Intravenous ketamine for subacute treatment of refractory chronic migraine: a case series.
Refractory migraine is a challenging condition with great impact on health related quality of life. Intravenous (IV) ketamine has been previously used to treat various refractory pain conditions. We present a series of patients with refractory migraine treated with intravenous ketamine in the hospital setting. Based on retrospective chart review, we identified six patients with refractory migraine admitted from 2010 through 2014 for treatment with intravenous ketamine. Ketamine was administered using a standard protocol starting with a dose of 0.1 mg/kg/hr and increased by 0.1 mg/kg/hr every 3 to 4 h as tolerated until the target pain score of 3/10 was achieved and maintained for at least 8 h. Visual Analogue Scale (VAS) scores at time of hospital admission were obtained as well as average baseline VAS scores prior to ketamine infusion. A phone interview was conducted for follow-up of migraine response in the 3 to 6 months following ketamine infusion. The study sample had a median age of 36.5 years (range 29-54) and 83% were women. Pre-treatment pain scores ranged from 9 to 10. All patients achieved a target pain level of 3 or less for 8 h; the average ketamine infusion rate at target was 0.34 mg/kg/hour (range 0.12-0.42 mg/kg/hr). One patient reported a transient out-of-body hallucination following an increase in the infusion rate, which resolved after decreasing the rate. There were no other significant side effects. IV ketamine was safely administered in the hospital setting to patients with refractory chronic migraine. Treatment was associated with short term improvement in pain severity in 6 of 6 patients with refractory chronic migraine. Prospective placebo-controlled trials are needed to assess short term and long-term efficacy of IV ketamine in refractory chronic migraine.


High versus low dose rate intracavitary irradiation for adenocarcinoma of the uterine cervix.
Traditionally, low dose rate (LDR) brachytherapy has been used as a standard modality in the treatment of patients with carcinoma of the uterine cervix. The purpose of this work was to evaluate the effects of high dose rate (HDR) brachytherapy on patients with adenocarcinoma of the uterine cervix and to compare them with the effects of LDR brachytherapy. From January 1971 to December 1992, 104 patients suffering from adenocarcinoma of the uterine cervix were treated with radiation therapy in the Department of Radiation Oncology, Yonsei University. LDR brachytherapy was carried out on 34 patients and HDR brachytherapy on 70 patients. In the LDR group, eight patients were in stage IB, six in IIA, 12 in IIB, three in IIIA and five in IIIB. External radiation therapy was delivered with 10 MV X-rays, 2 Gy fraction per day, total dose of whole pelvis 36-52 Gy (median 46 Gy). LDR radium intracavitary irradiation was performed with a Henschke applicator, 37-59 Gy targeted at point A (median 43 Gy). In the HDR group, there were 16 patients in stage IB, six in IIA, 32 in IIB and 16 in IIIB. The total whole pelvis dose of external radiation was 40-50 Gy (median 44 Gy), daily 1.8-2.0 Gy. HDR Co-60 intracavitary irradiation was performed with a remotely controlled after-loading system (RALS), 30-48 Gy (median 39 Gy) targeted at point A, three times per week, 3 Gy per fraction. The 5-year overall survival rate in the LDR group was 72.9, 61.9 and 35.7% in stage I, II and III, respectively and the corresponding figures for HDR were 87.1, 58.3 and 43.8% (p > 0.05). There was no statistical difference between the HDR group and the LDR group in terms of the 5-year overall survival rate from adenocarcinoma of the uterine cervix. There was a late complication rate of 12% in the LDR group and 27% in the HDR group. The incidence of late complications in stages II and III was higher in the HDR group than in the LDR group (31.6 vs 16.7% in stage II, 37.3% vs 12.5% in stage III, p > 0.05). No prognostic factors were evident in the comparison between the two groups. There was no difference in terms of 5-year survival rate in the patients with adenocarcinoma of the uterine cervix between those treated with HDR and those treated with LDR brachytherapy. Even though late complication rates were higher in the HDR group, most of them were classified as grade I. This retrospective study suggests that HDR brachytherapy may be able to replace LDR brachytherapy in the treatment of adenocarcinoma of the uterine cervix.


Use of the Quick Medical Reference (QMR) program as a tool for medical education.
The original goal of the INTERNIST-1 project, as formulated in the early 1970s, was to develop an expert consultant program for diagnosis in general internal medicine. By the early 1980s, it was recognized that the most valuable product of the project was its medical knowledge base (KB). The INTERNIST-1/QMR KB comprehensively summarizes information contained in the medical literature regarding diagnosis of disorders seen in internal medicine. The QMR program was developed to enable its users to exploit the contents of the INTERNIST-1/QMR KB in educationally, clinically, and computationally useful ways. Utilizing commonly available microcomputers, the program operates at three levels--as an electronic textbook, as an intermediate level spreadsheet for the combination and exploration of simple diagnostic concepts, and as an expert consultant program. The electronic textbook contains an average of 85 findings and 8 associated disorders relevant to the diagnosis of approximately 600 disorders in internal medicine. Inverting the disease profiles creates extensive differential diagnosis lists for the over 4250 patient findings known to the system. Unlike a standard printed medical textbook, the QMR knowledge base can be manipulated "on the fly" to format displays that match the information needs of users. Preliminary use of the program for education of medical students and medical house officers at several sites has met with an enthusiastic response.


Musical plus phonological input for young foreign language readers.
Based on previous studies showing that phonological awareness is related to reading abilities and that music training improves phonological processing, the aim of the present study was to test for the efficiency of a new method for teaching to read in a foreign language. Specifically, we tested the efficacy of a phonological training program, with and without musical support that aimed at improving early reading skills in 7-8-year-old Spanish children (n = 63) learning English as a foreign language. Of interest was also to explore the impact of this training program on working memory and decoding skills. To achieve these goals we tested three groups of children before and after training: a control group, an experimental group with phonological non-musical intervention (active control), and an experimental group with musical intervention. Results clearly point to the beneficial effects of the phonological teaching approach but the further impact of the music support was not demonstrated. Moreover, while children in the music group showed low musical aptitudes before training, they nevertheless performed better than the control group. Therefore, the phonological training program with and without music support seem to have significant effects on early reading skills.


Growth, immune and viral responses in HIV infected African children receiving highly active antiretroviral therapy: a prospective cohort study.
Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes. A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ), weight and height-for-age z scores (WAZ & HAZ) were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both virological and immunological success (VS/IS), virological failure and immunological success (VF/IS). virological success and immunological failure (VS/IF) and both virological and immunological failure (VF/IF). From March 2004 until May 2006, 124 HIV infected children were initiated on HAART. The median age (IQR) was 5.0 years (2.1 - 7.0) and 49% (61/124) were female. The median [95% confidence interval (CI)] BAZ, WAZ and HAZ at baseline were 0.29 (-2.9, -1.2), -1.2 (-2.1, -0.5) and -2.06 (-2.9, -1.2) respectively. Baseline median CD4 cell % and log10 HIV-1 RNA were; 11.8% (7.5-18.0) and 5.6 (5.2-5.8) copies/ml. By 48 weeks, mean WAZ and HAZ in the VF/IS group, which was younger, increased from - 0.98 (SD 1.7) to + 1.22 (SD 1.2) and from -1.99 (1.7) to + 0.76 (2.4) respectively. Mean increase in WAZ and HAZ in the VS/IF group, an older group was modest, from -1.84 (1.3) to - 0.41 (1.2) and -2.25 (1.2) to -1.16 (1.3) respectively. Baseline CD4 cell % [OR 6.97 95% CI (2.6 -18.6)], age [OR 4.6 95% CI (1.14 -19.1)] and WHO clinical stage [OR 3.5 95%CI (1.05 -12.7)] were associated with successful treatment outcome. HIV infected Ugandan children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART, including those who failed to completely suppress virus. Older children initiating HAART with severe immune suppression were less likely to achieve a successful treatment outcome. These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses.


Legal implications of tissue.
This paper reviews the legal rules that govern the way surgeons deal with human tissues during the course of diagnosing and treating their patients. The topic is dominated by the Human Tissue Act 2004, which was enacted in September 2006; thus, the article applies specifically only to England, Wales and Northern Ireland, since Scotland has separate legislation (Human Tissue (Scotland) Act 2006). Although the Human Tissue Act 2004 was built largely upon a plethora of legal principles that were developed throughout the Commonwealth and in the US, some of the principles underlying it will be equally familiar and applicable to surgeons across the world. Much everyday clinical activity falls outside the remit of the Act, and depends both upon other statutes, and on common law rules, principally those relating to consent.


