The effect of glutamine-supplemented total parenteral nutrition on nitrogen economy depends on severity of diseases in surgical patients.
Gln is an important substrate for enterocyte and rapid proliferation cells. Studies have shown that parenteral supplementation of Gln maintains the intracellular Gln pool, improves nitrogen balance and shortens hospital stay. However, some studies showed Gln-supplemented TPN had no effect on restoring the Gln pool in critically ill patients. To evaluate the effect of glutamine (Gln) dipeptide supplementation of total parenteral nutrition (TPN) on postoperative nitrogen balance and immune response of patients undergoing surgery. This study is a prospective, randomized double-blind clinical trial. APACHE II score and TISS were used to evaluate the patients after admission. Forty-eight patients with major abdominal surgery were allocated to two groups to receive isonitrogenous (0.228 g nitrogen/kg/day) and isoenergetic (30 kcal/kg/day) TPN for 6 days. Two groups (Conv and Ala-Gln) were further divided to high (APACHE>or=6) and low (APACHE <6) groups. Control group (Conv) received 1.5 g amino acids/kg/day, whereas the Ala-Gln group received 0.972 g amino acids/kg/day and 0.417 g of L-alanyl-L-glutamine (Ala-Gln)/kg/day. Blood samples were collected on day 1 and day 6 after surgery for plasma amino acid and CD4, CD8 cell and T lymphocyte analysis. Cumulative nitrogen balance were also measured on day 2, 3, 4, 5 postoperatively. Although there was a tendency to have better cumulative nitrogen balance on the postoperative days in the Ala-Gln group, no significant difference was observed between two groups. However, a better significant cumulative nitrogen balance was observed on the 2nd, 3rd and 5th postoperative day in the Ala-Gln group than in the Conv group in patients with APACHE II <6, whereas no significant difference was noted in patients with APACHE II >or= 6. No difference in urine 3-methylhistidine excretion were observed between the 2 groups. Patients in the Ala-Gln group had significant higher T lymphocyte and CD4 cells than did those in the Conv group. TPN supplemented with Gln dipeptide had beneficial effect on enhancing the immune response. However, the effect of Ala-Gln administration on improving nitrogen economy was only observed in patients with low APACHE II scores. These results may indicate that Gln required for reversing the catabolic condition may depend on the characteristics and severity of the diseases.


Risk models for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP): smoking and chronic liver disease are predictors of protection against PEP.
We investigated which variables independently associated with protection against or development of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and severity of PEP. Subsequently, we derived predictive risk models for PEP. In a case-control design, 6505 patients had 8264 ERCPs, 211 patients had PEP, and 22 patients had severe PEP. We randomly selected 348 non-PEP controls. We examined 7 established- and 9 investigational variables. In univariate analysis, 7 variables predicted PEP: younger age, female sex, suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate-difficult cannulation (MDC), pancreatic stent placement, and lower Charlson score. Protective variables were current smoking, former drinking, diabetes, and chronic liver disease (CLD, biliary/transplant complications). Multivariate analysis identified seven independent variables for PEP, three protective (current smoking, CLD-biliary, CLD-transplant/hepatectomy complications) and 4 predictive (younger age, suspected SOD, pancreatic sphincterotomy, MDC). Pre- and post-ERCP risk models of 7 variables have a C-statistic of 0.74. Removing age (seventh variable) did not significantly affect the predictive value (C-statistic of 0.73) and reduced model complexity. Severity of PEP did not associate with any variables by multivariate analysis. By using the newly identified protective variables with 3 predictive variables, we derived 2 risk models with a higher predictive value for PEP compared to prior studies.


Reported use and perceived understanding of sodium information on US nutrition labels.
Comparing nutrition labels and choosing lower sodium foods are tactics to help reduce excessive sodium intake, a major risk factor for hypertension. Our objective was to assess US adult consumers' reported use and perceived understanding of sodium information on nutrition labels by sociodemographic and health status. We analyzed responses to questions from 3,729 adults aged 18 years or older participating in 2 national cross-sectional mail panel surveys in 2010. We found that 19.3% (95% confidence interval [CI], 17.2%-21.6%) of respondents agreed they were confused about how to figure out how much sodium is in the foods they eat; 57.9% (95% CI, 55.4%-60.5%) reported that they or the person who shops for their food buy items labeled low salt or low sodium; and 46.8% (95% CI, 44.3%-49.4%) reported they check nutrition labels for sodium content as a tactic to limit salt. Consumers with a high school education or less were more likely than college graduates to report they were confused about sodium content on labels (adjusted odds ratio [AOR], 1.9; 95% CI, 1.4-2.8) and less likely to check labels for sodium as a tactic to limit salt intake (AOR, 0.7; 95% CI, 0.6-0.98). Most survey respondents in our study reported buying low sodium food items. However, a higher proportion of respondents with low education than respondents with high education reported confusion with and less use of sodium content information, suggesting enhanced efforts may be needed to assist this group. Opportunity exists for health care professionals to educate patients about using and understanding nutrition labels and consuming a diet consistent with the Dietary Approaches to Stop Hypertension (DASH) eating plan.


Cyclosporine and herbal supplement interactions.
Cyclosporine (CyA) is a well-known immunosuppressant with a narrow therapeutic window. Its bioavailability is affected by many other traditional drugs and herbal extracts. Cytochrome P-450 isoenzymes CYP3A4 and CYP3A5 and protein P-glycoprotein (P-gp) are involved in CyA bioavailability. Interactions of CyA with herbal extracts are not well known, but, given their increased concomitant use, it is important to know which extracts, many of which are commonly self-prescribed, can affect CyA blood concentrations. Decreased CyA blood concentration has been shown with St John's wort in case reports and, in vivo animal studies, with ginger, liquorice, scutellariae radix, and quercetin. Increased CyA concentration has been reported in patients with grapefruit juice, chamomile, or berberine, and with cannabidiol or resveratrol in animal studies. Effects of Echinacea and Serenoa repens on CyA levels have not been shown consistently, but concomitant use should be avoided. Although findings from animal studies cannot be directly translated into humans, avoiding concomitant use of herbal extracts is prudent until human clinical studies have ruled out any possible interaction. Clinicians should interview their patients carefully about their use of herbal supplements before CyA administration, and those receiving CyA should be warned about possible interactions between herbal preparations and CyA.


Development of a Monitoring System for Semicontinuous Measurements of Stable Carbon Isotope Ratios in Atmospheric Carbonaceous Aerosols: Optimized Methods and Application to Field Measurements.
Carbon content constitutes a major fraction of atmospheric particulate matter (PM) and directly influences the earth's climate and human health. The stable carbon isotope ratios (δ13C) can be used to track potential sources and atmospheric processes of carbonaceous aerosols. Previously, determination of δ13C was always conducted in offline carbonaceous aerosol samples. The poor time-resolution results cannot provide information regarding the temporal evolution of δ13C at a short-time scale. In this study, we developed a new system for online measurements of δ13C in atmospheric carbonaceous aerosols by combining a semicontinuous organic carbon/elemental carbon (OC/EC) analyzer and online cavity ring-down spectroscopy (CRDS) (OC/EC analyzer-CRDS). To provide better stability in the determination of δ13C, a carrier gas with CO2 (∼200 ppm) in "balance gas" was used, and Keeling analysis was employed to separate the δ13C signal of the sample from background CO2 gas. Our results showed that the accuracy and absolute precision of the δ13C measurements by the OC/EC analyzer-CRDS system were better than 0.1‰ and 0.5‰, respectively, for the samples containing carbon content more than 5 μg. Furthermore, we employed this system to monitor δ13C (δ13C-TC) in particulate total carbon (TC) with a time resolution of 2-4 h over Beijing in late summer and early autumn, 2019. During the sampling period, the TC concentrations varied from 0.1 to 12.0 μg m-3 with a mean value of 6.0 ± 2.4 μg m-3. The δ13C-TC ranged from -28.2 to -24.2‰ (mean value was -25.9 ± 0.9‰) without significant diurnal variations, suggesting similar contributing sources to TC. Comparing the δ13C signatures of different emissions, we found that liquid fuels and primary and secondary C3 plants were likely the dominant sources of particulate TC. Finally, we found that atmospheric heavy precipitation washed out the aged aerosols from the polluted air, resulting in significant depletion (∼2.4‰) of δ13C-TC in the atmosphere. This paper described a novel system for conducting online measurements of δ13C in atmospheric carbonaceous aerosols and provided us information to better understand the temporal evolution of emission sources and atmospheric processes of carbonaceous aerosols.


Exercising with a denervated heart after cardiac transplantation.
Heart transplantation (HTR) is now an accepted life-extending procedure for those dying of intractable heart failure (CHF). HTR patients expect a high quality of life which implies a reasonable exercise capacity. Nevertheless HTR present unique exercise challenges with both central and peripheral factors of limitation that result in peak oxygen uptakes of 60-70% of age-matched normal subjects. Among central factors persistent chronotropic incompetence questions the occurrence and role of the graft reinnervation. Among peripheral factors the energetic impairement of the skeletal muscle seem to result more from microvascular abnormalities than from an actual deficit in oxidative capacity, questioning the mechanism of recovery from the CHF peripheral myopathy and the role of immunosuppressive drugs. Endurance and resistance training programs may reverse at least in part most but not all of these abnormalities. Training permits patients to engage in sports and even to participate in competitive events that are rewarding to them but also to the community because it promotes organ donation and confidence in medical achievements. Mechanisms of exercise impairments and improvements resulting from training are discussed in the perspective of current literature. Areas of future research and recommendations for the practice of sports after HTR are suggested.


