Association of elevated fasting glucose with increased short-term and 6-month mortality in ST-segment elevation and non-ST-segment elevation acute coronary syndromes: the Global Registry of Acute Coronary Events.
Elevated blood glucose level at admission is associated with worse outcome after a myocardial infarction. The impact of elevated glucose level, particularly fasting glucose, is less certain in non-ST-segment elevation acute coronary syndromes. We studied the relationship between elevated fasting blood glucose levels and outcome across the spectrum of ST-segment elevation and non-ST-segment elevation acute coronary syndromes in a large multicenter population broadly representative of clinical practice. Fasting glucose levels were available for 13 526 patients in the Global Registry of Acute Coronary Events. A multivariate logistic regression analysis was used for assessing the association between admission or fasting glucose level and in-hospital or 6-month outcome, adjusted for the variables from the registry risk scores. Higher fasting glucose levels were associated with a graded increase in the risk of in-hospital death (odds ratios [95% confidence intervals] vs <100 mg/dL: 1.51 [1.12-2.04] for 100-125 mg/dL, 2.20 [1.64-2.60] for 126-199 mg/dL, 5.11 [3.52-7.43] for 200-299 mg/dL, and 8.00 [4.76-13.5] for > or =300 mg/dL). When taken as a continuous variable, higher fasting glucose level was related to a higher probability of in-hospital death, without detectable threshold and irrespective of whether patients had a history of diabetes mellitus. Higher fasting glucose levels were found to be associated with a higher risk of postdischarge death up to 6 months. The risk of postdischarge death at 6 months was significantly higher with fasting glucose levels between 126 and 199 mg/dL (1.71 [1.25-2.34]) and 300 mg/dL or greater (2.93 [1.33-6.43]), but not within the 200- to 299-mg/dL range (1.08 [0.60-1.95]). Short-term and 6-month mortality was increased significantly with higher fasting glucose levels in patients across the spectrum of acute coronary syndromes, thus extending this relation to patients with non-ST-segment elevation myocardial infarction. The relation between fasting glucose level and risk of adverse short-term outcomes is graded across different glucose levels with no detectable threshold for diabetic or nondiabetic patients.


High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation.
This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.


Contrasting effects of natural selection on human and chimpanzee CC chemokine receptor 5.
Human immunodeficiency virus type 1 (HIV-1) evolved via cross-species transmission of simian immunodeficiency virus (SIVcpz) from chimpanzees (Pan troglodytes). Chimpanzees, like humans, are susceptible to infection by HIV-1. However, unlike humans, infected chimpanzees seldom develop immunodeficiency when infected with SIVcpz or HIV-1. SIVcpz and most strains of HIV-1 require the cell-surface receptor CC chemokine receptor 5 (CCR5) to infect specific leukocyte subsets, and, subsequent to infection, the level of CCR5 expression influences the amount of HIV-1 entry and the rate of HIV-1 replication. Evidence that variants in the 5' cis-regulatory region of CCR5 (5'CCR5) affect disease progression in humans suggests that variation in CCR5 might also influence the response of chimpanzees to HIV-1/SIVcpz. To determine whether patterns of genetic variation at 5'CCR5 in chimpanzees are similar to those in humans, we analyzed patterns of DNA sequence variation in 37 wild-born chimpanzees (26 P. t. verus, 9 P. t. troglodytes, and 2 P. t. schweinfurthii), along with previously published 5'CCR5 data from 112 humans and 50 noncoding regions in the human and chimpanzee genomes. These analyses revealed that patterns of variation in 5'CCR5 differ dramatically between chimpanzees and humans. In chimpanzees, 5'CCR5 was less diverse than 80% of noncoding regions and was characterized by an excess of rare variants. In humans, 5'CCR5 was more diverse than 90% of noncoding regions and had an excess of common variants. Under a wide range of demographic histories, these patterns suggest that, whereas human 5'CCR5 has been subject to balancing selection, chimpanzee 5'CCR5 has been influenced by a selective sweep. This result suggests that chimpanzee 5'CCR5 might harbor or be linked to functional variants that influence chimpanzee resistance to disease caused by SIVcpz/HIV-1.


MutMap+: genetic mapping and mutant identification without crossing in rice.
Advances in genome sequencing technologies have enabled researchers and breeders to rapidly associate phenotypic variation to genome sequence differences. We recently took advantage of next-generation sequencing technology to develop MutMap, a method that allows rapid identification of causal nucleotide changes of rice mutants by whole genome resequencing of pooled DNA of mutant F2 progeny derived from crosses made between candidate mutants and the parental line. Here we describe MutMap+, a versatile extension of MutMap, that identifies causal mutations by comparing SNP frequencies of bulked DNA of mutant and wild-type progeny of M3 generation derived from selfing of an M2 heterozygous individual. Notably, MutMap+ does not necessitate artificial crossing between mutants and the wild-type parental line. This method is therefore suitable for identifying mutations that cause early development lethality, sterility, or generally hamper crossing. Furthermore, MutMap+ is potentially useful for gene isolation in crops that are recalcitrant to artificial crosses.


Conjugated polymer-porphyrin complexes for organic electronics.
We present the synthesis of novel conjugated polymer-porphyrin complexes for use in organic electronics. Linear and star-shaped platinated porphyrins were attached to regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT) arms to investigate whether porphyrin stacking and increased dimensionality can be used to control polymer morphology. The novel materials display similar optical properties to P3HT, but give higher mobilities when used in organic field-effect transistors. Atomic force microscopy measurements show that incorporation of only a small amount of porphyrin into the conjugated polymer backbone leads to increased aggregation. These materials demonstrate that polymer morphology and performance can be tuned and enhanced effectively through the use of conjugatively linked porphyrins.


A first-principles model of copper-boron interactions in Si: implications for the light-induced degradation of solar Si.
The recent discovery that Cu contamination of Si combined with light exposure has a significant detrimental impact on carrier life-time has drawn much concern within the solar-Si community. The effect, known as the copper-related light-induced degradation (Cu-LID) of Si solar cells, has been connected to the release of Cu interstitials within the bulk (2016 Sol. Energy Mater. Sol. Cells 147 115-26). In this paper, we describe a comprehensive analysis of the formation/dissociation process of the CuB pair in Si by means of first-principles modelling, as well as the interaction of CuB defects with photo-excited minority carriers. We confirm that the long-range interaction between the [Formula: see text] cation and the [Formula: see text] anion has a Coulomb-like behaviour, in line with the trapping-limited diffusivity of Cu observed by transient ion drift measurements. On the other hand, the short-range interaction between the d-electrons of Cu and the excess of negative charge on [Formula: see text] produces a repulsive effect, thereby decreasing the binding energy of the pair when compared to the ideal point-charge Coulomb model. We also find that metastable CuB pairs produce acceptor states just below the conduction band minimum, which arise from the Cu level emptied by the B acceptor. Based on these results, we argue that photo-generated minority carriers trapped by the metastable pairs can switch off the Coulomb interaction that holds the pairs together, enhancing the release of Cu interstitials, and acting as a catalyst for Cu-LID.


Biomarker tests for the diagnosis of Alzheimer's disease: Generating evidence to inform insurance coverage determinations.
Outside of their uses in drug development and clinical research trials, the current clinical value of performing any type of formal biomarker testing for the diagnosis or exclusion of Alzheimer's disease (AD) is controversial, and most biomarker tests for AD are not covered by public or private insurers. This situation raises the issue of how insurers determine whether there is "adequate" evidence to justify a positive coverage determination in this area. This article, a focused condensation of a larger white paper, is the product of an initiative led by the Institute for Clinical and Economic Review to convene a multiple-stakeholder AD Diagnostics Policy Development Group composed of patient advocates, clinicians, clinical researchers, manufacturers, and insurers. The larger white paper was the basis for the evidence review presented to the Medicare Evidence Development and Coverage Advisory Committee meeting on January 30, 2013, as part of its deliberations on positron emission tomography-amyloid imaging. Herein we focus on the description of the core elements of what insurers will be looking for in evidence on all potential diagnostic tests for AD. Corresponding research recommendations are also included, framed to serve as a guide for future AD diagnostics research.


Brain effects of TMS delivered over prefrontal cortex in depressed adults: role of stimulation frequency and coil-cortex distance.
Relative regional brain blood flow was measured in 23 clinically depressed adults by using ECD SPECT at baseline and again during actual prefrontal transcranial magnetic stimulation (TMS) following 5 daily sessions of TMS. TMS over prefrontal cortex caused increased activity in cortex directly under the stimulation (inversely correlated with distance from scalp to cortex) and decreased activity in remote regions (anterior cingulate and anterior temporal poles). High-frequency rTMS (20 Hz) caused more relative flow immediately below the TMS coil than did low-frequency rTMS (5 Hz). Confirming the hypotheses tested, repeated daily TMS over the prefrontal cortex in medication-free depressed adults appears to change both local and remote blood flow in a manner that may also depend on the frequency of stimulation and coil to outer cortex distance.