Patient perspective: fatigue as a recommended patient centered outcome measure in rheumatoid arthritis.
The Patient Perspective Workshop at OMERACT 8 considered evidence for the importance of fatigue to patients with rheumatoid arthritis (RA) and whether measurement of fatigue meets the requirements of the OMERACT filter. The workshop participants included 20 patients from 10 countries and 60 other OMERACT participants. Introductory papers and detailed notes for discussion group members set out the evidence from the literature and from recent analyses of clinical study data available to several participants. The workshop concluded that fatigue is a symptom that is important to patients, is commonly reported by patients, is often severe, can be measured by several current instruments that pass the OMERACT filter, is responsive to some interventions, and provides information additional to that commonly obtained from currently used outcomes. The final OMERACT plenary session endorsed by a very large majority (89%) the proposal that, in addition to the "core set" of outcome measures currently in widespread use, fatigue should be measured in future studies of RA whenever possible.


Ytm1, Nop7, and Erb1 form a complex necessary for maturation of yeast 66S preribosomes.
The essential, conserved yeast nucleolar protein Ytm1 is one of 17 proteins in ribosome assembly intermediates that contain WD40 protein-protein interaction motifs. Such proteins may play key roles in organizing other molecules necessary for ribosome biogenesis. Ytm1 is present in four consecutive 66S preribosomes containing 27SA2, 27SA3, 27SB, and 25.5S plus 7S pre-rRNAs plus ribosome assembly factors and ribosomal proteins. Ytm1 binds directly to Erb1 and is present in a heterotrimeric subcomplex together with Erb1 and Nop7, both within preribosomes and independently of preribosomes. However, Nop7 and Erb1 assemble into preribosomes prior to Ytm1. Mutations in the WD40 motifs of Ytm1 disrupt binding to Erb1, destabilize the heterotrimer, and delay pre-rRNA processing and nuclear export of preribosomes. Nevertheless, 66S preribosomes lacking Ytm1 remain otherwise intact.


Stem cell therapy: the great promise in lung disease.
Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.


Aetiologies of central nervous system infections in adults in Kathmandu, Nepal: a prospective hospital-based study.
We conducted a prospective hospital based study from February 2009-April 2011 to identify the possible pathogens of central nervous system (CNS) infections in adults admitted to a tertiary referral hospital (Patan Hospital) in Kathmandu, Nepal. The pathogens of CNS infections were confirmed in cerebrospinal fluid (CSF) using molecular diagnostics, culture (bacteria) and serology. 87 patients were recruited for the study and the etiological diagnosis was established in 38% (n = 33). The bacterial pathogens identified were Neisseria meningitidis (n = 6); Streptococcus pneumoniae (n = 5) and Staphylococcus aureus (n = 2) in 13/87(14%). Enteroviruses were found in 12/87 (13%); Herpes Simplex virus (HSV) in 2/87(2%). IgM against Japanese encephalitis virus (JEV) was detected in the CSF of 11/73 (15%) tested samples. This is the first prospective molecular and serology based CSF analysis in adults with CNS infections in Kathmandu, Nepal. JEV and enteroviruses were the most commonly detected pathogens in this setting.


Biochemical characterization of reactive nitrogen species by eosinophil peroxidase in tyrosine nitration.
It is well known that eosinophils are involved in tyrosine nitration. In this study, we evaluated tyrosine nitration by rat eosinophils isolated from peritoneal fluid and constituent eosinophils in the stomach. Rat peritoneal eosinophils activated with 1 microM phorbol myristate acetate (PMA) and 50 microM NO2- showed immunostaining for nitrotyrosine only in smaller cells, despite the fact that eosinophils are capable of producing superoxide (O2*-) Free tyrosine nitrating capacity after incubation with PMA and NO2- was 4-fold higher in eosinophils than in neutrophils. Catalase and alpha- and gamma-tocopherol inhibited free tyrosine nitration by reactive nitrogen species from eosinophils but not that by peroxynitrite. Superoxide dismutase augmented free tyrosine nitration by activated eosinophils and peroxynitrite. The concentration of nitric oxide released from eosinophils was relatively low (0.32 microM/10(6) cells/h) and did not contribute to the formation of nitrotyrosine. On the other hand, most constituent eosinophils constituent in the rat stomach stimulated by PMA and NO2- showed tyrosine nitration capacity. These results suggest that intact cells other than apoptotic-like eosinophils eluted in the intraperitoneal cavity could not generate reactive species responsible for nitration by a peroxidase-dependent mechanism. In contrast, normal eosinophils in the stomach were capable of nitration, suggesting that the characteristics of eosinophils in gastric mucosa are different from those eluted in the peritoneal cavity.


The impact of cardiac CT on the appropriate utilization of catheter coronary angiography.
The purpose of this study was to evaluate the impact of computed tomography coronary angiography (CTCA) on the appropriate utilization of catheter angiography (CA). This observational trial analyzed all patients undergoing CA in 2006 and 2007 in one hospital. In 2007, patients having a low to intermediate cardiovascular risk and suspicion of coronary artery disease (CAD) and those with suspicion of progression of known organic heart disease (OHD) underwent CTCA either prior to CA or as the sole imaging modality. Appropriate utilization of CA was defined as: (1) percentage of patients showing normal or non-significant findings at CA, (2) percentage of self-referred patients to CA, and (3) percentage of patients with known OHD undergoing CA without immediate operative or interventional consequences. Use of CTCA resulted in a significant drop in the percentage of CA examinations in patients with suspected CAD showing normal or non-significant findings (19% in 2006, 10% in 2007, P < 0.001). The percentage of self-referred CA significantly dropped (29% in 2006, 10% in 2007, P < 0.001). CT ruled-out CAD in 74/151 (49%) patients, obviating subsequent CA. During a follow-up of 15 +/- 4 months, CA and percutaneous interventions was considered necessary in 2/74 patients. CT ruled-out progression of known OHD in 53/60 (90%) patients, while one patient underwent CA and percutaneous intervention during a follow-up period of 16 +/- 4 months. No reduction of CA examinations without immediate consequences was found in patients with known OHD (13% in 2006, 27% in 2007). In patients with suspicion of CAD, CTCA improved the appropriate utilization of CA without jeopardizing patient safety, along with a decrease of self-referred patients for CA. CTCA did not influence the appropriate utilization of CA in patients with known OHD.


Variation in antiepileptic drug adherence among older patients with new-onset epilepsy.
Medication adherence among patients with epilepsy remains a significant challenge, even for patients prescribed newer antiepileptic drugs (AEDs), leading to increased risks of seizures, hospitalizations, and higher treatment costs. Despite substantial research identifying numerous risk factors, the role of specific medications has been neglected. To analyze adherence to 9 different AEDs in a national clinical sample of elderly patients with new-onset epilepsy. Patients over age 66 receiving care in the Veterans Health Administration were eligible if they met criteria for new-onset epilepsy with AED monotherapy of at least 3 months. A cross-sectional study design was used to assess adherence as defined by the medication possession ratio (MPR) and a 90-day or longer medication gap. Multivariable logistic regression modeled each dichotomous adherence outcome as a function of clinical and demographic measures. The sample (N = 6373) was primarily male (98%), white (79%), and exempt from medication copayments due to disability status; nearly 40% had a prior psychiatric or dementia diagnosis. Nearly half of the patients were poorly adherent, with rates ranging from 42% to 63% across AEDs. In multivariable models, patients on phenobarbital, valproate, and gabapentin were significantly less likely to be adherent on both outcomes, while lamotrigine and levetiracetam were positively associated with adherence per the MPR. Adherence difficulty in this elderly cohort is attributable to several factors, yet specific AEDs substantially increased this risk. Drugs that produce adverse effects such as cognitive difficulty or weight gain may prove detrimental to maintaining appropriate adherence early in the treatment course. Given comparable efficacy among AEDs, providers should be aware that certain medications impart differential risks of poor adherence in older patients with epilepsy.


