Defibrillation in children.
Defibrillation is the only effective treatment for ventricular fibrillation (VF). Optimal methods for defibrillation in children are derived and extrapolated from adult data. VF occurs as the initial rhythm in 8-20% of pediatric cardiac arrests. This has fostered a new interest in determining the optimal technique for pediatric defibrillation. This review will provide a brief background of the history of defibrillation and a review of the current literature on pediatric defibrillation. The literature search was performed through PubMed, using the MeSH headings of cardiopulmonary resuscitation, defibrillation and electric countershock. The authors' personal bibliographic files were also searched. Only published articles were chosen. The recommended energy dose has been 2 J/kg for 30 years, but recent reports may indicate that higher dosages may be more effective and safe. In 2005, the European Resuscitation Council recommended 4 J/kg as the initial dose, without escalation for subsequent shocks. Automated external defibrillators are increasingly used for pediatric cardiac arrest, and available reports indicate high success rates. Additional research on pediatric defibrillation is critical in order to be able to provide an equivalent standard of care for children in cardiac arrest and improve outcomes.


Safety and Efficacy of DPP4 Inhibitor and Basal Insulin in Type 2 Diabetes: An Updated Review and Challenging Clinical Scenarios.
The safety and efficacy of dipeptidyl peptidase-4 (DPP4) inhibitors as monotherapy or in combination with other oral antidiabetic agents or basal insulin are well established. DPP4 inhibitors stimulate glucose-dependent insulin secretion and inhibit glucagon production. As monotherapy, they reduce the hemoglobin A1c level by about 0.6-0.8%. The addition of a DPP4 inhibitor to basal insulin is an attractive option, because they lower both postprandial and fasting plasma glucose concentrations without increasing the risk of hypoglycemia or weight gain. The present review summarizes the extensive evidence on the combination therapy of DPP4 inhibitors and insulin-based regimens in patients with type 2 diabetes. We focus our discussion on challenging clinical scenarios including patients with chronic renal impairment, elderly persons and hospitalized patients. The evidence indicates that these drugs are highly effective and safe in the elderly and in the presence of mild, moderate and severe renal failure improving glycemic control with low risk of hypoglycemia. In addition, several randomized-controlled trials have shown that the use of DPP4 inhibitors in combination with basal insulin represents an alternative to the basal-bolus insulin regimen in hospitalized patients with type 2 diabetes.


Absolute quantitation of infectious salmon anaemia virus using different real-time reverse transcription PCR chemistries.
Routine laboratory diagnosis of infectious salmon anaemia virus (ISAV) infection is primarily by reverse transcription polymerase chain reaction (RT-PCR) because of the high sensitivity and rapid turnaround time of the test. This paper describes methods for highly reproducible absolute viral load measurements using external standard curves generated with either ISAV recombinant plasmid DNA (pDNA) standards or transcribed RNA standards prepared by in vitro transcription with T7 RNA polymerase, and using a two tube real-time or quantitative (q)RT-PCR with SYBR Green I chemistry and a single tube qRT-PCR with TaqMan probe chemistry. When applied to virus samples of known virus titer for the highly pathogenic ISAV strain NBISA01 and the low pathogenic ISAV strain RPC/NB-04-085-1, both methods showed a 100-fold lower detectable titer for RPC/NB-04-085-1 but with a higher number of viral RNA molecules compared to NBISA01. Overall, the SYBR Green I method overestimated copy numbers in samples having equivalent Ct values with the TaqMan probe method. Taken together, the findings suggest that the TaqMan probe method with the in vitro transcribed RNA standard curve is the preferred method for reliable and rapid quantitation of ISAV in samples.


Fluorine-19 MRI at 21.1 T: enhanced spin-lattice relaxation of perfluoro-15-crown-5-ether and sensitivity as demonstrated in ex vivo murine neuroinflammation.
Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of 19F MR that can be practically achieved when moving from 9.4 to 21.1 T. We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B0), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B0 with 2D-RARE and 2D-FLASH using 19F volume radiofrequency resonators together. T1 and T2 of PFCE were measured at both B0 strengths. Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of 19F T1 and T2 relaxation on B0 was demonstrated. High spatially resolved 19F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. Enhanced SNR and T1 shortening indicate the potential benefit of in vivo 19F MR at higher B0 to study inflammatory processes with greater detail.


Is there a standard of care for the management of advanced pancreatic cancer?. Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 25-27, 2008.
Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the outcome for this disease remains dismal. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. Many chemotherapeutic and targeted agents have been pitted against or combined with gemcitabine in randomized phase III trials and no drug was shown to be superior to single-agent gemcitabine except two gemcitabine-containing combinations: capecitabine plus gemcitabine vs. gemcitabine and erlotinib. In this article, the author debates: "Is there a standard of care for the treatment of advanced pancreatic cancer?". In addition, he summarizes the key studies presented at the "Gastrointestinal Cancers Symposium" held in Orlando, FL, USA on January 25-27, 2008. The studies discussed here include the following: i) a phase I study of a chemotherapy doublet gemcitabine plus capecitabine, combined with a biologic doublet (bevacizumab plus erlotinib) in patients with advanced pancreatic adenocarcinoma (abstract #141); ii) a phase II study of gemcitabine, bevacizumab, and erlotinib in locally advanced and metastatic adenocarcinoma of the pancreas (abstract #151); iii) final results of the multicenter phase II study on gemcitabine, capecitabine, and bevacizumab in patients with advanced pancreatic cancer (abstract #198); iv) interim results from a phase II study of volociximab in combination with gemcitabine in patients with metastatic pancreatic cancer (abstract #142); v) a pilot study of combination chemotherapy with S-1 and irinotecan for advanced pancreatic cancer (abstract #155); vi) a multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer (abstract #212); vii) a phase I/II study of PHY906 plus capecitabine in patients with advanced pancreatic carcinoma (abstract #260); and viii) the final results of a phase II trial of Genexol-PM(R), a novel cremophor-free, polymeric micelle formulation of paclitaxel in patients with advanced pancreatic cancer (abstract #269). Based on the results presented at the meeting, it comes to us that patients with locally advanced vs. metastatic pancreatic cancer should be studied separately, better understanding of the biology of pancreatic cancer is mandatory and evaluation of novel agents is crucial. We, as oncologist, have to change our attitudes towards clinical trials and need to think beyond a trial design such as gemcitabine vs. drug of our choice.


Psychiatry as a career: a survey of factors affecting students' interest in psychiatry as a career.
The objectives of this study were to determine the characteristics of medical students and graduates interested in choosing psychiatry as a career and the obstacles in choosing this field of medicine. Two private and two public medical institutes were surveyed from June 2007 to August 2007. A self-administered questionnaire was distributed to third, fourth and final year students and to medical graduates doing their internship in these four medical institutes. A total of 909 medical students and graduates participated in the study. Seventeen percent of participants responded positively regarding their interest in psychiatry as a career. Significantly higher proportion belonged to private medical institutes (14% vs. 24%, P-value =0.001). There was no significant difference in reporting interest for psychiatry in regard to age, sex, year in medical school and whether or not the participant had done a psychiatry ward rotation. However significantly higher proportion of participants (22%, n=43) were reporting their interest in the field of psychiatry who had done more than a month long psychiatry ward rotation as compared to those participants (14%, n=54) with less than a month or no psychiatry rotation (P-value=0.01). More students were reporting their interest in psychiatry with a family history of psychiatric illness as compared to without family history (24% vs 16%, P-value=0.03). In conclusion, students and graduates with more than a month long rotation in psychiatry, studying in private medical colleges and with a family history of psychiatric illness were more interested in choosing psychiatry as a career.


The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells.
The Notch ligand, Jagged-1, plays an essential role in tissue formation during embryonic development of primitive organisms. However, little is known regarding the role of Jagged-1 in the regulation of tissue-specific stem cells or its function in humans. Here, we show that uncommitted human hematopoietic cells and cells that comprise the putative blood stem cell microenvironment express Jagged-1 and the Notch receptors. Addition of a soluble form of human Jagged-1 to cultures of purified primitive human blood cells had modest effects in augmenting cytokine-induced proliferation of progenitors. However, intravenous transplantation of cultured cells into immunodeficient mice revealed that human (h)Jagged-1 induces the survival and expansion of human stem cells capable of pluripotent repopulating capacity. Our findings demonstrate that hJagged-1 represents a novel growth factor of human stem cells, thereby providing an opportunity for the clinical utility of Notch ligands in the expansion of primitive cells capable of hematopoietic reconstitution.


Effectiveness of multicomponent interventions on incidence of delirium in hospitalized older patients with hip fracture: a systematic review.
ABSTRACTBackground:Delirium is the most frequent complication among the hospitalized elderly with hip fracture. Although, delirium is associated with longer hospital stay, higher mortality rates, worse functional outcomes, and higher institutionalization rates yet health service planners have hugely ignored its existence. This review aims to identify the effectiveness of multicomponent interventions to prevent delirium in hospitalized elderly patients with hip fracture. This review includes experimental, non-experimental, and observational studies. Electronic searches were conducted in MEDLINE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials, Embase, and Web of science. After inclusion and exclusion criteria were applied, nine full text articles were included in the review. The studies reported the following effect on delirium: We pooled data regarding incidence of delirium from the three RCTs. The effect was in favor of the intervention group (odds ratio 0.64, 95% CI 0.46-0.87). All three RCTs reported that duration of delirium was shorter in the intervention group than in the usual care group (mean 2.9 vs. 3.1 days, median 3 vs. 4 days, median 5.0 vs. 10.2 days). Four other studies reported on the duration of delirium with Milisen and colleagues reported shorter duration of delirium within the intervention group. Four studies reported on severity of delirium with two research groups reporting significant results. Early engagement of multidisciplinary staff who addresses the risk factors of delirium as soon as the patient presents to the acute care environment is the key element of a successful delirium prevention program. Once delirium had developed, the multicomponent interventions did not appear to make a difference to the duration or severity of delirium.


