postnatal Day 3 and Postnatal Day 7. Compared with the control rats, the IUGR rats exhibited a significantly higher volume fraction of alveolar airspace on Postnatal Day 3 and Postnatal Day 7 and a significantly lower volume fraction of alveolar walls on Postnatal Day 3. Uteroplacental insufficiency causes defective alveolarization and transient increases in RAR-β expression in the lungs of newborn rats. The retinoid pathway may be one of the probable pathways mediating lung abnormalities caused by uteroplacental insufficiency.


Dimerization-Induced Allosteric Changes of the Oxyanion-Hole Loop Activate the Pseudorabies Virus Assemblin pUL26N, a Herpesvirus Serine Protease.
Herpesviruses encode a characteristic serine protease with a unique fold and an active site that comprises the unusual triad Ser-His-His. The protease is essential for viral replication and as such constitutes a promising drug target. In solution, a dynamic equilibrium exists between an inactive monomeric and an active dimeric form of the enzyme, which is believed to play a key regulatory role in the orchestration of proteolysis and capsid assembly. Currently available crystal structures of herpesvirus proteases correspond either to the dimeric state or to complexes with peptide mimetics that alter the dimerization interface. In contrast, the structure of the native monomeric state has remained elusive. Here, we present the three-dimensional structures of native monomeric, active dimeric, and diisopropyl fluorophosphate-inhibited dimeric protease derived from pseudorabies virus, an alphaherpesvirus of swine. These structures, solved by X-ray crystallography to respective resolutions of 2.05, 2.10 and 2.03 Å, allow a direct comparison of the main conformational states of the protease. In the dimeric form, a functional oxyanion hole is formed by a loop of 10 amino-acid residues encompassing two consecutive arginine residues (Arg136 and Arg137); both are strictly conserved throughout the herpesviruses. In the monomeric form, the top of the loop is shifted by approximately 11 Å, resulting in a complete disruption of the oxyanion hole and loss of activity. The dimerization-induced allosteric changes described here form the physical basis for the concentration-dependent activation of the protease, which is essential for proper virus replication. Small-angle X-ray scattering experiments confirmed a concentration-dependent equilibrium of monomeric and dimeric protease in solution.


Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren's syndrome.
Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjögren's syndrome (pSS). Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq). mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62-0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as 'high' or 'low' IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89-0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001). We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.


Aflatoxin Proficiency Testing and Control in Kenya.
Texas A&M AgriLife Research (hereafter AgriLife) introduced a quality systems approach to accurately measure and manage aflatoxin that resulted in improved food safety for approximately 10 million Kenyans. A quality systems approach contains elements that ensure laboratory testing competence. In this study, quality system elements included analyst training and qualification, proficiency testing, use of reference material to support analytical traceability and define analytical uncertainty, development and implementation of a food safety plan by commercial maize (Zea mays) millers, and verification of testing accuracy at the AgriLife laboratory accredited by the Kenya Accreditation Service under the International Organization for Standardization/International Electrotechnical Commission 17025:2005 standard. In 2014 and 2015, five proficiency rounds were performed, ranging in aflatoxin concentrations of 5 to 40 μg/kg. Five laboratories had a z-score of >3, and all of these were for the fifth proficiency round with an aflatoxin content of 5 μg/kg. In 2015, 31 analysts qualified to participate in the program at 15 maize mills. The analysts' qualification for seven test samples, which ranged from 3.1 to 28 μg/kg total aflatoxin, resulted in an average relative standard deviation of 19.2% across all participants and test methods. Independent testing of participating mill verification results before and after analyst implementation of the quality systems approach revealed an improvement in measure accuracy.


A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML.
Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.


Ischemia and reperfusion of rat small intestine using pentoxyfilline and prostaglandin E1.
To investigate the small intestinal tissue alterations in rats submitted to ischemia and tissue reperfusion using pentoxyfilline or prostaglandin E1. Thirty five Wistar rats were used, distributed into group control (A) n=10 were submitted to intestinal ischemia and reperfusion during 60 minutes and no one drug have been utilized. In the group pentoxyfilline (B) n=10 have been utilized during tissue ischemia and reperfusion as well as prostaglandin E1 (C) n=10, but separately. In the group sham (D) n=5, the animals were submitted to surgical. After euthanasia of the animals, a segment of the small intestine was cut, stained by hematoxilin-eosin and histological analysis according to Chiu criteria. Histological results showed that using pentoxyflline or prostaglandin E1 the results during tissue reperfusion were better, since the levels of criteria from Chiu that predominated were level 2 and 3, indicating less tissue damage in comparison to the control group (group A) that showed levels 4 and 5, what means more severe histological tissue alterations. Use of pentoxyfilline or prostaglandin E1 promoted a beneficial effect during intestinal reperfusion, demonstrated by less severe histological lesions in the small intestine mucosa of rats submitted to ischemia and tissue reperfusion when helped by the drugs.


Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine.
The prognosis of patients with Langerhans cell histiocytosis (LCH) involving the central nervous system (CNS) is generally poor, despite reports of clinical responses to chemotherapy, surgery, and radiation. We report on a patient with a 20-year history of relapsing multisystem LCH who developed progressive neuropsychiatric symptoms, including diplopia, ataxia, and mental deterioration. There was a regression of lesions in the brain stem and cerebellum following chemotherapy with cladribine (2-CdA) as evidenced by positron emission tomography (PET) scans. In conclusion, our experience is encouraging for the use of cladribine in CNS LCH. PET may be a useful modality for the monitoring of CNS disease activity in LCH and provides additional information in comparison with NMR imaging.


Children's experiences of domestic violence: developing an integrated response from police and child protection services.
Police notifications of incidents of domestic violence to child protection services constitute an acknowledgement of the harm that domestic violence inflicts on children. However, these notifications represent a substantial demand on child welfare services and the outcomes for children and victims of domestic violence have been questioned. This paper presents findings from the first UK study to examine these notifications in depth and examines the interface between the police and child protection services in responding to domestic violence incidents. The research reports on police interventions in 251 incidents of domestic violence involving children; the communication of information to child protection services and the subsequent filtering and service response. Social workers found that notifications conveyed little information on children's experiences of domestic violence. Forty per cent of families notified had had no previous contact with child protection services in that area, but those cases most likely to receive social work assessment or intervention were those where the case was already open. Notifications triggered a new social work intervention in only 5% of cases. The study also identified a range of innovative approaches for improving the co-ordination of police and child protective services in relation to children's exposure to domestic violence. Arrangements that maximized opportunities for police and social workers to share agency information appeared to offer the best option for achieving informed decisions about the appropriate level of service response to children and families experiencing domestic violence.


Multi-pass Shack-Hartmann planeness test: monitoring thermal stress.
The multi-pass solution for surface measurements with the help of a Shack-Hartmann sensor (SHS) on the basis of a Fizeau cavity enables fast access to surface deviation data due to the high speed of the SHS and easy referencing of the measured data through difference measurements. The multi-pass solution described in a previous publication [J. Schwider, Opt. Express 16, 362 (2008)], provides highly sensitive measurements of small displacements caused by thermal non-equilibrium states of the test set up. Here, we want to demonstrate how a pulsed thermal load changes the surface geometry. In addition the temporal response for different plate materials is monitored through a fast wave front measurement with very high sensitivity. The thermal load close to a delta-function in time will be applied from the back-side of a plane plate by heating a small Peltier element with a heat impulse of known order of magnitude. The development of the surface deviation on the time axis can be monitored by storing a set of successive deviation pictures.


