Clinical trials targeting hypoxia.
The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials.


The recruitment of occupational therapy students: a national survey.
This national survey was designed to study selected characteristics of entry level occupational therapy students and to compare recruitment variables in technical and professional students. The survey encompassed 116 programs with 1,843 students responding. Major findings include the following: the median age of professional students was 1 to 2 years older than that of technical students; the technical students had the larger percentage of older students; professional level students chose occupational therapy at an earlier age than did technical students; the majority of minority students were enrolled in technical programs; and students' initial exposure to occupational therapy differed between the technical and professional students: Technical students reported that their earliest contacts with the profession most often came from family friends, college and junior college contacts, high school counselors, and occupational therapy students, in that order. Professional level students reported that their most common initial contact came from occupational therapy students, family friends, parents, a volunteer or employment experience in the field, or health personnel in the field, in that order. Survey data form the basis for a discussion of potential expansion of recruitment strategies.


An on-chip Cell-SELEX process for automatic selection of high-affinity aptamers specific to different histologically classified ovarian cancer cells.
Ovarian cancer (OvCa) is the second most common type of gynecological cancer. More seriously, the prognosis for survival is relatively poor if an early OvCa diagnosis is not achieved. However, it is extremely challenging to diagnose very early stage OvCa, when treatments are the most effective, because of the lack of specific and sensitive biomarkers. Therefore, in order to achieve early detection of OvCa, screening and identifying biomarkers with high specificity and affinity are greatly needed. In this study, an integrated microfluidic system capable of performing cell-based systematic evolution of ligands by an exponential enrichment (Cell-SELEX) process was developed for automatic, high-throughput screening of multiple cell lines to competitively select aptamer-based biomarkers for OvCa. This on-chip Cell-SELEX process only required five rounds of aptamer selection, which is much faster than using a conventional SELEX process (22 rounds). Using this on-chip process, 13 aptamers specific to OvCa cells were successfully screened and three of them showed high affinity towards target cells with dissociation constants of 1.8 nM, 8.3 nM, and 1.3 nM. Analysis of stained fluorescence images and competitive testing against multiple cancer cell lines (cervical cancer, breast cancer, lung cancer, and liver cancer) were performed to verify the specificity of these selected aptamers. The results demonstrated that this developed system could perform the on-chip Cell-SELEX selection successfully and could be applied for personalized aptamer screening or targeted therapy monitoring in the near future.


Oral contraceptives and breast cancer. A prospective cohort study.
In 1976, information on oral contraceptive (OC) use as well as numerous risk factors for breast cancer was provided by 121,964 married female registered nurses aged 30 to 55 years. Ninety-two percent of women in the cohort completed follow-up questionnaires, and vital records were systematically searched to ascertain deaths among nonrespondents. After four years of follow-up, 592 incident cases of breast cancer were identified. Compared with never users, the age-adjusted relative risk (RR) of breast cancer, regardless of menopausal status, among all women who had ever used OCs was 1.0. Among premenopausal women compared with those who had never used OCs, the RR of breast cancer was 1.5 for current use of OCs in 1976 and 1.0 for past use. Among postmenopausal women, the RR for past use of OCs was 1.0. These estimates were essentially unaltered after controlling for other known risk factors for breast cancer in multiple logistic regression analysis. Furthermore, there was no modification of these effects by family history of breast cancer, age at first use, timing of the first birth, or other breast cancer risk factors. Data on past use of OCs provide substantial reassuring evidence that there is no large excess risk of breast cancer within a few years of cessation of pill use. The observed moderate elevation of breast cancer risk with current use was of borderline statistical significance. However, the observation was based on 29 cases and may reflect the effect of sampling variability, as most other studies have not observed a relationship between current use of OCs and breast cancer in women of this age.


An optimization criterion for generalized discriminant analysis on undersampled problems.
An optimization criterion is presented for discriminant analysis. The criterion extends the optimization criteria of the classical Linear Discriminant Analysis (LDA) through the use of the pseudoinverse when the scatter matrices are singular. It is applicable regardless of the relative sizes of the data dimension and sample size, overcoming a limitation of classical LDA. The optimization problem can be solved analytically by applying the Generalized Singular Value Decomposition (GSVD) technique. The pseudoinverse has been suggested and used for undersampled problems in the past, where the data dimension exceeds the number of data points. The criterion proposed in this paper provides a theoretical justification for this procedure. An approximation algorithm for the GSVD-based approach is also presented. It reduces the computational complexity by finding subclusters of each cluster and uses their centroids to capture the structure of each cluster. This reduced problem yields much smaller matrices to which the GSVD can be applied efficiently. Experiments on text data, with up to 7,000 dimensions, show that the approximation algorithm produces results that are close to those produced by the exact algorithm.


Scintigraphic method to quantify the passage from brain parenchyma to the deep cervical lymph nodes in rats.
In order to investigate the kinetics of the passage from the brain parenchyma to the lymphatic system in vivo a high resolution scintillation camera technique was developed. Albumin, albumin colloids and dextran labelled with 99mTc were injected into the right side of the thalamus of anesthetized rats. Continuous measurement of the activity distribution in head and neck were performed for 70 min. Rate constants were calculated by means of a computer program for compartment analysis. The animals were killed 10 h postinjection, to measure the activity in tissue samples. For some animals, images were registered up to 24 h after injection. This work presents an in vivo technique to clarify the particle flow paths in the brain and make quantification possible. The method is simple and does not require continuous blood or lymph sampling. Our work shows that there is a substantial flow of injected material from the brain via lamina cribriformis to the lymphatic system. This route is of great interest for the drainage of the interstitial fluid of the brain. We have also shown a difference in flow for dextran particles with different charge.


Observation of patients with vesicoureteral reflux off antibiotic prophylaxis: physician bias on patient selection and risk factors for recurrent febrile urinary tract infection.
Observation off continuous antibiotic prophylaxis is an option for vesicoureteral reflux. We evaluated the characteristics of patients observed off continuous antibiotic prophylaxis and risk factors for febrile urinary tract infection. We identified children 1 to 18 years old with primary vesicoureteral reflux between January 1, 2010 and December 31, 2010. We excluded patients with prior surgical correction from analysis. We recorded age, gender, race/ethnicity, primary language, insurance carrier, age at vesicoureteral reflux diagnosis, initial presentation and vesicoureteral reflux severity. We quantified bladder and bowel dysfunction with a validated questionnaire if toilet trained. We compared patients off vs on continuous antibiotic prophylaxis with the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. We used a univariate Cox proportional hazards model to assess predictors of febrile urinary tract infection during observation off continuous antibiotic prophylaxis. Of 529 eligible patients 224 were observed off continuous antibiotic prophylaxis. Patients off continuous antibiotic prophylaxis tended to be older (p <0.001), to be older at diagnosis (p <0.001), to have an initial presentation other than febrile urinary tract infection (p = 0.05), to have nondilating vesicoureteral reflux on most recent cystogram (p <0.001) and to have lower bladder/bowel dysfunction scores if toilet trained (p <0.001). Of the patients off continuous antibiotic prophylaxis a febrile urinary tract infection developed in 19 (8.5%). Risk factors associated with febrile urinary tract infection included initial presentation of multiple febrile urinary tract infections (p = 0.03), older age at diagnosis (p = 0.03) and older age starting observation off continuous antibiotic prophylaxis (p = 0.0003). Criteria to select patients with vesicoureteral reflux for observation off continuous antibiotic prophylaxis remain poorly defined in the literature. Observation will fail in a subset of patients with vesicoureteral reflux. Physician biases regarding patient selection for observation off continuous antibiotic prophylaxis should be considered when interpreting studies that evaluate treatment strategies.


