Outcomes in patients with gunshot wounds to the brain.
Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. 825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level II.


Effects of chronic renal insufficiency and metabolic acidosis on glutamine metabolism in man.
1. Arterial concentration and arterial-venous differences of glutamine across the kidney, forearm, hepato-splanchnic bed and brain were measured in patients with chronic renal insufficiency and in patients with normally functioning kidneys before and during chronic ammonium chloride acidosis. 2. In chronic renal insufficiency and in chronic metabolic acidosis there is a rise in glutamine release from the muscles and a suppression of glutamine uptake by the hepato-splanchnic bed and the brain. 3. In chronic renal insufficiency arterial glutamine concentrations is significantly increased in comparison with subjects with normal renal function and either normal acid-base balance or chronic metabolic acidosis. 4. In patients with chronic renal insufficiency the kidney extracts negligible amounts of glutamine, which cannot account for the renal ammonia production measured in the same patients.


Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review.
To determine the diagnostic accuracy of duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography, alone or in combination, for the assessment of lower limb peripheral arterial disease; to evaluate the impact of these assessment methods on management of patients and outcomes; and to evaluate the evidence regarding attitudes of patients to these technologies and summarise available data on adverse events. Systematic review. Searches of 11 electronic databases (to April 2005), six journals, and reference lists of included papers for relevant studies. Two reviewers independently selected studies, extracted data, and assessed quality. Diagnostic accuracy studies were assessed for quality with the QUADAS checklist. 107 studies met the inclusion criteria; 58 studies provided data on diagnostic accuracy, one on outcomes in patients, four on attitudes of patients, and 44 on adverse events. Quality assessment highlighted limitations in the methods and quality of reporting. Most of the included studies reported results by arterial segment, rather than by limb or by patient, which does not account for the clustering of segments within patients, so specificities may be overstated. For the detection of stenosis of 50% or more in a lower limb vessel, contrast enhanced magnetic resonance angiography had the highest diagnostic accuracy with a median sensitivity of 95% (range 92-99.5%) and median specificity of 97% (64-99%). The results were 91% (89-99%) and 91% (83-97%) for computed tomography angiography and 88% (80-98%) and 96% (89-99%) for duplex ultrasonography. A controlled trial reported no significant differences in outcomes in patients after treatment plans based on duplex ultrasonography alone or conventional contrast angiography alone, though in 22% of patients supplementary contrast angiography was needed to form a treatment plan. The limited evidence available suggested that patients preferred magnetic resonance angiography (with or without contrast) to contrast angiography, with half expressing no preference between magnetic resonance angiography or duplex ultrasonography (among patients with no contraindications for magnetic resonance angiography, such as claustrophobia). Where data on adverse events were available, magnetic resonance angiography was associated with the highest proportion of adverse events, but these were mild. The most severe adverse events, although rare, were mainly associated with contrast angiography. Contrast enhanced magnetic resonance angiography seems to be more specific than computed tomography angiography (that is, better at ruling out stenosis over 50%) and more sensitive than duplex ultrasonography (that is, better at ruling in stenosis over 50%) and was generally preferred by patients over contrast angiography. Computed tomography angiography was also preferred by patients over contrast angiography; no data on patients' preference between duplex ultrasonography and contrast angiography were available. Where available, contrast enhanced magnetic resonance angiography might be a viable alternative to contrast angiography.


Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations.
To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene. Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s). The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities. This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.


Role of the methylcitrate cycle in propionate metabolism and detoxification in Mycobacterium smegmatis.
Catabolism of odd-chain-length fatty acids yields acetyl-CoA and propionyl-CoA. A common pathway of propionyl-CoA metabolism in micro-organisms is the methylcitrate cycle, which includes the dedicated enzymes methylcitrate synthase (MCS), methylcitrate dehydratase (MCD) and methylisocitrate lyase (MCL). The methylcitrate cycle is essential for propionate metabolism in Mycobacterium tuberculosis. Unusually, M. tuberculosis lacks an MCL orthologue and this activity is provided instead by two isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL1 and ICL2). These bifunctional (ICL/MCL) enzymes are jointly required for propionate metabolism and for growth and survival in mice. In contrast, the non-pathogenic species Mycobacterium smegmatis encodes a canonical MCL enzyme in addition to ICL1 and ICL2. The M. smegmatis gene encoding MCL (prpB) is clustered with genes encoding MCS (prpC) and MCD (prpD). Here we show that deletion of the M. smegmatis prpDBC locus reduced but did not eliminate MCL activity in cell-free extracts. The residual MCL activity was abolished by deletion of icl1 and icl2 in the DeltaprpDBC background, suggesting that these genes encode bifunctional ICL/MCL enzymes. A DeltaprpB Deltaicl1 Deltaicl2 mutant was unable to grow on propionate or mixtures of propionate and glucose. We hypothesize that incomplete propionyl-CoA metabolism might cause toxic metabolites to accumulate. Consistent with this idea, deletion of prpC and prpD in the DeltaprpB Deltaicl1 Deltaicl2 background paradoxically restored growth on propionate-containing media. These observations suggest that the marked attenuation of ICL1/ICL2-deficient M. tuberculosis in mice could be due to the accumulation of toxic propionyl-CoA metabolites, rather than inability to utilize fatty acids per se.


Recent de novo origin of human protein-coding genes.
The origin of new genes is extremely important to evolutionary innovation. Most new genes arise from existing genes through duplication or recombination. The origin of new genes from noncoding DNA is extremely rare, and very few eukaryotic examples are known. We present evidence for the de novo origin of at least three human protein-coding genes since the divergence with chimp. Each of these genes has no protein-coding homologs in any other genome, but is supported by evidence from expression and, importantly, proteomics data. The absence of these genes in chimp and macaque cannot be explained by sequencing gaps or annotation error. High-quality sequence data indicate that these loci are noncoding DNA in other primates. Furthermore, chimp, gorilla, gibbon, and macaque share the same disabling sequence difference, supporting the inference that the ancestral sequence was noncoding over the alternative possibility of parallel gene inactivation in multiple primate lineages. The genes are not well characterized, but interestingly, one of them was first identified as an up-regulated gene in chronic lymphocytic leukemia. This is the first evidence for entirely novel human-specific protein-coding genes originating from ancestrally noncoding sequences. We estimate that 0.075% of human genes may have originated through this mechanism leading to a total expectation of 18 such cases in a genome of 24,000 protein-coding genes.


Effects of high intensity resistance aquatic training on body composition and walking speed in women with mild knee osteoarthritis: a 4-month RCT with 12-month follow-up.
To investigate the effects of 4-months intensive aquatic resistance training on body composition and walking speed in post-menopausal women with mild knee osteoarthritis (OA), immediately after intervention and after 12-months follow-up. Additionally, influence of leisure time physical activity (LTPA) will be investigated. This randomised clinical trial assigned eighty-seven volunteer postmenopausal women into two study arms. The intervention group (n = 43) participated in 48 supervised intensive aquatic resistance training sessions over 4-months while the control group (n = 44) maintained normal physical activity. Eighty four participants continued into the 12-months' follow-up period. Body composition was measured with dual-energy X-ray absorptiometry (DXA). Walking speed over 2 km and the knee injury and osteoarthritis outcome score (KOOS) were measured. LTPA was recorded with self-reported diaries. After the 4-month intervention there was a significant decrease (P = 0.002) in fat mass (mean change: -1.17 kg; 95% CI: -2.00 to -0.43) and increase (P = 0.002) in walking speed (0.052 m/s; 95% CI: 0.018 to 0.086) in favour of the intervention group. Body composition returned to baseline after 12-months. In contrast, increased walking speed was maintained (0.046 m/s; 95% CI 0.006 to 0.086, P = 0.032). No change was seen in lean mass or KOOS. Daily LTPA over the 16-months had a significant effect (P = 0.007) on fat mass loss (f2 = 0.05) but no effect on walking speed. Our findings show that high intensity aquatic resistance training decreases fat mass and improves walking speed in post-menopausal women with mild knee OA. Only improvements in walking speed were maintained at 12-months follow-up. Higher levels of LTPA were associated with fat mass loss. ISRCTN65346593.