The angiogenic effects of Angelica sinensis extract on HUVEC in vitro and zebrafish in vivo.
Angiogenesis plays an important role in a wide range of physiological processes such as wound healing and fetal development. Many diseases are associated with imbalances in regulation of angiogenesis, in which it is either excessive or there is insufficient blood vessel formation. Angelica sinensis (AS), commonly used in the prescriptions of Chinese medicine, is a potential candidate for curing such diseases. However, biological effects of AS on angiogenesis and underlying mechanisms are yet to be fully elucidated. This investigation describes the angiogenic effects of AS extract on human endothelial cells (HUVEC) in vitro and zebrafish in vivo. The extract was demonstrated, by XTT assay and microscopic cell counting, to stimulate the proliferation of HUVEC; in addition, flow cytometry analysis indicated that the extract increased the percentage of HUVEC in the S phase. The wound healing migration assay illustrated that a dramatic increase in migration could be measured in AS extract-treated HUVEC. Meanwhile, the number of invaded cells and the mean tube length were significantly increased in AS extract treatment groups. The extract was also demonstrated to promote changes in subintestinal vessels (SIVs) in zebrafish, one feature of angiogenesis. In addition, AS extract was found by real-time PCR to enhance vascular endothelial growth factor (VEGF) mRNA expression. In a bead-based immunoassay, higher levels of p38 and JNK 1/2 expression were also observed in effusions compared with control cells. All results suggest that Angelica sinensis extract can promote angiogenesis, and that the angiogenic effects involve p38 and JNK 1/2 phosphorylation.


The genesis of Collegiate Membership: a personal account by the first Chair of the Collegiate Members' Committee.
Just over 40 years ago, the then President of the Royal College of Physicians of Edinburgh, Christopher Clayson, responded to the publication of a Royal Commission on Medical Education by setting up a College Committee under the chairmanship of John Halliday Croom. This is a personal account of, and reflections on, the workings of that important committee, the College Council whose work led to the introduction of Collegiate Membership and the Collegiate Members' Committee of which I was the first Chair. This development led to the RCPE becoming much more concerned with, and responsive to, the needs of doctors in training and had a wider, positive impact upon medical training and education in the UK.


Investigation of parameters controlling the dielectrophoretic assembly of carbon nanotubes on microelectrodes.
Networks of single-walled carbon nanotubes were assembled onto microelectrodes by dielectrophoresis. The dependence of the obtained networks on several assembly parameters such as bias voltage, field application time, frequency, electrode geometry and the nanotube solvent were investigated both structurally and electrically. Reproducible differences in morphological and electrical properties were observed for the parameters investigated. Application of a bias voltage above 10 V for more than 30 seconds with nanotubes in an SDS solution, resulted in dense networks with a relatively low resistance in the 10 komega regime. On the other hand, individual nanotubes and bundles were assembled with lower voltages applied for less than 10 seconds and with other nanotubes solutions. The experimental results were combined with theoretical calculations in order to find a geometry and voltage independent threshold field for the successful assembly of nanotubes between electrodes using dielectrophoresis.


Identification of new genetic risk variants for type 2 diabetes.
Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r(2)<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49 × 10(-9) (1.15, 1.10-1.20), 1.45 × 10(-8) (1.13, 1.08-1.18), and 7.14 × 10(-7) (1.13, 1.08-1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.


Effects of quercetin supplementation on markers of muscle damage and inflammation after eccentric exercise.
The flavonoid quercetin is purported to have potent antioxidant and anti-inflammatory properties. This study examined if quercetin supplementation attenuates indicators of exercise-induced muscle damage in a double-blind laboratory study. Thirty healthy subjects were randomized to quercetin (QU) or placebo (PL) supplementation and performed 2 separate sessions of 24 eccentric contractions of the elbow flexors. Muscle strength, soreness, resting arm angle, upper arm swelling, serum creatine kinase (CK) activity, plasma quercetin (PQ), interleukin-6 (IL-6), and C-reactive protein (CRP) were assessed before and for 5 d after exercise. Subjects then ingested nutrition bars containing 1,000 mg/d QU or PL for 7 d before and 5 d after the second exercise session, using the opposite arm. PQ reached 202 ± 52 ng/ml after 7 d of supplementation and remained elevated during the 5-d postexercise recovery period (p < .05). Subjects experienced strength loss (peak = 47%), muscle soreness (peak = 39 ± 6 mm), reduced arm angle (-7° ± 1°), CK elevations (peak = 3,307 ± 1,481 U/L), and arm swelling (peak = 11 ± 2 mm; p < .0001), indicating muscle damage and inflammation; however, differences between treatments were not detected. Eccentric exercise did not alter plasma IL-6 (peak = 1.9 pg/ml) or CRP (peak = 1.6 mg/L) relative to baseline or by treatment. QU supplementation had no effect on markers of muscle damage or inflammation after eccentric exercise of the elbow flexors.


Comparison of Spontaneous Motor Tempo during Finger Tapping, Toe Tapping and Stepping on the Spot in People with and without Parkinson's Disease.
Spontaneous motor tempo (SMT), observed in walking, tapping and clapping, tends to occur around 2 Hz. Initiating and controlling movement can be difficult for people with Parkinson's (PWP), but studies have not identified whether PWP differ from controls in SMT. For community-based interventions, e.g. dancing, it would be helpful to know a baseline SMT to optimize the tempi of cued activities. Therefore, this study compared finger tapping (FT), toe tapping (TT) and stepping 'on the spot' (SS) in PWP and two groups of healthy controls [age-matched controls (AMC) and young healthy controls (YHC)], as SMT is known to change with age. Participants (PWP; n = 30, AMC; n = 23, YHC; n = 35) were asked to tap or step on the spot at a natural pace for two trials lasting 40 seconds. The central 30 seconds were averaged for analyses using mean inter-onset intervals (IOI) and coefficient of variation (CoV) to measure rate and variability respectively. PWP had faster SMT than both control groups, depending on the movement modality: FT, F(2, 87) = 7.92, p < 0.01 (PWP faster than YHC); TT, F(2, 87) = 4.89, p = 0.01 (PWP faster than AMC); and SS, F(2, 77) = 3.26, p = 0.04 (PWP faster than AMC). PWP had higher CoV (more variable tapping) than AMC in FT only, F(2, 87) = 4.10, p = 0.02. This study provides the first direct comparison of SMT between PWP and two control groups for different types of movements. suggest SMT is generally faster in PWP than control groups, and more variable when measured with finger tapping compared to stepping on the spot.


B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease.
Interactions of B7H1 (programmed death ligand 1 [PD-L1]) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report in this study that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1(-/-)CD4(+) conventional T (Tcon) cells in WT and B7H1(-/-) recipients revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction. This observation was recapitulated in an in vitro MLR assay. 2) Specific blockade of the B7H1/CD80 axis by anti-B7H1 mAb reduces WT-alloreactive Tcon cell proliferation, IL-2 production, expression of PD-1, and apoptosis, resulting in worsening GVHD. In contrast, specific blockade of B7H1/CD80 interaction reduces donor PD-1(-/-) Tcon cell proliferation without an impact on apoptosis, resulting in ameliorating GVHD. 3) B7H1 fused to an Ig Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1-Ig plasmid, ameliorates GVHD by augmenting proliferation and apoptosis of WT- alloreactive Tcon cells. Conversely, B7H1-Ig treatment has no impact on apoptosis but augments PD-1(-/-) T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 interaction augments Tcon cell proliferation, IL-2 production, and expression of PD-1, which leads to increased apoptosis mediated by the B7H1/PD-1 pathway. Additionally, by engaging both PD-1 and CD80, B7H1-Ig can be a powerful therapeutic reagent for downregulating the T cell immune response.