A dilemma at gray scale thyroid ultrasound: microcalcification or not? Differentiation with Acoustic Radiation Force Impulse Imaging-Virtual Touch Imaging.
To evaluate the capacity of virtual touch imaging (VTI) of the acoustic radiation force impulse (ARFI) techniquein the differential diagnosis of micro-echogenicities in thyroid nodules. The study comprised 28patients. Gray scale and ARFI displacement maps were used during ultrasound examination.In the same session, fine needleaspiration biopsy (FNAB) samples were obtained from the dominant nodule hav-ing micro-echogenicities. Two radiologists blinded to the FNAB results and clinical data of the patients evaluated these images and rated ARFI echogenicities according to the degree of shining points on the displacement maps and classified them as isohypoechogenic, isohyperechogenic, and obvious hyperechogenic. To differentiate between benignancy and malignancy, "a new sign" was defined as follows: in the ARFI maps obtained by VTI, iso-echogenic or hyper-echogenic appearance of micro-echogenic foci was evaluated as benignancy and hypo-echogenic appearance of micro-echogenic foci was evaluated as malignancy. The FNAB results indicated 14 cases and benign nodules in the other 14 cases. Interobserver agreement between the two radiologists was highly significant for the classification of the micro-echogenic foci (Kappa=0.659, p<0.001). When we reclassified the hyperechoic and isohyperechoic foci as "benign" and isohypoechoic foci as "malignant", the interobserver agreement between the two radiologists increased (Kappa=0.772, p<0.001). The evaluation of the first and second radiologists were highly concordant with the gold standard pathology results (Kappa=0.786, p<0.001 and Kappa=0.714, p<0.001, respectively). ARFI method with specific VTI features could be a very useful tool in the differentiation of malignant microcalcifications in thyroid nodules.


Chromium as a supplement.
Chromium (Cr) is an essential mineral element that has received considerable public attention. The suggestion that Cr intake is generally low has generated interest regarding the purported beneficial effects of Cr supplementation on biological function and health of animals and humans. This review briefly describes key aspects of Cr nutritional status and evaluates the effects of Cr supplementation on various components of biological function, body composition, and health. A novel biological role of Cr in regulation of insulin function is described. Although promising results of Cr supplementation are presented, the considerable challenge of developing methods for routine assessment of Cr nutriture in humans remains.


Markers of sulfadoxine-pyrimethamine resistance in Eastern Democratic Republic of Congo; implications for malaria chemoprevention.
Sulfadoxine-pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap. Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays. Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5-25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3-87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7-47.2%). The dhfr I164L mutation was found in one sample. The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.


A multimodal approach to assess the validity of atrophied T2-lesion volume as an MRI marker of disease progression in multiple sclerosis.
Atrophied T2-lesion volume (LV) is a novel MRI marker representing brain-lesion loss due to atrophy, able to predict long-term disability progression and conversion to secondary-progressive multiple sclerosis (MS). To better characterize atrophied T2-LV via comparison with other multidisciplinary markers of MS progression. We studied 127 MS patients (85 relapsing-remitting, RRMS and 42 progressive, PMS) and 20 clinically isolated syndrome (CIS) utilizing MRI, optical coherence tomography, and serum neurofilament light chain (sNfL) at baseline and at 5-year follow-up. Symbol Digit Modalities Test (SDMT) was obtained at follow-up. Atrophied T2-LV was calculated by combining baseline lesion masks with follow-up CSF partial-volume maps. Measures were compared between MS patients who developed or not disease progression (DP). Partial correlations between atrophied T2-LV and other biomarkers were performed, and corrected for multiple comparisons. Atrophied T2-LV was the only biomarker that significantly differentiated DP from non-DP patients over the follow-up (p = 0.007). In both DP and non-DP groups, atrophied T2-LV was associated with baseline T2-LV and T1-LV (both p = 0.003), absolute change of T1-LV (DP p = 0.038; non-DP p = 0.003) and percentage of brain volume change (both p = 0.003). Furthermore, in the DP group, atrophied T2-LV was related to baseline brain parenchymal (p = 0.017) and thalamic (p = 0.003) volumes, thalamic volume change and follow-up SDMT (both p = 0.003). In non-DP patients, atrophied T2-LV was significantly related to baseline sNfL (p = 0.008), contrast-enhancing LV (p = 0.02) and percentage ventricular volume change (p = 0.003). Atrophied T2-LV is associated with disability accrual in MS, and to several multimodal markers of disease evolution.


Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.
There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4-9·4) with pembrolizumab and 6·9 months (5·9-8·0) with standard of care (hazard ratio 0·80, 0·65-0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Merck Sharp & Dohme, a subsidiary of Merck & Co.


Psychopathic personality traits and delinquent careers: an empirical examination.
Few studies have simultaneously investigated psychopathic traits in relation to assorted dimensions of a delinquent career. The current study examined the role that psychopathy might play in facilitating research on the small subset of youth at risk for persistent antisocial behavior. This study examined psychopathic personality scores using the Antisocial Process Screening Device (APSD) and the Psychopathic Personality Inventory-Short Version (PPI-SV) in a statewide population of 723 juvenile offenders. Psychopathy scores revealed a linear score-response such that higher psychopathy scores were associated with increases in general delinquency (including violent and non-violent forms), hostile aggression, and three forms of early onset delinquency, including offending, police contact, and juvenile court referral. Moreover, negative binomial regression, hierarchical linear regression, and logistic regression models revealed that psychopathy factors possessed utility in predicting all dimensions of the delinquent career net the effects of demographic and available risk factors. Psychopathy should be fully incorporated into criminological investigations of delinquent and criminal careers.


Contextualizing group rape in post-apartheid South Africa.
Collective male sexual violence is part of a continuum of sexual coercion in South Africa. This paper is based on long-term ethnographic work in an urban township in the former Transkei region. Drawing on intensive participant observation and interviews with young men in particular, it attempts to make sense of emergent narratives relating to streamlining, a local term for a not uncommon form of collective sexual coercion involving a group of male friends and one or more women. The paper begins with an overview of existing anthropological literature on collective male sexual violence, going onto elaborate the different scenarios associated with group sexual violence in the fieldsite. It seeks to provide a multi-layered contextualization of the phenomenon by considering prevailing gender discourses, subcultural issues pertaining to the urban tsotsi phenomenon, the rural practice of ukuthwala (bride capture), young working-class Africans' experiences of marginalization, and the complex links between political economy and violence in this setting.


Multiple losses of sex within a single genus of Microsporidia.
Most asexual eukaryotic lineages have arisen recently from sexual ancestors and contain few ecologically distinct species, providing evidence for long-term advantages of sex. Ancient asexual lineages provide rare exceptions to this rule and so can yield valuable information relating to the evolutionary forces underlying the maintenance of sex. Microsporidia are parasitic, unicellular fungi. They include many asexual species which have traditionally been grouped together into large, presumably ancient taxonomic groups. However, these putative ancient asexual lineages have been identified on the basis of morphology, life cycles and small subunit ribosomal RNA (16S rRNA) gene sequences, all of which hold questionable value in accurately inferring phylogenetic relationships among microsporidia. The hypothesis of a single, ancient loss of sex within the Nosema/Vairimorpha group of microsporidia was tested using phylogenetic analyses based on alignments of rRNA and RPB1 gene sequences from sexual and asexual species. Neither set of gene trees supported ancient asexuality, instead indicating at least two, recent losses of sex. Sex has been lost on multiple, independent occasions within the Nosema/Vairimorpha group of microsporidia and there is no evidence for ancient asexual lineages. It appears therefore that sex confers important long-term advantages even upon highly simplified eukaryotes such as microsporidia. The rapid evolution of microsporidian life cycles indicated by this study also suggests that even closely related microsporidia cannot be assumed to have similar life cycles and the life cycle of each newly discovered species must therefore be completely described. These findings are relevant to the use of microsporidia as biological control agents, since several species under consideration as potential agents have life cycles that have been incompletely described.


A novel system to generate WTC dust particles for inhalation exposures.
First responders (FRs) present at Ground Zero within the critical first 72 h after the World Trade Center (WTC) collapse have progressively exhibited significant respiratory injury. The majority (>96%) of WTC dusts were >10 μm and no studies have examined potential health effects of this size fraction. This study sought to develop a system to generate and deliver supercoarse (10-53 μm) WTC particles to a rat model in a manner that mimicked FR exposure scenarios. A modified Fishing Line generator was integrated onto an intratracheal inhalation (ITIH) system that allowed for a bypassing of the nasal passages so as to mimic FR exposures. Dust concentrations were measured gravimetrically; particle size distribution was measured via elutriation. Results indicate that the system could produce dusts with 23 μm mass median aerodynamic diameter (MMAD) at levels up to ≥1200 mg/m(3). To validate system utility, F344 rats were exposed for 2 h to ≈100 mg WTC dust/m(3). Exposed rats had significantly increased lung weight and levels of select tracer metals 1 h after exposure. Using this system, it is now possible to conduct relevant inhalation exposures to determine adverse WTC dusts impacts on the respiratory system. Furthermore, this novel integrated Fishing Line-ITIH system could potentially be used in the analyses of a wide spectrum of other dusts/pollutants of sizes previously untested or delivered to the lungs in ways that did not reflect realistic exposure scenarios.


Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial.
The pathogenesis of reflex sympathetic dystrophy (RSD) is not clear, nor is there a definitive treatment for this syndrome. The morbidity, costs in health care, and loss of work time justify the search for a means to prevent post-traumatic dystrophy. Although the role of toxic oxygen radicals has not yet been clarified, we investigated vitamin C (ascorbic acid) as a prophylactic antioxidant drug. 123 adults with 127 conservatively treated wrist fractures were randomly allocated in a double-blind trial to take a capsule of 500 mg vitamin C or placebo daily for 50 days. Each participant's sex, age, side of fracture, dominance, fracture type, dislocation, reduction, and complaints with the plaster cast were recorded, and they were clinically scored for RSD. The follow-up lasted 1 year. Eight patients were withdrawn after randomisation. 52 patients with 54 fractures (male 22%, female 78%; mean age 57 years) received vitamin C and 63 patients with 65 fractures (male 20%, female 80%; mean age 60 years) received placebo. RSD occurred in four (7%) wrists in the vitamin C group and 14 (22%) in the placebo group 15% (95% CI for differences 2-26). Other significant prognostic variables for the occurrence of RSD were complaints while wearing the cast (relative risk 0.17 [0.07-0.41]) and fracture type (0.37 [0.16-0.89]). This prospective, double-blind study shows that vitamin C was associated with a lower risk of RSD after wrist fractures. Our hypothesis is that this beneficial effect of prophylaxis would be useful in other forms of trauma.


Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression.
Glycoprotein 130 (gp130) is the signal transducing receptor subunit for cytokines of the interleukin-6 (IL-6) family, and it is expressed in a multitude of cell types of the immune and nervous system. IL-6-like cytokines are not only key regulators of innate immunity and inflammation but are also essential factors for the differentiation and development of the somatosensory system. Mice with a null mutation of gp130 in primary nociceptive afferents (SNS-gp130(-/-)) are largely protected from hypersensitivity to mechanical stimuli in mouse models of pathological pain. Therefore, we set out to investigate how neuronal gp130 regulates mechanonociception. SNS-gp130(-/-) mice revealed reduced mechanosensitivity to high mechanical forces in the von Frey assay in vivo, and this was associated with a reduced sensitivity of nociceptive primary afferents in vitro. Together with these findings, transient receptor potential ankyrin 1 (TRPA1) mRNA expression was significantly reduced in DRG from SNS-gp130(-/-) mice. This was also reflected by a reduced number of neurons responding with calcium transients to TRPA1 agonists in primary DRG cultures. Downregulation of Trpa1 expression was predominantly discovered in nonpeptidergic neurons, with the deficit becoming evident during stages of early postnatal development. Regulation of Trpa1 mRNA expression levels downstream of gp130 involved the classical Janus kinase family-signal transducer and activator of transcription pathway. Our results closely link proinflammatory cytokines to the expression of TRPA1, both of which have been shown to contribute to hypersensitive pain states. We suggest that gp130 has an essential role in mechanonociception and in the regulation of TRPA1 expression.


Cellular immune responses induced in cattle by heterologous prime-boost vaccination using recombinant viruses and bacille Calmette-Guérin.
The development of novel vaccine strategies to replace or supplement bacille Calmette-Guérin (BCG) is urgently required. Here we study, in cattle, the use of heterologous prime-boost strategies based on vaccination with BCG and the mycobacterial mycolyl transferase Ag85A (Rv3804c) expressed either in recombinant modified vaccinia virus Ankara (MVA85A) or attenuated fowlpox strain FP9 (FP85A). Five different vaccination schedules were tested in the first experiment: MVA85A followed by BCG (group 1); BCG followed by MVA85A (group 2); BCG followed by FP85A and then MVA85A (group 3); MVA85A followed by MVA85A and then FP85A (group 4); and FP85A followed by FP85A and then MVA85A (group 5). Vaccine-induced levels of cellular immunity were assessed by determining interferon-gamma (IFN-gamma) responses in vitro. Prime-boost protocols, using recombinant MVA and BCG in combination (groups 1-3), resulted in significantly higher frequencies of Ag85-specific IFN-gamma-secreting cells than the two viral vectors used in combination (P=0.0055), or BCG used alone (groups 2 and 3, P=0.04). The T-cell repertoires of the calves in all five groups were significantly broader following heterologous booster immunizations than after the primary immunization. In a second experiment, the effects of BCG\MVA85A heterologous prime-boost vaccination were compared with BCG\BCG homologous revaccination. The results suggested a higher Ag85A-specific response with a wider T-cell repertoire in the MVA85A-boosted calves than in the BCG\BCG-vaccinated calves. In conclusion therefore, the present report demonstrates the effectiveness of heterologous prime-boost strategies based on recombinant MVA and BCG to induce strong cellular immune responses in cattle and prioritise such vaccination strategies for rapid assessment of protective efficacy in this natural target species of tuberculosis.


The physical state of potassium in frog skeletal muscle studied by ion-sensitive microelectrodes and by electron microscopy: interpretation of seemingly incompatible results.
According to the commonly accepted membrane pump theory most of cellular K+ ions are freely dissolved in free cellular water; the alternative association-induction hypothesis postulates that the bulk of cellular K+ is adsorbed (weakly bound) to cellular proteins which are maintained in a specific labile state in the cytoplasm of a living cell. K+ activities measured with ion-sensitive microelectrodes in the cytoplasm of frog skeletal muscle seem to confirm the claim that most of cellular K+ ions are free in cellular water. On the other hand, it is evident from electron microscopic ion binding studies that in frog skeletal muscle most of cellular K+ ions are adsorbed to cellular proteins. The conflicting results can be explained with the assumption that a damage of the cytoplasm caused by the impaling microelectrode leads to a liberation of adsorbed ions. The possibility that microelectrodes damage the muscle cytoplasm is tested by using the light microscope. It is found that microelectrodes produce visible traumas which increase with time. Electron microscopic ion binding studies with damaged muscle support the view that monovalent cations are liberated in the disturbed area of a muscle fiber. It is concluded that a K(+)-sensitive microelectrode is not suited to determine the concentration of free K+ ions in intact frog skeletal muscle.


Phase I trial of subcutaneous interleukin-1 alpha in children with malignant solid tumors.
Interleukin-1 alpha (IL-1 alpha) is myeloprotective in a variety of animal models of cancer chemotherapy and is similarly beneficial in adults treated with carboplatin, 5-fluorouracil, and after autologous bone marrow transplantation. There are no trials of this agent in children. Our purpose was to determine the toxicity and maximum tolerated dose (MTD) of recombinant human interleukin-1 alpha (rhuIL-1 alpha) in children with solid tumors receiving intensive cancer chemotherapy and to evaluate its myelo-protective effects. Cohorts of patients received rhuIL-1 alpha in doses of 0.1-10 micrograms/m2 for 4 days by subcutaneous injection prior to ICF chemotherapy (ifosfamide, 2 g/m2/day x 3, carboplatin targeted to an area under the curve of 8 mg/ml x min on day 1, and etoposide, 100 mg/m2 daily for 3 days). Patients were randomized to receive rhuIL-1 alpha before either the first or second course of therapy. After the MTD of rhuIL-1 alpha was determined an additional group of patients received rhuIL-1 alpha at the dose immediately following ICE chemotherapy. The dose-limiting toxicities of rhuIL-1 alpha in the 27 children tested comprised systemic symptoms of fever, chills, headache, and hypotension. The MTD was 3 micrograms/m2/day. There were no differences in chemotherapy-induced hematologic toxicity with increasing doses of rhuIL-1 alpha or in comparisons before or after ICE chemotherapy. Although rhuIL-1 alpha can be given safely to children receiving myelosuppressive chemotherapy, clinical usefulness would mandate a significant hematopoietic benefit in view of the trouble some side effects identified. We saw no evidence of a hematoprotective effect.


Visualizing Rank Time Series of Wikipedia Top-Viewed Pages.
Visual clutter is a common challenge when visualizing large rank time series data. WikiTopReader, a reader of Wikipedia page rank, lets users explore connections among top-viewed pages by connecting page-rank behaviors with page-link relations. Such a combination enhances the unweighted Wikipedia page-link network and focuses attention on the page of interest. A set of user evaluations shows that the system effectively represents evolving ranking patterns and page-wise correlation.


