Excitotoxicity-induced endocytosis mediates neuroprotection by TAT-peptide-linked JNK inhibitor.

ABSTRACT: Excitotoxicity and cerebral ischemia induce strong endocytosis in neurons, and we here investigate its functional role in neuroprotection by a functional transactivator of transcription (TAT)-peptide, the c-Jun N-terminal kinase (JNK) inhibitor D-JNKI1, against NMDA-excitotoxicity in vitro and neonatal ischemic stroke in P12 Sprague-Dawley rats. In both situations, the neuroprotective efficacy of D-JNKI1 was confirmed, but excessively high doses were counterproductive. Importantly, the induced endocytosis was necessary for neuroprotection, which required that the TAT-peptide be administered at a time when induced endocytosis was occurring. Uptake by other routes failed to protect, and even promoted cell death at high doses. Blocking the induced endocytosis of D-JNKI1 with heparin or with an excess of D-TAT-peptide eliminated the neuroprotection. We conclude that excitotoxicity-induced endocytosis is a basic property of stressed neurons that can target neuroprotective TAT-peptides into the neurons that need protection. Furthermore, it is the main mediator of neuroprotection by D-JNKI1. This may explain promising reports of strong neuroprotection by TAT-peptides without apparent side effects, and warns that the timing of peptide administration is crucial.

Alpine deformation and 40Ar/39Ar geochronology of synkinematic white mica in the Siviez-Mischabel Nappe, western Pennine Alps, Switzerland

We explore the timing of deformation and exhumation of the Siviez-Mischabel Nappe (western Swiss Alps), which has been considered a classic example of a midcrustal crystalline nappe since the studies of Argand [1916]. This study presents Ar-40/Ar-39 ages obtained on both synkinematic white mica from Permo-Triassic cover sediments and more complex white mica populations from basement gneisses of the Siviez-Mischabel and middle Pennine Nappes. Primary foliation developed in cover units by nucleation, growth, and rigid rotation of mica grains during noncoaxial Alpine deformation. Although some samples show a crenulation of this primary foliation, mica growth appears to have occurred only during the development of primary foliation, the main phase of greenschist facies deformation related to imbrication of the Siviez-Mischabel Nappe and other middle Pennine Nappes. Good agreement exists between independent estimates of the timing of deformation and reported Ar-40/Ar-39, white mica ages from cover units of the central and southern Siviez-Mischabel Nappe. In cover units from the central and southern Siviez-Mischabel regions of the study area, Ar-40/Ar-39 ages appear to date synkinematic white mica growth. Results suggest that the Siviez-Mischabel :Nappe was emplaced and developed foliation during a 5 m.y. period from 41 to 36 Ma. In cover units from the eastern Siviez-Mischabel, however, Ar-40/Ar-39 white mica ages appear to date postkinematic thermal events. These thermal events may be related to Oligocene magmatic activity in the lower Pennine Nappes or to Miocene development of the Simplon fault zone. Variations in the relation between Alpine age and grain size for cover samples from the central, eastern, and southern Siviez-Mischabel correlate well with the regional variations in temperature inferred from quartz microfabrics and the pattern of regional metamorphism. When considered in concert with other recent isotopic studies on the timing of major tectonic and thermal events in the western Swiss Alps, these data support arguments that the relative timing of events such as thrusting and back thrusting of crystalline nappes in hinterland units and exhumation of high-pressure units in the suture zone of the western Alps are intimately related and synchronous on the scale of a few million years. Copyright 1998 by the American Geophysical Union.

Sex of College Students Moderates Associations among Bedtime, Time in Bed, and Circadian Phase Angle.

Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.

ICD-11 for quality and safety: overview of the who quality and safety topic advisory group.

This paper outlines the approach that the WHO's Family of International Classifications (WHO-FIC) network is undertaking to create ICD-11. We also outline the more focused work of the Quality and Safety Topic Advisory Group, whose activities include the following: (i) cataloguing existing ICD-9 and ICD-10 quality and safety indicators; (ii) reviewing ICD morbidity coding rules for main condition, diagnosis timing, numbers of diagnosis fields and diagnosis clustering; (iii) substantial restructuring of the health-care related injury concepts coded in the ICD-10 chapters 19/20, (iv) mapping of ICD-11 quality and safety concepts to the information model of the WHO's International Classification for Patient Safety and the AHRQ Common Formats; (v) the review of vertical chapter content in all chapters of the ICD-11 beta version and (vi) downstream field testing of ICD-11 prior to its official 2015 release. The transition from ICD-10 to ICD-11 promises to produce an enhanced classification that will have better potential to capture important concepts relevant to measuring health system safety and quality-an important use case for the classification.

Molecular clock is involved in predictive circadian adjustment of renal function.

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.

Investigation of Warm-Mix Asphalt for Iowa Roadways, TR-635, 2013

Phase II of this study further evaluated the performance of plant-produced warm-mix asphalt (WMA) mixes by conducting additional mixture performance tests at a broader range of temperatures, adding additional pavements to the study, comparing virgin and recovered binder properties, performing pavement condition surveys, and comparing survey data with the Mechanistic Empirical Pavement Design Guide (MEPDG) forecast for pavement damage over 20 years of service life. Further objectives detailing curing behavior, quality assurance testing, and hybrid technologies were as follows: * Compare the predicted and observed field performance of existing WMA trials produced in the previous Phase I study to that of hot-mix asphalt (HMA) control sections to determine if Phase I conclusions are translating to the field; * Identify any curing effect (and timing of the effect) of WMA mixtures and binders in the field; * Determine how the field-compacted mixture properties and recovered binder properties of WMA compare to those of HMA over time for technologies common to Iowa; * Identify the protocols for WMA sample preparation for volumetric and performance testing that best simulate field conditions. The findings of this study indicate that WMA additives do show statistical differences in mixture properties in some of the mixes tested. These differences will not always be statistically different from mixture to mixture. Multiple factors, such as WMA additive type, amount of recycled asphalt material, construction conditions, and mixture variability all play a role in determining the extent of which WMA and HMA mixes differ. Other significant findings of this study include effects of curing, aging in recovered binders from HMA and WMA cores, and the influence of recycled asphalt shingles (RAS) used with WMA. These findings will be of interest to owner agencies and contractors utilizing WMA technologies.

Combined radioimmunotherapy and radiotherapy of liver metastases from colorectal cancer: a feasibility study.

BACKGROUND: A combination of radioimmunotherapy (RIT) and radiotherapy (RT) should allow one to increase the dose of radiation targeting a particular tumour without the concomitant increase of toxic side effects. This might be obtained if the dose limiting side effect of each individual radiation therapy concerned different organs. METHODS: Six patients with limited liver metastatic disease from colorectal cancer were treated with 6.9 GBq (range 4.7 to 8.4 GBq) 131I-labelled anti-CEA MAb F(ab')2 fragments combined with 20 Gy RT to the liver. Both treatments were given in close association, according to timing schedules evaluated in animals that gave the best results. RESULTS: Reversible bone marrow and liver toxicity was observed in 6 and 5 patients, respectively. Three patients who first received 20 Gy RT to the liver, showed a significant platelet drop upon completion of RT. Repeat computerized tomography (CT) after 2 months showed a minor response in 1 patient and stable disease in 3 patients. CONCLUSION: The study shows potential ways of combining RIT and RT, suggesting that this combination is feasible for the treatment of liver metastases.

Medical residents' feedback on needs and acquired skills following a short course on cross-cultural competence

Objectives The purpose of this study is to assess short and long term changes in knowledge, attitudes, and skills among medical residents following a short course on cultural competency and to explore their perspectives on the experience. Methods Eighteen medical residents went through a short training programme comprised of two seminars lasting 30' and 60' respectively over two days. Three months later, we conducted three focus groups, with 17 residents to explore their thoughts, perspectives and feedback about the course. To measure changes over time, we carried out a quantitative sequential survey before the seminars, three days after, and three months later using the Multicultural Assessment Questionnaire. Results Residents expressed a wide variety of perspectives on the main themes related to the content of the training - culture, trialogue, stereotypes, status, epidemiology, history and geopolitics - and related to its organization - relevance, volume, timing, target audience, training tools, and working material. Using the MAQ, we observed a higher global performance score (n=16) at three days (median=38) compared to results before the training (median=33) revealing a median difference of 5.5 points (z=2.4, p=0.015). This difference was still present at three months (∆=4.5, z=2.4, p=0.018), mainly due to knowledge acquisition (∆=3) rather than attitudes (∆=0) or skills (∆=1). Conclusions Cross-cultural competence training not only brings awareness of multicultural issues but also helps participants understand their own cultures, perception of others and preconceived ideas. Physicians' education should however also focus on improving implementation of acquired knowledge in cross-cultural competence.

Distinct levels in Pom1 gradients limit Cdr2 activity and localization to time and position division.