On the Challenge of Interpreting Census Data: Insights from a Study of an Endangered Pinniped.
Population monitoring is vital for conservation and management. However, simple counts of animals can be misleading and this problem is exacerbated in seals (pinnipeds) where individuals spend much time foraging away from colonies. We analyzed a 13-year-series of census data of Galapagos sea lions (Zalophus wollebaeki) from the colony of Caamaño, an islet in the center of the Galapagos archipelago where a large proportion of animals was individually marked. Based on regular resighting efforts during the cold, reproductive (cold-R; August to January) and the warm, non-reproductive (warm-nR; February to May) season, we document changes in numbers for different sex and age classes. During the cold-R season the number of adults increased as the number of newborn pups increased. Numbers were larger in the morning and evening than around mid-day and not significantly influenced by tide levels. More adults frequented the colony during the warm-nR season than the cold-R season. Raw counts suggested a decline in numbers over the 13 years, but Lincoln-Petersen (LP-) estimates (assuming a closed population) did not support that conclusion. Raw counts and LP estimates were not significantly correlated, demonstrating the overwhelming importance of variability in attendance patterns of individuals. The probability of observing a given adult in the colony varied between 16% (mean for cold-R season) and 23% (warm-nR season) and may be much less for independent 2 to 4 year olds. Dependent juveniles (up to the age of about 2 years) are observed much more frequently ashore (35% during the cold-R and 50% during the warm-nR seasons). Simple counts underestimate real population size by a factor of 4-6 and may lead to erroneous conclusions about trends in population size.


Hepatic differentiation and maturation of human embryonic stem cells cultured in a perfused three-dimensional bioreactor.
Drug-induced liver injury is a serious and frequently occurring adverse drug reaction in the clinics and is hard to predict during preclinical studies. Today, primary hepatocytes are the most frequently used cell model for drug discovery and prediction of toxicity. However, their use is marred by high donor variability regarding drug metabolism and toxicity, and instable expression levels of liver-specific genes such as cytochromes P450. An in vitro model system based on human embryonic stem cells (hESC), with their unique properties of pluripotency and self-renewal, has potential to provide a stable and unlimited supply of human hepatocytes. Much effort has been made to direct hESC toward the hepatic lineage, mostly using 2-dimensional (2D) cultures. Although the results are encouraging, these cells lack important functionality. Here, we investigate if hepatic differentiation of hESC can be improved by using a 3-dimensional (3D) bioreactor system. Human ESCs were differentiated toward the hepatic lineage using the same cells in either the 3D or 2D system. A global transcriptional analysis identified important differences between the 2 differentiation regimes, and we identified 10 pathways, highly related to liver functions, which were significantly upregulated in cells differentiated in the bioreactor compared to 2D control cultures. The enhanced hepatic differentiation observed in the bioreactor system was also supported by immunocytochemistry. Taken together, our results suggest that hepatic differentiation of hESC is improved when using this 3D bioreactor technology as compared to 2D culture systems.


Spatio-temporal patterns of genetic change amongst populations of cassava Bemisia tabaci whiteflies driving virus pandemics in East and Central Africa.
The greatest current threat to cassava in sub-Saharan Africa, is the continued expansion of plant virus pandemics being driven by super-abundant populations of the whitefly vector, Bemisia tabaci. To track the association of putatively genetically distinct populations of B. tabaci with pandemics of cassava mosaic disease (CMD) and cassava brown streak disease (CBSD), a comprehensive region-wide analysis examined the phylogenetic relationships and population genetics of 642 B. tabaci adults sampled from cassava in six countries of East and Central Africa, between 1997 and 2010, using a mitochondrial DNA cytochrome oxidase I marker (780 bases). Eight phylogenetically distinct groups were identified, including one, designated herein as 'East Africa 1' (EA1), not previously described. The three most frequently occurring groups comprised >95% of all samples. Among these, the Sub-Saharan Africa 2 (SSA2) group diverged by c. 8% from two SSA1 sub-groups (SSA1-SG1 and SSA1-SG2), which themselves were 1.9% divergent. During the 14-year study period, the group associated with the CMD pandemic expansion shifted from SSA2 to SSA1-SG1. Population genetics analyses of SSA1, using Tajima's D, Fu's Fs and Rojas' R2 statistics confirmed a temporal transition in SSA1 populations from neutrally evolving at the outset, to rapidly expanding from 2000 to 2003, then back to populations more at equilibrium after 2004. Based on available evidence, hybrid introgression appears to be the most parsimonious explanation for the switch from SSA2 to SSA1-SG1 in whitefly populations driving cassava virus pandemics in East and Central Africa.


A new species of the Cyrtodactylus (Geckoella) collegalensis (Beddome, 1870) complex (Squamata: Gekkonidae) from Western India.
A new species of Cyrtodactylus (Geckoella) from the C. collegalensis complex is described based on a series of specimens from western and central India. Morphological and molecular data support the distinctiveness of the new form, which can be diagnosed from other Cyrtodactylus (including other Geckoella) species by its small body size (snout to vent length to 56 mm), the absence of precloacal and femoral pores, no enlarged preanal or femoral scales, and a dorsal scalation consisting wholly of small, granular scales. The new species is most closely related to C. collegalensis, C. speciosus and C. yakhuna, from which it differs by the presence of a patch of enlarged roughly hexagonal scales on the canthus rostralis and beneath the angle of jaw, its relatively long limbs and narrow body, and a dorsal colour pattern of 4-6 pairs of dark spots.


Hospital volume, calendar age, and short term outcomes in patients undergoing repair of abdominal aortic aneurysms: the Ontario experience, 1988-92.
To determine, for abdominal aortic aneurysm surgery, whether a previously reported relationship between hospital case volume and mortality rate was observed in Ontario hospitals and to assess the potential impact of age on the mortality rate for elective surgery. Population based observational study using administrative data. All Ontario hospitals where repair of abdominal aortic aneurysm as a primary procedure was performed during 1988-92. These comprised 5492 patients with unruptured abdominal aortic aneurysms and 1203 patients with ruptured abdominal aortic aneurysms admitted to hospital between 1988-92 for repair of abdominal aortic aneurysm as a primary procedure. In-hospital death and length of in-hospital stay. The case fatality rate was 3.8% for unruptured abdominal aortic aneurysms and 40.0% for ruptured abdominal aortic aneurysms. For unruptured cases, after adjustment for patient and hospital covariates, each 10 case per year increase in hospital volume was related to a 6% reduction in relative odds of death (odds ratio (OR) 0.94, 95% confidence intervals 0.88, 0.99) and 0.29 days reduction (95% CI -0.22, -0.35) in postoperative in-hospital stay. Female sex (OR 1.53, 95% CI 1.08, 2.18) and transfer from another acute care hospital (OR 4.37, 95% CI 2.62, 7.29) were associated with increased case fatality rates among patients in the unruptured category. For ruptured cases, neither the case fatality rate nor postoperative in-hospital stay were significantly related to hospital volume. The case fatality rates increased linearly and substantially with advancing age both for unruptured and ruptured aneurysms, and the excess risk of postoperative death in ruptured as compared to unruptured aneurysms was substantially higher in older patients. The relationship between hospital volume and mortality or morbidity was very modest and observed only for elective surgery. Case fatality rates in patients with ruptured abdominal aortic aneurysms remained 10 times higher than for patients with unruptured abdominal aortic aneurysms, despite improvements in overall mortality in comparison to previously published data. More effective detection of aneurysms, including elective repair for those once considered "high risk" older patients, might further reduce the toll from ruptured aortic aneurysms.


Anterior cruciate ligament injuries in the skeletally immature patient.
Anterior cruciate ligament injury in the skeletally immature is becoming increasingly recognized and reported. History taking and physical examination based on the principles of ACL injuries in adults, with adjuncts such as arthroscopy and MRI, are effective in diagnosing ACL injury in the young patient. Evaluation of the young patient's true level of skeletal immaturity by comparison with family growth history, examination for signs of sexual maturity, and radiographic evaluation is critical. The risk of physeal damage with surgical treatment is related to the immaturity of the distal femoral and proximal tibial physes. The functional results of nonsurgical treatment of ACL injury, either as an attempt at definitive treatment or as a temporizing plan until skeletal maturity occurs, are poor and the risks of reinjury and further meniscal and cartilage damage are significant. Surgical treatment for primary repair or extra-articular reconstruction alone has not proven to be efficacious. In the adolescent patient who is approaching skeletal maturity, risk of physeal injury is low and intra-articular reconstruction can be performed as in the adult patient. Results with respect to decreased laxity and return to athletic activities mirror those described in adults. In patients with significant growth remaining, however, surgical treatment carries much higher risks of physeal damage and subsequent deformity. Yet, as noted above, intra-articular reconstruction in truly skeletally immature patients using a soft-tissue graft through a transphyseal tibial tunnel of moderate or small diameter and the over-the-top position on the femur has not been shown to cause early physeal closure, limb-length discrepancy, or angular deformity. In humans, the maximum diameter of graft tunnel that will not cause physeal closure has not been determined Animal studies have shown that the tibial physis can be very sensitive to drilling. Therefore it is wise to use moderate tunnel diameters. Bone-patellar tendon-bone grafts have been used with success in patients closer to skeletal maturity. Their use has not been reported in the very skeletally immature knee and cannot be recommended because of the presumed high risk of physeal closure with a bone plug traversing the physis. It is hoped that improved understanding of the ACL injury in the skeletally immature patient will provide treatment options that will restore enduring knee function and prevent early arthrosis.


Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse.
A growing number of studies suggest that the development of compulsive drug seeking and taking depends on dorsostriatal mechanisms. We previously observed that ex vivo acute exposure of the dorsal striatum to, and withdrawal from, alcohol induces long-term facilitation (LTF) of the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in a mechanism that requires the Src family protein tyrosine kinase (PTK), Fyn (Wang et al., 2007). In the present study, we first compared alcohol's actions in rat dorsomedial (DMS) and the dorsolateral (DLS) subregions of the striatum, which differ in their anatomical connectivity and function. We found that alcohol-mediated induction of LTF of NR2B-NMDAR activity is centered in the DMS. Next, we tested whether in vivo exposure of rats to alcohol leads to long-term adaptations of the NMDAR system in the DMS. We observed that repeated daily administration of alcohol results in a long-lasting increase in the activity of the NR2B-NMDARs in the DMS. The same procedure leads to a prolonged activation of Fyn, increased NR2B phosphorylation, and membrane localization of the subunit. Importantly, similar electrophysiological and biochemical modifications were observed in the DMS of rats that consumed large quantities of alcohol. Finally, we show that inhibition of NR2B-NMDARs or Src family PTKs in the DMS, but not in the DLS, significantly decreases operant self-administration of alcohol and reduces alcohol-priming-induced reinstatement of alcohol seeking. Our results suggest that the upregulation of NR2B-NMDAR activity within the DMS by alcohol contributes to the maladaptive synaptic changes that lead to excessive alcohol intake and relapse.


Study protocol. The Childhood Health, Activity, and Motor Performance School Study Denmark (The CHAMPS-study DK).
An increasingly passive life-style in the Western World has led to a rise in life-style related disorders. This is a major concern for all segments of society. The county council of the municipality of Svendborg in Denmark, created six Sport Schools with increased levels of suitable physical activities, which made it possible to study the health outcomes in these children whilst comparing them to children who attended the 'normal' schools of the region using the design of a "natural experiment". Children from the age of 6 till the age of 10, who accepted to be included in the monitoring process, were surveyed at baseline with questionnaires, physical examinations and physical and biological testing, including DXA scans. The physical examination and testing was repeated during the early stage of the study. Every week over the whole study period, the children will be followed with an automated mobile phone text message (SMS-Track) asking questions on their leisure time sports activities and the presence of any musculoskeletal problems. Children who report any such problems are monitored individually by health care personnel. Data are collected on demography, health habits and attitudes, physical characteristics, physical activity using accelerometers, motor performance, fitness, bone health, life-style disorders, injuries and musculoskeletal problems. Data collection will continue at least once a year until the children reach grade 9. This project is embedded in a local community, which set up the intervention (The Sport Schools) and thereafter invited researchers to provide documentation and evaluation. Sport schools are well matched with the 'normal' schools, making comparisons between these suitable. However, subgroups that would be specifically targeted in lifestyle intervention studies (such as the definitely obese) could be relatively small. Therefore, results specific to minority groups may be diluted. Nonetheless, the many rigorously collected data will make it possible to study, for example, the general effect that different levels of physical activity may have on various health conditions and on proxy measures of life-style conditions. Specifically, it will help answer the question on whether increased physical activity in school has a positive effect on health in children.


Establishing the range of perceptually natural visual walking speeds for virtual walking-in-place locomotion.
Walking-In-Place (WIP) techniques make it possible to facilitate relatively natural locomotion within immersive virtual environments that are larger than the physical interaction space. However, in order to facilitate natural walking experiences one needs to know how to map steps in place to virtual motion. This paper describes two within-subjects studies performed with the intention of establishing the range of perceptually natural walking speeds for WIP locomotion. In both studies, subjects performed a series of virtual walks while exposed to visual gains (optic flow multipliers) ranging from 1.0 to 3.0. Thus, the slowest speed was equal to an estimate of the subjects normal walking speed, while the highest speed was three times greater. The perceived naturalness of the visual speed was assessed using self-reports. The first study compared four different types of movement, namely, no leg movement, walking on a treadmill, and two forms of gestural input for WIP locomotion. The results suggest that WIP locomotion is accompanied by a perceptual distortion of the speed of optic flow. The second study was performed using a 4×2 factorial design and compared four different display field-of-views (FOVs) and two types of movement, walking on a treadmill and WIP locomotion. The results revealed significant main effects of both movement type and field of view, but no significant interaction between the two variables. Particularly, they suggest that the size of the display FOV is inversely proportional to the degree of underestimation of the virtual speeds for both treadmill-mediated virtual walking and WIP locomotion. Combined, the results constitute a first attempt at establishing a set of guidelines specifying what virtual walking speeds WIP gestures should produce in order to facilitate a natural walking experience.


The Amsterdam Studies of Acute Psychiatry I (ASAP-I); a prospective cohort study of determinants and outcome of coercive versus voluntary treatment interventions in a metropolitan area.
The overall number of involuntary admissions is increasing in many European countries. Patients with severe mental illnesses more often progress to stages in which acute, coercive treatment is warranted. The number of studies that have examined this development and possible consequences in terms of optimizing health care delivery in emergency psychiatry is small and have a number of methodological shortcomings. The current study seeks to examine factors associated with compulsory admissions in the Amsterdam region, taking into account a comprehensive model with four groups of predictors: patient vulnerability, social support, responsiveness of the health care system and treatment adherence. This paper describes the design of the Amsterdam Study of Acute Psychiatry-I (ASAP-I). The study is a prospective cohort study, with one and two-year follow-up, comparing patients with and without forced admission by means of a selected nested case-control design. An estimated total number of 4,600 patients, aged 18 years and over, consecutively coming into contact with the Psychiatric Emergency Service Amsterdam (PESA) are included in the study. From this cohort, a randomly selected group of 125 involuntary admitted subjects and 125 subjects receiving non-coercive treatment are selected for further evaluation and comparison.First, socio-demographic, psychopathological and network characteristics, and prior use of health services will be described for all patients who come into contact with PESA. Second, the in-depth study of compulsory versus voluntary patients will examine which patient characteristics are associated with acute compulsory admission, also taking into account social network and healthcare variables. The third focus of the study is on the associations between patient vulnerability, social support, healthcare characteristics and treatment adherence in a two-year follow-up for patients with or without involuntarily admittance at the index consultation. The current study seeks to establish a picture of the determinants of acute compulsory admissions in the Netherlands and tries to gain a better understanding of the association with the course of illness and patient's perception of services and treatment adherence. The final aim is to find specific patient and health care factors that can be influenced by adjusting treatment programs in order to reduce the number of involuntary admissions.


Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases.
Because O(6)-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.


Memory Glass: An Amorphous Material Formed from AlPO4.
A glass exhibiting structural memory has been produced through the compression of a single crystal of AlPO(4) berlinite to 18 gigapascals at 300 kelvin. The unique and extraordinary characteristic of this glass is that upon decompression below 5 gigapascals it transforms back into a single crystal with the same orientation as the starting crystal. This glass has a "memory" of the previous crystallographic orientation of the crystal from which it forms.


Analysis of lipoproteins by capillary zone electrophoresis in microfluidic devices: assay development and surface roughness measurements.
The development of a new assay for lipoproteins by capillary electrophoresis in fused-silica capillaries and in glass microdevices is described in this paper. The separation of low-density (LDL) and high-density (HDL) lipoproteins by capillary zone electrophoresis is demonstrated in fused-silica capillaries with both UV absorption and laser-induced fluorescence detection. This separation was accomplished using Tricine buffer (pH 9.0) with methylglucamine added as a dynamic coating. With UV detection, LDL eluted as a relatively sharp peak with a migration time of approximately 11 min and HDL eluted as a broad peak with a migration time of 12.5 min. Fluorescence detection of lipoproteins stained with NBD-ceramide was used with the same buffer system to give comparable results. Furthermore, fluorescence staining of human serum samples yielded results similar to the fluorescently stained LDL and HDL fractions, showing that this method can be used to quantify lipoproteins in serum samples. The method was also used to detect lipoproteins in glass micro-CE devices. Very similar results were obtained in microdevices although with much faster analysis times, LDL eluted as a sharp peak at approximately 25 s and HDL as a broad peak at slightly longer time. In addition, higher resolution was obtained on chips. To our knowledge, these results show the first separation and detection of lipoproteins in a microfluidic device using native serum samples. Atomic force microscopy was used to characterize the rms surface roughness (Rq) of microfluidic channels directly. Devices with different surface roughness values were fabricated using two different etchants for Pyrex wafers with a polysilicon masking layer. Using 49% HF, the measured roughness is Rq = 10.9 +/- 1.6 nm and with buffered HF (NH4F + HF) the roughness is Rq = 2.4 +/- 0.7 nm. At this level of surface roughness, there is no observable effect on the performance of the devices for this lipoprotein separation.