The validity and reliability of the German version of the Somatoform Dissociation Questionnaire (SDQ-20).
The present study investigated the validity of the German version of the Somatoform Dissociation Questionnaire (SDQ-20), a scale designed to measure somatoform dissociative symptoms. Somatoform dissociation involves physical manifestations of a dissociation of the personality and is considered a unique entity in the phenomenological spectrum of dissociation. The validity and reliability of the German version of the SDQ-20 was examined using a sample of 225 patients with (n = 39) and without dissociative disorders who were recruited from several in- and outpatient psychiatric clinics. Patients were assessed using structured diagnostic interviews; diagnostic checklists; and self-rating scales for dissociation, and posttraumatic stress. Patients with dissociative disorders reported significantly more (p < .001) somatoform dissociative symptoms than patients without dissociative disorders (criterion validity). Significant correlations (p < .001) were found between scores of somatoform dissociation, psychoform dissociation, posttraumatic stress symptoms, and traumatic childhood experiences (construct validity). Reliability was corroborated by a Cronbach's alpha coefficient of .91 and a test-retest correlation of .89. A component factor analysis suggested unidimensionality of the SDQ-20. In conclusion, the psychometric properties and cross-cultural validity of the German version of the SDQ-20 are excellent. Our results form the basis for the further study of somatoform dissociation in German-speaking populations.


The host-encoded Heme Regulated Inhibitor (HRI) facilitates virulence-associated activities of bacterial pathogens.
Here we show that cells lacking the heme-regulated inhibitor (HRI) are highly resistant to infection by bacterial pathogens. By examining the infection process in wild-type and HRI null cells, we found that HRI is required for pathogens to execute their virulence-associated cellular activities. Specifically, unlike wild-type cells, HRI null cells infected with the gram-negative bacterial pathogen Yersinia are essentially impervious to the cytoskeleton-damaging effects of the Yop virulence factors. This effect is due to reduced functioning of the Yersinia type 3 secretion (T3S) system which injects virulence factors directly into the host cell cytosol. Reduced T3S activity is also observed in HRI null cells infected with the bacterial pathogen Chlamydia which results in a dramatic reduction in its intracellular proliferation. We go on to show that a HRI-mediated process plays a central role in the cellular infection cycle of the Gram-positive pathogen Listeria. For this pathogen, HRI is required for the post-invasion trafficking of the bacterium to the infected host cytosol. Thus by depriving Listeria of its intracellular niche, there is a highly reduced proliferation of Listeria in HRI null cells. We provide evidence that these infection-associated functions of HRI (an eIF2α kinase) are independent of its activity as a regulator of protein synthesis. This is the first report of a host factor whose absence interferes with the function of T3S secretion and cytosolic access by pathogens and makes HRI an excellent target for inhibitors due to its broad virulence-associated activities.


Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.
Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.


Cdc42 regulation of kinase activity and signaling by the yeast p21-activated kinase Ste20.
The Saccharomyces cerevisiae kinase Ste20 is a member of the p21-activated kinase (PAK) family with several functions, including pheromone-responsive signal transduction. While PAKs are usually activated by small G proteins and Ste20 binds Cdc42, the role of Cdc42-Ste20 binding has been controversial, largely because Ste20 lacking its entire Cdc42-binding (CRIB) domain retains kinase activity and pheromone response. Here we show that, unlike CRIB deletion, point mutations in the Ste20 CRIB domain that disrupt Cdc42 binding also disrupt pheromone signaling. We also found that Ste20 kinase activity is stimulated by GTP-bound Cdc42 in vivo and this effect is blocked by the CRIB point mutations. Moreover, the Ste20 CRIB and kinase domains bind each other, and mutations that disrupt this interaction cause hyperactive kinase activity and bypass the requirement for Cdc42 binding. These observations demonstrate that the Ste20 CRIB domain is autoinhibitory and that this negative effect is antagonized by Cdc42 to promote Ste20 kinase activity and signaling. Parallel results were observed for filamentation pathway signaling, suggesting that the requirement for Cdc42-Ste20 interaction is not qualitatively different between the mating and filamentation pathways. While necessary for pheromone signaling, the role of the Cdc42-Ste20 interaction does not require regulation by pheromone or the pheromone-activated G beta gamma complex, because the CRIB point mutations also disrupt signaling by activated forms of the kinase cascade scaffold protein Ste5. In total, our observations indicate that Cdc42 converts Ste20 to an active form, while pathway stimuli regulate the ability of this active Ste20 to trigger signaling through a particular pathway.


Sugars, alkaloids, and heteroaromatics: exploring heterocyclic chemistry with alkoxyallenes.
As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal. With this in mind, this Account highlights the versatility of alkoxyallenes as precursors to valuable heterocyclic building blocks for such efforts as natural product synthesis. Accessed by the etherification of either propargyl alcohols or propargylic halides, alkoxyallenes are obtained after base-catalyzed isomerizations of the propargylic ethers. A host of umpolung synthons are available through this scheme after metalation, generating C(3) nucleophiles synthetically equivalent to vital anionic and zwitterionic synthons. Reactions with a diverse set of heteroatomic electrophiles yield carbohydrates, spiroketals, alkaloids, and heteroaromatics via [3 + 2] or [3 + 3] cyclizations. By employing lithiated alkoxyallenes into transformation routes, the natural product chemist can utilize this methodology as a viable resource in stereoselective synthesis. A survey of our own utilization of alkoxyallenes along synthetic pathways toward natural product targets reveals their suitability for generating advantageous precursors. A set of four stereoisomeric 2,6-dideoxyhexoses were stereoselectively obtained after an initial lithiated alkoxyallene and lactaldehyde cyclization, followed by the oxidative ring opening of the dihydrofurans. Through the addition of a lithiated alkoxyallene to a functionalized benzaldehyde, an essential spiroketal diastereomer was rapidly achieved in a few steps. We greatly benefitted from alkoxyallenes in the construction of complex nitrogen-containing synthetic targets, whether pyrrolidine alkaloids, substituted imidazole derivatives, or functionalized pyridines. A pinnacle example of their utility came from the coupling of alkoxyallenes to nitrones affording 1,2-oxazines, which served as a gateway to an array of novel polyfunctionalized compounds such as aminopolyols, hydroxylated pyrrolidines, or carbohydrate mimetics. Alkoxyallenes have proven themselves to be powerful C(3) building blocks toward complex molecular targets, revealing novel pathways to a variety of desirable highly functionalized heterocycles. In our view, the full extent of their synthetic utility has yet to be truly realized.


Coordination of protrusion and translocation of the keratocyte involves rolling of the cell body.
We have investigated the relationship between lamellipodium protrusion and forward translocation of the cell body in the rapidly moving keratocyte. It is first shown that the trailing, ellipsoidal cell body rotates during translocation. This was indicated by the rotation of the nucleus and the movement of cytoplasmic organelles, as well as of exogenously added beads used as markers. Activated or Con A-coated fluorescent beads that were overrun by cells were commonly endocytosed and rotated with the internal organelles. Alternatively, beads applied to the rear of the cell body via a micropipette adhered to the dorsal cell surface and also moved forward, indicating that both exterior and underlying cortical elements participated in rotation. Manipulation of keratocytes with microneedles demonstrated that pushing or restraining the cell body in the direction of locomotion, and squeezing it against the substrate, which temporarily increased the intracellular pressure, did not effect the rate of lamellipodium protrusion. Rotation and translocation of the cell body continued momentarily after arrest of lamellipodium protrusion by cytochalasin B, indicating that these processes were not directly dependent on actin polymerization. The cell body was commonly flanked by phase-dense "axles," extending from the cell body into the lamellipodium. Phalloidin staining showed these to be comprised of actin bundles that splayed forward into the flanks of the lamellipodium. Disruption of the bundles on one side of the nucleus by traumatic microinjection resulted in rapid retraction of the cell body in the opposite direction, indicating that the cell body was under lateral contractile stress. Myosin II, which colocalizes with the actin bundles, presumably provides the basis of tension generation across and traction of the cell body. We propose that the basis of coupling between lamellipodium protrusion and translocation of the cell body is a flow of actin filaments from the front, where they are nucleated and engage in protrusion, to the rear, where they collaborate with myosin in contraction. Myosin-dependent force is presumably transmitted from the ends of the cell body into the flanks of the lamellipodium via the actin bundles. This force induces the spindle-shaped cell body to roll between the axles that are created continuously from filaments supplied by the advancing lamellipodium.