Wood bark smoke induces lung and pleural plasminogen activator inhibitor 1 and stabilizes its mRNA in porcine lung cells.
Although aberrant fibrinolysis and plasminogen activator inhibitor 1 (PAI-1) are implicated in acute lung injury, the role of this serpin in the pathogenesis of wood bark smoke (WBS)-induced acute lung injury (SIALI) and its regulation in resident lung cells after exposure to smoke are unclear. A total of 22 mechanically ventilated pigs were included in this study. Immunohistochemical analyses were used to assess fibrin and PAI-1 in the lungs of pigs with SIALI in situ. Plasminogen activator inhibitor 1 was measured in bronchoalveolar lavage fluids by Western blotting. Induction of PAI-1 was determined at the protein and mRNA levels by Western and polymerase chain reaction analyses in primary porcine alveolar type II cells, fibroblasts, and pleural mesothelial cells. Plasminogen activator inhibitor 1 mRNA stability was determined by transcription chase studies. Gel shift analyses were used to characterize the mechanism regulating PAI-1 mRNA stability. Smoke-induced ALI induced PAI-1, with prominent extravascular fibrin deposition in large and small airways as well as alveolar and subpleural compartments. In pleural mesothelial cells, lung fibroblasts, and alveolar type II cells, PAI-1 mRNA was stabilized by WBS extract and contributed to induction of PAI-1. The mechanism involves dissociation of a novel 6-phospho-d-gluconate-NADP oxidoreductase-like PAI-1 mRNA binding protein from PAI-1 mRNA. Exposure to WBS induces prominent airway and mesothelial expression of PAI-1, associated with florid distribution of fibrin in SIALI in vivo Wood bark smoke components induce PAI-1 in vitro in part by stabilization of PAI-1 mRNA, a newly recognized pathway that may promote extravascular fibrin deposition and lung dysfunction in SIALI.


Behavioural disturbances in patients with frontotemporal lobe degeneration focusing on caregiver burden at home and in nursing homes.
To explore the challenges faced by family caregivers of people with frontotemporal dementia and other forms of dementia affecting the frontal and temporal lobes causing behavioural disturbances through a qualitative approach with in-depth interviews. Studies of different forms of dementia involving degeneration of the frontal and temporal lobes have mainly focused on the neurophysiology and physiology of the disease and on caregivers' health. Few studies have described the challenges and burdens connected with everyday life and in relation to suitable nursing home placement that are faced by family caregivers. This study used a descriptive and explorative design. Eleven semi-structured interviews with family caregivers of patients from special units in four nursing homes were conducted in 2014. Data were analysed based on Kvale and Brinkmann's three contexts of interpretation: self-understanding, common sense and theoretical understanding. Checklist for qualitative studies: Standards for Reporting Qualitative Research (SRQR) http://www.equator-network.org/reporting-guidelines/srqr/ RESULTS: Two central themes were derived from the data: changes in behaviour and personality were perceived as incomprehensible, frightening and increasingly difficult to manage. Family caregivers experienced challenges in finding suitable care facilities when they were not able to continue providing home care. Due to behavioural disturbances and lack of relevant competencies among health personnel, family members were often moved between nursing homes. Pronounced personality and behavioural disturbances such as tactlessness and aggression in a family member with dementia are experienced by caregivers as stressful and burdensome and may lead to feelings of shame and guilt. A lack of suitable care facilities adds to the stress and difficulties of the families and entails an additional and unresolved burden. The study reveals a need for more knowledge among those organising health services as well as healthcare professional dealing with this patient category to ease the burden on next of kin.


Decreased interleukin-4 and increased gamma interferon production by peripheral blood mononuclear cells of patients with Lyme borreliosis.
Spontaneous and Borrelia burgdorferi-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) and their interleukin-4 (IL-4), gamma interferon (IFN-gamma), and NO production were measured in 36 patients with second- or third-stage Lyme borreliosis (LB) and 11 control subjects. Spontaneous proliferation of PBMCs was significantly higher (P = 0.0003) in the LB patients than in the control subjects. Spontaneous production of IL-4 was significantly lower in patients than in control subjects (P = 0.0007), but spontaneous production of IFN-gamma was slightly higher in patients. The proliferative response of PBMCs to stimulation with B. burgdorferi was significantly higher (P = 0.01) in patients. The B. burgdorferi-induced production of IFN-gamma (P = 0.002) was also significantly higher in patients. The spontaneous and B. burgdorferi-induced production of NO showed no significant difference between patients and control subjects. These findings indicate that the activation of PBMCs in patients with late LB is enhanced in vivo. Furthermore, the production of IL-4 is effectively suppressed spontaneously, whereas the production of IFN-gamma by PBMCs is slightly increased spontaneously and significantly enhanced during stimulation with B. burgdorferi in vitro. The "spontaneous" or disease-induced alterations in cytokine levels of patients, in this case suppression of a Th2-type cytokine production and activation of a Th1-type cytokine production, may contribute to the pathogenesis of LB.


The angry brain: neural correlates of anger, angry rumination, and aggressive personality.
Very little is known about the neural circuitry guiding anger, angry rumination, and aggressive personality. In the present fMRI experiment, participants were insulted and induced to ruminate. Activity in the dorsal anterior cingulate cortex was positively related to self-reported feelings of anger and individual differences in general aggression. Activity in the medial prefrontal cortex was related to self-reported rumination and individual differences in displaced aggression. Increased activation in the hippocampus, insula, and cingulate cortex following the provocation predicted subsequent self-reported rumination. These findings increase our understanding of the neural processes associated with the risk for aggressive behavior by specifying neural regions that mediate the subjective experience of anger and angry rumination as well as the neural pathways linked to different types of aggressive behavior.


Putting global health high on the agenda of medical schools.
In this opinion paper, we reflect on global health and global health education as well as challenges that the coming generation are likely to face. As the field is rapidly changing, it is vital to critically reflect categories of "global south" and "global north" as geographical boundaries, and rather think in terms of inequalities that are present in all countries. Global perspectives on health are useful to analyze structural challenges faced in all health care systems and help understand the diversity of cultures and patients' concepts of disease. We first discuss burning questions and important challenges in the field and how those challenges are tackled. Rather than going into detail on topical issues, we reflect on approaches and attitudes that we think are important in global health education and present opportunities and challenges for young scholars who are interested in working in this field.


Labeling of cycling corneal endothelial cells during healing with a monoclonal antibody to the Ki67 antigen (MIB-1).
To assess the efficacy of labeling actively cycling corneal endothelial cells by using a monoclonal antibody to the Ki67 antigen (MIB-1) and to determine what changes in f-actin and ZO-1 organization are associated with entry into the cell cycle during wound healing under different culture conditions. Three corneal buttons (6 mm diameter) were punched from each cornea of 15 cats. After a mechanical scrape injury (2 mm diameter) was made, buttons were cultured for 24, 48, or 72 h in serum-free media (SFM), SFM plus 10% fetal calf serum, or SFM plus basic fibroblast growth factor (bFGF). Buttons were single and double labeled by using phalloidin, anti-ZO-1, and MIB-1. Counts of Ki67-positive cells were used to determine the number of actively cycling endothelial cells. After culture in SFM, wounds healed by cell spreading with maintenance of normal apical f-actin and ZO-1 organization; Ki67-positive cells were detected near the leading edge in some areas. A significant increase in the number of cycling cells was measured after 48 h of culture in bFGF as compared with SFM (p<0.05); serum increased the number of cycling cells more than both SFM and bFGF (p<0.05). In all cases, positive MIB-1 staining was not observed until 48 h after injury, was limited to cells actively spreading over the wound area, and was diminished after wound closure (72 h). Double labeling demonstrated that endothelial cells exhibited a fibroblastic phenotype in some central areas of cell proliferation after culture in serum or bFGF, but, in general, apical cell border-associated f-actin and ZO-1 organization was partially maintained in most Ki67-positive cells. The data suggest that spreading corneal endothelial cells are capable of proliferating and can respond to growth factors, but that dedifferentiation or fibroblastic transformation is not required before entry into the cell cycle. Overall, the MIB-1 antibody appears to be ideally suited to the study of corneal endothelial proliferation during wound healing.


Hands in the Real World.
Robots face a rapidly expanding range of potential applications beyond controlled environments, from remote exploration and search-and-rescue to household assistance and agriculture. The focus of physical interaction is typically delegated to end-effectors-fixtures, grippers or hands-as these machines perform manual tasks. Yet, effective deployment of versatile robot hands in the real world is still limited to few examples, despite decades of dedicated research. In this paper we review hands that found application in the field, aiming to discuss open challenges with more articulated designs, discussing novel trends and perspectives. We hope to encourage swift development of capable robotic hands for long-term use in varied real world settings. The first part of the paper centers around progress in artificial hand design, identifying key functions for a variety of environments. The final part focuses on the overall trends in hand mechanics, sensors and control, and how performance and resiliency are qualified for real world deployment.


Brake fluid toxicity feigning brain death.
Brake fluid (glycol-based) toxicity is known to have a protean of central and peripheral nervous system manifestations. The principal component of this household poison is ethylene glycol. Toxic effect is generally attributed to peri-vascular deposition of calcium oxalate crystals in various tissues. However, clinical features resembling brain death have rarely been reported. We report a case of brake fluid toxicity simulating brain death in a 21-year-old healthy man who ingested it as a recreational agent.


Contraception and Conception After Bariatric Surgery.
To examine contraceptive practices and conception rates after bariatric surgery. The Longitudinal Assessment of Bariatric Surgery-2 is a multicenter, prospective cohort study of adults undergoing first-time bariatric surgery as part of routine clinical care at 10 U.S. hospitals. Recruitment occurred between 2005 and 2009. Participants completed preoperative and annual postsurgical assessments for up to 7 years until January 2015. This report was restricted to women 18-44 years old with no history of menopause, hysterectomy, or estrogen and progesterone therapy. Primary outcomes were self-reported contraceptive practices, overall conception rate, and early (less than 18 months) postsurgical conception. Contraceptive practice (no intercourse, protected intercourse, unprotected intercourse, or tried to conceive) was classified based on the preceding year. Conception rates were determined from self-reported pregnancies. Of 740 eligible women, 710 (95.9%) completed follow-up assessment(s). Median (interquartile range) preoperative age was 34 (30-39) years. In the first postsurgical year, 12.7% (95% CI 9.4-16.0) of women had no intercourse, 40.5% (95% CI 35.6-45.4) had protected intercourse only, 41.5% (95% CI 36.4-46.6) had unprotected intercourse while not trying to conceive, and 4.3% (95% CI 2.4-6.3) tried to conceive. The prevalence of the first three groups did not significantly differ across the 7 years of follow-up (P for all >.05); however, more women tried to conceive in the second year (13.1%, 95% CI 9.3-17.0; P<.001). The conception rate was 53.8 (95% CI 40.0-71.1) per 1,000 woman-years across follow-up (median [interquartile range] 6.5 [5.9-7.0] years); 42.3 (95% CI 30.2-57.6) per 1,000 woman-years in the 18 months after surgery. Age (adjusted relative risk 0.41 [95% CI 0.19-0.89] per 10 years, P=.03), being married or living as married (adjusted relative risk 4.76 [95% CI 2.02-11.21], P<.001), and rating future pregnancy as important preoperatively (adjusted relative risk 8.50 [95% CI 2.92-24.75], P<.001) were associated with early conception. Postsurgical contraceptive use and conception rates do not reflect recommendations for an 18-month delay in conception after bariatric surgery. ClinicalTrials.gov, NCT00465829.


Optimizing home dialysis: role of hemodiafiltration.
Over the last 40 years the technical obstacles which prevented a convective contribution to diffusive dialysis have been overcome. Hemodiafiltration represents a natural evolution of intermittent extracorporeal blood purification and the technology is now available to offer this as standard treatment in-center. The first randomized control trial of dialysis dose (National Cooperative Dialysis Study) showed that for three times weekly dialysis a critical level of urea clearance was necessary to ensure complication-free survival, the effect being noticeable by 3 months. Following this, observational studies suggested that higher doses improved longer term outcome. In a second large randomized controlled study (HEMO), higher small molecule clearance did not further improve outcome, but high-flux membranes, which permitted enhanced clearance of middle molecules, appeared to confer survival benefit in patients who had already been on dialysis > 3.7 years. Recently, outcomes from the Membrane Permeability Outcome study confirmed a survival benefit of high-flux membranes in high-risk patients. These studies indicate that in the medium term survival is critically dependent on achieving a minimum level of small solute removal. However, longer term survival (measured in years or decades) not only requires better small solute clearance but also enhanced clearance of middle molecules, the toxicity of which manifest over longer time scales. The rationale for convective treatment is strongest, therefore in those patients who have the greatest potential for long-term survival. Patients who opt for self-care at home to allow frequent dialysis generally are constituents of this group. Hemodiafiltration is likely to become standard therapy in-center and in the home.


The impact of examining the meiotic spindle by polarization microscopy on assisted reproduction outcomes.
To examine the effect of submitting oocytes to polarization microscopy (PM) before intracytoplasmic sperm injection (ICSI). Retrospective observational study. University hospital in Brazil. Couples undergoing ICSI. PM before ICSI (PM group) compared with no PM before ICSI (No-PM group) Fertilization and cleavage rates, formation of top-quality embryos (TQEs), and implantation, clinical pregnancy, miscarriage, and live-birth rates. The PM group consisted of 1,000 consecutive oocytes from 201 couples submitted to PM during the year of 2008. The No-PM group consisted of 1,400 oocytes from 249 couples: 700 consecutive oocytes were retrieved before we started using PM and 700 consecutive oocytes were retrieved after we stopped using PM. In the PM group, we observed an increased fertilization rate (79.7% vs. 72.5%, PM group vs. No-PM group, respectively) but reduced cleavage rate (86.2% vs. 92.5%) and TQE formation (33.1% vs. 49.9%). Implantation (18.7% vs. 20.6%), clinical pregnancy (31.8% vs. 33.3%), miscarriage (21.9% vs. 15.7%), and live-birth (24.9% vs. 28.1%) rates were not significantly different between groups. Use of PM was associated with increased fertilization rate but reduced cleavage rate and TQE formation; no significant difference was observed for implantation, clinical pregnancy, or live-birth rates.


Value and limitations of adenosine in the diagnosis and treatment of narrow and broad complex tachycardias.
The diagnostic and therapeutic potential of intravenous adenosine was studied in 64 patients during 92 episodes of regular sustained tachycardia. In 40 patients who had narrow complex tachycardias (QRS less than 0.12 s) adenosine (2.5-25 mg) restored sinus rhythm in 25 with junctional tachycardias (46 of 48 episodes) and produced atrioventricular block to reveal atrial or sinus tachycardia in 15. In 24 patients with broad complex tachycardias (QRS greater than or equal to 0.12 s) adenosine terminated the tachycardias in six patients and revealed atrial or sinus arrhythmias in four. The tachycardias persisted in 14 patients despite doses up to 20 mg, but adenosine allowed the diagnosis of ventricular tachycardia with retrograde atrial activation in two patients by producing transient ventriculoatrial dissociation. Diagnosis based on adenosine induced atrioventricular nodal block was correct in all patients with narrow complex tachycardias and in 92% of those with broad complex tachycardias, compared with correct electrocardiographic diagnoses in 90% and 75% respectively. Adenosine gave diagnostic information additional to the electrocardiogram in 25%. The response to adenosine in broad complex tachycardias identified those of supraventricular origin with 90% sensitivity, 93% specificity, and 92% predictive accuracy. Adenosine restored sinus rhythm in all patients with junctional reentrant tachycardias, but in 10 (35%) the arrhythmias recurred within two minutes. Symptomatic side effects (dyspnoea, chest pain, flushing, headache) were reported by 40 (63%) patients and, although transient, were severe in 23 (36%). There were ventricular pauses of over 2 s in 16% of patients, the longest pause being 6.1 s. Adenosine is of value in the diagnosis and treatment of narrow and broad complex tachycardias, but its use is limited by symptomatic side effects, a tenfold range in minimal effective dosage, occasional action at sites other than the atrioventricular node, and early recurrence or arrhythmia.


Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients.
Cell surface GLUT4 levels in skeletal muscle from nine type 2 diabetic subjects and nine healthy control subjects have been assessed by a new technique that involves the use of a biotinylated photo-affinity label. A profound impairment in GLUT4 translocation to the skeletal muscle cell surface in response to insulin was observed in type 2 diabetic patients. Levels of insulin-stimulated cell surface GLUT4 above basal in type 2 diabetic patients were only approximately 10% of those observed in healthy subjects. The magnitude of the defect in GLUT4 translocation in type 2 diabetic patients was greater than that observed for glucose transport activity, which was approximately 50% of that in healthy subjects. Reduced GLUT4 translocation is therefore a major contributor to the impaired glucose transport activity in skeletal muscle from type 2 diabetic subjects. When a marked impairment in GLUT4 translocation occurs, the contribution of other transporters to transport activity becomes apparent. In response to hypoxia, marked reductions in skeletal muscle cell surface GLUT4 levels were also observed in type 2 diabetic patients. Therefore, a defect in a common late stage in signal transduction and/or a direct impairment in the GLUT4 translocation process accounts for reduced glucose transport in type 2 diabetic patients.


Financial stress in late adulthood and diverse risks of incident cardiovascular disease and all-cause mortality in women and men.
Financial stress may have adverse health effects. The main aim of this study was to investigate whether having a cash margin and living alone or cohabiting is associated with incident cardiovascular disease (CVD) and all-cause mortality. Representative population-based prospective cohort study of 60-year-old women (n = 2065) and men (n = 1939) in Stockholm County, Sweden. National registers were used to identify cases of incident CVD (n = 375) and all-cause mortality (n = 385). The presence of a cash margin was determined in the questionnaire with the following question: Would you, if an unexpected situation occurred, be able to raise 10,000 SEK within a week? (This was equivalent to US$ 1250 in 1998). Compared with cohabiting women with a cash margin, the risk of all-cause mortality was higher among cohabiting women without a cash margin, with hazard ratios (HRs) of 1.97 (95% confidence interval (CI) 1.06-3.66). Using cohabiting men with cash margin as referent, single men without a cash margin were at an increased risk of both incident CVD and all-cause mortality: HR 2.84 (95% CI 1.61-4.99) and 2.78 (95% CI 1.69-4.56), respectively. Single men with cash margins still had an increased risk of all-cause mortality when compared with cohabiting men with a cash margin: HR 1.67 (95% CI 1.22-2.28). Financial stress may increase the risks of incident CVD and all-cause mortality, especially among men. Furthermore these risks are likely to be greater in men living in single households and in women without cash margins. Living with a partner seems to protect men, but not women, from ill-health associated with financial stress due to the lack of a cash margin.


Generation of 3D shape, density, cortical thickness and finite element mesh of proximal femur from a DXA image.
Areal bone mineral density (aBMD), as measured by dual-energy X-ray absorptiometry (DXA), predicts hip fracture risk only moderately. Simulation of bone mechanics based on DXA imaging of the proximal femur, may help to improve the prediction accuracy. Therefore, we collected three (1-3) image sets, including CT images and DXA images of 34 proximal cadaver femurs (set 1, including 30 males, 4 females), 35 clinical patient CT images of the hip (set 2, including 27 males, 8 females) and both CT and DXA images of clinical patients (set 3, including 12 female patients). All CT images were segmented manually and landmarks were placed on both femurs and pelvises. Two separate statistical appearance models (SAMs) were built using the CT images of the femurs and pelvises in sets 1 and 2, respectively. The 3D shape of the femur was reconstructed from the DXA image by matching the SAMs with the DXA images. The orientation and modes of variation of the SAMs were adjusted to minimize the sum of the absolute differences between the projection of the SAMs and a DXA image. The mesh quality and the location of the SAMs with respect to the manually placed control points on the DXA image were used as additional constraints. Then, finite element (FE) models were built from the reconstructed shapes. Mean point-to-surface distance between the reconstructed shape and CT image was 1.0 mm for cadaver femurs in set 1 (leave-one-out test) and 1.4 mm for clinical subjects in set 3. The reconstructed volumetric BMD showed a mean absolute difference of 140 and 185 mg/cm(3) for set 1 and set 3 respectively. The generation of the SAM and the limitation of using only one 2D image were found to be the most significant sources of errors in the shape reconstruction. The noise in the DXA images had only small effect on the accuracy of the shape reconstruction. DXA-based FE simulation was able to explain 85% of the CT-predicted strength of the femur in stance loading. The present method can be used to accurately reconstruct the 3D shape and internal density of the femur from 2D DXA images. This may help to derive new information from clinical DXA images by producing patient-specific FE models for mechanical simulation of femoral bone mechanics.


Right thoracic curves in presumed adolescent idiopathic scoliosis: which clinical and radiographic findings correlate with a preoperative abnormal magnetic resonance image?
Prospective case control study. This study investigated preoperative presumed adolescent idiopathic scoliosis (AIS) patients with right thoracic curves to determine which clinical and radiographic findings correlate with neural axis abnormalities on magnetic resonance imaging (MRI). Neural axis abnormalities on MRI are not uncommon in patients with left thoracic curves, increased thoracic kyphosis, and in children less than 10 years old. For adolescents with right thoracic curves, less is known regarding which clinical and/or radiographic characteristics accompany neural axis abnormalities. A total of 529 presumed AIS patients with Lenke 1-4 right thoracic curve patterns had MRI evaluation before surgery. Thirty-six of these patients had abnormal MRIs (syrinx, Chiari malformation, and/or tethered cord). To differentiate between those with normal MRIs (n = 493) and those with abnormal MRIs (n = 36), the following preoperative clinical parameters were evaluated: age, gender, height, weight, asymmetric abdominal reflexes, thoracic rotation (scoliometer), coronal balance, trunk shift, shoulder elevation, and the Scoliosis Research Society (SRS)-30 questionnaire. Radiographically, thoracic curve magnitude, thoracic rotation (Nash-Moe), coronal balance, trunk shift, length of thoracic curve, location of curve apex, sagittal balance, thoracic kyphosis (T2-T12), and lumbar lordosis were evaluated. Neural axis abnormalities were found in 6.8%. Those with abnormal MRI findings had significantly greater clinical thoracic rotation (mean difference, 2.4°) and significantly greater radiographic thoracic kyphosis (mean difference 5.9°). However, there were no significant differences in: age (14.9 vs. 14.7 years), height for age (when adjusted for gender), asymmetric abdominal reflexes (3.5% normal MRI group vs. 6.1% abnormal group), coronal balance (clinical or radiographic), trunk shift(clinical or radiographic), shoulder elevation, thoracic curve magnitude (61.4° normal MRI group vs. 63.6° abnormal group), length of thoracic curves (7.0 segments normal group vs. 7.2 segments abnormal group), location of curve apexes, radiographic sagittal balance, or any domains of the preoperative SRS-30 questionnaire. Of preoperative presumed AIS patients with right thoracic curves who underwent MRI evaluation of the neural axis, 6.8% were found to have neural axis abnormalities, with those having increased rotation and/or increased kyphosis at higher risk. Surgeons should use this information when deciding whether a preoperative MRI is indicated in those with right thoracic AIS curve patterns.


Immunogenetics. Chromatin state dynamics during blood formation.
Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development.


Multiple radon entry modeling in a house with a cellar.
Combining a computational fluid dynamics (CFD) model and a multi-zonal model, a study was carried out on radon entry through the complex substructure of a house with a cellar. The uniqueness of the radon entry problem in this type of house was due to the involvement of two radon entry routes to two chambers: the cellar and the living area of the house. Soil gas carrying radon was driven through the two routes by two coupled disturbance pressures in the chambers. The effects of temperature differences were considered as another driving force for the radon entry. Examined in this study were the effects of the geometry of the substructure, air permeability of the soil, air-tightness of the cellar shell, and cellar ventilation on radon entry to both the cellar and the living area. The ground floor covering on top of the soil outside a cellar wall increased radon entry through this wall by about 68%, as radon built up to a very high level under the covering. The effect of cellar ventilation was found as follows: the cellar ventilation created a layer of airflow in the soil under the ground floor; the flow passed over a crack in the ground floor, the entry route to the living area, diluting the radon in the area. Hence, the soil gas entering the living area carried less radon. Cellar ventilation seems more effective in reducing radon entry to the living area in a more permeable soil and leaky cellar shell; a moderate cellar ventilation condition achieved 77% reduction in radon entry to the area. When permeability of these two materials was lower and soil radon content remained the same, the chances of radon entry was also lower; hence, the indoor radon level was lower and no radon control was needed. When such soil contains high radon concentration, other mitigation measures must be sought.


Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations.
We have investigated the genetic involvement of the CD4 and the LAG3 genes, two appealing candidates for MS due to their suggested role in MS pathology. We genotyped a Swedish case-control material consisting of 920 MS patients and 778 controls in an initial study of CD4, three SNPs showed a significant association with MS. An independent material consisting of 1720 Nordic MS patients and 1416 controls were used for confirmation of associated markers in CD4 and to do a confirmative study of the LAG3 gene from previous findings. The result, including a total of 2640 MS patients and 2194 controls shows no significant association with CD4 and LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS.


Experimental investigation of saturated degenerate four-wave mixing for quantitative concentration measurements.
Degenerate four-wave mixing (DFWM) line shapes and signal intensities are measured experimentally in well-characterized hydrogen-air flames operated over a wide range of equivalence ratios. We use both low (perturbative) and high (saturating) beam intensities in the phase-conjugate geometry. Resonances in the A 2Sigma+ -X 2II (0,0) band of OH are probed with multiaxial-mode laser radiation. The effects of saturation on the line-center signal intensity and the resonance linewidth are investigated. The DFWM signal intensities are used to measure OH number densities in a series of near-adiabatic flames at equivalence ratios ranging from 0.5 to 1.5. Use of saturating pump intensities minimizes the effects of beam absorption, providing more-accurate number density measurements. The saturated DFWM results are in excellent agreement with OH absorption measurements and equilibrium calculations of OH number density. The polarization dependence of the P(1)(2) and R(2)(1) resonances is investigated in both laser intensity regimes. There is a significant change in relative reflectivities for different polarization configurations when saturated.


Cardiovascular Event Risk in Rheumatoid Arthritis Compared with Type 2 Diabetes: A 15-year Longitudinal Study.
Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce. The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM). Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57-2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02-2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32-2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01-4.80, p = 0.046 and 2.67, 95% CI 1.30-5.46, p < 0.01, respectively). The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.


Primary blast wave protection in combat helmet design: A historical comparison between present day and World War I.
Since World War I, helmets have been used to protect the head in warfare, designed primarily for protection against artillery shrapnel. More recently, helmet requirements have included ballistic and blunt trauma protection, but neurotrauma from primary blast has never been a key concern in helmet design. Only in recent years has the threat of direct blast wave impingement on the head-separate from penetrating trauma-been appreciated. This study compares the blast protective effect of historical (World War I) and current combat helmets, against each other and 'no helmet' or bare head, for realistic shock wave impingement on the helmet crown. Helmets included World War I variants from the United Kingdom/United States (Brodie), France (Adrian), Germany (Stahlhelm), and a current United States combat variant (Advanced Combat Helmet). Helmets were mounted on a dummy head and neck and aligned along the crown of the head with a cylindrical shock tube to simulate an overhead blast. Primary blast waves of different magnitudes were generated based on estimated blast conditions from historical shells. Peak reflected overpressure at the open end of the blast tube was compared to peak overpressure measured at several head locations. All helmets provided significant pressure attenuation compared to the no helmet case. The modern variant did not provide more pressure attenuation than the historical helmets, and some historical helmets performed better at certain measurement locations. The study demonstrates that both historical and current helmets have some primary blast protective capabilities, and that simple design features may improve these capabilities for future helmet systems.


Effects of multiple concussions on retired national hockey league players.
The purpose of this study was to understand the meanings and lived experiences of multiple concussions in professional hockey players using hermeneutic, idiographic, and inductive approaches within an interpretative phenomenological analysis. The interviewer was an athlete who had suffered multiple concussions, and the interviewees were five former National Hockey League athletes who had retired due to medically diagnosed concussions suffered during their careers. The men discussed the physical and psychological symptoms they experienced as a result of their concussions and how the symptoms affected their professional careers, personal relationships, and quality of life. The former professional athletes related these symptoms to the turmoil that is ever present in their lives. These findings are of interest to athletes, coaches, sport administrators, family members, sport psychology practitioners, and medical professionals, as they highlight the severity of short- and long-term effects of concussions.


Tryptic activation of plasma renin activity.
Trypsinization of human plasma, like acid activation or cryoactivation, increases renin activity, as determined by subsequent enzymatic assay. In three plasma pools, tryptic activation was maximal within 2 min at a trypsin concentration of 500 micrograms/ml, decreasing at higher concentrations. Neither prolongation of trypsin exposure for up to 1 h nor temperature (0 or 37 C) mattered. In plasmas from 26 healthy volunteers ambulatory for 3 h, trypsin increased PRA 3-fold from 2.8 +/- 0.4 to 8.3 +/- 0.7 ng/ml.h (P less than 0.001). Plasma renin reactivity (the amount of angiotensin I generated in plasma by the addition of active renin) and plasma renin substrate were unaltered by trypsin in concentrations up to 500 micrograms/ml. By exclusion, these data support the concept that an inactive precursor form of renin normally exists in human plasma. At concentrations of trypsin of 1 mg/ml or greater, tryptic activation diminished due to degradative effects of trypsin on the renin assay system, indicating the need for careful selection of conditions to maximize tryptic activation.


The why, what, and how of global biodiversity indicators beyond the 2010 target.
The 2010 biodiversity target agreed by signatories to the Convention on Biological Diversity directed the attention of conservation professionals toward the development of indicators with which to measure changes in biological diversity at the global scale. We considered why global biodiversity indicators are needed, what characteristics successful global indicators have, and how existing indicators perform. Because monitoring could absorb a large proportion of funds available for conservation, we believe indicators should be linked explicitly to monitoring objectives and decisions about which monitoring schemes deserve funding should be informed by predictions of the value of such schemes to decision making. We suggest that raising awareness among the public and policy makers, auditing management actions, and informing policy choices are the most important global monitoring objectives. Using four well-developed indicators of biological diversity (extent of forests, coverage of protected areas, Living Planet Index, Red List Index) as examples, we analyzed the characteristics needed for indicators to meet these objectives. We recommend that conservation professionals improve on existing indicators by eliminating spatial biases in data availability, fill gaps in information about ecosystems other than forests, and improve understanding of the way indicators respond to policy changes. Monitoring is not an end in itself, and we believe it is vital that the ultimate objectives of global monitoring of biological diversity inform development of new indicators.


Pomegranate ( Punica granatum L.) expresses several nsLTP isoforms characterized by different immunoglobulin E-binding properties.
Pomegranate allergy is associated with sensitization to non-specific lipid transfer proteins (nsLTPs). Our aim was to identify and characterize the non-specific nsLTPs expressed in pomegranate at the molecular level and to study their allergenic properties in terms of immunoglobulin E (IgE)-binding and cross-reactivity with peach nsLTP (Pru p 3). A non-equilibrium two-dimensional (2-D) electrophoretic approach based on acid-urea PAGE and sodium dodecyl sulfate PAGE was set up to separate pomegranate nsLTPs. Their immunoreactivity was tested by immunoblotting carried out with anti-Pru p 3 polyclonal antibodies and sera from pomegranate-allergic patients. For final identification, pomegranate nsLTPs were purified by chromatography and subjected to trypsin digestion and mass spectrometry (MS) analysis. For this purpose, the sequences obtained by cDNA cloning of three pomegranate nsLTPs were integrated in the database that was subsequently searched for MS data interpretation. Four nsLTPs were identified by 2-D immunoblotting. The detected proteins showed different IgE-binding capacity and partial cross-reactivity with Pru p 3. cDNA cloning and MS analyses led to the identification of three nsLTP isoforms with 66-68% amino acid sequence identity named Pun g 1.0101, Pun g 1.0201 and Pun g 1.0301. By 2-D electrophoresis, we could separate different nsLTP isoforms possessing different IgE-binding properties, which might reflect peculiar allergenic potencies. The contribution of Pru p 3 to prime sensitization is not central as in other plant nsLTPs.


Morphology of femtosecond laser modification of bulk dielectrics.
Using 3D Finite-Difference-Time-Domain simulations, we study the morphology of the laser-created damage inside fused silica. Among the competing effects limiting the intensity in the dielectric, we find the most important is the pulse defocusing by the plasma lens, partially balanced by the Kerr effect. Less important are collisional energy dissipation and laser depletion by multi-photon absorption. We also found that the profile of generated plasma is asymmetrical in the transverse cross-section, with the plasma extended along the direction perpendicular to the laser polarization.


Emerging Insight into MAPK Inhibitors and Immunotherapy in Colorectal Cancer.
Our understanding of the genetic and non-genetic molecular alterations associated with colorectal cancer (CRC) progression and therapy resistance has markedly expanded in the recent years. In addition to their effects on tumor biology, targeted therapies can have effects on host immune responses. However, the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity need to be comprehensively defined. There is good evidence in the literature that alterations in different members of the MAPK superfamily (mainly ERKs and p38 MAPKs) modify the inflammatory response and antitumor immunity, enhancing metastatic features of the tumors. In addition, a plethora of alterations that emerge at relapse often converge on the activation of MAPKs, particularly, ERKs, which act in concert with other oncogenic signals to modulate cellular homeostasis and clonal evolution during targeted therapies. Herein, we discuss how this knowledge can be translated into drug development strategies aimed at increasing tumor antigenicity and antitumor immune responses. Insights from these studies could provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of CRC.


Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain.
The large TSH-bound ectodomain of the thyrotropin receptor (TSHR) activates the transmembrane domain (TMD) indirectly via an internal agonist (IA). The ectodomain/TMD interface consists of a converging helix, a Cys-Cys-bridge-linked IA, and extracellular loops (ECL). To investigate the intramolecular course of molecular activation, especially details of the indirect activation, we narrowed down allosteric inhibition sites of negative allosteric modulator (NAM) by mutagenesis, homology modeling, and competition studies with positive allosteric modulator (PAM). From the inhibitory effects of NAM S37a on: 1) chimeras with swapped ectodomain, 2) stepwise N-terminal truncations, 3) distinct constitutively active mutations distributed across the hinge region and ECL, but not across the TMD, we conclude that S37a binds at the ectodomain/TMD interface, between the converging helix, ECL1, and the IA. This is also supported by the noncompetitive inhibition of PAM-C2-activation by S37a in the TSHR-TMD construct lacking the ectodomain. Mutagenesis studies on the IA and ECL were guided by our refined model of the ectodomain/TMD interface and indicate an interaction with the TSHR-specific residues E404 (preceding IA) and H478 (ECL1). At this new allosteric interaction site, NAM S37a blocks both TSH- and PAM-induced activation of the TSHR. Our refined models, mutations, and new allosteric binding pocket helped us to gain more detailed insights into the intramolecular course of TSHR activation at the ectodomain/TMD interface, including the delocalization of the converging helix and rearrangement of the conformation of IA. These changes are embedded between the ECL and cooperatively trigger active conformations of TMD. SIGNIFICANCE STATEMENT: The intramolecular activation mechanisms of the TSHR appear to be distinct from those of other G protein-coupled receptors, as the TSHR has a uniquely large N-terminal ectodomain that includes the hormone binding site and an internal agonist sequence. We present new molecular and structural insights into the interface between ectodomain and transmembrane domain in the TSHR, as well as the transfer of activation to the transmembrane domain. This knowledge is critical for understanding activation or inhibition of the receptor by allosteric ligands. We have identified a new allosteric antagonist binding pocket that is located exactly at this interface and possesses specific features that may allow the generation of potent highly TSHR-selective drugs, of potential value for the treatment of Graves' orbitopathy.


A laboratory-based evaluation of tube blocking and microbial risks associated with one blended enteral feed recipe.
Concerns associated with blended enteral feeds include the risk of blocked tubes and microbial contamination, although the available evidence is limited. The present laboratory-based investigation aimed to examine these risks in a blended feed providing a nutritionally adequate intake for a hypothetical patient. A one-blended feed recipe was made using three different methods (professional, jug and stick blenders) and three storage procedures. Feed samples were syringed via 10-, 12- and 14-French (Fr) enteral feeding tubes and both blockages and the time taken were recorded. Feed samples were diluted, plated on agars, incubated and bacterial colony-forming units (CFU) counted. After storage at -80 °C, identification was undertaken using 16S rRNA polymerase chain reaction sequencing. Two blockages occurred during 27 administrations of feed made using a professional blender, although they were resolved with a water flush. No blockages occurred with the 14-Fr tube and administration was quicker with wider tubes (P < 0.00001). There was no significant difference between the total bacterial CFU of feeds prepared using different methods (P = 0.771) or stored differently. The genus of bacteria identified included Enterococcus, Bacillus, lactose-fermenting Enterobacteriaceae, Pseudomonas and Staphylococcus. Pathogens, such as Clostridium spp., Salmonella spp. and Vibrio spp., were not identified by phenotypic tests used. Sequencing identified Escherichia coli, Shigella spp., Streptococcus lutetiensis and Staphylococcus epidermidis. The present study found no risk of tube blockages when one blended feed recipe made using three methods was delivered via a 14-Fr tube. There is concern about bacterial contamination, although this was not influenced by the methods of preparation or storage used in the present study.


Calcium Carbonate Precipitation by Bacillus and Sporosarcina Strains Isolated from Concrete and Analysis of the Bacterial Community of Concrete.
Microbially induced calcium carbonate precipitation (CCP) is a long-standing but re-emerging environmental engineering process for production of self-healing concrete, bioremediation, and long-term storage of CO2. CCP-capable bacteria, two Bacillus strains (JH3 and JH7) and one Sporosarcina strain (HYO08), were isolated from two samples of concrete and characterized phylogenetically. Calcium carbonate crystals precipitated by the three strains were morphologically distinct according to field emission scanning electron microscopy. Energy dispersive X-ray spectrometry mapping confirmed biomineralization via extracellular calcium carbonate production. The three strains differed in their physiological characteristics: growth at alkali pH and high NaCl concentrations, and urease activity. Sporosarcina sp. HYO08 and Bacillus sp. JH7 were more alkali- and halotolerant, respectively. Analysis of the community from the same concrete samples using barcoded pyrosequencing revealed that the relative abundance of Bacillus and Sporosarcina species was low, which indicated low culturability of other dominant bacteria. This study suggests that calcium carbonate crystals with different properties can be produced by various CCP-capable strains, and other novel isolates await discovery.


The adaptiveness of defence strategies against cuckoo parasitism.
Host bird species of the Eurasian Cuckoo, Cuculus canorus, often display egg-discrimination behaviour but chick-rejection behaviour has never been reported. In this paper, we analyse a host-cuckoo association in which both population dynamics and evolutionary dynamics are explored in a discrete-time model. We introduce four host types, each with their own defence behaviour, displaying either egg or chick rejection, neither or both, We also introduce fitness functions for each of these host types. Although we can characterize the long term behaviour in many cases by a simple heuristic argument which is in accordance with common views in ecology, there are a number of other phenomena that are not explained within this framework: we describe stable oscillatory behaviour and coexistence of two defensive host types. We analyse the scenarios in which chick rejection may establish itself and give a first explanation as to why this defence trait has never been recorded in nature. We find that chick rejectors generally are at an intrinsic disadvantage with respect to a host type that rejects eggs. Hosts benefit more from rejecting cuckoo eggs than cuckoo chicks, and our model suggests that this is chiefly responsible for the absence of chick rejection. Moreover, even though it seems that chick rejection must be useful as an extra defence, it is shown that hosts with both defence strategies are less likely to establish themselves in competition with egg-rejectors than hosts which reject chicks only. These results provide insight in the extent to which adaptations may be perfected by natural selection.


A high sensitivity assay is more accurate than a classical assay for the measurement of plasma CRP levels in endometriosis.
Endometriosis is associated with chronic subclinical inflammation. C-reactive protein (CRP), a marker of inflammation, could serve as a biomarker of endometriosis. We tested the hypothesis that a high sensitivity CRP assay (hsCRP) is more accurate than a classical CRP assay in the detection of subclinical inflammation in plasma of women with endometriosis. CRP levels were measured by hsCRP and classical CRP assays in plasma of 204 women with endometriosis and 91 women without endometriosis. Both assays were compared with respect to their value for the diagnosis of endometriosis. The number of plasma samples with detectable CRP was significantly higher (100%) using the hsCRP assay when compared to the classical CRP assay (42.7%) (p < 0.0001). Significantly increased CRP plasma levels were found in women with endometriosis when compared with controls when the hsCRP assay was used in samples obtained during the luteal phase (p = 0.008). The highest discriminative ability for the diagnosis of endometriosis was also obtained using the hsCRP assay during the luteal phase, especially for moderate -severe endometriosis. At a cut-off level of hsCRP > 0.71 mg/L, moderate-severe stages were diagnosed with 80.7% sensitivity and 63.9% specificity during the luteal phase. Using a similar cut-off value for CRP analyzed by the classical method, moderate-severe endometriosis was diagnosed with lower sensitivity (67.7%, p = 0.06) and comparable specificity (63.9%). The hsCRP assay was superior to the classical CRP assay for the detection of low CRP levels and for revealing subclinical inflammation in plasma of women with endometriosis.


Reliability, Learnability and Efficiency of Two Tools for Cement Crowns Retrieval in Dentistry.
Tooth-supported fixed dentures are commonly used in restorative dentistry, and have definitely reached a high survival rate; nevertheless, their removal is sometimes required mainly due to caries or other failures (poor fit, poor cementation and so on). Removing a definitive partial denture is not trivial since the used cement is not always known and it may be very resistant; additionally, there are various clinical circumstances in which a conservative disassembly would be desirable. assessing the performance of different tools for cement crowns retrieval in terms of reliability, learnability and efficiency. An experimental study has been performed on two different devices for conservative crown/bridge removal: a manual tool that is a sliding hammer, and an automatic tool, powered by compressed air. Both skilled and unexperienced operators have been considered and an experimental set up has been appositely designed in order to measure force versus time patterns. The peak applied force has been taken as an output variable for the evaluation of tool performance. The automatic tool improves both the inter-operator and the intra-operator reliability, respectively from 79% to 95%, and from 69% to 92%. Additionally, the force pattern is significantly different between these two tools: the instrument powered by compressed air, produces a sharper peak force, as required to break fragile materials such as dental crown cement, and its efficiency can be estimated to be 75% higher. Both tools have a high learnability since the performances of experienced and unexperienced operators have not proved to be significantly different. A methodology has been set up to compare tools for cement crowns retrieval. The compressed-air tool has been proved to generally provide a better performance unless more ductile cement is to be broken.


A novel method for the determination of three volatile organic compounds in exhaled breath by solid-phase microextraction-ion mobility spectrometry.
A method was carried out for the quantitative determination of the concentrations of volatile organic compounds (VOCs) using solid-phase microextraction and ion mobility spectrometry (SPME-IMS). This method was optimized and evaluated. The best results were obtained at sorption temperature 70 °C, desorption temperature 200 °C, and extraction time 15 min. Under the optimized conditions, the linear dynamic range was found to be 0.01-4.0 ppb (R(2) > 0.995), 2.3-400 ppm (R(2) > 0.994), and 2.5-76 ppb (R(2) > 0.998) for acetone, acetaldehyde, and acetonitrile, respectively. The detection limits for acetone, acetaldehyde, and acetonitrile were 0.001 ppb, 0.18 ppm, and 0.22 ppb, respectively. As a practical application, the method was applied for the determination of acetone, acetaldehyde, and acetonitrile in human breath matrix. Therefore, the proposed method was found to be effective and simple enough to be strongly recommended for real sample analysis.


Radiological features of infantile glioblastoma and desmoplastic infantile tumors: British Columbia's Children's Hospital experience.
OBJECT Two of the more common infantile brain tumors, glioblastoma multiforme (GBM) and desmoplastic infantile tumors (DITs), can be difficult to distinguish on MRI. Both tumors occur in the supratentorial compartment and both have solid and cystic components. Differentiating between the 2 on MRI studies could assist the surgeon in discussions with family and child management. The authors report on their institutional experience with both tumors, focusing on radio-graphic features, especially the diffusion studies, which might be useful in distinguishing between infantile GBM and DIT. METHODS A retrospective review was undertaken of all infantile brain tumors treated at British Columbia's Children's Hospital between 1982 and 2012, and cases of GBM and DIT were recorded. Only cases that had imaging were included in the study. A literature review was completed to identify reported cases of infantile GBM and DIT. Only reports that described or included radiological studies (particularly MRI) of the tumors were included. Certain radiographic features of the tumors were reviewed, including location, size, consistency, pattern of enhancement, and features on MR diffusion studies. RESULTS Of 70 cases of infantile brain tumors, 2 GBM cases and 3 DIT cases (all 3 of which were desmoplastic infantile gangliogliomas [DIGs]) met the inclusion criteria. The radiological studies obtained in all 5 cases were reviewed by a neuroradiologist. All 5 patients had supratentorial tumors with cystic-solid consistency. Diffusion MRI studies showed restricted diffusion in the 2 GBM cases, but no evidence of restricted diffusion in the DIG tumors. The GBM tumors were heterogeneously enhancing, and the DIG tumors showed avid and homogeneous enhancement. The literature review revealed 29 cases of infantile GBM and 32 cases of DIG/DIT that met the inclusion criteria. The tumors were large in both groups. The tumors were cystic-solid in consistency in 10 of 30 (33%) of GBM cases and 28 of 32 (87.5%) of DIT cases. The contrast enhancement was heterogeneous in 9 of 30 (30%) GBM cases, and it was homogeneous and avid in 27 of 32 (84%) of DIT cases. Diffusion studies were recorded in 2 published infantile GBM cases, and in both of them diffusion was restricted. The authors only found 1 report that discussed DIG tumor features on MR diffusion studies, but the interpretation was difficult and unclear. CONCLUSIONS Magnetic resonance imaging, especially diffusion-weighted imaging, may be a useful aid in distinguishing between infantile GBM and DIT tumors, with infantile GBM demonstrating restricted diffusion.