Validation of the Sicca Symptoms Inventory for clinical studies of Sjögren's syndrome.
Oral, ocular, and other dryness are the hallmark features of Sjögren's syndrome (SS). We constructed a new measure of sicca symptoms, the Sicca Symptoms Inventory, for the evaluation of patients with primary SS. Female Caucasian groups of patients with primary SS, systemic lupus erythematosus, and rheumatoid arthritis and healthy controls were assessed for tear and saliva production and also completed a symptoms-profiling inventory construct-validated from primary SS patients' own vocabulary, augmented with sicca items from publications and participating clinicians. Multi-item facets of sicca and other discomfort were validated by factor analysis. Primary SS and other "sicca" conditions were highly discriminated from other rheumatic disorders and healthy controls on each dryness-related facet of oral and ocular discomfort. Selected symptom scores were as sensitive and specific to primary SS as the scores for saliva and tears, respectively, although the severity scores of symptoms and signs were only moderately correlated. These multiple-question scales distinguish patients with primary SS from controls more precisely than previously used measures. Future studies will test if change in these symptom scores can serve as an outcome measure for clinical trials in SS.


Cerivastatin, genetic variants, and the risk of rhabdomyolysis.
The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63). We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.


Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways.
Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high-dimensional data sets makes it difficult to fully understand the underlying biological features present in the data.The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first "Archetypal Analysis" of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data.


The role of acetylcholine in the cognitive function of frontal neurons in monkeys.
To study the role of acetylcholine (ACh) in the cognitive function of frontal lobes, ACh and atropine were applied iontophoretically to the task-related neurons recorded from an area around the superior ramus of arcuate sulcus in the frontal cortex of 4 rhesus monkeys during the performance of two tasks. The spontaneous discharges and task-related responses of most of the neurons which increased their discharge rate in the delay and differentiation periods of the discrimination response go/no-go task and in the cue and delay periods of the delayed discrimination go/no-go task, were further increased during the application of ACh and suppressed during atropine. These results suggest that ACh may be involved in the excitatory process of the activity of the neurons in the above-mentioned area of frontal cortex to play an important role in the cognitive functions of attention, discrimination and short-term memory.


MO-C-BRCD-03: The Role of Informatics in Medical Physics and Vice Versa.
Like Medical Physics, Imaging Informatics encompasses concepts touching every aspect of the imaging chain from image creation, acquisition, management and archival, to image processing, analysis, display and interpretation. The two disciplines are in fact quite complementary, with similar goals to improve the quality of care provided to patients using an evidence-based approach, to assure safety in the clinical and research environments, to facilitate efficiency in the workplace, and to accelerate knowledge discovery. Use-cases describing several areas of informatics activity will be given to illustrate current limitations that would benefit from medical physicist participation, and conversely areas in which informaticists may contribute to the solution. Topics to be discussed include radiation dose monitoring, process management and quality control, display technologies, business analytics techniques, and quantitative imaging. Quantitative imaging is increasingly becoming an essential part of biomedicalresearch as well as being incorporated into clinical diagnostic activities. Referring clinicians are asking for more objective information to be gleaned from the imaging tests that they order so that they may make the best clinical management decisions for their patients. Medical Physicists may be called upon to identify existing issues as well as develop, validate and implement new approaches and technologies to help move the field further toward quantitative imaging methods for the future. Biomedical imaging informatics tools and techniques such as standards, integration, data mining, cloud computing and new systems architectures, ontologies and lexicons, data visualization and navigation tools, and business analytics applications can be used to overcome some of the existing limitations. 1. Describe what is meant by Medical Imaging Informatics and understand why the medical physicist should care. 2. Identify existing limitations in information technologies with respect to Medical Physics, and conversely see how Informatics may assist the medical physicist in filling some of the current gaps in their activities. 3. Understand general informatics concepts and areas of investigation including imaging and workflow standards, systems integration, computing architectures, ontologies, data mining and business analytics, data visualization and human-computer interface tools, and the importance of quantitative imaging for the future of Medical Physics and Imaging Informatics. 4. Become familiar with on-going efforts to address current challenges facing future research into and clinical implementation of quantitative imaging applications.


Allocating scarce resources strategically--an evaluation and discussion of the Global Fund's pattern of disbursements.
The Global Fund is under pressure to improve its rationing of financial support. This study describes the GF's pattern of disbursements in relation to total health expenditure (THE), government health expenditure (GHE), income status and the burden of HIV/AIDS, TB and malaria. It also examines the potential for recipient countries to increase domestic public financing for health. This is a cross-sectional study of 104 countries that received Global Fund disbursements in 2009. It analyses data on Global Fund disbursements; health financing indicators; government revenue and expenditure; and burden of disease. Global Fund disbursements made up 0.37% of THE across all 104 countries; but with considerable country variation ranging from 0.002% to 53.4%. Global Fund disbursements to government amounted to 0.47% of GHE across the 104 countries, but again with considerable variation (in three countries more than half of GHE was based on Global Fund support). Although the Global Fund provides progressively more funding for lower income countries on average, there is much variation at the country such that here was no correlation between per capita GF disbursements and per capita THE, nor between per capita GF disbursement to government and per capita GHE. There was only a slight positive correlation between per capita GF disbursement and burden of disease. Several countries with a high degree of 'financial dependency' upon the Fund have the potential to increase levels of domestic financing for health. The Global Fund can improve its targeting of resources so that it better matches the pattern of global need. To do this it needs to: a) reduce the extent to which funds are allocated on a demand-driven basis; and b) align its funding model to broader health systems financing and patterns of health expenditure beyond the three diseases.


Comparison of the prevalence and distribution of human papillomavirus infection and cervical lesions between urban and native habitants of an Amazonian region of Peru.
We made a study of the prevalence of human papillomavirus (HPV) and cervix lesions in an Amazonian Bora native population (Bn) and compared it with the prevalence in an urban population in Iquitos (Iq). We also examined the distribution of HPV types among abnormal cervical smears in the Iq population. Swabs and cytologies were collected from 472 females. DNA consensus PCR, followed by direct sequencing, were used to determinate the HPV types in the swabs. Cytologies were classified based on the lesion grade. HPV prevalence was 43.9% in Iq and 35.4% in Bn. Cervix lesion prevalence was 20.0% in Iq and 0.3% in Bn. The frequency of high-risk HPV types among HPV+ females was 71.9% in Iq and 56.3% in Bn. The frequencies of low-risk and undetermined risk HPV types were 19.3/6.3% (Iq/ Bn) and 12.3/37.5% (Iq/Bn), respectively. In lesIq (women seeking cytological services with a previous cervix lesion diagnosis) the prevalence of HPV, was 72.9%. The incidence of carcinoma and high-grade squamous intraepithelial cervix lesions in lesIq were 31.2 and 18.8%, respectively. The Bn population had a lower incidence of high-risk HPV and cervix lesions. The high-risk strain HPV16 was significantly more frequent in Iq compared with Bn. lesIq high-risk HPVs were more frequent in high-grade squamous intraepithelial lesions and carcinoma. High-risk HPV16 prevalence was significantly higher than the prevalence of the other high-risk HPVs, especially in the high-grade squamous intraepithelial lesions and carcinoma.


Looking beyond the details: a rise in system-oriented approaches in genetics and molecular biology.
With the ever-increasing flow of high-throughput gene expression, protein interaction and genome sequence data, researchers gradually approach a system-level understanding of cells and even multi-cellular organisms. Systems biology is an emerging field that enables us to achieve in-depth understanding at the system level. For this, we need to establish methodologies and techniques that enable us to understand biological systems as systems, which means to understand: (1) the structure of the system, such as gene/metabolic/signal transduction networks and physical structures, (2) the dynamics of such systems, (3) methods to control systems, and (4) methods to design and modify systems to generate desired properties. However, the meaning of "system-level understanding" is still ambiguous. This paper reviews the current status of the field and outlines future research directions and issues that need to be addressed.


Immunomodulating and antiproteinuric effect of Hippophae rhamnoides (Badriphal) in idiopathic nephrotic syndrome.
The treatment of idiopathic nephrotic syndrome is still not well settled and at times is very frustrating. Number of protocols have been reported with variable results outcome in various conditions. The main pillar of treatment of idiopathic nephrotic syndrome is use of immunomodulating and suppressive drugs in various combinations. The herbal preparations have also been reported to have immunomodulating property. The study has been planned to record Immunomodulating and antiproteinuric effect of Hippophae rhamnoides. In the present study had 2 groups having 28 patients of idiopathic nephrotic syndrome in each group have been included. The patients were subjected to haematological, biochemical, immunological investigation at 0, 1, 2 and 3 months interval with dietic advise. Group A have been put on standard treatment, whereas group B on Badriphal in the well worked up doses. The hydroalcoholic extract of 350 mg twice daily of Badriphal was given to group B as add on treatment. Patients were followed up with definite protocol at monthly interval for 3 months. At the end of 3 month patients showed improvement in the symptoms of oedema, anorexia, oliguria in the herbal group. The urinary estimation of protein showed significant decrease in Group B with elevation of S. albumin levels. The inflammatory cytokines has showed significant decrease at the end of 3 month. Thus the pilot study showed beneficial effect of the herbal preparation Hippophae rhamnoides as add on treatment. A large perspective study is recommended to establish these findings.


Informal Control by Family and Risk Markers for Alcohol Abuse/Dependence in Seoul.
Although previous research documents a reliable relationship between physical intimate partner violence (IPV) victimization and alcoholism, relatively little research has examined new theoretical constructs in IPV research that may increase risk for or help buffer women from alcohol abuse/dependence. The purpose of the present study was to examine informal social control of IPV by family members as a protective factor against and coercive control as a risk factor for alcohol abuse/dependence in a small population sample of married women in Seoul, South Korea. We hypothesized that (a) informal social control by family members would be negatively associated with victim alcohol abuse/dependence and (b) husband's coercive control would be positively associated with victim alcohol abuse/dependence. We measured alcohol abuse/dependence (CAGE scale), IPV and coercive control by husbands, and informal social control of IPV (ISC_IPV) by extended family members in a three-stage random cluster sample of 462 married women in Seoul, South Korea. Both random effects regression and zero-inflated Poisson regression models found that ISC_IPV by extended family members was associated with a significantly lower CAGE scores, and coercive control was associated with significantly higher CAGE scores. Interventions to boost ISC_IPV by extended family members may mitigate some of the risk of alcohol abuse/dependence by victims.


Kinesio taping compared to physical therapy modalities for the treatment of shoulder impingement syndrome.
The purpose of this study was to determine and compare the efficacy of kinesio tape and physical therapy modalities in patients with shoulder impingement syndrome. Patients (n = 55) were treated with kinesio tape (n = 30) three times by intervals of 3 days or a daily program of local modalities (n = 25) for 2 weeks. Response to treatment was evaluated with the Disability of Arm, Shoulder, and Hand scale. Patients were questioned for the night pain, daily pain, and pain with motion. Outcome measures except for the Disability of Arm, Shoulder, and Hand scale were assessed at baseline, first, and second weeks of the treatment. Disability of Arm, Shoulder, and Hand scale was evaluated only before and after the treatment. Disability of Arm, Shoulder, and Hand scale and visual analog scale scores decreased significantly in both treatment groups as compared with the baseline levels. The rest, night, and movement median pain scores of the kinesio taping (20, 40, and 50, respectively) group were statistically significantly lower (p values were 0.001, 0.01, and 0.001, respectively) at the first week examination as compared with the physical therapy group (50, 70, and 70, respectively). However, there was no significant difference in the same parameters between two groups at the second week (0.109, 0.07, and 0.218 for rest, night, and movement median pain scores, respectively). Disability of Arm, Shoulder, and Hand scale scores of the kinesio taping group were significantly lower at the second week as compared with the physical therapy group. No side effects were observed. Kinesio tape has been found to be more effective than the local modalities at the first week and was similarly effective at the second week of the treatment. Kinesio taping may be an alternative treatment option in the treatment of shoulder impingement syndrome especially when an immediate effect is needed.


Tinnitus Retraining Therapy (TRT): outcomes after one-year treatment.
The aim of the study is to present our results regarding the efficacy of TRT for tinnitus relief in patients with clinically significant tinnitus compared to a group treated with vasoactive agents. In a nonrandomized prospective study, 63 patients with disabling tinnitus were recruited. Greek translation of the Tinnitus Handicap Inventory (THI) and visual analogue scale (VAS) for annoyance caused by tinnitus when conducting four major activities of everyday life (work, sleep, relaxation and concentration) were examined in a 12-month period. The THI score was significantly improved in the TRT group, as well as mean VAS scores, in all measures. Comparison of the mean improvement of THI and VAS scores after treatment showed significant differences between the two groups, favoring TRT treatment. Our data suggest that TRT is an effective treatment. It reduces the level of annoyance induced by tinnitus and improves the ability of patients to work, sleep, relax or be concentrated.


Retinotopic organization in children measured with fMRI.
Many measures of visual function reach adult levels by about age 5, but some visual abilities continue to develop throughout adolescence. Little is known about the underlying functional anatomy of visual cortex in human infants or children. We used fMRI to measure the retinotopic organization of visual cortex in 15 children aged 7-12 years. Overall, we obtained adult-like patterns for most children tested. We found that significant head motion accounted for poor quality maps in a few tested children who were excluded from further analysis. When the maps from 10 children were compared with those obtained from 10 adults, the magnitude of retinotopic signals in visual areas V1, V2, V3, V3A, VP, and V4v was essentially the same between children and adults. Furthermore, one measure of intra-area organization, the cortical magnification function, did not significantly differ between adults and children for V1 or V2. However, quantitative analysis of visual area size revealed some significant differences beyond V1. Adults had larger extrastriate areas (V2, V3, VP, and V4v), when measured absolutely or as a proportion of the entire cortical sheet. We found that the extent and laterality of retinotopic signals beyond these classically defined areas, in parietal and lateral occipital cortex, showed some differences between adults and children. These data serve as a useful reference for studies of higher cognitive function in pediatric populations and for studies of children with vision disorders, such as amblyopia.


The effect of mammography screening regimen on incidence-based breast cancer mortality.
Incidence-based mortality quantifies the distribution of cancer deaths and life-years lost, according to age at detection. We investigated the temporal distribution of the disease burden, and the effect of starting and stopping ages and interval between screening mammography examinations, on incidence-based mortality. Incidence-based mortality was estimated using an established breast cancer simulation model, adapted and validated to simulate breast cancer incidence, screening performance, and delivery of therapies in Canada. Ten strategies were examined, with varying starting age (40 or 50), stopping age (69 or 74), and interval (1, 2, 3 years), and "No Screening." Life-years lost were computed as the difference between model predicted time of breast cancer death and that estimated from life tables. Without screening, 70% of the burden in terms of breast cancer deaths extends between ages 45 and 75. The mean of the distribution of ages of detection of breast cancers that will be fatal in an unscreened population is 61.8 years, while the mean age of detection weighted by the number of life-years lost is 55, a downward shift of 6.8 years. Similarly, the mean age of detection for the distribution of life-years gained through screening is lower than that for breast cancer deaths averted. Incidence-based mortality predictions from modeling elucidate the age dependence of the breast cancer burden and can provide guidance for optimizing the timing of screening regimens to achieve maximal impact. Of the regimens studied, the greatest lifesaving effect was achieved with annual screening beginning at age 40.


Iron deficiency following bariatric surgery: a retrospective cohort study.
Iron deficiency is a common consequence of bariatric surgery and frequently leads to anemia. Our study reports the incidence and predictors of iron deficiency, iron deficiency anemia (IDA), and IV iron use after bariatric surgery. We conducted a retrospective study of all adult patients who underwent bariatric surgery from January to December 2012 at the regional bariatric surgery center in Hamilton, Ontario, Canada, and were followed for at least 6 months. Time-to-event data were presented as Kaplan-Meier curves. Cox regression analysis was used to identify outcome predictors. A total of 388 patients met the inclusion criteria. Iron deficiency, IDA, and the use of IV iron were reported in 43%, 16%, and 6% of patients, respectively, with a mean follow-up of 31 months. The cumulative incidence of iron deficiency and IDA increased with longer follow-up, and there was a significant increase in IV iron use starting 3 years after surgery. Malabsorptive procedures (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.20-3.06; P = .006) and low baseline ferritin (HR, 0.96; 95% CI, 0.95-0.97; P < .001) were associated with an increased risk of iron deficiency. Young age (HR, 0.90; 95% CI, 0.82-0.99; P = .028), baseline anemia (HR, 19.6; 95% CI, 7.85-48.9; P < .001), and low baseline ferritin (HR, 0.96; 95% CI, 0.95-0.98; P < .001) were associated with an increased risk of IDA. Our results suggest that IDA is a delayed consequence of bariatric surgery and that preoperative assessment of patient risk may be possible.


Simulation-based estimates of effectiveness and cost-effectiveness of smoking cessation in patients with chronic obstructive pulmonary disease.
The medico-economic impact of smoking cessation considering a smoking patient with chronic obstructive pulmonary disease (COPD) is poorly documented. Here, considering a COPD smoking patient, the specific burden of continuous smoking was estimated, as well as the effectiveness and the cost-effectiveness of smoking cessation. A multi-state Markov model adopting society's perspective was developed. Simulated cohorts of English COPD patients who are active smokers (all severity stages combined or patients with the same initial severity stage) were compared to identical cohorts of patients who quit smoking at cohort initialization. Life expectancy, quality adjusted life-years (QALY), disease-related costs, and incremental cost-effectiveness ratio (ICER: £/QALY) were estimated, considering smoking cessation programs with various possible scenarios of success rates and costs. Sensitivity analyses included the variation of model key parameters. At the horizon of a smoking COPD patient's remaining lifetime, smoking cessation at cohort intitialization, relapses being allowed as observed in practice, would result in gains (mean) of 1.27 life-years and 0.68 QALY, and induce savings of -1824 £/patient in the disease-related costs. The corresponding ICER was -2686 £/QALY. Smoking cessation resulted in 0.72, 0.69, 0.64 and 0.42 QALY respectively gained per mild, moderate, severe, and very severe COPD patient, but was nevertheless cost-effective for mild to severe COPD patients in most scenarios, even when hypothesizing expensive smoking cessation intervention programmes associated with low success rates. Considering a ten-year time horizon, the burden of continuous smoking in English COPD patients was estimated to cost a total of 1657 M£ while 452516 QALY would be simultaneously lost. The study results are a useful support for the setting of smoking cessation programmes specifically targeted to COPD patients.