Midline and off-midline infratentorial supracerebellar approaches to the pineal gland.
OBJECTIVE A common approach to lesions of the pineal region is along the midline below the torcula. However, reports of how shifting the approach off midline affects the surgical exposure and relationships between the tributaries of the vein of Galen are limited. The purpose of this study is to examine the microsurgical and endoscopic anatomy of the pineal region as seen through the supracerebellar infratentorial approaches, including midline, paramedian, lateral, and far-lateral routes. METHODS The quadrigeminal cisterns of 8 formalin-fixed adult cadaveric heads were dissected and examined with the aid of a surgical microscope and straight endoscope. Twenty CT angiograms were examined to measure the depth of the pineal gland, slope of the tentorial surface of the cerebellum, and angle of approach to the pineal gland in each approach. RESULTS The midline supracerebellar route is the shortest and provides direct exposure of the pineal gland, although the culmen and inferior and superior vermian tributaries of the vein of Galen frequently block this exposure. The off-midline routes provide a surgical exposure that, although slightly deeper, may reduce the need for venous sacrifice at both the level of the veins from the superior cerebellar surface entering the tentorial sinuses and at the level of the tributaries of the vein of Galen in the quadrigeminal cistern, and require less cerebellar retraction. Shifting from midline to off-midline exposure also provides a better view of the cerebellomesencephalic fissure, collicular plate, and trochlear nerve than the midline approaches. Endoscopic assistance may aid exposure of the pineal gland while preserving the bridging veins. CONCLUSIONS Understanding the characteristics of different infratentorial routes to the pineal gland will aid in gaining a better view of the pineal gland and cerebellomesencephalic fissure and may reduce the need for venous sacrifice at the level of the tentorial sinuses draining the upper cerebellar surface and the tributaries of the vein of Galen.


Tuberculosis Treatment Outcomes Among HIV/TB-Coinfected Children in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Network.
Management of tuberculosis (TB) is challenging in HIV/TB-coinfected children. The World Health Organization recommends nucleic acid amplification tests for TB diagnosis, a 4-drug regimen including ethambutol during intensive phase (IP) of treatment, and initiation of antiretroviral therapy (ART) within 8 weeks of TB diagnosis. We investigated TB treatment outcomes by diagnostic modality, IP regimen, and ART status. We conducted a retrospective cohort study among HIV/TB-coinfected children enrolled at the International Epidemiology Databases to Evaluate AIDS treatment sites from 2012 to 2014. We modeled TB outcome using multivariable logistic regression including diagnostic modality, IP regimen, and ART status. Among the 386 HIV-infected children diagnosed with TB, 20% had microbiologic confirmation of TB, and 20% had unfavorable TB outcomes. During IP, 78% were treated with a 4-drug regimen. Thirty-one percent were receiving ART at the time of TB diagnosis, and 32% were started on ART within 8 weeks of TB diagnosis. Incidence of ART initiation within 8 weeks of TB diagnosis was higher for those with favorable TB outcomes (64%) compared with those with unfavorable outcomes (40%) (P = 0.04). Neither diagnostic modality (odds ratio 1.77; 95% confidence interval: 0.86 to 3.65) nor IP regimen (odds ratio 0.88; 95% confidence interval: 0.43 to 1.80) was associated with TB outcome. In this multinational study of HIV/TB-coinfected children, many were not managed as per World Health Organization guidelines. Children with favorable TB outcomes initiated ART sooner than children with unfavorable outcomes. These findings highlight the importance of early ART for children with HIV/TB coinfection, and reinforce the need for implementation research to improve pediatric TB management.


Spatiotemporal gait parameters during dual task walking in need of care elderly and young adults. A cross-sectional study.
Up to now there have only been marginal data in the elderly in need of care regarding spatiotemporal gait parameters during single (ST) and dual tasking (DT). The aim of this study was to allocate data for gait speed, cadence and stride length cycle variability in the elderly in need of care and in young adults during ST and DT, to compare the two groups and to demonstrate the impact of ST and DT on gait parameters. This cross-sectional study investigated a group of 16 young healthy adults (mean age 23.0 ± 2.5 years) and a group of 16 elderly persons in need of care (mean age 85.5 ± 0.6 years). The RehaWatch system was used to collect the spatiotemporal gait parameters cadence, speed and stride length. The participants completed four different measurements during normal walking and fast walking during ST and DT over a walking distance of 20 m. The Wilcoxon rank sum test and Whitney-U test were used for statistical analysis. Gait speed (ST and DT: p < 0.001), cadence (ST and DT: p < 0.001) and gait variability (ST: p = 0.007, DT: p = 0.003) were significantly reduced in the elderly in need of care group compared to the young group. The gait speed in the elderly in need of care group decreased from normal to fast walking (ST = - 2.8%, DT = - 12.2%) compared to the young group (ST = 31.5%, DT = 25.2%). The results of this study are comparable with the results of existing studies, which investigated falling and non-falling participants. Elderly people in need of care cannot increase the normal gait speed.


Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines.
The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches.


Magnetic resonance imaging in the diagnosis of disc degeneration: correlation with discography.
One hundred and one disc levels in 36 patients with low-back pain were studied with magnetic resonance imaging (MRI) (T2-weighted) sagittal images and conventional roentgenographic discography to detect early disc degeneration. Thirty-nine discs also were evaluated after discography with roentgenographic CT MRI findings were compared with discography results. MRI was 99% accurate in predicting normality or abnormality as determined by discography. Changes in disc signal on MRI accurately reflected the presence or absence of degenerative changes seen on discography in patients with low-back pain. Clinically, MRI is a useful technique for detecting early disc degeneration and for assessing the affected disc level and adjacent levels in patients with low-back pain and spondylolithesis.


Establishment of an Embryotoxicity Assay with Green Fluorescence Protein-expressing Embryonic Cell-derived Cardiomyocytes.
Transgenic embryonic stem cells were used to determine the embryotoxic effects of chemicals on the development of embryonic tissues. This investigation supports an ongoing validation study, aimed at reducing the time-consuming procedure currently in use, and at providing more-objective and more-detailed information on the embryotoxic potentials of chemicals. Green fluorescence protein (GFP) was used as a reporter gene and was linked to a human α-cardiac-specific promoter. The expression of GFP was switched on after specific activation of the human α-actin promoter. This permitted the easy quantification of cardiac cells by using a fluorescence-activated cell sorter (FACS). The percentage of cardiac precursor cells was calculated from the FACS-distribution pattern of cells which fluoresced versus the total number of cells. The percentage of cardiac precursor cells increased from 25% in embryoid bodies on day 3, to 86% on day 7. However, in 11-day-old embryoid bodies, the percentage decreased to 35%. Five chemicals with known embryotoxic potentials were compared with respect to the IC50 (concentration causing 50% inhibition of measured effect) values obtained by various in vitro endpoints (for example, cytotoxicity, morphology). The results showed a higher sensitivity of endpoints used for the analysis of specific effects on the selected target tissue. The data also showed the need to develop in vitro methods with specific endpoints which account for the complexity of embryotoxicology.


Reducing length of stay for women who present as outpatients to delivery suite: A clinical practice improvement project.
Access block is an increasing problem in delivery suites due to the rising birth rates. As well as more labouring women, more women are presenting to delivery suite with pregnancy concerns (at 18 weeks gestation and over). Waiting times for women with pregnancy concerns were prolonged because, prior to the implementation of the present project, these women were required to be assessed by a midwife and then a medical officer. The aim of this project was to safely and effectively reduce the length of stay of pregnant women presenting with pregnancy concerns who were managed as outpatients in the delivery suite. PROJECT SETTING: The project was undertaken in the Delivery Suite of a major tertiary referral hospital, NSW, Australia. The project team used clinical practice improvement methodology (clinical audit, outpatient flow mapping, flowcharting, cause and effect diagrams, brainstorming, multi-voting and Pareto charting) to investigate and propose recommendations to improve the clinical process for this group of women. Five hundred thirty two pregnant women who were not in labour. The interventions involved developing the new clinical midwifery pathways and standing orders for the categories of cases where the midwives were able to assess, order tests and make independent clinical decisions; selecting, training and accrediting the advanced practice midwives; implementing the new clinical pathways; and evaluating the effectiveness, cost and stakeholder satisfaction levels with the changes. The average length of stay was reduced from 178.4 to 91.5min (49%) p<0.001. Approximately 8h a week of midwifery specialist time (AU$33.75 per hour) was estimated to have been saved each week during the project at a cost saving of about AU$270.00 per week. The yearly projected saving would be AU$14,040.00 per annum. The use of advanced practice midwives reduced the overall length of stay for women with pregnancy concerns. There were no adverse events or complaints. Women, midwives and doctors all evaluated the change positively. These findings provide evidence to support this advanced practice midwifery model in other similar maternity services.