Evolution of fungal sex chromosomes.
Sexual reproduction enables organisms to shuffle two parental genomes to produce recombinant progeny, and to purge the genome of deleterious mutations. Sex is conserved in virtually all organisms, from bacteria and fungi to plants and animals, and yet the mechanisms by which sexual identity are established share both conserved general features and are remarkably diverse. In animals, sexual identity is established by dimorphic sex chromosomes, whereas in fungi a specialized region of the genome, known as the mating-type locus, governs the establishment of cell type identity and differs in DNA sequence between cells of different mating-types. Recent studies on the mating-type loci of fungi and algae reveal features shared with the mammalian X and Y chromosomes, suggesting that these represent early steps in the evolution of sex chromosomes.


Application of Constrained Optimization Methods in Health Services Research: Report 2 of the ISPOR Optimization Methods Emerging Good Practices Task Force.
Constrained optimization methods are already widely used in health care to solve problems that represent traditional applications of operations research methods, such as choosing the optimal location for new facilities or making the most efficient use of operating room capacity. In this paper we illustrate the potential utility of these methods for finding optimal solutions to problems in health care delivery and policy. To do so, we selected three award-winning papers in health care delivery or policy development, reflecting a range of optimization algorithms. Two of the three papers are reviewed using the ISPOR Constrained Optimization Good Practice Checklist, adapted from the framework presented in the initial Optimization Task Force Report. The first case study illustrates application of linear programming to determine the optimal mix of screening and vaccination strategies for the prevention of cervical cancer. The second case illustrates application of the Markov Decision Process to find the optimal strategy for treating type 2 diabetes patients for hypercholesterolemia using statins. The third paper (described in Appendix 1) is used as an educational tool. The goal is to describe the characteristics of a radiation therapy optimization problem and then invite the reader to formulate the mathematical model for solving it. This example is particularly interesting because it lends itself to a range of possible models, including linear, nonlinear, and mixed-integer programming formulations. From the case studies presented, we hope the reader will develop an appreciation for the wide range of problem types that can be addressed with constrained optimization methods, as well as the variety of methods available. Constrained optimization methods are informative in providing insights to decision makers about optimal target solutions and the magnitude of the loss of benefit or increased costs associated with the ultimate clinical decision or policy choice. Failing to identify a mathematically superior or optimal solution represents a missed opportunity to improve economic efficiency in the delivery of care and clinical outcomes for patients. The ISPOR Optimization Methods Emerging Good Practices Task Force's first report provided an introduction to constrained optimization methods to solve important clinical and health policy problems. This report also outlined the relationship of constrained optimization methods relative to traditional health economic modeling, graphically illustrated a simple formulation, and identified some of the major variants of constrained optimization models, such as linear programming, dynamic programming, integer programming, and stochastic programming. The second report illustrates the application of constrained optimization methods in health care decision making using three case studies. The studies focus on determining optimal screening and vaccination strategies for cervical cancer, optimal statin start times for diabetes, and an educational case to invite the reader to formulate radiation therapy optimization problems. These illustrate a wide range of problem types that can be addressed with constrained optimization methods.


Interferon regulatory factor 7 is associated with Epstein-Barr virus-transformed central nervous system lymphoma and has oncogenic properties.
Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas.


Dimensioning of OFDMA PON with non-preselected independent ONUs sources and wavelength-control.
A simple and low cost method for wavelength control of economical random non-preselected independent ONU sources is shown to increase the number of users in an OFDMA-PON. The method is based on OLT monitoring and thermal tuning control; it has been validated through Monte-Carlo simulations and a probabilistic model. The minimum optical spectral gap between the ONUs wavelengths that guarantees a tolerable amount of optical beat interference has been determined through an experiment.


Targeting human oligodendrocyte progenitors for myelin repair.
Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that regulate development and become dysfunctional in disease may be, in key ways, divergent across species. Improvements in isolation techniques, applied to primary human neural and oligodendrocyte progenitors from both fetal and adult brain, as well as advancements in the derivation of defined progenitors from human pluripotent stem cells, have begun to reveal the extent of both species-conserved signaling pathways and potential key differences at cellular and molecular levels. In this article, we will review the commonalities and differences in myelin development between rodents and man, describing the approaches used to study human oligodendrocyte differentiation and myelination, as well as heterogeneity within targetable progenitor pools, and discuss the advances made in determining which conserved pathways may be both modeled in rodents and translate into viable therapeutic strategies to promote myelin repair.


Novel 2-amino-4-aryl-6-pyridopyrimidines and N-alkyl derivatives: Synthesis, characterization and investigation of anticancer, antibacterial activities and DNA/BSA binding affinities.
A series of new 2-amino-4-aryl-6-pyridopyrimidines, and their N-alkyl bromide derivatives were designed and synthesized by employing methyl substituted azachalcones. These novel compounds were evaluated and compared to the well-known chemotherapeutics in terms of their anti-cancer and anti-microbial functions, and their DNA/protein binding affinities. In order for the cell proliferation, cytotoxicity and microdilution features to be observed, various cancer cell lines (Hep3B, A549, HeLa, C6, HT29, MCF7) were treated with 2-amino-4-aryl-6-pyridopyrimidines (1-9) and their N-alkyl bromide derivatives (2a-c, 3a-c,5a-c,6a-c, 8a-c, 9a-c). Studies on the cells revealed that both pyrimidines and their alkyl derivatives (i) have a high anti-proliferative and anti-microbial activities, (ii) cause cell rounding, cytoplasmic blebs, and anomalous globular structure, and (iii) strongly bound to DNA/BSA macromolecules. Especially the length of the alkyl chain of the N-alkyl bromides has an increasing effect on the antiproliferative, antibacterial and cytotoxic functions, also DNA/protein binding affinity. Those results indicate the novel compounds to be promising antiproliferative agents, and their anti-cancer potential makes them candidates to be used for cancer therapy.


Contact pressure on ACL hamstring grafts in the bone tunnel with interference screw fixation--dynamic adaptation under load.
Interference screws used in fixation of anterior cruciate ligament (ACL) hamstring grafts create mechanical hold by forcing the graft into frictional contact with the bone tunnel. We analyzed the resultant graft-tunnel contact pressure using an in vitro model of human cadaver 8mm hamstring grafts. Contact characteristics were assessed using both pressure sensitive films and a force sensor. Two screw sizes were investigated (8 and 9 mm in an 8mm Sawbone tunnel), both with and without a bone wedge between graft and screw. Separately, time dependent relaxation of contact force was recorded over a one hour epoch and associated tendon water loss was measured. Pullout testing of 8mm tendon grafts from 8mm holes in Sawbone and porcine femora were performed after 1 min and 1h. During screw insertion, measured peak pressures (>40 MPa) exceeded the compressive failure stress of metaphyseal bone by more than an order of magnitude. Using a bone wedge between tendon and screw reduced local peak pressure by 85% but produced also inferior average contact pressure. In all approaches, initially achieved graft contact pressure rapidly decreased to approximately 25% within 30 min. Pullout strength was significantly reduced after 1h in comparison to 1 min in porcine bone as well as Sawbone. Viscoelastic adaptation of the tendon is severe and critically reduces effective graft-bone contact pressure. Consideration of this newly recognized effect may open new and improved approaches for tendon graft fixation.


Therapeutic biomechanics concepts and clinical procedures to reduce implant loading. Part II: therapeutic differential loading.
Practical laboratory procedures were suggested in order to provide a modified occlusal anatomy to reduce implant loading. The concept of differential mobility caused by the flexion between a natural tooth/periodontal ligament interface with its supporting bone, compared with the stiffness of the implant/bone interface, was described. When individual tooth-supported and implant-supported prostheses coexist in the same arch, this differential mobility can shift the loading disproportionately from the natural teeth to the implants. A new concept of therapeutic differential loading is introduced and a clinical technique of differential occlusal adjustment is described to bring about a more favorable distribution of loading to all the supporting bone. Long-term natural tooth intrusion can cause implant overload. Therefore, it is suggested that periodic differential occlusal adjustment procedures be used to re-establish a long-term balance of loading between individual implant- and tooth-supported prostheses within the same arch.


