FGFR2 amplification in colorectal adenocarcinoma.
FGFR2 is recurrently amplified in 5% of gastric cancers and 1%-4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.


Introduction of Typhoid Conjugate Vaccines in Africa and Asia.
Typhoid fever continues to be a major public health concern, particularly in many low- and middle-income countries. The current threats of increasing antimicrobial resistance, urbanization, and climate change elevate the urgency for better prevention and control efforts for typhoid fever. In 2017, the results of ground-breaking research on typhoid conjugate vaccines (TCVs), the World Health Organization prequalification of a TCV, and global policy and financing decisions have set the stage for the introduction of TCVs into routine immunization programs in endemic countries. Country-level decision-making and program planning are critical for local uptake and sustainability.


Prevalence and risk factors of dry eye disease in North India: Ocular surface disease index-based cross-sectional hospital study.
This study aims to study the prevalence of DED and analyze risk factors in North Indian population. This was a cross-section hospital-based, observational study. Cases enrolled over 2 years (systematic random sampling) were administered ocular surface disease index questionnaire to evaluate the prevalence and risk factors of DED. Schirmer's test and tear break-up time were performed only in the subset of patients giving consent. Categorical data were assessed with Chi-square/Fisher's Exact test, and odds ratio was analyzed using bivariate and multivariate logistic regression. P < 0.05 was statistically significant. A total of 15,625 patients were screened. The prevalence of DED was 32% (5000/15625); 9.9% (496/5000) had mild DED; 61.2% (3060/5000) had moderate DED; and 28.9% (1444/5000) had severe DED. Age group of 21-40 years, male sex, urban region, and desk job were associated with increased risk of DED. Hours of visual display terminal (VDT) usage significantly correlated with DED (P < 0.001), and 89.98% of patients with 4 h or more of VDT use had severe dry eye. Cigarette smoking and contact lens usage had increased odds of developing severe DED (P < 0.001). Objective tests were undertaken in 552 patients; of these, 81.3% (449/552) had severe DED. The prevalence of DED in North India is 32%, with the age group of 21-40 years affected most commonly. VDT use, smoking, and contact lens use were associated with increased odds of developing DED.


Feedback and Training to Improve Use of an Electronic Prescribing System: A Randomised Controlled Trial.
Excessive presentation of alerts in electronic prescribing systems (ePS) results in 'alert fatigue' which reduces alert effectiveness and frustrates users. Previous research at our study site showed high rates of duplication alerts, some of which were the result of doctors not using available short-cut functions in the ePS. This study aimed to improve uptake of short-cut functions and so reduce alert fatigue by trialing two interventions: feedback and training. Fifty doctors were randomised to one of three groups: Control, Feedback or Training. The Feedback group received an individualised feedback report via email and the Training group received brief face-to-face refresher training. Participants partook in informal interviews to discuss the training and the ePS in use. The proportion of orders which triggered a duplication alert was our primary outcome measure. Neither intervention had a significant impact on duplication alert rate (Feedback: 80.8% vs. 77.8% of orders, Training: 77.5% vs. 76.5% of orders; all p>0.05). We identified a number of factors related to the intervention, ePS and prescribing environment that contributed to this result. Rather than focusing on changing prescribing behaviour, we suggest a more effective and appropriate approach is to redesign the ePS so that fewer and more meaningful alerts are presented.


Structure and chemical composition of insoluble filamentous components of sperm flagellar microtubules.
By progressive solvent extraction, we have obtained a series of subfragments of flagellar microtubules. Mild treatment gives rise to ribbons that contain longitudinally arranged protofilaments. Further extraction leaves a distinctive residue containing thinner ribbons, of three and eventually two protofilaments. Finally, filaments 2-3 nm in diameter and fibrous ribbons apparently containing 6 or more 2 nm subfibrils are found. This latter solvent-resistant material is consistently enriched in a characteristic set of polypeptides, which are found in flagella of several different species, including echinoderms and a mollusc. These polypeptides appear different from alpha- and beta-tubulin on the basis of their solubilities, isoelectric points and electrophoretic mobilities in sodium dodecyl sulphate/polyacrylamide gels; these conclusions are reinforced by peptide mapping after limited proteolytic digestion, although the latter method reveals certain similarities between these unique flagellar proteins, tubulin, chicken gizzard desmin and rabbit actin. A remarkable feature of the protein in the final fraction is the high alpha-helical content: 71% as measured by circular dichroism. We consider the possible origins of these filaments in the microtubule, in particular the possibility that microtubule protofilaments are heterogeneous in protein composition, and we discuss some of the implications of our findings.


Comparison of Glucosamine-Chondroitin Sulfate with and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial.
Glucosamine, chondroitinsulfate are frequently used to prevent further joint degeneration in osteoarthritis (OA). Methylsulfonylmethane (MSM) is a supplement containing organic sulphur and also reported to slow anatomical joint progressivity in the knee OA. The MSM is often combined with glucosamine and chondroitin sulfate. However, there are controversies whether glucosamine-chondroitin sulfate or their combination with methylsulfonylmethane could effectively reduce pain in OA. This study is aimed to compare clinical outcome of glucosamine-chondroitin sulfate (GC), glucosamine-chondroitin sulfate-methylsulfonylmethane (GCM), and placeboin patients with knee osteoarthritis (OA) Kellgren-Lawrence grade I-II. a double blind, randomized controlled clinical trial was conducted on 147 patients with knee OA Kellgren-Lawrence grade I-II. Patients were allocated by permuted block randomization into three groups: GC (n=49), GCM (n=50), or placebo (n=48) groups. GC group received 1500 mg of glucosamine + 1200 mg of chondroitin sulfate + 500 mg of saccharumlactis; GCM group received 1500 mg of glucosamine + 1200 mg of chondroitin sulfate + 500 mg of MSM; while placebo group received three matching capsules of saccharumlactis. The drugs were administered once daily for 3 consecutive months VAS and WOMAC scores were measured before treatment, then at 4th, 8th and 12th week after treatment. on statistical analysis it was found that at the 12th week, there are significant difference between three treatment groups on the WOMAC score (p=0.03) and on the VAS score (p=0.004). When analyzed between weeks, GCM treatment group was found statistically significant on WOMAC score (p=0.01) and VAS score (p<0.001). Comparing the score difference between weeks, WOMAC score analysis showed significant difference between GC, GCM, and placebo in week 4 (p=0.049) and week 12 (p=0.01). In addition, VAS score also showed significant difference between groups in week 8 (p=0.006) and week 12 (p<0.001). combination of glucosamine-chondroitinsulfate-methylsulfonylmethane showed clinical benefit for patients with knee OAK ellgren-Lawrence grade I-II compared with GC and placebo. GC did not make clinical improvement in overall groups of patients with knee OA Kellgren Lawrence grade I-II.


The biological bases of conformity.
Humans are characterized by an extreme dependence on culturally transmitted information and recent formal theory predicts that natural selection should favor adaptive learning strategies that facilitate effective copying and decision making. One strategy that has attracted particular attention is conformist transmission, defined as the disproportionately likely adoption of the most common variant. Conformity has historically been emphasized as significant in the social psychology literature, and recently there have also been reports of conformist behavior in non-human animals. However, mathematical analyses differ in how important and widespread they expect conformity to be, and relevant experimental work is scarce, and generates findings that are both mutually contradictory and inconsistent with the predictions of the models. We review the relevant literature considering the causation, function, history, and ontogeny of conformity, and describe a computer-based experiment on human subjects that we carried out in order to resolve ambiguities. We found that only when many demonstrators were available and subjects were uncertain was subject behavior conformist. A further analysis found that the underlying response to social information alone was generally conformist. Thus, our data are consistent with a conformist use of social information, but as subjects' behavior is the result of both social and asocial influences, the resultant behavior may not be conformist. We end by relating these findings to an embryonic cognitive neuroscience literature that has recently begun to explore the neural bases of social learning. Here conformist transmission may be a particularly useful case study, not only because there are well-defined and tractable opportunities to characterize the biological underpinnings of this form of social learning, but also because early findings imply that humans may possess specific cognitive adaptations for effective social learning.


Multilocus phylogeny and taxonomy of European Melanoleuca subgenus Melanoleuca.
Revision of the taxonomically complicated European Melanoleuca taxa with well-developed macrocystidia (subgenus Melanoleuca) is presented. The species are delimited by macro- and micromorphological characters and by multilocus molecular data based on internal transcribed spacer (ITS), second largest subunit of RNA polymerase I (rpb2), and translation elongation factor 1-alpha (tef1) genes. The study is based on both type material and recent collections. Phylogenetically, these taxa form 10 clades recognized as 11 separate species: M. albomarginata, M. ammophila, M. bataillei, M. cavipes, M. friesii, M. granadensis, M. melaleuca, M. pallidicutis, M. polioleuca, M. strictipes, and M. variabilis. Three species, M. albomarginata, M. ammophila, and M. variabilis, are described as new. Melanoleuca melaleuca is discussed here as the type species of the genus. Discussion of other older names and their taxonomic status is also provided.