Mermaid health - identifying health issues related to mermaiding.
Mermaiding - swimming with a leg-covering monofin mimicking the tail of a mermaid - is an emerging aquatic activity, which has gained a marked popularity over the last few years. However, no study so far has documented the potential health issues or risks of injuries related to this practice. This study surveyed professional mermaids cumulating an estimated total of 19,147 h of in-water mermaiding, regarding their health issues and injuries. While mermaiding bears some risks, the occurrence of problematic conditions appears limited. Interestingly, the profile of health issues experienced by professional mermaids is unique and specific, and clearly different from both professional swimmers and surfers. Self-reported health issues related to mermaiding could be divided into issues specifically related to mermaiding activities (ear issues, reported by 87.5% of the respondents; sea life encounters, 50%; cold-related issues, 37.5%; compromised access to air, 25%), issues related to the tail and fins (back pain, 50%; lower limbs issues, 37.5%), and issues related to water quality (eye issues, 25%; waterborne diseases, 12.5%). Clear differences appear between professional and recreational mermaiding activities. The results presented here will help to build safer conditions for mermaiding activities and to develop adapted responses from health specialists to help this unique yet growing population of aquatic performers and athletes.


The Appearance and Diversification of Receptors for IgM During Vertebrate Evolution.
Three different receptors that interact with the constant domains of IgM have been identified: the polymeric immunoglobulin (Ig) receptor (PIGR), the dual receptor for IgA/IgM (FcαµR) and the IgM receptor (FcµR). All of them are related in structure and located in the same chromosomal region in mammals. The functions of the PIGRs are to transport IgM and IgA into the intestinal lumen and to saliva and tears, whereas the FcαµRs enhance uptake of immune complexes and antibody coated bacteria and viruses by B220+ B cells and phagocytes, as well as dampening the Ig response to thymus-independent antigens. The FcµRs have broad-spectrum effects on B-cell development including effects on IgM homeostasis, B-cell survival, humoral immune responses and also in autoantibody formation. The PIGR is the first of these receptors to appear during vertebrate evolution and is found in bony fish and all tetrapods but not in cartilaginous fish. The FcµR is present in all extant mammalian lineages and also in the Chinese and American alligators, suggesting its appearance with early reptiles. Currently the FcαµR has only been found in mammals and is most likely the evolutionary youngest of the three receptors. In bony fish, the PIGR has either 2, 3, 4, 5 or 6 extracellular Ig-like domains, whereas in amphibians, reptiles and birds it has 4 domains, and 5 in all mammals. The increase in domain number from 4 to 5 in mammals has been proposed to enhance the interaction with IgA. Both the FcαµRs and the FcµRs contain only one Ig domain; the domain that confers Ig binding. In both of these receptors this domain shows the highest degree of sequence similarity to domain 1 of the PIGR. All Ig domains of these three receptors are V type domains, indicating they all have the same origin although they have diversified extensively in function during vertebrate evolution by changing expression patterns and cytoplasmic signaling motifs.


Multiple conversion between the genes encoding bacterial class-I release factors.
Bacteria require two class-I release factors, RF1 and RF2, that recognize stop codons and promote peptide release from the ribosome. RF1 and RF2 were most likely established through gene duplication followed by altering their stop codon specificities in the common ancestor of extant bacteria. This scenario expects that the two RF gene families have taken independent evolutionary trajectories after the ancestral gene duplication event. However, we here report two independent cases of conversion between RF1 and RF2 genes (RF1-RF2 gene conversion), which were severely examined by procedures incorporating the maximum-likelihood phylogenetic method. In both cases, RF1-RF2 gene conversion was predicted to occur in the region encoding nearly entire domain 3, of which functions are common between RF paralogues. Nevertheless, the 'direction' of gene conversion appeared to be opposite from one another-from RF2 gene to RF1 gene in one case, while from RF1 gene to RF2 gene in the other. The two cases of RF1-RF2 gene conversion prompt us to propose two novel aspects in the evolution of bacterial class-I release factors: (i) domain 3 is interchangeable between RF paralogues, and (ii) RF1-RF2 gene conversion have occurred frequently in bacterial genome evolution.


Sleep Deprivation and Advice Taking.
Judgements and decisions in many political, economic or medical contexts are often made while sleep deprived. Furthermore, in such contexts individuals are required to integrate information provided by - more or less qualified - advisors. We asked if sleep deprivation affects advice taking. We conducted a 2 (sleep deprivation: yes vs. no) ×2 (competency of advisor: medium vs. high) experimental study to examine the effects of sleep deprivation on advice taking in an estimation task. We compared participants with one night of total sleep deprivation to participants with a night of regular sleep. Competency of advisor was manipulated within subjects. We found that sleep deprived participants show increased advice taking. An interaction of condition and competency of advisor and further post-hoc analyses revealed that this effect was more pronounced for the medium competency advisor compared to the high competency advisor. Furthermore, sleep deprived participants benefited more from an advisor of high competency in terms of stronger improvement in judgmental accuracy than well-rested participants.


A Case of Hypereosinophilia-Associated Multiple Mass Lesions of Liver Showing Non-Granulomatous Eosinophilic Hepatic Necrosis.
Hypereosinophilic syndrome (HES) is defined by elevation more than 1.5×109/L of presence of a peripheral blood count, evidence of organ involvement, and exclusion of secondary eosinophilia such as allergic, vasculitis, drugs, or parasite infection and also clonal eosinophilia. We present the HES case with hepatic involvement. The patient is 70-year-old male. He complained fever and back pain. Blood examination showed marked peripheral eosinophilia, elevation of transaminase and biliary enzymes. Multiple irregular mass lesions of the liver were pointed out by CT and MRI. The liver biopsy was done for differentiation from malignancy. In parenchyma, hepatic necrotic lesion was observed accompanying severe eosinophilic infiltration with Charcot-Leyden's crystals. There was granulomatous reaction. He was diagnosed as HES and got recovery due to steroid therapy. From the review of HES article, the hepatic histology is categorized into four types as below: 1) cholangitis type; 2) chronic active hepatitis type; 3) vasculopathic type, 4) hepatic necrosis type. Our case is classified in hepatic necrosis type. This type seems to be important to distinguish malignant tumor and also visceral larva migrans by liver biopsy.


Getting the justification for research ethics review right.
Dyck and Allen claim that the current model for mandatory ethical review of research involving human participants is unethical once the harms that accrue from the review process are identified. However, the assumptions upon which the authors assert that this model of research ethics governance is justified are false. In this commentary, I aim to correct these assumptions, and provide the right justificatory account of the requirement for research ethics review. This account clarifies why the subsequent arguments that Dyck and Allen make in the paper lack force, and why the 'governance problem' in research ethics that they allude to ought to be explained differently.


Inflammatory Biomarkers and Mortality Risk Among HIV-Suppressed Men: A Multisite Prospective Cohort Study.
Human immunodeficiency virus (HIV)-induced inflammation and immune activation persist after initiation of combination antiretroviral therapy (cART) and HIV suppression and may contribute to mortality risks that exceed those in HIV-uninfected populations, though associations are unclear. In the prospective Multicenter AIDS Cohort Study, comprising men who have sex with men from Baltimore, Chicago, Los Angeles, and Pittsburgh, concentrations of 24 biomarkers of inflammation and immune activation were measured in stored serum from HIV-positive men obtained after cART-induced HIV suppression between 1996 and 2009. The outcome was nonaccidental death, with follow-up until 2014. We used Cox proportional hazards models to test whether biomarker concentrations predict time from HIV suppression to death and adjusted for multiple tests. Exploratory factor analysis (EFA) was employed to identify groupings of biomarkers that predict mortality risk. Of 670 men followed up from HIV suppression, 54 died by the end of 2013. After adjustment for age, CD4(+) cell count, hepatitis B or C virus infection, and smoking, concentrations in the highest quartile of 4 biomarkers were significantly associated with mortality risk after controlling the false discovery rate at 5%: interleukin (IL) 6 (hazard ratio, 3.54; 95% confidence interval, 2.06-6.10), soluble IL 2Rα (3.29, 1.85-5.85), soluble CD14 (2.67, 1.55-4.61), and chemokine (CXC motif) ligand 13 (CXCL13; 2.26; 1.29-3.95). EFA yielded 2 biomarker groupings that were independent predictors of mortality risk. Despite having undetectable HIV RNA levels during cART, men with higher concentrations of several biomarkers (particularly IL 6, soluble IL 2Rα, soluble CD14, and CXCL13) had higher hazards of long-term mortality. Correlations observed among biomarker concentrations may represent underlying inflammatory processes that contribute to mortality risk.