Viral paratransgenesis in the malaria vector Anopheles gambiae.
Paratransgenesis, the genetic manipulation of insect symbiotic microorganisms, is being considered as a potential method to control vector-borne diseases such as malaria. The feasibility of paratransgenic malaria control has been hampered by the lack of candidate symbiotic microorganisms for the major vector Anopheles gambiae. In other systems, densonucleosis viruses (DNVs) are attractive agents for viral paratransgenesis because they infect important vector insects, can be genetically manipulated and are transmitted to subsequent generations. However, An. gambiae has been shown to be refractory to DNV dissemination. We discovered, cloned and characterized the first known DNV (AgDNV) capable of infection and dissemination in An. gambiae. We developed a flexible AgDNV-based expression vector to express any gene of interest in An. gambiae using a two-plasmid helper-transducer system. To demonstrate proof-of-concept of the viral paratransgenesis strategy, we used this system to transduce expression of an exogenous gene (enhanced green fluorescent protein; EGFP) in An. gambiae mosquitoes. Wild-type and EGFP-transducing AgDNV virions were highly infectious to An. gambiae larvae, disseminated to and expressed EGFP in epidemiologically relevant adult tissues such as midgut, fat body and ovaries and were transmitted to subsequent mosquito generations. These proof-of-principle data suggest that AgDNV could be used as part of a paratransgenic malaria control strategy by transduction of anti-Plasmodium peptides or insect-specific toxins in Anopheles mosquitoes. AgDNV will also be extremely valuable as an effective and easy-to-use laboratory tool for transient gene expression or RNAi in An. gambiae.


The p21-activated kinase is required for neuronal migration in the cerebral cortex.
The normal formation and function of the mammalian cerebral cortex depend on the positioning of its neurones, which occurs in a highly organized, layer-specific manner. The correct morphology and movement of neurones rely on synchronized regulation of their actin filaments and microtubules. The p21-activated kinase (Pak1), a key cytoskeletal regulator, controls neuronal polarization, elaboration of axons and dendrites, and the formation of dendritic spines. However, its in vivo role in the developing nervous system is unclear. We have utilized in utero electroporation into mouse embryo cortices to reveal that both loss and gain of Pak1 function affect radial migration of projection neurones. Overexpression of hyperactivated Pak1 predominantly caused neurones to arrest in the intermediate zone (IZ) with apparently misoriented and disorganized leading projections. Loss of Pak1 disrupted the morphology of migrating neurones, which accumulated in the IZ and deep cortical layers. Unexpectedly, a significant number of neurones with reduced Pak1 expression aberrantly entered into the normally cell-sparse marginal zone, suggesting their inability to cease migrating that may be due to their impaired dissociation from radial glia. Our findings reveal the in vivo importance of temporal and spatial regulation of the Pak1 kinase during key stages of cortical development.


Identifying psychophysiological indices of expert vs. novice performance in deadly force judgment and decision making.
To demonstrate that psychophysiology may have applications for objective assessment of expertise development in deadly force judgment and decision making (DFJDM). Modern training techniques focus on improving decision-making skills with participative assessment between trainees and subject matter experts primarily through subjective observation. OBJECTIVE metrics need to be developed. The current proof of concept study explored the potential for psychophysiological metrics in deadly force judgment contexts. Twenty-four participants (novice, expert) were recruited. All wore a wireless Electroencephalography (EEG) device to collect psychophysiological data during high-fidelity simulated deadly force judgment and decision-making simulations using a modified Glock firearm. Participants were exposed to 27 video scenarios, one-third of which would have justified use of deadly force. Pass/fail was determined by whether the participant used deadly force appropriately. Experts had a significantly higher pass rate compared to novices (p < 0.05). Multiple metrics were shown to distinguish novices from experts. Hierarchical regression analyses indicate that psychophysiological variables are able to explain 72% of the variability in expert performance, but only 37% in novices. Discriminant function analysis (DFA) using psychophysiological metrics was able to discern between experts and novices with 72.6% accuracy. While limited due to small sample size, the results suggest that psychophysiology may be developed for use as an objective measure of expertise in DFDJM. Specifically, discriminant function measures may have the potential to objectively identify expert skill acquisition. Psychophysiological metrics may create a performance model with the potential to optimize simulator-based DFJDM training. These performance models could be used for trainee feedback, and/or by the instructor to assess performance objectively.


Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences.
2-(2'-Hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-irradiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.


Evaluation of deep convolutional neural networks for glaucoma detection.
To investigate the performance of deep convolutional neural networks (DCNNs) for glaucoma discrimination using color fundus images STUDY DESIGN: A retrospective study PATIENTS AND METHODS: To investigate the discriminative ability of 3 DCNNs, we used a total of 3312 images consisting of 369 images from glaucoma-confirmed eyes, 256 images from glaucoma-suspected eyes diagnosed by a glaucoma expert, and 2687 images judged to be nonglaucomatous eyes by a glaucoma expert. We also investigated the effects of image size on the discriminative ability and heatmap analysis to determine which parts of the image contribute to the discrimination. Additionally, we used 465 poor-quality images to investigate the effect of poor image quality on the discriminative ability. Three DCNNs showed areas under the curve (AUCs) of 0.9 or more. The AUC of the DCNN using glaucoma-confirmed eyes against nonglaucomatous eyes was higher than that using glaucoma-suspected eyes against nonglaucomatous eyes by approximately 0.1. The image size did not affect the discriminative ability. Heatmap analysis showed that the optic disc area was the most important area for the discrimination of glaucoma. The image quality affected the discriminative ability, and the inclusion of poor-quality images in the analysis reduced the AUC by 0.1 to 0.2. DCNNs may be a useful tool for detecting glaucoma or glaucoma-suspected eyes by use of fundus color images. Proper preprocessing and collection of qualified images are essential to improving the discriminative ability.


Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptide.
HLA-B27 can form beta-2 microglobulin (beta2m)-associated heterotrimers (HLA-B27) and beta2m-free homodimers (B27(2)). Here, we study the role of complexed peptide in the interaction of these forms of B27 with the killer cell immunoglobulin (Ig)-like receptors KIR3DL1 and KIR3DL2 and with Ig-like transcripts LILRB1 and LILRB2. HLA-B27 tetramers complexed with three of five different naturally processed self peptides and three of seven pathogen-derived epitopes bound to KIR3DL1-expressing transfectants and NK cells. Heterotrimeric complexes containing peptides with charged amino acids at position 8 did not bind to KIR3DL1; however, studies with analogue peptides demonstrated that these are not the only peptide residues involved in binding. KIR3DL1 ligation by HLA-B27 inhibited NK cell IFN-gamma production in a peptide-dependent fashion. B27 but not HLA-A2, B7 or B57 heavy chains formed homodimers in the presence of peptide epitopes. B27(2) bound to KIR3DL1, KIR3DL2 and LILRB2 but not LILRB1. KIR3DL2 ligation by B27(2) inhibited NK and T cell IFN-gamma production. By contrast with HLA heterotrimers, B27(2) binding to KIR did not depend on the sequence of the bound peptide. Differences in KIR binding to classical HLA and B27(2) could be involved in the pathogenesis of spondyloarthritis.


Assessment of thermal coagulation in ex-vivo tissues using Raman spectroscopy.
Raman spectroscopy is used to study the effects of heating on specific molecular bonds present in albumen-based coagulation phantoms and ex-vivo tissues. Thermal coagulation is induced by submerging albumen-based phantoms in a 75°C water bath to achieve target temperatures of 45, 55, 65, and 75°C. Laser photocoagulation is performed on ex-vivo bovine muscle samples, yielding induced temperatures between 46 and 90°C, as reported by implanted microthermocouples. All phantoms and tissue samples are cooled to room temperature, and Raman spectra are acquired at the microthermocouple locations. Shifts in major Raman bands are observed with laser heating in bovine muscle, specifically from the amide-1 α-helix group (∼1655 cm(-1)), the CH(2)/CH(3) group (∼1446 cm(-1)), the Cα-H stretch group (∼1312 cm(-1)), and the CN stretch group (∼1121cm(-1)). Raman bands at 1334 cm(-1) (tryptophan), 1317 cm(-1) [ν(Cα-H)], and 1655 cm(-1) (amide-1 α-helix) also show a decrease in intensity following heating. The results suggest that Raman band locations and relative intensities are affected by thermal denaturation of proteins, and hence, may be a useful tool for monitoring the onset and progression of coagulation during thermal therapies.


Multi-scale genetic analysis of Uniola paniculata (Poaceae): a coastal species with a linear, fragmented distribution.
Geographic and fine-scale population genetic structures of Uniola paniculata, the dominant coastal dune grass in the southeastern USA, were examined. The linear, naturally fragmented distribution of this native perennial was hypothesized to lead to high genetic structure and lower genetic diversity at the margin of the species range. The extensive ramet production and low seed germination of this species were also expected to cause populations to be dominated by a few large clones. At 20 sites throughout the range of the species, leaf tissue was collected from 48 individuals. Clonal structure was examined using leaf tissue collected from an additional 60 individuals, each in four patches at two sites. Starch gel electrophoresis was used to resolve 27 allozyme loci. The results indicated that Uniola had greater genetic structure (G(ST) = 0.304) than most other outcrossing species, indicating moderate barriers to gene flow. There was a weak but significant positive relationship between genetic distance and geographic distance, supporting an isolation-by-distance model of gene flow. There were no obvious disjunctions between regions. Genetic diversity (H(e)) was relatively uniform throughout most of the range of the species but was lower in all western Gulf of Mexico populations. Clonal diversity varied both within and among sites, but clones were often small, suggesting that sexual reproduction and recruitment from seeds are important factors maintaining genetic diversity.


Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis.
Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.


The interplay between economics, legislative power and social influence examined through a social-ecological framework for marine ecosystems services.
In the last 15 years, conservation has shifted increasingly towards perspectives based on the instrumental value of nature, where what counts is what provides benefits to humans. The ecosystem services framework embraces this vision of nature through monetary valuation of the environment to correct market failures and government distortions that hinder efficient allocation of public goods, including goods and services provided by biodiversity and ecosystems. The popularity of this approach is reflected in different countries legislation; for instance, US, EU and UK have introduced economic criteria for comparing costs and benefits of environmental policies in protecting ecosystem services. From an operational perspective, the ecosystem services framework requires ecologists to estimate how the supply of services is affected by changes in the functionality and/or the extent of ecosystems; and economists to identify how changes in the supply affect the flow of direct and indirect benefits to people. However, this approach may be simplistic when faced with the complexity of social-ecological systems. We investigated this for three different marine services: assimilative capacity of waste, coastal defense and renewable energy. We find that economic valuation could provide efficient and fair allocations in the case of assimilative capacity, but leads to social clashes between outputs generated by cost benefit analysis and citizens' expectation in the case of coastal defense. In the case of renewable energy, controversies can be generated by regulatory mechanisms that are not necessarily aligned with the interests of industry or important social groups. We conclude that there is a need to integrate perspectives arising from utilitarian allocation of resources with those involving legislation and communal values in order to reconcile conflicting interests and better sustain marine social-ecological systems.


Identifying patients with undetected gastro-oesophageal cancer in primary care: External validation of QCancer® (Gastro-Oesophageal).
To evaluate the performance of QCancer® (Gastro-Oesophageal) for predicting the risk of undiagnosed gastro-oesophageal cancer in an independent UK cohort of patients from general practice records. Open cohort study to validate QCancer® (Gastro-Oesophageal) prediction model. Three hundred sixty-five practices from the United Kingdom contributing to The Health Improvement Network database. 2.1 million patients registered with a general practice surgery between 01 January 2000 and 30 June 2008, aged 30-84years (3.7 million person years) with 1766 gastro-oesophageal cancer cases. The outcome, gastro-oesophageal cancer was defined as incident diagnosis of gastro-oesophageal cancer during the 2years after study entry. The results from this independent and external validation of QCancer® (Gastro-Oesophageal) demonstrated good performance data on a large cohort of general practice patients. QCancer® (Gastro-Oesophageal) had very good discrimination with c-statistics of 0.93 and 0.94 for women and men respectively. QCancer® (Gastro-Oesophageal) was well calibrated across all tenths of risk and over all age ranges with predicted risks closely matching observed risks. QCancer® (Gastro-Oesophageal) explained 74.4% and 75.6% of the variation in men and women respectively. QCancer® (Gastro-Oesophageal) is a useful tool to identify undiagnosed gastro-oesophageal cancer in primary care in the United Kingdom.


Successful implementation of a clinical transition pathway for adolescents with juvenile-onset rheumatic and musculoskeletal diseases.
In 2008 a clinical transition pathway for young people with juvenile-onset rheumatic and musculoskeletal diseases (jRMD) aiming at improving transitional care was instituted. Historical data on drop-out rate in our clinic was 35%, one year before the implementation of the transition pathway. This study aims to I) evaluate the effectiveness of the clinical transition pathway, II) evaluate the experiences and satisfaction of YP with the transitional process and evaluate their perceived self-management skills. Young people with any jRMD transferred from the pediatric to the adult rheumatology department in our academic center were eligible to enroll in this quantitative cross-sectional observational study between 2009 and 2015. Notably in 2012, we created a dedicated adolescent JIA-clinic, located at the adult rheumatology department. Electronic patient records from all young people that were transferred between 2009 and 2015 were reviewed for drop-out of care. Young people were asked to rate a VAS for 'satisfaction with transition' and to complete the "on your own feet transfer experience scale" (OYOF-TES)-questionnaire regarding their experiences and satisfaction with transition. Self-management skills were measured with the "on your own feet self-efficacy scale" (OYOF-SES)-questionnaire. One hundred fifty-four young people were transferred to the adult department, of which 76 were transferred to the dedicated adolescent JIA-clinic. The mean age at transfer was 17.8 years for YP transferred to the adult clinic and 15.2 years for transfer to the adolescent clinic. Drop-out of care rate one year after transfer was 5.1% in the adult clinic and 1.3% in the adolescent JIA-clinic. Response rate of the returned questionnaires was 61% for the adolescent JIA clinic and 36% for the adult clinic. There was no difference between responders and non-responders in demographics and disease type besides age (non-responders were significantly younger). Young people transferred to the adult and adolescent JIA-clinic both had high scores on the satisfaction scale (7.7 and 7.5 on the VAS-scale and 72.0 and 74.5 on the OYOF-TES). Self-efficacy scores were high for both groups, with OYOF-SES 59.7 for those transferred to the adult clinic and 58.2 for those transferred to the adolescent JIA-clinic. The implementation of the clinical transition pathway has led to a substantial improvement of patient care during the transitional process leading to low drop-out of care rate and high scores on satisfaction with transition. High scores on the self-reported self-efficacy scale suggests confidence of young people to have achieved sufficient skills to successfully manage their disease.


Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy.
Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy. To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery. A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants. Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), quality assurance (statements 10 to 13: 94% to 100%), training, education, competency and privileges (statements 14 to 19: 97% to 100%), endoscopy reporting standards (statements 20 and 21: 97% to 100%) and patient perceptions (statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified. The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services. The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.


The allylic chalcogen effect in olefin metathesis.
Olefin metathesis has emerged as a powerful tool in organic synthesis. The activating effect of an allylic hydroxy group in metathesis has been known for more than 10 years, and many organic chemists have taken advantage of this positive influence for efficient synthesis of natural products. Recently, the discovery of the rate enhancement by allyl sulfides in aqueous cross-metathesis has allowed the first examples of such a reaction on proteins. This led to a new benchmark in substrate complexity for cross-metathesis and expanded the potential of olefin metathesis for other applications in chemical biology. The enhanced reactivity of allyl sulfide, along with earlier reports of a similar effect by allylic hydroxy groups, suggests that allyl chalcogens generally play an important role in modulating the rate of olefin metathesis. In this review, we discuss the effect of allylic chalcogens in olefin metathesis and highlight its most recent applications in synthetic chemistry and protein modifications.


Effect of apple vinegar intake on metabolic parameters and constipation in patients with schizophrenia treated with clozapine: a pilot study.
Clozapine is one of the drugs that cause the highest level of weight gain. Additionally, obese patients are at higher risk of developing various physical co-morbidities, such as type 2 diabetes and cardiovascular diseases. Forty-nine percent of patients on clozapine suffer from constipation. Apple vinegar (AV) had been assigned health benefits, such as weight loss, laxative properties, blood glucose lowering effects, and reducing the risk of heart disease. Our hypothesis was that AV would lower the mean glycated haemoglobin level and reduce the level of constipation. Pilot intervention study with a 12-week follow-up. All patients receiving clozapine treatment for schizophrenia at one outpatient clinic were eligible for inclusion. Intervention: Ten millilitres of AV diluted in 200 ml drinking water with breakfast and dinner. Forty patients were suitable for inclusion and nine completed the intervention. Women had much higher-than-recommended body mass index. Scores for constipation were high. The reduction in constipation was of clinical interest (2.6 (p = 0.017)). However, there were no statistically significant differences in glycated haemoglobin, cholesterol, HDL, LDL or triglyceride levels. Patients with problems of constipation prior to the intervention experienced much better bowel habits and relief of their constipation. AV lower the constipation problems faced by patients with schizophrenia treated with clozapine. Further research, repeating this pilot study with a meaningfully larger sample size and randomized with placebo, is needed.


Surgical Repair of Dynamic Snapping Biceps Femoris Tendon.
A snapping biceps tendon is an infrequently seen and commonly misdiagnosed pathology, leaving patients with persistent symptoms that can be debilitating. Patients will present with a visible, audible, and/or painful snap over the lateral aspect of their knee when performing squats, sitting in low seats, or participating in activities with deep knee flexion. A thorough knowledge of the anatomy is essential for surgical treatment of this pathology, which is caused by a detachment of the direct arms of the long and short heads of the biceps femoris off the fibular styloid. This Technical Note provides a diagnostic approach, postoperative management, and details of a surgical technique to treat a snapping biceps tendon with an anatomic repair of the long and short head attachments of the biceps femoris to the posterolateral fibular styloid.


Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).


Development of interdigitated array electrodes with surface-enhanced Raman scattering functionality.
Interdigitated array electrodes with surface-enhanced Raman scattering (SERS) functionality for in situ qualitative and quantitative analysis of electroactive species are demonstrated. Gold nanostructured interdigitated array electrodes (NIDAEs) were fabricated by electron beam lithography, and used for an electrochemical SERS study of K(3)[Fe(CN(6))] in aqueous KClO(4) solution in single and generation-collection modes. The generation-collection mode experiment showed amplification of the SERS band intensity for adsorbed ferricyanide ions at the negative end of the applied potential, while in single mode it was reduced to near zero. This new finding reveals that NIDAEs offer a new opportunity for analytical science by improving analytical sensitivity and detection ability of electroactive species. The electric fields accumulating at nanogaps are promising for manipulating linear and nonlinear optical phenomena. In addition, miniaturized NIDAEs are of great importance for developing lab-on-a-chip devices, and are useful for measurements within small space/volume domains, requiring only small amounts and/or concentrations of analytes.


Targeted temperature management: Current evidence and practices in critical care.
Targeted temperature management (TTM) in today's modern era, especially in intensive care units represents a promising multifaceted therapy for a variety of conditions. Though hypothermia is being used since Hippocratic era, the renewed interest of late has been since early 21(st) century. There have been multiple advancements in this field and varieties of cooling devices are available at present. TTM requires careful titration of its depth, duration and rewarming as it is associated with side-effects. The purpose of this review is to find out the best evidence-based clinical practice criteria of therapeutic hypothermia in critical care settings. TTM is an unique therapeutic modality for salvaging neurological tissue viability in critically ill patients viz. Post-cardiac arrest, traumatic brain injury (TBI), meningitis, acute liver failure and stroke. TTM is standard of care in post-cardiac arrest situations; there has been a lot of controversy of late regarding temperature ranges to be used for the same. In patients with TBI, it reduces intracranial pressure, but has not shown any favorable neurologic outcome. Hypothermia is generally accepted treatment for hypoxic ischemic encephalopathy in newborns. The current available technology to induce and maintain hypothermia allows for precise temperature control. Future studies should focus on optimizing hypothermic treatment to full benefit of our patients and its application in other clinical scenarios.


The interaction of p53 with replication protein A mediates suppression of homologous recombination.
The tumor suppressor protein p53 is emerging as a central regulator of homologous recombination (HR) processes and DNA replication. P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. Here, we investigated whether the interaction of p53 with human replication protein A (RPA) is necessary for the regulation of HR. By employing a plasmid-based HR assay in p53-null H1299 lung carcinoma cells, we studied the HR-suppressing properties of a panel of p53 mutants, which varied in their ability to interact with RPA. Both wild-type p53 and a transactivation-deficient p53 mutant (L22Q/W23S) suppressed HR and prevented RPA binding to ssDNA in vitro and in vivo. Conversely, p53 mutations that specifically disrupt the RPA-binding domain, while not compromising p53 transactivation function (D48H/D49H and W53S/F54S), did not affect HR. Suppression of HR was also not seen with missense mutations in the p53 core domain (His175 and His273), which retained the ability to interact with RPA, suggesting that the disruption of additional binding interactions of p53, for example, with Rad51 or recombination intermediates, also impacts on HR. We hypothesize that sequestration of RPA by p53 at the sites of recombination is one means by which p53 can inhibit HR processes. Our data support and extend the previously formulated 'dual model' of p53's role as guardian of the genome.


An efficient, non-viral dendritic vector for gene delivery in tissue engineering.
Recent developments within the field of tissue engineering (TE) have shown that biomaterial scaffold systems can be augmented via the incorporation of gene therapeutics. The objective of this study was to assess the potential of the activated polyamidoamine dendrimer (dPAMAM) transfection reagent (SuperfectTM) as a gene delivery system to mesenchymal stem cells (MSCs) in both monolayer and 3D culture on collagen based scaffolds. dPAMAM-pDNA polyplexes at a mass ratio (M:R) 10:1 (dPAMAM : pDNA) (1 ug pDNA) were capable of facilitating prolonged reporter gene expression in monolayer MSCs which was superior to that facilitated using polyethylenimine (PEI)-pDNA polyplexes (2 ug pDNA). When dPAMAM-pDNA polyplexes (1 ug pDNA) were soak loaded onto a collagen-chondroitin sulphate (CS) scaffold prolonged transgene expression was facilitated which was higher than that obtained for a PEI-pDNA polyplex (2 ug pDNA) loaded scaffold. Transgene expression was dependent on the composite nature of the collagen scaffold with varying expression profiles obtained from a suite of collagen constructs including a collagen alone, collagen-CS, collagen-hydroxyapatite, collagen-nanohydroxyapatite and collagen-hyaluronic acid scaffold. Therefore, the dPAMAM vector described herein represents a biocompatible, effective gene delivery vector for TE applications which, via matching with a particular composite scaffold type, can be tailored for regeneration of various tissue defects.


The Effects of Continuous Compared to Accumulated Exercise on Health: A Meta-Analytic Review.
Public health guidelines suggest that physical activity can be accumulated in multiple short bouts dispersed through the day. A synthesis of the evidence for this approach is lacking. Our objective was to undertake a systematic review and meta-analysis to examine if exercise interventions consisting of a single bout of exercise compared with interventions comprising the same total duration, mode, and intensity of exercise accumulated over the course of the day have different effects on health outcomes in adults. Six electronic databases were searched (Jan 1970-29 August 2018). Two authors identified studies that evaluated the effects of a single bout of exercise compared with the same intensity, total duration, and mode of exercise accumulated in multiple bouts over the course of a day, in community-dwelling adults. Risk of bias was assessed using the Cochrane Collaboration tool. Pooled effects were reported as standardised mean differences (MDs) and 95% confidence intervals (CIs) using a random effects model. A total of 19 studies involving 1080 participants met the inclusion criteria. There were no differences between accumulated and continuous groups for any cardiorespiratory fitness or blood pressure outcomes. A difference was found in body mass changes from baseline to post-intervention in favour of accumulated exercise compared with continuous (MD - 0.92 kg, 95% CI - 1.59 to - 0.25, I2 = 0%; five studies, 211 participants). In subgroup analyses, accumulating > 150 min of weekly exercise in multiple bouts per day resulted in small effects on body fat percentage (combined post-intervention and change from baseline values: MD - 0.87%, 95% CI - 1.71 to - 0.04, I2 = 0%; three studies, 166 participants) compared with 150 min of exercise amassed via single continuous bouts per day. There was a decrease in low-density lipoprotein (LDL) cholesterol with accumulated versus continuous exercise (MD - 0.39 mmol/l, 95% CI - 0.73 to - 0.06, I2 = 23%; two studies, 41 participants). No differences were observed for any other blood biomarker (total cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting blood glucose, and fasting insulin). There is no difference between continuous and accumulated patterns of exercise in terms of effects on fitness, blood pressure, lipids, insulin and glucose. There is some evidence from a small number of studies that changes in body mass and LDL cholesterol are more favourable following the accumulated condition. Collectively our findings suggest that adults are likely to accrue similar health benefits from exercising in a single bout or accumulating activity from shorter bouts throughout the day. This review will inform public health guidelines for physical activity at the global and national levels (PROSPERO 2016 CRD42016044122).


Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.
DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin(+) DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.


A costing analysis of a state-wide, nurse-led hepatitis C treatment model in prison.
Hepatitis C is highly prevalent among prisoners. The simplicity of direct-acting antiviral (DAA) treatment for hepatitis C makes it possible to use novel models of care to increase treatment uptake within prisons. We estimate the average non-drug cost of initiating a prisoner on treatment using real world data from the State-wide Hepatitis Program (SHP) in Victoria, Australia - a coordinated nurse-led model of care. Data were considered from prisoners presenting to the SHP (following antibody-positive diagnosis) during the evaluation period, November 2015 to December 2016. All costs associated with the SHP were estimated, including staffing salaries, medical tests, pharmacy costs and overhead costs. DAA costs were excluded as in Australia an unlimited number are available, covered by a federal government risk-sharing agreement with pharmaceutical companies. The average non-drug cost of treatment initiation through the SHP was compared to equivalent costs from primary and hospital-based models of care in the community. The total non-drug cost accumulated by prisoners in the SHP was AUD$749,470 (uncertainty range: AUD$728,905-794,111). 659/803 were PCR positive, 424/659 had sentences long enough to be eligible for treatment, and 416/424 were initiated on treatment, resulting in an average non-drug cost of AUD$1,802 (95% CI: AUD$1799-1841) per prisoner initiated. A protocol change allowing prisoners with short sentences to start treatment reduced the average non-drug cost to AUD$1263 (95% CI: AUD$1263-1287) per prisoner initiating treatment - 11% and 56% cheaper than estimated equivalent costs in primary (AUD$1654) and hospital-based (AUD$2847) models of care in the community, respectively. Delivering hepatitis C treatment in prison using a nurse-led model of care is cheaper than delivering treatment in the community. These findings provide an economic rationale for implementing coordinated prison-based hepatitis C treatment programs.


Vitamin D Deficiency and Its Influence on Bone Metabolism and Density in a Brazilian Population of Healthy Men.
Vitamin D supplementation is universal for postmenopausal women, but not for elderly men, in whom osteoporosis is also commonly neglected. This study aimed to evaluate vitamin D deficiency and its association with secondary hyperparathyroidism, bone resorption, and bone density in Brazilian men. A total of 120 men, 20-93 years, were evaluated for serum calcium, phosphorus, creatinine, 25-hydroxyvitamin D (25(OH)D), parathyroid hormone, biochemical markers of bone resorption (carboxy-terminal telopeptide, carboxy-terminal peptide of type I collagen), and bone mineral density (dual-energy X-ray absorptiometry). Glomerular filtration rate (GFR) below 30 mL/min/1.73 m2, chronic diseases, and medications affecting bone were the exclusion criteria. No participant reported previous low-impact fractures. In the overall population, 25(OH)D levels were below 30 ng/mL in 46.7%, and below 20 ng/mL in 27.6%. Among the 93 patients 50 years and older, 28 had osteoporosis. In those 70 years and older, the prevalence of vitamin D deficiency (42.1%), secondary hyperparathyroidism (46.4%), high bone resorption (39.6%), decreased GFR (39.2%), and osteoporosis (41.4%) was significantly higher than in the younger subjects (p < 0.005 for all comparisons). Serum parathyroid hormone increased with aging and declining GFR, but was not significantly associated with 25(OH)D or bone mineral density. There was a clear contribution of vitamin D deficiency to increased bone resorption and osteoporosis. Binary logistic regression model considering age, 25(OH)D, and bone resorption identified age ≥70 years as the main determinant of osteoporosis. Our data demonstrate a high prevalence of vitamin D deficiency in a male population living in Rio de Janeiro, and emphasize its participation on the pathogenesis of age-related bone loss. (Vitamin D deficiency and osteoporosis are common in elderly Brazilian men.).


Is there an optimal sampling time and number of samples for assessing exposure to fast elimination endocrine disruptors with urinary biomarkers?
In studies investigating the effects of endocrine disruptors (ED) such as phthalates, bisphenols and some pesticides on human health, exposure is usually characterized with urinary metabolites. The variability of biomarkers concentration, due to rapid elimination from the body combined with frequent exposure is however pointed out as a major limitation to exposure assessment. This study was conducted to assess variability of urinary metabolites of ED, and to investigate how sampling time and number of samples analyzed impacts exposure assessment. Urine samples were collected over 6 months from 16 volunteers according to a random sampling design, and analyzed for 16 phthalate metabolites, 9 pesticide metabolites and 4 bisphenols. The amount of biomarkers excreted in urine at different times of the day were compared. In parallel, 2 algorithms were developed to investigate the effect of the number of urine samples analyzed per subject on exposure assessment reliability. In the 805 urine samples collected from the participants, all the biomarkers tested were detected, and 18 were present in >90% of the samples. Biomarkers variability was highlighted by the low intraclass correlation coefficients (ICC) ranging from 0.09 to 0.51. Comparing the amount of biomarkers excreted in urine at different time did not allow to identify a preferred moment for urine collection between first day urine, morning, afternoon and evening. Algorithms demonstrated that between 10 (for monobenzyl (MBzP) phthalate) and 31 (for bisphenol S) samples were necessary to correctly classify 87.5% of the subjects into quartiles according to their level of exposure. The results illustrate the high variability of urinary biomarkers of ED over time and the impossibility to reliably classify subjects based on a single urine sample (or a limited number). Results showed that classifying individuals based on urinary biomarkers requires several samples per subject, and this number is highly different for different biomarkers.


ECM-Related Myopathies and Muscular Dystrophies: Pros and Cons of Protein Therapies.
Extracellular matrix (ECM) myopathies and muscular dystrophies are a group of genetic diseases caused by mutations in genes encoding proteins that provide critical links between muscle cells and the extracellular matrix. These include structural proteins of the ECM, muscle cell receptors, enzymes, and intracellular proteins. Loss of adhesion within the myomatrix results in progressive muscle weakness. For many ECM muscular dystrophies, symptoms can occur any time after birth and often result in reduced life expectancy. There are no cures for the ECM-related muscular dystrophies and treatment options are limited to palliative care. Several therapeutic approaches have been explored to treat muscular dystrophies including gene therapy, gene editing, exon skipping, embryonic, and adult stem cell therapy, targeting genetic modifiers, modulating inflammatory responses, or preventing muscle degeneration. Recently, protein therapies that replace components of the defective myomatrix or enhance muscle and/or extracellular matrix integrity and function have been explored. Preclinical studies for many of these biologics have been promising in animal models of these muscle diseases. This review aims to summarize the ECM muscular dystrophies for which protein therapies are being developed and discuss the exciting potential and possible limitations of this approach for treating this family of devastating genetic muscle diseases. © 2017 American Physiological Society. Compr Physiol 7:1519-1536, 2017.


Fast adaptive interferometer with a photorefractive GaP crystal.
The performance of an adaptive interferometer based on mixing of light waves with different polarization states in a photorefractive GaP crystal at lambda=0.633mum is described. Both high sensitivity and fast response time are achieved with a low-power He-Ne laser. The parameters of the interferometer are appropriate for remote ultrasound detection in an industrial environment.


New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection.
The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.


Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons.
Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states.