Do Orthopedic Surgeons or Neurosurgeons Detect More Hip Disorders in Patients with Hip-Spine Syndrome? A Nationwide Database Study.
Background: Disorders of the hip and lumbar spine can create similar patterns of pain and dysfunction. It is unknown whether all surgeons, regardless of orthopedic or neurosurgery training, investigate and diagnose concurrent hip and spine pathology at the same rate. Methods: Data were retrieved from Taiwan's National Health Insurance Research Database (NHIRD). Enrolled patients were stratified into hip and spine surgery at the same admission (Both), hip surgery before spine surgery (HS), or spine surgery before hip surgery (SH). The SH group was further subdivided based on whether spine surgery was performed by an orthopedic surgeon (OS) or neurosurgeon (NS), and differences in preoperative radiographic examinations and diagnoses were collected and analyzed. Results: In total, 1824 patients received lumbar spine surgery within 1 year before or after hip replacement surgery. Of these, 103 patients had spine and hip surgery in the same admission (Both), 1290 patients had spine surgery before hip surgery (SH), and 431 patients had hip surgery before spine surgery (HS). In the SH group, patients were categorized into spine surgery by orthopedic surgeons (OS) (n = 679) or neurosurgeons (NS) (n = 522). In the SH group, orthopedic surgeons investigated hip pathology with X-rays more often (52.6% vs. 38.1%, p < 0.001) and diagnosed more cases of hip disease (43.6% vs. 28.9%, p < 0.001) than neurosurgeons. Conclusions: Of patients in Taiwan's NHIRD who had concurrent surgical degenerative hip and lumbar spine disorders who had spine surgery before hip surgery, orthopedic surgeons obtained hip images and made hip-related diagnoses more frequently than did neurosurgeons.


Long-term study of mortality and vascular complications in juvenile-onset (type I) diabetes.
A cohort of 372 insulin-dependent diabetic children, diagnosed between October 1949 and December 1960, were followed-up until December 1976 by the same team of physicians. At the time of diagnosis all patients were under 16 yr of age and were given standardized treatment which did not change from 1949 to 1976. The therapy consisted of daily insulin adjustment based on clinical assessment, the degree of physical activity, and the results of semi-quantitative urine tests for sugar and ketone bodies. These tests were systematically performed before breakfast, lunch, and dinner. Diet was normal, unmeasured, rich in carbohydrates (approximately 60%), and quantitatively unrestricted unless the patient was overweight. Rates for mortality and for the principal complications among this cohort were computed by the actuarial method. During the 26 yr of study, 26 deaths occurred, 16 of which were directly connected with diabetes. After 16 yr of follow-up, rates of proteinuria and hypertension were 4% and 2.1% respectively. The incidence of retinopathy reached 27%, including 1.5% proliferative retinopathy. After 26 yr, the rates rose to 14% for proteinuria, 16% for hypertension, and 85% for retinopathy, including 18% in the proliferative phase.


Patterns of diversity and abundance of carrion insect assemblages in the Natural Park "Hoces del Río Riaza" (central Spain).
The patterns of diversity and abundance of the carrion insect species in the different habitats of the Natural Park "Hoces del Río Riaza" (central Spain) were studied with the use of carrion-baited traps. Representativeness of the inventories was assessed with the calculation of randomized species richness curves and nonparametric estimators. Coleoptera families, Silphidae and Dermestidae, and Diptera families, Calliphoridae and Muscidae, were dominant in every sampling habitat, but differences in the patterns of diversity and abundance were found. Lusitanian oakwood and riparian forest were the most diverse habitats with high abundance of saprophagous species, whereas more open (i.e., exposed to continuous sunlight during the day) habitats showed lower diversity values and a different species composition and distribution of species abundance, favoring thermophilous species and necrophagous species with high tolerance to different environmental conditions. Differences in the bioclimatical features of the sampled habitats are suggested to explain the composition and diversity of the carrion insect assemblages in different environments.


What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of 'centralized' pain?
Research suggests that fibromyalgia is a central, widespread pain syndrome supported by a generalized disturbance in central nervous system pain processing. Over the past decades, multiple lines of research have identified the locus for many functional, chronic pain disorders to the central nervous system, and the brain. In recent years, brain neuroimaging techniques have heralded a revolution in our understanding of chronic pain, as they have allowed researchers to non-invasively (or minimally invasively) evaluate human patients suffering from various pain disorders. While many neuroimaging techniques have been developed, growing interest in two specific imaging modalities has led to significant contributions to chronic pain research. For instance, resting functional connectivity magnetic resonance imaging (fcMRI) is a recent adaptation of fMRI that examines intrinsic brain connectivity - defined as synchronous oscillations of the fMRI signal that occurs in the resting basal state. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive magnetic resonance imaging technique that can quantify the concentration of multiple metabolites within the human brain. This review will outline recent applications of the complementary imaging techniques - fcMRI and 1H-MRS - to improve our understanding of fibromyalgia pathophysiology and how pharmacological and non-pharmacological therapies contribute to analgesia in these patients. A better understanding of the brain in chronic pain, with specific linkage as to which neural processes relate to spontaneous pain perception and hyperalgesia, will greatly improve our ability to develop novel therapeutics. Neuroimaging will play a growing role in the translational research approaches needed to make this a reality.


Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6β-Hydroxylation.
CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone). The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment. The kinetic parameters of midazolam and testosterone hydroxylation by wild-type CYP3A4 and 29 CYP3A4 variants (K m , k cat , and catalytic efficiency) were determined, and the causes of their kinetic differences were evaluated by three-dimensional structural modeling. Our findings offer insight into the mechanism underlying interindividual differences in CYP3A4-dependent drug metabolism. Moreover, our results provide guidance for improving drug administration protocols by considering the information on CYP3A4 genetic polymorphisms. SIGNIFICANCE STATEMENT: CYP3A4 metabolizes more than 30% of clinically used drugs. Interindividual differences in drug efficacy and adverse-effect rates have been linked to ethnicity-specific differences in CYP3A4 gene variants in Asian populations, including Japanese individuals, indicating the presence of CYP3A4 polymorphisms resulting in the increased expression of loss-of-function variants. This study detected alterations in CYP3A4 activity due to amino acid substitutions by assessing the enzymatic activities of coding variants for two representative CYP3A4 substrates.


Wavelength-dependent diffraction patterns from a liquid crystal display.
Liquid crystal displays (LCDs) are invaluable for a variety of optical applications, including the encoding of programmable diffractive optical elements. The pixel structure in these devices produces a set of diffracted orders of which the central order is the strongest. In most devices that we have examined, the intensity distribution of the diffraction pattern is independent of the wavelength of the illuminating light. Recently we have been examining the performance of LCDs having very small pixel sizes. We compare results for two devices from the same manufacturer. One of them exhibits the normal behavior. For the other, we find surprisingly strong wavelength dependence. The diffraction pattern varies from having most of the energy in the zero order for long wavelengths to having the energy distributed among 50-60 orders as the wavelength decreases. We attribute this behavior to a phase structure over each pixel. We analyze this behavior using a simple two-dimensional model that qualitatively explains the phenomenon. These results can be viewed in two ways--on the positive side this behavior might lead to optical logic or fan-out applications. On the negative side, there is less intensity available in the normally used zero order.


Protein Oxidation in Plant Protein-Based Fibrous Products: Effects of Encapsulated Iron and Process Conditions.
Plant protein-based fibrous structures have recently attracted attention because of their potential as meat replacer formulations. It is, however, unclear how the process conditions and fortification with micronutrients may affect the chemical stability of such products. Therefore, we aimed to investigate the effects of process conditions and the incorporation of iron (free and encapsulated) on protein oxidation in a soy protein-based fibrous product. First, the physicochemical stability of iron-loaded pea protein particles, used as encapsulation systems, was investigated when exposed to 100 or 140 °C. Second, protein oxidation was measured in the iron-fortified soy protein-based fibrous structures made at 100 or 140 °C. Exposure to high temperatures increased the carbonyl content in pea protein particles. The incorporation of iron (free or encapsulated) did not affect carbonyl content in the fibrous product, but the process conditions for making such products induced the formation of carbonyls to a fairly high extent.