Interaction between meta-materials and shallow donors in bulk GaN at THz frequency.
We report the coupling and interaction between shallow donors and microcavities in bulk GaN at THz frequencies. At 4K, the shallow donors lead to an absorption at 23.5 meV (5.7 THz) under optical pumping above the bandgap of GaN. The microcavities are based on metamaterials and are designed to resonate around 5.7 THz. At 4 K, the matter-cavity interaction is clearly demonstrated on differential transmission of the sample. The cavity resonance shifts when the absorption occurs. Our model and simulations are in good agreement with the experimental data.


SU-E-I-58: Objective Models of Breast Shape Undergoing Mammography and Tomosynthesis Using Principal Component Analysis.
To develop an objective model of the shape of the compressed breast undergoing mammographic or tomosynthesis acquisition. Automated thresholding and edge detection was performed on 984 anonymized digital mammograms (492 craniocaudal (CC) view mammograms and 492 medial lateral oblique (MLO) view mammograms), to extract the edge of each breast. Principal Component Analysis (PCA) was performed on these edge vectors to identify a limited set of parameters and eigenvectors that. These parameters and eigenvectors comprise a model that can be used to describe the breast shapes present in acquired mammograms and to generate realistic models of breasts undergoing acquisition. Sample breast shapes were then generated from this model and evaluated. The mammograms in the database were previously acquired for a separate study and authorized for use in further research. The PCA successfully identified two principal components and their corresponding eigenvectors, forming the basis for the breast shape model. The simulated breast shapes generated from the model are reasonable approximations of clinically acquired mammograms. Using PCA, we have obtained models of the compressed breast undergoing mammographic or tomosynthesis acquisition based on objective analysis of a large image database. Up to now, the breast in the CC view has been approximated as a semi-circular tube, while there has been no objectively-obtained model for the MLO view breast shape. Such models can be used for various breast imaging research applications, such as x-ray scatter estimation and correction, dosimetry estimates, and computer-aided detection and diagnosis.


Differentiating dengue virus infection from scrub typhus in Thai adults with fever.
Dengue fever and scrub typhus are common infections in Asia that often present as acute febrile illness of unclear etiology. We prospectively evaluated febrile adults presenting to the outpatient department of a hospital in northern Thailand to attempt to identify distinguishing characteristics between the two infections. Fifty-four patients were infected with scrub typhus and 35 were infected with dengue virus. Dengue virus infection was associated with hemorrhagic manifestations, particularly bleeding from the gums, which was reported by 27% of the dengue patients, but by none of the scrub typhus patients (P < 0.001, by Fisher's exact test). A low platelet count (< 140,000/mm3) and low white blood cell count (< 5,000/mm3) were strongly associated with dengue infections: odds ratio = 26.3 (95% confidence interval [CI] = 7.4-93.2) for platelet count and 8.2 (95% CI = 2.6-25.5) for leukocyte count. Prospective evaluations of the usefulness of these simple criteria to differentiate scrub typhus from dengue infection are needed in other areas, particularly where rapid confirmatory diagnostic tests are not available.


Inhaled oxygen and cluster headache sufferers in the United States: use, efficacy and economics: results from the United States Cluster Headache Survey.
To present results from the United States Cluster Headache Survey concerning the use of inhaled oxygen as acute treatment for cluster headache (CH). Several small clinic and community-based investigations have indicated that more than 50% of CH patients have never used oxygen for the treatment of their headaches. This statistic is alarming and the reasons why they have not tried oxygen have not been determined. The United States Cluster Headache Survey is the largest study ever completed looking at CH sufferers living in the United States. The total survey consisted of 187 multiple choice questions, 84 questions dealt with oxygen use, efficacy and economics. The survey was placed on a website from October to December 2008. A total of 1134 individuals completed the survey (816 male, 318 female). Among them 868 patients had episodic CH while 266 had chronic CH. Ninety-three percent of survey responders were aware of oxygen as a CH therapy; however, 34% had never tried oxygen. Forty-four percent of patients had to suggest oxygen to their physicians to get prescribed. Twelve percent of physicians refused to prescribe oxygen. Fifty percent using oxygen never received training on proper use. Forty-five percent had to find their own source for oxygen. On prescriptions only 45% specified flow rate, 50% stated CH as diagnosis and 28% indicated mask type. Seventy percent of the surveyed population felt oxygen was effective but only 25% was presently using oxygen. Potential reasons for this finding include: oxygen is slow to onset; prescribed oxygen flow rates are too low for efficacy and most CH patients need to raise flow rates during attacks to achieve response. The efficacy of oxygen does not vary by the age of the patient, gender, the number of CH attacks per day, and smoking history. Episodic CH responds better and faster to inhaled oxygen than chronic CH. Oxygen plus a triptan may be more efficacious and faster at aborting a CH than a triptan alone. Sixteen percent of CH patients state that oxygen is unaffordable while 12% are getting welder grade oxygen because of costs of medical grade oxygen, and this form of oxygen could be potentially dangerous to the individual user. Oxygen is underutilized by CH patients living in the United States. Current recommended oxygen treatment regime is not meeting the needs of many CH patients. Prescribed oxygen flow rates are too low for efficacy. Oxygen can be expensive and very difficult to obtain. Physicians need to be better educated on the use of inhaled oxygen for CH.


Dexmedetomidine versus Remifentanil for Sedation during Awake Fiberoptic Intubation.
This study compared remifentanil and dexmedetomidine as awake fiberoptic intubation (AFOI) anesthetics. Thirty-four adult ASA I-III patients were enrolled in a double-blinded randomized pilot study to receive remifentanil (REM) or dexmedetomidine (DEX) for sedation during AFOI (nasal and oral). Thirty patients completed the study and received 2 mg midazolam IV and topical anesthesia. The REM group received a loading dose of 0.75 mcg/kg followed by an infusion of 0.075 mcg/kg/min. The DEX group received a loading dose of 0.4 mcg/kg followed by an infusion of 0.7 mcg/kg/hr. Time to sedation, number of intubation attempts, Ramsay sedation scale (RSS) score, bispectral index (BIS), and memory recall were recorded. All thirty patients were successfully intubated by AFOI (22 oral intubations/8 nasal). First attempt success rate with AFOI was higher in the REM group than the DEX group, 72% and 38% (P = 0.02), respectively. The DEX group took longer to attain RSS of ≥3 and to achieve BIS <80, as compared to the REM group. Postloading dose verbal recall was poorer in the DEX group. Dexmedetomidine seems a useful adjunct for patients undergoing AFOI but is dependent on dosage and time. Further studies in the use of dexmedetomidine for AFOI are warranted.


Correction of total anomalous pulmonary venous connection of the cardiac type.
Surgical treatment of the cardiac type of total anomalous pulmonary venous connection requires special techniques. The treatment and outcome in 17 consecutive patients who had undergone primary repairs of the cardiac type between 1965 and 1996 were reviewed. The median age was 3 months and median weight 4.2 kg. The connection was the coronary sinus in ten patients, and the right atrium in six. Interatrial communication was routinely augmented. The right atrial cavity was partitioned using a patch to direct the anomalous pulmonary veins into the left atrium through the atrial septal defect in the first 13 patients. In the last four patients, the free wall flap of the right atrium was developed as a neoseptum. There were three early postoperative deaths during the early period of conventional repair. Two patients developed residual or recurrent diffuse obstruction in the individual lobar veins; reoperation to relieve the obstruction was attempted but unsuccessful. One sudden death occurred in a patient with occasional heart block. Ten survivors have been asymptomatic during follow-up, but two incomplete heart blocks and one atrial flutter were noted among patients who underwent conventional repair. The right atrial wall flap technique was not associated with any mortality or morbidity, such as arrhythmia and recurrent pulmonary vein stenosis during 12 to 63 months of postoperative obstruction. In conclusions, a flap technique using the right atrial wall appears to be a promising method to decrease the incidence of supraventricular arrhythmias and pulmonary vein drainage obstruction following repair of the cardiac type.


Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome.
Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome. VIDEO ABSTRACT.


Blastogenic responses of peripheral blood leukocytes from owl monkeys experimentally infected with Leishmania braziliensis panamensis.
The relationship of the progression and regression of cutaneous lesions of 6 owl monkeys (Aotus trivirgatus) to the responses of their peripheral blood leukocytes (PBL) in vitro to mitogens and to leishmanial antigens, as well as their delayed skin test responses (DTH) in vivo to leishmanin antigen, were studied after primary and challenge infections with Leishmania braziliensis panamensis (WR 128 or WR 539). All 6 infected monkeys developed primary and satellite cutaneous leishmanial lesions which were measured for up to 30 weeks in 3 of the monkeys and up to 52 weeks in the other 3 monkeys. Two owl monkeys which had recovered from cutaneous leishmaniasis demonstrated acquired resistance when challenged with an intradermal inoculation of L. b. panamensis (WR 128). Reactivity of PBL from infected owl monkeys to PHA, Con A, and PWM was similar during primary and challenge infections to that observed prior to infection. Reactivity to leishmanial antigens was detected at 20 to 28 weeks post-infection (PI), became statistically significant after 28 weeks and remained elevated up to 52 weeks PI and after challenge infections. During primary infections DTH responses to leishmanin antigen were detected as early as 8 weeks PI, and continued up to 27 weeks PI. After challenge infections DTH reactivity was positive at 25 and 37 weeks, the only times the response was evaluated. The immunological responses of owl monkeys to L. b. panamensis were similar in many respects to those observed in humans with localized cutaneous leishmaniasis. This nonhuman primate model should be useful for future studies involving the immunology and chemotherapy of cutaneous leishmaniasis.


Nanoimprinted plasmonic nanocavity arrays.
We demonstrate high resonant absorption of visible light with a plasmonic nanocavity chain structure fabricated through resistless nanoimprinting in metal (RNIM). The RNIM approach provides a simple, reproducible, and accurate means to fabricate metallic nanopatterns with high fidelity. The nanocavities are shown to be efficiently excited using normally incident light, and the resonant wavelength can be controlled by either the width or the depth of the cavity. Numerical simulations confirm the experimental observations, and illustrate the behavior of the nanocavity chain waveguide and insensitivity to incident angle. The resonant absorption is due to the excitation of a localized metal-insulator-metal cavity mode. The interacting surface waves allow cavity lengths on the order of ten nanometers for light having a free space wavelength of about four hundred nanometers. Coupling of the cavities with an intervening surface plasmon wave results in a collective excitation and a chain waveguide mode that should prove valuable for more sensitive detection based on surface enhanced Raman scattering.


Hepatitis C.
Hepatitis C virus (HCV) infection is a major health problem worldwide. The effects of chronic infection include cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As a result of shared routes of transmission, co-infection with HIV is a substantial problem, and individuals infected with both viruses have poorer outcomes than do peers infected with one virus. No effective vaccine exists, although persistent HCV infection is potentially curable. The standard of care has been subcutaneous interferon alfa and oral ribavirin for 24-72 weeks. This treatment results in a sustained virological response in around 50% of individuals, and is complicated by clinically significant adverse events. In the past 10 years, advances in HCV cell culture have enabled an improved understanding of HCV virology, which has led to development of many new direct-acting antiviral drugs that target key components of virus replication. These direct-acting drugs allow for simplified and shortened treatments for HCV that can be given as oral regimens with increased tolerability and efficacy than interferon and ribavirin. Remaining obstacles include access to appropriate care and treatment, and development of a vaccine.


The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors.
The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.


Coping and Anxiety in Caregivers of Dependent Older Adult Relatives.
The aim of this study was to analyze the relationship between coping and anxiety in caregivers of dependent older adult relatives. A cross-sectional study was carried out in the province of Jaén (Andalusia, Spain). The convenience sample consisted of 198 family caregivers of dependent older adults. The main measurements were anxiety (Hamilton scale), coping (Brief COPE), subjective burden (Caregiver Strain Index), objective burden and sex of the caregiver. The main analyses were bivariate analysis using the Pearson correlation coefficient, and multivariate analysis using multiple linear regression. An independent regression model was developed for anxiety and each type of coping, adjusting for sex, subjective burden and objective burden. Our results demonstrate that anxiety was negatively associated with planning (partial r = -0.18), acceptance (partial r = -0.22) and humor (partial r = -0.20), and it was positively associated with self-distraction (partial r = 0.19), venting (partial r = 0.22), denial (partial r = 0.27) and self-blame (partial r = 0.25). Planning, acceptance and humor coping strategies may be protective factors of anxiety. Strategies such self-management, relief, denial and self-blame may be risk factors for anxiety.


Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS.
Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited. To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden. We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF (n = 641) or interferons/glatiramer acetate (IFN/GA; n = 555) as the initial therapy, or DMF (n = 703) or fingolimod (FGL; n = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016. The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy (p < 0.05 and p = 0.20, respectively). Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.


Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy.
Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.


Centrum use and progression of age-related cataract in the Age-Related Eye Disease Study: a propensity score approach. AREDS report No. 21.
To evaluate the effect of the multivitamin Centrum on the development and progression of age-related lens opacities. Clinic-based prospective cohort study. Four thousand five hundred ninety individuals with at least one natural lens and photographic follow-up (median, 6.3 years) were assessed for development or progression of lens opacities. Progression of "any" lens opacity or type-specific opacity was ascertained from lens photographs taken at baseline and at annual visits beginning at year 2. The Age-Related Eye Disease Study (AREDS) showed no statistically significant effect of a high-dose antioxidant formulation on progression of lens opacities. Centrum also was provided to approximately two thirds of the study participants. Because Centrum use was elective, a logistic regression model of baseline characteristics was used to generate a propensity score for Centrum use. Repeated-measures logistic regression, adjusted for propensity score and other covariates, was used to evaluate associations of Centrum use and lens opacity. Centrum use, adjusted for propensity score and other covariates, was associated with a reduction in "any" lens opacity progression (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.72-0.98, P = 0.025). Results for individual lens opacity types suggested that Centrum use was protective for nuclear opacity events (OR = 0.75, 95% CI = 0.61-0.91, P = 0.004). Observational data from the AREDS and other studies suggest that use of a multivitamin may delay the progression of lens opacities. A National Eye Institute-sponsored clinical trial scheduled for completion in 2007 will provide additional data on Centrum use and cataract development.


Sepsis: an arginine deficiency state?
Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid L-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis. This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO. In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall. Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.


Major histocompatibility complex diversity influences parasite resistance and innate immunity in sticklebacks.
Proteins of the major histocompatibility complex (MHC) play a central role in the presentation of antigens to the adaptive immune system. The MHC also influences the odour-based choice of mates in humans and several animal taxa. It has recently been shown that female three-spined sticklebacks (Gasterosteus aculeatus) aim at a moderately high MHC diversity in their offspring when choosing a mate. Do they optimize the immune systems of their offspring? Using three-spined sticklebacks that varied in their individual numbers of MHC class IIB molecules, we tested, experimentally, whether allelic diversity at the MHC influences parasite resistance and immune parameters. We found that sticklebacks with low MHC diversity suffered more from parasite infection after experimental exposure to Schistocephalus solidus tapeworms and Glugea anomala microsporidians. They also showed the highest proportion of granulocytes and the strongest respiratory burst reaction, which are correlates of innate immunity. This indicates a strong activity of the innate immune system after challenge by parasites when MHC diversity is suboptimal. Individuals with very high allelic diversity at the MHC seemed inferior to those with moderately high diversity. Such a pattern is consistent with theoretical expectations of an optimal balance between the number of recognizable antigens and self-tolerance.


Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population.
Whether a recent large decline in use of postmenopausal hormone therapy after the release of the Women's Health Initiative findings in July 2002 and/or a decline in screening mammography use is related to a recently reported decline in breast cancer incidence in the United States is controversial. We prospectively collected data from four screening mammography registries from January 1997 through December 2003 for 603411 screening mammography examinations performed on women aged 50-69 years. Of these women, 3238 were diagnosed with breast cancer within 12 months of a screening examination. We calculated quarterly rates of self-reported current postmenopausal hormone therapy use and of invasive breast cancer, ductal carcinoma in situ (DCIS), and estrogen receptor (ER)-positive invasive breast cancer adjusted for age, registry, and time between screening examinations. All statistical tests were two-sided. Between 2000 and 2002 and between 2002 and 2003, annual rates of postmenopausal hormone therapy use declined by 7% and 34%, respectively (P(trend) < .001 for both). Between 2000 and 2003, annual rates of invasive cancer declined by 5% (P(trend) = .003). Between 2001 and 2003, annual rates of ER-positive invasive breast cancer declined by 13% (P(trend) = .002). Rates of DCIS were stable during the study period. Our finding of a statistically significant decline in the rate of ER-positive invasive breast cancer in a screening mammography population after the start of a concomitant substantial decline in postmenopausal hormone therapy use suggests that a decline in screening mammography rates is unlikely to account for the recent decline in US breast cancer incidence.