Redes En Acción. Increasing Hispanic participation in cancer research, training, and awareness.
Hispanics are affected by many health care disparities. The National Cancer Institute (NCI), through its Special Populations Branch, is supporting networking and capacity-building activities designed to increase Hispanic participation and leadership in cancer research. Redes En Acción established a national network of cancer research centers, community-based organizations, and federal partners to facilitate opportunities for junior Hispanic scientists to participate in training and research projects on cancer control. Since 2000, Redes En Acción has established a network of more than 1800 Hispanic leaders involved in cancer research and education. The project has sustained 131 training positions and submitted 29 pilot projects to NCI for review, with 16 awards for a total of $800,000, plus an additional $8.8 million in competing grant funding based on pilot study results to date. Independent research has leveraged an additional $32 million in non-Redes funding, and together the national and regional network sites have participated in more than 1400 community and professional awareness events. In addition, the program conducted extensive national survey research that provided the basis for the Redes En Acción Latino Cancer Report, a national agenda on Hispanic cancer issues. Redes En Acción has increased participation in cancer control research, training, and awareness among Hispanic scientists and within Hispanic communities. Cancer 2006. (c) 2006 American Cancer Society.


Alternating Pressure Overlay for Prevention of Intraoperative Pressure Injury.
The purpose of this study was to evaluate the effect of a low-profile alternating pressure (AP) overlay system on hospital-acquired pressure injuries (HAPIs). Prospective case series with historical controls. The study setting was the operating room and critical care unit of an urban quaternary care hospital in the Midwestern United States. One hundred neurosurgery patients undergoing surgery for 2 hours or longer in supine position were included in the study (AP group). The outcomes for the AP group were compared to a historical control group of 292 patients. A group of 100 patients were prospectively placed on the AP overlay during surgery. Participants were enrolled preoperatively and tracked by the research team during their hospital stay. Demographic data, details of the operation, and pressure injury risk factors were recorded. Following surgery, AP group patients were evaluated daily and continued on standard protocol for pressure injury prevention. The primary study outcome was HAPI rate during the perioperative period (up to 5 days postsurgery) for the AP group (plus standard of care) compared to the standard of care alone (historical control). Control group data were extracted from electronic health records for the prior 2 years. A written questionnaire was given to the care team that used the AP technology; items queried the degree of acceptance of the overlay by surgeons and the operating room and intensive care unit (ICU) staff. None of the patients in the AP group developed perioperative pressure injuries. Review of historical control group revealed a 6% perioperative pressure injury incidence (18 pressure injuries in a group of 292 patients). Responses on the written questionnaire indicated that the AP technology was well accepted by surgeons and the operating room and ICU staff. There were no adverse events. Study findings suggest that AP overlay system can safely and reliably be used during neurological surgeries. Findings further suggest that using the AP product may improve outcomes with respect to perioperative HAPIs, including patients deemed at high risk for pressure injury development. Further studies are underway to evaluate the use of this AP overlay system beyond the operating room for more comprehensive care.


Two-wavelength lidar inversion algorithm.
Potter [Appl. Opt. 26, 1250 (1987)] has presented a method to determine profiles of the atmospheric aerosol extinction coefficients by use of a two-wavelength lidar with the assumptions of a constant value for the extinction-to-backscatter ratio for each wavelength and a constant value for the ratio between the two extinction coefficients at the two wavelengths. Triggered by this idea, Ackermann [Appl. Opt. 36, 5134 (1997)] expanded this method to consider lidar returns that are a composition of scattering by atmospheric aerosols and molecules, assuming that the molecular scattering is known. In both papers the method is based on the well-known solutions of Bernoulli's differential equation in an iterative scheme with an unknown boundary transmission condition. This boundary condition is less sensitive to noise than boundary extinction conditions. My main purpose is to critically consider the principle behind Potter's method, because it seems that there are several reasons why the number of solutions is not limited to one, as suggested by his original work.


Restriction site-associated DNA sequencing generates high-quality single nucleotide polymorphisms for assessing hybridization between bighead and silver carp in the United States and China.
Bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix) are invasive species and listed as US federally injurious species under the Lacy Act. They have established populations in much of the Mississippi River Basin (MRB; Mississippi, Illinois, and Missouri rivers) and are capable of producing fertile hybrids and complex introgression. Characterizing the composition of this admixture requires a large set of high-quality, evolutionarily conserved, diagnostic genetic markers to aid in the identification and management of these species in the midst of morphological ambiguity. Restriction site-associated DNA (RAD) sequencing of 45 barcoded bighead and silver carp from the United States and China produced reads that were aligned to the silver carp transcriptome yielded 261 candidate single nucleotide polymorphisms (SNPs) with fixed allelic differences between the two species. We selected the highest quality 112 SNP loci for validation using 194 putative pure-species and F1 hybrids from the MRB and putative bighead carp and silver carp pure species from China (Amur, Pearl and Yangtze rivers). Fifty SNPs were omitted due to design/amplification failure or lack of diagnostic utility. A total of 57 species-diagnostic SNPs conserved between carp species in US and Chinese rivers were identified; 32 were annotated to functional gene loci. Twenty-seven of the 181 (15%) putative pure species were identified as hybrid backcrosses after validation, including three backcrosses from the Amur River, where hybridization has not been documented previously. The 57 SNPs identified through RAD sequencing provide a diagnostic tool to detect population admixture and to identify hybrid and pure-species Asian carps in the United States and China.


An Empirical Comparison of Meta- and Mega-Analysis With Data From the ENIGMA Obsessive-Compulsive Disorder Working Group.
Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses. Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods. Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models. Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging data.


Alpha-2-Macroglobulin in Inflammation, Immunity and Infections.
Alpha-2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor. By presenting itself as an optimal substrate for endopeptidases of all catalytic types, alpha-2-macroglobulin lures active proteases into its molecular cage and subsequently 'flags' their complex for elimination. In addition to its role as a regulator of extracellular proteolysis, alpha-2-macroglobulin also has other functions such as switching proteolysis towards small substrates, facilitating cell migration and the binding of cytokines, growth factors and damaged extracellular proteins. These functions appear particularly important in the context of immune-cell function. In this review manuscript, we provide an overview of all functions of alpha-2-macroglobulin and place these in the context of inflammation, immunity and infections.


Reducing refugee mental health disparities: a community-based intervention to address postmigration stressors with African adults.
Refugees resettled in the United States have disproportionately high rates of psychological distress. Research has demonstrated the roles of postmigration stressors, including lack of meaningful social roles, poverty, unemployment, lack of environmental mastery, discrimination, limited English proficiency, and social isolation. We report a multimethod, within-group longitudinal pilot study involving the adaptation for African refugees of a community-based advocacy and learning intervention to address postmigration stressors. We found the intervention to be feasible, acceptable, and appropriate for African refugees. Growth trajectory analysis revealed significant decreases in participants' psychological distress and increases in quality of life, and also provided preliminary evidence of intervention mechanisms of change through the detection of mediating relationships whereby increased quality of life was mediated by increases in enculturation, English proficiency, and social support. Qualitative data helped to support and explain the quantitative data. Results demonstrate the importance of addressing the sociopolitical context of resettlement to promote the mental health of refugees and suggest a culturally appropriate, and replicable model for doing so.


Novel 3-phenylcoumarin-lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease.
New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H2O2-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H2O2-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease.


Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice.
Previous studies have shown that modified apelin analogues exhibited enzyme resistance in plasma and improved circulating half-life compared to apelin-13. This study investigated the antidiabetic effects of chronic administration of stable long acting fatty acid modified apelin analogues, namely, (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide, in high-fat fed obese-diabetic mice. Male NIH Swiss mice (groups n = 8) were maintained either on a high-fat diet (45% fat) from 8 to 28 weeks old, or control mice were fed a normal diet (10% fat). When diet induced obesity-diabetes was established after high-fat feeding, mice were injected i.p. once daily with apelin analogues, liraglutide (25 nmol/kg) or saline (controls). Administration of (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide for 28 days significantly reduced food intake and decreased body weight. Non-fasting glucose was reduced (p<0.01 to p<0.001) and plasma insulin concentrations increased (p<0.01 to p<0.001). This was accompanied by enhanced insulin responses (p<0.01 to p<0.001) and significant reductions in glucose excursion after oral (p<0.01) or i.p. (p<0.01) glucose challenges and feeding. Apelin analogues also significantly improved HbA1c (p<0.01), enhanced insulin sensitivity (p<0.01), reduced triglycerides (p<0.001), increased HDL-cholesterol (p<0.01) and decreased LDL-cholesterol (p<0.01), compared to high-fat fed saline treated control mice. Cholesterol levels were decreased (p<0.01) by pGlu(Lys8GluPAL)apelin-13 amide and both apelin treated groups showed improved bone mineral content, reduced fat deposits and increased plasma GLP-1. Daily treatment with liraglutide mirrored many of these changes (not on bone or adipose tissue), but unlike apelin analogues increased plasma amylase. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were improved by apelin analogues. These results indicate that long-term treatment with acylated analogues (Lys8GluPAL)apelin-13 amide and particularly pGlu(Lys8GluPAL)apelin-13 amide resulted in similar or enhanced therapeutic responses to liraglutide in high-fat fed mice. Fatty acid derived apelin analogues represent a new and exciting development in the treatment of obesity-diabetes.