Catalytic transformation of dinitrogen into ammonia and hydrazine by iron-dinitrogen complexes bearing pincer ligand.
Synthesis and reactivity of iron-dinitrogen complexes have been extensively studied, because the iron atom plays an important role in the industrial and biological nitrogen fixation. As a result, iron-catalyzed reduction of molecular dinitrogen into ammonia has recently been achieved. Here we show that an iron-dinitrogen complex bearing an anionic PNP-pincer ligand works as an effective catalyst towards the catalytic nitrogen fixation, where a mixture of ammonia and hydrazine is produced. In the present reaction system, molecular dinitrogen is catalytically and directly converted into hydrazine by using transition metal-dinitrogen complexes as catalysts. Because hydrazine is considered as a key intermediate in the nitrogen fixation in nitrogenase, the findings described in this paper provide an opportunity to elucidate the reaction mechanism in nitrogenase.


Impact of HIV on inpatient mortality and complications in stroke in Thailand: a National Database Study.
The co-existence of stroke and HIV has increased in recent years, but the impact of HIV on post-stroke outcomes is poorly understood. We examined the impact of HIV on inpatient mortality, length of acute hospital stay and complications (pneumonia, respiratory failure, sepsis and convulsions), in hospitalized strokes in Thailand. All hospitalized strokes between 1 October 2004 and 31 January 2013 were included. Data were obtained from a National Insurance Database. Characteristics and outcomes for non-HIV and HIV patients were compared and multivariate logistic and linear regression models were constructed to assess the above outcomes. Of 610 688 patients (mean age 63·4 years, 45·4% female), 0·14% (866) had HIV infection. HIV patients were younger, a higher proportion were male and had higher prevalence of anaemia (P < 0·001) compared to non-HIV patients. Traditional cardiovascular risk factors, hypertension and diabetes, were more common in the non-HIV group (P < 0·001). After adjusting for age, sex, stroke type and co-morbidities, HIV infection was significantly associated with higher odds of sepsis [odds ratio (OR) 1·75, 95% confidence interval (CI) 1·29-2·4], and inpatient mortality (OR 2·15, 95% CI 1·8-2·56) compared to patients without HIV infection. The latter did not attenuate after controlling for complications (OR 2·20, 95% CI 1·83-2·64). HIV infection is associated with increased odds of sepsis and inpatient mortality after acute stroke.


Geometric attack resistant watermarking in wavelet transform domain.
In this paper, we propose an autocorrelation function (ACF) based watermarking scheme in the discrete wavelet transform (DWT) domain. Conventional ACF-based watermarking embeds a watermark in the spatial domain due to its detection mechanism.We show that the autocorrelation (AC) peaks, which play an important role in estimating the applied geometric attacks in ACF-based watermarking, can also be extracted by embedding the watermark in the DWT domain. In the proposed scheme, a periodic watermark is embedded in the DWT domain by considering the AC peak strength and noise visibility. The proposed scheme also deals efficiently with the image shift problem in the detection process by using the undecimated DWT. Experimental results show that the proposed scheme yields stronger AC peaks than the spatial domain scheme does and, as a result, shows improved robustness against combined geometric-removal.


The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis.
Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.


Narrow linewidth picosecond UV pulsed laser with mega-watt peak power.
We demonstrate a master oscillator power amplifier (MOPA) burst mode laser system that generates 66 ps/402.5 MHz pulses with mega-watt peak power at 355 nm. The seed laser consists of a single frequency fiber laser (linewidth < 5 KHz), a high bandwidth electro-optic modulator (EOM), a picosecond pulse generator, and a fiber based preamplifier. A very high extinction ratio (45 dB) has been achieved by using an adaptive bias control of the EOM. The multi-stage Nd:YAG amplifier system allows a uniformly temporal shaping of the macropulse with a tunable pulse duration. The light output from the amplifier is converted to 355 nm, and over 1 MW peak power is obtained when the laser is operating in a 5-μs/10-Hz macropulse mode. The laser output has a transform-limited spectrum with a very narrow linewidth of individual longitudinal modes. The immediate application of the laser system is the laser-assisted hydrogen ion beam stripping for the Spallation Neutron Source (SNS).


Cerebral bioimaging of Cu, Fe, Zn, and Mn in the MPTP mouse model of Parkinson's disease using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS).
Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been established as a powerful technique for the determination of metal and nonmetal distributions within biological systems with high sensitivity. An imaging LA-ICP-MS technique for Fe, Cu, Zn, and Mn was developed to produce large series of quantitative element maps in native brain sections of mice subchronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) as a model of Parkinson's disease. Images were calibrated using matrix-matched laboratory standards. A software solution allowing a precise delineation of anatomical structures was implemented. Coronal brain sections were analyzed crossing the striatum and the substantia nigra, respectively. Animals sacrificed 2 h, 7 d, or 28 d after the last MPTP injection and controls were investigated. We observed significant decreases of Cu concentrations in the periventricular zone and the fascia dentata at 2 h and 7d and a recovery or overcompensation at 28 d, most pronounced in the rostral periventricular zone (+40%). In the cortex Cu decreased slightly to -10%. Fe increased in the interpeduncular nucleus (+40%) but not in the substantia nigra. This pattern is in line with a differential regulation of periventricular and parenchymal Cu, and with the histochemical localization of Fe, and congruent to regions of preferential MPTP binding described in the rodent brain. The LA-ICP-MS technique yielded valid and statistically robust results in the present study on 39 slices from 19 animals. Our findings underline the value of routine micro-local analytical techniques in the life sciences and affirm a role of Cu availability in Parkinson's disease.


Can preoperative and postoperative CEA predict survival after colon cancer resection?
Although elevated preoperative carcinoembryonic antigen (CEA) levels are associated with a poor prognosis, little has been written regarding the correlation of CEA response following curative resection of colorectal cancer and its relationship to survival. The purpose of this study, therefore, was to retrospectively evaluate survival in three groups of patients undergoing curative resection (Dukes B and C) for colorectal carcinoma: 1) elevated preoperative CEA/elevated postoperative CEA (EL/EL); 2) elevated preoperative CEA/normal postoperative CEA (EL/NL); and 3) normal preoperative CEA/normal postoperative CEA (NL/NL). A normal CEA was defined as a value < 5.0 ng/mL. Levels were drawn the day before surgery and between 2 and 4 weeks postoperatively. Patients were evaluated for age, sex, histologic grade, CEA levels (pre and postoperative), nerve and venous invasion, tumor site, and survival. There were no significant differences with respect to age, sex, Dukes stage, tumor site, histologic grade, or incidence of nerve or vascular invasion among the three groups. Five-year survival was significantly worse for patients with elevated preoperative CEA levels compared to those with normal preoperative CEA (53% versus 64%, P < 0.05), and for the EL/EL group compared with either of the other two groups (EL/EL: 66.6 +/- 11.8; EL/NL: 87.7 +/- 10.2; Group 3: 93.4 +/- 9.5, P < 0.05 ANOVA). The results indicate that a preoperative elevated CEA, particularly one that fails to decrease to normal postoperatively following a curative resection for colorectal carcinoma, represents a poor prognostic factor. Use of the CEA response may be useful for identifying a subgroup of colorectal cancer patients who are candidates for adjuvant chemotherapy.


Stimulation of protein kinase C or protein kinase A mediated signal transduction pathways shows three modes of response among serum inducible genes.
Activation of the signal transduction pathways mediated by protein kinase A (PKA) or protein kinase C (PKC) led to different responses of several serum inducible genes including the jun gene family, c-fos, c-myc, krox 20 and krox 24. Whereas all of these genes were stimulated by the phorbol ester TPA, a chemical activator of protein kinase C, they were differently regulated upon cAMP stimulation of the PKA dependent pathway. The proto-oncogenes jun B, c-fos, and to a lesser extent jun D were stimulated by increasing the intracellular concentration of cAMP, whereas the TPA stimulation of c-jun and c-myc was inhibited under these conditions. Krox 20 and krox 24 were insensitive to this second messenger. This study allowed us to classify these growth stimulated genes into three distinct groups distinguished by their sensitivity to elevated concentrations of intracellular cAMP. The inhibition of c-jun and c-myc expression in the presence of increased cAMP levels may be at least partially responsible for the growth inhibitory effect of this agent in Balb/c-3T3 cells.


Prevailing sea surface temperatures inhibit summer reproduction of the kelp Laminaria digitata at Helgoland (North Sea).
The impact of abiotic factors on kelp sporophyte reproduction has rarely been investigated. Laminaria digitata (Hudson) J.V. Lamouroux is one of the few summer fertile Laminaria species worldwide and reproduction is subjected to relatively high water temperatures. We investigated the impact of prevailing summer temperatures (~18°C in August) on the induction of sporangia, meiospore release, and germination at the island of Helgoland (North Sea). At Helgoland, fertile sporophytes are found between April and December with a maximum in late summer. While released meiospore numbers were constant between June and October, germination rates decreased significantly in summer. Short-term exposure of mature sori to 17°C-22°C induced a significantly higher meiospore release indicating enhancement of sporulation by elevated temperatures. Induction of sporangia on vegetative blade disks was not possible at 20°C, and fertility was only 20% at 18°C-19°C, but it was 100% in cool temperatures of 1°C-10°C. It was shown for the first time in a kelp species that "sporogenesis" is the life-cycle process with the narrowest temperature window compared to growth or survival of the sporophyte or reproduction, growth, and survival of the gametophyte. We incorporated several parameters (induction time, fertile area, and relative fertility) into a "Reproductive efficiency index." This indicates that sporogenesis of L. digitata is a cold-adapted process with an optimum at (5)-10°C. The results show that the population at Helgoland is at its reproduction limit despite the existence of other geographically more southerly located populations.