The synergy of damage repair and retention promotes rejuvenation and prolongs healthy lifespans in cell lineages.
Damaged proteins are inherited asymmetrically during cell division in the yeast Saccharomyces cerevisiae, such that most damage is retained within the mother cell. The consequence is an ageing mother and a rejuvenated daughter cell with full replicative potential. Daughters of old and damaged mothers are however born with increasing levels of damage resulting in lowered replicative lifespans. Remarkably, these prematurely old daughters can give rise to rejuvenated cells with low damage levels and recovered lifespans, called second-degree rejuvenation. We aimed to investigate how damage repair and retention together can promote rejuvenation and at the same time ensure low damage levels in mother cells, reflected in longer health spans. We developed a dynamic model for damage accumulation over successive divisions in individual cells as part of a dynamically growing cell lineage. With detailed knowledge about single-cell dynamics and relationships between all cells in the lineage, we can infer how individual damage repair and retention strategies affect the propagation of damage in the population. We show that damage retention lowers damage levels in the population by reducing the variability across the lineage, and results in larger population sizes. Repairing damage efficiently in early life, as opposed to investing in repair when damage has already accumulated, counteracts accelerated ageing caused by damage retention. It prolongs the health span of individual cells which are moreover less prone to stress. In combination, damage retention and early investment in repair are beneficial for healthy ageing in yeast cell populations.


Quinidine delays IK activation in guinea pig ventricular myocytes.
A major action of the antiarrhythmic agent quinidine is prolongation of cardiac repolarization. In these experiments, the time-dependent effects of quinidine on the delayed rectifier potassium current, IK, a current contributing to cardiac repolarization, were investigated in acutely disaggregated guinea pig ventricular myocytes using the whole-cell recording configuration of the patch-clamp method. The effect of quinidine on IK was dependent on the duration of depolarization. After long (2,000 msec) pulses, IK was reduced by 30 +/- 27% (SD; n = 8, paired) by 10 microM quinidine; in contrast, after short (100 msec) pulses, the drug decreased IK 65 +/- 35% (p less than 0.05). This effect was found both in paired experiments as well as when quinidine-pretreated cells were compared to non-pretreated cells. Quinidine significantly delayed IK activation (9 +/- 20 msec at baseline vs. 44 +/- 25 msec in drug, p less than 0.05), but did not alter the subsequent time course of activation (time constant 659 +/- 118 msec). These findings are consistent with the hypothesis that quinidine promotes occupancy of a channel state from which opening does not occur.


Optimal impedance control for task achievement in the presence of signal-dependent noise.
There is an infinity of impedance parameter values, and thus different co-contraction levels, that can produce similar movement kinematics from which the CNS must select one. Although signal-dependent noise (SDN) predicts larger motor-command variability during higher co-contraction, the relationship between impedance and task performance is not theoretically obvious and thus was examined here. Subjects made goal-directed, single-joint elbow movements to either move naturally to different target sizes or voluntarily co-contract at different levels. Stiffness was estimated as the weighted summation of rectified EMG signals through the index of muscle co-contraction around the joint (IMCJ) proposed previously. When subjects made movements to targets of different sizes, IMCJ increased with the accuracy requirements, leading to reduced endpoint deviations. Therefore without the need for great accuracy, subjects accepted worse performance with lower co-contraction. When subjects were asked to increase co-contraction, the variability of EMG and torque both increased, suggesting that noise in the neuromotor command increased with muscle activation. In contrast, the final positional error was smallest for the highest IMCJ level. Although co-contraction increases the motor-command noise, the effect of this noise on the task performance is reduced. Subjects were able to regulate their impedance and control endpoint variance as the task requirements changed, and they did not voluntarily select the high impedance that generated the minimum endpoint error. These data contradict predictions of the SDN-based theory, which postulates minimization of only endpoint variance and thus require its revision.


Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma.
To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma. Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85. Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months. This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.


Interrelationship Between Kidney Function and Percutaneous Mitral Valve Interventions: A Comprehensive Review.
Percutaneous mitral valve repair is emerging as a reasonable alternative especially in those with an unfavorable surgical risk profile in the repair of mitral regurgitation. At this time, our understanding of the effects of underlying renal dysfunction on outcomes with percutaneous mitral valve repair and the effects of this procedure itself on renal function is evolving, as more data emerges in this field. The current evidence suggests that the correction of mitral regurgitation via percutaneous mitral valve repair is associated with some degree of improvement in cardiac function, hemodynamics and renal function. The improvement in renal function was more significant for those with greater renal dysfunction at baseline. The presence of Chronic Kidney Disease (CKD) in turn has been associated with poor long-term outcomes including increased mortality and hospitalization among patients who undergo percutaneous mitral valve repair. This was true regardless of the degree of improvement in GFR post repair advanced CKD. The adverse impact of CKD on long-term outcomes was consistent across all studies and was more prominent in those with GFR<30 mL/min/1.73 m². It is clear that from these contrasting evidences of improved renal function post mitral valve repair but poor long-term outcomes including increased mortality in patients with CKD, that proper patient selection for percutaneous mitral valve repair is key. There is a need to have better-standardized criteria for patients who should qualify to have percutaneous mitral valve replacement with Mitraclip. In this new era of percutaneous mitral valve repair, much work needs to be done to optimize long-term patient outcomes.


Malignant pleural effusion cells show aberrant glucose metabolism gene expression.
Malignant pleural effusion (MPE) accompanying lung adenocarcinoma indicates poor prognosis and early metastasis. This study aimed to identify genes related to MPE formation. Three tissue sample cohorts, seven from healthy lungs, 18 from stage I-III lung adenocarcinoma with adjacent healthy lung tissue and 13 from lung adenocarcinomas with MPE, were analysed by oligonucleotide microarray. The identified genes were verified by quantitative real-time PCR (qRT-PCR), immunohistochemical staining, and immunofluorescence confocal microscopy. 20 up- or down-regulated genes with a two-fold change in MPE cancer cells compared to healthy tissues were differentially expressed from early- to late-stage lung cancer. Of 13 genes related to cellular metabolism, aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1) were related to glucose metabolism. qRT-PCR validated their mRNA expressions in pleural metastatic samples. Immunohistochemical staining confirmed aberrant TKT, ALDOA, and TSC1 expressions in tumour cells. Immunofluorescence confirmed TKT co-localisation and co-distribution of ALDOA with thyroid transcription factor 1-positive cancer cells. TKT regulated the proliferation, vascular endothelial growth factor secretion in vitro and in vivo vascular permeability of cancer cell. Glucose metabolic reprogramming by ALDOA, SORD, TKT and TSC1 is important in MPE pathogenesis.


Stable public goods cooperation and dynamic social interactions in yeast.
Despite long-standing theoretical interest in the evolution of cooperation, empirical data on the evolutionary dynamics of cooperative traits remain limited. Here, we investigate the evolutionary dynamics of a simple public goods cooperative trait, invertase secretion, using a long-term selection experiment in Saccharomyces cerevisiae. We show that average investment in cooperation remains essentially constant over a period of hundreds of generations in viscous populations with high relatedness. Average cooperation remains constant despite transient local selection for high and low levels of cooperation that generate dynamic social interactions. Natural populations of yeast show similar variation in social strategies, which is consistent with the existence of similar selective pressures on public goods cooperation in nature.


The TATA-binding protein-associated factor yTafII19p functionally interacts with components of the global transcriptional regulator Ccr4-Not complex and physically interacts with the Not5 subunit.
The Saccharomyces cerevisiae HIS3 gene is a model system to characterize transcription initiation from different types of core promoters. The NOT genes were identified by mutations that preferentially increased transcription of the HIS3 promoter lacking a canonical TATA sequence. They encode proteins associated in a complex that also contains the Caf1 and Ccr4 proteins. It has been suggested that the Ccr4-Not complex represses transcription by inhibiting factors more specifically required for promoters lacking a TATA sequence. A potential target is the yTaf(II)19 subunit of TFIID, which, when depleted, leads to a preferential decrease of HIS3 TATA-less transcription. We isolated conditional taf19 alleles that display synthetic growth phenotypes when combined with not4 or specific not5 alleles. Inactivation of yTaf(II)19p by shifting these mutants to the restrictive temperature led to a more rapid and striking decrease in transcription from promoters that do not contain a canonical TATA sequence. We demonstrated by the two-hybrid assay and directly in vitro that yTaf(II)19p and Not5p could interact. Finally, we found by the two-hybrid assay that yTaf(II)19p also interacted with many components of the Ccr4-Not complex. Taken together, our results provide evidence that interactions between Not5p and yTaf(II)19p may be involved in transcriptional regulation by the Ccr4-Not complex.


Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas.
Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients.First-line treatment of prolactinomas is pharmacotherapy with dopamine agonists; recent reports of cardiac valve abnormalities associated with this class of medication in Parkinson's disease has prompted study in hyperprolactinemic populations. Patients with resistance to dopamine agonists may require other treatment.First-line treatment of Cushing's disease is pituitary surgery by a surgeon with experience in this condition. Current medical options for Cushing's disease block adrenal cortisol production, but do not treat the underlying disease. Pituitary-directed medical therapies are now being explored. In several small studies, the dopamine agonist cabergoline normalized urinary free cortisol in some patients. The multi-receptor targeted somatostatin analogue pasireotide (SOM230) shows promise as a pituitary-directed medical therapy in Cushing's disease; further studies will determine its efficacy and safety. Radiation therapy, with medical adrenal blockade while awaiting the effects of radiation, and bilateral adrenalectomy remain standard treatment options for patients not cured with pituitary surgery.In patients with acromegaly, surgery remains the first-line treatment option when the tumor is likely to be completely resected, or for debulking, especially when the tumor is compressing neurovisual structures. Primary therapy with somatostatin analogues has been used in some patients with large extrasellar tumors not amenable to surgical cure, patients at high surgical risk and patients who decline surgery. Pegvisomant is indicated in patients who have not responded to surgery and other medical therapy, although there are regional differences in when it is prescribed.In conclusion, the treatment of patients with pituitary adenomas requires a multidisciplinary approach. Dopamine agonists are an effective first-line medical therapy in most patients with a prolactinoma, and somatostatin analogues can be used as first-line therapy in selected patients with acromegaly. Current medical therapies for Cushing's disease primarily focus on adrenal blockade of cortisol production, although pasireotide and cabergoline show promise as pituitary-directed medical therapy for Cushing's disease; further long-term evaluation of efficacy and safety is important.


Volumetric changes in the basal ganglia after antipsychotic monotherapy: a systematic review.
Exposure to antipsychotic medication has been extensively associated with structural brain changes in the basal ganglia (BG). Traditionally antipsychotics have been divided into first and second generation antipsychotics (FGAs and SGAs) however, the validity of this classification has become increasingly controversial. To address if specific antipsychotics induce differential effects on BG volumes or whether volumetric effects are explained by FGA or SGA classification, we reviewed longitudinal structural magnetic resonance imaging (MRI) studies investigating effects of antipsychotic monotherapy. We systematically searched PubMed for longitudinal MRI studies of patients with schizophrenia or non-affective psychosis who had undergone a period of antipsychotic monotherapy. We used specific, predefined search terms and extracted studies were hand searched for additional studies. We identified 13 studies published in the period from 1996 to 2011. Overall six compounds (two classified as FGAs and four as SGAs) have been investigated: haloperidol, zuclophentixol, risperidone, olanzapine, clozapine, and quetiapine. The follow-up period ranged from 3-24 months. Unexpectedly, no studies found that specific FGAs induce significant BG volume increases. Conversely, both volumetric increases and decreases in the BG have been associated with SGA monotherapy. Induction of striatal volume increases is not a specific feature of FGAs. Except for clozapine treatment in chronic patients, volume reductions are not restricted to specific SGAs. The current review adds brain structural support to the notion that antipsychotics should no longer be classified as either FGAs or SGAs. Future clinical MRI studies should strive to elucidate effects of specific antipsychotic drugs.


Expression of a developmentally regulated gene, Mng10, in identified neurosecretory cells in the CNS of Manduca sexta.
We are interested in the molecular events underlying the development of the nervous system of Manduca sexta during the final 24 h of the pupal molt. In this article we describe a gene, Mng10, that is expressed in the abdominal nervous system of M. sexta and is developmentally regulated over this 24-h period. In situ hybridization analysis shows that the transcript is localized predominantly to a single pair of uniquely identifiable neurosecretory neurons, the NS-L1 cells in the abdominal ganglia. Mng10 is a single copy gene encoding a 229 amino acid protein with a predicted molecular mass of 26 kDa. At the amino acid level the protein shows 34% identity to the yeast transcription unit, Yer082. Northern blot analysis shows that the transcript of Mng10 is very rare, comprising about 0.001% of the poly (A)+ RNA from the CNS and is detectable at 4 h but not 24 h prior to pupal ecdysis. One of the physiological events that develops over the final 24 h of the pupal molt is the ability of the nervous system to respond to the neuropeptide eclosion hormone. In this context, it is interesting to note that the NS-L1 cells are members of the group of 50 neurons that show increased cGMP immunoreactivity when the nervous system is exposed to the neuropeptide eclosion hormone.


Let's Talk Critical. Development and Evaluation of a Communication Skills Training Program for Critical Care Fellows.
Although expert communication between intensive care unit clinicians with patients or surrogates improves patient- and family-centered outcomes, fellows in critical care medicine do not feel adequately trained to conduct family meetings. We aimed to develop, implement, and evaluate a communication skills program that could be easily integrated into a U.S. critical care fellowship. We developed four simulation cases that provided communication challenges that critical care fellows commonly face. For each case, we developed a list of directly observable tasks that could be used by faculty to evaluate fellows during each simulation. We developed a didactic curriculum of lectures/case discussions on topics related to palliative care, end-of-life care, communication skills, and bioethics; this month-long curriculum began and ended with the fellows leading family meetings in up to two simulated cases with direct observation by faculty who were not blinded to the timing of the simulation. Our primary measures of effectiveness were the fellows' self-reported change in comfort with leading family meetings after the program was completed and the quality of the communication as measured by the faculty evaluators during the family meeting simulations at the end of the month. Over 3 years, 31 critical care fellows participated in the program, 28 of whom participated in 101 family meeting simulations with direct feedback by faculty facilitators. Our trainees showed high rates of information disclosure during the simulated family meetings. During the simulations done at the end of the month compared with those done at the beginning, our fellows showed significantly improved rates in: (1) verbalizing an agenda for the meeting (64 vs. 41%; Chi-square, 5.27; P = 0.02), (2) summarizing what will be done for the patient (64 vs. 39%; Chi-square, 6.21; P = 0.01), and (3) providing a follow-up plan (60 vs. 37%; Chi-square, 5.2; P = 0.02). More than 95% of our participants (n = 27) reported feeling "slightly" or "much" more comfortable with discussing foregoing life-sustaining treatment and leading family discussions after the month-long curriculum. A communication skills program can be feasibly integrated into a critical care training program and is associated with improvements in fellows' skills and comfort with leading family meetings.


Vaccination coverage assessment survey in Mangalore (urban), Karnataka.
A vaccination coverage assessment survey regarding the U.I.P. vaccines, among 210 children aged 12-23 months and 210 mothers of infants was undertaken in Mangalore (urban) in February--March 1991, with the specific objectives of assessing the extent of achievement here of the U.I.P. objectives for the vaccine coverages, and identifying the reasons for immunization failures as well the sources of immunization. The sample population was selected by the standard WHO. 30 cluster sampling technique. A door-to-door survey was undertaken in the study population and the data was elicited by interview of mothers (and confirmed from vaccination cards or registers if available). The investigator inquired about DPT 3, OPV 3, one dose each of BCG and Measles vaccine and TT2/B for mothers. The coverages for the individual vaccines were observed as follows (and indicated in parentheses) DPT 3 (91.9%) OPV 3 (92.3%), BCG (91%), Measles vaccine (69.5%) and TT2/B for mothers (94.7%). The drop-out rates from first to third dose of both DPT and OPV were observed to be 2.5%. The major reasons for immunization failures were reported to be unawareness of need, illness of child, and fear of side reaction. Hospitals were availed of more than private sources for immunization services. The universal immunization coverage in Mangalore (urban) was found to be highly satisfactory.


Prediction of signal peptides in archaea.
Computational prediction of signal peptides (SPs) and their cleavage sites is of great importance in computational biology; however, currently there is no available method capable of predicting reliably the SPs of archaea, due to the limited amount of experimentally verified proteins with SPs. We performed an extensive literature search in order to identify archaeal proteins having experimentally verified SP and managed to find 69 such proteins, the largest number ever reported. A detailed analysis of these sequences revealed some unique features of the SPs of archaea, such as the unique amino acid composition of the hydrophobic region with a higher than expected occurrence of isoleucine, and a cleavage site resembling more the sequences of gram-positives with almost equal amounts of alanine and valine at the position-3 before the cleavage site and a dominant alanine at position-1, followed in abundance by serine and glycine. Using these proteins as a training set, we trained a hidden Markov model method that predicts the presence of the SPs and their cleavage sites and also discriminates such proteins from cytoplasmic and transmembrane ones. The method performs satisfactorily, yielding a 35-fold cross-validation procedure, a sensitivity of 100% and specificity 98.41% with the Matthews' correlation coefficient being equal to 0.964. This particular method is currently the only available method for the prediction of secretory SPs in archaea, and performs consistently and significantly better compared with other available predictors that were trained on sequences of eukaryotic or bacterial origin. Searching 48 completely sequenced archaeal genomes we identified 9437 putative SPs. The method, PRED-SIGNAL, and the results are freely available for academic users at http://bioinformatics.biol.uoa.gr/PRED-SIGNAL/ and we anticipate that it will be a valuable tool for the computational analysis of archaeal genomes.