Misconceptions regarding the adequacy of best medical intervention alone for asymptomatic carotid stenosis.
Medical intervention (risk factor identification, lifestyle coaching, and medication) for stroke prevention has improved significantly. It is likely that no more than 5.5% of persons with advanced asymptomatic carotid stenosis (ACS) will now benefit from a carotid procedure during their lifetime. However, some question the adequacy of medical intervention alone for such persons and propose using markers of high stroke risk to intervene with carotid endarterectomy (CEA) and/or carotid angioplasty/stenting (CAS). Our aim was to examine the scientific validity and implications of this proposal. We reviewed the evidence for using medical intervention alone or with additional CEA or CAS in persons with ACS. We also reviewed the evidence regarding the validity of using commonly cited makers of high stroke risk to select such persons for CEA or CAS, including markers proposed by the European Society for Vascular Surgery in 2017. Randomized trials of medical intervention alone versus additional CEA showed a definite statistically significant CEA stroke prevention benefit for ACS only for selected average surgical risk men aged less than 75 to 80 years with 60% or greater stenosis using the North American Symptomatic Carotid Endarterectomy Trial criteria. However, the most recent measurements of stroke rate with ACS using medical intervention alone are overall lower than for those who had CEA or CAS in randomized trials. Randomized trials of CEA versus CAS in persons with ACS were underpowered. However, the trend was for higher stroke and death rates with CAS. There are no randomized trial results related to comparing current optimal medical intervention with CEA or CAS. Commonly cited markers of high stroke risk in relation to ACS lack specificity, have not been assessed in conjunction with current optimal medical intervention, and have not been shown in randomized trials to identify those who benefit from a carotid procedure in addition to current optimal medical intervention. Medical intervention has an established role in the current routine management of persons with ACS. Stroke risk stratification studies using current optimal medical intervention alone are the highest research priority for identifying persons likely to benefit from adding a carotid procedure.


An In Vitro Comparison of the Neurotrophic and Angiogenic Activity of Human and Canine Adipose-Derived Mesenchymal Stem Cells (MSCs): Translating MSC-Based Therapies for Spinal Cord Injury.
The majority of research into the effects of mesenchymal stem cell (MSC) transplants on spinal cord injury (SCI) is performed in rodent models, which may help inform on mechanisms of action, but does not represent the scale and wound heterogeneity seen in human SCI. In contrast, SCI in dogs occurs naturally, is more akin to human SCI, and can be used to help address important aspects of the development of human MSC-based therapies. To enable translation to the clinic and comparison across species, we have examined the paracrine, regenerative capacity of human and canine adipose-derived MSCs in vitro. MSCs were initially phenotyped according to tissue culture plastic adherence, cluster of differentiation (CD) immunoprofiling and tri-lineage differentiation potential. Conditioned medium (CM) from MSC cultures was then assessed for its neurotrophic and angiogenic activity using established cell-based assays. MSC CM significantly increased neuronal cell proliferation, neurite outgrowth, and βIII tubulin immunopositivity. In addition, MSC CM significantly increased endothelial cell migration, cell proliferation and the formation of tubule-like structures in Matrigel assays. There were no marked or significant differences in the capacity of human or canine MSC CM to stimulate neuronal cell or endothelial cell activity. Hence, this study supports the use of MSC transplants for canine SCI; furthermore, it increases understanding of how this may subsequently provide useful information and translate to MSC transplants for human SCI.


Detection of trypanosomes in small ruminants and pigs in western Kenya: important reservoirs in the epidemiology of sleeping sickness?
Trypanosomosis is a major impediment to livestock farming in sub-Saharan Africa and limits the full potential of agricultural development in the 36 countries where it is endemic. In man, sleeping sickness is fatal if untreated and causes severe morbidity. This study was undertaken in western Kenya, an area that is endemic for both human and livestock trypanosomosis. While trypanosomosis in livestock is present at high levels of endemicity, sleeping sickness occurs at low levels over long periods, interspersed with epidemics, underscoring the complexity of the disease epidemiology. In this study, we sought to investigate the prevalence of trypanosomes in small ruminants and pigs, and the potential of these livestock as reservoirs of potentially human-infective trypanosomes. The study was undertaken in 5 villages, to address two key questions: i) are small ruminants and pigs important in the transmission dynamics of trypanosomosis? and ii), do they harbour potentially human infective trypanosomes? Answers to these questions are important in developing strategies for the control of both livestock and human trypanosomosis. Eighty-six animals, representing 21.3% of the 402 sampled in the 5 villages, were detected as positive by PCR using a panel of primers that identify trypanosomes to the level of the species and sub-species. These were categorised as 23 (5.7%) infections of T. vivax, 22 (5.5%) of T. simiae, 21 (5.2%) of the T. congolense clade and 20 (5.0%) of T. brucei ssp. The sheep was more susceptible to trypanosome infection as compared to goats and pigs. The 20 T. brucei positive samples were evaluated by PCR for the presence of the Serum Resistance Associated (SRA) gene, which has been linked to human infectivity in T. b. rhodesiense. Three samples (one pig, one sheep and one goat) were found to have the SRA gene. These results suggest that sheep, goats and pigs, which are kept alongside cattle, may harbour human-infective trypanosomes. We conclude that all livestock kept in this T. b. rhodesiense endemic area acquire natural infections of trypanosomes, and are therefore important in the transmission cycle. Sheep, goats and pigs harbour trypanosomes that are potentially infective to man. Hence, the control of trypanosomosis in these livestock is essential to the success of any strategy to control the disease in man and livestock.


Immunological changes in response to exercise: influence of age, puberty, and gender.
This study tested the hypothesis that exercise-induced perturbation and recovery of the immune system would vary with age, puberty, and gender in healthy children and adolescents. Twelve-year-old girls (YG; N = 14) and boys (YB; N = 20), and 14-yr-old girls (OG; N = 11) and boys (OB; N = 13) cycled for 60 min at 70% VO2max. Blood was collected before, at 30 and 60 min of exercise, and at 30 and 60 min of recovery to measure total leukocytes, leukocyte and lymphocyte subsets, and cytokines. Age and pubertal (Tanner stage) effects within genders and gender effects within age and pubertal groups were determined. Exercise-induced increases in lymphocytes, CD3-CD16+CD56+ counts, and IL-6 were approximately 83, 90, and 390% greater in OG versus YG (P < 0.05). Recovery leukocytosis and neutrophilia were approximately 56 and 35% greater in OB versus YB (P < 0.05). Pubertal stage did not have a statistically significant influence on responses in girls, but the lowest pubertal stage consistently showed smaller changes in lymphocytes and CD3-CD16+CD56+ counts. Recovery neutrophilia was approximately 120% greater in postpubertal boys versus prepubertal or pubertal boys (P < 0.05). Responses of lymphocytes and CD3-CD16+CD56+ counts, respectively, were approximately 120 and 82% greater in OG versus OB (P < 0.05), with no differences between YG and YB. Exercise-induced increases in total leukocytes, lymphocytes, and CD3-CD16+CD56+ counts were at least 35% greater in girls versus boys of similar pubertal status (P < 0.05). Regardless of age, puberty, or gender, IL-8 levels were significantly higher during recovery versus rest (P < 0.05). These results highlight the need to control for age, puberty, and gender when interpreting immunologic responses to exercise in a pediatric population.


Post-herpetic trigeminal neuralgia treated with deep brain stimulation.
Post-herpetic neuralgic affects up to 20% of patients after an attack of trigeminal Herpes Zoster infection. Past medical and surgical treatments have been unrewarding. We report the successful treatment of such a case with deep brain stimulation into the region of the contralateral periventricular grey area (PVG) and ventral posterior lateral thalamic nucleus (VPL).


Cracked mercury dental amalgam as a possible cause of fever of unknown origin: a case report.
Sudden fever of unknown origin is quite a common emergency and may lead to hospitalization. A rise in body temperature can be caused by infectious diseases and by other types of medical condition. This case report is of a woman who had fever at night for several days and other clinical signs which were likely related to cracked dental mercury amalgam. A healthy women developed fever many days after had cracked a mercury dental amalgam filling. Blood tests evidenced increased erythrocyte sedimentation rate, anemia and elevated white cell count; symptoms were headache and palpitations. Blood tests and symptoms normalized within three weeks of removal of the dental amalgam. This case highlights the possible link between mercury vapor exposure from cracked dental amalgam and early activation of the immune system leading to fever of unknown origin.