Pseudofolliculitis barbae and related disorders.
Pseudofolliculitis barbae, although not a serious medical problem, is certainly a distressing one for the affected patient. Its pathogenesis lies in an ingrown hair arising from the curved hair and follicle common in black men and women. Improper shaving techniques cause ingrown hairs through both transfollicular and extrafollicular mechanisms. Various treatment modalities exist, but there is no cure. Treatment must be individualized, as not all regimens will work for each patient. With diligence, pseudofolliculitis barbae can in many instances be controlled. Dermatitis papillaris capillitii is related to pseudofolliculitis barbae because its pathogenesis also lies in a curved hair and follicle. The treatment differs, however. Mild to moderately severe cases can be kept under good control with intralesional injections of steroid and a topical chloramphenicol and steroid cream mixture. Scarred or keloidal lesions may require surgery.


From gender identity disorder to gender identity creativity: true gender self child therapy.
True gender self child therapy is based on the premise of gender as a web that weaves together nature, nurture, and culture and allows for a myriad of healthy gender outcomes. This article presents concepts of true gender self, false gender self, and gender creativity as they operationalize in clinical work with children who need therapeutic supports to establish an authentic gender self while developing strategies for negotiating an environment resistant to that self. Categories of gender nonconforming children are outlined and excerpts of a treatment of a young transgender child are presented to illustrate true gender self child therapy.


Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development.
Chromatin modifications are associated with many aspects of gene expression, yet their role in cellular transitions during development remains elusive. Here, we use a new approach to obtain cell type-specific information on chromatin state and RNA polymerase II (Pol II) occupancy within the multicellular Drosophila melanogaster embryo. We directly assessed the relationship between chromatin modifications and the spatio-temporal activity of enhancers. Rather than having a unique chromatin state, active developmental enhancers show heterogeneous histone modifications and Pol II occupancy. Despite this complexity, combined chromatin signatures and Pol II presence are sufficient to predict enhancer activity de novo. Pol II recruitment is highly predictive of the timing of enhancer activity and seems dependent on the timing and location of transcription factor binding. Chromatin modifications typically demarcate large regulatory regions encompassing multiple enhancers, whereas local changes in nucleosome positioning and Pol II occupancy delineate single active enhancers. This cell type-specific view identifies dynamic enhancer usage, an essential step in deciphering developmental networks.


A Pilot Study in the Use of Activity Trackers for Assessing Response to Palliative Radiotherapy.
Purpose Radiation therapy (RT) has been a frequently used treatment for painful bone metastasis. The aim of this study was to determine the feasibility of using activity trackers (AT) to assess the patient prognosis and the effects of palliative RT. Methods and materials Twelve patients planned to receive palliative RT for axial metastases and were prospectively recruited to participate in this pilot clinical trial. The patients were eligible if there was no intent to change the analgesic medications prior to or within seven days of palliative RT. All the patients were lent a Misfit FlashTM activity tracker (Misfit, Burlingame, California, United States of America) and were asked to wear it from the time of baseline assessment prior to RT until seven days after RT. The patients completed the European Organisation for Research and Treatment of Cancer quality of life (QOL) questionnaire (EORTC-QLQ C30) and the Short Form Brief Pain Inventory (SF-BPI) before the treatment and at days seven, 30 and 90 after completion of the RT. The patients' Karnofsky Performance Status (KPS) was assessed at each visit. The patients' overall survival at the end of the RT was recorded. Average daily steps before and after RT were compared using paired Wilcoxon signed-rank test. The patients' overall survival was estimated using the Kaplan-Meier curve and analyzed using the Log-Rank test. Results The median age of the patients was 62 years (range: 40-79 years). Of the 12 patients, there were five prostate, three breasts, three lungs, and one colon cancer-related patients. Six patients received 20 Gray (Gy) in five fractions and six received 8 Gy in one fraction. By day seven, post-RT, there was a 30% (p <0.02) reduction in the patients' daily activity level. There was no correlation between improvements in the QOL or with the level of pain and with the number of daily steps. While baseline KPS was not prognostic of the patient survival, the patients who on average took more than 7800 steps per day prior to RT lived significantly (p=0.034) longer than those who were less active. Conclusions The baseline activity level is associated with the patient prognosis. A significant decline in the physical activity was observed at one week after palliative RT. The use of activity trackers was to prognosticate and to monitor the patients' response to the palliative RT and should be evaluated further.


[Carnitin-Palmitoyl Transferase type 2 deficiency: a rare cause of acute renal failure due to rhabdomyolysis].
Fatty acid oxidation disorders are inborn errors of metabolism. One of the possible alterations involves the failure of the carnitin-based transport of long-chain fatty acids into the mitochondria, necessary for muscle metabolism in case of prolonged physical exertion. Three kinds of Carnitin-Palmitoyl Transferase type 2 (CPT2) deficiency have been described: a myopathic form, a severe infantile form and a neonatal form. The clinical picture is characterized by recurrent attacks of rhabdomyolysis, muscular pains and fatigue, secondary to a prolonged physical exercise and sometimes aggravated by intercurrent events. Rhabdomyolysis episodes are associated with a significant increase in creatine phosphokinase and myoglobinuria and may result in acute renal failure. Patients are usually asymptomatic during intercurrent periods. When acute renal failure from rhabdomyolysis arises after intense physical activity, it is therefore necessary to also investigate the presence of metabolic myopathies due to enzymatic deficiency.


On the relation of energy and electron transfer in multidimensional chromophores based on polychlorinated triphenylmethyl radicals and triarylamines.
A star-like compound consisting of a polychlorinated triphenylmethyl radical (PCTM) core linked to three triarylamines (TAA) and a symmetric and an asymmetric hexaarylbenzene (HAB) both substituted with three PCTMs and three TAAs were synthesised. In the star-like compound a strong communication between the redox centres was observed by electron paramagnetic resonance spectroscopy and UV/Vis/NIR absorption measurements, whereas in the HABs only a weak interaction could be detected. The temporal evolution of the excited states was monitored by ultrafast transient absorption measurements. Within the first picosecond stabilisation of the charge transfer state was observed induced by solvent rotation. Anisotropic transient absorption measurements revealed that within the lifetime of the excited state (τ = 1-4 ps) energy transfer does not occur in the HABs whereas in the star-like system ultrafast and possibly coherent energy redistribution is observed. Taken this information together we made the identity between energy transfer and electron transfer in the specific systems apparent.


Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia.
A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed D-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the D-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes D-serine, a potent activator of the N-methyl-D-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.


Do soy isoflavones improve cognitive function in postmenopausal women? A meta-analysis.
Several studies have demonstrated that soy isoflavone (SIF) supplementation can improve aspects of cognitive function. However, these findings remain controversial. We aimed to quantify the effects of SIF supplementation on improving cognitive function in postmenopausal women. Databases and relevant Websites were searched for relevant studies up to March 2014. Two reviewers independently verified all potentially suitable randomized controlled trials (RCTs) using inclusion and exclusion criteria, and the quality of identified RCTs was assessed using the Jadad scale and the Risk of Bias Tool from the "Cochrane handbook for systematic reviews of interventions." Any disagreement on study quality or data extraction was resolved by consensus; a third reviewer was consulted if needed. Standardized mean differences (SMDs) in cognitive function test scores were calculated between SIF-treated and placebo-treated groups. We conducted a meta-analysis of 10 placebo-controlled RCTs of SIF supplementation (1,024 participants; treatment duration of 6 wk to 30 mo). The overall SMD in summary cognitive function test scores (0.08) was statistically significant (95% CI, 0.02-0.15; P = 0.014). The summary SMD for visual memory (0.10) was statistically significant (95% CI, 0.02-0.18; P = 0.016). In subgroup analyses, the statistically significant SMDs were as follows: 0.12 (95% CI, 0-0.25; P = 0.044) for non-US countries; 0.16 (95% CI, 0.05-0.28; P = 0.004) for mean age younger than 60 years; and 0.15 (95% CI, 0.03-0.27; P = 0.011) for treatment duration less than 12 months. SIF supplementation seems to have a positive effect on improving summary cognitive function and visual memory in postmenopausal women. There may be a critical window of opportunity in initiating SIF use at an earlier age in postmenopausal women, and geography and treatment duration seem to be factors influencing the effects of SIF supplementation. All individuals in the included studies should be followed up to observe the incidence rates of Alzheimer's disease and dementia, and future studies should report any adverse effects of SIF supplementation.


Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.
Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC) precursor, that act in the brain to reduce food intake and are potential mediators of leptin action. In the forebrain, melanocortins are derived from POMC-containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis that these POMC neurons are regulated by leptin, we used in situ hybridization to determine whether reduced leptin signaling (as occurs in fasting), genetic leptin deficiency (in obese ob/ob mice), or genetic leptin resistance (in obese db/db mice) lower expression of POMC mRNA. We further hypothesized that leptin administration would raise hypothalamic POMC mRNA levels in leptin-deficient animals, but not in mice with defective leptin receptors. In wild-type mice (n = 12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by 53%, relative to values in fed controls (n = 8; P < 0.001). Similarly, arcuate nucleus POMC mRNA levels were reduced by 46 and 70% in genetically obese ob/ob (n = 6) and db/db mice (n = 6), respectively, as compared with wild-type mice (n = 5) (P < 0.01 for both comparisons). Five daily intraperitoneal injections of recombinant murine leptin (150 microg) raised levels of POMC mRNA in the rostral arcuate nucleus of ob/ob mice (n = 8) by 73% over saline-treated ob/ob control values (n = 8; P < 0.01), but was without effect in db/db mice (n = 6). In normal rats, two injections of a low dose of leptin (3.5 microg) into the third cerebral ventricle (n = 15) during a 40-h period of fasting also increased POMC mRNA levels in the rostral arcuate nucleus to values 39% greater than those in vehicle-treated controls (n = 14; P = 0.02). We conclude that reduced central nervous system leptin signaling owing to fasting or to genetic defects in leptin or its receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that leptin reverses this effect in ob/ob, but not db/db, mice suggests that leptin stimulates arcuate nucleus POMC gene expression via a pathway involving leptin receptors. These findings support the hypothesis that leptin signaling in the brain involves activation of the hypothalamic melanocortin system.


Decellularised extracellular matrix-derived peptides from neural retina and retinal pigment epithelium enhance the expression of synaptic markers and light responsiveness of human pluripotent stem cell derived retinal organoids.
Tissue specific extracellular matrices (ECM) provide structural support and enable access to molecular signals and metabolites, which are essential for directing stem cell renewal and differentiation. To mimic this phenomenon in vitro, tissue decellularisation approaches have been developed, resulting in the generation of natural ECM scaffolds that have comparable physical and biochemical properties of the natural tissues and are currently gaining traction in tissue engineering and regenerative therapies due to the ease of standardised production, and constant availability. In this manuscript we report the successful generation of decellularised ECM-derived peptides from neural retina (decel NR) and retinal pigment epithelium (decel RPE), and their impact on differentiation of human pluripotent stem cells (hPSCs) to retinal organoids. We show that culture media supplementation with decel RPE and RPE-conditioned media (CM RPE) significantly increases the generation of rod photoreceptors, whilst addition of decel NR and decel RPE significantly enhances ribbon synapse marker expression and the light responsiveness of retinal organoids. Photoreceptor maturation, formation of correct synapses between retinal cells and recording of robust light responses from hPSC-derived retinal organoids remain unresolved challenges for the field of regenerative medicine. Enhanced rod photoreceptor differentiation, synaptogenesis and light response in response to addition of decellularised matrices from RPE and neural retina as shown herein provide a novel and substantial advance in generation of retinal organoids for drug screening, tissue engineering and regenerative medicine.


Synchronizability of EEG-based functional networks in early Alzheimer's disease.
Recently graph theory and complex networks have been widely used as a mean to model functionality of the brain. Among different neuroimaging techniques available for constructing the brain functional networks, electroencephalography (EEG) with its high temporal resolution is a useful instrument of the analysis of functional interdependencies between different brain regions. Alzheimer's disease (AD) is a neurodegenerative disease, which leads to substantial cognitive decline, and eventually, dementia in aged people. To achieve a deeper insight into the behavior of functional cerebral networks in AD, here we study their synchronizability in 17 newly diagnosed AD patients compared to 17 healthy control subjects at no-task, eyes-closed condition. The cross-correlation of artifact-free EEGs was used to construct brain functional networks. The extracted networks were then tested for their synchronization properties by calculating the eigenratio of the Laplacian matrix of the connection graph, i.e., the largest eigenvalue divided by the second smallest one. In AD patients, we found an increase in the eigenratio, i.e., a decrease in the synchronizability of brain networks across delta, alpha, beta, and gamma EEG frequencies within the wide range of network costs. The finding indicates the destruction of functional brain networks in early AD.


TLR4 and DC-SIGN receptors recognized Mycobacterium scrofulaceum promoting semi-activated phenotype on bone marrow dendritic cells.
Nontuberculous mycobacteria (NTM) are recognized as emerging pathogens and their immune regulatory mechanisms are not well described yet. From them, Mycobacterium avium is known to be a weak activator of dendritic cells (DCs) that impairs the response induced by BCG vaccine. However, whether other NTM such as Mycobacterium scrofulaceum may modulate the activation of DCs, has not been extensively studied. Here, we exposed bone marrow-derived DCs (BMDCs) to M. scrofulaceum and we analyzed the effect on the activation of DCs. We found that M. scrofulaceum has a comparable ability to induce a semi-mature DC phenotype, which was produced by its interaction with DC-SIGN and TLR4 receptors in a synergic effect. BMDCs exposed to M. scrofulaceum showed high expression of PD-L2 and production of IL-10, as well as low levels of co-stimulatory molecules and pro-inflammatory cytokines. In addition to immunophenotype induced on DCs, changes in morphology, re-organization of cytoskeleton and decreased migratory capacity are consistent with a semi-mature phenotype. However, unlike other pathogenic mycobacteria, the DC-semi-mature phenotype induced by M. scrofulaceum was reversed after re-exposure to BCG, suggesting that modulation mechanisms of DC-activation used by M. scrofulaceum are different to other known pathogenic mycobacteria. This is the first report about the immunophenotypic characterization of DC stimulated by M. scrofulaceum.


Classification of solar cells according to mechanisms of charge separation and charge collection.
In the last decade, photovoltaics (PV) has experienced an important transformation. Traditional solar cells formed by compact semiconductor layers have been joined by new kinds of cells that are constituted by a complex mixture of organic, inorganic and solid or liquid electrolyte materials, and rely on charge separation at the nanoscale. Recently, metal organic halide perovskites have appeared in the photovoltaic landscape showing large conversion efficiencies, and they may share characteristics of the two former types. In this paper we provide a general description of the photovoltaic mechanisms of the single absorber solar cell types, combining all-inorganic, hybrid and organic cells into a single framework. The operation of the solar cell relies on a number of internal processes that exploit internal charge separation and overall charge collection minimizing recombination. There are two main effects to achieve the required efficiency, first to exploit kinetics at interfaces, favouring the required forward process, and second to take advantage of internal electrical fields caused by a built-in voltage and by the distribution of photogenerated charges. These principles represented by selective contacts, interfaces and the main energy diagram, form a solid base for the discussion of the operation of future types of solar cells. Additional effects based on ferroelectric polarization and ionic drift provide interesting prospects for investigating new PV effects mainly in the perovskite materials.


Tick surveillance in Great Britain.
The ability for public/veterinary health agencies to assess the risks posed by tick-borne pathogens is reliant on an understanding of the main tick vector species. Crucially, the status, distribution, and changing trends in tick distribution and abundance are implicit requirements of any risk assessment; however, this is contingent on the quality of tick distribution data. Since 2005 the Health Protection Agency has promoted an enhanced tick surveillance program. Through engagement with a variety of public and veterinary health agencies and practitioners (e.g., clinicians and veterinarians), wildlife groups (deer society, zoos, animal refuge centers, and academics), and amateur entomologists, >4000 ticks from 900 separate records across Great Britain have been submitted, representing 14 tick species (Ixodes ricinus, Ixodes hexagonus, Ixodes acuminatus, Ixodes arboricola, Ixodes canisuga, Ixodes frontalis, Ixodes lividus, Ixodes trianguliceps, Ixodes ventalloi, Carios vespertilionis, Dermacentor reticulatus, Haemaphysalis punctata, Hyalomma marginatum, and Amblyomma species). The majority of ticks submitted were I. ricinus (81%), followed by I. hexagonus (10%) and I. frontalis (2.5%). Predominant host groups include companion animals (411 records), humans (198 records), wild birds (111 records), and large wild mammals (88 records), with records also from small/medium wild mammals, livestock, the environment and domestic/aviary birds. The scheme has elucidated the detection of two nonnative tick species, the expansion of previously geographically restricted D. reticulatus and produced ground data on the spread of I. ricinus in southwest England. It has also provided a forum for submission of ticks from the concerned public and particularly those infected with Lyme borreliosis, thus raising awareness among public health agencies of the increased peri-urban tick problem in Britain. Our results demonstrate that it is possible to run a cost-effective nationwide surveillance program to successfully monitor endemic tick species, identify subtle changes in their distribution, and detect the arrival and presence of exotic species.


Prevention of postpartum traumatic stress in mothers with preterm infants: manual development and evaluation.
Premature birth has been associated with multiple adverse maternal psychological outcomes that include depression, anxiety, and trauma as well as adverse effects on maternal coping ability and parenting style. Infants who are premature are more likely to have poorer cognitive and developmental functioning and, thus, may be harder to parent, both as infants and as they get older. In response to these findings, a number of educational and behavioral interventions have been developed that target maternal psychological functioning, parenting, and aspects of the parent-infant relationship. The current study aimed to both develop and evaluate a treatment that integrates, for the first time, effective interventions for reducing symptoms of posttraumatic stress disorder (PTSD) and enhancing maternal-infant interactions. Conclusions from the study indicate that the intervention is feasible, able to be implemented with a high level of fidelity, and is rated as highly satisfactory by participants. Though encouraging, these findings are preliminary, and future studies should strive to reproduce these findings with a larger sample size and a comparison group.