Prolonged Ambulation in Duchenne Patients with a Mutation Amenable to Exon 44 Skipping.
Duchenne muscular dystrophy has a severe disease course, though variability exists. Case reports suggest a milder disease course of patients amenable to exon 44 skipping. In this study, we analyzed this and show that age at wheelchair dependence in patients with a dystrophin deletion requiring exon 44 skipping is postponed compared to patients with a deletion skippable by exon 45, 51 and 53 (10.8 versus 9.8 years; P 0.020). This may be explained by more frequent spontaneous exon 44 skipping in patients with a deletion flanking exon 44. This finding has important implications for the development of future Duchenne trials.


Notes from the field: calls to poison centers for exposures to electronic cigarettes--United States, September 2010-February 2014.
Electronic nicotine delivery devices such as electronic cigarettes (e-cigarettes) are battery-powered devices that deliver nicotine, flavorings (e.g., fruit, mint, and chocolate), and other chemicals via an inhaled aerosol. E-cigarettes that are marketed without a therapeutic claim by the product manufacturer are currently not regulated by the Food and Drug Administration (FDA). In many states, there are no restrictions on the sale of e-cigarettes to minors. Although e-cigarette use is increasing among U.S. adolescents and adults, its overall impact on public health remains unclear. One area of concern is the potential of e-cigarettes to cause acute nicotine toxicity. To assess the frequency of exposures to e-cigarettes and characterize the reported adverse health effects associated with e-cigarettes, CDC analyzed data on calls to U.S. poison centers (PCs) about human exposures to e-cigarettes (exposure calls) for the period September 2010 (when new, unique codes were added specifically for capturing e-cigarette calls) through February 2014. To provide a comparison to a conventional product with known toxicity, the number and characteristics of e-cigarette exposure calls were compared with those of conventional tobacco cigarette exposure calls.


History of the prevention of mother-to-child transmission of HIV in Thailand.
Strategies for the prevention of mother-to-child transmission (PMTCT) of HIV have undergone considerable evolution based on scientific evidence, both at global and local levels. Because of the rapid expansion of the HIV epidemic among the heterosexual population, and the relatively advanced mother and child health infrastructure, Thailand has been the site of international study for more efficacious and cost-effective PMTCT regimens since mid-1990. The example of the Thai Red Cross Society in providing standard PMTCT care through public donations under the patronage of Her Royal Highness Princess Soamsawali is an example that non-governmental organisations in other countries can follow to accelerate access to standard PMTCT care. However, there are still many challenges before vertical transmission of HIV is completely eradicated.


The impact of memory T cells on rejection and the induction of tolerance.
Accumulating evidence suggests that alloreactive memory T cells (Tm) may be generated in transplant recipients that have not previously been exposed to alloantigen through mechanisms such as cross-reactivity and homeostatic proliferation. The presence of Tm correlates with both acute and chronic rejection episodes and, furthermore, may be responsible for the failure to induce tolerance in large animal and clinical settings. A clearer understanding of how Tm function and their requirements to mount an effective response to alloantigen will be key to further attempts to translate tolerance induction protocols from the experimental setting to the clinic.


Young children's perceptions of health warning labels on cigarette packages: a study in six countries.
Health warning labels on cigarette packages are one way to reach youth thinking about initiating tobacco use. The purpose of this study was to examine awareness and understanding of current health warning labels among 5 and 6 year old children. Researchers conducted one-on-one interviews with urban and rural 5 and 6 year olds from Brazil, China, India, Nigeria, Pakistan, and Russia. Among the 2,423 participating children, 62 % were unaware of the health warnings currently featured on cigarette packages, with the lowest levels of awareness in India and the highest levels in Brazil. When shown the messages, the same percentage of participating children (62 %) showed no level of message understanding. While youth are receiving social and informational messages promoting tobacco use, health warning labels featured on cigarette packages are not effectively reaching young children with anti-smoking messages.


Effectiveness of Nerve Gliding Exercises on Carpal Tunnel Syndrome: A Systematic Review.
The objective of this study was to review the literature regarding the effectiveness of neural gliding exercises for the management of carpal tunnel syndrome (CTS). A computer-based search was completed through May 2014 in PubMed, Physiotherapy Evidence Database (PEDro), Web of Knowledge, Cochrane Plus, and CINAHL. The following key words were included: nerve tissue, gliding, exercises, carpal tunnel syndrome, neural mobilization, and neurodynamic mobilization. Thirteen clinical trials met the inclusion/exclusion criteria, which were: nerve gliding exercise management of participants aged 18 years or older; clinical or electrophysiological diagnostics of CTS; no prior surgical treatment; and absence of systemic diseases, degenerative joint diseases, musculoskeletal affectations in upper limbs or spine, or pregnancy. All studies were independently appraised using the PEDro scale. The majority of studies reported improvements in pain, pressure pain threshold, and function of CTS patients after nerve gliding, combined or not with additional therapies. When comparing nerve gliding with other therapies, 2 studies reported better results from standard care and 1 from use of a wrist splint, whereas 3 studies reported greater and earlier pain relief and function after nerve gliding in comparison with conservative techniques, such as ultrasound and wrist splint. However, 6 of the 13 studies had a quality of 5 of 11 or less according to the PEDro scale. Limited evidence is available on the effectiveness of neural gliding. Standard conservative care seems to be the most appropriate option for pain relief, although neural gliding might be a complementary option to accelerate recovery of function. More high-quality research is still necessary to determine its effectiveness and the subgroups of patients who may respond better to this treatment.


[Immunosuppressor effect of Trypanosoma musculi (Mastigophora: Trypanosomatidae) on experimental toxoplasmosis].
The immunosuppression caused by species of the gender Trypanosoma has been widely documented. The influence over experimental infections with Toxoplasma gondii is evident when using Trypanosoma lewisi, a natural parasite of white rats. We decided to test the effect of Trypanosoma musculi from mice, an organism with very similar biological characteristics to T. lewisi, to see if this trypanosomatid could induce a similar effect. Four groups of Swiss mice were inoculated with T. musculi previously to infection with T. gondii, and we determined the survival of the animals, as well as the number of cysts developed in the brain of survivors. We isolated and tested different strains of T. gondii from different sources. In a first experiment, the animals were previously inoculated with T. musculi at different times prior to the infection with Toxoplasma; this allowed us to determine that the immunosuppression process resulted more evident when T. musculi inoculation was made four days before. In a second experiment, we used different inoculi dose and found that it did not influenced the process. Furthermore, the results were negative when evaluating if the amount of the inoculated trypomastigote influenced the process. In order to demonstrate if there were differences in the immnosuppressive effect, related to Toxoplasma strains, groups of mice were inoculated with brain cysts of TFC, TLP, TLW and TBT strains. Excluding the TLP strain, that resulted to be very pathogenic regardless the previous inoculation with T. lewisi, the other strains kept the same pattern of immunosuppression in mice, whose survival time was shorter as the presence of cysts in the brain was higher. These observations were in agreement with an experimental immunosuppression model, associated with immunosuppressive diseases, specially cancer and AIDS.


Cell type specific, traceable gene silencing for functional gene analysis during vertebrate neural development.
Many genes have several, sometimes divergent functions during development. Therefore, timing of gene knockdown for functional analysis during development has to be done with precise temporal control, as loss of a gene's function at early stages prevents its analysis later in development. RNAi, in combination with the accessibility of chicken embryos, is an effective approach for temporally controlled analysis of gene function during neural development. Here, we describe novel plasmid vectors that contain cell type-specific promoters/enhancers to drive the expression of a fluorescent marker, followed directly by a miR30-RNAi transcript for gene silencing. These vectors allow for direct tracing of cells experiencing gene silencing by the bright fluorescence. The level of knockdown is sufficient to reproduce the expected pathfinding defects upon perturbation of genes with known axon guidance functions. Mixing different vectors prior to electroporation enables the simultaneous knockdown of multiple genes in independent regions of the spinal cord. This permits complex cellular and molecular interactions to be examined during development, in a fast and precise manner. The advancements of the in ovo RNAi technique that we describe will not only markedly enhance functional gene analysis in the chicken, but also could be adapted to other organisms in developmental studies.


Automatic concept recognition using the human phenotype ontology reference and test suite corpora.
Concept recognition tools rely on the availability of textual corpora to assess their performance and enable the identification of areas for improvement. Typically, corpora are developed for specific purposes, such as gene name recognition. Gene and protein name identification are longstanding goals of biomedical text mining, and therefore a number of different corpora exist. However, phenotypes only recently became an entity of interest for specialized concept recognition systems, and hardly any annotated text is available for performance testing and training. Here, we present a unique corpus, capturing text spans from 228 abstracts manually annotated with Human Phenotype Ontology (HPO) concepts and harmonized by three curators, which can be used as a reference standard for free text annotation of human phenotypes. Furthermore, we developed a test suite for standardized concept recognition error analysis, incorporating 32 different types of test cases corresponding to 2164 HPO concepts. Finally, three established phenotype concept recognizers (NCBO Annotator, OBO Annotator and Bio-LarK CR) were comprehensively evaluated, and results are reported against both the text corpus and the test suites. The gold standard and test suites corpora are available from http://bio-lark.org/hpo_res.html. Database URL: http://bio-lark.org/hpo_res.html.


Your idea and your university: issues in academic technology transfer.
Research discoveries may lead to products for commercial development. A central consideration for the researcher is how involved she or he will be in the commercialization process. In some cases, a university out-licenses the intellectual property, whereas in other cases, the investigator may want to be involved in the development process and choose to start his or her own company to develop and possibly to manufacture and sell the product. Before undertaking such a challenge, however, the investigator-turned-entrepreneur must consider a variety of issues, including career goals, financial and time commitments, potential conflicts of interest and/or commitment, start-up funding, and his or her ability to run a company or step aside to allow business experts to make necessary decisions. This paper discusses some personal considerations in deciding to start a spinout company and provides information on some of the available government grants to assist you should you decide to undertake your product's commercial development. In particular, the Small Business Innovative Research and Small Business Technology Transfer programs of federal funding agencies often are the source of early funding for new biomedical companies.


Does population density and neighborhood deprivation predict schizophrenia? A nationwide Swedish family-based study of 2.4 million individuals.
People living in densely populated and socially disorganized areas have higher rates of psychiatric morbidity, but the potential causal status of such factors is uncertain. We used nationwide Swedish longitudinal registry data to identify all children born 1967-1989 (n = 2361585), including separate datasets for all cousins (n = 1715059) and siblings (n = 1667894). The nature of the associations between population density and neighborhood deprivation and individual risk for a schizophrenia diagnosis was investigated while adjusting for unobserved familial risk factors (through cousin and sibling comparisons) and then compared with similar associations for depression. We generated familial pedigree structures using the Multi-Generation Registry and identified study participants with schizophrenia and depression using the National Patient Registry. Fixed-effects logistic regression models were used to study within-family estimates. Population density, measured as ln(population size/km(2)), at age 15 predicted subsequent schizophrenia in the population (OR = 1.10; 95% CI: 1.09; 1.11). Unobserved familial risk factors shared by cousins within extended families attenuated the association (1.06; 1.03; 1.10), and the link disappeared entirely within nuclear families (1.02; 0.97; 1.08). Similar results were found for neighborhood deprivation as predictor and for depression as outcome. Sensitivity tests demonstrated that timing and accumulation effects of the exposures (mean scores across birth, ages 1-5, 6-10, and 11-15 years) did not alter the findings. Excess risks of psychiatric morbidity, particularly schizophrenia, in densely populated and socioeconomically deprived Swedish neighborhoods appear, therefore, to result primarily from unobserved familial selection factors. Previous studies may have overemphasized the etiological importance of these environmental factors.


Bazedoxifene and conjugated estrogen combination maintains metabolic homeostasis and benefits liver health.
The bazedoxifene and conjugated estrogens (CE+BZA) combination has been shown to prevent visceral adiposity and weight gain after ovariectomy. However, its impact on the liver transcriptomes associated with prevention of hepatosteatosis is yet to be determined. In the present study, we use liver transcriptomics and plasma metabolomics analysis to characterize the effects of various estrogens on liver. The CE+BZA combination was very effective at preventing ovariectomy-induced weight gain in mice fed a high-fat diet (HFD). In CE+BZA treated animals, liver weight and hepatic lipid deposition were significantly lower than in Vehicle (Veh) treated animals. Additionally, CE+BZA induced unique liver transcriptome and plasma metabolome profiles compared to estradiol, conjugated estrogens alone, and bazedoxifene alone. Blood plasma metabolite analysis identified several metabolites similar to and distinct from other estrogen treatments. Integrated pathway analysis showed that gene networks that were associated with inflammation, reactive oxygen species pathway and lipid metabolism and their relevant metabolites were regulated significantly by CE+BZA treatment. Thus, long-term CE+BZA treatment modulated hepatic metabolic gene networks and their associated metabolites and improves hepatic health without stimulating the uterus.


Measuring the impact of ambulatory red blood cell transfusion on home functional status: study protocol for a pilot randomized controlled trial.
Red blood cell (RBC) transfusion is frequently employed in both ambulatory and hospital environments with the aim of improving patient functional status. In the ambulatory setting, this practice is particularly common in patients with malignancy due to anemia associated with their cancer therapy. Increasingly, the efficacy of this US$10.5 billion per year practice has been called into question. While it is often standard of care for patients with chemotherapy-induced anemia to receive ambulatory RBC transfusions, it is unclear to what extent such transfusions affect home functional status. It is also unclear whether or not changes in functional status in this population can be objectively quantified using wearable activity monitors. We propose to directly measure the impact of outpatient RBC transfusions on at-home functional status by recording several physiological parameters and quantifiable physical activity metrics, e.g., daily energy expenditure and daily total step count, using the ActiGraph wGT3X-BT. This device is an accelerometer-based wearable activity monitor similar in size to a small watch and is worn at the waist. Study participants will wear the device during the course of their daily activities giving us quantifiable insight into activity levels in the home environment. This will be a randomized crossover pilot clinical trial with a participant study duration of 28 days. The crossover nature allows each patient to serve as their own control. Briefly, patients presenting at a tertiary medical center's Ambulatory Infusion Center (AIC) will be randomized to either: (1) receive an RBC transfusion as scheduled (transfusion) or (2) abstain from the scheduled transfusion (no transfusion). After an appropriate washout period, participants will crossover from the transfusion arm to the no-transfusion arm or vice versa. Activity levels will be recorded continuously throughout the study using an accelerometry monitor. In addition to device data, functional status and health outcomes will be collected via a weekly telephone interview. The primary outcome measure will be daily energy expenditure. Performance metrics, such as step count changes, will also be evaluated. Additional secondary outcome measures will include daily sedentary time and Patient-reported Outcomes Measurement Information System (PROMIS) Global 10 Survey scores. This trial will provide important information on the feasibility and utility of using accelerometry monitors to directly assess the impact of RBC transfusion on patients' functional status. The results of the study will inform the merit and methods of a more definitive future trial evaluating the impact of ambulatory RBC transfusions in the target population. ClinicalTrials.gov, identifier: NCT02835937 . Registered on 15 July 2016.


Control of somatic tissue differentiation by the long non-coding RNA TINCR.
Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR-mRNA interaction occurs through a 25-nucleotide 'TINCR box' motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR-STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.


Accelerating cine-MR imaging in mouse hearts using compressed sensing.
To combine global cardiac function imaging with compressed sensing (CS) in order to reduce scan time and to validate this technique in normal mouse hearts and in a murine model of chronic myocardial infarction. To determine the maximally achievable acceleration factor, fully acquired cine data, obtained in sham and chronically infarcted (MI) mouse hearts were 2-4-fold undersampled retrospectively, followed by CS reconstruction and blinded image segmentation. Subsequently, dedicated CS sampling schemes were implemented at a preclinical 9.4 T magnetic resonance imaging (MRI) system, and 2- and 3-fold undersampled cine data were acquired in normal mouse hearts with high temporal and spatial resolution. The retrospective analysis demonstrated that an undersampling factor of three is feasible without impairing accuracy of cardiac functional parameters. Dedicated CS sampling schemes applied prospectively to normal mouse hearts yielded comparable left-ventricular functional parameters, and intra- and interobserver variability between fully and 3-fold undersampled data. This study introduces and validates an alternative means to speed up experimental cine-MRI without the need for expensive hardware.


Elimination of thermodynamically infeasible loops in steady-state metabolic models.
The constraint-based reconstruction and analysis (COBRA) framework has been widely used to study steady-state flux solutions in genome-scale metabolic networks. One shortcoming of current COBRA methods is the possible violation of the loop law in the computed steady-state flux solutions. The loop law is analogous to Kirchhoff's second law for electric circuits, and states that at steady state there can be no net flux around a closed network cycle. Although the consequences of the loop law have been known for years, it has been computationally difficult to work with. Therefore, the resulting loop-law constraints have been overlooked. Here, we present a general mixed integer programming approach called loopless COBRA (ll-COBRA), which can be used to eliminate all steady-state flux solutions that are incompatible with the loop law. We apply this approach to improve flux predictions on three common COBRA methods: flux balance analysis, flux variability analysis, and Monte Carlo sampling of the flux space. Moreover, we demonstrate that the imposition of loop-law constraints with ll-COBRA improves the consistency of simulation results with experimental data. This method provides an additional constraint for many COBRA methods, enabling the acquisition of more realistic simulation results.


Novel Emergency Department Risk Score Discriminates Acute Coronary Syndrome Among Chest Pain Patients With Known Coronary Artery Disease.
Patients with known coronary artery disease presenting to the emergency department (ED) with chest pain are often admitted, yet may not be having an acute coronary syndrome (ACS). We assessed whether the use of a novel risk score and a modified thrombolysis in myocardial infarction risk score obtained in the ED could discriminate which of these high-risk patients have ACS. Chart review was performed on a cohort of 285 patients with known coronary artery disease presenting to the ED with chest pain thought to be of ischemic origin and admitted to the hospital. The ED variables were assessed with logistic regression for their association with eventual ACS diagnosis at hospital discharge. ACS was diagnosed in 74 (26%) of the patients. Non-ACS patients had a 2-day median length of stay and $6875 median inpatient (post ED) hospital charges (not including physician fees), totaling 566 hospital bed days and $1,871,250 for the 211 (74%) non-ACS patients. A novel risk score, including (1) history of prior revascularization, (2) comorbid chronic kidney disease, (3) onset of chest discomfort at rest, (4) dynamic electrocardiogram changes in the ED, (5) elevated troponin I (>0.05 ng/mL) in the ED, and (6) associated illness at presentation, discriminated ACS and non-ACS with a c statistic of 0.767; the c statistic for a modified thrombolysis in myocardial infarction risk score was 0.712. Application of these risk scores may reduce the number of potentially avoidable admissions and their associated hazards and costs.