Neuronal excitotoxicity after carotid angioplasty and stent placement procedures.
To investigate if glutamate levels also increase in carotid angioplasty and stent placement (CAS) procedures, since high plasma glutamate levels are associated with ischemic infarction and transient ischemic attacks, but the length of ischemia needed to elicit such elevation has not been assessed. All patients or their relatives signed informed consent. By using high-performance liquid chromatography, plasma glutamate concentrations were determined in 74 patients treated with CAS. Blood samples were obtained with arterial and peripheral venous catheterization before and after the procedure, and venous blood samples were obtained 24, 48, and 72 hours after CAS. Glutamate concentrations were also analyzed in two different control groups: 16 patients without carotid stenosis before and after diagnostic cerebral angiography and 20 patients treated with coronary angioplasty and stent placement. The χ(2) test, t test, and analysis of variance were used to compare glutamate concentrations among the groups. Baseline glutamate concentrations were similar between patients who underwent CAS and both control groups. In CAS patients, glutamate concentrations in venous blood increased immediately after the procedure (354.1 μmol/L ± 132.8) and returned to baseline levels at 24 hours (129.5 μmol/L ± 56.8) (P < .0001). Glutamate concentrations remained unchanged over time in both control groups. A rapid increase in plasma glutamate levels occurs after CAS procedures, unrelated to stroke.


No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration.
Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes. Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification. We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated. We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this collection of FTLD patients.


Predictors of long-term smoking cessation in head and neck cancer patients.
Cigarette smoking is a major risk factor for head and neck cancer, and individuals who continue to smoke past diagnosis and treatment are at elevated risk for further disease. In a randomized controlled trial, a state of the art provider-delivered smoking cessation intervention was compared to a usual care advice control condition. The intervention consisted of surgeon- or dentist-delivered advice to stop smoking, a contracted quit date, tailored written materials, and booster advice sessions. Subjects were 186 patients with newly diagnosed first primary squamous cell carcinomas of the upper aerodigestive tract who had smoked cigarettes within the past year. At randomization, 88.2% of subjects were current smokers. At 12-month follow-up, 70.2% of subjects completing the trial (n = 114) were continuous abstainers; among baseline smokers alone the continuous abstinence (CA) rate was 64.6%. The cotinine validation rate at 12 months was 89.6%. Modeling techniques were utilized in order to derive expected CA rates, which included noncompleter subjects (n = 72). The CA rate expected at 1 year for the entire patient population was 64.2%, and for smokers alone the expected CA rate was 59.4%. Logistic regression analysis carried out on baseline smokers identified predictors of 12-month CA status. These included medical treatment, stage of change, age, nicotine dependence, and race. The intervention effect was not significant, although the sign of the effect was positive. Based on these findings, we recommend systematic brief advice to stop smoking for head and neck cancer patients, with a stepped care approach for patients less able to quit.


Total electron scattering cross sections from thiophene for the (1-300 eV) impact energy range.
Experimental electron scattering cross sections for thiophene in the impact energy range from 1 to 300 eV have been measured with a magnetically confined electron transmission-beam apparatus. Random uncertainty limits have been estimated to be less than 5%, and systematic errors derived from acceptance angle limitations have also been identified and evaluated. Experimental values are compared with our previous low energy (1-15 eV) R-matrix and intermediate/high energy (15-300 eV) IAM-SCAR+I calculations finding reasonable agreement, within the combined uncertainty limits. Some of the low energy shape and core-excited resonances predicted by previous calculations are experimentally confirmed in this study.


The Cargo Protein MAP17 (PDZK1IP1) Regulates the Cancer Stem Cell Pool Activating the Notch Pathway by Abducting NUMB.
Purpose: Cancer stem cells (CSC) are self-renewing tumor cells, with the ability to generate diverse differentiated tumor cell subpopulations. They differ from normal stem cells in the deregulation of the mechanisms that normally control stem cell physiology. CSCs are the origin of metastasis and highly resistant to therapy. Therefore, the understanding of the CSC origin and deregulated pathways is important for tumor control.Experimental Design: We have included experiments in vitro, in cell lines and tumors of different origins. We have used patient-derived xenografts (PDX) and public transcriptomic databases of human tumors.Results: MAP17 (PDZKIP1), a small cargo protein overexpressed in tumors, interacts with NUMB through the PDZ-binding domain activating the Notch pathway, leading to an increase in stem cell factors and cancer-initiating-like cells. Identical behavior was mimicked by inhibiting NUMB. Conversely, MAP17 downregulation in a tumor cell line constitutively expressing this gene led to Notch pathway inactivation and a marked reduction of stemness. In PDX models, MAP17 levels directly correlated with tumorsphere formation capability. Finally, in human colon, breast, or lung there is a strong correlation of MAP17 expression with a signature of Notch and stem cell genes.Conclusions: MAP17 overexpression activates Notch pathway by sequestering NUMB. High levels of MAP17 correlated with tumorsphere formation and Notch and Stem gene transcription. Its direct modification causes direct alteration of tumorsphere number and Notch and Stem pathway transcription. This defines a new mechanism of Notch pathway activation and Stem cell pool increase that may be active in a large percentage of tumors. Clin Cancer Res; 23(14); 3871-83. ©2017 AACR.


Primary low-grade lymphoma of mucosa-associated lymphoid tissue of the urinary bladder: a case report with special reference to the use of ancillary diagnostic studies.
We report a case of primary low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type of the urinary bladder. The patient, a 77-year-old woman, presented with a sense of urinary retention. An intravenous pyelogram and cystoscopy revealed a wide-based submucosal mass measuring 3 cm in the left wall of the urinary bladder. Histological findings of the tissue obtained by transurethral resection (TUR) showed a dense, monomorphic atypical lymphoid (centrocyte-like) infiltrate with reactive lymph follicles in the subepithelial tissue. Monocytoid and plasmacytoid features were readily evident in a population of these cells. Lymphoepithelial lesions involving the urothelium were also noticed in some areas. These features were strongly suggestive of primary low-grade lymphoma of the MALT type. The diagnosis was confirmed by immunohistochemical and flow cytometric studies, both of which showed a clear immunoglobulin restriction to lambda light chain and also by polymerase chain reaction-based assay using a formalin-fixed paraffin-embedded TUR tissue sample, which showed a clonal Ig heavy-chain gene rearrangement. Clinical staging procedures revealed that the tumor was localized in the urinary bladder. The patient has not received chemotherapy and is alive and well with no evidence of recurrence, 3 years after TUR. This case demonstrates that these ancillary tests are worth performing for confirmation of B-cell clonality in TUR tissue samples showing dense B-lymphocytic infiltration.


Future directions in meditation research: Recommendations for expanding the field of contemplative science.
The science of meditation has grown tremendously in the last two decades. Most studies have focused on evaluating the clinical effectiveness of mindfulness-based interventions, neural and other physiological correlates of meditation, and individual cognitive and emotional aspects of meditation. Far less research has been conducted on more challenging domains to measure, such as group and relational, transpersonal and mystical, and difficult aspects of meditation; anomalous or extraordinary phenomena related to meditation; and post-conventional stages of development associated with meditation. However, these components of meditation may be crucial to people's psychological and spiritual development, could represent important mediators and/or mechanisms by which meditation confers benefits, and could themselves be important outcomes of meditation practices. In addition, since large numbers of novices are being introduced to meditation, it is helpful to investigate experiences they may encounter that are not well understood. Over the last four years, a task force of meditation researchers and teachers met regularly to develop recommendations for expanding the current meditation research field to include these important yet often neglected topics. These meetings led to a cross-sectional online survey to investigate the prevalence of a wide range of experiences in 1120 meditators. Results show that the majority of respondents report having had many of these anomalous and extraordinary experiences. While some of the topics are potentially controversial, they can be subjected to rigorous scientific investigation. These arenas represent largely uncharted scientific terrain and provide excellent opportunities for both new and experienced researchers. We provide suggestions for future directions, with accompanying online materials to encourage such research.