Acute Ischemic Stroke on Cancer Patients, a Distinct Etiology? A Case-Control Study.
It is still unclear whether the etiology of ischemic stroke differs between cancer and non-cancer patients. Stroke and cancer share common modifiable risk factors but evidence suggests that cancer patients have specific conditions that increase the risk of stroke. Our goal was to compare the etiology of ischemic stroke in cancer and non-cancer patients. Case-control study conducted in patients admitted to a stroke unit between January 2007 and December 2012. Cases had a concomitant diagnosis of cancer and acute ischemic stroke, controls of only stroke. Age, gender, vascular risk factors and etiology were compared between groups. Fifty-six cases were identified; 64.3% were men with a mean age of 71 years; 21 patients had evidence of active cancer. Gastrointestinal cancer (25.9%) was the most common; 151 controls were included matched for gender and age. Common modifiable vascular risk factors, between groups (cases versus controls) were not significantly different, except for diabetes mellitus, more frequent in the control group (16.1% vs 33.8%, p = 0.02). Previous thrombotic events were more frequent in the cancer cohort (8.9% vs 0.7%, p = 0.007). Other determined etiology subtype (TOAST classification) was more frequent in cancer patients when compared to controls (13.0% vs 0.8%, p < 0.01), and a hypercoagulable state was significantly more prevalent in active cancer patients. In our case-control study two subsets of cancer patients were delineated. In a subgroup, cancer and stroke co-exist, sharing traditional vascular risk factors. In another subset of patients, stroke appears to be directly related to the presence of a malignancy, where hypercoagulopathy turns out to be a decisive mechanism. In clinical grounds, hypercoagulopathy as stroke etiology should prompt the physician to screen the patient for occult cancer.


Paracetamol: new vistas of an old drug.
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.


Cleavage of circular, superhelical simian virus 40 DNA to a linear duplex by S1 nuclease.
S(1) nuclease, the single-strand specific nuclease from Aspergillus oryzae can cleave both strands of circular covalently closed, superhelical simian virus 40 (SV40) DNA to generate unit length linear duplex molecules with intact single strands. But circular, covalently closed, nonsuperhelical DNA, as well as linear duplex molecules, are relatively resistant to attack by the enzyme. These findings indicate that unpaired or weakly hydrogen-bonded regions, sensitive to the single strand-specific nuclease, occur or can be induced in superhelical DNA. Nicked, circular SV40 DNA can be cleaved on the opposite strand at or near the nick to yield linear molecules. S(1) nuclease may be a useful reagent for cleaving DNAs at regions containing single-strand nicks. Unlike the restriction endonucleases, S(1) nuclease probably does not cleave SV40 DNA at a specific nucleotide sequence. Rather, the sites of cleavage occur within regions that are readily denaturable in a topologically constrained superhelical molecule. At moderate salt concentrations (75 mM) SV40 DNA is cleaved once, most often within either one of the two following regions: the segments defined as 0.15 to 0.25 and 0.45 to 0.55 SV40 fractional length, clockwise, from the EcoR(I) restriction endonuclease cleavage site (defined as the zero position on the SV40 DNA map). In higher salt (250 mM) cleavage occurs preferentially within the 0.45 to 0.55 segment of the map.


Young children's representations of peers' distress: associations to children's social functioning and acceptance of distressed peers.
Children's mental representations of situations involving another child's distress were examined in two studies. Study 1 examined 3- to 7-year-old children's (n= 44) ideas about what victims and bystanders would think, feel and do in hypothetical situations. In Study 2, 7- to 8-year-olds (n= 40) described their own cognitive response to situations in which they were confronted with another's distress. In both studies, representational bias was examined in relation to children's display of prosocial and aggressive behavior and in relation to their acceptance of distressed peers. Although not entirely consistent, findings indicate that three types of representational biases are associated with low levels of considerate behavior and with relatively low acceptance of distressed peers: (a) mentally representing the victim's problem without giving thought to its implications for the victim, (b) significantly reducing the emotional significance of the problem and (c) exaggerating negative aspects of the problem.


A population profile of older adults with prescription encounters with nurse practitioners and family physicians in Ontario: a descriptive retrospective cohort study.
Compared with patients in family physician practices, there is a poor understanding at a population level of patients in nurse practitioner practices. The study aim was to use Ontario administrative databases to identify the sociodemographic characteristics and comorbidities of patients aged 65 years and older who were prescribed medications by nurse practitioners and family physicians between 2000 and 2015. This population-based descriptive retrospective cohort study included patients 65 years of age and older with Ontario Health Insurance Plan eligibility and at least 1 prescription encounter with a nurse practitioner or family physician during the study period. Prescription identification of patients permitted their characterization by age, sex, geographical location, rurality, neighbourhood income and comorbidities. Patients were categorized into 3 provider groups on the basis of the percentage of prescription encounters with nurse practitioners versus family physicians. In 2015, patients in the study cohort with prescriptions by nurse practitioners (n = 25 220) were younger than those with prescriptions by family physicians (40.3% were aged 65-69 yr) and they were more likely to be residents of low-income neighbourhoods (44.0% were in the lowest 2 neighbourhood income quintiles) and to be living outside of central Ontario. In contrast, patients who received prescriptions from family physicians (n = 1 952 904) tended to be older (26.8% were aged ≥ 80 yr), to have higher incomes (21.1% were in the highest neighbourhood income quintile) and to live in urban areas (86.5%). Mean Elixhauser Comorbidity Index scores were consistently lower among patients cared for by nurse practitioners than among those predominantly seen by family physicians (1.30 v. 2.04). The most prevalent conditions were hypertension and diabetes, regardless of provider. The patient characteristic with the highest variability between providers was geographic residence in the province. Elucidating patterns of care is critical for primary care policy and our results provide baseline data for future health care planning.


Observation of biexcitons in nanocrystal solids in the presence of photocharging.
In nanocrystal quantum dots (NQDs), generating multiexcitons offers an enabling tool for enhancing NQD-based devices. However, the photocharging effect makes understanding multiexciton kinetics in NQD solids fundamentally challenging, which is critically important for solid-state devices. To date, this lack of understanding and the spectral-temporal aspects of the multiexciton recombination still remain unresolved in solid NQD ensembles, which is mainly due to the confusion with recombination of carriers in charged NQDs. In this work, we reveal the spectral-temporal behavior of biexcitons (BXs) in the presence of photocharging using near-unity quantum yield CdSe/CdS NQDs exhibiting substantial suppression of Auger recombination. Here, recombinations of biexcitons and single excitons (Xs) are successfully resolved in the presence of trions in the ensemble measurements of time-correlated single-photon counting at variable excitation intensities and varying emission wavelengths. The spectral behaviors of BXs and Xs are obtained for three NQD samples with different core sizes, revealing the strength tunability of the X-X interaction energy in these NQDs. The extraction of spectrally resolved X, BX, and trion kinetics, which are otherwise spectrally unresolved, is enabled by our approach introducing integrated time-resolved fluorescence. The results are further experimentally verified by cross-checking excitation intensity and exposure time dependencies as well as the temporal evolutions of the photoluminescence spectra, all of which prove to be consistent. The BX and X energies are also confirmed by theoretical calculations. These findings fill an important gap in understanding the spectral dynamics of multiexcitons in such NQD solids under the influence of photocharging effects, paving the way to engineering of multiexciton kinetics in nanocrystal optoelectronics, including NQD-based lasing, photovoltaics, and photodetection.


Nonlinear absorption reversing between an electroactive ligand and its metal complexes.
We present the nonlinear absorption investigation of an electroactive ligand and two ruthenium and iron metal complexes under 532 nm, 30 ps laser excitation, by the "open aperture" Z-scan technique. Significant nonlinear optical parameters have in all cases been measured, while the nonlinear attribute has been found to change from saturable to reverse saturable absorption between the initial ligand and its complexes.


Opposite pressure effects in the orbitally-induced Peierls phase transition systems CuIr2S4 and MgTi2O4.
The iso-spinel structural systems CuIr2S4 and MgTi2O4 exhibit phase transitions of a similar nature at ∼230 K and ∼260 K respectively, which are explained as an orbitally-induced Peierls phase transition. However, in this work, we uncover that the applied pressure has opposite pressure effects on the phase transitions in CuIr2S4 and MgTi2O4. As the pressure increases, the phase transition temperature (TMI) for CuIr2S4 increases while that for MgTi2O4 decreases. In addition, the phase transition intensity becomes weaker for CuIr2S4 but gets stronger for MgTi2O4 under pressure. Our results indicate that the applied pressure suppresses the metallic phase in CuIr2S4, while enhances that in MgTi2O4. Combining the experimental observations with first-principles electronic structure calculations, we suggest that the opposite pressure effects in CuIr2S4 and MgTi2O4 originate from the different orbital ordering configurations (dxy, dyz/dxz) caused by different lattice distortions in these two systems. Our findings indicate directly that the interplay between the orbital and lattice degrees of freedom plays an important role in the orbitally-induced Peierls phase transition.