Elucidation of the mechanism of disulfide exchange between staphylococcal thioredoxin2 and thioredoxin reductase2: A structural insight.
The redox homeostasis of cytoplasm is maintained by a series of disulfide exchange reactions mediated by proteins belonging to the thioredoxin superfamily. Thioredoxin and thioredoxin reductase, being the major members of the family, play a key role in oxidative stress response of Staphylococcus aureus. In this report, we have identified and characterised an active thioredoxin system of the mentioned pathogen. Crystal structure of thioredoxin2 (SaTrx2) in its reduced form reveals that it contains the conserved redox active WCXXC motif and a thioredoxin fold. Thioredoxin reductase2 (SaTR2) is a flavoprotein and consists of two Rossmann folds as the binding sites for FAD and NADPH. Crystal structure of the SaTR2 holoenzyme shows that the protein consists of two domains and the catalytic site comprises of an intramolecular disulfide bond formed between two sequentially distal cysteine residues. Biophysical and biochemical studies unveil that SaTrx2 and SaTR2 can physically interact in solution and in the course of sustaining the redox equilibrium, the latter reduces the former. Molecular docking has been performed to illustrate the interface formed between SaTrx2 and SaTR2 during the disulfide exchange reaction.


Community structure of coral microbiomes is dependent on host morphology.
The importance of symbiosis has long been recognized on coral reefs, where the photosynthetic dinoflagellates of corals (Symbiodiniaceae) are the primary symbiont. Numerous studies have now shown that a diverse assemblage of prokaryotes also make-up part of the microbiome of corals. A subset of these prokaryotes is capable of fixing nitrogen, known as diazotrophs, and is also present in the microbiome of scleractinian corals where they have been shown to supplement the holobiont nitrogen budget. Here, an analysis of the microbiomes of 16 coral species collected from Australia, Curaçao, and Hawai'i using three different marker genes (16S rRNA, nifH, and ITS2) is presented. These data were used to examine the effects of biogeography, coral traits, and ecological life history characteristics on the composition and diversity of the microbiome in corals and their diazotrophic communities. The prokaryotic microbiome community composition (i.e., beta diversity) based on the 16S rRNA gene varied between sites and ecological life history characteristics, but coral morphology was the most significant factor affecting the microbiome of the corals studied. For 15 of the corals studied, only two species Pocillopora acuta and Seriotopora hystrix, both brooders, showed a weak relationship between the 16S rRNA gene community structure and the diazotrophic members of the microbiome using the nifH marker gene, suggesting that many corals support a microbiome with diazotrophic capabilities. The order Rhizobiales, a taxon that contains primarily diazotrophs, are common members of the coral microbiome and were eight times greater in relative abundances in Hawai'i compared to corals from either Curacao or Australia. However, for the diazotrophic component of the coral microbiome, only host species significantly influenced the composition and diversity of the community. The roles and interactions between members of the coral holobiont are still not well understood, especially critical functions provided by the coral microbiome (e.g., nitrogen fixation), and the variation of these functions across species. The findings presented here show the significant effect of morphology, a coral "super trait," on the overall community structure of the microbiome in corals and that there is a strong association of the diazotrophic community within the microbiome of corals. However, the underlying coral traits linking the effects of host species on diazotrophic communities remain unknown. Video Abstract.


Proadrenomedullin NH2-terminal 20 peptide is a potent angiogenic factor, and its inhibition results in reduction of tumor growth.
We have found through ex vivo and in vivo angiogenesis models that the adrenomedullin gene-related peptide, proadrenomedullin NH2-terminal 20 peptide (PAMP), exhibits a potent angiogenic potential at femtomolar concentrations, whereas classic angiogenic factors such as vascular endothelial growth factor and adrenomedullin mediate a comparable effect at nanomolar concentrations. We found that human microvascular endothelial cells express PAMP receptors and respond to exogenous addition of PAMP by increasing migration and cord formation. Exposure of endothelial cells to PAMP increases gene expression of other angiogenic factors such as adrenomedullin, vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor C. In addition, the peptide fragment PAMP(12-20) inhibits tumor cell-induced angiogenesis in vivo and reduces tumor growth in xenograft models. Together, our data demonstrate PAMP to be an extremely potent angiogenic factor and implicate this peptide as an attractive molecular target for angiogenesis-based antitumor therapy.


Self-reported data: reliability and role in determining program effectiveness.
This study was conducted to assess the reliability of self-reported hospitalization data, as well as the appropriateness of using self-reported data in evaluating the effectiveness of the Maine Ambulatory Diabetes Education and Follow-Up (ADEF) program. A Maine Blue Cross/Blue Shield (BC/BS) inpatient claims file was used as the reference source to verify self-reported hospitalization data. For a sample of 99 BC/BS subscribers who attended the ADEF program, 77% of the study participants accurately self-reported hospitalization patterns over a 12-mo time period before attending the education program, and 81% of the participants accurately self-reported hospitalization patterns during a posteducation follow-up time period. The reference BC/BS claims data documented a reduction in hospitalizations for the study participants similar to that reported using the ADEF self-reported hospitalization data. The Maine Diabetes Control Project used the self-reported hospitalization data in combination with selected reference claims data to secure third-party reimbursement for the Maine ADEF Program.


Mutations in the RING domain of TFB3, a subunit of yeast transcription factor IIH, reveal a role in cell cycle progression.
The RNA polymerase II general transcription factor TFIIH is composed of 9 known subunits and possesses DNA helicase and protein kinase activities. The kinase subunits of TFIIH in animal cells, Cdk7, cyclin H, and MAT1, were independently isolated as an activity termed CAK (Cdk-activating kinase), which phosphorylates and activates cell cycle kinases. However, CAK activity of TFIIH subunits could not be demonstrated in budding yeast. TFB3, the 38-kDa subunit of yeast TFIIH, is the homolog of mammalian MAT1. By random mutagenesis we have isolated a temperature-sensitive mutation in the conserved RING domain. The mutant Tfb3 protein associates less efficiently with the kinase moiety of TFIIH than the wild type protein. In contrast to lethal mutants in other subunits of TFIIH, this mutation does not impair general transcription. Transcription of CLB2, and possibly other genes, is reduced in the mutant. At the restrictive temperature, the cells display a defect in cell cycle progression, which is manifest at more than one phase of the cycle. To conclude, in the present study we bring another demonstration of the multifunctional nature of TFIIH.


The role of structure and the metal ion in the fluorescence sensing of nitro compounds for a series of lanthanide(iii) 9,10-anthracene dicarboxylate coordination polymers.
Twenty-eight lanthanide coordination polymers (CPs) containing 9,10-anthracene dicarboxylate (ADC) linkers have been synthesized and characterized. For the earlier class of lanthanides La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+ and Tb3+, the 3D pcu net was generated from dimethylformamide (DMF) while a 2D hcb net was formed using dimethylacetamide (DMA). Similarly for the later class of lanthanides, Dy3+, Ho3+, Er3+, Tm3+, Yb3+ and Lu3+, a 2D hcb net was formed when dimethylacetamide (DMA) was used. However, the formation of a crystalline product with DMF was possible only when DMSO was added together for these lanthanides, and they yielded 2D structures despite the usage of DMF. Only the single crystal structures of Er3+ and Ho3+ have been determined and the rest of the structures were confirmed by PXRD studies. These compounds have been used to sense various nitro compounds. In particular, they are the most sensitive to Brady's reagent, 2,4-dinitrohydrazobenzene. There was no difference in the quenching extent between the 3D and 2D early lanthanide CPs. For the later lanthanides which adopt 2D structures, the quenching efficiency is higher when DMA instead of DMSO is coordinated suggesting the solvent effect in emission quenching.


Innate cellular response to virus particle entry requires IRF3 but not virus replication.
Mammalian cells respond to virus infections by eliciting both innate and adaptive immune responses. One of the most effective innate antiviral responses is the production of alpha/beta interferon and the subsequent induction of interferon-stimulated genes (ISGs), whose products collectively limit virus replication and spread. Following viral infection, interferon is produced in a biphasic fashion that involves a number of transcription factors, including the interferon regulatory factors (IRFs) 1, 3, 7, and 9. In addition, virus infection has been shown to directly induce ISGs in the absence of prior interferon production through the activation of IRF3. This process is believed to require virus replication and results in IRF3 hyperphosphorylation, nuclear localization, and proteasome-mediated degradation. Previously, we and others demonstrated that herpes simplex virus type 1 (HSV-1) induces ISGs and an antiviral response in fibroblasts in the absence of both interferon production and virus replication. In this report, we show that the entry of enveloped virus particles from diverse virus families elicits a similar innate response. This process requires IRF3, but not IRF1, IRF7, or IRF9. Following virus replication, the large DNA viruses HSV-1 and vaccinia virus effectively inhibit ISG mRNA accumulation, whereas the small RNA viruses Newcastle disease virus, Sendai virus, and vesicular stomatitis virus do not. In addition, we found that IRF3 hyperphosphorylation and degradation do not correlate with ISG and antiviral state induction but instead serve as a hallmark of productive virus replication, particularly following a high-multiplicity infection. Collectively, these data suggest that virus entry triggers an innate antiviral response mediated by IRF3 and that subsequent virus replication results in posttranslational modification of IRF3, such as hyperphosphorylation, depending on the nature of the incoming virus.