Genes involved in regulation of stem cell properties: studies on their expression in a small cohort of neuroblastoma patients.
Cancer stem cells have been isolated from many tumors. Several evidences prove that neuroblastoma contains its own stem cell-like cancer cells. We chose to analyze 20 neuroblastoma tumor samples in the expression of 13 genes involved in the regulation of stem cell properties to evaluate if their misregulation could have a clinical relevance. In several specimens we detected the expression of genes belonging to the OCT3/SOX2/NANOG/KLF4 core circuitry that acts at the highest level in regulating stem cell biology. This result is in agreement with studies showing the existence of malignant stem cells in neuroblastoma. We also observed differences in the expression of some stemness-related genes that may be useful for developing new prognostic analyses. In fact, preliminary data suggests that the presence/absence of UTF1 along with differences in BMI1 mRNA levels could distinguish low grade neuroblastomas from IV stage tumors.


Evidence of a green luminescence band related to surface flaws in high purity silica glass.
Using luminescence confocal microscopy under 325 nm laser excitation, we explore the populations of defects existing in or at the vicinity of macroscopic surface flaws in fused silica. We report our luminescence results on two types of surface flaws: laser damage and indentation on fused silica polished surfaces. Luminescence cartographies are made to show the spatial distribution of each kind of defect. Three bands, centered at 1.89 eV, 2.75 eV and 2.25 eV are evidenced on laser damage and indentations. The band centered at 2.25 eV was not previously reported in photo luminescence experiments on indentations and pristine silica, for excitation wavelengths of 325 nm or larger. The luminescent objects, expected to be trapped in sub-surface micro-cracks, are possibly involved in the first step of the laser damage mechanism when fused silica is enlightened at 351 nm laser in nanosecond regime.


Machine learning mortality classification in clinical documentation with increased accuracy in visual-based analyses.
The role of machine learning on clinical documentation for predictive outcomes remains undefined. We aimed to compare three neural networks on inpatient providers' notes to predict mortality in neonatal hypoxic-ischaemic encephalopathy (HIE). Using Children's Hospitals Neonatal Database, non-anomalous neonates with HIE treated with therapeutic hypothermia were identified at a single-centre. Data were linked with the initial seven days of documentation. Exposures were derived using the databases and applying convolutional and two recurrent neural networks. The primary outcome was mortality. The predictive accuracy and performance measures for models were determined. The cohort included 52 eligible infants. Most infants survived (n = 36, 69%) and 23 had severe HIE (44%). Neural networks performed above baseline and differed in their median accuracy for predicting mortality (P = .0001): recurrent models with long short-term memory 69% (25th , 75th percentile 65, 73%) and gated-recurrent model units 65% (62, 69%) and convolutional 72% (64, 96%). Convolutional networks' median specificity was 81% (72, 97%). The neural network models demonstrated fundamental validity in predicting mortality using inpatient provider documentation. Convolutional models had high specificity for (excluding) mortality in neonatal HIE. These findings provide a platform for future model training and ultimately tool development to assist clinicians in patient assessments and risk stratifications.


Identification and Characterization of a New Protein Isoform of Human 5-Lipoxygenase.
Leukotrienes (LTs) are inflammatory mediators that play a pivotal role in many diseases like asthma bronchiale, atherosclerosis and in various types of cancer. The key enzyme for generation of LTs is the 5-lipoxygenase (5-LO). Here, we present a novel putative protein isoform of human 5-LO that lacks exon 4, termed 5-LOΔ4, identified in cells of lymphoid origin, namely the Burkitt lymphoma cell lines Raji and BL41 as well as primary B and T cells. Deletion of exon 4 does not shift the reading frame and therefore the mRNA is not subjected to non-mediated mRNA decay (NMD). By eliminating exon 4, the amino acids Trp144 until Ala184 are omitted in the corresponding protein. Transfection of HEK293T cells with a 5-LOΔ4 expression plasmid led to expression of the corresponding protein which suggests that the 5-LOΔ4 isoform is a stable protein in eukaryotic cells. We were also able to obtain soluble protein after expression in E. coli and purification. The isoform itself lacks canonical enzymatic activity as it misses the non-heme iron but it still retains ATP-binding affinity. Differential scanning fluorimetric analysis shows two transitions, corresponding to the two domains of 5-LO. Whilst the catalytic domain of 5-LO WT is destabilized by calcium, addition of calcium has no influence on the catalytic domain of 5-LOΔ4. Furthermore, we investigated the influence of 5-LOΔ4 on the activity of 5-LO WT and proved that it stimulates 5-LO product formation at low protein concentrations. Therefore regulation of 5-LO by its isoform 5-LOΔ4 might represent a novel mechanism of controlling the biosynthesis of lipid mediators.


Cardiopulmonary response to sodium fluoride infusion in the dog.
Because humans are occasionally acutely exposed to high levels of fluoride (F-), and cardiac and especially pulmonary tissue accumulate higher concentrations of F- than do the other soft tissues, the present study was undertaken to investigate the effects of acute exposure to toxic plasma levels of F- on cardiopulmonary hemodynamics. Anesthetized dogs were instrumented with right and left cardiac catheters to measure pulmonary arterial and wedge pressures, left ventricular and aortic pressures, left ventricular dP/dt, and cardiac output. An intravenous loading dose of NaF followed by a 3-h infusion produced a plasma F- level of 800 microM in the "low" group of 6 animals, and 1300 microM in the "high" group. The mean pulmonary arterial pressure peaked at 1 h, 83% above preinfusion values in the high group, while that of the low group attained the same level by the end of the infusion period. Impaired pulmonary gas exchange, as indicated by an increased alveolar-arterial PO2 gradient, occurred in half the animals, and an obvious hyperventilation was reflected in a decreased PCO2 value; there was no change in arterial pH, ECG T-wave peaking was common. The central venous pressure declined steadily, while there were no significant changes from controls in systemic arterial pressure, heart rate, cardiac output, or myocardial contractility (dP/dt). Thus, pulmonary hemodynamics and the systemic capacitance vessels are more affected by acute exposure to F- than is cardiac function.


Ethical principles as a guide in implementing policies for the management of food allergies in schools.
Food allergy in children is a growing public health problem that carries a significant risk of anaphylaxis such that schools and child care facilities have enacted emergency preparedness policies for anaphylaxis and methods to prevent the inadvertent consumption of allergens. However, studies indicate that many facilities are poorly prepared to handle the advent of anaphylaxis and policies for the prevention of allergen exposure are missing essential components. Furthermore, certain policies are inappropriate because they are blatantly discriminatory. This article aims to provide further guidance for school health officials involved in creating food allergy policies. By structuring policies around ethical principles of confidentiality and anonymity, fairness, avoiding stigmatization, and empowerment, policy makers gain another method to support better policy making. The main ethical principles discussed are adapted from key values in the bioethics and public health ethics literatures and will be framed within the specific context of food allergy policies for schools.


ATTR amyloidosis during the COVID-19 pandemic: insights from a global medical roundtable.
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient's preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis. ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19. Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.