Polyploids exhibit higher potassium uptake and salinity tolerance in Arabidopsis.
Genome duplication (or polyploidization) has occurred throughout plant evolutionary history and is thought to have driven the adaptive radiation of plants. We found that the cytotype of the root, and not the genotype, determined the majority of heritable natural variation in leaf potassium (K) concentration in Arabidopsis thaliana. Autopolyploidy also provided resistance to salinity and may represent an adaptive outcome of the enhanced K accumulation of plants with higher ploidy.


Tobacco smoking among government employees in six cities in China.
Employer-based tobacco control interventions have been highly successful in developed countries, and, recently, Chinese officials announced a focus on quitting among government employees. However, there are few data offering estimates of smoking prevalence among government workers from developing nations. In this study, we investigate smoking behaviours among government workers in six Chinese cities stratified by educational attainment and occupational grade. Individual-level study of Chinese government employees. Tobacco-Free Cities Initiative of China Tobacco Control Partnership. Employed adults aged 18-61 at government worksites in six cities were included (N=6176). Prevalence of current and former smoking across educational (postgraduate, graduate, high school, secondary school or less) and occupational (senior executives, mid-level managers, workers) groups were compared. Overall prevalence of male current smoking was 40.7% (95% CI 39.1% to 42.4%). Age-adjusted smoking prevalence was lowest among those with a postgraduate degree (26.2% (95% CI 21.0% to 31.4%)) compared with those with lower levels of education (college (39.8%; 37.7% to 41.8%); high school (51.0%; 95% CI 45.0% to 57.0%); secondary or less (45.1%; 95% CI 40.3% to 49.8%)). There was no evidence of an association between current smoking and occupational grade. Prevalence of smoking was low in women (1.5%). Smoking prevalence among male government employees at all levels of education was high and patterned by educational attainment. Government initiatives to address tobacco control among employees should consider targeted interventions for different educational levels.


Centering contraception: postpartum contraceptive choices of women enrolled in Centering group prenatal care versus traditional prenatal care.
To assess postpartum contraceptive choices of women participating in group versus traditional prenatal care. This is a retrospective cohort study assessing postpartum contraceptive choices of women participating in group versus traditional prenatal care. Patients were derived from a database of all deliveries from 1 January 2009 to 31 December 2014 at Christiana Hospital in Newark, Delaware, USA. Within this database, group prenatal care patients were identified and a two-to-one matched set of similar traditional prenatal care patients was created. Contraceptive methods utilised by these women were ascertained via chart review. The proportion of women using each method in each care model was calculated. Multinomial logistic regression was carried out for statistical analysis. Included in the final analysis were 867 patients: 289 group and 587 traditional prenatal care participants. Groups were similar in selection of sterilisation, condoms, injection, and other short-acting hormonal contraceptive methods (a composite of patch, vaginal ring, and pills). Group prenatal care patients were more likely to utilise contraception postpartum (as measured by use of no method with AOR 0.50, 95% CI 0.32 to 0.78, P=0.002), particularly long-acting reversible contraceptives (LARCs) (OR 1.67, 95% CI 1.16 to 2.40, P=0.005). This difference was most pronounced for women aged 20-24 years (AOR 1.98, 95% CI 1.10 to 3.56). Participation in group prenatal care as opposed to traditional prenatal care increases use of postpartum contraception and increases uptake of LARCs. The association of group prenatal care participation with LARC use is particularly apparent for women aged 20-24 years.


Modelling the neuromotor abnormalities of psychotic illness: Putative mechanisms and systems dysfunction.
Limitations in access to antipsychotic-naïve patients and in the incisiveness of studies that can be conducted on them, together with the inevitability of subsequent antipsychotic treatment, indicate an enduring role for animal models that can inform on the pathobiology of neuromotor abnormalities in schizophrenia and related psychotic illness. This review focusses particularly on genetically modified mouse models that involve genes associated with risk for schizophrenia and with mechanisms implicated in the neuromotor abnormalities evident in psychotic patients, as well as developmental models that seek to mirror the trajectory, phenomenology and putative pathophysiology of psychotic illness. Such abnormalities are inconsistent and subtle in mice mutant for some schizophrenia risk genes but more evident for others. The phenotype of dopaminergic and glutamatergic mutants indicates the involvement of these mechanisms, informs on the roles of specific receptor subtypes, and implicates the interplay of cortical and subcortical processes. Developmental models suggest a criticality in the timing of early adversity for diversity in the relative emergence of psychological symptoms vis-à-vis neuromotor abnormalities in the overall psychosis phenotype. These findings elaborate current concepts of dysfunction in a neuronal network linking the cerebral cortex, basal ganglia, thalamus and cerebellum. Both findings in model systems and clinical evidence converge in indicating that any distinction between 'psychomotor' and 'neuromotor' abnormality is artificial and arbitrary due to a unitary origin in developmentally determined systems/network dysfunction that underlies the lifetime trajectory of psychotic illness.


Prenatal diagnosis of esophageal atresia using sonography and magnetic resonance imaging.
The diagnosis of esophageal atresia may be suspected on prenatal ultrasound scan in fetuses with a small or absent stomach or unexplained polyhydramnios. However, these findings are thought to have a low positive predictive value and clinical decisions affecting timing or site of delivery may be made erroneously. The authors evaluated the accuracy of fetal sonography followed by magnetic resonance imaging (MRI) for the diagnosis of this lesion. Fetuses considered to be at risk for esophageal atresia based on detailed obstetric sonography underwent fetal MRI using a single-shot rapid-acquisition technique, and the T(2)-weighted images were evaluated prospectively. Scans were considered to be positive if the proximal esophagus was dilated, and the distal esophagus was not seen and negative if the esophagus was visualized throughout its length. Ten fetuses underwent MRI scanning. All had a small or absent stomach bubble with unexplained polyhydramnios. Four scans were considered to be negative for esophageal atresia; all 4 were found to have a normal esophagus after delivery. Six scans were considered to be positive; 5 had esophageal atresia (2 with tracheoesophageal fistula and 3 without), and one had a neurologic syndrome with a normal esophagus. Magnetic resonance imaging appears to be accurate for establishing or ruling out a prenatal diagnosis of esophageal atresia, and should be considered in fetuses who are at high risk based on ultrasound findings.


Effect of arterial pressure and inheritance on the sodium excretory capacity of normal young men.
1. In normal young adult sons of normotensive parents the rate of renal sodium excretion is highly correlated with mean arterial pressure after a large intravenous isotonic fluid load. The correlation appeared to strengthen with time and was improved when the rate of sodium excretion was corrected for variations in the rate of glomerular filtration. 2. There was no such correlation in normal, age-matched sons of hypertensive parents. 3. In eight of the 20 normotensive sons of hypertensive parents studied, the rate of renal sodium excretion per unit of mean arterial pressure was significantly higher than in the sons of normotensive parents. 4. Because the sons of hypertensive parents are much more likely to become hypertensive than those of normotensive parents, we suggest that an abnormality of renal sodium handling precedes the development of demonstrable hypertension.


Facial asymmetry tracks genetic diversity among Gorilla subspecies.
Mountain gorillas are particularly inbred compared to other gorillas and even the most inbred human populations. As mountain gorilla skeletal material accumulated during the 1970s, researchers noted their pronounced facial asymmetry and hypothesized that it reflects a population-wide chewing side preference. However, asymmetry has also been linked to environmental and genetic stress in experimental models. Here, we examine facial asymmetry in 114 crania from three Gorilla subspecies using 3D geometric morphometrics. We measure fluctuating asymmetry (FA), defined as random deviations from perfect symmetry, and population-specific patterns of directional asymmetry (DA). Mountain gorillas, with a current population size of about 1000 individuals, have the highest degree of facial FA (explaining 17% of total facial shape variation), followed by Grauer gorillas (9%) and western lowland gorillas (6%), despite the latter experiencing the greatest ecological and dietary variability. DA, while significant in all three taxa, explains relatively less shape variation than FA does. Facial asymmetry correlates neither with tooth wear asymmetry nor increases with age in a mountain gorilla subsample, undermining the hypothesis that facial asymmetry is driven by chewing side preference. An examination of temporal trends shows that stress-induced developmental instability has increased over the last 100 years in these endangered apes.


Mesoderm-inducing properties of INT-2 and kFGF: two oncogene-encoded growth factors related to FGF.
Many theories of neoplasia suggest that oncogenic transformations result from aberrations in the control mechanisms which normally regulate growth and differentiation during embryonic development. It has recently become clear that many proto-oncogenes are differentially expressed during embryonic development and may thus be important embryonic regulatory molecules. We report here that the products of two transforming oncogenes int-2 and hst/ks (now called kfgf) can, with different potencies, induce mesoderm formation in isolated Xenopus laevis animal pole explants and stimulate DNA synthesis in mammalian fibroblasts. The results suggest that these proteins may function as mesoderm inducers in mammalian embryogenesis and that similar receptor/signalling pathways may be utilized for developmental and oncogenic processes. Finally, we have shown that the Xenopus assay system used in this study provides a powerful screen for protein factors that are active in development.


IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia.
Infections and inflammation trigger neutrophilias that are supported by a hematopoietic program of accelerated granulopoiesis known as emergency granulopoiesis. The intrinsic factors that drive reactive neutrophilias and emergency granulopoiesis have been inferred but not demonstrated. Here, we show that alum cannot elicit reactive neutrophilias in IL-1R type I (IL-1RI)(-/-) mice, whereas other inflammatory responses, including eosinophilia and Ab production, remain intact. Analysis of this specific impairment revealed an unanticipated role for IL-1RI in supporting increased proliferation by granulocyte/macrophage progenitors and, surprisingly, multipotent progenitors and hematopoietic stem cells (HSC). Indeed, HSC and multipotent progenitor proliferative responses were most suppressed in IL-1RI(-/-) mice, suggesting a critical role for their proliferation in inflammatory granulopoiesis. Whereas IL-1 drives increased HSC proliferation directly in vitro, IL-1RI expression by radiation-resistant host cells was both necessary and sufficient for alum-induced HSC, multipotent progenitor, and granulocyte/macrophage progenitor proliferation and reactive neutrophilias in radiation chimeric mice. Thus, IL-1 plays a necessary, but indirect, role in the support of alum-induced neutrophilias by expanding both pluripotent and myeloid progenitor compartments to accelerate granulopoiesis.


Transactivated and chemically inducible gene expression in plants.
Several vector systems are available for tissue-specific transactivation or chemical induction of transgene expression in plants. The choice facing researchers is which promoter system to commit to as this determines the range and characteristics of the expression resources available. The decision will not be the same for all species or applications. We present some general discussion on the use of these technologies and review in detail the properties in various (mainly angiosperm) species of the most promising: mGal4:VP16/UAS and pOp/LhG4 for transactivation, and the alc-switch, GVE/VGE, GVG, pOp6/LhGR, and XVE systems for chemical induction.


Smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis.
To examine whether smoking is a risk factor for rheumatoid nodules in early rheumatoid arthritis, and if so to determine the quantitative effect of smoking. From a cohort (n = 1589) in a structured programme for follow up of newly diagnosed cases of rheumatoid arthritis (symptoms of swollen joints < or =12 months), 112 individuals with rheumatoid nodules at inclusion were identified. Nodular patients were each compared with two age and sex matched controls without nodules from the same cohort. A detailed self administered tobacco use questionnaire was answered by 210 patients (63%). Seventy patients were current smokers, 71 former smokers, and 69 had never smoked. Current smoking and former smoking were more common in patients with rheumatoid nodules compared with controls (86% v 59%) in both sexes. Positive rheumatoid factor (RF) was found more often among cases with nodules than controls (78% v 64%). Using detailed information from the questionnaires with conditional logistic regression analyses, ever having smoked was associated with an increased risk of the presence of rheumatoid nodules (odds ratio (OR) = 7.3 (95% confidence interval, 2.3 to 23.6); p = 0.001). The risk of having nodules was not obviously dose dependent when smoking duration as well as smoking amount were examined. A stratified analysis showed that only RF positive smokers had an increased risk of rheumatoid nodules. Smoking was associated with rheumatoid nodules among both men (p = 0.006) and women (p = 0.001). Tobacco use other than smoking (n = 31) was not associated with an increased risk of nodules (OR = 0.8 (0.2 to 3.4); p = 0.813). There is a strong association between smoking and rheumatoid nodules in early seropositive rheumatoid arthritis.


Global and comparative proteomic profiling of overwintering and developing mountain pine beetle, Dendroctonus ponderosae (Coleoptera: Curculionidae), larvae.
Mountain pine beetles, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae), are native to western North America, but have recently begun to expand their range across the Canadian Rocky Mountains. The requirement for larvae to withstand extremely cold winter temperatures and potentially toxic host secondary metabolites in the midst of their ongoing development makes this a critical period of their lives. We have uncovered global protein profiles for overwintering mountain pine beetle larvae. We have also quantitatively compared the proteomes for overwintering larvae sampled during autumn cooling and spring warming using iTRAQ methods. We identified 1507 unique proteins across all samples. In total, 33 proteins exhibited differential expression (FDR < 0.05) when compared between larvae before and after a cold snap in the autumn; and 473 proteins exhibited differential expression in the spring when measured before and after a steady incline in mean daily temperature. Eighteen proteins showed significant changes in both autumn and spring samples. These first proteomic data for mountain pine beetle larvae show evidence of the involvement of trehalose, 2-deoxyglucose, and antioxidant enzymes in overwintering physiology; confirm and expand upon previous work implicating glycerol in cold tolerance in this insect; and provide new, detailed information on developmental processes in beetles. These results and associated data will be an invaluable resource for future targeted research on cold tolerance mechanisms in the mountain pine beetle and developmental biology in coleopterans.


Sam68 from an immortalised B-cell line associates with a subset of SH3 domains.
The binding of proteins from an immortalised B-cell line to a panel of SH3 domains was investigated in vitro. One of the most prominent SH3 domain binding proteins was a 68 kD polypeptide which strongly associated with the SH3 domains of c-src, p85a and p47phox and weakly with the SH3 domain of PLCgamma and n-src with undetectable binding to the other SH3 domains tested. Immunoblotting identified this protein as human Sam68. The ability of proline-rich peptides homologous to the Sam68 primary sequence to inhibit the binding of Sam68 to SH3 domains was investigated. Only one peptide inhibited binding of Sam68 to the p85alpha SH3 domain, whereas several peptides inhibited binding of Sam68 to c-src SH3 domain, suggesting that Sam68 uses different proline-rich motifs to bind to different SH3 domains. A peptide derived from residues 32-44 of Sam68 which fits the class II SH3 domain binding consensus sequence inhibited binding of Sam68 to both p85alpha SH3 domain and c-src SH3 domain, but with differential potency, suggesting a differential affinity of these SH3 domains for this proline-rich motif.


Prevention and treatment of experimental autoimmune encephalomyelitis with clonotypic CDR3 peptides: CD4(+) Foxp3(+) T-regulatory cells suppress interleukin-2-dependent expansion of myelin basic protein-specific T cells.
T-cell receptor (TCR)-derived peptides are recognized by the immune system and are capable of modulating autoimmune responses. Using the myelin basic protein (MBP) TCR 1501 transgenic mouse model, we demonstrated that TCR CDR3 peptides from the transgenic TCR can provide a protective effect when therapy is initiated before the induction of experimental autoimmune encephalomyelitis (EAE). More importantly, TCR CDR3 peptide therapy can ameliorate the disease when administered after EAE onset. Concurrent with the therapeutic effects, we observed reduced T-cell proliferation and reduced interleukin-2 (IL-2) levels in response to stimulation with MBP-85-99 peptide in splenocyte cultures from mice receiving TCR CDR3 peptides compared with that of control mice. Moreover, we found that Foxp3(+) CD4 T cells from mice protected with TCR CDR3 peptide are preferentially expanded in the presence of IL-2. This is supportive of a proposed mechanism where Foxp3(+) T-regulatory cells induced by therapy with MBP-85-99 TCR CDR3 peptides limit expansion and the encephalitogenic activity of MBP-85-99-specific T cells by regulating the levels of secreted IL-2.


Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration.
Age-related macular degeneration (AMD) is the leading cause of vision loss in individuals over the age of 65. Histopathological changes become evident in the retinal pigment epithelium (RPE), a monolayer that provides metabolic support for the overlying photoreceptors, even at the earliest stages of AMD that precede vision loss. In a previous global RPE proteome analysis, changes were identified in the content of several mitochondrial proteins associated with AMD. In this study, the subproteome of mitochondria isolated from human donor RPE graded with the Minnesota Grading System (MGS) was analyzed. Human donor eye bank eyes were categorized into one of four progressive stages (MGS 1-4) based on the clinical features of AMD. After dissection of the RPE, mitochondrial proteins were isolated and separated by two-dimensional gel electrophoresis based on their charge and mass. Protein spot densities were compared between the four MGS stages. Peptides from spots that changed significantly with MGS stage were extracted and analyzed by using mass spectrometry to identify the protein. Western blot analyses verified that mitochondria were consistently enriched between MGS stages. The densities of eight spots increased or decreased significantly as a function of MGS stage. These spots were identified as the alpha-, beta-, and delta-ATP synthase subunits, subunit VIb of the cytochrome c oxidase complex, mitofilin, mtHsp70, and the mitochondrial translation factor Tu. The results are consistent with the hypothesis that mitochondrial dysfunction is associated with AMD and further suggest specific pathophysiological mechanisms involving altered mitochondrial translation, import of nuclear-encoded proteins, and ATP synthase activity.


