Sex Differences in the Association Between Gaming and Serious Violence Among Predominantly African American Youth.
Video gaming, a remarkably popular hobby in the United States, has been consistently identified as a correlate of aggressive behavior, and this association is not limited to violent video gaming. Prior studies of sex differences in the association between video gaming and aggression have not controlled for other well-known violence correlates (e.g., substance use, community violence exposure, violence attitudes) or focused primarily on high-risk youth. In this study, we used data from an emergency department in Flint, Michigan (N = 409, 59.9% female, 93.4% African American) to identify sex differences in the association between video gaming and serious peer violence. Youth aged 14 to 20 years were recruited from October 2011 to March 2015, and self-administered computerized surveys including measures of demographics, violence perpetration, gaming frequency, substance use, community violence exposure, and violence attitudes. The primary outcome was an indicator of any serious violence perpetration (e.g., choking, burning, weapon violence) in the past 2 months. Using logistic regression, we estimated the association between gaming and serious violence perpetration, and how it varied by sex, while controlling for demographics, substance use, community violence exposure, and violence attitudes. Approximately 36.6% of males and 27.3% of females reported past 2-month serious violence. On adjusted analysis, hours spent gaming was associated with violence among females (odds ratio [OR] = 1.40, 95% confidence interval [CI] = [1.16, 1.78]), but not males (OR = 1.03, 95% CI = [0.89, 1.19]); in the model including both males and females, the interaction between hours gaming and sex was significant (p < .01). Our findings suggest video gaming is a stronger marker of severe violence perpetration in females than males among at-risk youth. Violence interventions among females may be improved by including content related to video gaming and identifying other prosocial activities for youth as an alternative to video gaming. Additional research is required to clarify the causal process underlying the identified associations, and to determine what aspects of video gaming are risk-enhancing.


Anomalous hepatic venous drainage into the left atrium: an unusual cause of hypoxemia.
A 50-year-old woman with life-long hypoxemia and digital clubbing had a transient ischemic attack at age 47, without identifiable vascular or cardioembolic source. Extensive work-up revealed a 20% anatomic shunt (while breathing 100% oxygen) and evidence of an intrapulmonary shunt (an agitated saline, contrast-enhanced transesophageal echocardiogram showed bubbles in the left atrium and in 3 of the 4 visualized pulmonary veins) but without evidence of the hepatopulmonary syndrome, intrapulmonary arteriovenous malformations, or any intracardiac shunt. She had the congenital anomalies of cleft palate and lip and inferior vena caval interruption with azygos continuation, and anomalous hepatic venous drainage into the left atrium. In keeping with the sparse evidence of 12 previously reported patients with anomalous hepatic-venous-to-left-atrial drainage, the intrapulmonary shunt was believed to result from the diversion of hepatic venous blood from the pulmonary circulation. Surgical correction of the anomalous drainage and restoration of hepatic venous drainage into the right atrium immediately improved oxygenation, and follow-up contrast-enhanced echocardiography 3 months after the surgery showed resolution of the associated intrapulmonary shunt. This case extends the sparse available evidence with this unusual combination of congenital anomalies, reminds clinicians to consider unusual causes of right-to-left shunt and of paradoxical embolization, and invites clarification of the mechanism by which anomalous hepatic venous drainage into the left atrium allows reversible intra-pulmonary right-to-left shunt.


A luminescent cadmium metal-organic framework for sensing of nitroaromatic explosives.
A novel metal–organic framework [Cd3(TPT)2(DMF)2]·(H2O)0.5 (1) has been solvothermally synthesized using a new rigid unsymmetrical tricarboxylate ligand p-terphenyl-3,4′′,5-tricarboxylic acid (H3TPT). Single-crystal X-ray diffraction analysis reveals that 1 possesses a three-dimensional (3D) framework with an alb-4,8-C2/c topology constructed by the combination of Cd–carboxylate chains and TPT linkers. The π-electron rich ligand H3TPT enables 1 to have an excellent luminescent property. The micrometer-sized compound 1′ dispersed in ethanol exhibits high efficiency detection for picric acid (PA). The high efficiency, stability and recyclability of 1′ make it a potential chemosensor for nitroaromatic explosives.


Reprogramming of various cell types to a beta-like state by Pdx1, Ngn3 and MafA.
The three transcription factors, PDX1, NGN3 and MAFA, are very important in pancreatic development. Overexpression of these three factors can reprogram both pancreatic exocrine cells and SOX9-positive cells of the liver into cells resembling pancreatic beta cells. In this study we investigate whether other cell types can be reprogrammed. Eight cell types are compared and the results are consistent with the idea that reprogramming occurs to a greater degree for developmentally related cells (pancreas, liver) than for other types, such as fibroblasts. Using a line of mouse hepatocyte-derived cells we screened 13 compounds for the ability to increase the yield of reprogrammed cells. Three are active and when used in combination they can increase the yield of insulin-immunopositive cells by a factor of six. These results should contribute to the eventual ability to develop a new cure for diabetes based on the ability to reprogram other cells in the body to a beta cell phenotype.


Use of cells expressing the human thyrotropin (TSH) receptor for the measurement of thyroid stimulating and TSH-blocking antibodies.
A clone of Chinese hamster ovary cells (CHO) transfected with the cDNA of the human thyrotropin (TSH) receptor (CHO-R) was used to optimise assays for TSH receptor antibodies with either thyroid stimulating (TSAb) or TSH blocking (TSH-blocking Ab) activity. The study group included 89 patients with Graves' disease, 38 patients with goitrous Hashimoto's thyroiditis (HT) and 47 subjects with atrophic thyroiditis (AT). In the HT group, 8 patients had subclinical hypothyroidism (HT-SH) and 30 had overt hypothyroidism (HT-H). In the assay for TSAb, CHO-R cells were incubated with 1mg/ml of the immunoglobulin G (IgG) from patients with Grave's disease, while in the assay for TSH-blocking Ab cells were incubated with IgGs from patients with HT or AT alone (1mg/ml), or IgGs plus TSH (10 mU/L). After 2 h of incubation the extracellular cAMP was measured by a RIA. In these conditions a significant stimulation by Graves' IgG was obtained in patients with active hyperthyroidism (33/35, 94% untreated; 21/23, 91% relapsed after a course of medical treatment), in 12/20 (60%) patients euthyroid under methimazole and in 4/11 (36%) euthyroid after a course of antithyroid drugs. TSH-blocking Ab were detected in 1/8 (12.5%) patients with HT-SH, in 7/30 (23.3%) with HT-H and in 16/47 (34.0%) patients with AT. TSAb and TSH-blocking Ab coexisted in 4 IgGs that belonged to patients in whom spontaneous hypothyroidism developed after hyperthyroidism, or viceversa. TSAb and TSH-blocking Ab were also tested on FTRL-5 cells. TSAb were positive in both assays in 43/58 (74%) patients with active Graves' disease, negative in both assays in 3 (5%), negative in FRTL-5 and positive in CHO-R in 11 (19%), negative in CHO-R and positive in FRTL-5 in 1 (1.7%). In FTRL-5 cells TSH-blocking Ab were detected in 1/8 (12.5%) patients with HT-SH, in 5/30 (16.6%) with HT-H and in 15/47 (31.9%) with AT. The results of cAMP stimulation in FRTL-5 and CHO-R showed a fairly good correlation in TSAb (r = 0.60, p < 0.0001) and in TSH-blocking Ab (r = 0.74, p < 0.0001) assays. In conclusion, CHO cells transfected with the cloned human TSH receptor are suitable for the clinical assay of TSAb and TSH-blocking Ab. The sensitivity of this assay is higher than that obtained using FRTL-5 cells, having the additional advantages of expressing the human TSH receptor and requiring less cumbersome procedures for cell culture.


Folic Acid Supplementation in Postpolypectomy Patients in a Randomized Controlled Trial Increases Tissue Folate Concentrations and Reduces Aberrant DNA Biomarkers in Colonic Tissues Adjacent to the Former Polyp Site.
Low folate status is associated with an increased risk of colorectal carcinogenesis. Optimal folate status may be genoprotective by preventing uracil misincorporation into DNA and DNA hypomethylation. Adenomatous polyps have low folate status compared with normal colonic mucosa, and they are surrounded by histologically normal mucosa that also is of low folate status. In a randomized controlled trial conducted at a single Dublin hospital between April 2002 and March 2004, we assessed the effect of folic acid supplementation on tissue folate, uracil misincorporation into DNA, and global DNA hypomethylation in colonocytes isolated from sites of adenomatous polyps and from histologically normal tissue adjacent and 10-15 cm distal to them. Twenty patients with adenomatous polyps on initial colonoscopy and polypectomy were randomly assigned to receive either 600 μg folic acid/d [n = 12, 38% men, mean age 64.3 y, and body mass index (BMI, in kg/m(2)) 26.6] or placebo (n = 8, 50% men, mean age 68.4 y, and BMI 27.2) for 6 mo, and then repeat the colonoscopy. Blood and colonocyte tissue folate concentrations were measured with the use of a microbiological assay. Uracil misincorporation and global DNA hypomethylation were measured in colonocytes with the use of modified comet assays. Over time, folic acid supplementation, compared with placebo, increased tissue folate (mean ± SEM) from 15.6 ± 2.62 pg/10(5) cells to 18.1 ± 2.12 pg/10(5) cells (P < 0.001) and decreased the global DNA hypomethylation ratio from 1.7 ± 0.1 to 1.0 ± 0.1 (P < 0.001). The uracil misincorporation ratio decreased by 0.5 ± 0.1 for the site adjacent to the polyp over time (P = 0.05). A response to folic acid supplementation, which increased colonocyte folate and improved folate-related DNA biomarkers of cancer risk, was seen in the participants studied. Exploratory analysis points toward the area formerly adjacent to polyps as possibly driving the response. That these areas persist after polypectomy in the absence of folate supplementation is consistent with a potentially carcinogenic field's causing the appearance of the polyp.


Bridging nonliving and living matter.
Assembling non-biological materials (geomaterials) into a proto-organism constitutes a bridge between nonliving and living matter. In this article we present a simple step-by-step route to assemble a proto-organism. Many pictures have been proposed to describe this transition within the origins-of-life and artificial life communities, and more recently alternative pictures have been emerging from advances in nanoscience and biotechnology. The proposed proto-organism lends itself to both traditions and defines a new picture based on a simple idea: Given a set of required functionalities, minimize the physicochemical structures that support these functionalities, and make sure that all structures self-assemble and mutually enhance each other's existence. The result is the first concrete, rational design of a simple physicochemical system that integrates the key functionalities in a thermodynamically favorable manner as a lipid aggregate integrates proto-genes and a proto-metabolism. Under external pumping of free energy, the metabolic processes produce the required building blocks, and only specific gene sequences enhance the metabolic kinetics sufficiently for the whole system to survive. We propose an experimental implementation of the proto-organism with a discussion of our experimental results, together with relevant results produced by other experimental groups, and we specify what is still missing experimentally. Identifying the missing steps is just as important as providing the road map for the transition. We derive the kinetic and thermodynamic conditions of each of the proto-organism subsystems together with relevant theoretical and computational results about these subsystems. We present and discuss detailed 3D simulations of the lipid aggregation processes. From the reaction kinetics we derive analytical aggregate size distributions, and derive key properties of the metabolic efficiency and stability. Thermodynamics and kinetics of the ligation directed self-replication of the proto-genes is discussed, and we summarize the full life cycle of the proto-organism by comparing size, replication time, and energy with the biomass efficiency of contemporary unicells. Finally, we also compare our proto-organism picture with existing origins-of-life and protocell pictures. By assembling one possible bridge between nonliving and living matter we hope to provide a piece in the ancient puzzle about who we are and where we come from.


Infections with Wolbachia, Spiroplasma, and Rickettsia in the Dolichopodidae and other Empidoidea.
Vertically transmitted reproductive parasites are both extraordinarily widespread and diverse in their effects on their invertebrate hosts. In addition to causing skewed population sex ratios via male-killing or feminization, such bacteria can further cause cytoplasmic incompatibility or parthenogenesis. Previous surveys show that the microbes Wolbachia and Spiroplasma are common in some dipteran families, e.g. Drosophilidae or Scathophagidae, and are known to be heritable symbionts and affect reproduction in the Diptera. However, little is known of Rickettsia infections and detailed surveys targeting other Dipteran families are lacking. Here 329 samples of 247 species of Diptera belonging to the Dolichopodidae, Empididae, and Hybotidae (superfamily Empidoidea) are surveyed for the presence of the endosymbionts Wolbachia, Spiroplasma, and Rickettsia. The superfamily Empidoidea contains numerous species, which have been the targets of intense research concerning reproductive traits involved in sexual selection. 151 of the species (i.e. ca. 61%) screened here, including species from key genera such as Dolichopus, Poecilobothrus or Empis, harboured one or more symbionts. Reproductive parasites are thus also common in the Empidoidae, yet effects on hosts remain unclear. Potential endosymbiont-host interactions in this group would hence be worthy of further investigation.


Ultrastructure of blebbing and phagocytosis of blebs by hyperplastic thyroid epithelial cells in vivo.
In addition to pseudopods, somewhat pleomorphic blebs were consistently found protruding from the apical surfaces of hyperplastic rat thyroid epithelial cells into the follicular lumens in vivo. Many blebs were knobby, roughly hemispherical protrusions, with a diameter of 2-3 mum. Such blebs had a densely packed microfilamentous core and contained numerous apparent ribosomes. They were morphologically similar to blebs that have been observed in a variety of cultured cells. Other blebs were larger, more elongate, and less knobby, but had a similar ultrastructural organization. Blebs of all sizes appeared to be phagocytosed on some occasions by nearby epithelial cells. The phagocytic process involved partial engulfment of the bleb by a typical epithelial pseudopod, followed by an apparent pinching-off process, presumably resulting in the separation of the bleb from its cells or origin. The pinching-off process was associated with a band of approx. 6-nm diameter microfilaments that developed within the pseudopod cytoplasm surrounding the base of the bleb and is postulated to function as a contractile ring. The finding of blebbing is an intact tissue in vivo indicates that this phenomenon is not restricted to cultured cells, and thus tends to extend the significance of in vitro observations of the process. In relation to their occurrence in the hyperplastic thyroid gland in vivo, possible interconversions are considered between different types of blebs, and between blebs and pseudopods.


Malaria morbidity in Papua Indonesia, an area with multidrug resistant Plasmodium vivax and Plasmodium falciparum.
Multidrug resistance has emerged to both Plasmodium vivax and Plasmodium falciparum and yet the comparative epidemiology of these infections is poorly defined. All laboratory-confirmed episodes of malaria in Timika, Papua, Indonesia, presenting to community primary care clinics and an inpatient facility were reviewed over a two-year period. In addition information was gathered from a house-to-house survey to quantify the prevalence of malaria and treatment-seeking behaviour of people with fever. Between January 2004 and December 2005, 99,158 laboratory-confirmed episodes of malaria were reported, of which 58% (57,938) were attributable to P. falciparum and 37% (36,471) to P. vivax. Malaria was most likely to be attributable to pure P. vivax in children under one year of age (55% 2,684/4,889). In the household survey, the prevalence of asexual parasitaemia was 7.5% (290/3,890) for P. falciparum and 6.4% (248/3,890) for P. vivax. The prevalence of P. falciparum infection peaked in young adults aged 15-25 years (9.8% 69/707), compared to P. vivax infection which peaked in children aged 1 to 4 years (9.5% 61/642). Overall 35% (1,813/5,255) of people questioned reported a febrile episode in the preceding month. Of the 60% of people who were estimated to have had malaria, only 39% would have been detected by the surveillance network. The overall incidence of malaria was therefore estimated as 876 per 1,000 per year (Range: 711-906). In this region of multidrug-resistant P. vivax and P. falciparum, both species are associated with substantial morbidity, but with significant differences in the age-related risk of infection.


A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus.
To investigate whether Fas promoter polymorphisms show a genetic contribution to the development of systemic lupus erythematosus (SLE) in a Japanese population, and to study the functional difference in promoter activity of the polymorphisms. In 109 SLE patients and 140 controls, the frequencies of A/G polymorphisms at -670 nucleotide position and G/A at -1377 nucleotide position were determined by allele-specific polymerase chain reaction (PCR) or PCR-single strand conformation polymorphism analysis. The functional significance of the -670A/G polymorphism in the Fas gene was evaluated by a combination of Fas transcriptional activity in the reporter gene assay and binding activity of signal transducer and activator of transcription (STAT) 1 protein in the electrophoretic mobility shift assay. SLE patients exhibited significantly higher frequency of A allele at nucleotide position -670 (p = 0.004). There was no significant difference in the nucleotide position -1377 in Fas promoter gene between SLE patients and controls. The electrophoretic mobility shift assay demonstrated that the oligonucleotide with -670A in the Fas promoter had a higher binding ability to a GAS binding protein, STAT1, than that with -670G, although there was no statistically significant difference in the reporter gene assay. Fas promoter -670A/G polymorphism was significantly associated with SLE, suggesting a possibility that Fas promoter contributes, at least in part, to the pathogenesis of SLE.


Mapping of murine diabetogenic gene mody on chromosome 7 at D7Mit258 and its involvement in pancreatic islet and beta cell development during the perinatal period.
Mutation of the murine maturity-onset diabetes mellitus of the young (Mody) locus induces diabetes, but the effects of its homozygosity on the pancreas remain unknown. F2 mice were obtained by F1 (diabetic C57BL6 x normal Mus musculus castaneus) crosses. About 20% of the F2 progeny developed diabetes by 2 wk of age, 50% of the progeny were normal at 2 wk and developed diabetes between 5 and 8 wk of age, and the remaining 30% did not develop diabetes. Quantitative trait locus analysis using blood glucose levels of 118 F2 mice at 2 wk of age and 5-8 wk of age located Mody within 3 cM of D7Mit258. Histopathological investigation revealed hypoplastic islets (approximately 33% of that of wild-type mice) and a lower density of beta cells (approximately 20% of wild-type) with a reciprocal dominance of alpha cells (four times that of wild-type) in Mody homozygotes. Electron microscopic observations revealed a specific decrease in the number of insulin secretory granules and a lower density of beta cells. Ratios of insulin to glucagon contents confirmed specific decreases in insulin content: 0.01 for homozygotes, 0.54 for heterozygotes, and 1.11 for wild-type mice on day 14. These results suggest that Mody is involved in both islet growth and beta cell function.


Permutation tests for joinpoint regression with applications to cancer rates.
The identification of changes in the recent trend is an important issue in the analysis of cancer mortality and incidence data. We apply a joinpoint regression model to describe such continuous changes and use the grid-search method to fit the regression function with unknown joinpoints assuming constant variance and uncorrelated errors. We find the number of significant joinpoints by performing several permutation tests, each of which has a correct significance level asymptotically. Each p-value is found using Monte Carlo methods, and the overall asymptotic significance level is maintained through a Bonferroni correction. These tests are extended to the situation with non-constant variance to handle rates with Poisson variation and possibly autocorrelated errors. The performance of these tests are studied via simulations and the tests are applied to U.S. prostate cancer incidence and mortality rates.


Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine.
Covering: 1970 to 2020By definition total synthesis is the art and science of making the molecules of living Nature in the laboratory, and by extension, their analogues. Although obvious, its application to the synthesis of molecules for biology and medicine was not always the purpose of total synthesis. In recent years, however, the field has acquired momentum as its power to reach higher molecular complexity and diversity is increasing, and as the demand for rare bioactive natural products and their analogues is expanding due to their recognised potential to facilitate biology and drug discovery and development. Today this component of total synthesis endeavors is considered highly desirable, and could be part of interdisciplinary academic and/or industrial partnerships, providing further inspiration and momentum to the field. In this review we provide a brief historical background of the emergence of the field of total synthesis as it relates to making molecules for biology and medicine. We then discuss specific examples of this practice from our laboratories as they developed over the years. The review ends with a conclusion and future perspectives for natural products chemistry and its applications to biology and medicine and other added-value contributions to science and society.


Estimating heritability of drug-induced liver injury from common variants and implications for future study designs.
Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h(2)) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h(2) captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h(2) estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection.


Separate domains of fission yeast Cdk9 (P-TEFb) are required for capping enzyme recruitment and primed (Ser7-phosphorylated) Rpb1 carboxyl-terminal domain substrate recognition.
In fission yeast, discrete steps in mRNA maturation and synthesis depend on a complex containing the 5'-cap methyltransferase Pcm1 and Cdk9, which phosphorylates the RNA polymerase II (Pol II) carboxyl-terminal domain (CTD) and the processivity factor Spt5 to promote transcript elongation. Here we show that a Cdk9 carboxyl-terminal extension, distinct from the catalytic domain, mediates binding to both Pcm1 and the Pol II CTD. Removal of this segment diminishes Cdk9/Pcm1 chromatin recruitment and Spt5 phosphorylation in vivo and leads to slow growth and hypersensitivity to cold temperature, nutrient limitation, and the IMP dehydrogenase inhibitor mycophenolic acid (MPA). These phenotypes, and the Spt5 phosphorylation defect, are suppressed by Pcm1 overproduction, suggesting that normal transcript elongation and gene expression depend on physical linkage between Cdk9 and Pcm1. The extension is dispensable, however, for recognition of CTD substrates "primed" by Mcs6 (Cdk7). On defined peptide substrates in vitro, Cdk9 prefers CTD repeats phosphorylated at Ser7 over unmodified repeats. In vivo, Ser7 phosphorylation depends on Mcs6 activity, suggesting a conserved mechanism, independent of chromatin recruitment, to order transcriptional CDK functions. Therefore, fission yeast Cdk9 comprises a catalytic domain sufficient for primed substrate recognition and a multivalent recruitment module that couples transcription with capping.


Adsorption of a strong polyelectrolyte to model lignin surfaces.
The adsorption of a strong, highly charged cationic polyelectrolyte to a kraft lignin thin film was investigated as a function of the adsorbing solution conditions using the quartz crystal microbalance. The polyelectrolyte, PDADMAC, with a molecular weight of 100 kDa and one cationic charge group per monomer, was adsorbed to the anionically charged lignin film in the pH range 3.5-9.5 in electrolyte solution of 0.1 to 100 mM NaCl. At low pH, the adsorbed amount of PDADMAC was minimal, however, this increased as a function of increasing pH. Indeed, the surface excess increased significantly at about pH 8.5, where ionization of the phenolic groups on the lignin macromolecule may be expected. Furthermore, at this elevated pH, the adsorbed amount of PDADMAC decreased as the ionic strength of the solution increased above 1 mM. This is due to the competitive adsorption of counterions to the lignin surface and indicates that the adsorption of PDADMAC to lignin is of a pure electrosorption nature.


Analysis of genetic diversity and population structure of gene encoding cell-traversal protein for ookinetes and sporozoites (CelTOS) vaccine candidate antigen in global Plasmodium falciparum populations.
Plasmodium falciparum cell-traversal protein for ookinetes and sporozoites (PfCelTOS) has been reported as one of the most attractive malaria vaccine candidate antigens. To design a broadly effective malaria vaccine based on this antigen, it is crucial to have adequate information on genetic diversity in global PfCelTOS. Therefore, the extent of sequence diversity at the full-length of the pfceltos was assessed among both natural P. falciparum isolates collected from Iran (n = 93) and from available global pfceltos sequence data retrieved from PlasmoDB database (n = 159). Also, recombination, natural selection, the degree of genetic differentiation as well as the predicted immunodominant regions in PfCelTOS were analyzed. In total, 40 SNPs (including 1 synonymous and 39 non-synonymous) were detected in 34 positions, as compared to 3D7 sequence, which led to 66 distinct haplotypes with different frequencies. Among those haplotypes, 34 (51.5%, excluded from further analysis) were singleton haplotype and mostly detected among Senegalese parasite isolates. PfCelt-1 was found as predominant haplotype (32.6% total frequency) that was only detected in Iranian P. falciparum isolates. Nucleotide diversity was low in French Guiana (0.00236 ± 0.00203) and Iranian (0.00259 ± 0.00048) P. falciparum isolates in comparison with African populations. Evidence for positive selection by host immunity and intragenic recombination were detected that are two key factors responsible for gene evolution and genetic diversity of pfceltos gene. The results of Fst analysis and haplotype network revealed that PfCelTOS antigen displayed evident genetic structure between geographical parasite populations. In conclusion, the present analysis demonstrates that there is a limited antigenic diversity and geographic variation in global PfCelTOS, and this finding may be associated with the critical function of this antigen in cell traversal of the parasite in sporozoite and ookinete. Besides, most of the predicted B- and T-cell epitopes were located in the conserved region of the gene, but most of the amino acid replacements were located at the C-terminal region of PfCelTOS. The obtained results in this investigation could provide knowledge for better design of PfCelTOS-based malaria vaccine.


Absence of association between organic solvent exposure and risk of chronic renal failure: a nationwide population-based case-control study.
Exposure to organic solvents has been suggested to cause or exacerbate renal disease, but methodologic concerns regarding previous studies preclude firm conclusions. We examined the role of organic solvents in a population-based case-control study of early-stage chronic renal failure (CRF). All native Swedish residents aged 18 to 74 yr, living in Sweden between May 1996 and May 1998, formed the source population. Incident cases of CRF in a pre-uremic stage (n = 926) and control subjects (n = 998), randomly selected from the study base, underwent personal interviews that included a detailed occupational history. Expert rating by a certified occupational hygienist was used to assess organic solvent exposure intensity and duration. Relative risks were estimated by odds ratios (OR) in logistic regression models, with adjustment for potentially important covariates. The overall risk for CRF among subjects ever exposed to organic solvents was virtually identical to that among never-exposed (OR, 1.01; 95% confidence interval [CI], 0.81 to 1.25). No dose-response relationships were observed for lifetime cumulative solvent exposure, average dose, or exposure frequency or duration. The absence of association pertained to all subgroups of CRF: glomerulonephritis (OR, 0.96; 95% CI, 0.68 to 1.34), diabetic nephropathy (OR, 1.02; 95% CI, 0.74 to 1.41), renal vascular disease (OR, 1.16; 95% CI, 0.76 to 1.75), and other renal CRF (OR, 0.92; 95% CI, 0.66 to 1.27). The results from a nationwide, population-based study do not support the hypothesis of an adverse effect of organic solvents on CRF development, in general. Detrimental effects from subclasses of solvents or on specific renal diseases cannot be ruled out.


Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus.
MR imaging is used in the diagnostic evaluation of patients with idiopathic normal pressure hydrocephalus. The aim of this study was to describe the prevalence of several imaging features and their prognostic use in the selection of shunt candidates with idiopathic normal pressure hydrocephalus. Preoperative MR imaging scans of the brain were retrospectively evaluated in 108 patients with idiopathic normal pressure hydrocephalus who had undergone a standardized, clinical evaluation before and 12 months after shunt surgery. The MR imaging features investigated were the Evans index, callosal angle, narrow sulci at the high convexity, dilation of the Sylvian fissure, diameters of the third ventricle and temporal horns, disproportionately enlarged subarachnoid space hydrocephalus, flow void through the aqueduct, focal bulging of the roof of the lateral ventricles, deep white matter hyperintensities, periventricular hyperintensities, and focal widening of sulci and aqueductal stenosis. In logistic regression models, with shunt outcome as a dependent variable, the ORs for the independent variables, callosal angle, disproportionately enlarged subarachnoid space hydrocephalus, and temporal horns, were significant (P < .05), both in univariate analyses and when adjusted for age, sex, and previous stroke. A small callosal angle, wide temporal horns, and occurrence of disproportionately enlarged subarachnoid space hydrocephalus are common in patients with idiopathic normal pressure hydrocephalus and were significant predictors of a positive shunt outcome. These noninvasive and easily assessed radiologic markers could aid in the selection of candidates for shunt surgery.


Soy-derived isoflavones inhibit the growth of canine lymphoid cell lines.
This study aimed to evaluate the in vitro effects of genistein, both pure genistein and a commercially available form of genistein called Genistein Combined Polysacharride (GCP), against two canine B-cell lymphoid cell lines and determine the oral bioavailability of GCP when fed to normal dogs. The in vitro effect of genistein and GCP was evaluated using cell proliferation and apoptotic assays. The IC50 of both compounds was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay and propidium idodide staining. Apoptosis was evaluated using Annexin V staining, caspase 3 and 9 staining, and DNA laddering. Cell cycle analysis and Bcl-2/Bax ratios were also examined. An initial dose escalating pharmacokinetic study was used to determine if therapeutic serum levels of genistein could be reached with oral dosing of GCP in normal dogs. The 72-hour in vitro IC50 of genistein and GCP against the GL-1 and 17-71 cells were both 10 microg/mL and 20 microg/mL, respectively. GCP led to cell death in both cell lines via apoptosis and treated cells exhibited increased Bax:Bcl-2 ratios. The serum concentrations of genistein in normal dogs given increasing oral doses of GCP did not reach the 72-hour in vitro IC50 in a dose escalation study. The results of these studies support the notion that canine high-grade B-cell lymphoma may represent a relevant large animal model of human non-Hodgkin's lymphoma to investigate the utility of GCP in chemopreventive and/or treatment strategies that may serve as a prelude to human clinical lymphoma trials.


COEXPEDIA: exploring biomedical hypotheses via co-expressions associated with medical subject headings (MeSH).
The use of high-throughput array and sequencing technologies has produced unprecedented amounts of gene expression data in central public depositories, including the Gene Expression Omnibus (GEO). The immense amount of expression data in GEO provides both vast research opportunities and data analysis challenges. Co-expression analysis of high-dimensional expression data has proven effective for the study of gene functions, and several co-expression databases have been developed. Here, we present a new co-expression database, COEXPEDIA (www.coexpedia.org), which is distinctive from other co-expression databases in three aspects: (i) it contains only co-functional co-expressions that passed a rigorous statistical assessment for functional association, (ii) the co-expressions were inferred from individual studies, each of which was designed to investigate gene functions with respect to a particular biomedical context such as a disease and (iii) the co-expressions are associated with medical subject headings (MeSH) that provide biomedical information for anatomical, disease, and chemical relevance. COEXPEDIA currently contains approximately eight million co-expressions inferred from 384 and 248 GEO series for humans and mice, respectively. We describe how these MeSH-associated co-expressions enable the identification of diseases and drugs previously unknown to be related to a gene or a gene group of interest.


Isolation and properties of Gas8, a growth arrest-specific gene regulated during male gametogenesis to produce a protein associated with the sperm motility apparatus.
Growth arrest-specific (Gas) genes are expressed during serum starvation or contact inhibition of cells grown in culture. Here we report the isolation and characterization of Gas8, a novel gene identified on the basis of its growth arrest-specific expression in murine fibroblasts. We show that production of Gas8 mRNA and protein occurs in adult mice predominantly in the testes, where expression is regulated during postmeiotic development of male gametocytes. Whereas a low level of Gas8 mRNA was detected by Northern blotting in testes of murine male neonates and young adolescents, Gas8 mRNA increased rapidly postmeiotically. In adult males, both Gas8 mRNA and protein reached steady state levels in testes that were 10-fold higher than in other tissues. Immunohistochemical analyses showed that Gas8 protein accumulates in gametocytes as they approach the lumen of seminiferous tubules and is localized to the cytoplasm of round spermatids, the tails of elongating spermatids, and mature spermatid tail bundles protruding into the lumen; in epididymal spermatozoa Gas8 protein was present in the flagella. However, premeiotic murine gametocytes lacked detectable Gas8 protein, as did seminiferous tubules in biopsy specimens from seven human males having cytological evidence of non-obstructive azoospermia secondary to Sertoli cell-only syndrome. Our findings, which associate Gas8 production developmentally with the later stages of spermatogenesis and spatially with the sperm motility apparatus, collectively suggest that this growth arrest-specific gene product may have a role in sperm motility. This postulated role for Gas8 is supported by our observation that highly localized production of Gas8 protein occurs also in the cilia of epithelial cells lining pulmonary bronchi and fallopian tubes and by the flagellar association of a Trypanosoma brucei ortholog of Gas8.


The Role of Autophagy in Pancreatic Cancer-Recent Advances.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.


Amodal Volume Completion and the Thin Building Illusion.
We report results from an experiment showing that a tall pillar with a triangular base evokes radically different three-dimensional (3D) percepts depending on the vantage point from which it is observed. The base of the pillar is an isosceles right triangle, but the pillar is perceived as just a thin plane when viewed from some vantage points. Viewed from other vantage points, the perceived 3D shape of the pillar corresponds to a square or rectangular base. In general, our results suggest that the visual system uses a preference for rectangularity (or symmetry) to determine the 3D shape of objects. The amodal impressions of the invisible backside of the pillar are often quite compelling, and the corresponding illusions persist even when the observers know the true shape of the pillar. Interestingly, though, the compellingness and definiteness of the amodal impression of the pillar's backside depends on the vantage point. This is reflected in corresponding differences in the interobserver variability of the 3D shape judgments. We also discuss how variants of this illusion are used as a powerful tool in the art of magic.


Dissolution behavior and early bone apposition of calcium phosphate-coated machined implants.
Calcium phosphate (CaP)-coated implants promote osseointegration and survival rate. The aim of this study was to (1) analyze the dissolution behavior of the residual CaP particles of removed implants and (2) evaluate bone apposition of CaP-coated machined surface implants at the early healing phase. Mandibular premolars were extracted from five dogs. After eight weeks, the implants were placed according to drilling protocols: a nonmobile implant (NI) group and rotational implant (RI) group. For CaP dissolution behavior analysis, 8 implants were removed after 0, 1, 2, and 4 weeks. The surface morphology and deposition of the coatings were observed. For bone apposition analysis, block sections were obtained after 1-, 2-, and 4-week healing periods and the specimens were analyzed. Calcium and phosphorus were detected in the implants that were removed immediately after insertion, and the other implants were composed mainly of titanium. There were no notable differences between the NI and RI groups in terms of the healing process. The bone-to-implant contact and bone density in the RI group showed a remarkable increase after 2 weeks of healing. It can be speculated that the CaP coating dissolves early in the healing phase and chemically induces early bone formation regardless of the primary stability.


Reconstitution of adaptive immunity after umbilical cord blood transplantation: impact on infectious complications.
In comparison with allogeneic stem cell transplantation (alloHSCT) with other stem cell sources, umbilical cord blood transplantation (UCBT) was traditionally associated with increased risk of infections, particularly during the first 3 months after transplantation. Longitudinal studies of immune monitoring reported peculiar patterns of T- and B-cell recovery in the peripheral blood of UCB recipients during the first months post-transplantation. Overall, current data suggest delayed reconstitution of naive and memory CD4+ and CD8+ T-cell pools after UCBT. This is particularly true for adult recipients and for patients who received in vivo T-cell depleting approaches before the transplantation. Such delayed T-cell recovery may increase susceptibility of UCB recipients for developing opportunistic infections and viral reactivations. Regarding B-cell recovery, UCBT was associated with accelerated B-lymphopoiesis. Recent studies also reported evidence for faster functional memory B-cell recovery in UCB recipients. In this article, we briefly review T- and B-cell reconstitution after alloHSCT, with emphasis on peculiarities observed after UCBT. We further put these data in lines with risks of infections after UCBT.


Floral morphology and morphogenesis in Camptotheca (Nyssaceae), and its systematic significance.
Camptotheca is endemic to China and there are limited data about the breeding system and morphogenesis of the flowers. Camptotheca is thought to be related to Nyssa and Davidia in Nyssaceae, which has sometimes been included in Cornaceae. However, molecular phylogenetic studies confirmed the inclusion of Camptotheca in Nyssaceae and its exclusion from Cornaceae. The aim of this study was to reveal developmental features of the inflorescence and flowers in Camptotheca to compare with related taxa in Cornales. Inflorescences and flowers of Camptotheca acuminata at all developmental stages were collected and studied with a scanning electron microscope and stereo microscope. Camptotheca has botryoids which are composed of several capitate floral units (FUs) that are initiated acropetally. On each FU, flowers are grouped in dyads that are initiated acropetally. All floral organs are initiated centripetally. Calyx lobes are restricted to five teeth. The hypanthium, with five toothed calyx lobes, is adnate to the ovary. The five petals are free and valvate. Ten stamens are inserted in two whorls around the central depression, in which the style is immersed. Three carpels are initiated independently but the ovary is syncarpous and unilocular. The ovule is unitegmic and heterotropous. Inflorescences are functionally andromonoecious varying with the position of the FUs on the inflorescence system. Flowers on the upper FU often have robust styles and fully developed ovules. Flowers on the lower FU have undeveloped styles and aborted ovules, and the flowers on the middle FU are transitional. Camptotheca possesses several traits that unify it with Nyssa, Mastixia and Diplopanax. Inflorescence and floral characters support a close relationship with Nyssaceae and Mastixiaceae but a distant relationship with Cornus. Our results corroborate molecular inferences and support a separate family Nyssaceae.


Effects of chronic electrical stimulation on contractile properties of long-term denervated rat skeletal muscle.
1. The contractile properties of fast-twitch (extensor digitorum longus or EDL) and slow-twitch (soleus) muscles in the rat were followed for periods of between 4 and 10 months after denervation. The effects of chronic electrical stimulation during the last 3-8 weeks of denervation were investigated. 2. The fall in tetanic tension that follows axotomy ended after about 4 months' denervation. The equilibrium tension was about 0.75% of control tension in EDL and 0.2-0.3% in soleus. 3. The low tension in soleus was due partly to the small diameter of the muscle fibres (atrophy) and partly to their necrosis that resulted in an 8-fold fall in specific tension (the force per unit cross-sectional area). Similar but less extreme changes occurred in EDL. 4. It is speculated that the final level of tension reached by unstimulated denervated muscles is an equilibrium between decrease in force due to atrophy and necrosis and increase due to regeneration. Differences between the final tension levels in soleus and EDL cannot be accounted for quantitatively by known differences in atrophy alone. Therefore, the rate of necrosis in soleus and of regeneration in EDL may be higher. 5. Chronic stimulation of long-term denervated muscle increased force generation by about 7-fold in EDL and between 20 and 55 times in soleus. The final tension reached was between 4 and 5% of normal in both muscles. Specific tension of fibres was almost completely restored by stimulation and the number of fibres was normal. The failure to recover full tension was largely due to failure to reverse denervation atrophy completely. 6. Twitch contraction and relaxation times were identical in denervated-stimulated soleus and EDL. There was no evidence for dependence on duration of stimulation or tension of the muscle. The normalized maximum rate of rise of tetanic tension remained higher in EDL than soleus.


MICRORNA-AUGMENTED PATHWAYS (mirAP) AND THEIR APPLICATIONS TO PATHWAY ANALYSIS AND DISEASE SUBTYPING.
MicroRNAs play important roles in the development of many complex diseases. Because of their importance, the analysis of signaling pathways including miRNA interactions holds the potential for unveiling the mechanisms underlying such diseases. However, current signaling pathway databases are limited to interactions between genes and ignore miRNAs. Here, we use the information on miRNA targets to build a database of miRNA-augmented pathways (mirAP), and we show its application in the contexts of integrative pathway analysis and disease subtyping. Our miRNA-mRNA integrative pathway analysis pipeline incorporates a topology-aware approach that we previously implemented. Our integrative disease subtyping pipeline takes into account survival data, gene and miRNA expression, and knowledge of the interactions among genes. We demonstrate the advantages of our approach by analyzing nine sample-matched datasets that provide both miRNA and mRNA expression. We show that integrating miRNAs into pathway analysis results in greater statistical power, and provides a more comprehensive view of the underlying phenomena. We also compare our disease subtyping method with the state-of-the-art integrative analysis by analyzing a colorectal cancer database from TCGA. The colorectal cancer subtypes identified by our approach are significantly different in terms of their survival expectation. These miRNA-augmented pathways offer a more comprehensive view and a deeper understanding of biological pathways. A better understanding of the molecular processes associated with patients' survival can help to a better prognosis and an appropriate treatment for each subtype.


Laparoscopic versus open abdominal surgery in children with sickle cell disease is associated with a shorter hospital stay.
Limited information exists comparing the post-operative complication rate of laparoscopic or open abdominal surgeries in children with sickle cell disease (SCD). The primary objective of this study was to compare the outcomes in children with SCD who required laparoscopic or open abdominal surgery for a cholecystectomy or splenectomy. We conducted a retrospective analysis of laparoscopic and open abdominal surgeries performed in children with SCD (ages 0-20 years) at two medical centers from 1984 to 2004. The primary outcome measures were the rates of post-operative pain and acute chest syndrome (ACS) episodes following laparoscopic or open abdominal surgery. The secondary outcome was length of hospital stay following surgery. We also examined the potential contribution of pre-operative (transfusion) and intra-operative factors (operating time, estimated blood loss, and end-operative temperature) to post-operative SCD-related complications. A total of 140 cases were identified, 98 laparoscopic and 42 open. Episodes of post-operative pain and ACS episodes were comparable between laparoscopic and open procedures (pain: 4% vs. 3%, P = 0.619; ACS: 5% vs. 5%, P = 0.933). Additionally, laparoscopic surgeries were associated with a significantly shorter hospital stay (2.9 vs. 5.4 days, 95% CI -3.7 to -1.4, P < 0.001). There was no difference in the number of hospital readmissions within 1 month of the surgery. For children with SCD who need a cholecystectomy or splenectomy, laparoscopy is the preferred strategy because of a shorter hospital stay with a similar complication rate compared to open surgeries.


Mechanism of suppression of cell-mediated immunity by measles virus.
The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.


Calibrating the performance of SNP arrays for whole-genome association studies.
To facilitate whole-genome association studies (WGAS), several high-density SNP genotyping arrays have been developed. Genetic coverage and statistical power are the primary benchmark metrics in evaluating the performance of SNP arrays. Ideally, such evaluations would be done on a SNP set and a cohort of individuals that are both independently sampled from the original SNPs and individuals used in developing the arrays. Without utilization of an independent test set, previous estimates of genetic coverage and statistical power may be subject to an overfitting bias. Additionally, the SNP arrays' statistical power in WGAS has not been systematically assessed on real traits. One robust setting for doing so is to evaluate statistical power on thousands of traits measured from a single set of individuals. In this study, 359 newly sampled Americans of European descent were genotyped using both Affymetrix 500K (Affx500K) and Illumina 650Y (Ilmn650K) SNP arrays. From these data, we were able to obtain estimates of genetic coverage, which are robust to overfitting, by constructing an independent test set from among these genotypes and individuals. Furthermore, we collected liver tissue RNA from the participants and profiled these samples on a comprehensive gene expression microarray. The RNA levels were used as a large-scale set of quantitative traits to calibrate the relative statistical power of the commercial arrays. Our genetic coverage estimates are lower than previous reports, providing evidence that previous estimates may be inflated due to overfitting. The Ilmn650K platform showed reasonable power (50% or greater) to detect SNPs associated with quantitative traits when the signal-to-noise ratio (SNR) is greater than or equal to 0.5 and the causal SNP's minor allele frequency (MAF) is greater than or equal to 20% (N = 359). In testing each of the more than 40,000 gene expression traits for association to each of the SNPs on the Ilmn650K and Affx500K arrays, we found that the Ilmn650K yielded 15% times more discoveries than the Affx500K at the same false discovery rate (FDR) level.


High-density dental implants and radiotherapy planning: evaluation of effects on dose distribution using pencil beam convolution algorithm and Monte Carlo method.
High atomic number and density of dental implants leads to major problems at providing an accurate dose distribution in radiotherapy and contouring tumors and organs caused by the artifact in head and neck tumors. The limits and deficiencies of the algorithms using in the treatment planning systems can lead to large errors in dose calculation, and this may adversely affect the patient's treatment. In the present study, four commercial dental implants were used: pure titanium, titanium alloy (Ti-6Al-4V), amalgam, and crown. The effects of dental implants on dose distribution are determined with two methods: pencil beam convolution (PBC) algorithm and Monte Carlo code for 6 MV photon beam. The central axis depth doses were calculated on the phantom for a source-skin distance (SSD) of 100 cm and a 10 × 10 cm2 field using both of algorithms. The results of Monte Carlo method and Eclipse TPS were compared to each other and to those previously reported. In the present study, dose increases in tissue at a distance of 2 mm in front of the dental implants were seen due to the backscatter of electrons for dental implants at 6 MV using the Monte Carlo method. The Eclipse treatment planning system (TPS) couldn't precisely account for the backscatter radiation caused by the dental prostheses. TPS underestimated the back scatter dose and overestimated the dose after the dental implants. The large errors found for TPS in this study are due to the limits and deficiencies of the algorithms. The accuracy of the PBC algorithm of Eclipse TPS was evaluated in comparison to Monte Carlo calculations in consideration of the recommendations of the American Association of Physicists in Medicine Radiation Therapy Committee Task Group 65. From the comparisons of the TPS and Monte Carlo calculations, it is verified that the Monte Carlo simulation is a good approach to derive the dose distribution in heterogeneous media.


Posterior spinal fusion using a pedicle nail system with polymethylmethacrylate in a paraplegic patient after vertebral collapse caused by osteoporosis.
Because posterior decompression and fusion for vertebral collapse in an osteoporotic spine sometimes results in a pullout of the pedicle screw. Several authors reported that fixation of pedicle screws in severely osteoporotic bone could be improved by inserting polymethylmethacrylate (PMMA) into the hole before inserting the screw. However, pedicle screws were not designed to be used with PMMA. To report a patient with vertebral collapse who were treated using a novel-concept, pedicle nail using with PMMA. Case report. The patient was a 74-year-old female who experienced back pain after some heavy lifting 3 months before. She was laid up for 2 months because of the back pain and weakness of her lower legs. Radiographs and magnetic resonance imaging showed vertebral collapse and neural severe compression from the posterior wall of vertebra T12. The pedicle nail consists of an outer sheath with evenly spaced holes and an internal, removable, threaded component. The outer sheath and the internal component were connected before insertion. The pedicle nail attaches to and is bound by the PMMA through the holes of the outer sheath. We performed a T11-L1 posterior fusion and laminectomy using the pedicle nail, and we used a hydroxyapatite block to perform a transpedicular vertebroplasty of T12. Bone union was observed on a lateral radiograph without pedicle nail loosening. The authors speculate that posterior spinal fusion and vertebroplasty using the pedicle nail will be a reasonable choice for delayed paraplegia after osteoporotic vertebral fracture.


Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study.
A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.


Chemoprevention of oral cancer by black raspberries.
Oral cavity cancers represent 2.5% of the cancers that occur in the United States and are ranked sixth worldwide. Since current therapeutic protocols are relatively ineffective, alternative strategies for prevention need to be developed and tested in appropriate animal models. In the study reported herein, the hamster cheek pouch (HCP) was used to evaluate the ability of black raspberries to inhibit oral cavity tumors. Male Syrian Golden hamsters, 3-4 weeks of age, were fed 5% and 10% lyophilized black raspberries (LBR) in the diet for two weeks prior to treatment with 0.2% 7,12-dimethylbenz(a) anthracene in dimethylsulfoxide and for 10 weeks thereafter. HCPs were painted 3X/week for eight weeks. The animals were sacrificed 12-13 weeks from the beginning of DMBA treatment and the number and volume of tumors (mm3) determined. There was a significant difference (p = 0.02) in the number of tumors between the 5% LBR and control groups (27 tumors/14 animals and 48 tumors/15 animals, respectively) and an intermediate number of tumors in the 10% berry-treated animals (39 tumors/15 animals). These experiments support previous studies from our laboratories showing the chemopreventive activity of black raspberries and show, for the first time, that dietary black raspberries will inhibit tumor formation in the oral cavity.


Knowledge expectations, self-care, and health complaints of heart failure patients scheduled for cardiac resynchronization therapy implantation.
To describe what knowledge heart failure patients expect to acquire in relation to their upcoming cardiac resynchronization therapy (CRT) device implantation, to describe their self-care and health complaints, and to explore the relationship between knowledge expectations and self-care, health complaints, and background factors. Cross-sectional multicenter study with 104 patients scheduled for a first-time, elective CRT implantation in Swedish and Icelandic hospitals. Data were collected with the Knowledge Expectations of hospital patient Scale, European Heart Failure Self-care Behavior Scale, and Adjusted Postoperative Recovery Profile. Patients expected most knowledge related to their disease and its treatment (median 4.0, interquartile range 0.13) and least on social issues (median 3.5, interquartile range 0.83). Their self-care was average (standardized mean 51.0±19.6) before the procedure. Patients had on average 8.2 (±4.7) health complaints and rated fatigue and sexual problems as the most severe. Age was independently associated with knowledge expectations (Expβ 0.049, P=0.033). Heart failure patients waiting for a CRT device implantation have high expectations for multiple aspects of knowledge, including self-care issues, before their procedure. These expectations are similar to those of other surgical patients and they increase with age.


Comparison of traffic-injury related hospitalisation between bicyclists and motorcyclists in Taiwan.
Bicyclists and motorcyclists contribute substantially to the morbidity and mortality rates of road crash casualties. The objective of the study was to investigate the crash characteristics of bicyclist and motorcyclist casualties presented to hospitals in Taiwan resulting from crashes. By using linked data from The National Traffic Crash Dataset and the National Health Insurance Database between 2003 and 2012, logistic regression models were used to examine the determinants of hospitalisation among motorcyclist and bicyclist casualties. The examined variables include demographic characteristics, road and weather conditions, and vehicle characteristics. A total of 1,998,606 two-wheelers were enrolled in the study, of whom 216,600 were hospitalised: 203,623 were motorcyclists and 12,964 were bicyclists. Bicyclists were more likely to be hospitalised than motorcyclists were (14.0% vs. 10.7%). The pooled logistic regression model shows that bicyclists had higher odds of hospitalisation than motorcyclists (adjusted odds ratio [AOR] = 1.11, 95% confident interval [CI] = 1.08-1.14). In the motorcyclist and bicyclist models, helmet non-use appears to be a determinant of hospitalisation for motorcyclists (AOR = 1.14, CI = 1.12-1.16), although insignificant for cyclists (AOR = 1.03, CI = 0.94-1.12). Other important determinants of hospitalisation for motorcyclists and cyclists include female riders, elderly riders, rural roadways, unlicensed riding (for motorcyclists only), curved roadways, defective roadways, alcohol consumption (only for motorcyclists), and single-vehicle crashes (for motorcyclists only). The result that bicyclists had an increased probability of being hospitalised than motorcyclists is particularly noteworthy, because there have recently been much more users of bikesharing systems in metropolitan cities where cycle helmets are not provided. We further found that helmet non-use was also a risk factor for motorcyclists, but insignificant for cyclists, possibly due to lower helmet utilization rates among bicyclists. Our findings regarding the increased hospitalisation percentage emphasize the importance of helmet use.


The Evolving Field of Wound Measurement Techniques: A Literature Review.
Wound healing is a complex and multifactorial process that requires the involvement of a multidisciplinary approach. Methods of wound measurement have been developed and continually refined with the purpose of ensuring precision in wound measurement and documentation as the primary indicator of healing. This review aims to ascertain the efficacies of current wound area measurement techniques, and to highlight any perceived gaps in the literature so as to develop suggestions for future studies and practice. Med- line, PubMed, CliniKey, and CINAHL were searched using the terms "wound/ulcer measurement techniques," "wound assessment," "digi- tal planimetry," and "structured light." Articles between 2000 and 2014 were selected, and secondary searches were carried out by exam- ining the references of relevant articles. Only papers written in English were included. A universal, standardized method of wound as- sessment has not been established or proposed. At present, techniques range from the simple to the more complex - most of which have char- acteristics that allow for applicability in both rural and urban settings. Techniques covered are: ruler measurements, acetate tracings/contact planimetry, digital planimetry, and structured light devices. Conclu- sion. In reviewing the literature, the precision and reliability of digital planimetry over the more conventional methods of ruler measurements and acetate tracings are consistently demonstrated. The advent and utility of the laser or structured light approach, however, is promising, has only been analyzed by a few, and opens up the scope for further evaluation of this technique.


Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease.
Many patients with inflammatory bowel disease (IBD) fail to respond to anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective for treatment of Crohn's disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including IgG1. TNF-neutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs. Biopsy specimens from inflamed colon of 8 patients with Crohn's disease and 8 patients with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn's disease and 33 patients with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab. MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab')2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients who did not respond to treatment vs responders. Proteolytic degradation may contribute to the nonresponsiveness of patients with IBD to anti-TNF agents.


Acute and long-term cost implications of coronary stenting.
We compared the acute and one year medical costs and outcomes of coronary stenting with those for balloon angioplasty (percutaneous transluminal coronary angioplasty) in contemporary clinical practice. While coronary stent implantation reduces the need for repeat revascularization, it has been associated with significantly higher acute costs compared with coronary angioplasty. We studied patients treated at Duke University between September 1995 and June 1996 who received either coronary stent (n = 384) or coronary angioplasty (n = 159) and met eligibility criteria. Detailed cost data were collected initially and up to one year following the procedure. Our primary analyses compared six and 12 month cumulative costs for coronary angioplasty- and stent-treated cohorts. We also compared treatment costs after excluding nontarget vessel interventions; after limiting analysis to those without prior revascularization; and after risk-adjusting cumulative cost estimates. Baseline clinical characteristics were generally similar between the two treatment groups. The mean in-hospital cost for stent patients was $3,268 higher than for those receiving coronary angioplasty ($14,802 vs. $11,534, p < 0.001). However, stent patients were less likely to be rehospitalized (22% vs. 34%, p = 0.002) or to undergo repeat revascularization (9% vs. 26%, p = 0.001) than coronary angioplasty patients within six months of the procedure. As such, mean cumulative costs at 6 months ($19,598 vs. $19,820, p = 0.18) and one year ($22,140 vs. $22,571, p = 0.26) were similar for the two treatments. Adjusting for baseline predictors of cost and selectively examining target vessel revascularization, or those without prior coronary intervention yielded similar conclusions. In contemporary practice, coronary stenting provides equivalent or better one-year patient outcomes without increasing cumulative health care costs.


The monaural nuclei of the lateral lemniscus in an echolocating bat: parallel pathways for analyzing temporal features of sound.
In echolocating bats, three cell groups in the lateral lemniscus are conspicuous for their large size and high degree of differentiation. These cell groups are the intermediate nucleus (INLL), columnar nucleus (VNLLc), and multipolar cell area (VNLLm). All receive projections from the contralateral cochlear nucleus. Previous anatomical studies suggest the hypothesis that these nuclei are important for analyzing the temporal structure of sound. To investigate this possibility, we recorded responses of single units in the INLL, VNLLc, and VNLLm of Eptesicus fuscus. The results show that each cytoarchitectural division contains a complete tonotopic representation. Certain response properties are common to all three nuclei. First, virtually all units are monaural. Second, all are broadly tuned to frequency; their average Q10dB value of 9.1 is considerably lower than values measured in the inferior colliculus of Eptesicus. Third, most units have little or no spontaneous activity. Fourth, all have short integration times, responding robustly to stimuli less than 5 msec in duration. The broad tuning, lack of spontaneous activity, and short integration time all make these neurons well suited for the accurate encoding of temporal information. Although there are many similarities, there are also important differences among nuclei. The clearest evidence of specialization is in VNLLc. Neurons here are more broadly tuned than those in INLL or VNLLm, have no spontaneous activity, and always respond with one spike per stimulus. The latency of the spike is precisely locked to the stimulus onset, with variability from trial to trial as low as 0.03 msec. In addition, the latency remains constant over large variations in frequency or intensity. In INLL and VNLLm, response patterns are about equally distributed between tonic, chopping, and phasic; there are no single-spike constant-latency responses of the type seen in VNLLc, although some choppers and pausers do respond with constant first-spike latency. The results indicate that VNLLc is specialized to encode very precisely the onset of sound; the other nuclei may encode ongoing properties of a sound.


Management recommendations for osteoporosis in clinical guidelines.
Numerous guidelines advise about management of osteoporosis, but little research has been conducted on their recommendations. We analysed recommendations on management of bone health in clinical guidelines. We surveyed recommendations on assessment, treatment and monitoring of bone health in 78 clinical guidelines (22 primary focus osteoporosis, 56 primary focus not osteoporosis) lodged at the Agency for Health Research and Quality National Guidelines Clearinghouse between 1/1/2009 and 12/31/2014. Governance of guidelines; discussion of fracture risk in the target population; recommendations for assessment, treatment and monitoring of bone health. Only 14% of guidelines discussed fracture risk in the target population. When guidelines discussed assessment, 98% recommended bone mineral density (BMD) measurement but only 27% recommended estimation of fracture risk. When guidelines discussed treatment, 63-71% recommended calcium and/or vitamin D, while <12% recommended avoiding low body weight or smoking cessation. When guidelines discussed intervention, 53% did so on the basis of BMD measurement, and only 27% on the basis of estimated fracture risk. When guidelines discussed monitoring, >90% recommended BMD measurements, and only 3% recommended estimation of fracture risk. About 65% of guidelines that suggested a BMD monitoring interval recommended one of ≤3 years. Compared to guidelines with a primary focus on osteoporosis, guidelines whose primary focus was not osteoporosis were less likely to discuss fracture risk in the target population (2% vs 45%), recommend estimation of fracture risk (11% vs 55%) and recommend intervention on the basis of estimated fracture risk (10% vs 67%) (all P < 0·005). Our findings highlight a strong focus in clinical guidelines on BMD, a surrogate measure, rather than fracture risk, the clinically important outcome, particularly when bone health is not the primary focus. Addressing this issue might facilitate more rational use of resources and improve patient care.


The Scope of Rape Victimization and Perpetration Among National Samples of College Students Across 30 years.
Research Questions: Rape prevention practice and policy have roots in data from 1985. This study uses 2015 national data to project recent prevalence, assesses whether rates now differ from those of 30 years ago, and disaggregates 2015 prevalence into rape of alcohol incapacitated victims, rapes combining both alcohol and physical tactics, and violent rape. Methods: Cross-sectional analyses were conducted comparing two national samples. The first was collected in 1984-85 (Koss, Gidycz, & Wisniewski, 1987); the second was collected 30 years later in 2014-2015. Both surveys used in-person administration and measurement by the most current version at the time of the Sexual Experiences Survey (SES). Prevalence rates were compared using Bayesian binomial tests. Results: In 2015, 33.4% (1 in 3) of women reported experiencing rape or attempted rape and 12.7% of men reported perpetration (1 in 8). Using Jeffreys' label for effect size of the Bayes binomial (1961), both results are "decisively" greater than expected given the 1985 benchmarks of 27.9% for victimization and 7.7% for perpetration. Victimization when incapacitated characterized approximately 75% of incidents in 2015 up from 50% in 1985. Cautions apply as cross-sectional data does not establish causality and the recent data set involved the revised SES. Conclusions: Across 30 years, neither containment nor reduction of rape was demonstrated and the increasingly prominent association with alcohol was apparent. Among the men who disclosed raping, 9 of 10 incidents were alcohol-involved. Prevention focus might profitably be directed to constraining alcohol environments and policies that facilitate rape of incapacitated persons and on misconduct responses that are proportional to the harm caused to rape victims, thereby raising the perceived risks of perpetration.


Narrow groove plasmonic nano-gratings for surface plasmon resonance sensing.
We present a novel surface plasmon resonance (SPR) configuration based on narrow groove (sub-15 nm) plasmonic nano-gratings such that normally incident radiation can be coupled into surface plasmons without the use of prism-coupling based total internal reflection, as in the classical Kretschmann configuration. This eliminates the angular dependence requirements of SPR-based sensing and allows development of robust miniaturized SPR sensors. Simulations based on Rigorous Coupled Wave Analysis (RCWA) were carried out to numerically calculate the reflectance - from different gold and silver nano-grating structures - as a function of the localized refractive index of the media around the SPR nano-gratings as well as the incident radiation wavelength and angle of incidence. Our calculations indicate substantially higher differential reflectance signals, on localized change of refractive index in the narrow groove plasmonic gratings, as compared to those obtained from conventional SPR-based sensing systems. Furthermore, these calculations allow determination of the optimal nano-grating geometric parameters - i. e. nanoline periodicity, spacing between the nanolines, as well as the height of the nanolines in the nano-grating - for highest sensitivity to localized change of refractive index, as would occur due to binding of a biomolecule target to a functionalized nano-grating surface.


Host miR155 promotes tumor growth through a myeloid-derived suppressor cell-dependent mechanism.
miR155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR155 functions in immunosuppression and tumor promotion. Host miR155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4(+)Foxp3(+) regulatory T cells. Importantly, we demonstrated that miR155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR155 promotes or inhibits tumor growth.


Increase in Total Joint Arthroplasty Projected from 2014 to 2046 in Australia: A Conservative Local Model With International Implications.
The incidence of joint arthroplasty is increasing worldwide. International estimates of future demand for joint arthroplasty have used models that propose either an exponential future increase, despite obvious system constraints, or static increases, which do not account for past trends. Country-specific projection estimates that address limitations of past projections are necessary. In Australia, a high-income country with the 7th highest incidence of TKA and 15th highest incidence of THA of the Organization for Economic Cooperation and Development (OECD) countries, the volume of TKAs and THAs increased 198% between 1994 and 2014. To determine the projected incidence and volume of primary TKAs and THAs from 2014 to 2046 in the Australian population older than 40 years. Australian State and Territory Health Department data were used to identify TKAs and THAs performed between 1994 and 1995 and 2013 and 2014. The Australian Bureau of Statistics was the source of the population estimates for the same periods and population-projected estimates until 2046. The incidence rate (IR), 95% CI, and prediction interval (PI) of TKAs and THAs per 100,000 Australian citizens older than 40 years were calculated. Future IRs were estimated using a logistic model, and volume was calculated from projected IR and population. The logistic growth model assumes the existence of an upper limit of the TKA and THA incidences and a growth rate directly related to this incidence. At the beginning, when the observed incidence is much lower than the asymptote, the increase is exponential, but it decreases as it approaches the upper limit. A 66% increase in the IR of primary THAs between 2013 and 2046 is projected for Australia (2013: IR = 307 per 100,000, [95% CI, 262-329 per 100,000] compared with 2046: IR= 510 per 100,000, [95% PI, 98-567 per 100,000]), which translates to a 219% increase in the volume during this period. For TKAs the IR is expected to increase by 26% by 2046 (IR = 575 per 100,000; 95% PI, 402-717 per 100,000) compared with 2013 (IR = 437 per 100,000; 95% CI, 397-479 per 100,000) and the volume to increase by 142%. A large increase in the volume of arthroplasties is expected using a conservative projection model that accounts for past surgical trends and future population changes in Australia. These findings have international implications, as they show that using country- specific, conservative projection approaches, a substantial increase in the number of these procedures is expected. This increase in joint arthroplasty volume will require appropriate workforce planning, resource allocation, and budget planning so that demand can be met. Level II, economic and decision analysis.


The relationship of season of birth with refractive error in very young children in eastern China.
To determine the association of season of birth and refractive error in very young Chinese children in China. We conducted a population-based study of Chinese children aged 0 to 3 years residing in eastern China. Refraction was determined by non-cyclopegic autorefraction using a hand-held autorefractor. Date of birth was retrieved from birth certificate of the individual subjects. A generalized linear regression model was fitted to estimate the regression coefficient and 95% confidence interval (CI) of refractive error for season of birth, adjusting for confounders. Of the 1385 children eligible to participate, 1222 (88.2%) were examined. Refractive error data were available for 1219 children. The mean spherical equivalent were 1.21 diopters (D) in children born Spring, 1.24 D in those born in Summer, 1.23 D in those born in Autumn, 1.15 D in Winter. After adjusting for age, sex, father's educational level, birth weight and the number of summers between birth and examination date the children have been exposed to, children born in winter had a 0.12 D more myopic refraction compared with those born in summer (regression coefficient: -0.12; 95% CI, -0.27,-0.06; P = 0.006). The association between season of birth and cylinder power was not statistically significant. In China, children born in winter had a more myopic refraction compared with those born in other seasons. The observed association between season of birth and refractive error was independent of parental educational level and birth weight, suggesting that light level may have a small impact on refractive development in early life.


A combination of approaches evidenced seed storage behaviour in the miracle berry Synsepalum dulcificum (Schumach. et Thonn.) Daniell.
Knowledge on seed storage behaviour is crucial for planning conservation strategies of plant genetic resources particularly in economically promising but endangered species like Synsepalum dulcificum, viewed as recalcitrant-seeded species albeit sound evidence was lacking. In this study, we combined an experimental approach based on critical moisture content and storage environment analysis, and the seed-coat ratio-seed dry mass (SCR-SM) model to clarify the seed storage behaviour in the species. Seed moisture content at shedding was determined and effects of dehydration and cold storage on seed viability, germination and subsequent seedling vigour were analysed. The probability for dessication-senstivity [P(D-S)] was also determined. Our findings indicated that S. dulcificum seed moisture content at shedding was 36.60% with nearly 100% viability. Seed dehydration below 20% moisture content induced a total loss of viability whereas low temperature storage (at 10 °C or 4 °C reduced shelf life to a maximum of 7 days. More importantly, S. dulcificum seed storage at 0 °C was highly detrimental and resulted in a total loss of viability whatever the storage duration. Only a storage at 25 °C helped expand the shelf life to 28 days. However, at 28 days storage the viability was extremely low with almost no germination. The probability for dessication-senstivity P(D-S) in the species is largely greater than 0.5. Seed dehydration and storage environment highly affected subsequent germination rate and seedling vigour. While dehydration improved seedling performance storage at low temperature rather inhibited seedling growth. Taken together, these findings are the first to set evidence of recalcitrance in S. dulcificum and serve hands-on information for practical handling of the seeds and designing sustainable conservation practices for adequate future breeding programme in the species.


Intraoperative performance and longterm outcome of phacoemulsification in age-related cataract.
To evaluate intraoperative performance and longterm surgical outcome after phacoemulsification of age-related cataracts. Prospective, observational, non-comparative study of 165 consecutive eyes undergoing phacoemulsification with nuclear sclerosis Grade I to III (Scale I to V). Preoperative evaluation included specular microscopy. Phacoemulsification was performed by a single surgeon using a standardised surgical technique under topical anaesthesia. Intraoperatively, effective phaco time (EPT), wound site thermal injury (WSTI), serious complications (eg. vitreous loss, posterior capsule rupture, zonulolysis) and intraoperative posterior capsule opacification (plaque) were evaluated. Postoperatively, posterior capsule opacification (PCO), Neodymium:YAG (Nd:YAG) laser posterior capsulotomy rate, corneal endothelial count, best corrected visual acuity and cystoid macular oedema were evaluated. Eyes were examined at 6 months and then yearly for 3 years. Mean ages of 78 males and 87 females were 59.12 +/- 8.56 and 58.34 +/- 7.45 years respectively. EPT was 36 +/- 19 seconds and WSTI occurred in 7 eyes (4.7%). No serious intraocular complications occurred. Intraoperative posterior capsule opacification (plaque) was present in 21 eyes (13.93%). Postoperatively, PCO occurred in 8 eyes (4.84%) and Nd:YAG laser posterior capsulotomy was performed in 3 eyes (1.8%). Endothelial cell loss was 7.1% at 3 years follow-up. At the end of 3 years follow-up, 146 eyes (88.89%) maintained a best corrected visual acuity of > or = 6/12. Cystoid macular oedema did not occur in any eye at 1 and 6 months' follow-up. PCO rates and endothelial cell loss were acceptable. Consistent and reproducible outcome can be obtained after phacoemulsification of age related cataracts (grade I to III).


Avoiding the Obturator Jerk during TURBT.
Bladder cancer is the seventh most common cancer in the UK. Transurethral resection of bladder tumor (TURBT) is a relatively common procedure used to treat cancer of the bladder. A serious complication of TURBT is bladder perforation, the risk of which is greatly increased in the presence of an "obturator jerk". A literature search was performed on PubMed using the following search criteria "obturator nerve block", "obturator nerve block in transurethral resection of bladder tumor", "adductor spasm during transurethral resection of bladder tumor", "bi-polar diathermy obturator nerve", and "transvesical obturator nerve block". Articles describing surgical and anesthetic techniques for reducing adductor spasm during resection of bladder tumors were included. TURBT is a relatively common urological operation performed to remove tumors of the bladder. Every measure should be taken to avoid serious complications from both anesthesia and surgery. Surgical measures to reduce the likelihood of an obturator jerk include reducing the diathermy current, avoiding over-distention bladder, and using bipolar diathermy as opposed to monopolar diathermy (although there is conficting evidence for this in the literature). Anesthetists should consider the use of neuromuscular blockade or an obturator nerve block to reduce the incidence of obturator jerk and risk of bladder perforation.


A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy.
After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions - post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.


Overexpressed Ca(v)beta3 inhibits N-type (Cav2.2) calcium channel currents through a hyperpolarizing shift of ultra-slow and closed-state inactivation.
It has been shown that beta auxiliary subunits increase current amplitude in voltage-dependent calcium channels. In this study, however, we found a novel inhibitory effect of beta3 subunit on macroscopic Ba(2+) currents through recombinant N- and R-type calcium channels expressed in Xenopus oocytes. Overexpressed beta3 (12.5 ng/cell cRNA) significantly suppressed N- and R-type, but not L-type, calcium channel currents at "physiological" holding potentials (HPs) of -60 and -80 mV. At a HP of -80 mV, coinjection of various concentrations (0-12.5 ng) of the beta3 with Ca(v)2.2alpha(1) and alpha(2)delta enhanced the maximum conductance of expressed channels at lower beta3 concentrations but at higher concentrations (>2.5 ng/cell) caused a marked inhibition. The beta3-induced current suppression was reversed at a HP of -120 mV, suggesting that the inhibition was voltage dependent. A high concentration of Ba(2+) (40 mM) as a charge carrier also largely diminished the effect of beta3 at -80 mV. Therefore, experimental conditions (HP, divalent cation concentration, and beta3 subunit concentration) approaching normal physiological conditions were critical to elucidate the full extent of this novel beta3 effect. Steady-state inactivation curves revealed that N-type channels exhibited "closed-state" inactivation without beta3, and that beta3 caused an approximately 40-mV negative shift of the inactivation, producing a second component with an inactivation midpoint of approximately -85 mV. The inactivation of N-type channels in the presence of a high concentration (12.5 ng/cell) of beta3 developed slowly and the time-dependent inactivation curve was best fit by the sum of two exponential functions with time constants of 14 s and 8.8 min at -80 mV. Similar "ultra-slow" inactivation was observed for N-type channels without beta3. Thus, beta3 can have a profound negative regulatory effect on N-type (and also R-type) calcium channels by causing a hyperpolarizing shift of the inactivation without affecting "ultra-slow" and "closed-state" inactivation properties.


Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
The aim of this guideline is to provide a synopsis of best clinical practices in the rehabilitative care of adults recovering from stroke. Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council's Scientific Statement Oversight Committee and the AHA's Manuscript Oversight Committee. The panel reviewed relevant articles on adults using computerized searches of the medical literature through 2014. The evidence is organized within the context of the AHA framework and is classified according to the joint AHA/American College of Cardiology and supplementary AHA methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive AHA internal and external peer review, Stroke Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. Stroke rehabilitation requires a sustained and coordinated effort from a large team, including the patient and his or her goals, family and friends, other caregivers (eg, personal care attendants), physicians, nurses, physical and occupational therapists, speech-language pathologists, recreation therapists, psychologists, nutritionists, social workers, and others. Communication and coordination among these team members are paramount in maximizing the effectiveness and efficiency of rehabilitation and underlie this entire guideline. Without communication and coordination, isolated efforts to rehabilitate the stroke survivor are unlikely to achieve their full potential. As systems of care evolve in response to healthcare reform efforts, postacute care and rehabilitation are often considered a costly area of care to be trimmed but without recognition of their clinical impact and ability to reduce the risk of downstream medical morbidity resulting from immobility, depression, loss of autonomy, and reduced functional independence. The provision of comprehensive rehabilitation programs with adequate resources, dose, and duration is an essential aspect of stroke care and should be a priority in these redesign efforts. (Stroke.2016;47:e98-e169. DOI: 10.1161/STR.0000000000000098.).


Patterns of symptom reporting during pregnancy comparing opioid maintained and control women.
To characterize the range of symptoms experienced by pregnant methadone-maintained (MM) and buprenorphine-maintained (BM) women to determine whether these differ from those experienced by a control group of nonopioid exposed pregnant women. Opioid-maintained (OM) patients report high rates of symptoms related to direct opioid effects and withdrawal. Pregnancy is associated with a range of symptoms, some overlapping with opioid effects and withdrawal. Prospective, nonrandomized, open-label comparison study undertaken in a large teaching maternity hospital in South Australia. Pregnant BM (n = 25), MM (n = 25) and nonopioid exposed controls (n = 25) were recruited and matched for age, parity, gravidity, alcohol consumption, and smoking status. Symptom report patterns, maternal withdrawal, and additional substance use were assessed. MM women reported 10 and BM women reported 2 symptoms throughout pregnancy at rates greater than controls. Methadone-maintained women reported significantly (P < 0.05) more symptoms than BM women compared to controls throughout pregnancy. Methadone-maintained women reported 8 and BM women reported 3 symptoms in the third trimester at rates greater than controls. Methadone-maintained women reported greater opioid withdrawal than controls; this did not occur in BM women. Additional substance use was comparable between BM and MM women but greater than controls. Patterns of symptom reports may have clinical implications for maternal and fetal health during pregnancy for OM women including optimization of opioid dosing regimens, education regarding maternal nutritional intake and preventing postnatal depression, thereby ensuring maternal health and fetal development during pregnancy and enhancing mother-infant bonding and healthy child development postnatally.