Frequency of New Silent MRI Lesions in Myelin Oligodendrocyte Glycoprotein Antibody Disease and Aquaporin-4 Antibody Neuromyelitis Optica Spectrum Disorder.
In multiple sclerosis, magnetic resonance imaging (MRI) new silent lesions contribute to the diagnostic criteria, have prognostic value, and are used in treatment monitoring; but in aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD), they are rare between attacks. Their frequency and their association with relapses in adults with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are still unclear. To examine the frequency and characteristics of MRI new silent lesions in MOGAD and AQP4-NMOSD. This retrospective cohort study analyzed clinical and MRI data of 404 patients with MOGAD or AQP4-NMOSD between February 1, 1994, and April 1, 2021; data were prospectively recorded on the Oxford NMOSD clinical database under follow-up. The study was conducted at the Oxford National Referral Center for NMOSD. Participants included patients with MOGAD and AQP4-NMOSD who were treated within the Oxford National NMO Specialist Service. Seropositive MOGAD and AQP4-NMOSD patients who had MRIs during attacks and the remission phase of their disease. Frequency of new silent lesions detected by either attack MRIs (during the acute clinical event) or remission MRIs (performed outside of a relapse and at least 3 months from last attack). Median time to next relapse in the presence of definite (reference MRI performed at least 4 weeks from last attack onset), probable (reference MRI performed during last attack), and no new silent lesions on remission MRIs was also evaluated. One hundred eighty-two MOGAD patients and 222 AQP4-NMOSD patients were included. Of the MOGAD patients, 113 (62%) were female, median age at onset was 28 years (range, 2-72), and median follow-up was 52 months (range, 11-253). Of the AQP4-NMOSD patients, 189 (85%) were female, median age at onset was 43 years (range, 2-82), and median follow-up was 87.5 months (range, 11-260). MOGAD patients had 296 attack MRI sessions and 167 remission MRI sessions. New attack silent lesions were found in 97 of 296 (33%) attack MRI sessions, whereas new remission silent lesions were found in 5 of 167 (3.0%) remission MRI sessions. Median time from remission scan to the next relapse in the presence of definite or probable new remission lesions was 2 months (IQR, 1-6), whereas in the absence of any new remission lesions it was 73 months (IQR, 20-104; hazard ratio, 23.86; 95% CI, 7.51-75.79; P < .001). AQP4-NMOSD patients had 470 attack MRI sessions and 269 remission MRI sessions. New attack silent lesions were detected in 88 of 470 (18.7%) attack MRI sessions, whereas new remission silent lesions were found in 7 of 269 (2.6%) remission MRI sessions. Median time from remission scan to the next relapse in the presence of definite or probable new remission lesions was 5 months (IQR, 2-6), whereas in the absence of any new remission lesions it was 85 months (IQR, 29-167; hazard ratio, 21.23; 95% CI, 8.05-53.65; P < .001). In contrast to that reported in multiple sclerosis, results of this cohort study suggest that new remission silent lesions are rare on follow-up scans in MOGAD and AQP4-NMOSD and appear to indicate a high risk of imminent relapse.


The molecular basis for the pH-dependent calcium affinity of the pattern recognition receptor langerin.
The C-type lectin receptor langerin plays a vital role in the mammalian defense against invading pathogens. Langerin requires a Ca2+ cofactor, the binding affinity of which is regulated by pH. Thus, Ca2+ is bound when langerin is on the membrane but released when langerin and its pathogen substrate traffic to the acidic endosome, allowing the substrate to be degraded. The change in pH is sensed by protonation of the allosteric pH sensor histidine H294. However, the mechanism by which Ca2+ is released from the buried binding site is not clear. We studied the structural consequences of protonating H294 by molecular dynamics simulations (total simulation time: about 120 μs) and Markov models. We discovered a relay mechanism in which a proton is moved into the vicinity of the Ca2+-binding site without transferring the initial proton from H294. Protonation of H294 unlocks a conformation in which a protonated lysine side chain forms a hydrogen bond with a Ca2+-coordinating aspartic acid. This destabilizes Ca2+ in the binding pocket, which we probed by steered molecular dynamics. After Ca2+ release, the proton is likely transferred to the aspartic acid and stabilized by a dyad with a nearby glutamic acid, triggering a conformational transition and thus preventing Ca2+ rebinding. These results show how pH regulation of a buried orthosteric binding site from a solvent-exposed allosteric pH sensor can be realized by information transfer through a specific chain of conformational arrangements.


Study of the Association of PEAR1, P2Y12, and UGT2A1 Polymorphisms with Platelet Reactivity in Response to Dual Antiplatelet Therapy in Chinese Patients.
Genetic variation is thought to contribute to considerable interindividual variability in platelet function, and there is a pressing need to identify genetic markers that can be used to predict the response to treatment. Our study investigated whether PEAR1, P2Y12, and UGT2A1 polymorphisms were associated with platelet reactivity in response to dual antiplatelet therapy in Chinese patients with acute coronary syndrome. Patients with inhibition of platelet aggregation (IPA) < 30% after treatment were classified as the high platelet reactivity (HPR) group. Patients with IPA > 30% were classified as the normal platelet reactivity (NPR) group. ADP-induced platelet aggregation was measured by thromboelastography (TEG) platelet-mapping assay. Thirteen single nucleotide polymorphisms (SNPs) of PEAR1, P2Y12 and UGT2A1 were genotyped using the Mass-ARRAY platform. Seven SNPs were significantly associated with ADP-induced platelet aggregation by univariate analysis. Major allele G at rs12041331, minor allele G at rs2644592, minor allele C at rs11264580, and minor allele C at rs11249454 were significantly associated with HPR, whereas minor allele T at rs57731889, minor allele A at rs16863356, and minor allele T at rs7634096 were significantly associated with NPR. The mean IPA was significantly lower in patients suffering recurrent ischemic events than in patients without recurrent events in our study (p = 0.048). Our findings suggest that PEAR1, P2Y12, and UGT2A1 genetic variants may be potential biomarkers that can be used to guide clinical applications of clopidogrel and aspirin in Chinese patients.


Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells.
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits. Here, we used in vitro [2D, invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question. Colon and breast cancer cells were identified where CAV1 levels were low due to epigenetic suppression and could be reverted by treatment with the methyltransferase inhibitor 5'-azacytidine. Exposure of these cells to anti-neoplastic drugs for short periods of time (24-48 h) increased CAV1 expression through ROS production and MEK/ERK activation. In colon cancer cells, increased CAV1 expression enhanced migration and invasion in vitro via pathways requiring Src-family kinases, as well as Rac-1 activity. Finally, elevated CAV1 expression in colon cancer cells following exposure in vitro to sub-cytotoxic drug concentrations increased their metastatic potential in vivo. Therefore exposure of cancer cells to anti-neoplastic drugs at non-lethal drug concentrations induces signaling events and changes in transcription that favor CAV1-dependent migration, invasion and metastasis. Importantly, this may occur in the absence of selection for drug-resistance.


Isoxyl aerosols for tuberculosis treatment: preparation and characterization of particles.
Isoxyl is a potent antituberculosis drug effective in treating various multidrug-resistant strains in the absence of known side effects. Isoxyl has been used exclusively, but infrequently, via the oral route and has exhibited very poor and highly variable bioavailability due to its sparing solubility in water. These properties resulted in failure of some clinical trials and, consequently, isoxyl's use has been limited. Delivery of isoxyl to the lungs, a major site of Mycobacterium tuberculosis infection, is an attractive alternative route of administration that may rescue this abandoned drug for a disease that urgently requires new therapies. Particles for pulmonary delivery were prepared by antisolvent precipitation. Nanofibers with a width of 200 nm were obtained by injecting isoxyl solution in ethanol to water at a volume ratio of solvent to antisolvent of 1:5. Based on this preliminary result, a well-controlled method, involving nozzle mixing, was employed to prepare isoxyl particles. All the particles were 200 to 400 nm in width but had different lengths depending on properties of the solvents. However, generating these nanoparticles by simultaneous spray drying produced isoxyl microparticles (Feret's diameter, 1.19-1.77 microm) with no discernible nanoparticle substructure. The bulking agent, mannitol, helped to prevent these nanoparticles from agglomeration during process and resulted in nanoparticle aggregates in micron-sized superstructures. Future studies will focus on understanding difference of these isoxyl microparticles and nanoparticles/nanoparticle aggregates in terms of in vivo disposition and efficacy.


Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice.
The role of interleukin-6 (IL-6) in the pathogenesis of toxoplasmic encephalitis (TE) was examined by using IL-6-targeted mutant (IL-6(-/-)) mice. At 4 and 8 weeks after infection with the ME49 strain of Toxoplasma gondii, significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of IL-6(-/-) mice than in those of control mice. Large areas of necrosis were observed only in brains of IL-6(-/-) mice. Tachyzoites were frequently detected in the areas of necrosis, suggesting that necrosis was caused by proliferation of the parasite. These results indicate that IL-6 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in brains of infected mice. Whereas in brains of control mice, large numbers of inflammatory cells were always observed in areas where tachyzoites were detected, in brains of IL-6(-/-) mice, only small numbers of inflammatory cells were observed in many areas with tachyzoites. Lymphocyte preparations isolated from brains of infected control mice had significantly higher ratios of gamma/delta T cells and CD4+ alpha/beta T cells but lower ratios of CD8+ alpha/beta T cells compared to those of infected IL-6(-/-) mice. There were no differences in the ratios of these T-cell subsets in spleens between these mice. The amounts of mRNA for gamma interferon (IFN-gamma) detected by reverse transcriptase PCR were significantly smaller in brains of IL-6(-/-) mice than in those of control mice, whereas amounts of IL-10 mRNA were greater in the former than in the latter. IL-6 mRNA was detected only in infected control mice. The protective activity of IL-6 against development of TE appears to be through its ability to stimulate IFN-gamma production and induce infiltration and accumulation of different T-cell subsets in brains of infected mice.


Willingness to donate genomic and other medical data: results from Germany.
This paper reports findings from Germany-based participants in the "Your DNA, Your Say" study, a collaborative effort among researchers in more than 20 countries across the world to explore public attitudes, values and opinions towards willingness to donate genomic and other personal data for use by others. Based on a representative sample of German residents (n = 1506) who completed the German-language version of the survey, we found that views of genetic exceptionalism were less prevalent in the German-language arm of the study than in the English-language arm (43% versus 52%). Also, people's willingness to make their data available for research was lower in the German than in the English-language samples of the study (56% versus 67%). In the German sample, those who were more familiar with genetics, and those holding views of genetic exceptionalism were more likely to be willing to donate data than others. We explain these findings with reference to the important role that the "right of informational self-determination" plays in German public discourse. Rather than being a particularly strict interpretation of privacy in the sense of a right to be left alone, the German understanding of informational self-determination bestows on each citizen the responsibility to carefully consider how their personal data should be used to protect important rights and to serve the public good.


Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa.
Reactive oxygen metabolites are known to disrupt sperm-oocyte fusion, sperm movement, and DNA integrity; however, the relative sensitivities of these elements to oxidative stress are unknown. In this study these factors were assessed in human spermatozoa exposed to increasing levels of oxidative stress achieved through the stimulation of endogenous oxidant generation with NADPH or direct exposure to hydrogen peroxide. At low levels of oxidative stress, DNA fragmentation was significantly reduced while the rates of sperm-oocyte fusion were significantly enhanced. As the level of oxidative stress increased, the spermatozoa exhibited significantly elevated levels of DNA damage (p < 0.001) and yet continued to express an enhanced capacity for sperm-oocyte fusion. At the highest levels of oxidative stress, extremely high rates of DNA fragmentation were observed but the spermatozoa exhibited a parallel loss in their capacities for movement and oocyte fusion. These studies emphasize how redox mechanisms can either enhance or disrupt the functional and genomic integrity of human spermatozoa depending on the intensity of the oxidative stimulus. Because these qualities are affected at different rates, spermatozoa exhibiting significant DNA damage are still capable of fertilizing the oocyte. These results may have long-term implications for the safety of assisted conception procedures in cases associated with oxidative stress.


Multidrug-resistant tuberculosis that required 2 years for diagnosis.
Isoniazid (H) or rifampicin (R) mono-resistant disease can be treated easily and effectively with first-line drugs, while combined H and R resistance (ie, multidrug-resistant tuberculosis (MDRTB)) requires treatment with at least four agents, including a quinolone and an injectable agent. Drug-resistant Mycobacterium tuberculosis strains are reported to be extremely difficult to cultivate invitro. The authors report a case of MDRTB that required 2 years for diagnosis, and was detected only in sputum culture on solid medium. Physicians should consider MDRTB if TB is suspected but pathogens are not detected.


Simplifying consent for HIV testing is associated with an increase in HIV testing and case detection in highest risk groups, San Francisco January 2003-June 2007.
Populations at highest risk for HIV infection face multiple barriers to HIV testing. To facilitate HIV testing procedures, the San Francisco General Hospital Medical Center eliminated required written patient consent for HIV testing in its medical settings in May 2006. To describe the change in HIV testing rates in different hospital settings and populations after the change in HIV testing policy in the SFDH medical center, we performed an observational study using interrupted time series analysis. Data from all patients aged 18 years and older seen from January 2003 through June 2007 at the San Francisco Department of Public Health (SFDPH) medical care system were included in the analysis. The monthly HIV testing rate per 1000 had patient-visits was calculated for the overall population and stratified by hospital setting, age, sex, race/ethnicity, homelessness status, insurance status and primary language. By June 2007, the average monthly rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17-6.60, p<0.001) over the number predicted if the policy change had not occurred (representing a 44% increase). The monthly average number of new positive HIV tests increased from 8.9 (CI, 6.3-11.5) to 14.9 (CI, 10.6-19.2, p<0.001), representing a 67% increase. Although increases in HIV testing were seen in all populations, populations at highest risk for HIV infection, particularly men, the homeless, and the uninsured experienced the highest increases in monthly HIV testing rates after the policy change. The elimination of the requirement for written consent in May 2006 was associated with a significant and sustained increase in HIV testing rates and HIV case detection in the SFDPH medical center. Populations facing the higher barriers to HIV testing had the highest increases in HIV testing rates and case detection in response to the policy change.


'Children will always be children': exploring perceptions and experiences of HIV-positive children who may not take their treatment and why they may not tell.
HIV-positive children and young people may face substantial social barriers to maintaining appropriate levels of adherence to antiretroviral therapy (ART) during childhood and adolescence. In this paper, we focus on these children's voices and the challenges they face growing up living with HIV in Uganda. Drawing on retrospective self-reports of 26 children living with HIV, taking ART and attending a clinic in central Uganda, we examine the reasons for non-adherence to ART among children and why they may not report when they miss their treatment. The reasons why children may not take their treatment are socially complex and similar to adult experiences and the struggles people face in adhering to life-long treatment of a condition that is stigmatised. Children are aware of the stigma that surrounds their condition and respond to adults who stress the importance of keeping their condition secret. The causes of non-adherence are not necessarily due to forgetting, but because of concerns about secrecy and children deliberately avoiding being seen taking their treatment, for example, to avoid identification. Children's desire to maintain and protect relationships explains non-adherence as well as their failure to report it to adults. The clinical focus on exemplary adherence makes it more difficult for healthcare workers to discuss with children the social challenges that they may experience in taking treatment every day. If adults could approach non-adherence with greater empathy, recognising that children too are juggling treatment taking and social concerns then children may feel more willing to tell them about missed doses. Their poor adherence is not an inevitable element of the experience of being a child, but rather, like many adults, a substantial challenge if they are to manage their life-long treatment.


Treatment of hepatic venous outflow obstruction after piggyback liver transplantation.
To evaluate retrospectively the endovascular management of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation. The study was performed with the approval and under the guidelines of the institutional review board and complied with the Health Insurance Portability and Accountability Act. Informed consent from patients was not required by the institutional review board for this retrospective study. From 1995 to 2003, 13 patients (eight male, five female), including 12 adults and one adolescent (age range, 14-67 years; median age, 52 years), underwent endovascular treatment of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation. Patients gave informed consent for all procedures. Eleven patients received whole livers, and two received living-related donor right liver lobes. Four underwent repeat piggyback orthotopic liver transplantation prior to intervention. Primary stent placement was performed in 12 patients. One patient refused primary stent placement and chose venoplasty alone, but required a stent 5 months later. Short balloon-expandable stents (mean diameter, 14.6 mm +/- 1.1 [standard deviation]) were used to minimize jailing of branch vessels and to resist recoil. Pre- and post-procedural pressure gradients were measured. Follow-up included venography, cross-sectional imaging, and laboratory tests. The Wilcoxon signed rank test or the sign test was performed to compare pre- and post-procedural pressure gradients, body weights, and laboratory values. Technical success (pressure gradient < or = 3 mm Hg) was achieved in 13 of 13 patients, and clinical success, in 12 of 13. Mean pre- and post-procedural pressure gradients were 13.0 mm Hg +/- 1.4 and 0.8 mm Hg +/- 0.3. Mean interval from transplantation to intervention was 348 days +/- 159. Mean follow-up was 678 days (range, 16-2880 days). Technical success did not result in clinical improvement in one patient. Biopsy demonstrated severe hepatic necrosis, likely from prolonged venous congestion, and the patient required repeat transplantation. Only one patient required reintervention for stent migration, and no other complications occurred. No significant restenosis was encountered after stent placement. Hepatic venous outflow obstruction is an uncommon but potentially fatal complication of piggyback orthotopic liver transplantation. Endovascular treatment with balloon-expandable stents is effective, safe, and apparently durable.