Computer analysis of the tonic, phasic, and kinesthetic activity of pallidal discharges in Parkinson patients.
Intraoperative analysis of microrecording data during pallidotomy often depends on subjective interpretation of the oscilloscope signal, especially during the analysis of phasic activity. The goals of this project were: 1) to develop an inexpensive system that allowed on-line, objective characterization of single-unit pallidal discharges, and 2) to have objective criteria to differentiate the internal part (GPi) from the external part (GPe) of the globus pallidus. A computer program was developed that allowed the analysis of firing rates (mean, median, and quartiles), spike count per unit time, and interspike interval (ISI) histograms with Chi-square statistical evaluation. Indices were developed that measured phasic activity, including burst index (BI) for the measurement of bursts, pause index (PI) for the measurement of pauses, and pause ratio (PR) for analysis of time spent in pauses. Single-unit activity of 152 GPe and 203 GPi cells in 47 Parkinson patients were digitized using the computer soundcard during pallidotomy and analyzed using this software. GPe discharges had a mean firing rate = 42 Hz, BI = 0.81, PI = 0.21, and PR = 1.41. GPi had a mean firing rate = 81, BI = 1.61, PI = 0.04, and PR = 0.21. The PR was the best index that differentiated GPe from GPi, followed by PI, BI, and firing rates, in that order. Kinesthetic cells were recorded equally in GPe from GPi, and their responses to generalized movements were not significantly different. (1) Signal analysis using the digitization process of a computer sound card and dedicated software is satisfactory for the objective "on-line" and "off-line" analysis of microrecordings (including phasic activity); (2) PI and PR are most helpful in differentiating neurons of GPi from those of GPe; (3) no single parameter can differentiate GPe from GPi activity in all cases; and (4) unlike the findings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, GPe and GPi of Parkinson patients have similar prevalence of kinesthetic cells and similar responses to generalized somatotopic effects.


Arginase impedes the resolution of colitis by altering the microbiome and metabolome.
Arginase 1 (Arg1), which converts l-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1fl/fl) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Arg1 deletion was reduced by an l-arginine-free diet, but rescued by simultaneous deletion of other l-arginine-metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires l-arginine. Fecal microbiota transfers from Tie2-Cre Arg1fl/fl mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of l-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.


Developmental adaptations of trypanosome motility to the tsetse fly host environments unravel a multifaceted in vivo microswimmer system.
The highly motile and versatile protozoan pathogen Trypanosoma brucei undergoes a complex life cycle in the tsetse fly. Here we introduce the host insect as an expedient model environment for microswimmer research, as it allows examination of microbial motion within a diversified, secluded and yet microscopically tractable space. During their week-long journey through the different microenvironments of the fly´s interior organs, the incessantly swimming trypanosomes cross various barriers and confined surroundings, with concurrently occurring major changes of parasite cell architecture. Multicolour light sheet fluorescence microscopy provided information about tsetse tissue topology with unprecedented resolution and allowed the first 3D analysis of the infection process. High-speed fluorescence microscopy illuminated the versatile behaviour of trypanosome developmental stages, ranging from solitary motion and near-wall swimming to collective motility in synchronised swarms and in confinement. We correlate the microenvironments and trypanosome morphologies to high-speed motility data, which paves the way for cross-disciplinary microswimmer research in a naturally evolved environment.


Structure/function relationships in RecA protein-mediated homology recognition and strand exchange.
RecA family proteins include RecA, Rad51, and Dmc1. These recombinases are responsible for homology search and strand exchange. Homology search and strand exchange occur during double-strand break repair and in eukaryotes during meiotic recombination. In bacteria, homology search begins when RecA binds an initiating single-stranded DNA (ssDNA) in the primary DNA-binding site to form the presynaptic filament. The filament is a right-handed helix, where the initiating strand is bound deep within the filament. Once the presynaptic filament is formed, it interrogates nearby double-stranded DNA (dsDNA) to find a homologous sequence; therefore, we provide a detailed discussion of structural features of the presynaptic filament that play important functional roles. The discussion includes many diagrams showing multiple filament turns. These diagrams illustrate interactions that are not evident in single turn structures. The first dsDNA interactions with the presynaptic filament are insensitive to mismatches. The mismatch insensitive interactions lead to dsDNA deformation that triggers a homology testing process governed by kinetics. The first homology test involves ∼8 bases. Almost all interactions are rejected by this initial rapid test, leading to a new cycle of homology testing. Interactions that pass the initial rapid test proceed to a slower testing stage. That slower stage induces nonhomologous dsDNA to reverse strand exchange and begin a new cycle of homology testing. In contrast, homologous dsDNA continues to extend the heteroduplex strand-exchange product until ATP hydrolysis makes strand exchange irreversible.


Parameterization of treatment effects for meta-analysis in multi-state Markov models.
Standard approaches to analysis of randomized controlled trials (RCTs) using Markov models make it difficult to generalize treatment effects to new patient groups and synthesize evidence across trials. This paper demonstrates how pair-wise and mixed treatment comparison meta-analysis can be applied to event history data for disease progression reported by RCTs. The data, in the form of aggregated discrete time transitions, have a multi-nomial likelihood. In order for evidence synthesis to be performed a structured approach to modelling the differences in the effects of the different treatments must be taken. A multi-state continuous-time Markov model similar to others used in published economic evaluations of asthma treatments is developed, with transition rates related to the likelihood via Kolmogorov's forward equations. The formulation in terms of rates allows a flexible characterization of summary treatment effects. These ideas are applied to an illustrative data set consisting of a set of five trials comparing eight different treatments for asthma. A range of models is developed in which the relative treatment effects act on forward, backward transitions, or both, and models are compared using the DIC. Bayesian inferential techniques are used and the parameters are estimated using MCMC simulation in WinBUGS. An intuitively appealing mechanism of action involving a single parameter acting on all backward transitions was identified for the relative effects of the treatments, which allowed the estimation of a pooled treatment effect, allowing us to rank the different treatment options within each connected evidence network to ascertain which were the most clinically effective.


A computational modelling framework to quantify the effects of passaging cell lines.
In vitro cell culture is routinely used to grow and supply a sufficiently large number of cells for various types of cell biology experiments. Previous experimental studies report that cell characteristics evolve as the passage number increases, and various cell lines can behave differently at high passage numbers. To provide insight into the putative mechanisms that might give rise to these differences, we perform in silico experiments using a random walk model to mimic the in vitro cell culture process. Our results show that it is possible for the average proliferation rate to either increase or decrease as the passaging process takes place, and this is due to a competition between the initial heterogeneity and the degree to which passaging damages the cells. We also simulate a suite of scratch assays with cells from near-homogeneous and heterogeneous cell lines, at both high and low passage numbers. Although it is common in the literature to report experimental results without disclosing the passage number, our results show that we obtain significantly different closure rates when performing in silico scratch assays using cells with different passage numbers. Therefore, we suggest that the passage number should always be reported to ensure that the experiment is as reproducible as possible. Furthermore, our modelling also suggests some avenues for further experimental examination that could be used to validate or refine our simulation results.


Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts.
Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a >80% reduction in COL1A1 mRNA, and a >70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease.


Stretching to reduce work-related musculoskeletal disorders: a systematic review.
This article reviewed the literature to clarify the physiological effects and benefits of, and misconceptions about, stretches used to reduce musculoskeletal disorders. Nine databases were reviewed to identify studies exploring the effectiveness of stretching to prevent work-related musculoskeletal disorders. Included studies were reviewed and their methodological quality was assessed using the PEDro scale. The physiological effects of stretches may contribute to reducing discomfort and pain. However, if other measures are not in place to remediate their causes, stretches may suppress awareness of risks, resulting in more debilitating injuries. If inadequately performed, stretches may also cause or aggravate injuries. Careful analysis and stretching program design are required before implementing stretches. Seven studies evaluating the effectiveness of stretching to prevent musculoskeletal disorders in different occupations were identified and reviewed. The studies provided mixed findings, but demonstrated some beneficial effect of stretching in preventing work-related musculoskeletal disorders. However, due to the relatively low methodological quality of the studies available in the literature, future studies are necessary for a definite response. Future studies should minimize threats to internal and external validity, have control groups, use appropriate follow-up periods, and present a more detailed description of the interventions and worker population.