Significance of a positive family history for coronary heart disease in patients with a zero coronary artery calcium score (from the Multi-Ethnic Study of Atherosclerosis).
Although a coronary artery calcium (CAC) score of 0 is associated with a very low 10-year risk for cardiac events, this risk is nonzero. Subjects with a family history of coronary heart disease (CHD) has been associated with more subclinical atherosclerosis than subjects without a family history of CHD. The purpose of this study was to assess the significance of a family history for CHD in subjects with a CAC score of 0. The Multi-Ethnic Study of Atherosclerosis cohort includes 6,814 participants free of clinical cardiovascular disease (CVD) at baseline. Positive family history was defined as reporting a parent, sibling, or child who had a heart attack. Time to incident CHD or CVD event was modeled using the multivariable Cox regression; 3,185 subjects were identified from the original Multi-Ethnic Study of Atherosclerosis cohort as having a baseline CAC score of 0 (mean age 58 years, 37% men). Over a median follow-up of 10 years, 101 participants (3.2%) had CVD events and 56 (1.8%) had CHD events. In age- and gender-adjusted analyses, a family history of CHD was associated with an ∼70% increase in CVD (hazard ratio 1.73, 95% confidence interval 1.17 to 2.56) and CHD (hazard ratio 1.72, 95% confidence interval 1.01 to 2.91) events. CVD events remained significant after further adjustment for ethnicity, risk factors, and baseline medication use. In conclusion, asymptomatic subjects with a 0 CAC score and a positive family history of CHD are at increased risk for CVD and CHD events compared with those without a family history of CHD, although absolute event rates remain low.


Arachidonic Acid Metabolites of CYP450 Enzymes and HIF-1α Modulate Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats under Acute and Intermittent Hyperbaric Oxygenation.
Acetylcholine-induced vasorelaxation (AChIR) and responses to reduced pO2 (hypoxia-induced relaxation (HIR), 0% O2) were assessed in vitro in aortic rings of healthy male Sprague-Dawley rats (N = 252) under hyperbaric (HBO2) protocols. The studied groups consisted of the CTRL group (untreated); the A-HBO2 group (single HBO2; 120 min of 100% O2 at 2.0 bars); the 24H-HBO2 group (examined 24 h after single exposure) and the 4D-HBO2 group (four consecutive days of single HBO2). AChIR, sensitivity to ACh and iNOS expression were decreased in the A-HBO2 group. HIR was prostanoid- and epoxyeicosatrienoic acid (EET)-mediated. HIF-1α expression was increased in the 24H-HBO2 and 4D-HBO2 groups. LW6 (HIF-1α inhibitor) decreased HIR in the 24H-HBO2 group. HBO2 affected the expression of COX-1 and COX-2. CYP2c11 expression was elevated in the 24H-HBO2 and 4D-HBO2 groups. Concentrations of arachidonic acid (AA) metabolites 14(15)-DiHET, 11(12)-DiHET and 8(9)-DiHET were increased in A-HBO2 and 24H-HBO2. An increased concentration of 8(9)-EET was observed in the A-HBO2 and 24h-HBO2 groups vs. the CTRL and 4D-HBO2 groups, and an increased concentration of 5(6)-DiHET was observed in the 24H-HBO2 group vs. the 4D-HBO2 group. The 20-HETE concentration was increased in the A-HBO2 group. All were determined by LC-MS/MS of the aorta. The results show that AChIR in all groups is mostly NO-dependent. HIR is undoubtedly mediated by the CYP450 enzymes' metabolites of AA, whereas HIF-1α contributes to restored HIR. Vasoconstrictor metabolites of CYP450 enzymes contribute to attenuated AChIR and HIR in A-HBO2.


Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature.
Objective Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1. Design and methods A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed. Results Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells. Conclusions ACC associated with MEN1 is rare and may occur in familial aggregates.


The Copenhagen Consensus Conference 2016: children, youth, and physical activity in schools and during leisure time.
From 4 to 7 April 2016, 24 researchers from 8 countries and from a variety of academic disciplines gathered in Snekkersten, Denmark, to reach evidence-based consensus about physical activity in children and youth, that is, individuals between 6 and 18 years. Physical activity is an overarching term that consists of many structured and unstructured forms within school and out-of-school-time contexts, including organised sport, physical education, outdoor recreation, motor skill development programmes, recess, and active transportation such as biking and walking. This consensus statement presents the accord on the effects of physical activity on children's and youth's fitness, health, cognitive functioning, engagement, motivation, psychological well-being and social inclusion, as well as presenting educational and physical activity implementation strategies. The consensus was obtained through an iterative process that began with presentation of the state-of-the art in each domain followed by plenary and group discussions. Ultimately, Consensus Conference participants reached agreement on the 21-item consensus statement.


Global Tracheostomy Collaborative: data-driven improvements in patient safety through multidisciplinary teamwork, standardisation, education, and patient partnership.
There is growing recognition of the need for a coordinated, systematic approach to caring for patients with a tracheostomy. Tracheostomy-related adverse events remain a pervasive global problem, accounting for half of all airway-related deaths and hypoxic brain damage in critical care units. The Global Tracheostomy Collaborative (GTC) was formed in 2012 to improve patient safety and quality of care, emphasising knowledge, skills, teamwork, and patient-centred approaches. Inspired by quality improvement leads in Australia, the UK, and the USA, the GTC implements and disseminates best practices across hospitals and healthcare trusts. Its database collects patient-level information on quality, safety, and organisational efficiencies. The GTC provides an organising structure for quality improvement efforts, promoting safety of paediatric and adult patients. Successful implementation requires instituting key drivers for change that include effective training for health professionals; multidisciplinary team collaboration; engagement and involvement of patients, their families, and carers; and data collection that allows tracking of outcomes. We report the history of the collaborative, its database infrastructure and analytics, and patient outcomes from more than 6500 patients globally. We characterise this patient population for the first time at such scale, reporting predictors of adverse events, mortality, and length of stay indexed to patient characteristics, co-morbidities, risk factors, and context. In one example, the database allowed identification of a previously unrecognised association between bleeding and mortality, reflecting ability to uncover latent risks and promote safety. The GTC provides the foundation for future risk-adjusted benchmarking and a learning community that drives ongoing quality improvement efforts worldwide.


Folate, vitamin B12, and neuropsychiatric disorders.
Folate and vitamin B12 are required both in the methylation of homocysteine to methionine and in the synthesis of S-adenosylmethionine. S-adenosylmethionine is involved in numerous methylation reactions involving proteins, phospholipids, DNA, and neurotransmitter metabolism. Both folate and vitamin B12 deficiency may cause similar neurologic and psychiatric disturbances including depression, dementia, and a demyelinating myelopathy. A current theory proposes that a defect in methylation processes is central to the biochemical basis of the neuropsychiatry of these vitamin deficiencies. Folate deficiency may specifically affect central monoamine metabolism and aggravate depressive disorders. In addition, the neurotoxic effects of homocysteine may also play a role in the neurologic and psychiatric disturbances that are associated with folate and vitamin B12 deficiency.


Exceptional resistance of human H2 glioblastoma cells to complement-mediated killing by expression and utilization of factor H and factor H-like protein 1.
Of over 20 nucleated cell lines we have examined to date, human H2 glioblastoma cells have turned out to be the most resistant to complement-mediated cytolysis in vitro. H2 cells expressed strongly the membrane attack complex inhibitor protectin (CD59), moderately CD46 (membrane cofactor protein) and CD55 (decay-accelerating factor), but no CD35 (complement receptor 1). When treated with a polyclonal anti-H2 Ab, anti-CD59 mAb, and normal human serum, only 5% of H2 cells became killed. Under the same conditions, 70% of endothelial-like EA.hy 926 cells and 40% of U251 control glioma cells were killed. A combined neutralization of CD46, CD55, and CD59 increased H2 lysis only minimally, demonstrating that these complement regulators are not enough to account for the resistance of H2 cells. After treatment with Abs and serum, less C5b-9 was deposited on H2 than on U251 and EA.hy 926 cell lines. A reason for the exceptional resistance of H2 cells was revealed when RT-PCR and protein biochemical methods showed that the H2 cells, unlike the other cell lines tested, actively produced the soluble complement inhibitors factor H and factor H-like protein 1. H2 cells were also capable of binding human factor H from the fluid phase to their cell surface and promoted the cleavage of C3b to its inactive form iC3b more efficiently than U251 and EA.hy 926 cells. In accordance, anti-factor H mAbs enhanced killing of H2 glioblastoma cells. Taken together, our results show that production and binding of factor H and factor H-like protein 1 is a novel mechanism that these malignant cells utilize to escape complement-mediated killing.


Tumor Cell-Derived Periostin Regulates Cytokines That Maintain Breast Cancer Stem Cells.
Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin α(v)β(3), are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin-integrin β3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-κB-mediated transcription of key cytokines, namely IL6 and IL8, which in turn control downstream activation of STAT3. In summary, these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs. The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines.