The STAT3/Slug Axis Enhances Radiation-Induced Tumor Invasion and Cancer Stem-like Properties in Radioresistant Glioblastoma.
Glioblastoma multiforme (GBM) requires radiotherapy (RT) as a part of definitive management strategy. RT is highly effective, destroying cancer cells that may exist around the surgical tumor bed. However, GBM still has a poor prognosis and a high local recurrence rate after RT. Accumulating research indicates that GBM contains cancer stem-like cells (CSCs), which are radioresistant and result in therapeutic failure. Additionally, GBM cells can aggressively invade normal brain tissue, inducing therapeutic failure. Using clinical observations, we evaluated the effect of radiation on tumor control. We also explored the biomolecular pathways that connect radioresistance and CSC- and epithelial-mesenchymal transition (EMT)-associated phenotypes in patient-derived GBM cells. Transwell and microarray assay demonstrated that radioresistant GBM cells (GBM-R2I2) exhibit increased invasion and self-renewal abilities compared with parental GBM cells. Finally, to identify potential mechanisms underlying these observations, we used a PCR array to search for molecular markers of cell motility. Signal transducer and activator of transcription 3 (STAT3) directly bound to the Slug promoter in a chromatin immunoprecipitation assay. Reduced STAT3 decreased Slug expression and suppressed cell invasion in GBM-R2I2 cells while increasing Slug reversed these effects. In addition, STAT3 knockdown significantly inhibited CSC properties, synergistically increased the radiotherapeutic effect, and effectively increased the survival rate in vivo. We deciphered a new pathway of GBM radioresistance, invasion, and recurrence via the STAT3/Slug axis that could be a new target of GBM therapy.


Electroacupuncture alleviates nerve injury after cerebra ischemia in rats through inhibiting cell apoptosis and changing the balance of MMP-9/TIMP-1 expression.
Accumulating evidence demonstrates that acupuncture and electroacupuncture (EA) can exert a neuroprotective role for cerebral ischemia, but their precise mechanism remains largely unknown. Therefore, in this study, the effects of EA stimulation on cerebral ischemia reperfusion and its neuroprotective mechanisms were investigated. A rat model of middle cerebral artery occlusion (MCAO) was developed, and EA stimulation (2Hz, 1mA) at Baihui and Siguan acupoints was applied 30min after MCAO and then once daily for 7 consecutive days. The results indicated that EA stimulation significantly reduced the cerebral infarct area and neurological deficit scores, decreased the number of apoptotic cells, up-regulated Bcl-2 protein expression, and down-regulated Bax protein expression. EA stimulation resulted in a significant increase of proliferative cells in the cerebral tissues. Additionally, EA stimulation significantly down-regulated the expression levels of matrix metalloproteinase -9 (MMP-9) mRNA and protein, and simultaneously up-regulated the expression levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA and protein, which resulted in an imbalance of MMP-9/TIMP-1expression, although it did not significantly change MMP-2 and TIMP-2 expression. These findings indicate that EA stimulation at Baihui and Siguan acupoints exerts a neuroprotective role against cerebral ischemia-reperfusion injury, which is probably associated with the inhibition of apoptosis and altering the balance of MMP-9/TIMP-1 expression.


Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy.
Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second-line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. NCT00866697.


Emotional intelligence as a moderator in the stress-burnout relationship: a questionnaire study on nurses.
To investigate inter-relationships between emotional intelligence (EI), work stress and burnout in a group of nurses in the Western Cape Province, South Africa. The moderating effect of EI in the stress-burnout relationship and group differences (nurses working in different wards) in burnout were also investigated. Stress and subsequent burnout commonly threaten the occupational health and well-being of nurses in South Africa and elsewhere. Developing EI in nurses may increase individual stress resistance and combat burnout. A cross-sectional research design with anonymous questionnaires was conducted. Self-report data were used. Survey data were collected from 122 nurses working in different wards at four hospitals from a private hospital group. The Swinburne University Emotional Intelligence Test, Sources of Work Stress Inventory and Maslach Burnout Inventory were used to measure EI, stress and burnout, respectively. Consistent inverse relationships between emotional control and management as dimensions of EI, and stress and burnout emerged. A differential effect of high vs. low EI on the stress-burnout relationship was evident. Workload and the work/family interface emerged as significant predictors of burnout. Respondents working in maternity, paediatric and ER wards reported more feelings of personal accomplishment than those working in general wards. Higher EI is significantly related with lower stress and burnout in a sample of South African nurses. The moderator effect of EI in the stress-burnout relationship suggests that enhanced EI may help diminish burnout development when chronic stress is experienced. EI developmental interventions, if introduced in nursing curricula, may increase emotional coping resources and enhanced social skills, which may benefit the long-term occupational health of nurses. This may be relevant in developing countries, where environmental stressors related to the organisational context (budget constraints) and wider social factors (shortage of qualified nurses) are difficult to address.


Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors.
While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3β-hydroxysteroid dehydrogenase (3β-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3β-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3β-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury.


Hepatotoxicity and metabolic effects of cellular extract of cyanobacterium Radiocystis fernandoi containing microcystins RR and YR on neotropical fish (Hoplias malabaricus).
The toxicological effect of cellular extract of cyanobacterium Radiocystis fernandoi strain R28 containing RR and YR microcystins was analyzed in the fish Hoplias malabaricus with emphasis on the liver structure and energetic metabolism, after short-term exposure. Fish were intraperitoneally (i.p.) injected with 100 μg of equivalent MC-LR kg-1 body mass containing in the cellular extract of R. fernandoi strain R28. Twelve and 96 h post-injection, the plasma, liver and white muscle were sampled for biochemical analyses and liver was also sampled for morphological analyses. After i.p. injection, the activity of acid phosphatase (ACP), alanine aminotransferase (ALT) and direct bilirubin increased in the plasma, while ALT and aspartate aminotransferase (AST) decreased in the liver. Glucose, lactate and pyruvate increased while protein decreased in the plasma; glycogen, pyruvate and lactate decreased in the liver; and glycogen and glucose increased in the muscle. Ammonia increased in the plasma, liver and muscle. The hepatocyte cell shape changed from polyhedral to round after cellular extract injection; there was loss of biliary canaliculus organization, but the biliary duct morphology was conserved in the liver parenchyma. In conclusion, microcystins present in the cellular extract of R. fernandoi strain R28 affect the liver structure of H. malabaricus, but the liver was able to continuously produce energy by adjusting its intermediate metabolism; glycogenolysis and gluconeogenesis maintained glucose homeostasis and energy supply.


Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate.
The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val→IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 × 10(-12), replication cohort p = 3 × 10(-14), combined cohort p = 9 × 10(-24)). We imputed 61 SNPs in CR1, and a "possibly damaging" SNP (rs2274567, His→Arg) in linkage disequilibrium (r(2) = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 × 10(-11), replication p = 7 × 10(-17), and combined cohort p = 2 × 10(-25)). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions.


Gastric-type extremely well-differentiated adenocarcinoma arising in the blind pouch of a bypassed stomach, presenting as colonic pseudo-obstruction.
Gastric carcinoma after gastric bypass is rare. Extremely well-differentiated adenocarcinoma (EWDA) of the stomach is a rare variant that has been mostly reported in Japan. We present a case of a 68-year-old man with EWDA arising in the bypassed stomach that presented as a colonic pseudo-obstruction (CPO). Several imaging, endoscopic and pathologic studies performed in the course of 2 months were non-diagnostic. An iatrogenic duodenal perforation during a diagnostic procedure led to an emergent exploratory laparotomy in which the dilated colonic segment was resected. Pathologic examination showed metastatic EWDA in the colonic wall. Post-operative complications led to the patient's demise. At autopsy the primary tumor was identified in the blind pouch of the bypassed stomach. A literature review on gastric EWDA and carcinomas arising in bypassed stomachs is discussed. EWDA of the stomach is rare, difficult to diagnose, and shows an aggressive clinical course discordant with its near-benign histology. Gastric cancer arising in a bypassed stomach is uncommon; when it occurs it is usually diagnosed at advanced stage. Surveillance of the blind pouch is not currently recommended. Malignant infiltration of the colonic wall should be included in the differential diagnosis of CPO of unclear etiology.