TRP Channels and Migraine: Recent Developments and New Therapeutic Opportunities.
Migraine is the second-most disabling disease worldwide, and the second most common neurological disorder. Attacks can last many hours or days, and consist of multiple symptoms including headache, nausea, vomiting, hypersensitivity to stimuli such as light and sound, and in some cases, an aura is present. Mechanisms contributing to migraine are still poorly understood. However, transient receptor potential (TRP) channels have been repeatedly linked to the disorder, including TRPV1, TRPV4, TRPM8, and TRPA1, based on their activation by pathological stimuli related to attacks, or their modulation by drugs/natural products known to be efficacious for migraine. This review will provide a brief overview of migraine, including current therapeutics and the link to calcitonin gene-related peptide (CGRP), a neuropeptide strongly implicated in migraine pathophysiology. Discussion will then focus on recent developments in preclinical and clinical studies that implicate TRP channels in migraine pathophysiology or in the efficacy of therapeutics. Given the use of onabotulinum toxin A (BoNTA) to treat chronic migraine, and its poorly understood mechanism, this review will also cover possible contributions of TRP channels to BoNTA efficacy. Discussion will conclude with remaining questions that require future work to more fully evaluate TRP channels as novel therapeutic targets for migraine.


Human transcription elongation factor CA150 localizes to splicing factor-rich nuclear speckles and assembles transcription and splicing components into complexes through its amino and carboxyl regions.
The human transcription elongation factor CA150 contains three N-terminal WW domains and six consecutive FF domains. WW and FF domains, versatile modules that mediate protein-protein interactions, are found in nuclear proteins involved in transcription and splicing. CA150 interacts with the splicing factor SF1 and with the phosphorylated C-terminal repeat domain (CTD) of RNA polymerase II (RNAPII) through its WW and FF domains, respectively. WW and FF domains may, therefore, serve to link transcription and splicing components and play a role in coupling transcription and splicing in vivo. In the study presented here, we investigated the subcellular localization and association of CA150 with factors involved in pre-mRNA transcriptional elongation and splicing. Endogenous CA150 colocalized with nuclear speckles, and this was not affected either by inhibition of cellular transcription or by RNAPII CTD phosphorylation. FF domains are essential for the colocalization to speckles, while WW domains are not required for colocalization. We also performed biochemical assays to understand the role of WW and FF domains in mediating the assembly of transcription and splicing components into higher-order complexes. Transcription and splicing components bound to a region in the amino-terminal part of CA150 that contains the three WW domains; however, we identified a region of the C-terminal FF domains that was also critical. Our results suggest that sequences located at both the amino and carboxyl regions of CA150 are required to assemble transcription/splicing complexes, which may be involved in the coupling of those processes.


Interactions between physicians and the pharmaceutical industry: what does the literature say?
To determine the effect of three types of interaction between physicians and the pharmaceutical industry--company-funded clinical trials, company-sponsored continuing medical education (CME) and information for physicians supplied by pharmaceutical detailers--on orientation and quality of clinical trials, content of CME courses and physicians' prescribing behaviour. MEDLINE and HEALTH searches for English-language articles published from 1978 to 1993, supplemented by material from the author's personal collection. A total of 227 papers from the MEDLINE and HEALTH searches and about 2000 items from the author's library were initially reviewed. The following selection criteria were used: studies conducted in Australia, Canada, New Zealand, Britain and the United States; studies conducted after 1977; quantitative surveys containing details of the survey methods; studies on the orientation and quality of company-funded clinical trials and on the content of CME courses giving explicit criteria used in the evaluation; and reports on the outcome of interactions stating how the outcomes were assessed. Thirty-six studies met these criteria. Information was extracted on five topics: physicians' attitudes toward drug industry interactions, frequency with which physicians participate in the interactions, orientation and quality of company-funded clinical trials, content of company-sponsored CME courses and changes in physicians' prescribing behaviour as a result of an interaction. Although most physicians participate only occasionally in company-sponsored clinical trials, most see detailers and attend company-sponsored CME courses. However, physicians do not have a very high opinion of the information from detailers or of company-sponsored CME events. Many doctors regard pharmaceutical companies as an important source of funding for clinical trials, but they also have concerns about accepting money from this source. Company funding of clinical trials may affect the quality of the trials and the types of research that physicians undertake. Company-sponsored CME courses may have a commercial bias even if conducted under guidelines designed to ensure the independence of the event. All three types of interactions affect physicians' prescribing behaviour and, in the case of obtaining information from detailers, physicians' prescribing practices are less appropriate as a result of the interaction. Physicians are affected by their interactions with the pharmaceutical industry. Further research needs to be done in most cases to determine whether such interactions lead to more or less appropriate prescribing practices. The CMA's guidelines on this topic should be evaluated to see whether they are effective in controlling physician-industry interactions. Further measures may be necessary if the guidelines fail to prevent negative effects on prescribing practices.


People with higher interoceptive sensitivity are more altruistic, but improving interoception does not increase altruism.
People consistently show preferences and behaviors that benefit others at a cost to themselves, a phenomenon termed altruism. We investigated if perception of one's body signals - interoception - may be underlying such behaviors. We tested if participants' sensitivity to their own heartbeat predicted their decision on a choice between self-interest and altruism, and if improving this sensitivity through training would make participants more altruistic. Across these two experiments, interoceptive sensitivity predicted altruism measured through monetary generosity. Improving interoceptive sensitivity did, however, not lead to more altruistic behaviour. We conclude that there is a unique link between interoception and altruistic behaviour, likely established over an individual's history of altruistic acts, and the body responses they elicit. The findings suggest that humans might literally 'listen to their heart' to guide their altruistic behavior.


Enhanced understanding of the host-pathogen interaction in sepsis: new opportunities for omic approaches.
Progress in sepsis research has been severely hampered by a heterogeneous disease phenotype, limiting the interpretation of clinical trials and the development of effective therapeutic interventions. Application of omics-based methodologies is advancing understanding of the dysregulated host immune response to infection in sepsis. However, the frequently elusive nature of the infecting organism in sepsis has limited efforts to understand the effect of disease heterogeneity involving the pathogen. Recent advances in nucleic acid sequencing-based pathogen analysis provide the opportunity for more accurate and comprehensive microbiological diagnosis. In this Review, we explore how better understanding of the host-pathogen interaction can substantially enhance, and in turn benefit from, current and future application of omics-based approaches to understand the host response in sepsis. We illustrate this using recent work accounting for heterogeneity involving the pathogen. We propose that there is a timely opportunity to further resolve sepsis heterogeneity by considering host-pathogen interactions, enabling progress towards a precision medicine approach.


Regional changes in the sequence of cotton leaf curl multan betasatellite.
Cotton leaf curl disease (CLCuD) in Pakistan and northwestern India is caused by monopartite begomoviruses in association with an essential, disease-specific satellite, Cotton leaf curl Multan betasatellite (CLCuMB). Following a recent upsurge in CLCuD problems in Sindh province (southern Pakistan), sequences of clones of CLCuMB were obtained from Sindh and Punjab province (central Pakistan), where CLCuD has been a problem since the mid-1980s. The sequences were compared to all sequences of CLCuMB available in the databases. Analysis of the sequences shows extensive sequence variation in CLCuMB, most likely resulting from recombination. The range of sequence variants differ between Sindh, the Punjab and northwestern India. The possible significance of the findings with respect to movement of the CLCuD between the three regions is discussed. Additionally, the lack of sequence variation within the only coding sequence of CLCuMB suggests that the betasatellite is not involved in resistance breaking which became a problem after 2001 in the Punjab and subsequently also in northwestern India.


Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol-Prins Strategy.
A direct and general method for the synthesis of naturally occurring 2,3,4,5,6-pentasubstituted tetrahydropyrans has been developed, employing β,γ-unsaturated N-acyl oxazolidin-2-ones as key starting materials. The combination of the Evans aldol addition and the Prins cyclization allowed the diastereoselective and efficient generation of the desired oxacycles in two fashions: a one-pot Evans aldol-Prins protocol, in which five new σ bonds and five contiguous stereocenters were straightforwardly generated, and a two-step version, which additionally permitted the isolation of β,γ-unsaturated alcohol precursors bearing an N-acyl oxazolidin-2-one in the α position. From these alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as 2,3,4,5-tetrasubstituted tetrahydrofurans, shedding light on the mechanism of the process. Computational studies were consistent with the experimental findings, and this innovative Evans aldol-Prins strategy was performed for the preparation of a battery of more than 30 densely substituted tetrahydropyrans, unprecedentedly fused to a 1,3-oxazinane-2,4-dione ring, both in a racemic fashion and in an enantiomeric fashion. These novel molecules were successfully submitted to several transformations to permit simple access to a variety of differently functionalized tetrahydropyrans. Most of these unique molecules were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria and the yeast Candida albicans, and some structure-activity relationships were established.


Adrenal androgen production in response to adrenocorticotropin infusions in men.
The responses of several adrenal steroids to adrenocorticotropin (ACTH) were investigated in a group of healthy young men. The protocol consisted of overnight adrenal suppression with dexamethasone followed by 1 hr infusions of ACTH in increasing (4X) doses ranging from 30-30,720 ng/1.5M2 followed by 0.25 mg ACTH/1.5M2. Whereas cortisol, androstenedione and androstenediol concentrations tended to plateau at the higher ACTH infusion rates, those of dehydroepiandrosterone (DHEA) and 17-hydroxyprogesterone (17-OH P) did not. The cortisol concentration achieved after the highest dose of ACTH was over 50 fold higher than that at baseline. DHEA levels rose to values about 13 times baseline whereas the other steroids increased to lesser extents (3-5 fold). The ACTH infusion rate required to significantly increase each steroid over the baseline level was extrapolated from dose response curves and was considered to be an index of the sensitivity of each steroid to ACTH. Cortisol was the most sensitive, rising significantly at approximately 35 ng ACTH/1.5M2, followed by androstenediol, DHEA, androstenedione and 17-OH P.


Intraoperative Vein Graft Preservation: What Is the Solution?
Saphenous vein graft (SVG) disease and subsequent vein graft failure remain a major problem after coronary artery bypass graft operations. In an effort to mitigate loss of endothelial viability, the vein is stored, intraoperatively, in a preservation solution. However, human SVG samples demonstrate endothelial denudation and dysfunction after such storage, the severity of which varies, depending on the medium. The paucity of clinical data evaluating preservation solutions is illustrated by the absence of optimal procedural protocol. This review evaluates the potential efficacy of different storage solutions in preserving vein grafts, in relation to a mechanistic understanding of SVG pathophysiology.


Microbispora clausenae sp. nov., an endophytic actinobacterium isolated from the surface-sterilized stem of a Thai medicinal plant, Clausena excavala Burm. f.
An endophytic actinobacterium, strain CLES2T, was discovered from the surface-sterilized stem of a Thai medicinal plant, Clausena excavala Burm. f., collected from the Phujong-Nayoa National Park, Ubon Ratchathani Province, Thailand. The results of a polyphasic taxonomic study identified this strain as a member of the genus Microbispora and a Gram-stain-positive, aerobic actinobacterium. It had well-developed substrate mycelia, which were non-motile and possessed paired spores. A phylogenetic evaluation based on 16S rRNA gene sequence analysis placed this strain in the family Streptosporangiaceae, being most closely related to Microbispora bryophytorum NEAU-TX2-2T (99.4 %), Microbispora camponoti 2C-HV3T (99.2 %), Microbispora catharanthi CR1-09T (99.2 %) and Microbispora amethystogenes JCM 3021T and Microbispora fusca NEAU-HEGS1-5T (both at 99.1 %). The major cellular fatty acid of this strain was iso-C16 : 0 and major menaquinone was MK-9(H4). The polar lipid profile of strain CLES2T contained diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylinositol and phosphatidylinositol dimannosides. These chemotaxonomic data confirmed the affiliation of strain CLES2T to the genus Microbispora. The DNA G+C content of this strain was 70 mol%. Digital DNA-DNA hybridization and average nucleotide identity blast values between strain CLES2T and M. catharanthi CR1-09T were 62.4 and 94.0 %, respectively. The results of the polyphasic study allowed the genotypic and phenotypic differentiation of strain CLES2T from its closest species with valid names. The name proposed for the new species is Microbispora clausenae sp. nov. The type strain is CLES2T (=DSM 101759T=NRRL B-65340T).


Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis.
The nucleotide salvage pathway is used to recycle degraded nucleotides (purines and pyrimidines); one of the enzymes that helps to recycle purines is hypoxanthine guanine phosphoribosyl transferase 1 (HGPRT1). Therefore, defects in this enzyme lead to the accumulation of DNA and nucleotide lesions and hence replication errors and genetic disorders. Missense mutations in hypoxanthine phosphoribosyl transferase 1 (HPRT1) are associated with deficiencies such as Lesch-Nyhan disease and chronic gout, which have manifestations such as arthritis, neurodegeneration, and cognitive disorders. In the present study, we collected 88 non-synonymous single nucleotide polymorphisms (nsSNPs) from the UniProt, dbSNP, ExAC, and ClinVar databases. We used a series of sequence-based and structure-based in silico tools to prioritize and characterize the most pathogenic and stabilizing or destabilizing nsSNPs. Moreover, to obtain the structural impact of the pathogenic mutations, we mapped the mutations to the crystal structure of the HPRT protein. We further subjected these mutant proteins to a 50 ns molecular dynamics simulation (MDS). The MDS trajectory showed that all mutant proteins altered the structural conformation and dynamic behavior of the HPRT protein and corroborated its association with LND and gout. This study provides essential information regarding the use of HPRT protein mutants as potential targets for therapeutic development.


Postoperative hemodynamics in children with polytetrafluoroethylene shunts.
Twenty-two consecutive infants and children underwent aortopulmonary shunt operations with polytetrafluoroethylene grafts. Thirteen infants younger than 6 months of age (group I) received 14 grafts (4--5 mm in diameter, 0.5--2.5 cm long). Two shunts became obstructed, including kinking in the single 2.5-cm graft. Eight of the nine long-term survivors had pulmonary artery pressures measured a mean of 14 months postoperatively. In all infants, pulmonary resistance was normal and mean pulmonary artery pressure was less than or equal to 20 mm Hg, except in the infant with a 5-mm graft. In nine children 7 months to 15 years of age (group 2), the rate of graft occlusion was higher (five of nine). There was no evidence of pulmonary artery distortion secondary to shunt placement in either group. On late follow-up, blood hemoglobins were less than 20 g% as late as 30 months of age; acceptable palliation may be expected until at least 2 years of age and 12 kg in weight are reached. We conclude that short, 4-mm-diameter polytetrafluoroethylene grafts provide good palliation in infants with cyanotic congenital heart disease, with minimal risks from pulmonary hypertension or pulmonary artery distortion. Such grafts are less successful in older children, and should only be considered when other forms of surgical relief are not feasible.


Neurofilament light and tau as blood biomarkers for sports-related concussion.
To compare neurofilament light (NfL) and tau as blood-based biomarkers for acute sports-related concussion (SRC) and determine whether their concentrations at different time points after the injury are associated with prolonged time to return to play (RTP). A total of 288 professional hockey players were followed longitudinally from September 1, 2012, to April 30, 2015. Data collection and biomarker analyses were conducted between 2015 and 2017. Associations were tested between blood concentrations of NfL and tau, and RTP time. Serum concentrations of S100B and neuron-specific enolase (NSE) were also measured for comparison. Of 288 players, 105 sustained an SRC. Of these, 87 underwent blood sampling 1, 12, 36, and 144 hours after SRC and at the RTP time point. Serum NfL concentrations 1, 12, 36, and 144 hours after SRC were related to prolonged RTP time, and could separate players with RTP >10 days from those with RTP ≤10 days (area under the receiver operating characteristic curve [AUROC] 0.82). Also, serum NfL 144 hours after SRC discriminated players who resigned from the game due to persistent postconcussion symptoms (PCS) from those who returned to play (AUROC 0.89). Plasma tau 1 hour after SRC was related to RTP but less strongly than NfL, while S100B and NSE showed no such associations. Serum NfL outperformed tau, S100B, and NSE as a biomarker for SRC. From a clinical standpoint, serum NfL may be useful to identify individuals at risk of prolonged PCS, and may aid in biomarker-informed decisions with regard to when RTP should be considered.


Induction of myocardial hypertrophy after coronary ligation in rats decreases ventricular dilatation and improves systolic function.
Previous studies have shown that hypertrophy of surviving myocytes after myocardial infarction (MI) is limited. Progressive ventricular dilatation after MI may occur when compensatory hypertrophy cannot restore left ventricular (LV) wall stress to normal. To test whether induction of additional myocyte hypertrophy might prevent pathological LV remodeling after large MI, we administered 2-tetradecylglycidic acid (TDGA) 20 mg/kg/day to sham-operated (n = 12) and MI (n = 10) rats for 10 days, beginning the third day after infarction. We have previously shown that chronic inhibition of long-chain fatty acid oxidation with TDGA in rats results in myocardial hypertrophy without any apparent impairment of LV systolic function. When compared with untreated MI rats (n = 9), we found that TDGA-treated MI rats had increases in LV weight/body wt, myocyte cross-sectional area, and peak developed LV pressure during abrupt aortic occlusion. MI rats treated with TDGA had lower LV end-diastolic pressures and smaller end-diastolic volumes, whereas stroke volume was maintained. The ex vivo passive LV pressure-volume relation was shifted toward the pressure axis compared with untreated infarct rats. In sham-operated rats, TDGA caused increases in LV weight/body wt, myocyte size, peak developed LV pressure, cardiac index, and stroke volume index, and a shift of the passive LV pressure-volume relation toward the pressure axis. Induction of myocardial hypertrophy with an inhibitor of long-chain fatty acid oxidation retarded the process of LV dilatation and produced beneficial effects on systolic function after large myocardial infarction. These data support the hypothesis that inadequate hypertrophy of residual myocardium after infarction may contribute to LV dilatation and the development of congestive heart failure.


Pulsed Radiofrequency Ablation of Pudendal Nerve for Treatment of a Case of Refractory Pelvic Pain.
Pudendal neuralgia (PN) is a result of pudendal nerve entrapment or injury, also called "Alcock syndrome." Pain that develops is often chronic, and at times debilitating. If conservative measures fail, invasive treatment modalities can be considered. The goal of this case report is to add to a small body of literature that a pulsed radiofrequency (PRF) ablation can be effectively used to treat PN and to show that high resolution MR neurography imaging can be used to detect pudendal neuropathy. We present a case of a 51-year-old woman with 5 years of worsening right groin and vulva pain. Various medication trials only lead to limited improvement in pain. The first diagnostic right pudendal nerve block was done using 3 mL of 0.25% bupivacaine with 6mg of betamethasone using a transgluteal technique and a target of the right ischial spine; this procedure resulted in ~8 hours of > 50% pain relief. The patient was then referred for MR neurography of the lumbosacral plexus. This study revealed increased signal of the right pudendal nerve at the ischial spine and in the pudendal canal, findings consistent with the clinical picture of PN. Six weeks after the initial block, the patient underwent a second right transgluteal pudendal nerve block, utilizing 3 mL of 0.25% bupivacaine with 40 mg of triamcinolone acetonide; this procedure resulted in ~8 hours of 100% pain relief. Satisfied with these results the patient decided to undergo pudendal nerve PRF ablation for possible long-term relief. For this therapeutic procedure, a right transgluteal approach was again utilized. PRF ablation was performed for 240 seconds at 42° Celsius. Following this ablation the patient reported at least 6 weeks of significant (> 50%) pain relief. In this paper we presented a case of successful treatment of PN with PRF ablation and detection of pudendal neuropathy on MR neurography. We believe that transgluteal PRF ablation for PN might be an effective, minimally invasive option for those patients that have failed conservative management. MR neurography employed in this case is not only helpful in confirming the diagnosis of PN but could also be useful in ruling out other causes of pelvic pain, such as genitofemoral neuropathy, endometriosis, adenomyosis, or pelvic mass lesion. To conclude, transgluteal PRF ablation can serve as a viable treatment option for mitigating symptoms of pudendal neuropathy and MR neurography is useful in confirming a clinically suspected diagnosis of PN.Key words: Pelvic pain, pudendal neuralgia, MR neurography, pulsed radiofrequency ablation, transgluteal technique, Alcock canal syndrome.


Relationship between neuroleptic extrapyramidal syndromes and patients' all-cause mortality.
It is important to understand factors contributing to a neuroleptic-related increased mortality risk. The objective of this study was to test whether the occurrence of neuroleptic-induced extrapyramidal syndromes (EPS) including tardive dyskinesia (TD) is associated with an increased patients' all-cause mortality. In 1995, a sample of 200 patients on neuroleptics was assessed with regard to the presence of Parkinson syndrome, akathisia, and TD. By 2003-2004, i.e., during the following 8-9 year period, 63 patients had died. Patients who had died were compared with 120 patients known to be still alive with regard to several socio-demographic variables and the presence of EPS at the first examination. At the basic assessment, there were no significant differences between patients later still alive and deceased patients with regard to TD. The deceased patients were more frequently women, older, suffered more frequently from an organic disorder, had higher average scores for Parkinson syndrome and less frequently akathisia. Multivariate analysis confirmed age as the only factor contributing to the group difference. Repeating the meta-analysis by Ballesteros et al. (2000) after inclusion of our data, TD remains a weak but a significant predictor of death (OR=1.4). Neuroleptic-induced EPS of parkinsonism, akathisia, and TD did not contribute to the patients' all-cause mortality in this study. The association between TD and mortality merits further attention.


Anatomic Labral Repair in the Hip Using a Knotless Tensionable Suture Anchor.
To perform a proper labral repair, most surgeons use anchors to secure the labrum to the acetabular bone. We aim to describe a technique for labral repair with a knotless tensionable suture anchor. This technique uses a looped suture configuration, allowing selective tensioning of the repair to maintain the anatomic suction seal of the hip. The use of this technique is easily reproducible and reduces the surgical time compared with previous techniques.


Calculation of critical nucleation rates by the persistent embryo method: application to quasi hard sphere models.
We study the crystal nucleation of the Weeks-Chandler-Andersen (WCA) model, using the recently introduced persistent embryo method (PEM). The method provides detailed characterization of pre-critical, critical and post-critical nuclei, as well as nucleation rates that compare favorably with those obtained using other methods (umbrella sampling, forward flux sampling or seeding). We further map our results to a hard sphere model allowing comparison with other existing predictions. Implications for experiments are also discussed.


MAITs and their mates: "Innate-like" behaviors in conventional and unconventional T cells.
Most CD4 and CD8 T cells are restricted by conventional major histocompatibility complex (MHC) molecules and mount TCR-dependent adaptive immune responses. In contrast, MAIT, iNKT, and certain γδ TCR bearing cells are characterized by their abilities to recognize antigens presented by unconventional antigen-presenting molecules and to mount cytokine-mediated TCR-independent responses in an "innate-like" manner. In addition, several more diverse T-cell subsets have been described that in a similar manner are restricted by unconventional antigen-presenting molecules but mainly depend on their TCRs for activation. Vice versa, innate-like behaviour was reported in defined subpopulations of conventional T cells, particularly in barrier sites, showing that these two features are not necessarily linked. The abilities to recognize antigens presented by unconventional antigen-presenting molecules or to mount TCR-independent responses creates unique niches for these T cells and is linked to wide range of functional capabilities. This is especially exemplified by unconventional and innate-like T cells present at barrier sites where they are involved in pathogen defense, tissue homeostasis as well as in pathologic processes.


Modulation of Threat Response in Larval Zebrafish.
High-throughput, whole-organism phenotypic drug screening is made possible using live zebrafish larvae. Many human drugs have now been shown to affect zebrafish larvae in similar ways, through homologous molecular mechanisms. At this stage in life, zebrafish are small enough to fit in multi-well, microliter plates, yet developed enough to exhibit complex phenotypes, such as hunting behaviors and avoidance of predators. Importantly, zebrafish larvae can be easily dosed via automated pipetting of chemical compounds directly into their liquid medium, without injection. Only microgram amounts of small molecules are required, making animal husbandry and dosing regimens cost effective. This chapter describes how the stereotyped zebrafish larval responses to darkness and strobe light-which cause hyperactivity and freezing behavior, respectively-can be used to efficiently screen small molecules for brain and behavior-modulating activity.


Regeneration of injured axons in the adult mammalian central nervous system.
The axons of peripheral nerves have a high capacity for regeneration after injury, whereas injury to the axons in the adult central nervous system (CNS) of higher species does not generally result in regeneration. In recent years, significant developments in neuroscience research have resulted in an improved understanding of the processes involved in the axonal response to CNS trauma. Myelin-associated proteins in the CNS white matter play a crucial role as strong inhibitors of the growth of nerve fibers. Neutralization of these proteins by monoclonal antibody IN-1 directed against the inhibitory proteins led to pronounced axonal regeneration in the adult spinal cords of lesioned rats. The morphological findings were recently complemented by the demonstration of very significant functional improvements in rats with transection lesions of their spinal cords after treatment with the antibody IN-1 that neutralizes the myelin-associated nerve growth inhibitors. Moreover, several neurotrophic factors that promote axonal survival and sprouting in the peripheral nervous system and the CNS have been identified in recent years. The combined use of specific neurotrophic factors and the IN-1 antibody in different experimental procedures, including spinal cord injury, have significantly improved regenerative axonal growth. We briefly review these recent developments in CNS axonal regeneration research and discuss possible clinical applications.


Use of physical barriers for delayed adjustable strabismus surgery: the effect of interceed and polyglactin 910 mesh.
In the course of adjustable strabismus surgery there is only a limited period after surgery before the formation of firm adhesions prevents successful adjustment. To determine if this period could be increased by the interposition of suitable physical barriers, the use of Interceed and polyglactin 910 mesh was investigated in an animal model. A total of 39 rabbit eyes were divided into three groups. After recession of the superior rectus muscle (SRM), balanced salt solution was applied to the control group between the free muscle end and the sclera; in each of the two experimental groups, Interceed and polyglactin 910 mesh were applied. Delayed adjustment was performed once on each SRM at 1, 2, or 3 weeks postoperatively. The length and force of the adjustment, the degree of adhesions, and the degree of fibrous proliferation were recorded. Adjustment was not possible in any of the eyes in the control group. At 1 week postoperatively, adjustment was possible in four out of five eyes with Interceed and in three out of five eyes with polyglactin 910 mesh as a physical barrier. Interceed may be clinically useful in delaying the timing of adjustment up to 1 week. Further study of the use of other materials could be carried out to see if it was possible to delay the timing of adjustment for more than 1 week.


Appraising the extractable tidal energy resource of the UK's western coastal waters.
A two-dimensional west coast tidal model, built on the ADCIRC platform (an unstructured grid two-dimensional depth-integrated shallow water model), has been developed to examine the scope for reliable and fully predictable electricity generation from UK coastal waters using an ambitious combination of estuary barrages, tidal lagoons and tidal stream generator arrays. The main emphasis has been towards conjunctive operation of major estuary barrages, initially including the presence of pilot-scale tidal stream developments, though ambitious exploitation of extensive tidal streams has also been explored.


Obesity-susceptibility loci and their influence on adiposity-related traits in transition from adolescence to adulthood--the HUNT study.
Obesity-susceptibility loci have been related to adiposity traits in adults and may affect body fat estimates in adolescence. There are indications that different sets of obesity-susceptibility loci influence level of and change in obesity-related traits from adolescence to adulthood. To investigate whether previously reported obesity-susceptible loci in adults influence adiposity traits in adolescence and change in BMI and waist circumference (WC) from adolescence into young adulthood. We also examined whether physical activity modifies the effects of these genetic loci on adiposity-related traits. Nine obesity-susceptibility variants were genotyped in 1 643 adolescents (13-19 years old) from the HUNT study, Norway, who were followed-up into young adulthood. Lifestyle was assessed using questionnaires and anthropometric measurements were taken. The effects of genetic variants individually and combined in a genetic predisposition score (GPS) on obesity-related traits were studied cross-sectionally and longitudinally. A modifying effect of physical activity was tested. The GPS was significantly associated to BMI (B: 0.046 SD/allele [0.020, 0.073], p = 0.001) in adolescence and in young adulthood (B: 0.041 SD/allele [0.015, 0.067], p = 0.002) as it was to waist circumference (WC). The GPS was not associated to change in BMI (p = 0.762) or WC (p = 0.726). We found no significant interaction effect between the GPS and physical activity. Our observations suggest that obesity-susceptibility loci established in adults affect BMI and WC already in adolescence. However, an association with change in adiposity-related traits from adolescence to adulthood could not be verified for these loci. Neither could an attenuating effect of physical activity on the association between the obesity-susceptibility genes and body fat estimates be revealed.


Expression, induction, and catalytic activity of the ethanol-inducible cytochrome P450 (CYP2E1) in human fetal liver and hepatocytes.
The mechanisms responsible for ethanol-mediated teratogenesis have not been resolved. However, possible etiologies include the local formation of the teratogen acetaldehyde or oxygen radicals by fetal ethanol-oxidizing enzymes. As alcohol dehydrogenases are expressed at very low concentrations in human embryonic tissues, the ethanol-inducible P450 enzyme, CYP2E1, could be the sole catalyst of fetal ethanol oxidation. With this in mind, we examined the expression of this P450 in liver samples from fetuses ranging in gestational age from 16 to 24 weeks. Immunoblot analysis of fetal liver microsomes revealed the presence of a protein immunoreactive with CYP2E1 antibodies that exhibited a slightly lower molecular weight than that found in adult liver samples. Embryonic CYP2E1 expression was further confirmed by the reverse transcriptase reaction with RNA from a 19-week gestational fetal liver used as template. Catalytic capabilities of human fetal microsomes were assessed by measurement of the rate of ethanol oxidation to acetaldehyde, which were 12-27% of those exhibited by adult liver microsomes. Immunoinhibition studies with CYP2E1 antibodies revealed that the corresponding antigen was the major catalyst of this reaction in both fetal and adult tissues. We then assessed whether embryonic CYP2E1 was, like the adult enzyme, inducible by xenobiotics. Treatment of primary fetal hepatocyte cultures with either ethanol or clofibrate demonstrated a 2-fold increase in CYP2E1 levels compared with untreated cells. Collectively, our results indicate that CYP2E1 is present in human fetal liver, that the enzyme is functionally similar to CYP2E1 from adults, and that fetal hepatocyte CYP2E1 is inducible in culture by xenobiotics, including ethanol. Because fetal CYP2E1 mediates ethanol metabolism, the enzyme may play a pivotal role in the local production of acetaldehyde and free radicals, both of which have potential deleterious effects on the developing fetus.


Oxidative stress in the splenotoxicity of aniline.
Aniline-induced splenic toxicity is characterized by hemorrhage, capsular hyperplasia, fibrosis, and a variety of sarcomas in rats. Early biochemical events responsible for the observed effects are not known. To understand the mechanism(s) of aniline-induced splenic toxicity, single and multiple (four and seven) doses of 1 mmol/kg of aniline hydrochloride(AH) were given in rats. Apart from changes in the hematological parameters, these studies demonstrated that AH could induce lipid peroxidation and protein oxidation in the spleen, and significant increases were observed at four doses. Subsequently, a dose-response study of AH was performed. Male SD rats were given four doses each (one dose/day) of 0.25, 0.5, 1, and 2 mmol/kg of AH in water by gavage, while controls received water only. Animals were euthanized 24 hr following the last dose and tissues obtained. Spleen weight increased by 32 and 80% at 1 and 2 mmol/kg doses, respectively. Splenic lipid peroxidation showed dose-dependent increases of 24, 32, and 43% at 0.5, 1, and 2 mmol/kg, respectively. Protein oxidation in the spleen, quantitated by carbonyl content per milligram protein, showed 10, 28, and 27% increases at 0.5, 1, and 2 mmol/kg, respectively. Iron content in the spleen also showed dose-dependent increases of 72, 172, and 325% at 0.5, 1, and 2 mmol/kg, respectively. Dose-related histopathologic expansion of splenic red pulp was characterized by increasing vascular congestion (most pronounced at 2 mmol/kg), increased red pulp cellularity, erythrophagocytosis, and cellular fragmentation at 1 and 2 mmol/kg; iron deposition in red pulp also increased dramatically with dose. These studies establish that aniline induces lipid peroxidation and protein oxidation in the spleen and suggest that oxidative stress plays a role in the splenic toxicity of aniline.


FADS1 FADS2 gene cluster, PUFA intake and blood lipids in children: results from the GINIplus and LISAplus studies.
Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids. The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype. Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [β between -0.04 (p = 0.0074) to -0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype. Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life.


Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent to exposure.
Carcinogenic and other toxic effects in rats and mice were examined during a 12-mo period following exposure to vinyl chloride (VC) or vinylidene chloride (VDC). Exposure of male and female mice to 50, 250, or 1000 ppm VC for 6 h/d, 5 d/wk, for 1, 3, or 6 mo resulted in increased numbers of deaths and increased moribundity at all dose levels during the exposure and postexposure periods, as compared with air-exposed controls. Similar observations were made with rats after 1, 3, 6, or 10 mo exposure to VC. Cumulative tumor incidence at various organ sites also increased in both species during the postexposure period in proportion to dose or duration of exposure at higher dose levels. However, except for mammary gland tumors in female mice, no significant increase in cumulative tumor incidence occurred in either species at 50 ppm VC or 55 ppm VDC, regardless of duration of exposure. These results suggest that exposure to vinyl halides at dose levels lower than those that elicit a significant increase in cancer incidence during the lifetime of the animal may, nonetheless, increase the risk of early death or moribundity from toxic pre- or subcarcinogenic effects. At dose levels higher than those consistent with the physiological defense or repair capabilities of the cell, ultimate tumor incidence becomes proportionate to length of exposure and may reflect the number of carcinogenic events elicited during the exposure period.


[Ulcerative colitis and pregnancy].
The evolution of ulcerative colitis in pregnancy is far from clear. While some authors state that the disease aggravates during this period, others do not share this opinion. To assess the evolution of ulcerative colitis in pregnancy. A paired case-control design was used in which 15 women, with diagnosed ulcerative colitis at the moment of becoming pregnant, were followed for 12 months and the activity of the disease was compared with that of the 12 months preceding the pregnancy. The activity of the disease in the period preceding the pregnancy was gathered retrospectively from the patient's charts. The mean age of the first ulcerative colitis crisis was 24 years. It was moderate in 49% and severe in 35% of women. During pregnancy 55% of women did not have a crisis, compared with 26.7% during the period preceding pregnancy (relative risk of not having a crisis during pregnancy of 1.7). During both periods, seven women had digestive complications, whereas extra digestive complications were not observed in 60% of patients during pregnancy and 11.8% of patients during the preceding period. Perinatal results were similar to those of the general population. In our group of patients the evolution of ulcerative colitis was better during pregnancy, reflected by a lower number of crisis.


Cloning and characterization of ntTMK1 gene encoding a TMK1-homologous receptor-like kinase in tobacco.
A cDNA encoding a receptor-like kinase, designated NtTMK1, was isolated from Nicotiana tabacum. The kinase domain of NtTMK1 contained all of 12 subdomains and invariant amino acid residues found in eukaryotic protein kinases. The extracellular domain contained 11 leucine-rich repeats which have been implicated in protein-protein interactions. The amino acid sequence of NtTMK1 exhibited high homology with those of TMK1 of Arabidopsis and TMK of rice in both kinase and extracellular domains, suggesting that NtTMK1 is a TMK homologue of tobacco. The NtTMK1 transcripts were present in all major plant organs, but its level varied in different developmental stages in anthers and floral organs. NtTMK1 mRNA accumulation in leaves was stimulated by CaCl2, methyl jasmonate, wounding, fungal elicitors, chitins, and chitosan. The NtTMK1 mRNA level also increased upon infection with tobacco mosaic virus.


Circuits Regulating Pleasure and Happiness in Bipolar Disorder.
According to our model, the motivation for appetitive-searching vs. distress-avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side to the centromedial amygdala on the other side, control the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). From an evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula-projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward-driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities.


Yangjing Capsule extract promotes proliferation of GC-1 spg cells via up-regulated POU3F1 pathway.
As is similar to glial cell line-derived neurotrophic factor (GDNF), the Yangjing Capsule (YC) extract could also lead to proliferation of spermatogonial stem cells (SSCs) by stimulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway; however, the regulatory effect of YC extract on the expression of POU3F1 still remains unknown. The objective of this study is to determine whether the transcription factor POU3F1 is up-regulated by YC extract through the PI3K/AKT signaling pathway to regulate SSCs survival and proliferation. Cultured GC-1 spermatogonial (spg) cells were treated with 0.01, 0.1, and 1 mg/mL YC extract for 48 h. Cell viability was analyzed using MTT assay, while POU3F1 expression was quantitatively detected using real time-polymerase chain reaction and Western blot analysis. POU3F1, GDNF family receptor alpha1 (GFRα1) short interfering ribonucleic acid (siRNA), and LY294002 (PI3K inhibitor) were applied as blockers to explore the underlying pathway. After 48 h treatment with YC extract, GC-1 spg cells proliferated and POU3F1 expression was significantly increased in a dose-dependent manner. POU3F1 siRNA partially blocked those effects of YC extract. Both GFRα1 siRNA and LY294002, as upstream blockers, reduced POU3F1 expression induced by YC extract. The conclusion is that YC extract promotes proliferation of GC-1 spg cells via up-regulation of POU3F1. The potential mechanism is that YC extract triggers the activation of the PI3K/AKT pathway and then up-regulates POU3F1 expression.


Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region.
Recurrent rearrangements of Chromosome 8p23.1 are associated with congenital heart defects and developmental delay. The complexity of this region has led to inconsistencies in the current reference assembly, confounding studies of genetic variation. Using comparative sequence-based approaches, we generated a high-quality 6.3-Mbp alternate reference assembly of an inverted Chromosome 8p23.1 haplotype. Comparison with nonhuman primates reveals a 746-kbp duplicative transposition and two separate inversion events that arose in the last million years of human evolution. The breakpoints associated with these rearrangements map to an ape-specific interchromosomal core duplicon that clusters at sites of evolutionary inversion (P = 7.8 × 10-5). Refinement of microdeletion breakpoints identifies a subgroup of patients that map to the same interchromosomal core involved in the evolutionary formation of the duplication blocks. Our results define a higher-order genomic instability element that has shaped the structure of specific chromosomes during primate evolution contributing to rearrangements associated with inversion and disease.


Socioeconomic status and treatment outcomes for individuals with HIV on antiretroviral treatment in the UK: cross-sectional and longitudinal analyses.
Few studies have assessed the effect of socioeconomic status on HIV treatment outcomes in settings with universal access to health care. Here we aimed to investigate the association of socioeconomic factors with antiretroviral therapy (ART) non-adherence, virological non-suppression, and virological rebound, in HIV-positive people on ART in the UK. We used data from the Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. Participants self-completed a confidential questionnaire on sociodemographic, health, and lifestyle issues. In participants on ART, we assessed associations of financial hardship, employment, housing, and education with: self-reported ART non-adherence at the time of the questionnaire; virological non-suppression (viral load >50 copies per mL) at the time of questionnaire in those who started ART at least 6 months ago (cross-sectional analysis); and subsequent virological rebound (viral load >200 copies per mL) in those with initial viral load of 50 copies per mL or lower (longitudinal analysis). Of the 3258 people who completed the questionnaire, 2771 (85%) reported being on ART at the time of the questionnaire, and 2704 with complete data were included. 873 (32%) of 2704 participants reported non-adherence to ART and 219 (9%) of 2405 had virological non-suppression in cross-sectional analysis. Each of the four measures of lower socioeconomic status was strongly associated with non-adherence to ART, and with virological non-suppression (prevalence ratios [PR] adjusted for gender/sexual orientation, age, and ethnic origin: greatest financial hardship vs none 2·4, 95% CI 1·6-3·4; non-employment 2·0, 1·5-2·6; unstable housing vs homeowner 3·0, 1·9-4·6; non-university education 1·6, 1·2-2·2). 139 (8%) of 1740 individuals had subsequent virological rebound (rate=3·6/100 person-years). Low socioeconomic status was predictive of longitudinal rebound risk (adjusted hazard ratio [HR] for greatest financial hardship vs none 2·3, 95% CI 1·4-3·9; non-employment 3·0, 2·1-4·2; unstable housing vs homeowner 3·3, 1·8-6·1; non-university education 1·6, 1·1-2·3). Socioeconomic disadvantage was strongly associated with poorer HIV treatment outcomes in this setting with universal health care. Adherence interventions and increased social support for those most at risk should be considered. National Institute for Health Research.


Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIα-derived peptides in human fertilization.
The recognition and association between the Ca2+/calmodulin-activated protein kinase II-α (CaMKIIα) and the multi-PDZ domain protein 1 (MUPP1) plays an important role in the sperm acrosome reaction and human fertilization. Previously, we have demonstrated that the MUPP1 PDZ11 domain is the primary binding partner of the CaMKIIα C-terminal tail, which can be targeted by a rationally designed sia peptide with nanomolar affinity. Here, we further introduced an orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the PDZ11 domain with the sia [Asn-1Phe] peptide mutant, where the halogen bond was formed by substituting the o-hydrogen atom of the benzene ring of the peptide Phe-1 residue with a halogen atom (F, Cl, Br or I). Molecular dynamics simulations and high-level theoretical calculations suggested that bromine (Br) is a good compromise between the halogen-bonding strength and steric hindrance effect due to introduction of a bulkier halogen atom into the tightly packed complex interface. Fluorescence spectroscopy assays revealed that the resulting o-Br-substituted peptide (Kd = 18 nM) exhibited an ∼7.6-fold affinity increase relative to its native counterpart (Kd = 137 nM). In contrast, the p-Br-substituted peptide, a negative control that is unable to establish the ONI according to structure-based analysis, has decreased affinity (Kd = 210 nM) upon halogenation.


CCL21-loaded 3D hydrogels for T cell expansion and differentiation.
Recent achievements in the field of immunotherapy, such as the development of engineered T cells used in adoptive cell therapy, are introducing more efficient strategies to combat cancer. Nevertheless, there are still many limitations. For example, these T cells are challenging to manufacture, manipulate, and control. Specifically, there are limitations in producing the large amounts of therapeutic T cells needed for these therapies in a short period of time and in an economically viable manner. In this study, three-dimensional (3D) poly(ethylene) glycol (PEG) hydrogels covalently combined with low molecular weight heparin are engineered to resemble the lymph nodes, where T cells reproduce. In these hydrogels, PEG provides the needed structural and mechanical properties, whereas heparin is used as an anchor for the cytokine CCL21, which is present in the lymph nodes, and can affect cell migration and proliferation. The 3D structure of the hydrogel in combination with its loading capacity result in an increased primary human CD4+ T cell proliferation compared to the state-of-the-art expansion systems consisting of artificial antigen presenting cells. Thus, we present a new tool for adoptive cell therapy to help achieving the large numbers of cells required for therapy of selected phenotypes targeted against cancer cells, by mimicking the lymph nodes.


Maternal cytomegalovirus infection prevention: the role of Dutch primary care midwives.
to assess the knowledge of cytomegalovirus (CMV) infection among Dutch primary care midwives, and clinical approaches to informing women about CMV. cross-sectional study, using self-administered questionnaires. 330 Dutch primary care midwives. primary midwifery care practices across the Netherlands. Midwives' knowledge of CMV transmission routes and maternal symptoms, and clinical practice behaviours regarding CMV, the information typically provided or reasons for not informing pregnant women about CMV. the overall median knowledge score was 8.0 out of a maximum possible score of 13.0. Of all participants, 10.6% reported always informing pregnant women about CMV infection prevention and 41.0% reported never informing pregnant women. The main reason indicated for not informing pregnant women was lack of knowledge about preventive methods (45.7%). Dutch primary care midwives have limited knowledge of CMV infection. Improvement in providing education to pregnant women about strategies to prevent CMV is necessary.


Invasive mold disease of the central nervous system in children and adolescents with cancer or undergoing hematopoietic stem cell transplantation: Analysis of 29 contemporary patients.
Invasive mold disease (IMD) is a severe infectious complication in immunocompromised patients. The outcome of central nervous system (CNS) IMD is poor, but contemporary data, in particular in the pediatric setting, are lacking. For this retrospective multicenter analysis, pediatric patients < 18 years with proven or probable CNS IMD receiving chemotherapy or undergoing allogeneic HSCT were reported by the local investigator. CNS IMD had to be diagnosed between 2007 and 2016. Proven CNS IMD was defined as compatible CNS imaging or macroscopic autopsy findings in conjunction with a positive microscopic or microbiological result in the brain tissue or cerebrospinal fluid. Probable CNS IMD was defined as compatible CNS imaging findings in combination with proven or probable IMD at a site outside the CNS. A total of 29 patients (median age, 14 years; 14 allogeneic HSCT recipients) were diagnosed with proven (n = 12) or probable (n = 17) CNS IMD. Aspergillus spp. was the most common fungal pathogen. All but one patient had IMD sites outside the CNS and eight patients (27.6%) were neurologically asymptomatic at diagnosis of CNS IMD. Forty-nine percent of the patients survived CNS IMD; however, 46.7% of the survivors suffered from severe long-term neurological sequelae. Our data suggest that (1) outcome of CNS IMD has improved in children as compared with previous series, (2) half of surviving patients suffer from severe neurological sequelae, and (3) imaging of the CNS should be performed in all children with IMD irrespective of neurological symptoms.


Signaling mechanism of renal fibrosis in unilateral ureteral obstructive kidney disease in ROCK1 knockout mice.
It has been shown that blockade of Rho kinase with pharmacologic inhibitors inhibits renal fibrosis. This study examined the role of Rho kinase in renal fibrosis in the unilateral ureteral obstruction (UUO) model in mice that do not express the ROCK1 gene, a critical downstream mediator of Rho GTPase. Unexpected, real-time PCR, Western blot, and immunohistochemistry demonstrated that, compared with the wild-type mice, mice with ROCK1 knockout (KO) were not protected against renal fibrosis at both the early (day 5) and late (day 10) UUO, as determined by histology and expression of both mRNA and protein levels of alpha-smooth muscle actin, collagen types I and III, and fibronectin within the diseased kidney. Then the mechanisms of loss of protective effect on renal fibrosis in ROCK1 KO mice were investigated. It is interesting that mice that lacked ROCK1 did not have altered expression of ROCK2 but significantly increased TGF-beta expression and Smad2/3 activation (phosphorylation and nuclear translocation) in the diseased kidney at day 5, which remained high at day 10 of UUO. Similarly, primary cultures of kidney fibroblasts that were obtained from both ROCK1 wild-type and KO mice showed that deletion of ROCK1 did not prevent TGF-beta-induced activation of Smad2/3 and collagen I expression. This also was observed in the presence of Rho kinase inhibitor Y-27632. Taken together, results from this study suggest that Rho/Rho kinase may not be a necessary or a central pathway for renal fibrosis in the UUO model. The interplay between the Rho/Rho kinase pathway and the Smad signaling pathway may be a key mechanism by which loss of ROCK1 does not prevent renal fibrosis in the UUO model.


Phthalate and Bisphenol Exposure during Pregnancy and Offspring Nonverbal IQ.
Prenatal exposures to phthalates and bisphenols are associated with impaired brain development in animals. However, epidemiological studies investigating the association between prenatal phthalate or bisphenol exposure and cognition have produced mixed findings and mostly had modest sample sizes and measured the exposure during the third trimester. We examined the association between pregnancy maternal urinary biomarkers of phthalate or bisphenol exposure and nonverbal intelligence quotient (IQ) in children 6 years of age. The study sample consisted of 1,282 mother-child pairs participating in the Generation R Study, a population-based birth cohort in Rotterdam, Netherlands (enrollment 2002-2006). We measured maternal urinary concentrations of 18 phthalate metabolites and 8 bisphenols at <18, 18-25, and >25 wks of gestation. Child nonverbal IQ was measured at 6 years of age using the Snijders-Oomen Nonverbal Intelligence Test-Revised. Linear regression models were fit for each of the three collection phases separately, the three collection phases jointly, and for the averaged prenatal exposure across pregnancy. Higher urinary concentrations of phthalate metabolites during early pregnancy were associated with lower child nonverbal IQ score [e.g., B per 10-fold increase in summed low-molecular weight phthalates=-1.7 (95% CI: -3.1, -0.3)]. This association remained unchanged when adjusted for mid and late pregnancy exposures. We also observed an inverse association between late pregnancy di-n-octyl phthalate (DNOP) exposure and nonverbal IQ. Maternal urinary concentrations of bisphenols were not associated with child nonverbal IQ. There was no effect estimate modification by sex. We did not observe that maternal biomarkers of bisphenol exposure are associated with nonverbal IQ. We found that phthalate exposure in early pregnancy and DNOP exposure in late pregnancy are associated with lower nonverbal IQ scores in children. Our results might suggest that particularly early pregnancy is a sensitive window of phthalate exposure, but future studies are needed to replicate our findings. https://doi.org/10.1289/EHP6047.


Implementation and Use of a Patient Symptom Diary During Chemotherapy: A Mixed-Methods Evaluation of the Nurse Perspective.
To gain a deeper understanding of nurses' experience working with a patient diary for tracking and treating side effects during chemotherapy. . A mixed-methods design was used to learn about oncology nurses' use and perceptions of a symptom diary. . Six oncology wards and two outpatient clinics at the University Hospitals Leuven, Belgium. . 79 nurses completed a survey, and 14 nurses participated in focus group discussions. . First, a survey sampled nurses' use and perceptions of the diary. Next, focus group discussions were held with the aim of arriving at a deeper understanding of the survey results. . Use and perceptions of a symptom diary. . Most nurses reported performing diary-related behavior to some extent. The survey and focus groups indicated that many nurses strongly believed in the value of the diary, but some were still hesitant or had concerns about patients' perceptions of the diary. The focus group results showed that nurses' use of the diary in daily practice was influenced by their personal beliefs about the value of the diary, the team's, and those of their patients. . Although a positive trend was noted, nurses' use of the symptom diary was suboptimal six months after its implementation. . This study highlights important issues that need to be addressed to advance the successful implementation of the symptom diary.


Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination antiretroviral therapy-treated adults in Botswana: results from a clinical trial.
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥ 4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08-1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1-1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03-3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.


Overall Low Extended-Spectrum Cephalosporin Resistance but high Azithromycin Resistance in Neisseria gonorrhoeae in 24 European Countries, 2015.
Surveillance of Neisseria gonorrhoeae antimicrobial susceptibility in Europe is performed through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), which additionally provides data to inform the European gonorrhoea treatment guideline; currently recommending ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. We present antimicrobial susceptibility data from 24 European countries in 2015, linked to epidemiological data of patients, and compare the results to Euro-GASP data from previous years. Antimicrobial susceptibility testing by MIC gradient strips or agar dilution methodology was performed on 2134 N. gonorrhoeae isolates and interpreted using EUCAST breakpoints. Patient variables associated with resistance were established using logistic regression to estimate odds ratios (ORs). In 2015, 1.7% of isolates were cefixime resistant compared to 2.0% in 2014. Ceftriaxone resistance was detected in only one (0.05%) isolate in 2015, compared with five (0.2%) in 2014. Azithromycin resistance was detected in 7.1% of isolates in 2015 (7.9% in 2014), and five (0.2%) isolates displayed high-level azithromycin resistance (MIC ≥ 256 mg/L) compared with one (0.05%) in 2014. Ciprofloxacin resistance remained high (49.4%, vs. 50.7% in 2014). Cefixime resistance significantly increased among heterosexual males (4.1% vs. 1.7% in 2014), which was mainly attributable to data from two countries with high cefixime resistance (~11%), however rates among men-who-have-sex-with-men (MSM) and females continued to decline to 0.5% and 1%, respectively. Azithromycin resistance in MSM and heterosexual males was higher (both 8.1%) than in females (4.9% vs. 2.2% in 2014). The association between azithromycin resistance and previous gonorrhoea infection, observed in 2014, continued in 2015 (OR 2.1, CI 1.2-3.5, p < 0.01). The 2015 Euro-GASP sentinel system revealed high, but stable azithromycin resistance and low overall resistance to ceftriaxone and cefixime. The low cephalosporin resistance may be attributable to the effectiveness of the currently recommended first-line dual antimicrobial therapy; however the high azithromycin resistance threatens the effectiveness of this therapeutic regimen. Whether the global use of azithromycin in mono- or dual antimicrobial therapy of gonorrhoea is contributing to the global increases in azithromycin resistance remains to be elucidated. The increasing cefixime resistance in heterosexual males also needs close monitoring.


systemPipeR: NGS workflow and report generation environment.
Next-generation sequencing (NGS) has revolutionized how research is carried out in many areas of biology and medicine. However, the analysis of NGS data remains a major obstacle to the efficient utilization of the technology, as it requires complex multi-step processing of big data demanding considerable computational expertise from users. While substantial effort has been invested on the development of software dedicated to the individual analysis steps of NGS experiments, insufficient resources are currently available for integrating the individual software components within the widely used R/Bioconductor environment into automated workflows capable of running the analysis of most types of NGS applications from start-to-finish in a time-efficient and reproducible manner. To address this need, we have developed the R/Bioconductor package systemPipeR. It is an extensible environment for both building and running end-to-end analysis workflows with automated report generation for a wide range of NGS applications. Its unique features include a uniform workflow interface across different NGS applications, automated report generation, and support for running both R and command-line software on local computers and computer clusters. A flexible sample annotation infrastructure efficiently handles complex sample sets and experimental designs. To simplify the analysis of widely used NGS applications, the package provides pre-configured workflows and reporting templates for RNA-Seq, ChIP-Seq, VAR-Seq and Ribo-Seq. Additional workflow templates will be provided in the future. systemPipeR accelerates the extraction of reproducible analysis results from NGS experiments. By combining the capabilities of many R/Bioconductor and command-line tools, it makes efficient use of existing software resources without limiting the user to a set of predefined methods or environments. systemPipeR is freely available for all common operating systems from Bioconductor ( http://bioconductor.org/packages/devel/systemPipeR ).


Manipulation and Motion of Organelles and Single Molecules in Living Cells.
The biomolecule is among the most important building blocks of biological systems, and a full understanding of its function forms the scaffold for describing the mechanisms of higher order structures as organelles and cells. Force is a fundamental regulatory mechanism of biomolecular interactions driving many cellular processes. The forces on a molecular scale are exactly in the range that can be manipulated and probed with single molecule force spectroscopy. The natural environment of a biomolecule is inside a living cell, hence, this is the most relevant environment for probing their function. In vivo studies are, however, challenged by the complexity of the cell. In this review, we start with presenting relevant theoretical tools for analyzing single molecule data obtained in intracellular environments followed by a description of state-of-the art visualization techniques. The most commonly used force spectroscopy techniques, namely optical tweezers, magnetic tweezers, and atomic force microscopy, are described in detail, and their strength and limitations related to in vivo experiments are discussed. Finally, recent exciting discoveries within the field of in vivo manipulation and dynamics of single molecule and organelles are reviewed.


Obstetric clinicians' experiences and educational preparation for caring for pregnant women with physical disabilities: A qualitative study.
Women with physical disabilities (WPD) experience major barriers to care during pregnancy. Lack of education about disability in health professionals' education is a pervasive barrier to quality care. In an effort to explore this issue, this study examined the issue from the perspective of obstetric clinicians who provide care to WPD. This qualitative descriptive study explored perspectives of obstetric clinicians who provide perinatal care for WPD to inform the educational preparation of clinicians to care for women with disabilities. We contacted 33 obstetric clinicians who care for pregnant WPD. Thirteen obstetricians and one nurse midwife participated in semi-structured telephone interviews. Interview transcriptions were content analyzed to identify initial themes. Investigators discussed and revised the themes as additional transcripts were reviewed and new themes were identified. Themes identified from transcript analyses included: lack of education at any level including during postgraduate residency and fellowship on care of pregnant WPD, unplanned career pathway, educating other clinicians, and positive and negative experiences providing obstetrical care to women with physical disability. Several clinicians provided this care because of requests from other clinicians and did not begin their careers with the goal of providing obstetric care to women with physical disabilities. None had received formal education or training including during their residencies or fellowships. The clinicians described very rewarding experiences caring for WPD. The experiences reported by this study's participants suggest the need to include disability in undergraduate and postgraduate education and training to improve obstetric care to WPD.


Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex.
The human ability to infer the thoughts and beliefs of others, often referred to as "theory of mind," as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor.


Lack of association between mannose-binding lectin gene polymorphisms and juvenile idiopathic arthritis in a Han population from the Hubei province of China.
Many studies have reported that polymorphisms of the mannose-binding lectin (MBL) gene are associated with autoimmune disease. Here, we investigate the relationship between MBL gene polymorphisms and susceptibility to juvenile idiopathic arthritis (JIA) in a Han-nationality population from the Hubei province of China. PCR-restriction fragment length polymorphism was used to investigate polymorphisms of codons 54 and 57 in exon 1 of the MBL gene in 93 patients with JIA and 48 control children. Neither group showed codon 57 polymorphisms. There was no significant difference in the genotypic frequencies of codon 54 between patients with JIA and healthy controls (wild type, 71.0% versus 75.0%, respectively; heterozygous type, 25.8% versus 25.0%, respectively; and homozygous type, 3.2% versus 0.0%, respectively). In addition, no association was found between the subgroups of patients with JIA and control individuals. Our results provide no evidence for a relationship between MBL gene mutation and susceptibility to JIA.


Dental fluorosis and urinary fluoride concentration as a reflection of fluoride exposure and its impact on IQ level and BMI of children of Laxmisagar, Simlapal Block of Bankura District, W.B., India.
There has been growing public concern about intellectual performance of children at high levels of fluoride exposure. A cross-sectional study was conducted in Simlapal Block of Bankura District, West Bengal, to find out the relationship between fluoride (F) exposure as exposure dose (ED) with dental fluorosis (DF), urinary fluoride concentration (UF), intelligence quotient (IQ) and body mass index (BMI). Fifty groundwater samples were collected from the target area. One hundred forty-nine children belonging to age group 6 to 18 years were considered for this study. Experimental results reveal that mean F(-) concentration of that area is 2.11 mg/L (±SD 1.64). On the basis of F concentration in groundwater and water consumption pattern, ED was calculated to explore the impact of F(-) on DF, UF, IQ, and BMI. Paired t test results suggest that exposure rate of F does not show any significant differences (<0.05) among the children of 12 different places. As a result of F exposure, DF cases are mostly found in the order of moderate > severe > mild > very mild > questionable > normal conditions. The highest UF concentration was recorded as 17 mg/L, but the status of DF in the affected children was recorded as moderate. The results also reveal that ED has a positive correlation with DF (r = 0.299, P < 0.01) and UF (r = 0.513, P < 0.01) and a negative correlation with IQ (r = -0.343, P < 0.01) along with BMI (r = 0.083, non-significant). Therefore, from this study, it may be concluded that UF and DF concentration could act as a biomarker of fluoride toxicity.


Reactive immunization.
For almost 200 years inert antigens have been used for initiating the process of immunization. A procedure is now described in which the antigen used is so highly reactive that a chemical reaction occurs in the antibody combining site during immunization. An organophosphorus diester hapten was used to illustrate this concept coined "reactive immunization." The organophosphonate recruited chemical potential from the immune response that resembled the way these compounds recruit the catalytic power of the serine hydrolases. During this recruitment, a large proportion of the isolated antibodies catalyzed the formation and cleavage of phosphonylated intermediates and subsequent ester hydrolysis. Reactive immunization can augment traditional immunization and enhance the scope of catalytic antibody chemistry. Among the compounds anticipated to be effective are those that contain appropriate reactive functionalities or those that are latently reactive, as in the mechanism-based inhibitors of enzymes.


Subsurface imaging of coupled carrier transport in GaAs/AlGaAs core-shell nanowires.
We demonstrate spatial probing of carrier transport within GaAs/AlGaAs core-shell nanowires with nanometer lateral resolution and subsurface sensitivity by energy-variable electron beam induced current imaging. Carrier drift that evolves with applied electric field is distinguished from a coupled drift-diffusion length. Along with simulation of injected electron trajectories, combining beam energy tuning with precise positioning for selective probing of core and shell reveals axial position- and bias-dependent differences in carrier type and transport along parallel conduction channels. These results indicate how analysis of transport within heterostructured nanomaterials is no longer limited to nonlocal or surface measurements.


Ran GTPase in nuclear envelope formation and cancer metastasis.
Ran is a small ras-related GTPase that controls the nucleocytoplasmic exchange of macromolecules across the nuclear envelope. It binds to chromatin early during nuclear formation and has important roles during the eukaryotic cell cycle, where it regulates mitotic spindle assembly, nuclear envelope formation and cell cycle checkpoint control. Like other GTPases, Ran relies on the cycling between GTP-bound and GDP-bound conformations to interact with effector proteins and regulate these processes. In nucleocytoplasmic transport, Ran shuttles across the nuclear envelope through nuclear pores. It is concentrated in the nucleus by an active import mechanism where it generates a high concentration of RanGTP by nucleotide exchange. It controls the assembly and disassembly of a range of complexes that are formed between Ran-binding proteins and cellular cargo to maintain rapid nuclear transport. Ran also has been identified as an essential protein in nuclear envelope formation in eukaryotes. This mechanism is dependent on importin-β, which regulates the assembly of further complexes important in this process, such as Nup107-Nup160. A strong body of evidence is emerging implicating Ran as a key protein in the metastatic progression of cancer. Ran is overexpressed in a range of tumors, such as breast and renal, and these perturbed levels are associated with local invasion, metastasis and reduced patient survival. Furthermore, tumors with oncogenic KRAS or PIK3CA mutations are addicted to Ran expression, which yields exciting future therapeutic opportunities.


Evaluation of non cyanide methods for hemoglobin estimation.
The hemoglobincyanide method (HiCN) method for measuring hemoglobin is used extensively worldwide; its advantages are the ready availability of a stable and internationally accepted reference standard calibrator. However, its use may create a problem, as the waste disposal of large volumes of reagent containing cyanide constitutes a potential toxic hazard. As an alternative to drabkin`s method of Hb estimation, we attempted to estimate hemoglobin by other non-cyanide methods: alkaline hematin detergent (AHD-575) using Triton X-100 as lyser and alkaline- borax method using quarternary ammonium detergents as lyser. The hemoglobin (Hb) results on 200 samples of varying Hb concentrations obtained by these two cyanide free methods were compared with a cyanmethemoglobin method on a colorimeter which is light emitting diode (LED) based. Hemoglobin was also estimated in one hundred blood donors and 25 blood samples of infants and compared by these methods. Statistical analysis used was Pearson`s correlation coefficient. The response of the non cyanide method is linear for serially diluted blood samples over the Hb concentration range from 3 gm/dl -20 gm/dl. The non cyanide methods has a precision of + 0.25 g/dl (coefficient of variation= (2.34%) and is suitable for use with fixed wavelength or with colorimeters at wavelength- 530 nm and 580 nm. Correlation of these two methods was excellent (r=0.98). The evaluation has shown it to be as reliable and reproducible as HiCN for measuring hemoglobin at all concentrations. The reagents used in non cyanide methods are non-biohazardous and did not affect the reliability of data determination and also the cost was less than HiCN method. Thus, non cyanide methods of Hb estimation offer possibility of safe and quality Hb estimation and should prove useful for routine laboratory use. Non cyanide methods is easily incorporated in hemoglobinometers by using very minute quantities of reagents and test sample; hence, these methods can be used to provide point of care testing in blood banks for hemoglobin (Hb) estimation in blood donors.


Nuclear translocation of Skp2 facilitates its destruction in response to TGFβ signaling.
Skp2, a F-box protein that determines the substrate specificity for SCF ubiquitin ligase, has recently been demonstrated to be degraded by Cdh1/APC in response to TGFβ signaling. The TGFβ-induced Skp2 proteolysis results in the stabilization of p27 that is necessary to facilitate TGFβ cytostatic effect. Previous observation from immunocytochemistry indicates that Cdh1 principally localizes in the nucleus while Skp2 mainly localizes in the cytosol, which leaves us a puzzle on how Skp2 is recognized and then ubiquitylated by Cdh1/APC in response to TGFβ stimulation. Here, we report that Skp2 is rapidly translocated from the cytosol to the nucleus upon the cellular stimulation with TGFβ. Using a combinatorial approach of immunocytochemistry, biochemical-fraction-coupled immunoprecipitation, mutagenesis as well as protein degradation assay, we have demonstrated that the TGFβ-induced Skp2 nucleus translocation is critical for TGFβ cytostatic effect that allows physical interaction between Cdh1 and Skp2 and in turn facilitates the Skp2 ubquitylation by Cdh1/APC. Disruption of nuclear localization motifs on Skp2 stabilizes Skp2 in the presence of TGF-β signaling, which attenuates TGFβ-induced p27 accumulation and antagonizes TGFβ-induced growth inhibition. Our finding reveals a cellular mechanism that facilitates Skp2 ubiquitylation by Cdh1/APC in response to TGFβ.


Capturing chromosome conformation.
We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.


Smaller Body Size, Early Postnatal Lethality, and Cortical Extracellular Matrix-Related Gene Expression Changes of Cyfip2-Null Embryonic Mice.
Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is a key component of the WAVE regulatory complex (WRC) which regulates actin polymerization and branching in diverse cellular compartments. Recent whole exome sequencing studies identified de novo hotspot variants in CYFIP2 from patients with early-onset epileptic encephalopathy and microcephaly, suggesting that CYFIP2 may have some functions in embryonic brain development. Although perinatal lethality of Cyfip2-null (Cyfip2 -/-) mice was reported, the exact developmental time point and cause of lethality, and whether Cyfip2 -/- embryonic mice have brain abnormalities remain unknown. We found that endogenous Cyfip2 is mainly expressed in the brain, spinal cord, and thymus of mice at late embryonic stages. Cyfip2 -/- embryos did not show lethality at embryonic day 18.5 (E18.5), but their body size was smaller than that of wild-type (WT) or Cyfip2 +/- littermates. Meanwhile, at postnatal day 0, all identified Cyfip2 -/- mice were found dead, suggesting early postnatal lethality of the mice. Nevertheless, the brain size and cortical cytoarchitecture were comparable among WT, Cyfip2 +/-, and Cyfip2 -/- mice at E18.5. Using RNA-sequencing analyses, we identified 98 and 72 differentially expressed genes (DEGs) from the E18.5 cortex of Cyfip2 +/- and Cyfip2 -/- mice, respectively. Further bioinformatic analyses suggested that extracellular matrix (ECM)-related gene expression changes in Cyfip2 -/- embryonic cortex. Together, our results suggest that CYFIP2 is critical for embryonic body growth and for early postnatal survival, and that loss of its expression leads to ECM-related gene expression changes in the embryonic cortex without severe gross morphological defects.


HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention.
Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence. In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected. Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner. Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence.


Correction to: Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature.
The original article [1] contains a minor error whereby the dates for year of first launch and year of first report of adverse reaction for iophendylate in e-Appendix Table 1 are mistakenly presented as 1946 and 1975 respectively.


Family functioning, resilience, and depression among North Korean refugees.
North Korean refugees in South Korea are at high risk of depression, but there are few studies exploring protective factors in this population. We hypothesized that family functioning (family adaptability and cohesion) and resilience would protect North Korean refugees from developing depressive symptoms. A subsample of 304 adult North Korean refugees drawn from the cross-sectional 2010 Nationwide Survey of Domestic Violence in South Korea was analyzed. Approximately 44% of respondents were identified as having depression, using scores on the Center for Epidemiological Studies Depression scale. In models capturing the full spectrum of depressive symptoms (continuous), family cohesion was significantly associated with depression, and the relationship was partially mediated by resilience. In models predicting clinical depression (dichotomous), resilience fully mediated the relationship between family cohesion and clinical depression. In contrast, family adaptability was not associated with depression or resilience in this sample. These findings suggest that assessing and enhancing family cohesion and resilience may be essential for professionals working with refugees, and that refugees without family support may be at particularly high risk for depression.


Unambiguous phase retrieval as a cophasing sensor for phased array telescopes.
Cophasing a multiple-aperture optical telescope (MAOT) or optical interferometer requires the knowledge of the tips/tilts and of the differential pistons on its subapertures. In this paper we demonstrate in the case of a point source object that a single focal-plane image is sufficient for MAOT cophasing. Adopting a least-square approach allows us to derive an analytic estimator of the subaperture aberrations, provided that these are small enough (typically for closed-loop operation) and that the pupil is diluted noncentrosymmetric. We then provide the validation of this estimator by simulations as well as a performance comparison with a more conventional iterative algorithm of phase retrieval. Finally, we present the experimental validation of both estimators on a laboratory test bench; our results, especially subnanometric repeatability, demonstrate that focal-plane sensors are appropriate for the cophasing of phased array telescopes.


Gestational age and adolescent mental health: evidence from Hong Kong's 'Children of 1997' birth cohort.
Preterm, and more recently early term, birth has been identified as a risk factor for poor health. Whether the sequelae of late preterm or early term birth extends to poor mental health and well-being in adolescence is unclear and has not been systematically assessed. Linear regression was used to assess the adjusted associations of gestational age (very/moderate preterm (<34 weeks, n=85), late preterm (34-36 weeks, n=305), early term (37-38 weeks, n=2228), full term (39-40 weeks, n=4018), late term (41 weeks, n=809), post-term (≥42 weeks, n=213)) with self-reported self-esteem at ∼11 years (n=6935), parent-reported Rutter score assessing the common emotional and behavioural problems at ∼7 years (n=6292) and ∼11 years (n=5596) and self-reported depressive symptoms at ∼13 years (n=5795) in a population-representative Hong Kong Chinese birth cohort 'Children of 1997' where gestational age has little social patterning. Very/moderate preterm birth was associated with higher Rutter subscore for hyperactivity (ß coefficients 0.5, 95% CI 0.01 to 1.00) at ∼7 years but not at ∼11 years, adjusted for sex, age, socio-economic position, parents' age at birth, birth order and secondhand smoke exposure. Similarly adjusted, late preterm, early term, late term and post-term birth were not associated with self-esteem or depressive symptoms. In a population-representative birth cohort from a non-Western-developed setting, gestational age had few associations with mental health and well-being in adolescence, whereas very preterm birth was specifically associated with hyperactivity in childhood. Inconsistencies with studies from Western settings suggest setting specific unmeasured confounding may underlie any observed associations.


Clinical and demographic characteristics among patients with urothelial carcinomas of the upper urinary tract and bladder in Taiwan.
Urothelial carcinoma (UC) is derived from the urothelium of the urinary tract, and includes cancers of the bladder, renal pelvis and ureter. The aim of this study was to investigate the clinical and demographic features among patients with bladder cancer and urothelial carcinoma of the upper urinary tract (UTUC) in Taiwan. The present study recruited a total of 736 histopathologically confirmed UC cases, which consisted of 470 bladder cancer and 266 UTUC between September 1998 and December 2009. Clinical and demographic features were collected by an interview utilizing a structured questionnaire, and supplemented by medical chart review. This study was approved by institutional review boards of the collaborating hospitals. The multivariate Cox proportional hazards model was performed to investigate prognostic factors for disease-free survival (DFS) and overall survival (OS). All statistical analyses were performed using the Statistical Analysis Software for Windows, version 9.1 (SAS Institute, Cary, NC, USA). UTUC patients had higher proportions of advanced clinical stage (T2-4) and poor cell differentiation (G3). Bladder cancer patients with advanced clinical stages (T2-3 and T4) had increased risks of poorer OS (hazard ratio, HR = 1.7 and 3.9, respectively). UTUC patients with the advanced clinical stage (T4) had a significantly greater risk of poorer OS (HR = 8.7). Bladder cancer patients with a high grade (G2-3) had a significantly increased risk of poorer OS (HR = 3.8). Based on the limited parameters and heterogeneous data, the present study merely observed that bladder cancer and UTUC patients with the higher tumor stage have a significant increased risk of poor overall survival. Therefore, the causal mechanisms of UC prognosis remained to be further explored in a larger population.


Natural categories or fundamental dimensions: on carving nature at the joints and the rearticulation of psychopathology.
The question of whether to view psychopathology as categorical or dimensional continues to provoke debate. We review the many facets of this argument. These include the pragmatics of measurement; the needs of clinical practice; our ability to distinguish categories from dimensions empirically; methods of analysis appropriate to each and how they relate; and the potential theoretical biases associated with each approach. We conclude that much of the debate is misconceived in that we do not observe pathology directly; rather, we observe its properties. The same pathology can have some properties that are most easily understood using a dimensional conceptualization while at the same time having other properties that are best understood categorically. We suggest replacing Meehl's analogy involving qualitatively distinct species with an alternative analogy with the "duality" of light, a phenomenon with both wave- and particle-like properties.


Nanoparticle superlattice engineering with DNA.
A current limitation in nanoparticle superlattice engineering is that the identities of the particles being assembled often determine the structures that can be synthesized. Therefore, specific crystallographic symmetries or lattice parameters can only be achieved using specific nanoparticles as building blocks (and vice versa). We present six design rules that can be used to deliberately prepare nine distinct colloidal crystal structures, with control over lattice parameters on the 25- to 150-nanometer length scale. These design rules outline a strategy to independently adjust each of the relevant crystallographic parameters, including particle size (5 to 60 nanometers), periodicity, and interparticle distance. As such, this work represents an advance in synthesizing tailorable macroscale architectures comprising nanoscale materials in a predictable fashion.