Perceptions of methicillin-resistant Staphylococcus aureus and hand hygiene provider training and patient education: results of a mixed method study of health care providers in Department of Veterans Affairs spinal cord injury and disorder units.
The goal of this study was to assess current practices for training of spinal cord injury and disorder (SCI/D) health care workers and education of veterans with SCI/D in Department of Veterans Affairs (VA) spinal cord injury (SCI) centers on methicillin-resistant Staphylococcus aureus (MRSA) prevention. Mixed methods. A Web-based survey was distributed to 673 VA SCI/D providers across 24 SCI centers; 21 acute care and 1 long-term care facility participated. There were 295 that responded, 228 had complete data and were included in this analysis. Semistructured interviews were conducted with 30 SCI/D providers across 9 SCI centers. Nurses, physicians, and therapists represent most respondents (92.1%, n = 210); over half (56.6%, n = 129) were nurses. Of providers, 75.9% (n = 173) reported receiving excellent or good training on how to educate patients about MRSA. However, nurses were more likely to report having excellent or good training for how to educate patients about MRSA (P = .005). Despite this, only 63.6% (n = 82) of nurses perceived the education they provide patients on how MRSA is transmitted as excellent or good. Despite health care workers reporting receiving excellent or good training on MRSA-related topics, this did not translate to excellent or good education for patients, suggesting that health care workers need additional training for educating patients. Population-specific MRSA prevention educational materials may also assist providers in educating patients about MRSA prevention for individuals with SCI/D.


Progress towards the achievement of MDG4 in the Commonwealth of Independent States: uncertain data, clear priorities.
Data on under five mortality in the twelve countries of the Commonwealth of Independent States show important fluctuations over time due to variations in quality of data, definitions of neonatal deaths and methods of mortality estimation. Despite the uncertainties regarding mortality trends, the analysis of health and social information from different sources offers clues to identify priority areas and key strategic directions for accelerating the achievement of the 4th Millennium Development Goal. Neonatal deaths represent from 40% to over 50% of under five deaths in all these countries. Maternal mortality was above 50 per 100,000 in 2005, despite the good coverage with antenatal care and births assisted by skilled birth attendants. The scanty information on quality of perinatal care indicates widespread substandard care at all levels. Stunting in children under five is above 10% in ten out of twelve countries and coexists with emerging overweight. Exclusivity and duration of breastfeeding fall short of what is recommended. There are important inequalities in child and maternal mortality, malnutrition and access and use of health services within countries. Taken as a whole, the available information clearly indicates that priority should be given to improvement of the health of women in reproductive age and of the quality of perinatal care, including the establishment of reliable data collection systems. To achieve this, action will need to focus on strengthening the capacity of the health system to improve the technical content of service provision, and on improving access and appropriate use of services by the most disadvantaged groups. The involvement of other sectors will be necessary to improve reproductive health and nutrition at community level and to tackle inequity. Comparisons between countries with similar socioeconomic background but different health policies seem to indicate that gradual progression towards universal coverage with essential health care through a national health insurance system is associated with larger reduction of child mortality than troubled transition towards a privatized and unregulated health system.


Effects of Fruit and Pollen Exudates on Growth of Botrytis cinerea and Infection of Plum and Nectarine Fruit.
Sugars in exudates from Harry Pickstone plum and Sunlite nectarine fruit and from pollen of weeds commonly found in orchards were determined by gas-liquid chromatography, and their effect on the development of Botrytis cinerea was determined in vitro and in vivo. Fructose, glucose, and sorbitol were the only sugars detected in exudates of immature fruit. They occurred at low concentrations, but their concentration generally increased as fruit ripened. Sucrose was first detected during maturation. In nectarine, an increase in sugar concentration, especially sucrose, was pronounced during the period of rapid cell enlargement, which occurred approximately 2 weeks before harvest. Absorbance readings of culture media amended with sugar indicated that the hexose sugars (fructose and glucose) and sucrose did not markedly influence growth of B. cinerea at concentrations below 0.22 and 0.12 mM, respectively. The hexose sugars caused a steady increase in growth when supplied at concentrations in excess of 0.44 mM, and sucrose caused a steady increase in growth at 0.23 mM. The stimulatory effect of fruit exudates on growth of B. cinerea on glass slides coincided with the period of rapid sugar release from the fruit and the shift in susceptibility to decay. Only fructose (1.72 mM) and glucose (0.72 mM) were detected in nectarine pollen exudates. Pollen exudates from weeds stimulated fungal growth and significantly increased the aggressiveness of the pathogen on plum and nectarine fruit when added to conidia during the last 4 weeks prior to the picking-ripe stage. The study showed that changes in the composition of nectarine and plum fruit exudates may contribute to the late-season susceptibility of these fruit to B. cinerea infection.


Functional amyloid materials at surfaces/interfaces.
With the development of nanotechnology, functional amyloid materials are drawing increasing attention, and numerous remarkable applications are emerging. Amyloids, defined as a class of supramolecular assemblies of misfolded proteins or peptides into β-sheet fibrils, have evolved in many new respects and offer abundant chemical/biological functions. These proteinaceous micro/nano-structures provide excellent biocompatibility, rich phase behaviours, strong mechanical properties, and stability at interfaces not only in nature but also in functional materials, displaying versatile interactions with surfaces/interfaces that have been widely adopted in bioadhesion, synthetic biology, and composites. Overall, functional amyloids at surfaces/interfaces have excellent potential applications in next-generation biotechnology and biomaterials.


Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes.
Chimeric antigen receptors (CARs) are generated by fusing the antigen-binding motif of a monoclonal antibody (mAb) with the signal transduction machinery of the T-cell receptor (TCR). The genetic modification of T lymphocytes with chimeric receptors specific for tumor-associated antigens (TAAs) allows for the redirection towards tumor cells. Clinical experience with CAR-redirected T cells suggests that antitumor efficacy associates with some degree of toxicity, especially when TAA expression is shared with healthy tissues. This situation closely resembles the case of allogeneic hematopoietic stem cell transplantation (HSCT), wherein allorecognition causes both the graft-versus-leukemia (GVL) effect and graft-versus-host disease (GVHD). Suicide gene therapy, i.e. the genetic induction of a conditional suicide phenotype into donor T cells, enables dissociating the GVL effect from GVHD. Applying suicide gene modification to CAR-redirected T cells may therefore greatly increase their safety profile and facilitate their clinical development.


Biochemical characteristics and subcellular localizations of rat liver neuraminidase isozymes: a paradox resolved.
A striking discrepancy in the abilities of two analytical approaches (fluorometric and electrophoretic) to detect the effect of a gene, Neu-2, on rat liver neuraminidase phenotypes led us to examine the biochemical and physical properties of the liver isozymes NEU-1 and NEU-2 that might be responsible for this difference. Cell fractionation via Percoll gradient centrifugation revealed NEU-1 activity almost exclusively in the lysosomal cell fraction, while NEU-2 was strictly cytosolic in distribution. The two isozymes were also found to differ in pH activity curves and optima (optima: 4.6-4.8 and 5.4-5.8 for NEU-1 and NEU-2, respectively) and in solubility characteristics (NEU-2 highly soluble; NEU-1 relatively insoluble but solubilized by freezing/thawing). Both isozymes were found to be freeze-thaw stable in crude, whole-cell extracts, but NEU-1 was destabilized in the enriched (partially purified) lysosomal subcellular fraction. Consideration of these properties relative to those described previously for unidentified cytosolic and membrane bound (lysosomal) rat liver neuraminidases (Tulsiani, D. R. P., and Carubelli, R., J. Biol. Chem. 245:1821, 1970) leads us to believe that NEU-2 also is destabilized by partial purification and that NEU-1 and NEU-2 have very different relative abundances within the cell. The biochemical and physical differences between NEU-1 and NEU-2 can account for the discrepant abilities of the fluorometric and electrophoretic approaches to detect the effects of Neu-2. Ways to increase the sensitivity of the fluorometric approach for quantitative assays of specific NEU-1 and NEU-2 activity are discussed.