Detrusor contraction strength in men undergoing prostatectomy.
Elective prostatectomy is a frequently performed operation but the outcome may not always be satisfactory. This is probably because a significant number of men, despite subjective symptoms, are not urodynamically obstructed before operation and the preoperative assessment of obstruction is not easy using conventional urodynamic criteria. We have calculated detrusor contraction strength (WF) in men before and after prostatectomy. Our aim was to determine its relationship with symptomatic and urodynamic findings before and after prostatectomy and whether it was associated with clinical outcome. One hundred and twenty nine men listed for operation because of symptoms and low urinary flow rates were studied by means of urodynamic investigation and symptom scoring both before and 6 months after prostatectomy. A significant association was found between persistent obstructive symptoms after operation and a low WF before operation (P = 0.01), suggesting that weak detrusor function before operation was the cause of persistent symptoms afterwards. A significant correlation was also found between a high pre-operative WF and a high post-operative urinary flow rate; (P = 0.003); men with high detrusor power achieving the better flow rates after operation. Despite this relationship, the overall subjective clinical outcome was not strongly associated with WF and WF was no better than simple measurement of voiding pressure in predicting outcome in a multivariate analysis. The measurement of detrusor contraction strength provides some insight into the relationship between bladder function and clinical outcome after prostatectomy, but we have found it unable to predict outcome for the individual patient.


The effects of systemic isotretinoin and antibiotic therapy on the microbial floras in patients with acne vulgaris.
Although there are several studies about the alteration in skin flora, limited number of reports about changes in the microbial contents and their resistance profile of other body sites in patients treated with isotretinoin for acne vulgaris. The aim of this study was to investigate the effects of systemic isotretinoin and antibiotic therapy on the microbial floras of oropharynx, nose and feces in acne patients. Treatment groups of isotretinoin and antibiotics consisting of 20 and 15 patients, respectively were included. Microbiological culture samples were taken at baseline and once a month during 4-6 months of treatment period. Difference in microbial flora throughout the treatment period was detected at least among one of all culture samples of 15 (75%) and 5 (33%) patients in isotretinoin and antibiotic groups. There was statistically significant difference between two groups in means of alteration of the microbial flora (P = 0.013). The difference was definitely observed among nasal cultures (65%) in isotretinoin group and fecal cultures (20%) in the other. Staphylococcus aureus colonization was prominent in the microbial floras of nose and oropharynx and 2 of 14 nasal isolates were detected to be methicilline resistant while Escherichia coli with extended spectrum beta lactamase activity was detected in fecal floras of patients in isotretinoin group. Systemic isotretinoin and antibiotic treatments in acne patients precisely caused variations in the microbial floras of several sites of the body, while isotretinoin was commonly more responsible than antibiotics. Knowing that alterations in the microbial colonization of the flora regions may preceede infectious disease and bacterial resistance, treatment options and follow-up procedures in acne vulgaris should be carefully determined to reduce the risk of destruction of the microbial flora.


The lack of the C-terminal domain of adipose triglyceride lipase causes neutral lipid storage disease through impaired interactions with lipid droplets.
The molecular mechanisms by which triglycerides in lipid droplets (LDs) are synthesized, stored, and degraded need to be elucidated. The objectives were to report siblings with neutral lipid storage disease with myopathy (NLSDM) with a novel mutation of adipose triglyceride lipase (ATGL) and determine whether the C-terminal part of ATGL containing the hydrophobic region plays a role in the interaction with LDs. Skin fibroblasts and peripheral blood leukocytes were obtained from NLSDM patients. In vitro experiments were performed with fibroblasts and COS7 cells. Transfection studies were used to assess the effects of various recombinant ATGL proteins on lipase activities and lipid contents. Fluorescence microscopy were used for determination of intracellular distribution of ATGL proteins. The direct sequence of ATGL cDNA reveals that a patient is a homozygote for the 4-bp deletion, leading to a premature stop codon and causes the lack of the C terminus of the protein including the hydrophobic domain. Overexpressed control ATGL in NLSDM fibroblasts was found around the rims of LDs and caused significantly reduced cellular lipid accumulation. In contrast, NLSDM ATGL was homogeneously located in the cytoplasm despite the presence of LDs and had almost no effect on LD degradation despite its similar lipase activity. A series of C-terminal truncated ATGLs without the intact hydrophobic domain failed to localize around and degrade LDs. These findings indicate that the domain including the hydrophobic region of ATGL was essential for association with LDs.


Schizophrenia and violence: systematic review and meta-analysis.
Although expert opinion has asserted that there is an increased risk of violence in individuals with schizophrenia and other psychoses, there is substantial heterogeneity between studies reporting risk of violence, and uncertainty over the causes of this heterogeneity. We undertook a systematic review of studies that report on associations between violence and schizophrenia and other psychoses. In addition, we conducted a systematic review of investigations that reported on risk of homicide in individuals with schizophrenia and other psychoses. Bibliographic databases and reference lists were searched from 1970 to February 2009 for studies that reported on risks of interpersonal violence and/or violent criminality in individuals with schizophrenia and other psychoses compared with general population samples. These data were meta-analysed and odds ratios (ORs) were pooled using random-effects models. Ten demographic and clinical variables were extracted from each study to test for any observed heterogeneity in the risk estimates. We identified 20 individual studies reporting data from 18,423 individuals with schizophrenia and other psychoses. In men, ORs for the comparison of violence in those with schizophrenia and other psychoses with those without mental disorders varied from 1 to 7 with substantial heterogeneity (I(2) = 86%). In women, ORs ranged from 4 to 29 with substantial heterogeneity (I(2) = 85%). The effect of comorbid substance abuse was marked with the random-effects ORs of 2.1 (95% confidence interval [CI] 1.7-2.7) without comorbidity, and an OR of 8.9 (95% CI 5.4-14.7) with comorbidity (p<0.001 on metaregression). Risk estimates of violence in individuals with substance abuse (but without psychosis) were similar to those in individuals with psychosis with substance abuse comorbidity, and higher than all studies with psychosis irrespective of comorbidity. Choice of outcome measure, whether the sample was diagnosed with schizophrenia or with nonschizophrenic psychoses, study location, or study period were not significantly associated with risk estimates on subgroup or metaregression analysis. Further research is necessary to establish whether longitudinal designs were associated with lower risk estimates. The risk for homicide was increased in individuals with psychosis (with and without comorbid substance abuse) compared with general population controls (random-effects OR = 19.5, 95% CI 14.7-25.8). Schizophrenia and other psychoses are associated with violence and violent offending, particularly homicide. However, most of the excess risk appears to be mediated by substance abuse comorbidity. The risk in these patients with comorbidity is similar to that for substance abuse without psychosis. Public health strategies for violence reduction could consider focusing on the primary and secondary prevention of substance abuse. Please see later in the article for Editors' Summary.


Single-use technology for solvent/detergent virus inactivation of industrial plasma products.
Virus inactivation of plasma products is conducted using stainless-steel vessels. Single-use technology can offer significant benefits over stainless such as operational flexibility, reduced capital infrastructure costs, and increased efficiency by minimizing the time and validation requirements associated with hardware cleaning. This study qualifies a single-use bag system for solvent/detergent (S/D) virus inactivation. Human plasma and immunoglobulin test materials were S/D-treated in Mobius single-use bags using 1% tri-n-butyl phosphate (TnBP) with 1% Triton X-100 or 1% Tween 80 at 31°C for 4 to 6 hours to evaluate the impact on protein quality. Volatile and nonvolatile organic leachables from low-density polyethylene film (Pureflex film) used in 1-L-scale studies after exposure to S/D in phosphate-buffered saline were identified compared to controls in glass containers. Virus inactivation studies were performed with xenotropic murine leukemia virus (XMuLV) and bovine viral diarrhea virus (BVDV) to determine the kinetics of virus inactivation, measured using infectivity assays. S/D treatment in Mobius bags did not impact the protein content and profile of plasma and immunoglobulin, including proteolytic enzymes and thrombin generation. Cumulative leachable levels after exposure to S/D were 1.5 and 1.85 ppm when using 0.3% TnBP combined with 1% Tween 80 or 1% Triton X-100, respectively. Efficient inactivation of both XMuLV and BVDV was observed, with differences in the rate of inactivation dependent on both virus and S/D mixture. Effective S/D virus inactivation in single-use container technology is achievable. It does not alter plasma proteins and induces minimal release of leachables.


Assessment of brain mechanisms involved in the processes of thermal sensation, pleasantness/unpleasantness, and evaluation.
The conscious perception of thermal stimuli is divided into two categories: thermal sensation (i.e., discriminative component) and pleasantness/unpleasantness (i.e., hedonic component). There have been very few studies which clearly dissociated the two components. The aim of the present study was 1) to identify brain regions involved in perception of thermal stimuli per se, dissociating those related to the two components, and additionally 2) to examine brain regions of the explicit evaluation processes for the two components. Sixteen participants received local thermal stimuli of either 41.5 °C or 18.0 °C during whole-body thermal stimuli of 47.0 °C, 32.0 °C, or 17.0 °C. The local stimuli were delivered to the right forearm with the Peltier device. The whole-body stimuli delivered through a water-perfusion suit was aimed to modulate thermal pleasantness/unpleasantness to the local stimulus. The local stimulation at the same temperature was conducted five times with 30-s intervals. Brain activation was assessed by functional magnetic resonance imaging (fMRI), and the participants were asked to report their ratings of thermal sensation and pleasantness/unpleasantness following the cessation of each local stimulus. Local thermal stimulation activated specific brain regions such as the anterior cingulate cortex, insula, and inferior parietal lobe, irrespective of the temperature of local and whole-body stimuli; however, no specific activation for hot or cold sensation was observed. Different brain regions were associated with pleasantness and unpleasantness; the caudate nucleus and frontal regions for pleasantness, and the medial frontal and anterior cingulate cortex for unpleasantness. In addition, the explicit evaluation process for the discriminative and hedonic components immediately following the cessation of local stimulus involved different brain regions; the medial prefrontal cortex extending to the anterior cingulate cortex, insula, middle frontal cortex, and parietal lobes during the explicit evaluation of thermal sensation, and the medial prefrontal cortex, posterior cingulate cortex, and inferior parietal lobes during that of pleasantness/unpleasantness.


Physical activity for preschool children--how much and how?
Alarming trends in childhood obesity even among preschool children have re-focused attention on the importance of physical activity in this age group. With this increased attention comes the need to identify the amount and type of physical activity appropriate for optimal development of preschool children. The purpose of this paper is to provide the scientific evidence to support a link between physical activity and biological and psychosocial development during early childhood (ages 2-5 years). To do so, we summarize pertinent literature informing the nature of the physical activity required to promote healthy physical, cognitive, emotional, and social development during these early years. A particular focus is on the interaction between physical activity and motor skill acquisition. Special emphasis is also placed on the nature of physical activity that promotes healthy weight gain during this period of childhood. The paper also discusses the strongest determinants of physical activity in preschool-age children, including the role of the child's environment (e.g., family, child-care, and socio-economic status). We provide recommendations for physical activity based on the best available evidence, and identify future research needs.


Early Maya writing at San Bartolo, Guatemala.
The ruins of San Bartolo, Guatemala, contain a sample of Maya hieroglyphic writing dating to the Late Preclassic period (400 B.C. to 200 A.D.). The writing appears on preserved painted walls and plaster fragments buried within the pyramidal structure known as "Las Pinturas," which was constructed in discrete phases over several centuries. Samples of carbonized wood that are closely associated with the writing have calibrated radiocarbon dates of 200 to 300 B.C. This early Maya writing implies that a developed Maya writing system was in use centuries earlier than previously thought, approximating a time when we see the earliest scripts elsewhere in Mesoamerica.


pn-Heterojunction effects of perylene tetracarboxylic diimide derivatives on pentacene field-effect transistor.
We investigated the heterojunction effects of perylene tetracarboxylic diimide (PTCDI) derivatives on the pentacene-based field-effect transistors (FETs). Three PTCDI derivatives with different substituents were deposited onto pentacene layers and served as charge transfer dopants. The deposited PTCDI layer, which had a nominal thickness of a few layers, formed discontinuous patches on the pentacene layers and dramatically enhanced the hole mobility in the pentacene FET. Among the three PTCDI molecules tested, the octyl-substituted PTCDI, PTCDI-C8, provided the most efficient hole-doping characteristics (p-type) relative to the fluorophenyl-substituted PTCDIs, 4-FPEPTC and 2,4-FPEPTC. The organic heterojunction and doping characteristics were systematically investigated using atomic force microscopy, 2D grazing incidence X-ray diffraction studies, and ultraviolet photoelectron spectroscopy. PTCDI-C8, bearing octyl substituents, grew laterally on the pentacene layer (2D growth), whereas 2,4-FPEPTC, with fluorophenyl substituents, underwent 3D growth. The different growth modes resulted in different contact areas and relative orientations between the pentacene and PTCDI molecules, which significantly affected the doping efficiency of the deposited adlayer. The differences between the growth modes and the thin-film microstructures in the different PTCDI patches were attributed to a mismatch between the surface energies of the patches and the underlying pentacene layer. The film-morphology-dependent doping effects observed here offer practical guidelines for achieving more effective charge transfer doping in thin-film transistors.


The recovery experience of people who were sex trafficked: the thwarted journey towards goal pursuit.
In 2010, a shelter programme was established in the Netherlands to provide social and health services for trafficked people. This article describes how service users in this programme conceptualized and experienced their own process of recovery. In 2012, 14 people of non-Dutch nationality who had been trafficked for the purpose of sexual exploitation were interviewed at all three shelters of the programme. Data analysis followed a grounded theory approach. Participants felt a strong need to turn over a new leaf in life, leaving negative experiences of the past behind and moving towards a life with a job, a family and friends. In contrast with their willingness to work towards realizing that future, they experienced a lack of autonomy and a thwarted sense of agency in redressing their present situation. Together with the ostracized nature of their place in Dutch society this left them 'in limbo': a feeling of standing still, while wanting to move forward. This led participants to find it more difficult to deal with problems related to their pasts and futures. They particularly appreciated Dutch language training, vocational skills training and opportunities for volunteer work. Participants exhibited a strong desire to fulfil the basic psychological needs of competence, relatedness and autonomy, but were thwarted in pursuing these goals. Seemingly against all odds, while faced with several external regulators that limited their agency to change their situation, participants found ways to pursue these goals, through their enthusiasm for activities that helped them get closer to their envisioned futures (language and skills training and volunteer work). Identifying pathways toward attaining their goals allowed them to hope for a better future. That hope and pursuing their goals helped them to cope with the problems of their past and their worries about the future. Therefore, to facilitate service users' recovery in a post-trafficking setting, there is a need to provide them with opportunities to hope for, pursue and attain their personal goals within the structural boundaries of their situation. A future-orientated, strengths-based approach towards service provision and responsive and supportive environments help to do this.


Effect of cyclosporin on generalized Shwartzman reaction in diabetic rats.
The effect of cyclosporin (CsA) on the endotoxin-induced generalized Shwartzman reaction (GSR) was studied in diabetic and nondiabetic rats. After 4.5 wk of diabetes, CsA (20 mg/kg) or intralipid as a control substance was given intraperitoneally daily for 10 days. Next, diabetic rats were given either high-dose (2 mg/kg or low-dose (0.1 mg/kg) endotoxin (Escherichia coli 026:B6 lipopolysaccharide B) as a single injection. The rats were killed at intervals of 1, 4, 8, and 24 h. No significant glomerular thrombi were seen in the nondiabetic control animals, whereas the severity of glomerular thrombi in the diabetic animals was dependent on the presence or absence of CsA, endotoxin dose, and degree of glycemic control. In the diabetic rats, glomerular thrombi occurred maximally at 4 h but were no longer present at 24 h. The CsA/high-dose-endotoxin rats had fewer glomerular thrombi than rats receiving the intralipid/high-dose endotoxin, but this difference was not statistically significant. The CsA/low-dose-endotoxin rats had increased glomerular thrombi compared with the intralipid/low-dose-endotoxin rats (P less than 0.01). Insulin treatment reduced the glomerular capillary thrombi in the CsA/low-dose-endotoxin diabetic animals. Thus, CsA aggravates the GSR with low-dose endotoxin but has no significant effect when high-dose endotoxin is given. Improved glycemic control reduces the GSR in CsA-treated rats. Thus, the interrelationships of diabetes, endotoxin, and CsA on the GSR are complex, and the pathogenesis of these events is unclear.


Next generation diversity-oriented synthesis: a paradigm shift from chemical diversity to biological diversity.
Diversity-oriented synthesis has historically focused on the generation of small-molecule collections with considerable scaffold, stereochemical, and appendage diversity. Recently, this focus has begun to shift to the production of small-molecule libraries with diverse biological activities. It is currently not clear which properties and structural features of molecules are predictive of diverse performance in biological assays, and a better understanding of this relationship is critical for the development of performance-diverse small-molecule libraries for the discovery of novel probes for challenging targets. This review explores recent synthetic strategies for the production of bioactive small molecules and concludes with a presentation of current methods that enable the assessment of the biological performance diversity of small-molecule libraries.


Asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum (AVID): an imaging triad.
A series of 20 cases from 2 academic institutions is presented with a characteristic imaging triad of asymmetric ventriculomegaly, a large interhemispheric cyst, and partial or complete agenesis of the corpus callosum. Most cases were initially referred as aqueduct stenosis and hydrocephalus or focal porencephaly. We describe the imaging findings that identify an abnormal or absent corpus callosum associated with a type 1 interhemispheric cyst in fetuses initially thought to have hydrocephalus attributable to aqueductal stenosis. We suggest that the acronym AVID (asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum) may be useful in recognition of these cases. All cases presented with markedly asymmetric ventriculomegaly on initial sonography, with progressive hydrocephalus throughout gestation. Fetal magnetic resonance imaging was performed in 15 of 20 cases. Thirteen of 20 cases were identified in male fetuses. Associated fetal and postnatal abnormalities are also reported. Technological improvements in sonography and fetal magnetic resonance imaging allow improved characterization of associated intracranial anomalies in the setting of hydrocephalus. Accurate diagnosis can aid parental counseling, especially because isolated aqueductal stenosis suggests a better prognosis than hydrocephalus with anomalies. Markedly asymmetric ventriculomegaly in this series was the key to excluding isolated aqueductal stenosis and was associated with callosal malformation with a type 1a interhemispheric cyst.


A systematic review of the incidence and prevalence of cancer in multiple sclerosis.
Studies of cancer incidence and prevalence in multiple sclerosis (MS) have produced conflicting results. To estimate the incidence and prevalence of cancer in persons with MS and review the quality of included studies. We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I (2) statistic, and conducted meta-analyses for population-based studies. We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected. The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed.