Intraoperative ultrasound with contrast medium in resective pancreatic surgery: a pilot study.
The introduction of contrast-enhanced ultrasound has been a major innovation in liver and pancreatic imaging. Previous studies have validated its intraoperative use during liver surgery, while there is a lack of data regarding its use during pancreatic surgery. The purpose of the present study was to prospectively evaluate the possible role of contrast-enhanced intraoperative ultrasound (CEIOUS) during resective pancreatic surgery for primary lesion characterization and intraoperative staging. Thirty-four patients (70% males, mean age 67.9 years) were selected for pancreatic surgery between October 2006 and July 2009. All patients underwent intraoperative ultrasound with intravenous injection of 4.8 mL sulfur-hexafluoride microbubbles. Location of the primary tumor, relation to the main vessels, contrast medium uptake modalities, presence of liver metastases, and multifocal pancreatic involvement were evaluated. The majority of operations were pancreatoduodenectomies (70.6%) performed for pancreatic ductal adenocarcinoma (64.7%). Additional lesions were detected by ultrasound in six patients (17.6%: liver metastases in four patients, a hemangioma in one patient, and a further pancreatic lesion in one patient). In five of these patients (5/34, 14.7%) surgical management was modified by these findings. All these new findings were diagnosed before injection of contrast medium, except for a metastasis from a neuroendocrine tumor; the characterization of the hemangioma was possible only after contrast injection. Intraoperative findings regarding location of primary tumor, relation to the main vessels, and lesion characterization did not differ from those obtained with preoperative imaging. In our experience intraoperative ultrasound is a valid technique for intraoperative staging prior to pancreatic resection; it is unclear whether, in pancreatic surgery, the addition of contrast enhancement adds any benefit to traditional intraoperative ultrasound.


Evaluating Financial Conflicts of Interest Among Contributors to Clinical Practice Guidelines of the American College of Obstetricians and Gynecologists.
Patient care is an essential part of the practice of obstetrics and gynecology, and patient care is directed by clinical practice guidelines. To increase the validity of these guidelines, we must make sure that there is no outside influence by financial conflicts of interest. To investigate the existence of and reporting patterns regarding payments received by contributors to guidelines from the American College of Obstetricians and Gynecologists (ACOG), ACOG executive committee members, and companies making these payments and to examine the compliance of those receiving payments to ACOG's conflict of interest policies. The Center for Medicare and Medicaid's Open Payments database was used to search practice bulletin committee members and practice bulletin collaborators from 2014-2016, as well as current executive committee board members. Open Payments was also used to evaluate companies that provided payments, and amounts were totaled. The main outcome measure was the monetary values of payments received and the compliance with disclosure statements enforced by ACOG. Manufacturer payments to physicians in the database were analyzed descriptively. General and research payments were calculated among 65 physicians in the Open Payments database: 44 physician members of both the obstetrics and the gynecology practice bulletin committees, 4 2016 ACOG executive board physician members, and 17 contributing physician authors. Research payments accounted for greater than 78% of all payments. Consulting, travel and lodging, and speaking fees totaled greater than $90,000 and contributed to more than 90% of the total amount of general payments. Food and beverage payments contributed to 10% of all general payments. Three covered members were noncompliant with the financial conflicts of interest guidelines, receiving industry payments exceeding $5000. A small number of companies provide the majority of contributions; however, there is no evidence to suggest bias toward manufactures within ACOG practice bulletins. Future investigations into pharmaceutical manufacturer payments, specifically for consulting fees, may be warranted. (Clinical Trial Registry UMIN-CTR, UMIN000029165).


Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons.
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the misfolded conformation of SOD1. These results suggest that an increased expression level of wild-type SOD1 may accelerate the ALS pathology and that our in vitro model would be a useful tool for misfolded SOD1 research.


Coherent transient amplification in inhomogeneously broadened rubidium atoms by diode-laser frequency switching.
We report observation of coherent transient amplification that is due to free-induction decay and optical nutation in inhomogeneously broadened rubidium atoms by a sudden switch of diode-laser frequency. An amplification coefficient of 2.2 x 10(-2) cm(-1) is observed when the diode-laser frequency, initially tuned to the blue side of the Doppler-broadened absorption profile, is switched to be out of resonance by application of a step-function pulsed injection current. The transition from free-induction decay to optical nutation is observed and discussed.


Clinical Results and Prognostic Factors of Arthroscopic Surgeries for Discoid Lateral Menisci Tear: Analysis of 179 Cases with Minimum 2 Years Follow-up.
The purpose of this study was to evaluate the clinical results and prognostic factors of arthroscopic surgeries for tears of the discoid lateral menisci. From March 1997 to September 2005, 260 patients received arthroscopic surgeries due to discoid lateral menisci tears. Among these patients, 179 knees in 168 patients were followed up for at least 2 years and were enrolled into this study. The following prognostic factors were evaluated: sex, age, symptom duration, and type of meniscal tear. Visual analogue score (VAS), Lysholm score, and Ikeuchi grade were assessed as clinical results of arthroscopic surgeries. The mean VAS and Lysholm score improved at the last follow-up. According to the Ikeuchi grade, 104 cases were rated as excellent, 51 cases as good, and 23 cases as fair. Male sex (p<0.033), age younger than 20 years (p=0.0474), and symptom duration less than 12 months (p<0.044) were good prognostic factors. However, there was no correlation between tear types of discoid lateral menisci and clinical results. Sex, age, and symptom duration could be significant prognostic factors of arthroscopic surgeries for tears of discoid lateral menisci.


Examining health promotion interventions for patients with chronic conditions using a novel patient-centered complexity model: protocol for a systematic review and meta-analysis.
Successful chronic care self-management requires adherence to healthy lifestyle behaviors, but many healthcare-based health promotion interventions have resulted in small and unsustainable changes in patient behavior. Patients with chronic conditions may already be overwhelmed by burdensome illnesses and treatments, and not have the capacity to respond well to the additional work required of behavior modifications. To explore this phenomenon, we will apply the cumulative complexity model (CCM), a patient-centered model of patient complexity, to a systematic review and meta-analysis of healthcare-based health behavior interventions. This systematic review will include randomized trials published between 2002 and 2012 that compared healthcare-based interventions aimed at improving healthy diet and physical activity in community dwelling adult patients with chronic conditions. After extracting study and risk of bias features from each trial, we will classify the interventions according to the conceptual model. We will then use meta-analysis and subgroup analysis to test hypotheses based on the conceptual model. Healthcare providers need evidence of successful health promoting interventions for patients with chronic conditions who display common behavioral risk factors. To better understand how patients respond to interventions, we will apply the CCM, which accounts for both the capacity of patients with chronic conditions and their treatment-related workload, and posits that a balance between capacity and workload predicts successful enactment of self-care. Analysis will also include whether patients with multiple chronic conditions respond differently to interventions compared to those with single chronic conditions. The results of this review will provide insights as to how patients with chronic conditions respond to health-promoting interventions. PROSPERO registration number: CRD42012003428.


Visceral adiposity is related to insulin sensitivity and inflammation in adolescents with obesity and mild sleep disordered breathing.
To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO2; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO2; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO2 nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.


Settings and artefacts relevant for Doppler ultrasound in large vessel vasculitis.
Ultrasound is used increasingly for diagnosing large vessel vasculitis (LVV). The application of Doppler in LVV is very different from in arthritic conditions. This paper aims to explain the most important Doppler parameters, including spectral Doppler, and how the settings differ from those used in arthritic conditions and provide recommendations for optimal adjustments. This is addressed through relevant Doppler physics, focusing, for example, on the Doppler shift equation and how angle correction ensures correctly displayed blood velocity. Recommendations for optimal settings are given, focusing especially on pulse repetition frequency (PRF), gain and Doppler frequency and how they impact on detection of flow. Doppler artefacts are inherent and may be affected by the adjustment of settings. The most important artefacts to be aware of, and to be able to eliminate or minimize, are random noise and blooming, aliasing and motion artefacts. Random noise and blooming artefacts can be eliminated by lowering the Doppler gain. Aliasing and motion artefacts occur when the PRF is set too low, and correct adjustment of the PRF is crucial. Some artefacts, like mirror and reverberation artefacts, cannot be eliminated and should therefore be recognised when they occur. The commonly encountered artefacts, their importance for image interpretation and how to adjust Doppler setting in order to eliminate or minimize them are explained thoroughly with imaging examples in this review.


Angiogenesis in pituitary adenomas - relationship to endocrine function, treatment and outcome.
Angiogenesis has been shown to be related to tumour behaviour, prognosis and response to treatment in many different tumour types. The aim of this study was to examine the relationship between angiogenesis and tumour behaviour and response to treatment in pituitary adenomas. The microvessel density (MVD) of pituitary tumours was assessed by counting blood vessels labelled with 3 different endothelial markers using antibodies to CD31, factor eight-related antigen and biotinylated Ulex europaeus (agglutinin I UEAI). One hundred and forty-two surgically removed pituitary adenomas (46 GH secreting, 6 microprolactinomas, 19 macroprolactinomas, 18 ACTH secreting and 53 functionless tumours) were carefully characterized and assessed. There was a significant negative correlation between age and MVD of GH secreting tumours (R(2)=33.8, P=0.005). Age was not related to MVD in other tumour types. Pre-treatment hormone production by the adenomas was related to MVD in prolactinomas (P<0.05), but not in GH secreting tumours. Invasive prolactinomas were significantly more vascular than non-invasive tumours (P<0.05). Drug treatment with metyrapone or bromocriptine did not appear to influence tumour angiogenesis. Surgical cure was more likely in macroprolactinomas and in ACTH secreting tumours with lower MVD. These results show that factors related to angiogenesis are very important in determining a number of clinical features of pituitary tumours, in particular the invasiveness of macroprolactinomas, the effect of age in tumours secreting GH and the outcome of surgical treatment in macroprolactinomas and ACTH secreting tumours.


An approach to predict the ductus-arteriosus dilating effect induced by lipo-prostaglandin E1 in newborn rats lacking plasma concentration-time data by the pharmacological response kinetic model.
The usefulness of kinetic analysis of pharmacological response data was discussed in investigating the ductus arteriosus dilating effect (DADE) of lipo-PGE1 (a lipid emulsion preparation of prostaglandin E1 for injection) preparations. Lipo-PGE1 was administered intravenously via the umbilical vein by a bolus injection or an infusion in newborn rats 60 min after the delivery. The DADE data were expressed as the inner diameter ratio between the ductus arteriosus and the main pulmonary artery, and were analyzed by a pharmacological response kinetic (PRK) model consisting of an Emax model and a simple pharmacokinetic model as the pharmacodynamic- and the pharmacokinetic-component, respectively. The latter component includes the release process of free-PGE1 from the lipid phase of lipo-PGE1, followed by distribution to the effect compartment. The Emax value was estimated by the maximal DADE observed 10 min after the bolus administration of each dose, and the value was fixed in the PRK analysis. The regression curves given by simultaneous non-linear least squares regression analysis were satisfactorily fitted to the observed DADE data at all doses. Prediction of the DADE of lipo-PGE1 in an infusion study was satisfactorily done using the estimated parameters in the i.v.-study. These findings indicate that PRK modeling based on the intensities of the observed pharmacological response-time data is a meaningful tool in some targeting-type drugs, for which pharmacokinetic analysis itself is meaningless or acquisition of pharmacokinetic data is technically impossible, in predicting the time courses of the drug's pharmacological response in different dosage regimens.


Evolution of epitope-specific memory CD4(+) T cells after clearance of hepatitis C virus.
The generation of memory lymphocytes is one of the hallmarks of the specific immune response. The CD4(+) T cell response is of critical importance in maintaining long-term protective immunity after clearing many infections. However, accurate characterization of these memory CD4(+) T cells has relied mainly on mouse studies and is poorly understood in humans. We have detected and counted epitope-specific populations of CD4(+) memory cells in patients who have cleared hepatitis C virus. The kinetics of the recall response and the expression of the chemokine receptor CCR7 suggested the presence of distinct populations. A population of memory cells measured in an ex vivo IFN-gamma ELISPOT assay steadily declined after viral clearance. However, memory CD4(+) T cells only characterized after short-term culture with Ag and IL-2, and, recognizing the same epitopes, developed into a long-term stable population. Depletion of CCR7(+) cells from PBMCs markedly reduced the responses in the culture-positive population while having little effect on the ex vivo responses. The demonstration of these key memory subsets in man opens the way to defining their role in protective immune responses.


Beyond registration--measuring the public-health potential of new treatments for malaria in Africa.
Malaria claims over one million lives a year in some of the poorest countries of the world. Affected populations and governments cannot afford to pay for expensive new therapies. Most antimalarial treatments are purchased from local shops and administered in the home. These factors make for a complex set of requirements for any new treatment for malaria if a substantial reduction in mortality is ever to be achieved. Thankfully there are several treatments being developed, mostly within public-private partnerships. Typically, the goal of public-private partnerships is the granting of a product license, so work plans end after phase III trials. As these drugs will ultimately be used unsupervised, malaria control programme managers will require further data on safety and whether the drug is as efficacious when used outside of controlled clinical trials before allowing widespread use of these new products. These data need to be collected in highly specific phase IV programmes. We explain why public-private partnerships should extend their development plans well beyond drug registration, and set out the requirements of such a programme. We aim to generate debate and discussion so that guidelines that are internationally accepted and adhered to can be developed not only for antimalarials but for all drugs that are being developed specifically for use in resource-poor settings.


Mixed-phenotype acute leukemia: state-of-the-art of the diagnosis, classification and treatment.
Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of hematopoietic malignancies in which blasts show markers of multiple developmental lineages and cannot be clearly classified as acute myeloid or lymphoblastic leukemias. Historically, various names and classifications were used for this rare entity accounting for 2-5% of all acute leukemias depending on the diagnostic criterias used. The currently valid classification of myeloid neoplasms and acute leukemia published by the World Health Organization (WHO) in 2016 refers to this group of diseases as MPAL. Because adverse cytogenetic abnormalities are frequently present, MPAL is generally considered a disease with a poor prognosis. Knowledge of its treatment is limited to retrospective analyses of small patient cohorts. So far, no treatment recommendations verified by prospective studies have been published. The reported data suggest that induction therapy for acute lymphoblastic leukemia followed by allogeneic hematopoietic cell transplantation is more effective than induction therapy for acute myeloid leukemia or consolidation chemotherapy. The establishment of cooperative groups and international registries based on the recent WHO criterias are required to ensure further progress in understanding and treatment of MPAL. This review summarizes current knowledge on the diagnosis, classification, prognosis and treatment of MPAL patients.


Corticotropin-releasing hormone interacts with interleukin-1β to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor.
The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor. Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression. In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6-18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH. CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators.


Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.
We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis. We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12. Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group. Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).


Perceiving the passage of time: neural possibilities.
Although the study of time has been central to physics and philosophy for millennia, questions of how time is represented in the brain and how this representation is related to time perception have only recently started to be addressed. Emerging evidence subtly yet profoundly challenges our intuitive notions of time over short scales, offering insight into the nature of the brain's representation of time. Numerous different models, specified at the neural level, of how the brain may keep track of time have been proposed. These models differ in various ways, such as whether time is represented by a centralized or distributed neural system, or whether there are neural systems dedicated to the problem of timing. This paper reviews the insight offered by behavioral experiments and how these experiments refute and guide some of the various models of the brain's representation of time.


Upfront triple combination therapy in severe paediatric pulmonary arterial hypertension.
Treatment strategies in paediatric pulmonary arterial hypertension (PAH) have evolved over the last years, but survival is still poor. Recently, in adults with severe PAH, upfront triple combination therapy (uTCT) from diagnosis has been reported to show significant clinical improvement and excellent long-term outcome. This retrospective, observational study aimed to assess the efficacy of uTCT in paediatric PAH.Children diagnosed with PAH between 2010 and 2019 and started with uTCT were included. World Health Organization Functional Class (WHO-FC), haemodynamics, echocardiography, 6-min walking distance and serum level of N-terminal pro-brain-natriuretic-peptide were assessed at baseline, after 3 and 6 months and at last available follow-up. Events were defined as death, lung transplantation or Potts shunt.21 children (median age 4.8 years (2.5-12.8), 57% females) were included. All children except one were in WHO-FC III or IV (28% and 67%, respectively). After 3 months, one child had died and one child had received a Potts shunt. The remaining 19 children showed clinical and echocardiographic improvement, which persisted at 6 months. Children with idiopathic and heritable PAH showed one-, two- and three-year transplant-free survival estimates of 100%, 94% and 87%, albeit 47% of them receiving a Potts shunt during follow-up.Children with severe PAH, but not pulmonary veno-occlusive disease, improved significantly with uTCT and showed beneficial up to 3-year survival rates, albeit 47% of them receiving a Potts shunt during follow-up. The role of a Potts shunt in conjunction to uTCT in paediatric PAH needs to be further established.


Determining crystal phase purity in c-BP through X-ray absorption spectroscopy.
We employ X-ray absorption near-edge spectroscopy at the boron K-edge and the phosphorus L2,3-edge to study the structural properties of cubic boron phosphide (c-BP) samples. The X-ray absorption spectra are modeled from first-principles within the density functional theory framework using the excited electron core-hole (XCH) approach. A simple structural model of a perfect c-BP crystal accurately reproduces the P L2,3-edge, however it fails to describe the broad and gradual onset of the B K-edge. Simulations of the spectroscopic signatures in boron 1s excitations of intrinsic point defects and the hexagonal BP crystal phase show that these additions to the structural model cannot reproduce the broad pre-edge of the experimental spectrum. Calculated formation enthalpies show that, during the growth of c-BP, it is possible that amorphous boron phases can be grown in conjunction with the desired boron phosphide crystalline phase. In combination with experimental and theoretically obtained X-ray absorption spectra of an amorphous boron structure, which have a similar broad absorption onset in the B K-edge spectrum as the cubic boron phosphide samples, we provide evidence for the presence of amorphous boron clusters in the synthesized c-BP samples.


Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Patients with Rheumatoid Arthritis: A Posthoc Analysis of Data from 6 Phase III Studies.
Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies. Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (≤ 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI ≤ 10) and remission (CDAI ≤ 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)-erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score. Of 3200 tofacitinib-treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone. Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone.


A systematic review of generic multidimensional patient-reported outcome measures for children, part I: descriptive characteristics.
To identify generic, multidimensional patient-reported outcome measures (PROMs) for children up to 18 years old and describe their characteristics and content assessed using the International Classification of Functioning, Disability and Health Children and Youth version (ICF-CY). The search strategy, developed by an information specialist, included four groups of terms related to "measure," "health," "children and young people," and "psychometric performance." The search was limited to publications from 1992. Five electronic databases and two online-specific PROM databases were searched. Two groups of reviewers independently screened all abstracts for eligible PROMs. Descriptive characteristics of the eligible PROMs were collected, and items and domains of each questionnaire were mapped onto the ICF-CY chapters. We identified 35 PROMs, of which 29 were generic PROMs and 6 were preference-based measures. Many PROMs cover a range of aspects of health; however, social functioning is represented most often. Content covered differs both in which aspects of health are assessed and whether individual questions focus on functioning (what the subject can or does do) and/or well-being (how the subject feels about a certain aspect of his or her health). A broad variety of PROMs is available to assess children's health. Nevertheless, only a few PROMs can be used across all age ranges to 18 years. When mapping their content on the ICF-CY, it seems that most PROMs exclude at least one major domain, and all conflate aspects of functioning and well-being in the scales.


Selection in Early Generations to Shift Allele Frequency for Seminal Root Angle in Wheat.
A current challenge for plant breeders is the limited ability to phenotype and select for root characteristics to enhance crop productivity. The development of a high-throughput phenotyping method has recently offered new opportunities for the selection of root characteristics in breeding programs. Here, we investigated prospects for phenotypic and molecular selection for seminal root angle (SRA), a key trait associated with mature root system architecture in wheat ( L.). We first investigated genetic diversity for this trait in a panel of 22 wheat lines adapted to Australian environments. The angle between the first pair of seminal roots ranged from 72 to 106°. We then evaluated selection gain via direct phenotypic selection in early generations by comparing the resulting shift in population distribution in tail populations selected for "narrow" and "wide" root angle. Overall, two rounds of selection significantly shifted the mean root angle as much as 10°. Furthermore, comparison of allele frequencies in the tail populations revealed genomic regions under selection, for which marker-assisted selection appeared to be successful. By combining efficient phenotyping and rapid generation advance, lines enriched with alleles for either narrow or wide SRA were developed within only 18 mo. These results suggest that there is a valuable source of allelic variation for SRA that can be harnessed and rapidly introgressed into elite wheat lines.


Antimicrobial Efficacy of a New Chlorhexidine-based Device Against Staphylococcus aureus Colonization of Venous Catheters.
Vascular catheters are a major cause of nosocomial bloodstream infections. ChloraLock (ATTWILL Medical Solutions, Inc, West Jordan, UT, and ICU Medical, Inc, San Clemente, CA) is a novel antimicrobial device containing chlorhexidine digluconate (CHG) that is fitted onto a syringe and infuses CHG into the catheter lumen during locking. The objective of this study was to evaluate the antimicrobial efficacy of ChloraLock with in vitro tests and its ability to reduce Staphylococcus aureus contamination of catheters in the external jugular veins of Yorkshire swine. ChloraLock significantly reduced the bacterial load in the in vitro tests by up to 6 log10 colony-forming units (CFU) and by 3 to 4 log10 CFU/lumen in vivo in a swine model with 0.9% NaCl catheter locks.


Rituximab in neurological disease: principles, evidence and practice.
Rituximab is a widely used B-cell-depleting monoclonal antibody. It is unlicensed for use in neurological disorders and there are no treatment guidelines. However, as a rapidly acting, targeted therapy with growing evidence of efficacy and tolerability in several neuroinflammatory disorders, it is an attractive alternative to conventional immunomodulatory medications. This practical review aims to explain the basic principles of B-cell depletion with therapeutic monoclonal antibodies. We present the evidence for using rituximab in neurological diseases, and describe the practical aspects of prescribing, including dosing, monitoring, safety, treatment failure and its use in special circumstances such as coexisting viral hepatitis, pregnancy and lactation. We provide an administration guide, checklist and patient information leaflet, which can be adapted for local use. Finally, we review the safety data of rituximab and ocrelizumab (a newer and recently licensed B-cell-depleting therapy for multiple sclerosis) and suggest monitoring and risk reduction strategies.


Putative periodontopathic bacteria and herpes viruses interactions in the subgingival plaque of patients with aggressive periodontitis and healthy controls.
The microbial profile of aggressive periodontitis patients is considered to be complex with variations among populations in different geographical areas. The aim of this study was to assess the presences of 4 putative periodontopathic bacteria (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) and 2 periodontal herpes viruses (Epstein-Barr virus type 1 [EBV-1] and human cytomegalovirus [HMCV]) in subgingival plaque of Sudanese subjects with aggressive periodontitis and healthy controls. The study group consisted of 34 subjects, 17 aggressive periodontitis patients and 17 periodontally healthy controls (14-19 years of age). Pooled subgingival plaque samples were collected and analyzed for detection of bacteria and viruses using loop-mediated isothermal amplification. Prevalence of subgingival A. actinomycetemcomitans, HCMV, and P. gingivalis were significantly higher among aggressive periodontitis patients than periodontally healthy controls. Coinfection with A. actinomycetemcomitans, HCMV, and/or EBV-1 was restricted to the cases. Increased risk of aggressive periodontitis was the highest when A. actinomycetemcomitans was detected together with EBV-1 (OD 49.0, 95% CI [2.5, 948.7], p = .01) and HCMV (OD 39.1, 95% CI [2.0, 754.6], p = .02). In Sudanese patients, A. actinomycetemcomitans and HCMV were the most associated test pathogens with aggressive periodontitis.


Human Toxicity Caused by Indole and Indazole Carboxylate Synthetic Cannabinoid Receptor Agonists: From Horizon Scanning to Notification.
The emergence of novel psychoactive substances (NPS), particularly synthetic cannabinoid receptor agonists (SCRA), has involved hundreds of potentially harmful chemicals in a highly dynamic international market challenging users', clinicians', and regulators' understanding of what circulating substances are causing harm. We describe a toxicovigilance system for NPS that predicted the UK emergence and identified the clinical toxicity caused by novel indole and indazole carboxylate SCRA. To assist early accurate identification, we synthesized 5 examples of commercially unavailable indole and indazole carboxylate SCRA (FUB-NPB-22, 5F-NPB-22, 5F-SDB-005, FUB-PB-22, NM-2201). We analyzed plasma and urine samples from 160 patients presenting to emergency departments with severe toxicity after suspected NPS use during 2015 to 2016 for these and other NPS using data-independent LC-MS/MS. We successfully synthesized 5 carboxylate SCRAs using established synthetic and analytical chemistry methodologies. We identified at least 1 SCRA in samples from 49 patients, including an indole or indazole carboxylate SCRA in 17 (35%), specifically 5F-PB-22 (14%), FUB PB-22 (6%), BB-22 (2%), 5F NPB-22 (20%), FUB NPB-22 (2%), and 5F-SDB-005 (4%). In these 17 patients, there was analytical evidence of other substances in 16. Clinical features included agitation and aggression (82%), reduced consciousness (76%), acidosis (47%), hallucinations and paranoid features (41%), tachycardia (35%), hypertension (29%), raised creatine kinase (24%), and seizures (12%). This toxicovigilance system predicted the emergence of misuse of indole and indazole carboxylate SCRA, documented associated clinical harms, and notified relevant agencies. Toxicity appears consistent with other SCRA, including mental state disturbances and reduced consciousness.