Heat dissipation performance of a high-brightness LED package assembly using high-thermal conductivity filler.
This paper presents a thermal analysis and experimental validation of natural convective heat transfer of a high-brightness light-emitting diode (LED) package assembly. The substrate materials used in the LED package assembly were filled and doped using boron nitride (BN) filler. The thermal conductivity of the BN-filled substrate was measured. The temperature distribution and heat flow of the LED package were assessed by thermal profile measurement using an infrared (IR) camera and thermocouples. In addition, the heat transfer process of the LED package assembly in natural convection was also simulated using the computational fluid dynamics method. The optical performance of the LED package was monitored and investigated with various filler contents. The heat conduction mechanism in the substrate was analyzed. IR thermogram showed that the BN-doped substrate could effectively lower the surface temperature of the LED package by 21.5°C compared with the traditional FR4 substrate. According to the IESNA LM 80 lifetime testing method, reduction in LED temperature can prolong the LED's lifetime by 19,000 h. The optical performance of the LED package assembly was also found to be improved significantly in lighting power by 10%. As a result, the overall heat dissipation capability of the LED package to the surrounding is enhanced, which improves the LED's efficacy.


Functional outcome after open repair of abdominal aortic aneurysm.
Detailed information on functional outcome after open abdominal aortic aneurysm (AAA) repair is sparse. Information about functional outcome of open AAA repair is essential to allow comparison of treatment modalities. To determine the functional outcome of patients after open repair of AAA, we reviewed 154 consecutive, nonemergency open repairs of infrarenal AAAs between 1990 and 1997 and each patient's medical records. Clinical variables were recorded for each patient, as were multiple outcomes, including ambulatory status, independent living status, current medical condition, and the patient's perception of recovery and satisfaction. Eighty-seven patients or their families were available for current telephone interview to obtain information about objective functional activities, including walking and driving, and subjective functional information, including assessment of complete recovery and willingness to undergo AAA repair again. Chart data were available for all 154 patients. There were 42 women and 112 men. A total of 139 operations were elective, and 15 were urgent. The operative mortality rate was 4%, mean hospital stay was 10.7 +/- 1.3 days, and mean intensive care unit stay was 4.57 +/- 1.17 days. Seventeen (11%) patients required transfer to a skilled nursing facility with a mean stay of 3.66 +/- 2.9 months. All patients were ambulatory preoperatively, whereas at last follow-up (median, 25 months; range, 0.13-108.5 months), 100 (64%) of the patients remained ambulatory, 34 (22%) required assistance, and 12 (14%) were nonambulatory. At current assessment by telephone interview, 33% of patients described a decrease in their functional activity including driving, shopping, and traveling compared with their preoperative status, whereas 67% were unchanged. When asked to assess their own degree of recovery, 64% of patients stated that they experienced complete recovery with an average time to recovery of 3.9 months, whereas 33% said they had not fully recovered at a mean follow-up of 34 months. Sixteen (18%) patients said they would not undergo AAA repair again knowing the recovery process, even though they appeared to fully understand the implication of AAA rupture. Patients undergoing open AAA repair generally experienced significant freedom from surgical complications. However, substantial functional impairment was present. It is unclear whether the functional disability resulted from the AAA surgery or from aging and comorbidities unrelated to surgery.


Zernike-moment-based image super resolution.
Multiframe super-resolution (SR) reconstruction aims to produce a high-resolution (HR) image using a set of low-resolution (LR) images. In the process of reconstruction, fuzzy registration usually plays a critical role. It mainly focuses on the correlation between pixels of the candidate and the reference images to reconstruct each pixel by averaging all its neighboring pixels. Therefore, the fuzzy-registration-based SR performs well and has been widely applied in practice. However, if some objects appear or disappear among LR images or different angle rotations exist among them, the correlation between corresponding pixels becomes weak. Thus, it will be difficult to use LR images effectively in the process of SR reconstruction. Moreover, if the LR images are noised, the reconstruction quality will be affected seriously. To address or at least reduce these problems, this paper presents a novel SR method based on the Zernike moment, to make the most of possible details in each LR image for high-quality SR reconstruction. Experimental results show that the proposed method outperforms existing methods in terms of robustness and visual effects.


Mediation of hidradenitis suppurativa by androgens.
Forty two women with hidradenitis suppurativa were assessed clinically and biochemically for evidence of androgen excess. Thirteen had irregular menses; 22 of 36 experienced exacerbation of hidradenitis suppurativa premenstrually; 19 had or had had acne vulgaris; and seven were hirsute. Comedones (blackheads) were found in apocrine sites in 37, but also in retroauricular sites in 18 and were considered to be an important physical sign for early diagnosis. Eight had evidence of pilonidal (postanal) sinus. The patients had a higher concentration of total testosterone (p less than 0.01) and free androgen index (testosterone to sex hormone binding globulin concentrations) (p less than 0.01) than normal controls. Patients with hidradenitis suppurativa appear to have endocrine abnormalities sufficient to suggest an androgenic basis for the disease.


Unfolding linac photon spectra and incident electron energies from experimental transmission data, with direct independent validation.
In a recent computational study, an improved physics-based approach was proposed for unfolding linac photon spectra and incident electron energies from transmission data. In this approach, energy differentiation is improved by simultaneously using transmission data for multiple attenuators and detectors, and the unfolding robustness is improved by using a four-parameter functional form to describe the photon spectrum. The purpose of the current study is to validate this approach experimentally, and to demonstrate its application on a typical clinical linac. The validation makes use of the recent transmission measurements performed on the Vickers research linac of National Research Council Canada. For this linac, the photon spectra were previously measured using a NaI detector, and the incident electron parameters are independently known. The transmission data are for eight beams in the range 10-30 MV using thick Be, Al and Pb bremsstrahlung targets. To demonstrate the approach on a typical clinical linac, new measurements are performed on an Elekta Precise linac for 6, 10 and 25 MV beams. The different experimental setups are modeled using EGSnrc, with the newly added photonuclear attenuation included. For the validation on the research linac, the 95% confidence bounds of the unfolded spectra fall within the noise of the NaI data. The unfolded spectra agree with the EGSnrc spectra (calculated using independently known electron parameters) with RMS energy fluence deviations of 4.5%. The accuracy of unfolding the incident electron energy is shown to be ∼3%. A transmission cutoff of only 10% is suitable for accurate unfolding, provided that the other components of the proposed approach are implemented. For the demonstration on a clinical linac, the unfolded incident electron energies and their 68% confidence bounds for the 6, 10 and 25 MV beams are 6.1 ± 0.1, 9.3 ± 0.1, and 19.3 ± 0.2 MeV, respectively. The unfolded spectra for the clinical linac agree with the EGSnrc spectra (calculated using the unfolded electron energies) with RMS energy fluence deviations of 3.7%. The corresponding measured and EGSnrc-calculated transmission data agree within 1.5%, where the typical transmission measurement uncertainty on the clinical linac is 0.4% (not including the uncertainties on the incident electron parameters). The approach proposed in an earlier study for unfolding photon spectra and incident electron energies from transmission data is accurate and practical for clinical use.


Oslo government district bombing and Utøya island shooting July 22, 2011: the immediate prehospital emergency medical service response.
On July 22, 2011, a single perpetrator killed 77 people in a car bomb attack and a shooting spree incident in Norway. This article describes the emergency medical service (EMS) response elicited by the two incidents. A retrospective and observational study was conducted based on data from the EMS systems involved and the public domain. The study was approved by the Data Protection Official and was defined as a quality improvement project. We describe the timeline and logistics of the EMS response, focusing on alarm, dispatch, initial response, triage and evacuation. The scenes in the Oslo government district and at Utøya island are described separately. Many EMS units were activated and effectively used despite the occurrence of two geographically separate incidents within a short time frame. Important lessons were learned regarding triage and evacuation, patient flow and communication, the use of and need for emergency equipment and the coordination of helicopter EMS.


Interactions Between the Corticospinal Tract and Premotor-Motor Pathways for Residual Motor Output After Stroke.
Brain imaging has continuously enhanced our understanding how different brain networks contribute to motor recovery after stroke. However, the present models are still incomplete and do not fit for every patient. The interaction between the degree of damage of the corticospinal tract (CST) and of corticocortical motor connections, that is, the influence of the microstructural state of one connection on the importance of another has been largely neglected. Applying diffusion-weighted imaging and probabilistic tractography, we investigated cross-network interactions between the integrity of ipsilesional CST and ipsilesional corticocortical motor pathways for variance in residual motor outcome in 53 patients with subacute stroke. The main finding was a significant interaction between the CST and corticocortical connections between the primary motor and ventral premotor cortex in relation to residual motor output. More specifically, the data indicate that the microstructural state of the connection primary motor-ventral premotor cortex plays only a role in patients with significant damage to the CST. In patients with slightly affected CST, this connection did not explain a relevant amount of variance in motor outcome. The present data show that patients with stroke with different degree of CST disruption differ in their dependency on structural premotor-motor connections for residual motor output. This finding might have important implications for future research on recovery prediction models and on responses to treatment strategies.


Greenbeards.
Greenbeards are genes that can identify the presence of copies of themselves in other individuals, and cause their bearer to behave nepotistically toward those individuals. In recent years, a number of examples have been discovered, and it has been suggested that greenbeards represent one of the fundamental routes to social behaviors such as cooperation. However, despite their possible theoretical and empirical importance, many basic aspects of greenbeard biology are commonly misunderstood. Here, we distinguish between four different types of greenbeard, which differ in their evolutionary dynamics. We show that all four types exist, and that they differ in the ease with which they can be empirically detected. We clarify the inclusive fitness explanation of greenbeards, and show that they are not intragenomic outlaws. Finally, we argue that although greenbeards are likely to be most common and easiest to detect in microorganisms, they are unlikely to important in organisms such as humans.


Monitoring plasmonic hot-carrier chemical reactions at the single particle level.
Plasmon excitation in metal nanoparticles triggers the generation of highly energetic charge carriers that, when properly manipulated and exploited, can mediate chemical reactions. Single-particle techniques are key to unearthing the underlying mechanisms of hot-carrier generation, transport and injection, as well as to disentangling the role of the temperature increase and the enhanced near-field at the nanoparticle-molecule interface. Gaining nanoscopic insight into these processes and their interplay could aid in the rational design of plasmonic photocatalysts. Here, we present three different approaches to monitor hot-carrier reactivity at the single-particle level. We use a combination of dark-field microscopy and photoelectrochemistry to track a hot-hole driven reaction on a single Au nanoparticle. We image hot-electron reactivity with sub-particle spatial resolution using nanoscopy techniques. Finally, we push the limits by looking for a hot-electron induced chemical reaction that generates a fluorescent product, which should enable imaging plasmonic photocatalysis at the single-particle and single-molecule levels.


Effects of prolonged exposure to low dose metformin in thyroid cancer cell lines.
Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). The proposed mechanisms include activation of the Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway and inhibition of the mTOR pathway (which promotes growth and proliferation). By inhibiting hepatic gluconeogenesis and increasing glucose uptake by muscles, metformin decreases blood glucose and circulating Insulin levels. Aims: Explore the effect of metformin on the growth and proliferation of thyroid cancer cell lines. Methods: The effects of metformin on thyroid cancer cell lines (FTC-133, K1E7, RO82-W-1, 8305C and TT) and normal thyroid follicular cells (Nthy-ori 3-1) were investigated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay for cell proliferation; clonogenic assays; FACS analysis for apoptosis and cell cycle, H2A.X phosphorylation (γH2AX) assay for DNA repair and scratch assay for cell migration. Results: Metformin inhibited cell proliferation and colony formation at 0.03 mM and above and inhibited cell migration at 0.3 mM. At concentrations of 0.1 mM and above metformin increased the percentage of apoptotic cells and induced cell cycle arrest in G0/G1 phase at minimum concentration of 0.3 mM. Unlike previous reports, no effect on DNA repair response was demonstrated. Conclusion: Metformin suppressed growth of all thyroid cancer cell lines, at concentrations considered to be within in the therapeutic range for diabetic patients on metformin (<0.3 mM).


Determination of subcellular compartment sizes for estimating dose variations in radiotherapy.
The variation in specific energy absorbed to different cell compartments caused by variations in size and chemical composition is poorly investigated in radiotherapy. The aim of this study was to develop an algorithm to derive cell and cell nuclei size distributions from 2D histology samples, and build 3D cellular geometries to provide Monte Carlo (MC)-based dose calculation engines with a morphologically relevant input geometry. Stained and unstained regions of the histology samples are segmented using a Gaussian mixture model, and individual cell nuclei are identified via thresholding. Delaunay triangulation is applied to determine the distribution of distances between the centroids of nearest neighbour cells. A pouring simulation is used to build a 3D virtual tissue sample, with cell radii randomised according to the cell size distribution determined from the histology samples. A slice with the same thickness as the histology sample is cut through the 3D data and characterised in the same way as the measured histology. The comparison between this virtual slice and the measured histology is used to adjust the initial cell size distribution into the pouring simulation. This iterative approach of a pouring simulation with adjustments guided by comparison is continued until an input cell size distribution is found that yields a distribution in the sliced geometry that agrees with the measured histology samples. The thus obtained morphologically realistic 3D cellular geometry can be used as input to MC-based dose calculation programs for studies of dose response due to variations in morphology and size of tumour/healthy tissue cells/nuclei, and extracellular material.


Orientia and Rickettsia: different flowers from the same garden.
Recent discoveries of basal extracellular Rickettsiales have illuminated divergent evolutionary paths to host dependency in later-evolving lineages. Family Rickettsiaceae, primarily comprised of numerous protist- and invertebrate-associated species, also includes human pathogens from two genera, Orientia and Rickettsia. Once considered sister taxa, these bacteria form distinct lineages with newly appreciated lifestyles and morphological traits. Contrasting other rickettsial human pathogens in Family Anaplasmataceae, Orientia and Rickettsia species do not reside in host-derived vacuoles and lack glycolytic potential. With only a few described mechanisms, strategies for commandeering host glycolysis to support cytosolic growth remain to be discovered. While regulatory systems for this unique mode of intracellular parasitism are unclear, conjugative transposons unique to Orientia and Rickettsia species provide insights that are critical for determining how these obligate intracellular pathogens overtake eukaryotic cytosol.


Homicide trends in the Mthatha area between 1993 and 2005.
Absolute poverty and gross income inequity can foment violence through various and multiple mechanisms. Poor people are highly prone to exploitation and manipulation by those who are wealthy and more powerful. The poor are as susceptible to being victims as being perpetrators of crime. To study the trends in homicides in the Mthatha area. A review of records of 5 583 medico-legal autopsies in Mthatha General Hospital of murder victims between 1993 and 2005. During the 13-year period, 12 063 autopsies were performed on people who died following trauma and other fatal injuries. Of this total, 5 583 (46%) were homicides. The average annual homicide rate during this period was 108/100 000 population. The rate increased from 94/100 000 in 1993 to 133/100 000 in 2005. Firearm-related deaths averaged 48/100 000, stab wounds 35/100 000, and blunt trauma (assault) 25/100 000 per year. Gunshot-related homicides increased from 27/100 000 in 1993 to a peak of 68/100 000 in 2001, decreasing to 42/100 000 in 2005. Stab-related homicides ranged from 42/100 000 in 1993 to a 'low' of 26/100 000 in 1995, then rose to 53/100 000 in 2005; assault with blunt objects increased from 25/100 000 to 38/100 000 in the same period. Murdered males (82%) outnumbered females in the proportion of 5:1, although there was an increasing incidence of females. About half of these deaths were in the 21 - 40-year-old range. There has been a progressive increase in homicides in the Mthatha area. To a certain extent, poverty has contributed to the causation of these deaths.


Craniopharyngioma in children: trends from a third consecutive single-center cohort study.
The management of children with craniopharyngioma has evolved over time, with a trend toward less invasive neurosurgical approaches as surgeons have sought to balance oncological control and treatment-related morbidity. To this end, the aim of this study was to evaluate the safety and effectiveness of the current management of children with craniopharyngioma compared to the previous management methods used at the authors' treatment center. A prospectively maintained database was searched over a 14-year period between January 1, 2005, and December 31, 2018, to identify all children 17 years of age or younger with a new diagnosis of craniopharyngioma. A retrospective case note review was performed for each child to extract data on the presentation, investigation, treatment, and outcome of their illness. Morbidity was assessed in the same fashion as in previous cohorts, according to the following categories: visual loss, pituitary dysfunction, hypothalamic dysfunction, neurological deficits, and cognitive impairment. In total, 59 children were identified with craniopharyngioma during the study period. A total of 92 operations were performed, including cyst drainage (35/92; 38.0%), craniotomy and resection (30/92; 32.6%), and transsphenoidal resection (16/92; 17.4%). Approximately two-thirds of all operations were performed using image guidance (66/92; 71.7%) and one-third were performed using endoscopy (27/92; 29.3%). The majority of children had adjuvant therapy comprising proton beam therapy (18/59; 30.5%) or conventional radiotherapy (16/59; 27.1%). The median follow-up duration was 44 months (range 1-142 months), and approximately one-half of the children had no evidence of residual disease on MRI studies (28/59; 47.5%). Of the remaining 31 children, there was a reduction in the volume of residual disease in 8 patients (8/59; 13.6%), stable residual disease in 18 (18/59; 30.5%), and tumor growth in 5 patients (5/59; 8.5%). There was significantly reduced morbidity (p < 0.05) in all categories in the current cohort compared with our last cohort (1996-2004). The authors' institutional experience of pediatric craniopharyngioma confirms a trend toward less invasive neurosurgical procedures, most of which are now performed with the benefit of image guidance or endoscopy. Moreover, the authors have identified an expanding role for more targeted radiotherapy for children with residual disease. These advances have allowed for tumor control comparable to that achieved in previous cohorts, but with significantly reduced morbidity and mortality.


Mapping the interaction site and effect of the Siglec-9 inflammatory biomarker on human primary amine oxidase.
Human primary amine oxidase (hAOC3), also known as vascular adhesion protein 1, mediates leukocyte rolling and trafficking to sites of inflammation by a multistep adhesion cascade. hAOC3 is absent on the endothelium of normal tissues and is kept upregulated during inflammatory conditions, which is an applicable advantage for imaging inflammatory diseases. Sialic acid binding immunoglobulin like-lectin 9 (Siglec-9) is a leukocyte ligand for hAOC3. The peptide (CARLSLSWRGLTLCPSK) based on the region of Siglec-9 that interacts with hAOC3, can be used as a specific tracer for hAOC3-targeted imaging of inflammation using Positron Emission Tomography (PET). In the present study, we show that the Siglec-9 peptide binds to hAOC3 and triggers its amine oxidase activity towards benzylamine. Furthermore, the hAOC3 inhibitors semicarbazide and imidazole reduce the binding of wild type and Arg/Ala mutated Siglec-9 peptides to hAOC3. Molecular docking of the Siglec-9 peptide is in accordance with the experimental results and predicts that the R3 residue in the peptide interacts in the catalytic site of hAOC3 when the topaquinone cofactor is in the non-catalytic on-copper conformation. The predicted binding mode of Siglec-9 peptide to hAOC3 is supported by the PET studies using rodent, rabbit and pig AOC3 proteins.


The Effect of Ankle Kinesio Tape on Ankle Muscle Activity During a Drop Landing.
The use of Kinesio Tape among health care professional has grown recently in efforts to efficiently prevent and treat joint injuries. However, limited evidence exists regarding the efficacy of this technique in enhancing joint stability and neuromuscular control. To determine how Kinesio Tape application to the ankle joint alters forces and muscle activity during a drop-jump maneuver. Single-group pretest- posttest. University laboratory. 22 healthy adults with no previous history of ankle injury. Participants were instrumented with electromyography on the lower-leg muscles as they jumped from a 35-cm platform onto force plates. Test trials were performed without tape (BL), immediately after application of Kinesio Tape to the ankle (KT-I), and after 24 h of continued use (KT-24). Peak ground-reaction forces (GRFs) and time to peak GRF were compared across taping conditions, and the timing and amplitude of muscle activity from the tibialis anterior, peroneus longus, and lateral gastrocnemius were compared across taping conditions. No significant differences in amplitude or timing of GRFs were observed (P > .05). However, muscle activity was observed to decrease from BL to KT-I in the tibialis anterior (P = .027) and from BL to KT-24 in the PL (P = .022). The data suggest that Kinesio Tape decreases muscle activity in the ankle during a drop-jump maneuver, although no changes in GRFs were observed. This is contrary to the proposed mechanisms of Kinesio Tape. Further research might investigate how this affects participants with a history of injury.


Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta-analysis of Published Studies.
It has been proposed that night shift work could increase breast cancer incidence. A 2007 World Health Organization review concluded, mainly from animal evidence, that shift work involving circadian disruption is probably carcinogenic to humans. We therefore aimed to generate prospective epidemiological evidence on night shift work and breast cancer incidence. Overall, 522 246 Million Women Study, 22 559 EPIC-Oxford, and 251 045 UK Biobank participants answered questions on shift work and were followed for incident cancer. Cox regression yielded multivariable-adjusted breast cancer incidence rate ratios (RRs) and 95% confidence intervals (CIs) for night shift work vs no night shift work, and likelihood ratio tests for interaction were used to assess heterogeneity. Our meta-analyses combined these and relative risks from the seven previously published prospective studies (1.4 million women in total), using inverse-variance weighted averages of the study-specific log RRs. In the Million Women Study, EPIC-Oxford, and UK Biobank, respectively, 673, 28, and 67 women who reported night shift work developed breast cancer, and the RRs for any vs no night shift work were 1.00 (95% CI = 0.92 to 1.08), 1.07 (95% CI = 0.71 to 1.62), and 0.78 (95% CI = 0.61 to 1.00). In the Million Women Study, the RR for 20 or more years of night shift work was 1.00 (95% CI = 0.81 to 1.23), with no statistically significant heterogeneity by sleep patterns or breast cancer risk factors. Our meta-analysis of all 10 prospective studies included 4660 breast cancers in women reporting night shift work; compared with other women, the combined relative risks were 0.99 (95% CI = 0.95 to 1.03) for any night shift work, 1.01 (95% CI = 0.93 to 1.10) for 20 or more years of night shift work, and 1.00 (95% CI = 0.87 to 1.14) for 30 or more years. The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer incidence.


Costs to Health Services and the Patient of Treating Tuberculosis: A Systematic Literature Review.
Novel tuberculosis (TB) drugs and the need to treat drug-resistant tuberculosis (DR-TB) are likely to bring about substantial transformations in TB treatment in coming years. An evidence base for cost and cost-effectiveness analyses of these developments is needed. Our objective was to perform a review of papers assessing provider-incurred as well as patient-incurred costs of treating both drug-susceptible (DS) and multidrug-resistant (MDR)-TB. Five databases (EMBASE, Medline, the National Health Service Economic Evaluation Database, the Cost-Effectiveness Analysis Registry, and Latin American and Caribbean Health Services Literature) were searched for cost and economic evaluation full-text papers containing primary DS-TB and MDR-TB treatment cost data published in peer-reviewed journals between January 1990 and February 2015. No language restrictions were set. The search terms were a combination of 'tuberculosis', 'multidrug-resistant tuberculosis', 'cost', and 'treatment'. In the selected papers, study methods and characteristics, quality indicators and costs were extracted into summary tables according to pre-defined criteria. Results were analysed according to country income groups and for provider costs, patient costs and productivity losses. All values were converted to $US, year 2014 values, so that studies could be compared. We selected 71 treatment cost papers on DS-TB only, ten papers on MDR-TB only and nine papers that included both DS-TB and MDR-TB. These papers provided evidence on the costs of treating DS-TB and MDR-TB in 50 and 16 countries, respectively. In 31 % of the papers, only provider costs were included; 26 % included only patient-incurred costs, and the remaining 43 % estimated costs incurred by both. From the provider perspective, mean DS-TB treatment costs per patient were US$14,659 in high-income countries (HICs), US$840 in upper middle-income countries (UMICs), US$273 in lower middle-income (LMICs), and US$258 in low-income countries (LICs), showing a strong positive correlation. The respective costs for treating MDR-TB were US$83,365, US$5284, US$6313 and US$1218. Costs incurred by patients when seeking treatment for DS-TB accounted for an additional 3 % of the provider costs in HICs. A greater burden was seen in the other income groups, increasing the costs of DS-TB treatment by 72 % in UMICs, 60 % in LICs and 31 % in LMICs. When provider costs, patient costs and productivity losses were combined, productivity losses accounted for 16 % in HICs, 29 % in UMICs, 40 % in LMICs and 38 % in LICs. Cost data for MDR-TB treatment are limited, and the variation in delivery mechanisms, as well as the rapidly evolving diagnosis and treatment regimens, means that it is essential to increase the number of studies assessing the cost from both provider and patient perspectives. There is substantial evidence available on the costs of DS-TB treatment from all regions of the world. The patient-incurred costs illustrate that the financial burden of illness is relatively greater for patients in poorer countries without universal healthcare coverage.


Structural and kinetic characterizations of the polysialic acid O-acetyltransferase OatWY from Neisseria meningitidis.
The neuroinvasive pathogen Neisseria meningitidis has 13 capsular serogroups, but the majority of disease is caused by only 5 of these. Groups B, C, Y, and W-135 all display a polymeric sialic acid-containing capsule that provides a means for the bacteria to evade the immune response during infection by mimicking host sialic acid-containing cell surface structures. These capsules in serogroups C, Y, and W-135 can be further acetylated by a sialic acid-specific O-acetyltransferase, a modification that correlates with decreased immunoreactivity and increased virulence. In N. meningitidis serogroup Y, the O-acetylation reaction is catalyzed by the enzyme OatWY, which we show has clear specificity toward the serogroup Y capsule ([Glc-(alpha1-->4)-Sia](n)). To understand the underlying molecular basis of this process, we have performed crystallographic analysis of OatWY with bound substrate as well as determined kinetic parameters of the wild type enzyme and active site mutants. The structure of OatWY reveals an intimate homotrimer of left-handed beta-helix motifs that frame a deep active site cleft selective for the polysialic acid-bearing substrate. Within the active site, our structural, kinetic, and mutagenesis data support the role of two conserved residues in the catalytic mechanism (His-121 and Trp-145) and further highlight a significant movement of Tyr-171 that blocks the active site of the enzyme in its native form. Collectively, our results reveal the first structural features of a bacterial sialic acid O-acetyltransferase and provide significant new insight into its catalytic mechanism and specificity for the capsular polysaccharide of serogroup Y meningococci.


Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.
According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimer's disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.


Investigating the potential impact of 1.5, 2 and 3 °C global warming levels on crop suitability and planting season over West Africa.
West African rainfed agriculture is highly vulnerable to climate variability and change. Global warming is projected to result in higher regional warming and have a strong impact on agriculture. This study specifically examines the impact of global warming levels (GWLs) of 1.5°, 2° and 3 °C relative to 1971-2000 on crop suitability over West Africa. We used 10 Coupled Model Intercomparison Project Phase5 Global Climate Models (CMIP5 GCMs) downscaled by Coordinated Regional Downscaling Experiment (CORDEX) Rossby Centre's regional Atmospheric model version 4, RCA4, to drive Ecocrop, a crop suitability model, for pearl millet, cassava, groundnut, cowpea, maize and plantain. The results show Ecocrop simulated crop suitability spatial representation with higher suitability, observed to the south of latitude 14°N and lower suitability to its north for 1971-2000 for all crops except for plantain (12°N). The model also simulates the best three planting months within the growing season from September-August over the past climate. Projected changes in crop suitability under the three GWLs 1.5-3.0 °C suggest a spatial suitability expansion for legume and cereal crops, notably in the central southern Sahel zone; root and tuber and plantain in the central Guinea-Savanna zone. In contrast, projected decreases in the crop suitability index value are predicted to the south of 14°N for cereals, root and tuber crops; nevertheless, the areas remain suitable for the crops. A delay of between 1-3 months is projected over the region during the planting month under the three GWLs for legumes, pearl millet and plantain. A two month delay in planting is projected in the south, notably over the Guinea and central Savanna zone with earlier planting of about three months in the Savanna-Sahel zones. The effect of GWL2.0 and GWL3.0 warming in comparison to GWL1.5 °C are more dramatic on cereals and root and tuber crops, especially cassava. All the projected changes in simulated crop suitability in response to climatic variables are statistically significant at 99% confidence level. There is also an increasing trend in the projected crop suitability change across the three warming except for cowpea. This study has implications for improving the resilience of crop production to climate changes, and more broadly, to food security in West Africa.


Norovirus vaccine against experimental human GII.4 virus illness: a challenge study in healthy adults.
Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission. In this randomized, double-blind, placebo-controlled trial, 18- to 50-year-olds received 2 injections of placebo or norovirus GI.1/GII.4 bivalent vaccine-like particle (VLP) vaccine with 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and alum. Participants were challenged as inpatients with GII.4 virus (4400 reverse transcription polymerase chain reaction [RT-PCR] units), and monitored for illness and infection. Per protocol, 27 of 50 (54.0%) vaccinees and 30 of 48 (62.5%) controls were infected. Using predefined illness and infection definitions, vaccination did not meet the primary endpoint, but self-reported cases of severe (0% vaccinees vs. 8.3% controls; P = .054), moderate or greater (6.0% vs. 18.8%; P = .068), and mild or greater severity of vomiting and/or diarrhea (20.0% vs. 37.5%; P = .074) were less frequent. Vaccination also reduced the modified Vesikari score from 7.3 to 4.5 (P = .002). Difficulties encountered were low norovirus disease rate, and inability to define illness by quantitative RT-PCR or further antibody rise in vaccinees due to high vaccine-induced titers. By day 10, 11 of 49 (22.4%) vaccinees were shedding virus compared with 17 of 47 (36.2%) placebo recipients (P = .179). Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration. NCT01609257.


Temperature treatments during larval development reveal extensive heritable and plastic variation in gene expression and life history traits.
Little is known about variation in gene expression that affects life history traits in wild populations of outcrossing species. Here, we analyse heritability of larval development traits and associated variation in gene expression in the Glanville fritillary butterfly (Melitaea cinxia) across three ecologically relevant temperatures. We studied the development of final-instar larvae, which is greatly affected by temperature, and during which stage larvae build up most of the resources for adult life. Larval development time and weight gain varied significantly among families sampled from hundreds of local populations, indicating substantial heritable variation segregating in the large metapopulation. Global gene expression analysis using common garden-reared F2 families revealed that 42% of the >8000 genes surveyed exhibited significant variation among families, 39% of the genes showed significant variation between the temperature treatments, and 18% showed a significant genotype-by-environment interaction. Genes with large family and temperature effects included larval serum protein and cuticle-binding protein genes, and the expression of these genes was closely correlated with the rate of larval development. Significant expression variation in these same categories of genes has previously been reported among adult butterflies originating from newly established versus old local populations, supporting the notion of a life history syndrome put forward based on ecological studies and involving larval development and adult dispersal capacity. These findings suggest that metapopulation dynamics in heterogeneous environments maintain heritable gene expression variation that affects the regulation of life history traits.


CLIPPERS: A case report with radiology, three serial biopsies and a literature review.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disorder primarily affecting the brainstem and cerebellum. We report a case of CLIPPERS in a 45-year-old man presenting with left facial numbness and dizziness. Imaging studies were conducted repeatedly over an 8-year follow-up period. Given diagnostic uncertainty in the early stages of the disease, three serial biopsies were obtained, which together with the clinical and radiological findings, led to the diagnosis. This case highlights the diagnostic challenges regarding the rare entity of CLIPPERS and discusses the main differential diagnoses that are necessary to consider. Additionally, some of the atypical features of this case, including the presenting finding of a large, solidly enhancing lesion on radiological imaging and prominent plasma cells on pathology, contribute to expanding the spectrum of appearances for CLIPPERS.


Contaminant deposition building shielding factors for US residential structures.
This paper presents validated building shielding factors designed for contemporary US housing-stock under an idealized, yet realistic, exposure scenario from contaminant deposition on the roof and surrounding surfaces. The building shielding factors are intended for use in emergency planning and level three probabilistic risk assessments for a variety of postulated radiological events in which a realistic assessment is necessary to better understand the potential risks for accident mitigation and emergency response planning. Factors are calculated from detailed computational housing-units models using the general-purpose Monte Carlo N-Particle computational code, MCNP5, and are benchmarked from a series of narrow- and broad-beam measurements analyzing the shielding effectiveness of ten common general-purpose construction materials and ten shielding models representing the primary weather barriers (walls and roofs) of likely US housing-stock. Each model was designed to scale based on common residential construction practices and include, to the extent practical, all structurally significant components important for shielding against ionizing radiation. Calculations were performed for floor-specific locations from contaminant deposition on the roof and surrounding ground as well as for computing a weighted-average representative building shielding factor for single- and multi-story detached homes, both with and without basement as well for single-wide manufactured housing-unit.


Waves of endemic foot-and-mouth disease in eastern Africa suggest feasibility of proactive vaccination approaches.
Livestock production in Africa is key to national economies, food security and rural livelihoods, and > 85% of livestock keepers live in extreme poverty. With poverty elimination central to the Sustainable Development Goals, livestock keepers are therefore critically important. Foot-and-mouth disease is a highly contagious livestock disease widespread in Africa that contributes to this poverty. Despite its US$2.3 billion impact, control of the disease is not prioritized: standard vaccination regimens are too costly, its impact on the poorest is underestimated, and its epidemiology is too weakly understood. Our integrated analysis in Tanzania shows that the disease is of high concern, reduces household budgets for human health, and has major impacts on milk production and draft power for crop production. Critically, foot-and-mouth disease outbreaks in cattle are driven by livestock-related factors with a pattern of changing serotype dominance over time. Contrary to findings in southern Africa, we find no evidence of frequent infection from wildlife, with outbreaks in cattle sweeping slowly across the region through a sequence of dominant serotypes. This regularity suggests that timely identification of the epidemic serotype could allow proactive vaccination ahead of the wave of infection, mitigating impacts, and our preliminary matching work has identified potential vaccine candidates. This strategy is more realistic than wildlife-livestock separation or conventional foot-and-mouth disease vaccination approaches. Overall, we provide strong evidence for the feasibility of coordinated foot-and-mouth disease control as part of livestock development policies in eastern Africa, and our integrated socioeconomic, epidemiological, laboratory and modelling approach provides a framework for the study of other disease systems.


Penta-Pt2N4: an ideal two-dimensional material for nanoelectronics.
Since the discovery of graphene, two-dimensional (2D) materials have paved new ways to design high-performance nanoelectronic devices. To facilitate applications of such devices, there are three key requirements that a material needs to fulfill: sizeable band gap, high carrier mobility, and robust environmental stability. However, among the most popular 2D materials studied in recent years, graphene is gapless, hexagonal boron nitride has a very large band gap, transition metal dichalcogenides have low carrier mobility, and black phosphorene is ambience-sensitive. Thus far, these three characteristics could seldom be satisfied by only a single material. Therefore, it is a great challenge to find an ideal 2D material that can overcome these limitations. In this study, we theoretically predicted a novel planar 2D material penta-Pt2N4, which was designed using the Cairo pentagonal tiling as well as the rare nitrogen double bonds. Most significantly, 2D penta-Pt2N4 exhibits excellent intrinsic properties, including large direct band gap (up to 1.51 eV), high carrier mobility (up to 105 cm2·V-1·s-1), very high Young's modulus (up to 0.70 TPa), and robust dynamic, thermal, and ambient stabilities. Moreover, penta-Pt2N4 is the global minimum structure among 2D materials with PtN2 stoichiometry. We also propose a CVD/MBE scheme to enable its experimental synthesis. We envision that 2D penta-Pt2N4 may find wide applications in the field of nanoelectronics.


Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.
Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.