Rapid onset of seizure suppression with pregabalin adjunctive treatment in patients with partial seizures.
To determine the time at which pregabalin demonstrates seizure-suppressing activity when given as adjunctive treatment to patients with refractory partial seizures. Data from four similar 12-week, randomized, double-blind, placebo-controlled, parallel-group trials in patients with refractory partial seizures were pooled to provide an adequate sample to compare the proportion of patients free of seizures on each study day between pregabalin (combined 150-600 mg/day groups) and placebo (combined groups). A generalized estimating equation (GEE) statistical model was used to perform pairwise comparisons on each study day. In several pregabalin dosage groups the dosage was escalated during days 1-7, whereas in others pregabalin was initiated at a fixed dosage without escalation. The proportion of patients free of seizures on any treatment day was greater in the combined pregabalin groups compared with baseline. Differences were not observed between the placebo group and baseline. A significantly greater proportion of patients were free of seizures in the combined pregabalin 150-600 mg/day and the pregabalin 600 mg/day fixed-dosage groups compared with the placebo groups from treatment day 2 onward (p < 0.05). From day 8 (coinciding with completion of the 1-week dosage-escalation period in two studies) onward, the proportion of patients free of seizures per day in the pregabalin groups remained relatively constant. This exploratory analysis of a refractory population using a rigorous endpoint demonstrates that pregabalin rapidly reduced the frequency of partial seizures. At the dosing schemes most commonly used in placebo-controlled trials, significant seizure-suppressing activity was observed after only 2 days of treatment.


New perspectives on dry needling following a medical model: are we screening our patients sufficiently?
Myofascial trigger points are not an isolated neuromusculoskeletal phenomenon and have been implicated in systemic, visceral, and metabolic pathology, as a side effect of some medications and in the presence of psychological risk factors. This complexity can complicate adequate screening of patients prior to choosing dry needling as a treatment intervention. Regardless of whether clinicians practice in a direct access setting, they should be cognizant of medical conditions, comorbidities, and risk factors that will influence clinical decisions for dry-needling appropriateness, technique chosen, and potential adverse responses to treatment. Of primary concern are conditions that can either manifest with myalgia and/or myopathy or masquerade as a more common musculoskeletal condition. This clinical commentary reviews system-specific considerations and other common disorders that should be screened for and discusses not only whether dry needling is appropriate but comments on technique and dosage considerations when initiating dry needling.


Distinguishing between-individual from within-individual predictors of gun carrying among Black and White males across adolescence.
Longitudinal studies have found that male adolescents who deal drugs, associate with delinquent peers, and engage in aggressive behavior are at increased risk for carrying a gun (between-individual risks). However, it is unclear whether changes in these risk factors help to explain fluctuations in youth gun carrying across adolescence (within-individual risks). The current study examined this issue using a community sample of 970 adolescent males (58% Black, 42% White) assessed annually from ages 14 to 18. Multilevel models examined the extent to which between-individual differences and within-individual changes in drug dealing, peer delinquency, aggressive behavior, and neighborhood disadvantage were associated with gun carrying across adolescence. Each of these predictors, except for disadvantage, exerted a between-individual and within-individual influence for Black youth. For White youth, drug dealing was significant on both levels, peer delinquency was a significant between-individual predictor, and aggression was a significant within-individual predictor. Neighborhood disadvantage did not significantly predict gun carrying in the model, on either the between- or within-individual level, for Black or White youth. These results stress the importance of examining race-specific predictors of gun carrying among Black and White adolescents and point to drug dealing as a robust predictor of gun carrying, at both the between-individual and within-individual levels for youth of either race. Efforts to prevent drug market involvement and reduce aggressive behaviors in adolescence may in turn prove useful for preventing firearm violence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Cryopreservation of winter-dormant apple buds: II - tissue water status after desiccation at -4C and before further cooling.
The established protocol for the cryopreservation of winter-dormant Malus buds requires that stem explants, containing a single, dormant bud are desiccated at -4 degree C, for up to 14 days, to reduce their water content to 25-30 percent of fresh weight. Using three apple cultivars, with known differences in response to cryopreservation, the pattern of evaporative water loss has been characterised, including early freezing events in the bud and cortical tissues that allow further desiccation by water migration to extracellular ice. There were no significant differences between cultivars in this respect or in the proportions of tissue water lost during the desiccation process. Differential Scanning Calorimetry (to -90 degree C) of intact buds indicated that bud tissues of the cultivar with the poorest response to cryopreservation had the highest residual water content at the end of the desiccation process and froze at the highest temperature.


Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines.
Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination. We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person's susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years' durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails' rate of patency and lifespan, and force of infection to snails. To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms.


The Significance of Interfacial Water Structure in Soluble Salt Flotation Systems.
Flotation of soluble salts with dodecyl amine hydrochloride (DAH) and sodium dodecyl sulfate (SDS) collectors has demonstrated that the interfacial water structure and hydration states of soluble salt surfaces together with the precipitation tendency of the corresponding collector salts are of considerable importance in explaining their flotation behavior. In particular, the high concentration of ions in these soluble salt brines and their hydration appear to modify the bulk and interfacial structure of water as revealed by contact angle measurements and this effect is shown to be an important feature in the flotation chemistry of soluble salt minerals including alkali halide and alkali oxyanion salts. Depending on characteristic chemical features (salt type), the salt can serve either as a structure maker, in which intermolecular hydrogen bonding between water molecules is facilitated, or as a structure breaker, in which intermolecular hydrogen bonding between water molecules is disrupted. For structure making salts the brine completely wets the salt surface and no contact angle can be measured. For structure breaking salts the brine does not completely wet the salt surface and a finite contact angle is measured. In this regard it has been found that soluble salt flotation either with the cationic DAH or anionic SDS collector is possible only if the salt is a structure breaker. Copyright 2001 Academic Press.


Ibuprofen Decreases Spontaneous Activity and Enhances Nerve-Evoked Contractions to Minimize Mitomycin C-Induced Bladder Dysfunction.
Inflammation may play a causal role in urological side effects reported following intravesical mitomycin C (MMC). Our aim was to investigate the effects of the nonsteroidal anti-inflammatory drug ibuprofen (IBU) on the cytotoxic potency of MMC and the potential for IBU to protect against bladder dysfunction. Malignant (RT4, T24) and normal (UROtsa) urothelial lines were treated with MMC followed by ibuprofen, with cell viability and caspase-3 activity assessed. Female C57BL/6JArc mice (Saline/Control, MMC, Saline + IBU, and MMC + IBU) received intravesical treatment (1 hour) with saline or MMC (2 mg/ml), with IBU (1 mg/ml) delivered in drinking water (for 7 days). Voiding pattern analysis was conducted prior to and following (1, 3, 7 days) treatment. A whole-bladder preparation was used to assess compliance, contractile responses, and urothelial-mediator release. Ibuprofen selectively increased the cytotoxic potency of MMC and caspase-3 activity in both malignant cells lines but not in UROtsa. MMC significantly increased voiding frequency at 24 hours and 3 days, whereas administration of ibuprofen significantly reduced this effect. MMC significantly increased the frequency of spontaneous contractions from 2.3 ± 0.5 contractions/min in saline controls to 4.8 ± 0.16 contractions/min, with ibuprofen protecting against this change. Interestingly, although nerve-evoked responses were not altered by MMC, they were increased in both IBU groups. Ibuprofen improved voiding dysfunction following MMC treatment by reducing spontaneous phasic activity and enhancing nerve-mediated contractions. Ibuprofen use in bladder cancer patients may help to minimize the urological adverse effects associated with intravesical MMC.


Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance.
Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.


Protective effects of lipoic acid against acrylamide-induced neurotoxicity: involvement of mitochondrial energy metabolism and autophagy.
Acrylamide (ACR) is a chronic neurotoxin that is generated in high-starch foods during heat processing. Alpha-lipoic acid (LA) is an antioxidant that occurs in most plants and animals. The objective of this study was to reveal the mechanism of ACR-triggered neurotoxicity and identify the protective role of LA in SH-SY5Y cells. In this study, LA restored ACR-stimulated depletion of glutathione content and mitochondrial membrane potential, moderated the activation of inflammatory pathways, and recovered the Keap1/Nrf2 pathway. Moreover, LA upregulated the activities of oxidative phosphorylation complexes and diminished ACR-induced variation in AMPK/GSK3β, Ca2+ disturbance, and ATP depletion. The Sirt1/PGC-1α pathway was inhibited by ACR. Notably, autophagy was activated in the mitochondria-mediated apoptosis induced by ACR, which was also blocked by LA. Overall, our study demonstrated the pivotal roles of the mitochondrial energy metabolism and autophagy in the protective effects of LA and cytotoxicity of ACR in SH-SY5Y cells.


Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study.
There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.