Simulation, human factors and defence anaesthesia.
Simulation in healthcare has come a long way since it's beginnings in the 1960s. Not only has the sophistication of simulator design increased, but the educational concepts of simulation have become much clearer. One particularly important area is that of non-technical skills (NTS) which has been developed from similar concepts in the aviation and nuclear industries. NTS models have been developed for anaesthetists and more recently for surgeons too. This has clear value for surgical team working and the recently developed Military Operational Surgical Training (MOST) course uses simulation and NTS to improve such team working. The scope for simulation in Defence medicine and anaesthesia does not stop here. Uses of simulation include pre-deployment training of hospital teams as well as Medical Emergency Response Team (MERT) and Critical Care Air Support Team (CCAST) staff. Future projects include developing Role 1 pre-deployment training. There is enormous scope for development in this important growth area of education and training.


Preferential Acquisition and Activation of Plasminogen Glycoform II by PAM Positive Group A Streptococcal Isolates.
Plasminogen (Plg) circulates in the host as two predominant glycoforms. Glycoform I Plg (GI-Plg) contains glycosylation sites at Asn289 and Thr346, whereas glycoform II Plg (GII-Plg) is exclusively glycosylated at Thr346. Surface plasmon resonance experiments demonstrated that Plg binding group A streptococcal M protein (PAM) exhibits comparative equal affinity for GI- and GII-Plg in the "closed" conformation (for GII-Plg, KD = 27.4 nM; for GI-Plg, KD = 37.0 nM). When Plg was in the "open" conformation, PAM exhibited an 11-fold increase in affinity for GII-Plg (KD = 2.8 nM) compared with that for GI-Plg (KD = 33.2 nM). The interaction of PAM with Plg is believed to be mediated by lysine binding sites within kringle (KR) 2 of Plg. PAM-GI-Plg interactions were fully inhibited with 100 mM lysine analogue ε-aminocaproic acid (εACA), whereas PAM-GII-Plg interactions were shown to be weakened but not inhibited in the presence of 400 mM εACA. In contrast, binding to the KR1-3 domains of GII-Plg (angiostatin) by PAM was completely inhibited in the presence 5 mM εACA. Along with PAM, emm pattern D GAS isolates express a phenotypically distinct SK variant (type 2b SK) that requires Plg ligands such as PAM to activate Plg. Type 2b SK was able to generate an active site and activate GII-Plg at a rate significantly higher than that of GI-Plg when bound to PAM. Taken together, these data suggest that GAS selectively recruits and activates GII-Plg. Furthermore, we propose that the interaction between PAM and Plg may be partially mediated by a secondary binding site outside of KR2, affected by glycosylation at Asn289.


PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation.
The bHLH factors HAND1 and HAND2 are required for heart, vascular, neuronal, limb, and extraembryonic development. Unlike most bHLH proteins, HAND factors exhibit promiscuous dimerization properties. We report that phosphorylation/dephosphorylation via PKA, PKC, and a specific heterotrimeric protein phosphatase 2A (PP2A) modulates HAND function. The PP2A targeting-subunit B56delta specifically interacts with HAND1 and -2, but not other bHLH proteins. PKA and PKC phosphorylate HAND proteins in vivo, and only B56delta-containing PP2A complexes reduce levels of HAND1 phosphorylation. During RCHOI trophoblast stem cell differentiation, B56delta expression is downregulated and HAND1 phosphorylation increases. Mutations in phosphorylated residues result in altered HAND1 dimerization and biological function. Taken together, these results suggest that site-specific phosphorylation regulates HAND factor functional specificity.


Nurse-led hypertension referral system in an emergency department for asymptomatic elevated blood pressure.
To determine the characteristics of asymptomatic elevated blood pressure patients in an accident and emergency setting and assess the effect of a nurse-led intervention system. Cross-sectional study. Accident and Emergency Department of a regional hospital in Hong Kong. Patients with blood pressures of 140/90 mm Hg or above recorded twice (at triage and discharge) with no previous history of hypertension. Exclusion criteria were: (1) admission to hospital; (2) known hypertension; (3) referral for hypertension; (4) blood pressure higher than 180/120 mm Hg on rechecking. Patients were issued a referral by the discharge nurse to follow-up for blood pressure monitoring in primary care. Diagnosis of hypertension, follow-up rate, and risk factors of hypertension. Of 245 patients with asymptomatic elevated blood pressure, we were able to contact 222 for follow-up, of whom 136 (61%) claimed to have been followed up for their blood pressure, and 48 (22%) were diagnosed to have hypertension. The nurse time for finding one case was 28 minutes. The projected impact could be large. If this simple nursing guideline is implemented territory-wide, more than 7000 new cases of asymptomatic hypertension might be picked up annually. The implementation of a simple nurse-led hypertension referral system is a cost-effective way to screen asymptomatic subjects with elevated blood pressures in the accident and emergency department.


Posterior AD-type pathology: cognitive subtypes emerging from a cluster analysis.
"Posterior shift" of the neuropathological changes of Alzheimer's disease (AD) produces a syndrome (posterior cortical atrophy) (PCA) dominated by high-level visual deficits. To explore in patients with AD-type pathology whether a data-driven analysis (cluster analysis) based on neuropsychological findings resulted in the emergence of different subgroups of patients; in particular to find out whether it was possible to identify patients with visuospatial deficits consistent with the hypothesis that PCA is a "dorsal stream" syndrome or, rather, whether there were subgroups of patients with different types of impairment within the high-level visual domain. 23 PCA and 16 DAT patients were studied. By a principal component analysis performed on a wide range of neuropsychological tasks, 15 variables were obtained that loaded onto five main factors (memory, language, perceptual, visuospatial, and calculation) which entered a hierarchical cluster analysis. Four clusters of cognitive impairment emerged: visuospatial/perceptual, memory, perceptual/calculation, and language. Only in the first cluster a visuospatial deficit clearly emerged. conclusions: AD pathology produces not only variants dominated by memory (DAT) and, to a lesser extent, visuospatial deficit (PCA), but also other distinct syndromic subtypes with disorders in visual perception and language which reflect a different vulnerability of specific functional networks.


Disturbance regulates the density-body-mass relationship of soil fauna.
Theory on the density-body-mass (DBM) relationship predicts that the density of animal species decreases by the power of -0.75 per unit increase in their body mass, or by the power of -1 when taxa across trophic levels are studied. This relationship is, however, largely debated, as the slope often deviates from the theoretical predictions. Here, we tested the ability of the DBM relationship to reflect changes in the structure of communities subjected to an anthropogenic disturbance. The slope would become less steep if smaller animals were more impacted by the disturbance than the larger ones, whereas the slope would become steeper if larger animals were more affected than the smaller ones. We tested the changes in the DBM relationship by sampling soil fauna, i.e., nematodes, Collembola, and larger arthropods, from a semiarid grassland before and after spraying diesel fuel as disturbance. We applied three different treatments: a control, a light disturbance, and an intense disturbance. We found that the slopes of the DBM relationships before the disturbance were around -1 as predicted by theory. The slope became more positive (i.e., less steep) just after the disturbance, especially after the intense disturbance as smaller fauna suffered the most and early colonizers had larger body mass. Interestingly, we observed that the slopes converged back to -1 by 2 months post-disturbance. Our findings show that the response of soil fauna communities to anthropogenic disturbances could explain the large variation in observed slopes of the DBM relationships. We experimentally demonstrate that an animal community, when disturbed, shows a temporal pattern of DBM relationships ranging from deviations from the predicted slope to convergence to the predicted slope with time. We recommend that deviations in the DBM relationships after disturbances can provide insights in the trajectory of community recovery, and hence could be used for biomonitoring.


Mapping brain response to pain in fibromyalgia patients using temporal analysis of FMRI.
Nociceptive stimuli may evoke brain responses longer than the stimulus duration often partially detected by conventional neuroimaging. Fibromyalgia patients typically complain of severe pain from gentle stimuli. We aimed to characterize brain response to painful pressure in fibromyalgia patients by generating activation maps adjusted for the duration of brain responses. Twenty-seven women (mean age: 47.8 years) were assessed with fMRI. The sample included nine fibromyalgia patients and nine healthy subjects who received 4 kg/cm(2) of pressure on the thumb. Nine additional control subjects received 6.8 kg/cm(2) to match the patients for the severity of perceived pain. Independent Component Analysis characterized the temporal dynamics of the actual brain response to pressure. Statistical parametric maps were estimated using the obtained time courses. Brain response to pressure (18 seconds) consistently exceeded the stimulus application (9 seconds) in somatosensory regions in all groups. fMRI maps following such temporal dynamics showed a complete pain network response (sensory-motor cortices, operculo-insula, cingulate cortex, and basal ganglia) to 4 kg/cm(2) of pressure in fibromyalgia patients. In healthy subjects, response to this low intensity pressure involved mainly somatosensory cortices. When matched for perceived pain (6.8 kg/cm(2)), control subjects showed also comprehensive activation of pain-related regions, but fibromyalgia patients showed significantly larger activation in the anterior insula-basal ganglia complex and the cingulate cortex. The results suggest that data-driven fMRI assessments may complement conventional neuroimaging for characterizing pain responses and that enhancement of brain activation in fibromyalgia patients may be particularly relevant in emotion-related regions.


Mucosal Humoral Immune Response to SIVmac239∆nef Vaccination and Vaginal Challenge.
Live attenuated vaccines such as SIV with a deleted nef gene have provided the most robust protection against subsequent vaginal challenge with wild-type (WT) SIV in the SIV-rhesus macaque model of HIV-1 transmission to women. Hence, identifying correlates of this protection could enable design of an effective HIV-1 vaccine. One such prechallenge correlate of protection from vaginal challenge has recently been identified as a system with three components: 1) IgG Abs reacting with the viral envelope glycoprotein trimeric gp41; 2) produced by plasma cells in the submucosa and ectopic tertiary lymphoid follicles in the ectocervix and vagina; and 3) concentrated on the path of virus entry by the neonatal FcR in the overlying epithelium. We now examine the mucosal production of the Ab component of this system after vaginal challenge. We show that vaginal challenge immediately elicits striking increases in plasma cells not only in the female reproductive tract but also at other mucosal sites, and that these increases correlate with low but persistent replication at mucosal sites. We describe vaginal ectopic follicles that are structurally and functionally organized similar to follicles in secondary lymphoid organs, and we provide inferential evidence for a key role of the female reproductive tract epithelium in facilitating Ab production, affinity maturation, and class switch recombination. Vaccination thus accesses an epithelial-immune system axis in the female reproductive tract to respond to exposure to mucosal pathogens. Designing strategies to mimic this system could advance development of an effective HIV-1 vaccine.


Retirement and cognitive decline. A longitudinal analysis using SHARE data.
We show that a new measure of cognitive decline, that can be computed in longitudinal surveys where respondents perform the same recall memory tests over the years, is highly predictive of the onset of dementia. Using SHARE data, we investigate the way retirement affects cognitive decline over time controlling for age, education and other confounding factors. We find that retirement has a long-term detrimental effect on cognition for individuals who retire at the statutory eligibility age. It plays instead a protective role for those who retire on an early retirement scheme.


The Maastricht Study: an extensive phenotyping study on determinants of type 2 diabetes, its complications and its comorbidities.
The Maastricht Study is an extensive phenotyping study that focuses on the etiology of type 2 diabetes (T2DM), its classic complications, and its emerging comorbidities. The study uses state-of-the-art imaging techniques and extensive biobanking to determine health status in a population-based cohort of 10,000 individuals that is enriched with T2DM individuals. Enrollment started in November 2010 and is anticipated to last 5-7 years. The Maastricht Study is expected to become one of the most extensive phenotyping studies in both the general population and T2DM participants world-wide. The Maastricht study will specifically focus on possible mechanisms that may explain why T2DM accelerates the development and progression of classic complications, such as cardiovascular disease, retinopathy, neuropathy and nephropathy and of emerging comorbidities, such as cognitive decline, depression, and gastrointestinal, musculoskeletal and respiratory diseases. In addition, it will also examine the association of these variables with quality of life and use of health care resources. This paper describes the rationale, overall study design, recruitment strategy and methods of basic measurements, and gives an overview of all measurements that are performed within The Maastricht Study.


Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty.
Arthrofibrosis, occurring in 3%-4% of patients following total knee arthroplasty (TKA), is a challenging condition for which there is no defined cause. The hypothesis for this study was that disregulated production of reactive oxygen species (ROS) and nitrogen species (RNS) mediates matrix protein and DNA modifications, which result in excessive fibroblastic proliferation. We found increased numbers of macrophages and lymphocytes, along with elevated amounts of myeloperoxidase (MPO) in arthrofibrotic tissues when compared to control tissues. MPO expression, an enzyme that generates ROS/RNS, is usually limited to neutrophils and some macrophages, but was found by immunohistochemistry to be expressed in both macrophages and fibroblasts in arthrofibrotic tissue. As direct measurement of ROS/RNS is not feasible, products including DNA hydroxylation (8-OHdG), and protein nitrosylation (nitrotyrosine) were measured by immunohistochemistry. Quantification of the staining showed that 8-OHdg was significantly increased in arthrofibrotic tissue. There was also a direct correlation between the intensity of inflammation and ROS/RNS to the amount of heterotopic ossification (HO). In order to investigate the aberrant expression of MPO, a real-time oxidative stress polymerase chain reaction array was performed on fibroblasts isolated from arthrofibrotic and control tissues. The results of this array confirmed the upregulation of MPO expression in arthrofibrotic fibroblasts and highlighted the downregulated expression of the antioxidants, superoxide dismutase1 and microsomal glutathione S-transferase 3, as well as the significant increase in thioredoxin reductase, a known promoter of cell proliferation, and polynucleotide kinase 3'-phosphatase, a key enzyme in the base excision repair pathway for oxidative DNA damage. Based on our current findings, we suggest that ROS/RNS initiate and sustain the arthrofibrotic response driving aggressive fibroblast proliferation and subsequent HO.


The immune privilege of corneal grafts.
Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation. In the United States, over 33,000 corneal transplants are performed each year. Unlike other forms of tissue transplantation, keratoplasties are routinely performed without the aid of tissue typing or systemic immunosuppressive drugs. In spite of this, 90% of the first-time corneal transplants will succeed-a condition that demonstrates the immune privilege of keratoplasties. The avascular nature of the corneal allograft bed led many to suspect that corneal grafts were sequestered from the immune apparatus. Although pleasing in its simplicity, this explanation has given way to a more comprehensive hypothesis that embodies multiple, interdependent mechanisms, which promote the long-term survival of corneal allografts. These mechanisms conspire to interrupt the transmission of immunogenic stimuli to peripheral lymphoid tissues; induce the generation of a deviated immune response; and neutralize immune effector elements at the host-graft interface. This paradigm is analogous to a three-legged stool. Disassembly of any one of the three components results in the collapse of immune privilege. Strategies to re-establish corneal immune privilege may have clinical application for high-risk hosts who have rejected previous corneal allografts.


Distress Management Through Mind-Body Therapies in Oncology.
Distress is highly prevalent in cancer survivors, from the point of diagnosis through treatment and recovery, with rates higher than 45% reported worldwide. One approach for helping people cope with the inherent stress of cancer is through the use of mind-body therapies (MBTs) such as mediation, yoga, hypnosis, relaxation, and imagery, which harness the power of the mind to affect physical and psychological symptoms. One group of MBTs with a growing body of research evidence to support their efficacy focus on training in mindfulness meditation; these are collectively known as mindfulness-based interventions (MBIs). Research supports the role of MBIs for dealing with common experiences that cause distress around cancer diagnosis, treatment, and survivorship including loss of control, uncertainty about the future, fears of recurrence, and a range of physical and psychological symptoms including depression, anxiety, insomnia, and fatigue. Growing research also supports their cost-effectiveness, and online and mobile adaptations currently being developed and evaluated increase promise for use in a global context.


Sheathless electrospray from polymer microchips.
In this study, sheathless electrospray from polymer microchips with conducting layer on the emitter tip is described for the first time. The electrospray emitter tips were fabricated directly from the end of the microchips that were made of polycarbonate or poly(methyl methacrylate) with injection molding. A variety of tip shapes and conducting coatings were evaluated using an electrospray time-of-flight mass spectrometer run in the sheathless mode. Stable electrospray was obtained both from hand-polished and machine-milled three-dimensional tips coated with either polymer-embedded gold particles or graphite particles as the conducting layer. Sputtered gold, on the other hand, suffered from poor stability mainly due to bad adhesion to the polymer tip. The durability of the different coatings was confirmed with electrochemical experiments under simulated electrospray conditions. The relative standard deviations of the response received from the ion current of the MS analysis were in the range of 3.5-12%. The detection limit for a standard mixture containing five neuropeptides was lower than 0.5 fmol. The low detection limit makes the emitter tips highly attractive for the analysis of low-abundance biological species.


Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.
Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies. We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OH)D) as instruments for MR studies on vitamin D. We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OH)D. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP) which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA) meta-analyses on 25(OH)D. We analyzed SNP associations with 25(OH)D and evaluated the use of allele scores dividing genes to those affecting 25(OH)D synthesis (DHCR7, CYP2R1) and metabolism (GC, CYP24A1, CYP27B1). In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2) showed evidence for association with 25(OH)D, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between -0.02 and -0.08 nmol/L (P≤0.02 for all), with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OH)D between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha) suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score. Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.


Which Features of the Environment Impact Community Participation of Older Adults? A Systematic Review and Meta-Analysis.
The objective of this study is to identify features of the environment associated with community participation of older adults. A systematic review of studies that examined associations between environment and community participation in older adults was conducted. Environmental features were extracted and grouped using the International Classification of Functioning, Disability, and Health's environmental categories. Meta-analysis of environmental categories was conducted by calculating combined effect size (ES) estimates. Significant, small to moderate, random ESs were found for six of seven environmental categories: neighborliness (ES = 0.52, 95% confidence interval [CI] = [0.18, 0.87]), social support (ES = 0.38, 95% CI = [0.13, 0.62]), land-use diversity (ES = 0.29, 95% CI = [0.16, 0.42]), transportation (ES = 0.29, 95% CI = [0.15, 0.43]), civil protection (e.g., safety; ES = 0.27, 95% CI = [0.0, 0.54]), and street connectivity/walkability (ES = 0.20, 95% CI = [0.15, 0.26]). Community initiatives that address specific features of the social environment and street-level environment may increase community participation of older adults.


Estimating the potential population impact of stepwise screening strategies for identifying and treating individuals at high risk of Type 2 diabetes: a modelling study.
Diabetes risk assessment has been proposed as part of the National Health Service Health Checks programme, and HbA(1c) has recently been recommended as a diagnostic test for diabetes at a threshold of 48 mmol/mol (6.5%). We estimated the potential population impact of different stepwise screening strategies to identify individuals at high risk who might be offered preventive interventions. Using data from 5910 participants in the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with HbA(1c) measurements, we modelled different stepwise screening strategies for identifying and treating individuals at high risk of Type 2 diabetes using different HbA(1c) cut-off points with and without a stage of prestratification. For each strategy, we estimated the number needed to have a diagnostic test, the number needed to treat to prevent one new case of Type 2 diabetes, and the number of new cases that could be prevented in the population over 3 years. Relative risk reductions for estimated effects of intensive lifestyle intervention were derived from the US Diabetes Prevention Program. Compared with inviting all individuals in an average primary care trust for a diagnostic test, a stepwise screening approach using simple routine data such as age and anthropometric indices could prevent a slightly lower number (lower-upper estimates) of new cases of Type 2 diabetes over 3 years (224 [130-359] and 193 [109-315] cases respectively) but would only require half the population to be invited for a diagnostic blood test. A total of 162 (88-274) cases could be prevented by inviting individuals with a Cambridge risk score of ≥ 0.15, with only 40% of the total population requiring diagnostic blood tests. Using a participant completed questionnaire for risk assessment (FINDRISC) was less effective, mainly relating to the questionnaire response rate. Providing preventive interventions to those with a lower HbA(1c) of 37-< 48 mmol/mol (5.5-< 6.5%) could prevent more cases but with a disproportionately higher workload, compared with using the recommended HbA(1c) threshold of 42-< 48 mmol/mol (6.0-< 6.5%). Compared with mass screening, an approach using routine data for risk stratification followed by an HbA(1c) test with a threshold of 42-< 48 mmol/mol (6.0-< 6.5%) for identifying individuals suitable for preventive interventions might prevent slightly fewer cases of Type 2 diabetes but with potential cost-savings.


Skewed by Cues? The Motivational Role of Audiovisual Stimuli in Modelling Substance Use and Gambling Disorders.
The similarity between gambling disorder (GD) and drug addiction has recently been recognized at the diagnostic level. Understanding the core cognitive processes involved in these addiction disorders, and in turn their neurobiological mechanisms, remains a research priority due to the enormous benefits such knowledge would have in enabling effective treatment design. Animal models can be highly informative in this regard. Although numerous rodent behavioural paradigms that capture different facets of gambling-like behaviour have recently been developed, the motivational power of cues in biasing individuals towards risky choice has so far received little attention despite the central role played by drug-paired cues in successful laboratory models of chemical dependency. Here, we review some of the comparatively simple paradigms in which reward-paired cues are known to modulate behaviour in rodents, such as sign-tracking, Pavlovian-to-instrumental transfer and conditioned reinforcement. Such processes are thought to play an important role in mediating responding for drug reward, and the need for future studies to address whether similar processes contribute to cue-driven risky choice is highlighted.


T cells reactive with a small synthetic peptide of the acetylcholine receptor can provide help for a clonotypically heterogeneous antibody response and subsequently impaired muscle function.
The influence of T cell specificity was evaluated with regard to its role in the antibody response against the acetylcholine receptor (AChR) and resulting AChR-dependent muscle dysfunction. The reactivity of immune Th cells was restricted to a small region of the AChR alpha-subunit (amino acid residues 100-116) reported to be highly immunogenic. T cells primed to this peptide were found to demonstrate significant proliferation when challenged in vitro with either the homologous peptide or the intact AChR. Adoptive transfer of the peptide-immune T cells into immunologically naive recipient rats followed by AChR challenge resulted in the production of anti-AChR antibodies very similar to those produced under the regulation of T cells immune to the entire intact AChR with regard to overall clonotypic heterogeneity (measured by IEF) and their ability to interfere with AChR-dependent muscle contraction. Interestingly, when the threonine at position 106 was substituted with a proline, the resulting peptide continued to be equally, if not exceedingly, capable of stimulating T cell-proliferative responses, but was found to be ineffective at stimulating the levels of anti-AChR antibodies necessary for producing neuromuscular dysfunction.


Adaptive prior probability and spatial temporal intensity change estimation for segmentation of the one-year-old human brain.
The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2 years of age, as appearance homogeneity is greatly improved by the age of 24 months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2 years. The proposed IGM method revealed low regression values of 1-10% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1 year. However, in the prefrontal and temporal lobes we observed regression values of 20-25%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM-corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual 'ground truth' segmentations.


[Smoking and student survival at Universidad Santiago de Cali, 2004-2007].
This article presents the results of monitoring students who enrolled at Universidad Santiago de Cali (USC) during the second half of 2004. Its purpose was to determine the influence of smoking, the academic programme and the cost of enrollment on student survival over a three-year period (2004-2007). The study involved a prospective cohort of 970 students who entered the university in 2004. Cox regression was used for survival analysis to determine the relationship between independent variables and university stay. The results of this model established associations between smoking and department with survival in the university, but discarded association with the cost of enrollment. The risk of university desertion was higher amongst students from the Health faculty adjusted for smoking (RR = 1.277 (1.121-1.455)). Similarly, the risk of desertion was higher in smokers adjusted by faculty (RR = 1.194 (1.026-1.390). It was found that habitual smokers had shorter university stay than nonsmokers. University stay was longer in students enrolled in academic programmes other than health.


White light wavefront control with a spatial light modulator.
Spatial light modulators are ubiquitous tools for wavefront control and laser beam shaping but have traditionally been used with monochromatic sources due to the inherent wavelength dependence of the calibration process and subsequent phase manipulation. In this work we show that such devices can also be used to shape broadband sources without any wavelength dependence on the output beam's phase. We outline the principle mathematically and then demonstrate it experimentally using a supercontinuum source to shape rotating white-light Bessel beams carrying orbital angular momentum.


Generation of nanobodies acting as silent and positive allosteric modulators of the α7 nicotinic acetylcholine receptor.
The α7 nicotinic acetylcholine receptor (nAChR), a potential drug target for treating cognitive disorders, mediates communication between neuronal and non-neuronal cells. Although many competitive antagonists, agonists, and partial-agonists have been found and synthesized, they have not led to effective therapeutic treatments. In this context, small molecules acting as positive allosteric modulators binding outside the orthosteric, acetylcholine, site have attracted considerable interest. Two single-domain antibody fragments, C4 and E3, against the extracellular domain of the human α7-nAChR were generated through alpaca immunization with cells expressing a human α7-nAChR/mouse 5-HT3A chimera, and are herein described. They bind to the α7-nAChR but not to the other major nAChR subtypes, α4β2 and α3β4. E3 acts as a slowly associating positive allosteric modulator, strongly potentiating the acetylcholine-elicited currents, while not precluding the desensitization of the receptor. An E3-E3 bivalent construct shows similar potentiating properties but displays very slow dissociation kinetics conferring quasi-irreversible properties. Whereas, C4 does not alter the receptor function, but fully inhibits the E3-evoked potentiation, showing it is a silent allosteric modulator competing with E3 binding. Both nanobodies do not compete with α-bungarotoxin, localizing at an allosteric extracellular binding site away from the orthosteric site. The functional differences of each nanobody, as well as the alteration of functional properties through nanobody modifications indicate the importance of this extracellular site. The nanobodies will be useful for pharmacological and structural investigations; moreover, they, along with the extracellular site, have a direct potential for clinical applications.


Cataract induced glaucoma--an insight into management.
The problem of phacomorphic glaucoma is a rather common entity in rural India owing to the delay in getting the cataract removed and the preponderance of cortical matter, compared with the Western world. The authors in India, South East Asia and Australia, have managed the problem differently leading to controversies. The pathogenesis has been investigated and is well understood. An aspect of phacomorphic glaucoma that remains quite unanswered, is of the relatively poor visual outcome and increased incidence of operative and post-operative complications. We endeavour to evaluate the management, intraoperative and post-operative complications of phacomorphic glaucoma (senile cataract induced). The effect of high intraocular pressure (I.O.P) and surgical trauma on the corneal endothelium is also assessed.


Motometrics: A Toolbox for Annotation and Efficient Analysis of Motor Evoked Potentials.
Stimulating the nervous system and measuring muscle response offers a unique opportunity to interrogate motor system function. Often, this is performed by stimulating motor cortex and recording muscle activity with electromyography; the evoked response is called the motor evoked potential (MEP). To understand system dynamics, MEPs are typically recorded through a range of motor cortex stimulation intensities. The MEPs increase with increasing stimulation intensities, and these typically produce a sigmoidal response curve. Analysis of MEPs is often complex and analysis of response curves is time-consuming. We created an MEP analysis software, called Motometrics, to facilitate analysis of MEPs and response curves. The goal is to combine robust signal processing algorithms with a simple user interface. Motometrics first enables the user to annotate data files acquired from the recording system so that the responses can be extracted and labeled with the correct subject and experimental condition. The software enables quick visual representations of entire datasets, to ensure uniform quality of the signal. It then enables the user to choose a variety of response curve analyses and to perform near real time quantification of the MEPs for quick feedback during experimental procedures. This is a modular open source tool that is compatible with several popular electrophysiological systems. Initial use indicates that Motometrics enables rapid, robust, and intuitive analysis of MEP response curves by neuroscientists without programming or signal processing expertise.


Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions.
Endogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize aging. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for Rev1, a core factor in DNA translesion synthesis (TLS), the postreplicative bypass of damaged nucleotides. Rev1 hematopoietic stem and progenitor cells displayed compromised proliferation, and replication stress that could be rescued with an antioxidant. The additional disruption of Xpc, essential for global-genome nucleotide excision repair (ggNER) of helix-distorting nucleotide lesions, resulted in the perinatal loss of hematopoietic stem cells, progressive loss of bone marrow, and fatal aplastic anemia between 3 and 4 months of age. This was associated with replication stress, genomic breaks, DNA damage signaling, senescence, and apoptosis in bone marrow. Surprisingly, the collapse of the Rev1Xpc bone marrow was associated with progressive mitochondrial dysfunction and consequent exacerbation of oxidative stress. These data reveal that, to protect its genomic and functional integrity, the hematopoietic system critically depends on the combined activities of repair and replication of helix-distorting oxidative nucleotide lesions by ggNER and Rev1-dependent TLS, respectively. The error-prone nature of TLS may provide mechanistic understanding of the accumulation of mutations in the hematopoietic system upon aging.


Two-dimensional optical thermal ratchets based on Fibonacci spirals.
An ensemble of symmetric potential energy wells arranged at the vertices of a Fibonacci spiral can serve as the basis for an irreducibly two-dimensional thermal ratchet. Periodic rotation of the potential energy landscape through a three-step cycle drives trapped Brownian particles along spiral trajectories through the pattern. Which spiral is selected depends on the angular displacement at each step, with transitions between selected spirals arising at rational proportions of the golden angle. Fibonacci spiral ratchets therefore display an exceptionally rich range of transport properties, including inhomogeneous states in which different parts of the pattern induce motion in different directions. Both the radial and angular components of these trajectories can undergo flux reversal as a function of the scale of the pattern or the rate of rotation.


Insulin secretion in fetal and newborn sheep.
The relationships between arterial plasma insulin, glucose, and fructose concentrations during the fed and fasted state were studied in seven fetal lambs and their mothers. A significant correlation between insulin and glucose concentration was noted in all fetal lambs and in their mothers. Fetal sensitivity to glucose, as measured by the slopes of the insulin-response curves, was equal to that of the adult although the fetal response was shifted to the left of the maternal. Glucose infusion in four fetal lambs caused significant insulin elevations but no early insulin response (phase I). Maternal fasting caused no alteration in glucose-induced response in the fetus. Similar glucose infusions in newborn and 1-mo-old lambs demonstrated significant early-phase insulin secretion. Basal insulin to glucose ratios were consistent with an adult pattern as early as 3 days after birth.


Social Cooperation and Disharmony in Communities Mediated through Common Pool Resource Exploitation.
It was theorized that when a society exploits a shared resource, the system can undergo extreme phase transition from full cooperation in abiding by a social agreement, to full defection from it. This was shown to happen in an integrated society with complex social relationships. However, real-world agents tend to segregate into communities whose interactions contain features of the associated community structure. We found that such social segregation softens the abrupt extreme transition through the emergence of multiple intermediate phases composed of communities of cooperators and defectors. Phase transitions thus now occur through these intermediate phases which avert the instantaneous collapse of social cooperation within a society. While this is beneficial to society, it nonetheless costs society in two ways. First, the return to full cooperation from full defection at the phase transition is no longer immediate. Community linkages have rendered greater societal inertia such that the switch back is now typically stepwise rather than a single change. Second, there is a drastic increase in social disharmony within the society due to the greater tension in the relationship between segregated communities of defectors and cooperators. Intriguingly, these results on multiple phases with its associated phenomenon of social disharmony are found to characterize the level of cooperation within a society of Balinese farmers who exploit water for rice production.


Treatment of Distal Anterior Circulation Aneurysms With the Pipeline Embolization Device: A US Multicenter Experience.
Utilization of the Pipeline embolization device (PED) to treat distal carotid circulation aneurysms has not been well studied. To report the collective experience of using PED to treat distal anterior circulation aneurysms. We retrospectively reviewed clinical and radiographic records of all patients who underwent Pipeline embolization of distal anterior circulation aneurysms at 10 US neurosurgical centers between 2011 and 2013. Twenty-eight patients (mean age 51.7 years; 18 women) with 28 aneurysms were included in the analyses. Fifteen aneurysms were fusiform, 5 dissecting, and 8 saccular. Average aneurysm size was 12.3 mm; 7 were giant. Twenty aneurysms were located along the middle cerebral artery, 6 along the anterior cerebral artery, and 2 along the anterior communicating artery. PED deployment was successful in 27 patients, with coils utilized in 6 cases. Clinical follow-up was available for an average of 10.7 months (range 3-26). Twenty-seven patients had follow-up neurovascular imaging: 21 aneurysms had complete occlusion, 4 had residual neck filling, and 2 had residual dome filling. Periprocedural complications (<30 days) occurred in 3 patients (10.7%), including 1 case of device failure resulting in stroke. Outcomes were good (modified Rankin Scale score 0 to 2) in 27 patients (96.4%) and fair (modified Rankin Scale 3) in 1. PED can be utilized in the treatment of distal anterior circulation aneurysms with difficult anatomy for conventional surgical or endovascular techniques. Larger-scale studies with long-term follow-up are needed to further elucidate the durability of PED treatment and its effect on perforator-rich vascular segments. ACA, anterior cerebral arteryAcomA, anterior communicating arteryDSA, digital subtraction angiographyMCA, middle cerebral arterymRS, modified Rankin scalePED, Pipeline embolization device.


Optically Evolved Assembly Formation in Laser Trapping of Polystyrene Nanoparticles at Solution Surface.
Assembling dynamics of polystyrene nanoparticles by optical trapping is studied with utilizing transmission/reflection microscopy and reflection microspectroscopy. A single nanoparticle assembly with periodic structure is formed upon the focused laser irradiation at solution surface layer and continuously grows up to a steady state within few minutes. By controlling nanoparticle and salt concentrations in the colloidal solution, the assembling behavior is obviously changed. In the high concentration of nanoparticles, the assembly formation exhibits fast growth, gives large saturation size, and leads to dense packing structure. In the presence of salt, one assembly with the elongated aggregates was generated from the focal spot and 1064 nm trapping light was scattered outwardly with directions, while a small circular assembly and symmetrical expansion of the 1064 nm light were found without salt. The present nanoparticle assembling in optical trapping is driven through multiple scattering in gathered nanoparticles and directional scattering along the elongated aggregates derived from optical association of nanoparticles, which dynamic phenomenon is called optically evolved assembling. Repetitive trapping and release processes of nanoparticles between the assembly and the surrounding solution always proceed, and the steady state at the circular assembly formed by laser trapping is determined under optical and chemical equilibrium.


The role of sigma factors in plastid transcription.
Expression of plastid genes is controlled at both transcriptional and post-transcriptional levels in response to developmental and environmental signals. In many cases this regulation is mediated by nuclear-encoded proteins acting in concert with the endogenous plastid gene expression machinery. Transcription in plastids is accomplished by two distinct RNA polymerase enzymes, one of which resembles eubacterial RNA polymerases in both subunit structure and promoter recognition properties. The holoenzyme contains a catalytic core composed of plastid-encoded subunits, assembled with a nuclear-encoded promoter-specificity factor, sigma. Based on examples of transcriptional regulation in bacteria, it is proposed that differential activation of sigma factors may provide the nucleus with a mechanism to control expression of groups of plastid genes. Hence, much effort has focused on identifying and characterizing sigma-like factors in plants. While fractionation studies had identified several candidate sigma factors in purified RNA polymerase preparations, it was only 4 years ago that the first sigma factor genes were cloned from two photosynthetic eukaryotes, both of which were red algae. More recently this achievement has extended to the identification of families of sigma-like factor genes from several species of vascular plants. Now, efforts in the field are directed at understanding the roles in plastid transcription of each member of the rapidly expanding plant sigma factor gene family. Recent results suggest that accumulation of individual sigma-like factors is controlled by light, by plastid type and/or by a particular stage of chloroplast development. These data mesh nicely with accumulating evidence that the core sigma-binding regions of plastid promoters mediate regulated transcription in response to light-regime and plastid type or developmental state. In this review I will outline progress made to date in identifying and characterizing the sigma-like factors of plants, and in dissecting their potential roles in chloroplast gene expression.


Prevention of stromal ulceration in the alkali-burned rabbit cornea by glued-on contact lens. Evidence for the role of polymorphonuclear leukocytes in collagen degradation.
Stromal ulceration of the alkali-burned rabbit cornea was found to be associated invariably with phagocytically active polymorphonuclear leukocytes (PMNs). A glued-on methylmethacrylate lens applied to corneas soon after burning, however, prevented re-epithelialization and also prevented PMN infiltration of the stroma and stromal ulceration. Subsequent partial detachment or complete removal of the lens resulted in epithelial resurfacing of the stroma, PMN infiltration, and stromal ulceration. Glued-on lenses applied to already ulcerating corneas arrested further ulceration by prohibiting additional PMN infiltration. Either surface debridement or glued-on methylmethacrylate rings also prevented re-epithelialization and ulceration in stromas not infiltrated by PMNs, but neither treatment was sufficient to prevent ulceration in corneas already containing numerous PMNs. The data suggest the possibility that the epithelium stimulates infiltration of the stroma by PMNs which then participate in stromal matrix degradation. Although no claim is made that only PMNs mediate matrix destruction in corneal ulceration, the efficacy of the lens would seem to be due to exclusion of the epithelium and the consequent prevention of stromal infiltration by PMNs.


Osteopathic manipulative treatment and its relationship to autonomic nervous system activity as demonstrated by heart rate variability: a repeated measures study.
The relationship between osteopathic manipulative treatment (OMT) and the autonomic nervous system has long been acknowledged, but is poorly understood. In an effort to define this relationship, cervical myofascial release was used as the OMT technique with heart rate variability (HRV) as a surrogate for autonomic activity. This study quantifies that relationship and demonstrates a cause and effect. Seventeen healthy subjects, nine males and eight females aged 19-50 years from the faculty, staff, and students at Oklahoma State University Center for Health Sciences College of Osteopathic Medicine, acted as their own controls and received interventions, administered in separate sessions at least 24 hours apart, of cervical myofascial OMT, touch-only sham OMT, and no-touch control while at a 50-degree head-up tilt. Each group was dichotomized into extremes of autonomic activity using a tilt table. Comparisons were made between measurements taken at tilt and those taken at pre- and post-intervention in the horizontal.The variance of the spectral components of HRV, expressed as frequencies, measured the response to change in position of the subjects. Normalized low frequency (LF) and high frequency (HF) values, including LF/HF ratio, were calculated and used to determine the effect of position change on HRV. Predominantly parasympathetic responses were observed with subjects in the horizontal position, while a 50-degree tilt provided a significantly different measure of maximum sympathetic tone (p < 0.001). Heart rate changed in all subjects with change in position; respirations remained constant. When OMT was performed in a sympathetic environment (tilt), a vagal response was produced that was strong enough to overcome the sympathetic tone. There was no HRV difference between sham and control in either the horizontal or tilt positions. The vagal response produced by the myofascial release procedure in the maximally stimulated sympathetic environment could only have come from the application of the OMT. This demonstrates the association between OMT and the autonomic nervous system. The lack of significance between control and sham in all positions indicates that HRV may be a useful method of developing sham controls in future studies of OMT. clinicaltrials.gov NCT00516984.


Identification of risk factors for toxicity in patients with hormone receptor-positive advanced breast cancer treated with bevacizumab plus letrozole: a CALGB 40503 (alliance) correlative study.
In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer. CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined. One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events. Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring.


Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer.
Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers.


Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development.
Goblet cell metaplasia and mucus overproduction contribute to the pathogenesis of chronic lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notch signaling regulates cell fate decisions and is crucial in controlling goblet cell differentiation in the gut epithelium. Little is known, however, about how endogenous Notch signaling influences the goblet cell differentiation program that takes place in the postnatal lung. Using a combination of genetic and in vitro approaches here we provide evidence of a novel role for Notch in restricting goblet cell differentiation in the airway epithelium during the postnatal period. Conditional inactivation of the essential Notch pathway component Pofut1 (protein O-fucosyltransferase1) in Tgfb3-Cre-expressing mice resulted in an aberrant postnatal airway phenotype characterized by marked goblet cell metaplasia, decreased Clara cell number and increase in ciliated cells. The presence of the same phenotype in mice in which the Notch transcriptional effector Rbpjk was deleted indicated the involvement of the canonical Notch pathway. Lineage study in vivo suggested that goblet cells originated from a subpopulation of Clara cells largely present in proximal airways in which Notch was disrupted. The phenotype was confirmed by a panel of goblet cell markers, showed no changes in cell proliferation or altered expression of proinflammatory cytokines and was associated with significant downregulation of the bHLH transcriptional repressor Hes5. Luciferase reporter analysis suggested that Notch directly repressed MUC5AC transcription in lung epithelial cells. The data suggested that during postnatal life Notch is required to prevent Clara cells from differentiating into goblet cells.