Where and when cells divide are fundamental questions. In rod-shaped fission yeast cells, the DYRK-family kinase Pom1 is organized in concentration gradients from cell poles and controls cell division timing and positioning. Pom1 gradients restrict to mid-cell the SAD-like kinase Cdr2, which recruits Mid1/Anillin for medial division. Pom1 also delays mitotic commitment through Cdr2, which inhibits Wee1. Here, we describe quantitatively the distributions of cortical Pom1 and Cdr2. These reveal low profile overlap contrasting with previous whole-cell measurements and Cdr2 levels increase with cell elongation, raising the possibility that Pom1 regulates mitotic commitment by controlling Cdr2 medial levels. However, we show that distinct thresholds of Pom1 activity define the timing and positioning of division. Three conditions-a separation-of-function Pom1 allele, partial downregulation of Pom1 activity, and haploinsufficiency in diploid cells-yield cells that divide early, similar to pom1 deletion, but medially, like wild-type cells. In these cells, Cdr2 is localized correctly at mid-cell. Further, Cdr2 overexpression promotes precocious mitosis only in absence of Pom1. Thus, Pom1 inhibits Cdr2 for mitotic commitment independently of regulating its localization or cortical levels. Indeed, we show Pom1 restricts Cdr2 activity through phosphorylation of a C-terminal self-inhibitory tail. In summary, our results demonstrate that distinct levels in Pom1 gradients delineate a medial Cdr2 domain, for cell division placement, and control its activity, for mitotic commitment.

MHC class I expression dependent on bacterial infection and parental factors in whitefish embryos (Salmonidae).

Ecological conditions can influence not only the expression of a phenotype, but also the heritability of a trait. As such, heritable variation for a trait needs to be studied across environments. We have investigated how pathogen challenge affects the expression of MHC genes in embryos of the lake whitefish Coregonus palaea. In order to experimentally separate paternal (i.e. genetic) from maternal and environmental effects, and determine whether and how stress affects the heritable variation for MHC expression, embryos were produced in full-factorial in vitro fertilizations, reared singly, and exposed at 208 degree days (late-eyed stage) to either one of two strains of Pseudomonas fluorescens that differ in their virulence characteristics (one increased mortality, while both delayed hatching time). Gene expression was assessed 48 h postinoculation, and virulence effects of the bacterial infection were monitored until hatching. We found no evidence of MHC class II expression at this stage of development. MHC class I expression was markedly down-regulated in reaction to both pseudomonads. While MHC expression could not be linked to embryo survival, the less the gene was expressed, the earlier the embryos hatched within each treatment group, possibly due to trade-offs between immune function and developmental rate or further factors that affect both hatching timing and MHC expression. We found significant additive genetic variance for MHC class I expression in some treatments. That is, changes in pathogen pressures could induce rapid evolution in MHC class I expression. However, we found no additive genetic variance in reaction norms in our study population.

Evidence-Based Recommendations for Optimal Dietary Protein Intake in Older People: A Position Paper From the PROT-AGE Study Group.

New evidence shows that older adults need more dietary protein than do younger adults to support good health, promote recovery from illness, and maintain functionality. Older people need to make up for age-related changes in protein metabolism, such as high splanchnic extraction and declining anabolic responses to ingested protein. They also need more protein to offset inflammatory and catabolic conditions associated with chronic and acute diseases that occur commonly with aging. With the goal of developing updated, evidence-based recommendations for optimal protein intake by older people, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group). To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.0 to 1.2 g protein per kilogram of body weight per day. Both endurance- and resistance-type exercises are recommended at individualized levels that are safe and tolerated, and higher protein intake (ie, ≥1.2 g/kg body weight/d) is advised for those who are exercising and otherwise active. Most older adults who have acute or chronic diseases need even more dietary protein (ie, 1.2-1.5 g/kg body weight/d). Older people with severe kidney disease (ie, estimated GFR <30 mL/min/1.73m(2)), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake. Protein quality, timing of ingestion, and intake of other nutritional supplements may be relevant, but evidence is not yet sufficient to support specific recommendations. Older people are vulnerable to losses in physical function capacity, and such losses predict loss of independence, falls, and even mortality. Thus, future studies aimed at pinpointing optimal protein intake in specific populations of older people need to include measures of physical function.

Le "neurally adjusted ventilatory assist": vers une révolution de la ventilation mécanique [Neurally adjusted ventilatory assist: a revolution of mechanical ventilation?].

Neurally adjusted ventilatory assist or NAVA is a new assisted ventilatory mode which, in comparison with pressure support, leads to improved patient-ventilator synchrony and a more variable ventilatory pattern. It also improves arterial oxygenation. With NAVA, the electrical activity of the diaphragm is recorded through a nasogastric tube equipped with electrodes. This electrical activity is then used to pilot the ventilator. With NAVA, the patient's respiratory pattern controls the ventilator's timing of triggering and cycling as well as the magnitude of pressurization, which is proportional to inspiratory demand. The effect of NAVA on patient outcome remains to be determined through well-designed prospective studies.

Phase-sensitive dual-inversion recovery for accelerated carotid vessel wall imaging.

OBJECTIVES: Dual-inversion recovery (DIR) is widely used for magnetic resonance vessel wall imaging. However, optimal contrast may be difficult to obtain and is subject to RR variability. Furthermore, DIR imaging is time-inefficient and multislice acquisitions may lead to prolonged scanning times. Therefore, an extension of phase-sensitive (PS) DIR is proposed for carotid vessel wall imaging. METHODS: The statistical distribution of the phase signal after DIR is probed to segment carotid lumens and suppress their residual blood signal. The proposed PS-DIR technique was characterized over a broad range of inversion times. Multislice imaging was then implemented by interleaving the acquisition of 3 slices after DIR. Quantitative evaluation was then performed in healthy adult subjects and compared with conventional DIR imaging. RESULTS: Single-slice PS-DIR provided effective blood-signal suppression over a wide range of inversion times, enhancing wall-lumen contrast and vessel wall conspicuity for carotid arteries. Multislice PS-DIR imaging with effective blood-signal suppression is enabled. CONCLUSIONS: A variant of the PS-DIR method has successfully been implemented and tested for carotid vessel wall imaging. This technique removes timing constraints related to inversion recovery, enhances wall-lumen contrast, and enables a 3-fold increase in volumetric coverage at no extra cost in scanning time.

Hypercalcaemia and acute renal failure after major burns: An under-diagnosed condition.

BACKGROUND: Hypercalcaemia has been shown to occur in about 20% of patients with major burns requiring prolonged intensive care unit (ICU) treatment, and it may be associated with renal failure. Having observed the early onset of hypercalcaemia, the study aimed to determine the frequency and timing of this condition in a European patient cohort. METHODS: A retrospective cohort study on a prospectively collected, computerised database of the 225 burn-injury ICU admissions between 2001 and 2007 was undertaken. The inclusion criteria included: burns &gt;20% of the body surface area (BSA) or in-hospital stay &gt;20 days. Hypercalcaemia was defined as an ionised plasma calcium (Ca(2+)) concentration &gt;1.32 mmol l(-1) (or total corrected calcium=[Ca]c&gt;2.55 mmol l(-1)). Four emblematic cases are reported in this article. RESULTS: A total of 73 patients met the inclusion criteria (age: 13-88 years, burns: 12-85% BSA): of these, 22 (30%) developed hypercalcaemia. The median time to the first hypercalcaemia value was 21 days. Only 11 patients had both high Ca(2+) and elevated [Ca]c (which remained normal in others). The risk factors of the disorder were burned surface (p=0.017) and immobilisation (fluidised bed use: p&lt;0.05, duration: p=0.02) followed by burned BSA. Acute renal failure tended to be more frequent in hypercalcaemic patients (five (23%) vs. three (6%): p=0.11), while mortality was not increased. The disorder resolved with hydration and mobilisation in most cases: pamidronate was successful in three cases that were most severe. CONCLUSION: Hypercalcaemia and associated acute renal failure occur more frequently and earlier than previously reported. Determining the ionised Ca rather than the total Ca with albumin correction enables earlier detection of hypercalcaemia. Bisphosphonates are an effective treatment option in controlling severe hypercalcaemia and preventing bone loss.

Decision criteria for optimizing postemergence johnsongrass control in soybean crops in Argentina

Field studies were established in Zavalla and Oliveros, Argentina, during four years in order to optimize Johnsongrass (Sorghum halepense (L.) Pers.) chemical control by means of the thermal calendar model in comparison with other criteria (weed height or days after sowing). The effect of three application dates of postemergence herbicides was determined by visual control, density of tillers originated from rhizome bud regrowth, and from crown and shoot bud regrowth, and soybean yield. Following the thermal calendar model criterion, applications during the second date afforded the best control. Weed height for the first date showed little variability between experiments but was highly variable in the second and third application dates, achieving in some cases values greater than 120 cm. For all years, no significant differences were detected for crop yield between the first and second application dates, and yields were always lower for the third date. The greatest rhizome bud regrowth was observed for the earliest application date and the highest crown and shoot bud regrowth was determined for the last application date. Parameters associated with control efficiency showed the best behaviour for the second date. However, plant height at this moment may interfere with herbicide application and the variability exhibited by this parameter highlights the risk of determining control timing using only one decision criterion.