ERISA and health plans.
This Issue Brief is designed to provide a basic understanding of the relationship of the Employee Retirement Income Security Act of 1974 (ERISA) to health plans. It is based, in part, on an Employee Benefit Research Institute-Education and Research Fund (EBRI-ERF) educational briefing held in March 1995. This report includes a section by Peter Schmidt of Arnold & Porter, a section about multiemployer plans written by Judy Mazo of The Segal Company; and a section about ERISA and state health reform written by Kala Ladenheim of the Intergovernmental Health Policy Project. Starting in the late 1980s, three trends converged to make ERISA a critical factor in state health reforms: increasingly comprehensive state health policy experimentation; changes in the makeup of the insurance market (including the rise in self-insurance and the growth of managed care); and increasingly expansive interpretations of ERISA by federal courts. The changing interpretations of ERISA's relationship to three categories of state health initiatives--insurance mandates, medical high risk pools, and uncompensated care pools--illustrate how these forces are playing out today. ERISA does have a very broad preemptive effect. Federal statutes do not need to say anything about preemption in order to preempt state law. For example, if there is a direct conflict, it would be quite clear under the Supremacy Clause [of the U.S. Constitution] that ERISA, or any federal statue, would preempt a directly conflicting state statute. States can indirectly regulate health care plans that provide benefits through insurance contracts by establishing the terms of the contract. And they also raise money by imposing premium taxes. But they cannot do the same with respect to self-funded plans. That is one of the factors that has caused a great rise in the number of self-funded plans. State regulation [of employee benefits] can create three kinds of problems: cost of taxes, fees, or other charges; cost of dealing with substantive, possibly inconsistent, benefit standards; and cost of identifying, understanding, and complying with the regulations themselves.


Making research matter: a civil society perspective on health research.
Complex global public health challenges such as the rapidly widening health inequalities, and unprecedented emergencies such as the pandemic of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) demand a reappraisal of existing priorities in health policies, expenditure and research. Research can assist in mounting an effective response, but will require increased emphasis on health determinants at both the national and global levels, as well as health systems research and broad-based and effective public health initiatives. Civil society organizations (CSOs) are already at the forefront of such research. We suggest that there are at least three ways in which the participation of CSOs in research can be increased: namely, influencing commissioning and priority-setting; becoming involved in the review process and in conducting research; and through formal partnerships between communities and universities that link CSOs with academic researchers.


Analysis of the electrostatics in Dy(III) single-molecule magnets: the case study of Dy(Murex)3.
A Dy(III)-based single-molecule magnet is reported. Ab initio calculations highlight that molecular symmetry plays a predominant role over site symmetry in determining the shape and orientation of Dy(III) magnetic anisotropy. Moreover the dipolar component of the electrostatic potential created by the surrounding ligands is shown to be the driving force of its magnetic behaviour.


Real-time analysis of nanopore-based metagenomic sequencing from infected orthopaedic devices.
Prosthetic joint infections are clinically difficult to diagnose and treat. Previously, we demonstrated metagenomic sequencing on an Illumina MiSeq replicates the findings of current gold standard microbiological diagnostic techniques. Nanopore sequencing offers advantages in speed of detection over MiSeq. Here, we report a real-time analytical pathway for Nanopore sequence data, designed for detecting bacterial composition of prosthetic joint infections but potentially useful for any microbial sequencing, and compare detection by direct-from-clinical-sample metagenomic nanopore sequencing with Illumina sequencing and standard microbiological diagnostic techniques. DNA was extracted from the sonication fluids of seven explanted orthopaedic devices, and additionally from two culture negative controls, and was sequenced on the Oxford Nanopore Technologies MinION platform. A specific analysis pipeline was assembled to overcome the challenges of identifying the true infecting pathogen, given high levels of host contamination and unavoidable background lab and kit contamination. The majority of DNA classified (> 90%) was host contamination and discarded. Using negative control filtering thresholds, the species identified corresponded with both routine microbiological diagnosis and MiSeq results. By analysing sequences in real time, causes of infection were robustly detected within minutes from initiation of sequencing. We demonstrate a novel, scalable pipeline for real-time analysis of MinION sequence data and use of this pipeline to show initial proof of concept that metagenomic MinION sequencing can provide rapid, accurate diagnosis for prosthetic joint infections. The high proportion of human DNA in prosthetic joint infection extracts prevents full genome analysis from complete coverage, and methods to reduce this could increase genome depth and allow antimicrobial resistance profiling. The nine samples sequenced in this pilot study have shown a proof of concept for sequencing and analysis that will enable us to investigate further sequencing to improve specificity and sensitivity.


Teaching Old Dogs New Tricks? The Plasticity of Lung Alveolar Macrophage Subsets.
Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.


Postischemic (S)-emopamil therapy ameliorates focal ischemic brain injury in rats.
(S)-Emopamil is a calcium channel blocker of the phenylalkylamine class, having potent serotonin S2 antagonistic properties and high blood-brain barrier penetrability. Previous studies have documented cerebroprotective effect in animal models of both focal and global ischemia. The present study was undertaken to define the postischemic "window" of therapeutic efficacy for this agent. Sprague-Dawley rats were subjected to permanent proximal middle cerebral artery occlusion, combined with an initial 30-minute period of halothane-induced hypotension (50 mm Hg). (S)-Emopamil (20 mg/kg) was administered intraperitoneally either 20-30 minutes prior to middle cerebral artery occlusion or 1 hour, 2 hours, or 3 hours following occlusion. Treated groups received a second similar dose 2.5 hours later and twice daily for 2 days thereafter. Brains were perfusion-fixed on the third day. Planimetric analysis of hemotoxylin and eosin-stained coronal brain sections documented a cortical infarct averaging 72.9 +/- 33.3 mm3 (mean +/- SD) in untreated rats. Cortical infarct volume was reduced by 48% (to 37.6 +/- 27.6 mm3) when therapy was initiated 1 hour postischemia (p less than 0.05). When treatment was deferred to 2 hours postichemia, mean cortical infarct volume was reduced by 34%, but this difference did not attain statistical significance. Infarct volume in rats with treatment initiated at 3 hours postischemia was indistinguishable from that in controls. Striatal infarct volume was similar in all groups. These results document a postischemic therapeutic window of cerebroprotection for (S)-emopamil lying between 1 and 2 hours after middle cerebral artery occlusion.


Derivation and external validation of a simple risk tool to predict 30-day hospital readmissions after transcatheter aortic valve replacement.
Patients undergoing transcatheter aortic valve replacement (TAVR) possess a higher risk of recurrent healthcare resource utilisation due to multiple comorbidities, frailty, and advanced age. We sought to devise a simple tool to identify TAVR patients at increased risk of 30-day readmission. We used the Nationwide Readmissions Database from January 2013 to September 2015. Complex survey methods and hierarchical regression in R were implemented to create a prediction tool to determine probability of 30-day readmission. Boot-strapped internal validation and cross-validation were performed to assess model accuracy. External validation was performed using a single-centre data set. Of 39,305 patients who underwent endovascular TAVR, 6,380 (16.2%) were readmitted within 30 days. The final 30-day readmission risk prediction tool included the following variables: chronic kidney disease, end-stage renal disease on dialysis (ESRD), anaemia, chronic lung disease, chronic liver disease, atrial fibrillation, length of stay, acute kidney injury, and discharge disposition. ESRD (OR 2.11, 95% CI: 1.7-2.63), length of stay ≥5 days (OR 1.64, 95% CI: 1.50-1.79), and short-term hospital discharge disposition (OR 1.81, 95% CI: 1.2-2.7) were the strongest predictors. The c-statistic of the prediction model was 0.63. The c-statistic in the external validation cohort was 0.69. On internal calibration, the tool was extremely accurate in predicting readmissions up to 25%. A simple and easy-to-use risk prediction tool utilising standard clinical parameters identifies TAVR patients at increased risk of 30-day readmission. The tool may consequently inform hospital discharge planning, optimise transitions of care, and reduce resource utilisation.


A pilot study of diabetes education via telemedicine in a rural underserved community--opportunities and challenges: a continuous quality improvement process.
Telemedicine technology may offer an avenue to implement diabetes self-management education (DSME) for people with diabetes in underserved rural communities. The continuous quality improvement process was used to identify the problem, collect and analyze data, and develop and implement a DSME program via telemedicine (DSME-T) in an underserved rural community. A pilot study was conducted in 2006, implementing a DSME-T utilizing facilities at the University of Arkansas for Medical Sciences and a rural community hospital in Arkansas (Ozark Health, Inc). A total of 38 people were enrolled to receive DSME-T. Participant knowledge, self-efficacy, and self-care practices were assessed before participants began the education program and after they had completed it. Also, select clinical measures (glycosylated hemoglobin, lipid profile, and urine microalbumin) were collected. A total of 66% of participants (n = 25) completed the DSME-T program. A significantly greater proportion of participants demonstrated improved knowledge (39% vs 83%; P = .012), endorsed greater self-efficacy (54% vs 86%; P = .016), and reported more frequent self-care practices to manage their diabetes at the conclusion of the study period. The results of this pilot study suggest that DSME-T may offer opportunities for DSME among rural residents with diabetes. Plans are in place to explore the possibility of sustaining and expanding the program to other underserved rural communities.


Differential Regulation of RasGAPs in Cancer.
Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell- and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.