Effects of dental magnification lenses on indirect vision: a pilot study.
The purpose of this pilot study was to evaluate the effect of magnification lenses on the indirect vision skills of dental hygiene students. This pilot study examined the accuracy and efficiency of dental hygiene students' indirect vision skills while using traditional safety lenses and magnification lenses. The sample was comprised of 14 students in their final semester of a dental hygiene program. A crossover study approach was utilized, with each participant randomly assigned to a specific order of eyewear. The study included evaluation of each participant taking part in 2 separate clinical sessions. During the first session, each participant completed a clinical exercise on a dental manikin marked with 15 dots throughout the oral cavity while wearing the randomly as signed eyewear, and then completed a similar exercise on a differently marked dental manikin while wearing the randomly assigned eyewear. This procedure was repeated at a second clinical session, however, the dental manikin and eyewear pairings were reversed. Accuracy was measured on the number of correctly identified dots and efficiency was measured by the time it took to identify the dots. Perceptions of the participants' use of magnification lenses and the participants' opinion of the use of magnification lenses in a dental hygiene curriculum were evaluated using a questionnaire. Comparing the mean of the efficiency scores, students are more efficient at identifying indirect vision points with the use of magnification lenses (3 minutes, 36 seconds) than with traditional safety lenses (3 minutes, 56 seconds). Comparing the measurement of accuracy, students are more accurate at identifying indirect vision points with traditional safety lenses (84%) as com pared to magnification lenses (79%). Overall, the students report ed an increased quality of dental hygiene treatment provided in the clinical setting and an improved clinical posture while treating patients with the use of magnification lenses. This study did not produce statistically significant data to support the use of magnification lenses to enhance indirect vision skills among dental hygiene students, however, students perceived that their indirect vision skills were enhanced by the use of magnification lenses.


Subxiphoid mediastinal lymphadenectomy.
Video-assisted thoracoscopic surgery (VATS) has experience an exponential growth in lung anatomic resections. Since its beginnings in early 90s with the conventional multiport VATS to the more recent uniportal approach, a continuous search for a less invasive procedure has fueled the development of minimally invasive thoracic surgery. In this sense, subxiphoid uniportal VATS has surge as a uniportal option that avoids damage to the intercostal nerve created in a transthoracic approach. In order for this technique to become as an acceptable choice for lung cancer, oncologic principles must be respected, including a feasible and safe mediastinal lymphadenectomy. Although technically more difficult than other VATS approaches, a complete lymphadenectomy is possible in the hands of expert VATS surgeons through a subxiphoid approach.


The Cl(-) channel blocker niflumic acid releases Ca(2+) from an intracellular store in rat pulmonary artery smooth muscle cells.
The effect of the Cl- channel blockers niflumic acid (NFA), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), and anthracene-9-carboxylic acid (A-9-C), on Ca2+ signalling in rat pulmonary artery smooth muscle cells was examined. Intracellular Ca2+ concentration ([Ca2+]i) was monitored with either fura-2 or fluo-4, and caffeine was used to activate the ryanodine receptor, thereby releasing Ca2+ from the sarcoplasmic reticulum (SR). NFA and NPPB significantly increased basal [Ca2+]i and attenuated the caffeine-induced increase in [Ca2+]i. These Cl- channel blockers also increased the half-time (t1/2) to peak for the caffeine-induced [Ca2+]i transient, and slowed the removal of Ca2+ from the cytosol following application of caffeine. Since DIDS and A-9-C were found to adversely affect fura-2 fluorescence, fluo-4 was used to monitor intracellular Ca2+ in studies involving these Cl- channel blockers. Both DIDS and A-9-C increased basal fluo-4 fluorescence, indicating an increase in intracellular Ca2+, and while DIDS had no significant effect on the t1/2 to peak for the caffeine-induced Ca2+ transient, it was significantly increased by A-9-C. In the absence of extracellular Ca2+, NFA significantly increased basal [Ca2+]i, suggesting that the release of Ca2+ from an intracellular store was responsible for the observed effect. Depleting the SR with the combination of caffeine and cyclopiazonic acid prevented the increase in basal [Ca2+]i induced by NFA. Additionally, incubating the cells with ryanodine also prevented the increase in basal [Ca2+]i induced by NFA. These data show that Cl- channel blockers have marked effects on Ca2+ signalling in pulmonary artery smooth muscle cells. Furthermore, examination of the NFA-induced increase in [Ca2+]i indicates that it is likely due to Ca2+ release from an intracellular store, most probably the SR.


New exposure-based metric approach for evaluating O(3) risk to North American aspen forests.
The United States and Canada currently use exposure-based metrics to protect vegetation from O(3). Using 5 years (1999-2003) of co-measured O(3), meteorology and growth response, we have developed exposure-based regression models that predict Populus tremuloides growth change within the North American ambient air quality context. The models comprised growing season fourth-highest daily maximum 8-h average O(3) concentration, growing degree days, and wind speed. They had high statistical significance, high goodness of fit, include 95% confidence intervals for tree growth change, and are simple to use. Averaged across a wide range of clonal sensitivity, historical 2001-2003 growth change over most of the 26 Mha P. tremuloides distribution was estimated to have ranged from no impact (0%) to strong negative impacts (-31%). With four aspen clones responding negatively (one responded positively) to O(3), the growing season fourth-highest daily maximum 8-h average O(3) concentration performed much better than growing season SUM06, AOT40 or maximum 1h average O(3) concentration metrics as a single indicator of aspen stem cross-sectional area growth.


Variation in stochastic demography between and within central and peripheral regions in a widespread short-lived herb.
Analyzing intraspecific variation in population dynamics in relation to environmental factors is crucial to understand the current and future distributions of plant species. Across ranges, peripheral populations are often expected to show lower and more temporally variable vital rates than central populations, although it remains unclear how much any differences in vital rates actually contribute to differences in population growth rates. Moreover, few demographic studies accounting for environmental stochasticity have been carried out both at continental and regional scales. In this study we calculated stochastic growth rates in five central and six northern peripheral populations of the widespread shortlived herb Plantago coronopus along the Atlantic Coast in Europe. To evaluate at two spatial scales how mean values and variability of vital rates (i.e., fecundity, recruitment, survival, growth, and shrinkage) contributed to the differences in stochastic growth rates, we performed Stochastic Life Table Response Experiment (SLTRE) analyses between and within central and peripheral regions. Additionally, we searched for correlations between vital rate contributions and local environmental conditions. Lower mean values and greater variability for some vital rates in peripheral than in central populations had an overall negative but nonsignificant effect on the stochastic growth rates in the periphery. Different life cycle components accounted for differences in population growth depending on spatial scale, although recruitment was the vital rate with the highest influence both between and within regions. Interestingly, the same pattern of differentiation among populations was found within central and peripheral areas: in both regions, one group of populations displayed positive contributions of growth and shrinkage and negative contributions of recruitment and survival; the opposite pattern was found in the remaining populations. These differences in vital rate contributions among populations within regions were correlated with precipitation regime, whereas at the continental scale, differences in contribution patterns were related to temperature. Altogether, our results show how populations of P. coronopus exhibit life cycle differences that may enable the species to persist in locations with widely varying environmental conditions. This demographic flexibility may help to explain the success of widespread plants across large and heterogeneous ranges.