Automated peritoneal lavage: An extremely rapid and safe way to induce hypothermia in post-resuscitation patients

Introduction: Mild therapeutic hypothermia (MTH) is a worldwide used therapy to improve neurological outcome in patients successfully resuscitated after cardiac arrest (CA). Preclinical data suggest that timing and speed of induction are related to reduction of secondary brain damage and improved outcome.Methods: Aiming at a rapid induction and stable maintenance phase, MTH induced via continuous peritoneal lavage (PL) using the Velomedix® Inc. automated PL system was evaluated and compared to historical controls in which hypothermia was achieved using cooled saline intravenous infusions and cooled blankets. Results: In 16 PL patients, time to reach the core target temperature of 32.5°C was 30 minutes (interquartile range (IQR): 19 to 60), which was significantly faster compare to 150 minutes (IQR: 112 to 240) in controls. The median rate of cooling during the induction phase in the PL group of 4.1°C/h (IQR: 2.2 to 8.2) was significantly faster compared to 0.9°C/h (IQR: 0.5 to 1.3) in controls. During the 24-hour maintenance phase mean core temperature in the PL patients was 32.38 ± 0.18°C (range: 32.03 to 32.69°C) and in control patients 32.46 ± 0.48°C (range: 31.20 to 33.63°C), indicating more steady temperature control in the PL group compared to controls. Furthermore, the coefficient of variation (VC) for temperature during the maintenance phase was lower in the PL group (VC: 0.5%) compared to the control group (VC: 1.5%). In contrast to 23% of the control patients, none of the PL patients showed an overshoot of hypothermia below 31°C during the maintenance phase. Survival and neurological outcome was not different between the two groups. Neither shivering nor complications related to insertion or use of the PL method were observed.Conclusions: Using PL in post-CA patients results in a rapidly reached target temperature and a very precise maintenance, unprecedented in clinical studies evaluating MTH techniques. This opens the way to investigate the effects on neurological outcome and survival of ultra-rapid cooling compared to standard cooling in controlled trials in various patient groups.Trial Registration: ClinicalTrials.gov: NCT01016236. © 2013 de Waard et al.; licensee BioMed Central Ltd

Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival

Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer

To assess the relation between urinary endogenous sex steroid levels and the risk of postmenopausal breast cancer, a nested case–cohort study was conducted within a large cohort (the DOM cohort) in the Netherlands (n¼9 349). Until the end of follow-up (1 January 1996), 397 postmenopausal breast cancer cases were identified and a subcohort of 424 women was then taken from all eligible women. Women using hormones were excluded, leaving 364 breast cancer cases and 382 women in the subcohort for the analyses. Concentrations of oestrone, oestradiol, testosterone, 5a-androstane-3a, 17b-diol and creatinine were measured in first morning urine samples, which had been stored since enrolment at -201C. A Cox proportional Hazards model was used, with Barlow’s adjustment for case–cohort sampling, to estimate breast cancer risk in quartiles of each of the, creatinine corrected, hormone levels, the lowest quartile being the reference group. Women with higher levels of all four of the hormones were at increased risk for postmenopausal breast cancer (highest vs lowest quartile: incidence rate ratio for oestrone (IRRoestrone=2.5, 95% CI: 1.6–3.8; IRRoestradiol=1.5, 95% CI: 1.0–2.3; IRRtestosterone=1.6, 95% CI: 1.0–2.4; IRR5a-androstane-3a, 17b-diol=1.7, 95% CI: 1.1–2.7). In conclusion, women with higher excretion levels of both oestrogens and androgens have an increased risk of breast cancer

An intracellular pH gradient in the anammox bacterium Kuenenia stuttgartiensis as evaluated by 31P NMR

The cytoplasm of anaerobic ammonium oxidizing (anammox) bacteria consists of three compartments separated by membranes. It has been suggested that a proton motive force may be generated over the membrane of the innermost compartment, the “anammoxosome”. 31P nuclear magnetic resonance (NMR) spectroscopy was employed to investigate intracellular pH differences in the anammox bacterium Kuenenia stuttgartiensis. With in vivo NMR, spectra were recorded of active, highly concentrated suspensions of K. stuttgartiensis in a wide-bore NMR tube. At different external pH values, two stable and distinct phosphate peaks were apparent in the recorded spectra. These peaks were equivalent with pH values of 7.3 and 6.3 and suggested the presence of a proton motive force over an intracytoplasmic membrane in K. stuttgartiensis. This study provides for the second time—after discovery of acidocalcisome-like compartments in Agrobacterium tumefaciens—evidence for an intracytoplasmic pH gradient in a chemotrophic prokaryotic cell

FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni

Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway

Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

International audienc

STEM education in the twenty-first century: learning at work-an exploration of design and technology teacher perceptions and practices

Teachers’ knowledge of STEM education, their understanding, and pedagogical application of that knowledge is intrinsically linked to the subsequent effectiveness of STEM delivery within their own practice; where a teacher’s knowledge and understanding is deficient, the potential for pupil learning is ineffective and limited. Set within the context of secondary age phase education in England and Wales (11–16 years old), this paper explores how teachers working within the field of design and technology education acquire new knowledge in STEM; how understanding is developed and subsequently embedded within their practice to support the creation of a diverse STEM-literate society. The purpose being to determine mechanisms by which knowledge acquisition occurs, to reconnoitre potential implications for education and learning at work, including consideration of the role which new technologies play in the development of STEM knowledge within and across contributory STEM subject disciplines. Underpinned by an interpretivist ontology, work presented here builds upon the premise that design and technology is an interdisciplinary educational construct and not viewed as being of equal status to other STEM disciplines including maths and science. Drawing upon the philosophical field of symbolic interactionism and constructivist grounded theory, work embraces an abductive methodology where participants are encouraged to relate design and technology within the context of STEM education. Emergent findings are discussed in relation to their potential to support teachers’ educational development for the advancement of STEM literacy, and help secure design and technology’s place as a subject of value within a twenty-first Century curriculum

N-Acetylcysteine and Allopurinol Synergistically Enhance Cardiac Adiponectin Content and Reduce Myocardial Reperfusion Injury in Diabetic Rats

Background: Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Methodology/Principal Findings: Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. Conclusions/Significance: NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats. © 2011 Wang et al.published_or_final_versio

Mycobacterium tuberculosis ecology in Venezuela: epidemiologic correlates of common spoligotypes and a large clonal cluster defined by MIRU-VNTR-24

<p>Abstract</p> <p>Background</p> <p>Tuberculosis remains an endemic public health problem, but the ecology of the TB strains prevalent, and their transmission, can vary by country and by region. We sought to investigate the prevalence of <it>Mycobacterium tuberculosis </it>strains in different regions of Venezuela. A previous study identified the most prevalent strains in Venezuela but did not show geographical distribution nor identify clonal genotypes. To better understand local strain ecology, we used spoligotyping to analyze 1298 <it>M. tuberculosis </it>strains isolated in Venezuela from 1997 to 2006, predominantly from two large urban centers and two geographically distinct indigenous areas, and then studied a subgroup with MIRU-VNTR 24 loci.</p> <p>Results</p> <p>The distribution of spoligotype families is similar to that previously reported for Venezuela and other South American countries: LAM 53%, T 10%, Haarlem 5%, S 1.9%, X 1.2%, Beijing 0.4%, and EAI 0.2%. The six most common shared types (SIT's 17, 93, 605, 42, 53, 20) accounted for 49% of the isolates and were the most common in almost all regions, but only a minority were clustered by MIRU-VNTR 24. One exception was the third most frequent overall, SIT 605, which is the most common spoligotype in the state of Carabobo but infrequent in other regions. MIRU-VNTR homogeneity suggests it is a clonal group of strains and was named the "Carabobo" genotype. Epidemiologic comparisons showed that patients with SIT 17 were younger and more likely to have had specimens positive for Acid Fast Bacilli on microscopy, and patients with SIT 53 were older and more commonly smear negative. Female TB patients tended to be younger than male patients. Patients from the high incidence, indigenous population in Delta Amacuro state were younger and had a nearly equal male:female distribution.</p> <p>Conclusion</p> <p>Six SIT's cause nearly half of the cases of tuberculosis in Venezuela and dominate in nearly all regions. Strains with SIT 17, the most common pattern overall may be more actively transmitted and SIT 53 strains may be less virulent and associated with reactivation of past infections in older patients. In contrast to other common spoligotypes, strains with SIT 605 form a clonal group centered in the state of Carabobo.</p