Developing COPD: a 25 year follow up study of the general population.
Smokers are more prone to develop chronic obstructive pulmonary disease (COPD) than non-smokers, but this finding comes from studies spanning 10 years or less. The aim of this study was to determine the 25 year absolute risk of developing COPD in men and women from the general population. As part of the Copenhagen City Heart Study, 8045 men and women aged 30-60 years with normal lung function at baseline were followed for 25 years. Lung function measurements were collected and mortality from COPD during the 25 year observation period was analysed. The percentage of men with normal lung function ranged from 96% of never smokers to 59% of continuous smokers; for women the proportions were 91% and 69%, respectively. The 25 year incidence of moderate and severe COPD was 20.7% and 3.6%, respectively, with no apparent difference between men and women. Smoking cessation, especially early in the follow up period, decreased the risk of developing COPD substantially compared with continuous smoking. During the follow up period there were 2912 deaths, 109 of which were from COPD. 92% of the COPD deaths occurred in subjects who were current smokers at the beginning of the follow up period. The absolute risk of developing COPD among continuous smokers is at least 25%, which is larger than was previously estimated.


Interaction of α-melanocortin and its pentapeptide antisense LVKAT: effects on hepatoprotection in male CBA mice.
The genetic code defines nucleotide patterns that code for individual amino acids and their complementary, i.e., antisense, pairs. Peptides specified by the complementary mRNAs often bind to each other with a higher specificity and efficacy. Applications of this genetic code property in biomedicine are related to the modulation of peptide and hormone biological function, selective immunomodulation, modeling of continuous and linear epitopes, modeling of mimotopes, paratopes and antibody mimetics, peptide vaccine development, peptidomimetic and drug design. We have investigated sense-antisense peptide interactions and related modulation of the peptide function by modulating the effects of a-MSH on hepatoprotection with its antisense peptide LVKAT. First, transcription of complementary mRNA sequence of a-MSH in 3'→5' direction was used to design antisense peptide to the central motif that serves as a-MSH pharmacophore for melanocortin receptors. Second, tryptophan spectrofluorometric titration was applied to evaluate the binding of a-MSH and its central pharmacophore motif to the antisense peptide, and it was concluded that this procedure represents a simple and efficient method to evaluate sense-antisense peptide interaction in vitro. Third, we showed that antisense peptide LVKAT abolished potent hepatoprotective effects of a-MSH in vivo.


Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation.
Apolipoprotein E (apoE) has long been known to play an important role in the clearance of plasma lipoproteins. More recently, a direct role for apoE in delaying atherogenesis has been proposed. Macrophage production of apoE in the artery wall has been demonstrated to provide protection against atherosclerotic lesion development independently from its role in lipoprotein clearance. However, whether macrophage apoE can affect lesion growth at all stages of atherogenesis remains to be established. To evaluate the role of macrophage apoE in different stages of atherogenesis, as well as to establish a novel gene therapy approach to atherosclerotic vascular disease, we used an apoE-expressing retrovirus to transduce apoE-deficient (-/-) bone marrow for transplantation into apoE(-/-) recipient mice. Three weeks after bone marrow transplantation, apoE was expressed from arterial macrophages and was detectable in plasma associated with lipoproteins at 0.5% to 1% of normal levels but did not affect plasma cholesterol levels. We used 2 groups of recipient mice: younger mice with lesions consisting primarily of foam cells and older mice with more advanced lesions. When either the mouse or human apoE transgenes were expressed in mice from 5 to 13 weeks of age, there was a significant reduction in lesion area, whereas no effects were detected in mice that expressed apoE from 10 to 26 weeks of age. We demonstrate that arterial macrophage apoE secretion can delay atherogenesis if expressed during foam cell formation but is not beneficial during the later stages of atherogenesis. These data also provide evidence that apoE transgene expression from arterial macrophages may have therapeutic applications.


The posterior deltoid-splitting approach to the shoulder.
Since 1980, the authors have used a posterior approach to the glenohumeral joint in which the posterior deltoid is split caudally in line with its fibers from the posterior acromion to the upper border of the teres minor. The extent of this deltoid splitting approach exceeds that of a similar anterior approach because of the distal emergence of the axillary nerve from the quadrilateral space. This technique gives complete access to the infraspinatus and teres minor muscles and tendons, posterior capsule, and posterior glenoid. Unlike traditional posterior approaches to the shoulder joint that detach a portion or all of the origin of the deltoid, this technique preserves the deltoid origin from the scapular spine and posterior acromion. Over the past 11 years, this posterior approach has been performed in 35 patients (42 shoulders): 31 for posterior instability, one for posterior glenohumeral fracture-dislocation, eight for infection, and two for removal of foreign bodies. The median age of the patients was 33.8 years (range, 13-65 years). The mean duration of follow-up contact was 20 months (range, one month to 11.4 years). Two patients died of unrelated causes and three were lost to follow-up examination. The posterior deltoid-splitting approach is advocated for any procedure requiring posterior access to the glenohumeral joint because it provides excellent exposure, has been associated with no complications, and preserves the strength and function of the posterior deltoid.


The evolution of dispersal in reserve networks.
The fragmentation of an environment into developed and protected areas may influence selection pressure on dispersal by increasing the chance of moving from a favorable to an unfavorable habitat. We theoretically explore this possibility through two cases: (1) marine systems in which reduced predation and/or increased feeding drive the evolution of planktonic larval duration and (2) more generally, where stochasticity in reproductive yield drives the evolution of the proportion of offspring dispersing. Model results indicate that habitat fragmentation generally shifts selection pressure toward reduced dispersal, particularly when areas outside reserves are uninhabitable. However, shifts to increased dispersal may occur when temporal heterogeneity is the primary selective force and constant-quota harvest occurs outside reserves. In addition, model results suggest the potential for changes in the genetic variability in dispersal after habitat fragmentation. The predicted evolutionary changes in dispersal will depend on factors such as the relative genetic and environmental contributions to dispersal-related traits and the extent of anthropogenic impacts outside reserves. If the predicted evolutionary changes are biologically attainable, they may suggest altering current guidelines for the appropriate size and spacing of marine reserves necessary to achieve conservation and fisheries goals.


Hormetic Neurobehavioral effects of low dose toxic chemical mixtures in real-life risk simulation (RLRS) in rats.
The current study aims to assess the long-term effects of very low dose exposures to a complex chemical mixture on motor performance and behavioural changes in rats. For twelve months (equivalent to thirty years in human terms), four groups of Sprague Dawley rats (five males and five females per group) were exposed to a thirteen chemical mixture (in drinking water) in doses of 0, 0.25, 1 and 5xADI/TDI (acceptable daily intake/tolerable daily intake) (mg/kg body weight/day). After twelve month exposure, the rats' motor performances were assessed by rotarod test, and their behavioural changes were assessed by open field exploratory test and elevated plus maze test. Exposure to the chemical mixture resulted in a statistically significant increase in the locomotor activity quantified by the number of crossings over external squares and in the spatial orientation activity quantified as the number of rearings in the lower dose group (0.25xADI/TDI) compared with the control group (p < 0.05). No significant changes were observed in the two higher dose groups (1xADI/TDI, 5xADI/TDI) compared with the control group. The administration of a very low doses of a cocktail of 13 chemicals led to a dose-dependent stimulation of the nervous system, rather than its inhibition.


Beta 2-microglobulin amyloid deposition in hip revision arthroplasty tissues.
Hip joint disease associated with progressive amyloid deposition in uraemic patients receiving chronic haemodialysis treatment often requires treatment by joint arthroplasty. The aim of this study was to determine whether beta 2-microglobulin amyloid deposition occurred in the periprosthetic tissues of arthroplasties that had undergone aseptic loosening and required a revision procedure. Sections of the pseudocapsule, acetabular and femoral pseudomembrane surrounding failed total hip replacements of five uraemic patients known to have beta 2-microglobulin amyloid deposits at the time of primary joint replacement were examined for the presence of beta 2-microglobulin amyloid deposition by Congo red staining and immunohistochemical staining for beta 2-microglobulin and other amyloid proteins. Clinical and radiological features of each case, including postoperative history and extent of osteolysis, were also noted. In all cases evidence of beta 2-microglobulin amyloid deposits were found in one or more of the above periprosthetic tissues. In three of these cases amyloid deposition was extensive. This study shows that beta 2-microglobulin amyloid deposition occurs in revision arthroplasty tissues. Accelerated loosening of the prosthesis is known to occur in uraemic patients and it is possible that beta 2-microglobulin amyloid deposition may contribute to early arthroplasty failure in uraemic patients who remain on haemodialysis treatment.


Lactate threshold predicting time-trial performance: impact of heat and acclimation.
The relationship between exercise performance and lactate and ventilatory thresholds under two distinct environmental conditions is unknown. We examined the relationships between six lactate threshold methods (blood- and ventilation-based) and exercise performance in cyclists in hot and cool environments. Twelve cyclists performed a lactate threshold test, a maximal O(2) uptake (Vo(2max)) test, and a 1-h time trial in hot (38°C) and cool (13°C) conditions, before and after heat acclimation. Eight control subjects completed the same tests before and after 10 days of identical exercise in a cool environment. The highest correlations were observed with the blood-based lactate indexes; however, even the indirect ventilation-based indexes were well correlated with mean power during the time trial. Averaged bias was 15.4 ± 3.6 W higher for the ventilation- than the blood-based measures (P < 0.05). The bias of blood-based measures in the hot condition was increased: the time trial was overestimated by 37.7 ± 3.6 W compared with only 24.1 ± 3.2 W in the cool condition (P < 0.05). Acclimation had no effect on the bias of the blood-based indexes (P = 0.51) but exacerbated the overestimation by some ventilation-based indexes by an additional 34.5 ± 14.1 W (P < 0.05). Blood-based methods to determine lactate threshold show less bias and smaller variance than ventilation-based methods when predicting time-trial performance in cool environments. Of the blood-based methods, the inflection point between steady-state lactate and rising lactate (INFL) was the best method to predict time-trial performance. Lastly, in the hot condition, ventilation-based predictions are less accurate after heat acclimation, while blood-based predictions remain valid in both environments after heat acclimation.


Replication and fine mapping for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in the Chinese population.
Prostate cancer represents the leading cause of male death across the world. A recent genome-wide association study (GWAS) identified five novel susceptibility loci for prostate cancer in the Japanese population. This study is to replicate and fine map the potential association of these five loci with prostate cancer in the Chinese Han population. In Phase I of the study, we tested the five single nucleotide polymorphisms (SNPs) which showed the strongest association evidence in the original GWAS in Japanese. The study sample consists of 1,169 Chinese Hans, comprising 483 patients and 686 healthy controls. Then in phase II, flanking SNPs of the successfully replicated SNPs in Phase I were genotyped and tested for association with prostate cancer to fine map those significant association signals. We successfully replicated the association of rs13385191 (located in the C2orf43 gene, P = 8.60×10(-5)), rs12653946 (P = 1.33×10(-6)), rs1983891 (FOXP4, P = 6.22×10(-5)), and rs339331 (GPRC6A/RFX6, P = 1.42×10(-5)) with prostate cancer. The most significant odds ratio (OR) was recorded as 1.41 (95% confidence interval 1.18-1.68) for rs12653946. Rs9600079 did not show significant association (P = 8.07×10(-2)) with prostate cancer in this study. The Phase II study refined these association signals, and identified several SNPs showing more significant association with prostate cancer than the very SNPs tested in Phase I. Our results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations. This study also characterized the novel loci reported in the original GWAS with more details. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.


Voluntary strength and muscle characteristics in untrained men and women and male bodybuilders.
Eight untrained women (F), 13 untrained men (M), and 11 male bodybuilders (BB) did maximal elbow flexions on an isokinetic dynamometer at velocities of 30, 120, 180, 240, and 300 degrees/s, from which impact torque (IT), peak torque (PT), and work (W) were measured. Biceps and total flexor cross-sectional area (CSA) were measured by computerized tomographic scanning. Muscle fiber area, fiber composition, and collagen volume density were determined from single needle biopsies of biceps brachii. Biceps fiber number was estimated as the ratio of biceps CSA (corrected for connective tissue) to mean fiber area. PT and W decreased at higher velocities in M and BB but not in F; consequently, the correlation between CSA and PT and W was lower at 300 degrees/s (r = 0.58, 0.60) than 30 degrees/s (r = 0.80, 0.79). The ratio of PT to flexor CSA was similar in all groups at 30 degrees/s, whereas F had greater ratios than M and BB at the remaining velocities. F had greater W/CSA ratios than M and BB at all velocities. IT increased at higher velocities in all groups; the increase was greater in F and M than in BB. In contrast to PT and W, the correlation between IT and CSA was greater at 300 degrees/s (r = 0.67) than 30 degrees/s (r = 0.58), and there were no differences among groups in the IT/CSA ratios. Flexor CSA correlated negatively with the ratio of IT, PT, and W to CSA. Muscle fiber composition failed to correlate with any measure of strength. M and BB had greater biceps area, fiber number, and fiber area than F.(ABSTRACT TRUNCATED AT 250 WORDS)


Linear demosaicing inspired by the human visual system.
There is an analogy between single-chip color cameras and the human visual system in that these two systems acquire only one limited wavelength sensitivity band per spatial location. We have exploited this analogy, defining a model that characterizes a one-color per spatial position image as a coding into luminance and chrominance of the corresponding three colors per spatial position image. Luminance is defined with full spatial resolution while chrominance contains subsampled opponent colors. Moreover, luminance and chrominance follow a particular arrangement in the Fourier domain, allowing for demosaicing by spatial frequency filtering. This model shows that visual artifacts after demosaicing are due to aliasing between luminance and chrominance and could be solved using a preprocessing filter. This approach also gives new insights for the representation of single-color per spatial location images and enables formal and controllable procedures to design demosaicing algorithms that perform well compared to concurrent approaches, as demonstrated by experiments.


Interplay of RsbM and RsbK controls the σ(B) activity of Bacillus cereus.
The alternative transcription factor σ(B) of Bacillus cereus controls the expression of a number of genes that respond to environmental stress. Four proteins encoded in the sigB gene cluster, including RsbV, RsbW, RsbY (RsbU) and RsbK, are known to be essential in the σ(B)-mediated stress response. In the context of stress, the hybrid sensor kinase RsbK is thought to phosphorylate the response regulator RsbY, a PP2C serine phosphatase, leading to the dephosphorylation of the phosphorylated RsbV. The unphosphorylated RsbV then sequesters the σ(B) antagonist, RsbW, ultimately liberating σ(B). The gene arrangement reveals an open reading frame, bc1007, flanked immediately downstream by rsbK within the sigB gene cluster. However, little is known about the function of bc1007. In this study, the deletion of bc1007 resulted in high constitutive σ(B) expression independent of environmental stimuli, indicating that bc1007 plays a role in σ(B) regulation. A bacterial two-hybrid analysis demonstrated that BC1007 interacts directly with RsbK, and autoradiographic studies revealed a specific C(14)-methyl transfer from the radiolabelled S-adenosylmethionine to RsbK when RsbK was incubated with purified BC1007. Our data suggest that BC1007 (RsbM) negatively regulates σ(B) activity by methylating RsbK. Additionally, mutagenic substitution was employed to modify 12 predicted methylation residues in RsbK. Certain RsbK mutants were able to rescue σ(B) activation in a rsbK-deleted bacterial strain, but RsbK(E439A) failed to activate σ(B), and RsbK(E446A) only moderately induced σ(B). These results suggest that Glu439 is the preferred methylation site and that Glu446 is potentially a minor methylation site. Gene arrays of the rsbK orthologues and the neighbouring rsbM orthologues are found in a wide range of bacteria. The regulation of sigma factors through metylation of RsbK-like sensor kinases appears to be widespread in the microbial world.


In vitro characterization of a koala retrovirus.
Recently, a new endogenous koala gammaretrovirus, designated KoRV, was isolated from koalas. The KoRV genome shares 78% nucleotide identity with another gammaretrovirus, gibbon ape leukemia virus (GALV). KoRV is endogenous in koalas, while GALV is exogenous, suggesting that KoRV predates GALV and that gibbons and koalas acquired the virus at different times from a common source. We have determined that subtle adaptive differences between the KoRV and GALV envelope genes account for differences in their receptor utilization properties. KoRV represents a unique example of a gammaretrovirus whose envelope has evolved to allow for its expanded host range and zoonotic potential.


Interleukin-17-mediated protective cytokine signaling against degeneration of the retinal pigment epithelium.
Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal γδ T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to characterize the profiles of immune cells in mouse choroid. We found that γδ T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6. This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal γδ T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia.