Neuromechanical adaptation to hopping with an elastic ankle-foot orthosis.
When humans hop or run on different surfaces, they adjust their effective leg stiffness to offset changes in surface stiffness. As a result, the overall stiffness of the leg-surface series combination remains independent of surface stiffness. The purpose of this study was to determine whether humans make a similar adjustment when springs are placed in parallel with the leg via a lower limb orthosis. We studied seven human subjects hopping in place on one leg while wearing an ankle-foot orthosis. We used an ankle-foot orthosis because the ankle joint is primarily responsible for leg stiffness during hopping. A spring was added to the ankle-foot orthosis so that it increased orthosis stiffness by providing plantar flexor torque during ankle dorsiflexion. We hypothesized that subjects would decrease their biological ankle stiffness when the spring was added to the orthosis, keeping total ankle stiffness constant. We collected kinematic, kinetic, and electromyographic data during hopping with and without the spring on the orthosis. We found that total ankle stiffness and leg stiffness did not change across the two orthosis conditions (ANOVA, P > 0.05). This was possible because subjects decreased their biological ankle stiffness to offset the orthosis spring stiffness (P < 0.0001). The reduction in biological ankle stiffness was accompanied by decreases in soleus, medial gastrocnemius, and lateral gastrocnemius muscle activation (P < 0.0002). These results suggest that an elastic exoskeleton might improve human running performance by reducing muscle recruitment.


The European Society of Thoracic Surgeons (ESTS) lung neuroendocrine tumors (NETs) database.
Histological characteristics and clinical behaviour define lung neuroendocrine tumors (NETs), which are classified into four groups: typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine carcinomas (LCNCs) and small-cell lung cancers (SCLCs). Historically, outcome and treatment of these rare neoplasms have been based on small, usually mono-institutional clinical series. Furthermore, their rarity makes quite impossible to design randomised clinical trial to compare different treatments especially in unusual clinical presentations. In 2012, the European Society of Thoracic Surgeons (ESTS) launched a new working-group, specifically dedicated to lung NETs, with the aim to develop modern knowledge on biology and behaviour of these tumors, and to disseminate it within the scientific community. A dedicated retrospective database was at first developed and sent to all the ESTS centres interested to this project. More than 2,000 operated NETs cases have been rapidly collected, and they represented the clinical substrate of several published scientific studies. The retrospective data collection intrinsic limitations in term of patients' selection and treatment, along with the problem of possible missing data, were the reasons why the ESTS NETs working-group decided in 2015 to design and promote a new prospective database, employing the official ESTS platform. The aim of this review paper is to report the ESTS Lung NETs working-group history and to explain the architecture and use of the lung NETs databases.


Accessibility and suitability of residential alcohol treatment for older adults: a mixed method study.
Whilst alcohol misuse is decreasing amongst younger adults in many countries, it is increasing in older adults. Residential rehabilitation (rehab) is a vital component of the alcohol treatment system, particularly for those with relatively complex needs and entrenched alcohol problems. In this study, we sought to find out to what extent rehabs in England have upper age limits that exclude older adults, whether rehabs are responsive to older adults' age-related needs and how older adults experience these services. This is a mixed method study. A search was carried out of Public Health England's online directory of rehabs to identify upper age thresholds. Semi-structured qualitative interviews were carried out with 16 individuals who had attended one of five residential rehabs in England and Wales since their 50th birthday. A researcher with experience of a later life alcohol problem conducted the interviews. Of the 118 services listed on Public Health England's online directory of rehabs, 75% stated that they had an upper age limit that would exclude older adults. Perceived differences in values, attitudes and behaviour between younger and older residents had an impact on older residents' experience of rehab. Activities organised by the rehabs were often based on physical activity that some older adults found it difficult to take part in and this could create a sense of isolation. Some older adults felt unsafe in rehab and were bullied, intimidated and subjected to ageist language and attitudes. This study identified direct and indirect age discrimination in rehabs contrary to the law. Further research is required to find out if age discrimination exists in rehabs in other countries. Rehabs should remove arbitrary age limits and ensure that they are responsive to the needs of older adults.


Nrf2-dependent and -independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative stress.
Nrf2, an NF-E2-related transcription factor, plays a critical role in transcriptional upregulation of many target genes, including those for metabolizing enzymes and transporters essential for cellular defense in response to oxidative and/or electrophilic stress. In the present study, we have studied the potential involvement of Nrf2 in induction of human ABC transporter genes under oxidative stress. We created a real-time PCR primer set to quantitatively investigate the induction of human ABC transporters by a redox-active compound tert-butylhydroquinone (tBHQ) in HepG2 cells. We found that mRNA levels of ABCC1, ABCC2, ABCC3, and ABCG2 were significantly elevated in dose- and time-dependent manners. Translocation of Nrf2 into the nuclei occurred concomitantly with the induction of ABCC1 and ABCC2 as well as both heavy and light chains of gamma-glutamylcysteine synthetase (gamma-GCSh and gamma-GCSI) during tBHQ treatments. To examine the potential involvement of Nrf2 in upregulation of the ABC transporters, we treated cells with siRNA to knockdown the expression of Nrf2. Under such Nrf2-knockdown conditions, tBHQ-induced mRNA levels of ABCC2 and ABCG2 were significantly suppressed as were mRNA levels of gamma-GCSh and gamma-GCSI. Interestingly, however, the elevated mRNA level of ABCC1 was little affected by Nrf2 siRNA treatment. We also addressed the involvement of Keap1, which is a negative regulator of Nrf2 by retrieving it in the cytoplasm. When HepG2 cells were treated with Keap1-specifc siRNA, a significant increase was observed in mRNA levels of ABCC1, ABCC2, and ABCG2 as well as gamma-GCSI, suggesting that induction of ABCC2 and ABCG2 by tBHQ is mediated by the Nrf2/Keap1 system, whereas the induction of ABCC1 may involve a Keap1-dependent but Nrf2-independent mechanism.


Static and dynamic human flexor tendon-pulley interaction.
The aim of the study was to investigate the influence of a preceding flexion or extension movement on the static interaction of human finger flexor tendons and pulleys concerning flexion torque being generated. Six human fresh frozen cadaver long fingers were mounted in an isokinetic movement device for the proximal interphalangeal (PIP) joint. During flexion and extension movement both flexor tendons were equally loaded with 40N while the generated moment was depicted simultaneously at the fingertip. The movement was stopped at various positions of the proximal interphalangeal joint to record dynamic and static torque. The static torque was always greater after a preceding extension movement compared to a preceding flexion movement in the corresponding same position of the joint. This applied for the whole arc of movement of 0-105 degrees . The difference between static extension and flexion torque was maximal 11% in average at about 83 degrees of flexion. Static torque was always smaller than dynamic torque during extension movement and always greater than dynamic torque during flexion movement. The kind of preceding movement therefore showed an influence to the torque being generated in the proximal interphalangeal joint. The effect could be simulated on a mechanical finger device.


Effects of salinity and ascorbic acid on growth, water status and antioxidant system in a perennial halophyte.
Salinity causes oxidative stress in plants by enhancing production of reactive oxygen species, so that an efficient antioxidant system, of which ascorbic acid (AsA) is a key component, is an essential requirement of tolerance. However, antioxidant responses of plants to salinity vary considerably among species. Limonium stocksii is a sub-tropical halophyte found in the coastal marshes from Gujarat (India) to Karachi (Pakistan) but little information exists on its salt resistance. In order to investigate the role of AsA in tolerance, 2-month-old plants were treated with 0 (control), 300 (moderate) and 600 (high) mM NaCl for 30 days with or without exogenous application of AsA (20 mM) or distilled water. Shoot growth of unsprayed plants at moderate salinity was similar to that of controls while at high salinity growth was inhibited substantially. Sap osmolality, AsA concentrations and activities of AsA-dependant antioxidant enzymes increased with increasing salinity. Water spray resulted in some improvement in growth, indicating that the growth promotion by exogenous treatments could partly be attributed to water. However, exogenous application of AsA on plants grown under saline conditions improved growth and AsA dependent antioxidant enzymes more than the water control treatment. Our data show that AsA-dependent antioxidant enzymes play an important role in salinity tolerance of L. stocksii.


Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects.
Nattokinase, a serine proteinase from Bacillus subtilis, is considered to be one of the most active functional ingredients found in natto. In this study, we hypothesized that nattokinase could reduce certain factors of blood clotting and lipids that are associated with an increase risk for cardiovascular disease (CVD). Thus, an open-label, self-controlled clinical trial was conducted on subjects of the following groups: healthy volunteers (Healthy Group), patients with cardiovascular risk factors (Cardiovascular Group), and patients undergoing dialysis (Dialysis Group). All subjects ingested 2 capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for 2 months. The laboratory measurements were performed on the screening visit and, subsequently, regularly after the initiation of the study. The intent-to-treat analysis was performed on all 45 enrolled subjects. By use of mixed model analysis, a significant time effect, but not group effect, was observed in the change from baseline of fibrinogen (P = .003), factor VII (P < .001), and factor VIII (P < .001), suggesting that the plasma levels of the 3 coagulation factors continuously declined during intake; also, the extents of decrease were similar between groups. After 2 months of administration, fibrinogen, factor VII, and factor VIII decreased 9%, 14%, and 17%, respectively, for the Healthy Group; 7%, 13%, and 19%, respectively, for the Cardiovascular Group; and 10%, 7%, and 19%, respectively, for the Dialysis Group, whereas blood lipids were unaffected by nattokinase. No significant changes of uric acid or notable adverse events were observed in any of the subjects. In summary, this study showed that oral administration of nattokinase could be considered as a CVD nutraceutical by decreasing plasma levels of fibrinogen, factor VII, and factor VIII.


Higher Network Activity Induced by Tactile Compared to Electrical Stimulation of Leech Mechanoreceptors.
The tiny ensemble of neurons in the leech ganglion can discriminate the locations of touch stimuli on the skin as precisely as a human fingertip. The leech uses this ability to locally bend the body-wall away from the stimulus. It is assumed that a three-layered feedforward network of pressure mechanoreceptors, interneurons, and motor neurons controls this behavior. Most previous studies identified and characterized the local bend network based on electrical stimulation of a single pressure mechanoreceptor, which was sufficient to trigger the local bend response. Recent studies showed, however, that up to six mechanoreceptors of three types innervating the stimulated patch of skin carry information about both touch intensity and location simultaneously. Therefore, we hypothesized that interneurons involved in the local bend network might require the temporally concerted inputs from the population of mechanoreceptors representing tactile stimuli, to decode the tactile information and to provide appropriate synaptic inputs to the motor neurons. We examined the influence of current injection into a single mechanoreceptor on activity of postsynaptic interneurons in the network and compared it to responses of interneurons to skin stimulation with different pressure intensities. We used voltage-sensitive dye imaging to monitor the graded membrane potential changes of all visible cells on the ventral side of the ganglion. Our results showed that stimulation of a single mechanoreceptor activates several local bend interneurons, consistent with previous intracellular studies. Tactile skin stimulation, however, evoked a more pronounced, longer-lasting, stimulus intensity-dependent network dynamics involving more interneurons. We concluded that the underlying local bend network enables a non-linear processing of tactile information provided by population of mechanoreceptors. This task requires a more complex network structure than previously assumed, probably containing polysynaptic interneuron connections and feedback loops. This small, experimentally well-accessible neuronal system highlights the general importance of selecting adequate sensory stimulation to investigate the network dynamics in the context of natural behavior.


Five ethical doctrines for medical education.
In recent years a relative barrage of journal articles has surfaced concerning the formal instruction of medical ethics in our medical schools. Philosophical debates usually ensue over either the conspicuous absence (or, in some cases, the questionable need (I) (2) of a formal ethics course, or the manner and method by which ethics is to be taught (3). There is, however, a paucity of literature as to what constitutes ethical medical 'pedagogy'. Germane is the principle that the physician-teacher should strive to be ethical both in what he or she teaches as well as the manner in which it is taught. This is also to review medical ethics from a broader perspective including the institution of instruction itself. The following discourse focuses upon five doctrines which would augment the medical curriculum by adding to the mere instruction of facts and skills a respect for the human values and rights innate to the practice of medicine.


Marine bacterial community structure resilience to changes in protist predation under phytoplankton bloom conditions.
To test whether protist grazing selectively affects the composition of aquatic bacterial communities, we combined high-throughput sequencing to determine bacterial community composition with analyses of grazing rates, protist and bacterial abundances and bacterial cell sizes and physiological states in a mesocosm experiment in which nutrients were added to stimulate a phytoplankton bloom. A large variability was observed in the abundances of bacteria (from 0.7 to 2.4 × 10(6) cells per ml), heterotrophic nanoflagellates (from 0.063 to 2.7 × 10(4) cells per ml) and ciliates (from 100 to 3000 cells per l) during the experiment (∼3-, 45- and 30-fold, respectively), as well as in bulk grazing rates (from 1 to 13 × 10(6) bacteria per ml per day) and bacterial production (from 3 to 379 μg per C l per day) (1 and 2 orders of magnitude, respectively). However, these strong changes in predation pressure did not induce comparable responses in bacterial community composition, indicating that bacterial community structure was resilient to changes in protist predation pressure. Overall, our results indicate that peaks in protist predation (at least those associated with phytoplankton blooms) do not necessarily trigger substantial changes in the composition of coastal marine bacterioplankton communities.


Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis.
To determine whether osteopontin (OPN) is increased in patients with AS and to investigate its relationship to inflammatory disease activity and bone remodelling process. This cross-sectional study included 30 patients with AS and 23 age- and sex-matched healthy controls. We assessed clinical characteristics and laboratory parameters including the ESR, CRP, lipid profiles, the Bath AS disease activity index (BASDAI) and the Bath AS radiographic index (BASRI). To evaluate bone metabolism, we tested ALP, OCN and C-telopeptide of type I collagen (CTX-I). Plasma levels of OPN, TNF-alpha and IL-6 were measured by ELISA, and mRNA expression in peripheral blood mononuclear cells (PBMCs) was performed by RT-PCR. Changes in OPN level were also evaluated in eight patients after the treatment with a TNF-alpha blocker. Patients with AS had significantly higher plasma OPN, TNF-alpha and IL-6 levels and more mRNA expression than healthy controls. Plasma OPN levels were correlated with serum ALP, OCN and CTX-I levels, but not with ESR, CRP, lipid profiles, BASDAI or BASRI. Treatment with a TNF-alpha blocker did not alter OPN levels, although it reduced the disease activity. Patients with AS had higher levels of OPN compared with controls. The plasma OPN level was correlated with serum ALP, OCN and CTX-I levels, but not with disease activity in AS. OPN might be involved in bone remodelling rather than in inflammation in AS.


How to Identify Responders and Nonresponders to Dorsal Root Ganglion-Stimulation Aimed at Eliciting Motor Responses in Chronic Spinal Cord Injury: Post Hoc Clinical and Neurophysiological Tests in a Case Series of Five Patients.
While integrity of spinal pathways below injury is generally thought to be an important factor in the success-rate of neuromodulation strategies for spinal cord injury (SCI), it is still unclear how the integrity of these pathways conveying the effects of stimulation should be assessed. In one of our institutional case series of five patients receiving dorsal root ganglion (DRG)-stimulation for elicitation of immediate motor response in motor complete SCI, only two out of five patients presented as responders, showing immediate muscle activation upon DRG-stimulation. The current study focuses on post hoc clinical-neurophysiological tests performed within this patient series to illustrate their use for prediction of spinal pathway integrity, and presumably, responder-status. In a series of three nonresponders and two responders (all male, American Spinal Injury Association [ASIA] impairment scale [AIS] A/B), a test-battery consisting of questionnaires, clinical measurements, as well as a series of neurophysiological measurements was performed less than eight months after participation in the initial study. Nonresponders presented with a complete absence of spasticity and absence of leg reflexes. Additionally, nonresponders presented with close to no compound muscle action potentials (CMAPs) or Hofmann(H)-reflexes. In contrast, both responders presented with clear spasticity, elicitable leg reflexes, CMAPs, H-reflexes, and sensory nerve action potentials, although not always consistent for all tested muscles. Post hoc neurophysiological measurements were limited in clearly separating responders from nonresponders. Clinically, complete absence of spasticity-related complaints in the nonresponders was a distinguishing factor between responders and nonresponders in this case series, which mimics prior reports of epidural electrical stimulation, potentially illustrating similarities in mechanisms of action between the two techniques. However, the problem remains that explicit use and report of preinclusion clinical-neurophysiological measurements is missing in SCI literature. Identifying proper ways to assess these criteria might therefore be unnecessarily difficult, especially for nonestablished neuromodulation techniques.


A higher circulating concentration of 25-hydroxyvitamin-D decreases the risk of renal cell carcinoma: a case-control study.
To investigate the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25 (OH) D], and renal cell carcinoma (RCC) risk in a case-control study, because the association between the two is unclear in China. A total of 135 incident RCC cases were matched with 135 controls by age and sex. The blood samples were collected on the first day of hospitalization before surgery to measure plasma 25 (OH) D. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confi dence intervals (95% CIs) with adjustment for several confounders (e.g. age, gender, smoking and season of blood draw). Furthermore, the association of RCC with 25 (OH) D in units of 10 ng / mL as a continuous variable were also examined. The average plasma 25 (OH) D concentrations in RCC were signifi cantly lower compared with those of the controls (21.5 ± 7.4 ng / mL vs. 24.1 ± 6.6 ng / mL, respectively; P = 0.003). In the adjusted model, inverse associations were observed between circulating 25 (OH) D levels and RCC risk for 25 (OH) D insuffi ciency (20-30 ng / mL) with OR of 0.50 (95% CI: 0.29-0.88; P = 0.015) and a normal 25 (OH) D level (≥ 30 ng / mL) with OR of 0.30 (95% CI: 0.13-0.72; P = 0.007), compared with 25 (OH) D deficiency (< 20 ng / mL). Furthermore, results with 25 (OH) D as a linear variable indicated that each 10 ng / mL increment of plasma 25 (OH) D corresponded to a 12% decrease in RCC risk. This case-control study on a Chinese Han population supports the protective effect of a higher circulating concentration of 25 (OH) against RCC, whether the confounding factors are adjusted or not.


Mycobacterium abscessus bacteremia in an immunocompetent patient following a coronary artery bypass graft.
Sternal osteomyelitis with bacteremia due to Mycobacterium abscessus is rarely seen in immunocompetent hosts. Routine pyogenic cultures in these cases are often negative causing a delay in diagnosis and treatment. Clinicians and microbiologists should rule out the possibility of infection due to nontuberculous mycobacteria while managing cases of nonhealing culture-negative wounds with conventional antibiotic therapy. We report a case of bacteremia secondary to a nonhealing sternal wound due to M. abscessus. A combination of radical debridement and prolonged antimicrobial therapy helped in the complete eradication of the infection.


Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity.
Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.


Studies on the biocompatibility of materials: fibroblast reorganization of substratum-bound fibronectin on surfaces varying in wettability.
The ability of human fibroblasts to remove and reorganize fibronectin (FN) bound on material surfaces was studied as a novel feature of material surface biocompatibility. Other traditional parameters of biocompatibility analyzed included cell spreading, clustering of fibronectin receptors into focal adhesions, development of stress fibers, and cell growth. Five different materials with surface wettability ranging from hydrophilic (underwater contact angle 25 degrees) to hydrophobic (underwater contact angle 111 degrees) were used, i.e., clean glass (GLASS), aminopropylsilane (APS), octadecylsilane (ODS), polylactate (PL), and silicone (SI). When cells were cultured on these materials in serum-containing medium, formation of FN receptor-rich focal adhesions and actin stress fibers were more evident on the hydrophilic surfaces (GLASS and APS) compared to the hydrophobic ones (PL, ODS, and SI). Cell growth showed a similar pattern, that is, increased cell proliferation with increasing material surface wettability. Preadsorption of FN on the material surfaces increased subsequent cell spreading and cytoskeletal reorganization on hydrophobic surfaces except SI. Removal and reorganization of FN from the material surfaces into extracellular matrixlike structures occurred on GLASS but not on less wettable surfaces, suggesting that this removal/reorganization process may be more sensitive to changes in surface wettability than other parameters of biocompatibility.


Structure and Properties of Silica Glass Densified in Cold Compression and Hot Compression.
Silica glass has been shown in numerous studies to possess significant capacity for permanent densification under pressure at different temperatures to form high density amorphous (HDA) silica. However, it is unknown to what extent the processes leading to irreversible densification of silica glass in cold-compression at room temperature and in hot-compression (e.g., near glass transition temperature) are common in nature. In this work, a hot-compression technique was used to quench silica glass from high temperature (1100 °C) and high pressure (up to 8 GPa) conditions, which leads to density increase of ~25% and Young's modulus increase of ~71% relative to that of pristine silica glass at ambient conditions. Our experiments and molecular dynamics (MD) simulations provide solid evidences that the intermediate-range order of the hot-compressed HDA silica is distinct from that of the counterpart cold-compressed at room temperature. This explains the much higher thermal and mechanical stability of the former than the latter upon heating and compression as revealed in our in-situ Brillouin light scattering (BLS) experiments. Our studies demonstrate the limitation of the resulting density as a structural indicator of polyamorphism, and point out the importance of temperature during compression in order to fundamentally understand HDA silica.


Hepatitis C testing practices and prevalence in a high-risk urban ambulatory care setting.
Approximately 3.2 million persons are chronically infected with the hepatitis C virus (HCV) in the U.S.; most are not aware of their infection. Our objectives were to examine HCV testing practices to determine which patient characteristics are associated with HCV testing and positivity, and to estimate the prevalence of HCV infection in a high-risk urban population. The study subjects were all patients included in the baseline phase of the Hepatitis C Assessment and Testing Project (HepCAT), a serial cross-sectional study of HCV screening strategies. We examined all patients with a clinic visit to Montefiore Medical Center from 1/1/08 to 2/29/08. Demographic information, laboratory data and ICD-9 diagnostic codes from 3/1/97-2/29/08 were extracted from the electronic medical record. Risk factors for HCV were defined based on birth date, ICD-9 codes and laboratory data. The prevalence of HCV infection was estimated assuming that untested subjects would test positive at the same rate as tested subjects, based on risk-factors. Of 9579 subjects examined, 3803 (39.7%) had been tested for HCV and 438 (11.5%) were positive. The overall prevalence of HCV infection was estimated to be 7.7%. Risk factors associated with being tested and anti-HCV positivity included: born in the high-prevalence birth-cohort (1945-64), substance abuse, HIV infection, alcohol abuse, diagnosis of cirrhosis, end-stage renal disease, and alanine transaminase elevation. In a high-risk urban population, a significant proportion of patients were tested for HCV and the prevalence of HCV infection was high. Physicians appear to use a risk-based screening strategy to identify HCV infection.


Bacteroides fragilis toxin exhibits polar activity on monolayers of human intestinal epithelial cells (T84 cells) in vitro.
Strains of Bacteroides fragilis associated with diarrhea in children (termed enterotoxigenic B. fragilis, or ETBF) produce a heat-labile ca. 20-kDa protein toxin (BFT). The purpose of this study was to examine the activity of BFT on polarized monolayers of human intestinal epithelial cells (T84 cells). In Ussing chambers, BFT had two effects. First, BFT applied to either the apical or basolateral surfaces of T84 monolayers diminished monolayer resistance. However, the time course, magnitude, and concentration dependency differed when BFT was applied to the apical versus basolateral membranes. Second, only basolateral BFT stimulated a concentration-dependent and short-lived increase in short circuit current (Isc; indicative of C1- secretion). Time course experiments indicated that Isc returned to baseline as resistance continued to decrease, indicating that these two electrophysiologic responses to BFT are distinct. Light microscopic studies of BFT-treated monolayers revealed only localized cellular changes after apical BFT, whereas basolateral BFT rapidly altered the morphology of nearly every cell in the monolayer. Transmission and scanning electron microscopy after basolateral BFT confirmed a striking loss of cellular microvilli and complete dissolution of some tight junctions (zonula occludens) and zonula adherens without loss of desmosomes. The F-actin structure of BFT-treated monolayers (stained with rhodamine-phalloidin) revealed diminished and flocculated staining at the apical tight junctional ring and thickening of F-actin microfilaments in focal contacts at the basolateral monolayer surface compared to those in similarly stained control monolayers. BFT did not injure T84 monolayers, as assessed by lactic dehydrogenase release and protein synthesis assays. These studies indicate that BFT is a nonlethal toxin which acts in a polar manner on T84 monolayers to stimulate C1- secretion and to diminish monolayer resistance by altering the apical F-actin structure of these cells. BFT may contribute to diarrheal disease associated with ETBF infection by altering epithelial barrier function and stimulating C1- secretion.


Influence of polarization and a source model for dose calculation in MRT.
Microbeam Radiation Therapy (MRT), an alternative preclinical treatment strategy using spatially modulated synchrotron radiation on a micrometer scale, has the great potential to cure malignant tumors (e.g., brain tumors) while having low side effects on normal tissue. Dose measurement and calculation in MRT is challenging because of the spatial accuracy required and the arising high dose differences. Dose calculation with Monte Carlo simulations is time consuming and their accuracy is still a matter of debate. In particular, the influence of photon polarization has been discussed in the literature. Moreover, it is controversial whether a complete knowledge of phase space trajectories, i.e., the simulation of the machine from the wiggler to the collimator, is necessary in order to accurately calculate the dose. With Monte Carlo simulations in the Geant4 toolkit, the authors investigate the influence of polarization on the dose distribution and the therapeutically important peak to valley dose ratios (PVDRs). Furthermore, the authors analyze in detail phase space information provided by Martínez-Rovira et al. ["Development and commissioning of a Monte Carlo photon model for the forthcoming clinical trials in microbeam radiation therapy," Med. Phys. 39(1), 119-131 (2012)] and examine its influence on peak and valley doses. A simple source model is developed using parallel beams and its applicability is shown in a semiadjoint Monte Carlo simulation. Results are compared to measurements and previously published data. Polarization has a significant influence on the scattered dose outside the microbeam field. In the radiation field, however, dose and PVDRs deduced from calculations without polarization and with polarization differ by less than 3%. The authors show that the key consequences from the phase space information for dose calculations are inhomogeneous primary photon flux, partial absorption due to inclined beam incidence outside the field center, increased beam width and center to center distance due to the beam propagation from the collimator to the phantom surface and imperfect absorption in the absorber material of the Multislit Collimator. These corrections have an effect of approximately 10% on the valley dose and suffice to describe doses in MRT within the measurement uncertainties of currently available dosimetry techniques. The source for the first clinical pet trials in MRT is characterized with respect to its phase space and the photon polarization. The results suggest the use of a presented simplified phase space model in dose calculations and hence pave the way for alternative and fast dose calculation algorithms. They also show that the polarization is of minor importance for the clinical important peak and valley doses inside the microbeam field.


Diagnosis and pharmacotherapy of stable chronic obstructive pulmonary disease: the finnish guidelines.
The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD). The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma-COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short-acting β2 -agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol-ipratropium) is recommended in patients with less symptoms. If short-acting bronchodilators are not enough to control symptoms, a long-acting β2 -agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting β2 -agonist (budesonide-formoterol, beclomethasone dipropionate-formoterol, fluticasone propionate-salmeterol or fluticasone furoate-vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium-indacaterol or umeclidinium-vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting β2 -agonist and a long-acting anticholinergic. If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD. Thus, evidence-based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (β2 -agonist or anticholinergic or both).


Pancreatic differentiation of Pdx1-GFP reporter mouse induced pluripotent stem cells.
Efficient induction of defined lineages in pluripotent stem cells constitutes the determinant step for the generation of therapeutically relevant replacement cells to potentially treat a wide range of diseases, including diabetes. Pancreatic differentiation has remained an important challenge in large part because of the need to differentiate uncommitted pluripotent stem cells into highly specialized hormone-secreting cells, which has been shown to require a developmentally informed step-by-step induction procedure. Here, in the framework of using induced pluripotent stem cells (iPSCs) to generate pancreatic cells for pancreatic diseases, we have generated and characterized iPSCs from Pdx1-GFP transgenic mice. The use of a GFP reporter knocked into the endogenous Pdx1 promoter allowed us to monitor pancreatic induction based on the expression of Pdx1, a pancreatic master transcription factor, and to isolate a pure Pdx1-GFP+ population for downstream applications. Differentiated cultures timely expressed markers specific to each stage and end-stage progenies acquired a rather immature beta-cell phenotype, characterized by polyhormonal expression even among cells highly expressing the Pdx1-GFP reporter. Our findings highlight the utility of employing a fluorescent protein reporter under the control of a master developmental gene in order to devise novel differentiation protocols for relevant cell types for degenerative diseases such as pancreatic beta cells for diabetes.


Long noncoding RNA in genome regulation: prospects and mechanisms.
Long noncoding RNAs (lncRNAs) are pervasively transcribed and critical regulators of the epigenome[1, 2]. These long, polyadenylated RNAs do not code for proteins, but function directly as RNAs, recruiting chromatin modifiers to mediate transcriptional changes in processes ranging from X-inactivation (XIST) to imprinting (H19)[3]. The recent discovery that lncRNA HOTAIR can link chromatin changes to cancer metastasis[4] furthers the relevance of lncRNAs to human disease. Here, we discuss lncRNAs as regulatory modules and explore the implications for disease pathogenesis. Although large-scale analyses of mammalian transcriptomes have revealed that more than 50% of transcripts have no protein coding potential[2, 5, 6], the functions of these putative transcripts are largely unknown. A subset of these noncoding transcripts are termed long noncoding RNAs (lncRNAs), based on an arbitrary minimum length of 200 nucleotides. LncRNAs are roughly classified based on their position relative to protein-coding genes: intergenic (between genes), intragenic/intronic (within genes), and antisense[2]. Initial efforts to characterize these molecules demonstrated that they function in cis, regulating their immediate genomic neighbors. Examples include AIR, XIST, and Kcnq1ot (reviewed in [1, 7, 8]), which recruit chromatin modifying complexes to silence adjacent sites. The scope of lncRNAs in gene regulation was advanced with the finding that lncRNA HOTAIR exhibited trans regulatory capacities. HOTAIR is transcribed at the intersection of opposing chromatin domains in the HOXC locus, but targets Polycomb Repressive Complex 2 (PRC2) to silence 40 kilobases of HOXD[9], a locus involved in developmental patterning. A subsequent study revealed that HOTAIR is overexpressed in approximately one quarter of human breast cancers, directing PRC2 to approximately 800 ectopic sites in the genome, which leads to histone H3 lysine 27 trimethylation and changes in gene expression[4]. The impacts of lncRNA-mediated chromatin changes are noteworthy: not only did HOTAIR drive metastasis in a mouse model, but HOTAIR expression in human breast cancer was found to be an independent prognostic marker for death and metastasis[4]. The fact that HOTAIR drives chromatin reprogramming genome-wide suggests that long-range regulation by lncRNAs may be a widespread mechanism. This is supported by a study showing that > 20% of tested lncRNAs are bound by PRC2 and other chromatin modifiers[10]. Furthermore, this is an underestimate of the total RNAs involved in chromatin modification, as PRC2 target genes also transcribe smaller 50-200 nt RNAs that interact with SUZ12 to mediate gene repression[11]. These findings provoke questions regarding the initial triggers for HOTAIR overexpression and whether understanding of lncRNA mechanics may have clinical relevance.


External review and validation of the Swedish national inpatient register.
The Swedish National Inpatient Register (IPR), also called the Hospital Discharge Register, is a principal source of data for numerous research projects. The IPR is part of the National Patient Register. The Swedish IPR was launched in 1964 (psychiatric diagnoses from 1973) but complete coverage did not begin until 1987. Currently, more than 99% of all somatic (including surgery) and psychiatric hospital discharges are registered in the IPR. A previous validation of the IPR by the National Board of Health and Welfare showed that 85-95% of all diagnoses in the IPR are valid. The current paper describes the history, structure, coverage and quality of the Swedish IPR. In January 2010, we searched the medical databases, Medline and HighWire, using the search algorithm "validat* (inpatient or hospital discharge) Sweden". We also contacted 218 members of the Swedish Society of Epidemiology and an additional 201 medical researchers to identify papers that had validated the IPR. In total, 132 papers were reviewed. The positive predictive value (PPV) was found to differ between diagnoses in the IPR, but is generally 85-95%. In conclusion, the validity of the Swedish IPR is high for many but not all diagnoses. The long follow-up makes the register particularly suitable for large-scale population-based research, but for certain research areas the use of other health registers, such as the Swedish Cancer Register, may be more suitable.


Skin microvascular morphology and hemodynamics during treatment with veno-arterial extra-corporeal membrane oxygenation.
To explore the potentials of microcirculatory assessments for predicting outcome of patients treated with extra corporeal membrane oxygenation for cardiogenic shock. Eight patients with acute cardiogenic shock treated with ECMO and eight healthy controls were examined with skin vital microscopy and laser Doppler perfusion measurements. Three patients died on ECMO (group 1). Five patients were successfully weaned off ECMO (group 2). Four patients were discharged from hospital and one died after successful weaning from bleeding complications. Patients surviving ECMO (group 2) had microcirculatory findings comparable with healthy controls. Patients in group 1 showed major skin microvascular pathology: pericapillary bleedings (n = 1), pericapillary dark haloes (n = 2) and capillary micro thrombi (n = 1). As compared with survivors they had lower functional capillary density (FCD) (n = 3), higher heterogeneity of functional capillary density (n = 3) and significantly reduced capillary mean flow-categorical velocity (n = 2). Laser Doppler measurements in group 1 had non-significant lower laser Doppler flux values as compared with survivors and controls. Skin microvascular pathology as detected with video microscopy (pericapillary bleedings or haloes, micro-thrombi/capillaries with "no flow", low FCD with high spatial distribution heterogeneity or low mean flow-categorial velocity) seems to be associated with poor prognosis.


The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3).
Regulation of gene transcription is controlled in part by nuclear receptors that function coordinately with coregulator proteins. The human constitutive androstane receptor (CAR; NR1I3) is expressed primarily in liver and regulates the expression of genes involved in xenobiotic metabolism as well as hormone, energy, and lipid homeostasis. In this report, DAX-1, a nuclear receptor family member with corepressor properties, was identified as a potent CAR regulator. Results of transaction and mutational studies demonstrated that both DAX-1's downstream LXXLL and its PCFQVLP motifs were critical contributors to DAX-1's corepression activities, although two other LXXM/LL motifs located nearer the N terminus had no impact on the CAR functional interaction. Deletion of DAX-1's C-terminal transcription silencing domain restored CAR1 transactivation activity in reporter assays to approximately 90% of control, demonstrating its critical function in mediating the CAR repression activities. Furthermore, results obtained from mammalian two-hybrid experiments assessing various domain configurations of the respective receptors showed that full-length DAX-1 inhibited the CAR-SRC1 interaction by approximately 50%, whereas the same interaction was restored to 90% of control when the DAX-1 transcription silencing domain was deleted. Direct interaction between CAR and DAX-1 was demonstrated with both alpha-screen and coimmunoprecipitation experiments, and this interaction was enhanced in the presence of the CAR activator 6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). Results obtained in primary human hepatocytes further demonstrated DAX-1 inhibition of CAR-mediated CITCO induction of the CYP2B6 target gene. The results of this investigation identify DAX-1 as a novel and potent CAR corepressor and suggest that DAX-1 functions as a coordinate hepatic regulator of CAR's biological function.


A new micro-intervention to increase the enjoyment and continued practice of meditation.
New health behaviors are difficult to maintain and meditation is no different. We tested two key pathways of the upward spiral theory of lifestyle change (Fredrickson, 2013), which identifies positive emotions as critical ingredients for the maintenance of new health behaviors. The present experiment combined a laboratory session that introduced novices to meditation with a 3-week follow-up period to assess the extent to which study participants maintained this new health behavior. In a 2 × 2 experimental design, midlife adults (N = 240) were randomized to (a) learn about judicious ways to prioritize positivity (labeled "prioritizing positivity plus") or about a control topic that also featured the science of positive emotions and (b) follow a guided meditation based on either loving-kindness, which provided an opportunity to self-generate positive emotions, or mindfulness, which did not. All participants rated their emotions following the initial guided meditation and reported, week by week, whether they meditated during the ensuing 21 days. Analyses revealed that being exposed to the prioritizing positivity plus microintervention, relative to a control passage, amplified the effect of engaging in loving-kindness (vs. mindfulness) meditation on positive emotions. Additionally, the degree to which participants experienced positive emotions during first exposure to either meditation type predicted the frequency and duration at which they practiced meditation over the next 21 days. These findings show that the enjoyment of meditation can be experimentally amplified and that initial enjoyment predicts continued practice. Discussion spotlights the importance of differentiating effective and ineffective ways to pursue happiness. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Compressive MRI quantification using convex spatiotemporal priors and deep encoder-decoder networks.
We propose a dictionary-matching-free pipeline for multi-parametric quantitative MRI image computing. Our approach has two stages based on compressed sensing reconstruction and deep learned quantitative inference. The reconstruction phase is convex and incorporates efficient spatiotemporal regularisations within an accelerated iterative shrinkage algorithm. This minimises the under-sampling (aliasing) artefacts from aggressively short scan times. The learned quantitative inference phase is purely trained on physical simulations (Bloch equations) that are flexible for producing rich training samples. We propose a deep and compact encoder-decoder network with residual blocks in order to embed Bloch manifold projections through multi-scale piecewise affine approximations, and to replace the non-scalable dictionary-matching baseline. Tested on a number of datasets we demonstrate effectiveness of the proposed scheme for recovering accurate and consistent quantitative information from novel and aggressively subsampled 2D/3D quantitative MRI acquisition protocols.


[Relation of asymmetric dimethylarginine levels with conventional risk score systems in the healthy subjects with positive family history for coronary artery disease].
Coronary artery disease is the most common cause of death in Turkey and the world. Asymmetric dimethylarginine is the major inhibitor of nitric oxide synthesis in humans. It has been shown that increased levels of asymmetric dimethylarginine is associated with endothelial dysfunction and increased atherogenesis. In this study, we aimed to investigate whether asymmetric dimethylarginine level is related with conventional risk score systems in subjects who had family history of coronary artery disease. Fifty two subjects within 20-40 years old of whom first degree relatives had myocardial infarction at young ages and 26 age and sex matched control subjects were included in this cross-sectional observational study. Frequency of diabetes, hyperlipidemia, smoking and serum levels of homocysteine, high-sensitive C-reactive protein (hsCRP) and asymmetric dimethylarginine were compared between risk group and control subjects. Relation of asymmetric dimethylarginine level with Framingham and TEKHARF risk scores was also compared. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Fasting serum glucose, triglyceride, high-density lipoprotein, diastolic blood pressure, waist circumference and TEKHARF scores were increased in the subjects who had family history of myocardial infarction. Total cholesterol, low-density lipoprotein, hsCRP, homocysteine, creatinine and Framingham risk score were similar in studied groups . Asymmetric dimethylarginine levels were 0.1 µmol/L higher in the risk group; however this difference could not reach significance (0.7±0.1 µmol/l vs 0.8±0.1 µmol/l; p=0.061). Measurement of serum asymmetric dimethylarginine levels did not reveal utility in defining conventional coronary artery disease risk score systems in cases that had positive family history. Larger studies including patients with different risk tertiles are needed.


Evaluation of an online, real-time, soft-photon ionisation time-of-flight mass spectrometer for mainstream tobacco smoke analysis.
Mainstream tobacco smoke is a complex and dynamic aerosol, consisting of particulate and vapour phases. Most approaches to determine mainstream smoke toxicant yields are based on offline techniques that limit the opportunity to observe in real time the processes leading to smoke formation. The recent development of online real-time analytical methods offers many advantages over traditional techniques. Here we report the LM2X-TOFMS (Borgwaldt GmbH, Germany), a commercial instrument that couples a linear smoking engine with a time-of-flight mass spectrometer for real-time per-puff measurement of the vapour phase of mainstream cigarette smoke. Total cigarette and puff-by-puff (μg/puff) yields were evaluated, in line with International Council of Harmonisation recommendations, for seven smoke toxicants: acetaldehyde, acetone, 1,3-butadiene, 2-butanone, benzene, isoprene and toluene. Measurements were unaffected by small system changes including replacing the sampling capillary or time of day (all P > 0.05), indicating that the LM2X-TOFMS is rugged. Control charts showed that the system has good stability and control. Analysis of certified gas mixtures of six concentrations of each analyte showed a highly linear response for all seven analytes (R2 = 0.9922-0.9999). In terms of repeatability, the lowest variation was observed for isoprene with a coefficient of variation (CV) of < 6% for each concentration. Acetaldehyde showed the highest CV, increasing from 8.0 to 26.6% with decreasing gas concentration. Accuracy was analysed in terms of relative error, which was ± 16% for six of the analytes; however, the relative error for acetaldehyde was (- 36.2%), probably due to its low ionisation efficiency under the instrument's vacuum ultraviolet lamp. Three cigarette products (reference and commercial) with different ISO tar levels were analysed by the LM2X-TOFMS puff by puff under ISO regulatory smoking conditions. The relative standard deviation based on average yield per cigarette for each analyte in each product (summed puffs per product, n = 30) ranged from ≤ 9.3 to ≤ 16.2%. Measurements were consistent with published data per cigarette. In conclusion, the LM2X-TOFMS is suitable for determining the vapour-phase yields of seven analytes on a real-time, puff-by-puff basis, and can be utilised for both fast screening (qualitative) and quantitative measurements of mainstream cigarette smoke.


Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1.
Epidemiologic and animal studies revealed that capsaicin can act as a carcinogen or cocarcinogen. However, the molecular mechanisms of the cancer-promoting effects of capsaicin are not clear. Here, we report that capsaicin has a cocarcinogenic effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin carcinogenesis in vivo and is mediated through the epidermal growth factor receptor (EGFR), but not the transient receptor potential vanilloid subfamily member 1 (TRPV1). Topical application of capsaicin on the dorsal skin of 7,12-dimetylbenz(a)anthracene-initiated and TPA-promoted TRPV1 wild-type (WT) and TRPV1 knockout (KO) mice induced more and larger skin tumors in TRPV1/KO mice, suggesting a TRPV1-independent mechanism. Cyclooxygenase-2 (COX-2) was highly elevated by capsaicin treatment in tumors and murine embryonic fibroblasts from TRPV1/KO mice. Inhibitors of EGFR/MEK signaling suppressed TPA/capsaicin-induced COX-2 expression in TRPV1/KO cells, indicating that activation of EGFR and its downstream signaling is involved in COX-2 elevation. Capsaicin induced a further induction of TPA-increased COX-2 expression in EGFR/WT cells, but not in EGFR/KO cells. TPA/capsaicin cotreatment caused EGFR tyrosine phosphorylation and activated EGFR downstream signaling, including ERKs and Akt in EGFR/WT, but not EGFR/KO cells. Specific inhibition of EGFR and TRPV1 indicated that capsaicin-induced ERK activation in A431 cells was dependent on EGFR, but not TRPV1. Together, these findings suggest that capsaicin might act as a cocarcinogen in TPA-induced skin carcinogenesis through EGFR-dependent mechanisms.


Metatranscriptomic analyses of honey bee colonies.
Honey bees face numerous biotic threats from viruses to bacteria, fungi, protists, and mites. Here we describe a thorough analysis of microbes harbored by worker honey bees collected from field colonies in geographically distinct regions of Turkey. Turkey is one of the World's most important centers of apiculture, harboring five subspecies of Apis mellifera L., approximately 20% of the honey bee subspecies in the world. We use deep ILLUMINA-based RNA sequencing to capture RNA species for the honey bee and a sampling of all non-endogenous species carried by bees. After trimming and mapping these reads to the honey bee genome, approximately 10% of the sequences (9-10 million reads per library) remained. These were then mapped to a curated set of public sequences containing ca. Sixty megabase-pairs of sequence representing known microbial species associated with honey bees. Levels of key honey bee pathogens were confirmed using quantitative PCR screens. We contrast microbial matches across different sites in Turkey, showing new country recordings of Lake Sinai virus, two Spiroplasma bacterium species, symbionts Candidatus Schmidhempelia bombi, Frischella perrara, Snodgrassella alvi, Gilliamella apicola, Lactobacillus spp.), neogregarines, and a trypanosome species. By using metagenomic analysis, this study also reveals deep molecular evidence for the presence of bacterial pathogens (Melissococcus plutonius, Paenibacillus larvae), Varroa destructor-1 virus, Sacbrood virus, and fungi. Despite this effort we did not detect KBV, SBPV, Tobacco ringspot virus, VdMLV (Varroa Macula like virus), Acarapis spp., Tropilaeleps spp. and Apocephalus (phorid fly). We discuss possible impacts of management practices and honey bee subspecies on microbial retinues. The described workflow and curated microbial database will be generally useful for microbial surveys of healthy and declining honey bees.


Cellular and network contributions to vestibular signal processing: impact of ion conductances, synaptic inhibition, and noise.
Head motion-related sensory signals are transformed by second-order vestibular neurons (2°VNs) into appropriate commands for retinal image stabilization during body motion. In frogs, these 2°VNs form two distinct subpopulations that have either tonic or highly phasic intrinsic properties, essentially compatible with low-pass and bandpass filter characteristics, respectively. In the present study, physiological data on cellular properties of 2°VNs of the grass frog (Rana temporaria) have been used to construct conductance-based spiking cellular models that were fine-tuned by fitting to recorded spike-frequency data. The results of this approach suggest that low-threshold, voltage-dependent potassium channels in phasic and spike-dependent potassium channels in tonic 2°VNs are important contributors to the differential, yet complementary response characteristics of the two vestibular subtypes. Extension of the cellular model with conductance-based synapses allowed simulation of afferent excitation and evaluation of the emerging properties of local feedforward inhibitory circuits. This approach revealed the relative contributions of intrinsic and synaptic factors on afferent signal processing in phasic 2°VNs. Additional extension of the single-cell model to a population model allowed testing under more natural conditions including asynchronous afferent labyrinthine input and synaptic noise. This latter approach indicated that the feedforward inhibition from the local inhibitory network acts as a high-pass filter, which reinforces the impact of the intrinsic membrane properties of phasic 2°VNs on peak response amplitude and timing. Thus, the combination of cellular and network properties enables phasic 2°VNs to work as a noise-resistant detector, suitable for central processing of short-duration vestibular signals.


Tea and flavonoid intake predict osteoporotic fracture risk in elderly Australian women: a prospective study.
Observational studies have linked tea drinking, a major source of dietary flavonoids, with higher bone density. However, there is a paucity of prospective studies examining the association of tea drinking and flavonoid intake with fracture risk. The objective of this study was to examine the associations of black tea drinking and flavonoid intake with fracture risk in a prospective cohort of women aged >75 y. A total of 1188 women were assessed for habitual dietary intake with a food-frequency and beverage questionnaire. Incidence of osteoporotic fracture requiring hospitalization was determined through the Western Australian Hospital Morbidity Data system. Multivariable adjusted Cox regression was used to examine the HRs for incident fracture. Over 10 y of follow-up, osteoporotic fractures were identified in 288 (24.2%) women; 212 (17.8%) were identified as a major osteoporotic fracture, and of these, 129 (10.9%) were a hip fracture. In comparison with the lowest tea intake category (≤1 cup/wk), consumption of ≥3 cups/d was associated with a 30% decrease in the risk of any osteoporotic fracture (HR: 0.70; 95% CI: 0.50, 0.96). Compared with women in the lowest tertile of total flavonoid intake (from tea and diet), women in the highest tertile had a lower risk of any osteoporotic fracture (HR: 0.65; 95% CI: 0.47, 0.88), major osteoporotic fracture (HR: 0.66; 95% CI: 0.45, 0.95), and hip fracture (HR: 0.58; 95% CI: 0.36, 0.95). For specific classes of flavonoids, statistically significant reductions in fracture risk were observed for higher intake of flavonols for any osteoporotic fracture and major osteoporotic fracture, as well as flavones for hip fracture (P < 0.05). Higher intake of black tea and particular classes of flavonoids were associated with lower risk of fracture-related hospitalizations in elderly women at high risk of fracture.


Category learning induces position invariance of pattern recognition across the visual field.
Human object recognition is considered to be largely invariant to translation across the visual field. However, the origin of this invariance to positional changes has remained elusive, since numerous studies found that the ability to discriminate between visual patterns develops in a largely location-specific manner, with only a limited transfer to novel visual field positions. In order to reconcile these contradicting observations, we traced the acquisition of categories of unfamiliar grey-level patterns within an interleaved learning and testing paradigm that involved either the same or different retinal locations. Our results show that position invariance is an emergent property of category learning. Pattern categories acquired over several hours at a fixed location in either the peripheral or central visual field gradually become accessible at new locations without any position-specific feedback. Furthermore, categories of novel patterns presented in the left hemifield are distinctly faster learnt and better generalized to other locations than those learnt in the right hemifield. Our results suggest that during learning initially position-specific representations of categories based on spatial pattern structure become encoded in a relational, position-invariant format. Such representational shifts may provide a generic mechanism to achieve perceptual invariance in object recognition.


The Role of Access to Head Start and Quality Ratings for Spanish-Speaking Dual Language Learners' (DLLs) Participation in Early Childhood Education.
Data from the Head Start Impact Study (N = 4,442) were used to test for differences between Spanish-speaking Dual Language Learners (DLLs) and monolingual English-speaking children in: (1) Head Start attendance rates when randomly assigned admission; and (2) quality ratings of other early childhood education (ECE) programs attended when not randomly assigned admission to Head Start. Logistic regressions showed that Spanish-speaking DLL children randomly assigned a spot in Head Start were more likely than monolingual-English learners to attend. Further, Spanish-speaking DLLs not randomly assigned a spot in Head Start were more likely to attend higher-quality ECE centers than non-DLL children. Policy implications are discussed, suggesting that, if given access, Spanish-speaking DLL families will take advantage of quality ECE programs.


Regulation of sexual development in the basal termite Cryptotermes secundus: mutilation, pheromonal manipulation or honest signal?
Social insect colonies are not the harmonious entities they were once considered. Considerable conflicts exist between colony members, as has been shown for Hymenoptera. For termites, similar studies are lacking, but aggressive manipulations have been claimed to regulate sexual development, and even to account for the evolution of workers. This study on a basal termite, Cryptotermes secundus (Kalotermitidae), suggests that the importance of aggressive manipulations in termites has been overemphasized. Wing-bud mutilations, a means proposed to regulate the development of dispersing sexuals (alates), seem to be artifacts of handling conditions that cause disturbance. Aggressive behaviors never occurred unless colonies were disturbed. Theoretical considerations further showed that the potential for intense conflict among termite nestmates is low compared to hymenopteran societies. Strong conflicts are only expected to occur over the replacement of natal reproductives that died, while less intense conflicts should exist over the development into alates when food in the colony becomes limiting. Accordingly, intracolonial aggressive interactions over replacement are common, whereas nestmates seem to manipulate alate development via proctodeal feeding when food resources decline. However, the latter is rather an honest signal than a manipulation because only the most competent prospective dispersers can impede the development of nestmates.


The effect of community and family interventions on young people's physical activity levels: a review of reviews and updated systematic review.
Next to the school environment, the family and community environment are key for young people's behaviour and for promoting physical activity (PA). A review of reviews was conducted, after which a literature search was conducted (in PubMed, Scopus and PsychInfo) from August 2007 (search date of the most recent review) to October 2010. Inclusion criteria were study population aged 18 years or younger, controlled trial, no PA control condition, PA promotion intervention and reported analyses of a PA-related outcome. Methodological quality was assessed, and data on intervention details, methods and effects on primary and secondary outcomes (PA, body composition and fitness) were extracted. Three previous reviews were reviewed, including 13 family-based and three community-based interventions. Study inclusion differed for each review, but all concluded that the evidence was limited, although the potential of family-based interventions delivered in the home and including self-monitoring was highlighted. A further six family-based and four community-based interventions were included in the updated review, with a methodological quality score ranging from 2 to 10 and five studies scoring 6 or higher. Significant positive effects on PA were observed for one community-based and three family-based studies. No distinctive characteristics of the effective interventions compared with those that were ineffective were identified. The effect of family- and community-based interventions remains uncertain despite improvements in study quality. Of the little evidence of effectiveness, most comes from those targeted at families and set in the home. Further detailed research is needed to identify key approaches for increasing young people's PA levels in family and community settings.


SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis.
The three enzymes that constitute the de novo thymidylate synthesis pathway in mammals, cytoplasmic serine hydroxymethyltransferase (SHMT1), thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR) undergo sumoylation and nuclear import during S-phase. In this study, we demonstrate that purified intact mouse liver nuclei convert dUMP to dTMP in the presence of NADPH and serine. Neither nuclear extracts nor intact nuclei exposed to aminomethylphosphonate, a SHMT inhibitor, exhibit thymidylate synthesis activity. Nuclei isolated from Shmt1(-/-) mouse livers retained 25% of thymidylate synthesis activity exhibited by nuclei isolated from wild type mice. This residual activity was due to the presence of a cytoplasmic/nuclear isozyme of SHMT encoded by Shmt2. Shmt2 is shown to encode two transcripts, one which encodes a protein that localizes exclusively to the mitochondria (SHMT2), and a second transcript that lacks exon 1 and encodes a protein that localizes to the cytoplasm and nucleus during S-phase (SHMT2alpha). The ability of Shmt2 to encode a cytoplasmic isozyme of SHMT may account for the viability of Shmt1(-/-) mice and provide redundancy that permitted the expansion of the human SHMT1 L474F polymorphism that impairs SHMT1 sumoylation and nuclear translocation.


Self-regulated learning of a natural category: do people interleave or block exemplars during study?
Despite decades of research focused on the representation of concepts, little is known about the influence of self-regulatory processes when learning natural categories. Such work is vital, as many contexts require self-regulation when we form complex concepts. Previous research has demonstrated that interleaving, as compared to blocking, can improve classification. Thus, as an initial step to explore self-regulated learning of natural concepts, we evaluated whether people chose to block or interleave their practice. According to the search-for-differences hypothesis, people attempt to identify features of birds that distinguish one category (i.e., bird family) from another, and hence should interleave their study. According to the search-for-similarities hypothesis, people attempt to identify features that indicate inclusion into a single category, and hence are expected to block their study. To evaluate these hypotheses, we had participants learn exemplar birds (e.g., Song Sparrow) with their respective bird families (e.g., Sparrow) by selecting the order in which to study bird families. Across four experiments, different formats for selecting exemplars for study were used, so as to provide converging evidence for how participants regulated their learning. Participants overwhelmingly preferred to block their study, even though interleaving is normatively better for learning.


Equity in healthcare resource allocation decision making: A systematic review.
To identify elements of endorsed definitions of equity in healthcare and classify domains of these definitions so that policy makers, managers, clinicians, and politicians can form an operational definition of equity that reflects the values and preferences of the society they serve. Systematic review where verbatim text describing explicit and implicit definitions of equity were extracted and subjected to a thematic analysis. The full holdings of the AMED, CINAHL plus, OVID Medline, Scopus, PsychInfo and ProQuest (ProQuest Health & Medical Complete, ProQuest Nursing and Allied Health Source, ProQuest Social Science Journals) were individually searched in April 2015. Studies were included if they provided an original, explicit or implicit definition of equity in regards to healthcare resource allocation decision making. Papers that only cited earlier definitions of equity and provided no new information or extensions to this definition were excluded. The search strategy yielded 74 papers appropriate for this review; 60 of these provided an explicit definition of equity, with a further 14 papers discussing implicit elements of equity that the authors endorsed in regards to healthcare resource allocation decision making. FIVE KEY THEMES EMERGED: i) Equalisation across the health service supply/access/outcome chain, ii) Need or potential to benefit, iii) Groupings of equalisation, iv) Caveats to equalisation, and v) Close enough is good enough. There is great inconsistency in definitions of equity endorsed by different authors. Operational definitions of equity need to be more explicit in addressing these five thematic areas before they can be directly applied to healthcare resource allocation decisions.


Generation and manipulation of sodium cationized peptides in the gas phase.
Sodiated peptides are often generated by electrospray ionization (ESI) of solutions containing peptides and a sodium salt. Fragmentation of singly sodiated, singly charged peptide ions commonly provides specific sequence information. However, these ions may be difficult to form by directly electrospraying a mixture. In the application of a recently described technique for forming metal containing peptide ions in the gas phase, singly sodiated, singly charged ions are formed via cation-switching ion/ion reactions of multiply protonated peptides. Proton transfer ion/ion reactions can also be used to form [M + Na]+ through the reduction of charge states of multiply charged, singly sodiated ions. The specificity and flexibility of the techniques employed provide a highly controlled means of generating sodiated peptide and protein ions. Thus, the methodologies presented here have potential for forming ions not readily observed via ESI or MALDI. Furthermore, the use of ion/ion reactions to form sodiated peptides facilitates direct comparisons of the fragmentation behavior of [M + Na]+ peptides formed in the absence of solvent with that of [M + Na]+ peptides generated by directly electrospraying a sodium salt/peptide mixture. Thus, in addition to descriptions of the formation of [M + Na]+ peptides in the gas phase using ion/ion reactions, results from CID of reaction products are presented herein.


The usefulness of the validated SkinEthic™ RHE test method to identify skin corrosive UN GHS subcategories.
The SkinEthic™ Reconstructed Human Epidermis (RHE) test method has been adopted within the context of OECD TG 431 for distinguishing corrosive and non-corrosive chemicals. The EU CLP classification system requires subcategorising of corrosive chemicals into the three UN GHS subcategories 1A, 1B and 1C. Since the SkinEthic™ RHE method was originally validated to discriminate corrosives from non-corrosives, the present study was undertaken to investigate its usefulness to discriminate skin corrosive UN GHS subcategories. In total 84 substances were tested in three independent runs and two prediction models (PM) were assessed, representing a pre-defined validated prediction model (PM-A) and an alternative one defined post-hoc (PM-B). The results obtained with both PM were reproducible, as shown by the ⩾92.9% concordance of classification between runs for discriminating corrosives versus non-corrosives, and the ⩾85% concordance for discriminating the GHS subcategories versus non-corrosives. Moreover results confirmed a high sensitivity of the SkinEthic™ RHE method to predict corrosives (94.9%) and good specificity (⩾73.7%) independent of the PM applied. Regarding the identification of UN GHS corrosive subcategories, PM-A resulted in 86.1% correct classifications of the GHS subcategory 1A. When using the PM-B, the identification of GHS subcategory 1B-and-1C substances improved, with 63.4% correct sub-categorisation. If considering the 30 reference chemicals as recommended in the recently revised OECD TG 431 (2013), PM-A and PM-B achieved 78.9% and 83.3% accuracy respectively for the identification of GHS subcategories and non-corrosives. They correctly predicted 90% of GHS subcategory 1A and 80% of GHS non-corrosive substances independent of the PM used. In conclusion, the SkinEthic™ RHE test method is highly reproducible and sensitive for discriminating corrosive from non-corrosive substances. Furthermore it allows reliable identification of skin corrosive GHS subcategory 1B-and-1C substances using the PM-A and PM-B, and of GHS subcategories 1A using the PM-B. Due to its high sensitivity, the test method provides high safety standards for skin corrosion testing.


Infarct topography and hemiparesis profiles with cerebral convexity infarction: the Stroke Data Bank.
For the 183 of 1276 patients in the NINDS Stroke Data Bank with convexity infarction in the middle cerebral artery territory, the size of the infarct did not differ between the two sides but the location of the main site of the infarct differed: on the left side, it was centred in the inferior parietal region, and was mid-frontal on the right. There was a good correlation between infarct size and weakness severity whether estimated by overall motor function on one side, arm, or hand alone. There was a poor correlation, however, for lesion location (lower third, middle third or upper third on either side of the Rolandic fissure) and any of the specific syndromes of focal weakness, no two cases sharing the same lesion for the same syndrome and several cases sharing the same lesion with a different syndrome. The findings indicated a difference in weakness syndromes between the two hemispheres and great individual variation of the acute syndrome caused by a given site of focal infarction along the Rolandic convexity. These variations may explain some of the difficulties showing effects of a given therapeutic agent in studies of acute ischaemic stroke. Large sample sizes will be required for the reliable assessment of any treatment using currently popular clinical stroke scales.


Localization of jointless-2 gene in the centromeric region of tomato chromosome 12 based on high resolution genetic and physical mapping.
Abscission is a universal process whereby plants shed their organs, such as flowers, fruit and leaves. In tomato, the non-allelic mutations jointless and jointless-2 have been discovered as recessive mutations that completely suppress the formation of pedicel abscission zones. A high resolution genetic map of jointless-2 was constructed using 1,122 jointless F2 plants. Restriction fragment length polymorphism (RFLP) marker RPD140 completely co-segregated with the jointless-2 locus and mapped in a 2.4 cM interval between RFLP markers CD22 and TG618. To chromosome walk to jointless-2, all three markers were used to screen a bacterial artificial chromosome (BAC) library and contigs were developed. Intensive efforts to expand and merge the BAC contigs were unsuccessful because of the highly repetitive sequence content on the distal ends of each contig. To determine the physical distance between and the orientation of the three contigs, we used high resolution pachytene fluorescence in situ hybridization (FISH) mapping. The RPD140 contig was positioned in the centromeric region of chromosome 12 between two large pericentric heterochromatin blocks, about 50 Mb from the TG618 contig on the short arm and 10 Mb from the CD22 contig on the long arm, respectively. Based on high resolution genetic and physical mapping, we conclude that the jointless-2 gene is located within or near the chromosome 12 centromere where 1 cM is approximately 25 Mb in length.


Muscle Pain Induces a Shift of the Spatial Distribution of Upper Trapezius Muscle Activity During a Repetitive Task: A Mechanism for Perpetuation of Pain With Repetitive Activity?
An association exists between repetitive movements and the development or perpetuation of neck-shoulder muscle pain. The mechanisms underlying this association remain unclear. This observational study investigated the effect of upper trapezius muscle pain on the distribution of upper trapezius activity during repetitive lifting. It was hypothesized that nociception would change the distribution of activity resulting in activation of muscle regions which would not normally be active during the task. Healthy men repeatedly lifted a box with a cycle time of 3 seconds for 50 cycles, at baseline, following injection of isotonic and hypertonic saline into the upper trapezius muscle and 15 minutes after the last injection. High-density surface electromyography (EMG) was recorded from the upper trapezius using a grid of 64 electrodes. The EMG amplitude was computed for each location to form a map of the EMG amplitude distribution. During the painful condition, the overall EMG amplitude was lower compared with all other conditions (P<0.05) and in addition, the center of upper trapezius activity was shifted toward the caudal region of the muscle (P<0.01), a region not normally active during the task. The described alterations of muscle activity likely play an important role in the perpetuation of pain during repetitive activity. Novel mapping of the spatial distribution of upper trapezius muscle activity showed that nociception induced a redistribution of activity during repetitive lifting. This knowledge provides new insights into the mechanisms underlying the perpetuation of pain with repetitive activity.


Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter.
MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant ('s-group') of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele ('l-group'). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (Ns-group = 48; Nl-group = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced -independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect.


Reduced CD1d expression in colonic epithelium in microscopic colitis.
CD1d is a member of a major histocompatibility complex class I-like molecule family. Its function may involve presenting microbial nonpeptide or lipidic antigens to T lymphocytes, therefore to serve as an important factor in normal mucosal immunity of the gastrointestinal tract. In this study, the expression level of CD1d in microscopic colitis (ie, collagenous and lymphocytic colitis) was examined, and compared with that in normal colonic mucosa. Formalin-fixed, paraffin-embedded colon biopsies with diagnosis of lymphocytic colitis (19 cases), collagenous colitis (6 cases), and no pathologic change (20 cases) were studied immunohistochemically using monoclonal antibodies against human CD1d, CD3, CD4, and CD8. CD1d staining in the epithelium and lamina propria was graded along a scale of 0 to 4. Intraepithelial CD3-positive lymphocytes were counted in an area of 300 epithelial cells for each specimen. The results show that CD1d was expressed in normal colonic epithelial cells, primarily on the basolateral membranes with a concentrated intracellular pool in the subnuclear region. The expression level was markedly reduced in both lymphocytic colitis (P<0.001) and collagenous colitis (P<0.001), along with a significant increase in the number of intraepithelial CD3/CD8 lymphocytes (P<0.001). These findings suggest that microscopic colitis is associated with decreased epithelial expression of CD1d, an important immunoregulatory molecule in the gastrointestinal tract.


Conservation of the Ethiopian church forests: Threats, opportunities and implications for their management.
In the central and northern highlands of Ethiopia, native forest and forest biodiversity is almost confined to sacred groves associated with churches. Local communities rely on these 'church forests' for essential ecosystem services including shade and fresh water but little is known about their region-wide distribution and conservation value. We (1) performed the first large-scale spatially-explicit assessment of church forests, combining remote-sensing and field data, to assess the number of forests, their size, shape, isolation and woody plant species composition, (2) determined their plant communities and related these to environmental variables and potential natural vegetation, (3) identified the main challenges to biodiversity conservation in view of plant population dynamics and anthropogenic disturbances, and (4) present guidelines for management and policy. The 394 forests identified in satellite images were on average ~2ha in size and generally separated by ~2km from the nearest neighboring forest. Shape complexity, not size, decreased from the northern to the central highlands. Overall, 148 indigenous tree, shrub and liana species were recorded across the 78 surveyed forests. Patch α-diversity increased with mean annual precipitation, but typically only 25 woody species occurred per patch. The combined results showed that >50% of tree species present in tropical northeast Africa were still present in the 78 studied church forests, even though individual forests were small and relatively species-poor. Tree species composition of church forests varied with elevation and precipitation, and resembled the potential natural vegetation. With a wide distribution over the landscape, these church forests have high conservation value. However, long-term conservation of biodiversity of individual patches and evolutionary potential of species may be threatened by isolation, small sizes of tree species populations and disturbance, especially when considering climate change. Forest management interventions are essential and should be supported by environmental education and other forms of public engagement.


Coping With a Mass Casualty: Insights into a Hospital's Emergency Response and Adaptations After the Formosa Fun Coast Dust Explosion.
The study provides a comprehensive insight into how an initial receiving hospital without adequate capacity adapted to coping with a mass casualty incident after the Formosa Fun Coast Dust Explosion (FFCDE). Data collection was via in-depth interviews with 11 key participants. This was combined with information from medical records of FFCDE patients and admission logs from the emergency department (ED) to build a detailed timeline of patients flow and ED workload changes. Process tracing analysis focused on how the ED and other units adapted to coping with the difficulties created by the patient surge. The hospital treated 30 victims with 36.3% average total body surface area burn for over 5 hours alongside 35 non-FFCDE patients. Overwhelming demand resulted in the saturation of ED space and intensive care unit beds, exhaustion of critical materials, and near-saturation of clinicians. The hospital reconfigured human and physical resources differently from conventional drills. Graphical timelines illustrate anticipatory or reactive adaptations. The hospital's ability to adapt was based on anticipation during uncertainty and coordination across roles and units to keep pace with varying demands. Adapting to beyond-surge capacity incident is essential to effective disaster response. Building organizational support for effective adaptation is critical for disaster planning.


The demise of repetitive strain injury in sceptical governing rationalities of workplace managers.
In the mid-1990s, RSI (repetitive strain injury) loomed as an occupational health epidemic in industrialised countries. A decade later, the problem appears to have faded away, but there has been little explanation for how this problem might have diminished. This paper offers an explanation for the decline of RSI in the social relations of workplaces, in the pragmatic, day-to-day governance of occupational health by workplace managers. Using the conceptual lens of governmentality theory, this study examined how workplace managers conceptualised, rationalised and responded to RSI in their work organisations. Open-ended interviews were conducted with 35 managers at four Ontario newspaper workplaces. This paper describes managers as guided by a discourse of scepticism about the legitimacy of RSI complaints. This discourse was 'practised' in different ways at each newspaper in varied RSI-management strategies, but each strategy privileged ideas about RSI being problematic in certain types of workers rather than in types of physical work environments. This conceptualisation of RSI splintered, subordinated and collapsed the problem within a broad human resources framework. This paper suggests that the 'taming' of RSI might have occurred in the context of micro-political, workplace-level shifts in the conceptualisation and management of RSI as an occupational health problem.


Effect of bacille Calmette-Guérin vaccination on C-peptide secretion in children newly diagnosed with IDDM.
To determine whether administration of bacille Calmette-Guérin (BCG) vaccination to newly diagnosed IDDM patients can help preserve C-peptide secretion over the subsequent 18 months. Twenty-six IDDM patients, all of whom had been diagnosed within the previous year, had basal C-peptide levels >0.06 nmol/l, and had negative reactions to Mantoux's test, were randomized pairwise as they presented and were given either 0.1 ml (100 microg) BCG vaccine or 0.1 ml saline intradermally Both the patients and the investigators were blinded to the treatment. Fasting and glucagon-induced C-peptide levels and HbA1c were measured in all patients at enrollment and at 1, 3, 6, 9, 12, and 18 months after vaccination, and insulin dose was recorded at each visit. At enrollment, there was no significant difference in age, duration of diabetes, insulin dose, HbA1c, or fasting C-peptide levels between the BCG-vaccinated and control groups. The mean basal and stimulated C-peptide levels in the BCG-treated group did not differ significantly from those in the control group at any time during the 18 months of follow-up, and there was no difference in insulin dose or HbA1c at any time between the groups. BCG vaccination in children who have been recently diagnosed with IDDM does not affect the progressive decline in C-peptide levels or alter the clinical course of the disease.


ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.
Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.


A randomized placebo-controlled crossover trial of aloe vera on bioavailability of vitamins C and B(12), blood glucose, and lipid profile in healthy human subjects.
Several factors limit the absorption and bioavailability of vitamins. Vitamin C, a commonly used water-soluble supplement reduces the risk of disease. Vitamin B(12) is necessary for the development of RBC, growth, and nervous system. Vitamin B(12) deficiency is common among elderly. Thus, agents that improve bioavailability of vitamin C and B(12), especially in older individuals would be important. Aloe Vera is a botanical with immunomodulatory properties. Aloe is processed using the hand-filleted technique or whole leaf procedure. The aim of this study is to examine the effect of two different aloe vera preparations (aloe inner leaf gel, [AG] and aloe whole leaf decolorized gel, [AL]) compared to placebo on the bioavailability of vitamins, C and B(12), in healthy human volunteers in a randomized crossover trial. Subjects (n = 15) received in a random fashion either aloe whole leaf extract (AL with vitamins B(12), 1 mg and vitamin C 500 mg) or aloe fillet gel (AG with B(12) 1 mg and vitamin C 500 mg) or water (with vitamin B(12) 1 mg and vitamin C 500 mg). Blood was obtained fasting, followed by 1, 2, 4, 6, 8, and 24 hours postingestion of aloe/water. When given with vitamins C and B(12), AG significantly increased plasma oxygen radical absorbance capacity (ORAC) at both 4 and 24 hours and AL at 4 hours compared to baseline and placebo. AG significantly increased plasma vitamin C at 4, 6, 8, and 24 hours and AL at 4 and 6 hours compared to baseline and placebo (p <.01). Also, both aloes significantly increased serum vitamin B(12) levels at 1 and 2 hours compared to baseline and placebo (p <.01). Thus, AG and AL preparations are safe, well tolerated, and enhance the bioavailability of vitamins C and B(12) and antioxidant potential.


Determination of the rotational diffusion tensor of macromolecules in solution from nmr relaxation data with a combination of exact and approximate methods--application to the determination of interdomain orientation in multidomain proteins.
In this paper we present a method for determining the rotational diffusion tensor from NMR relaxation data using a combination of approximate and exact methods. The approximate method, which is computationally less intensive, computes values of the principal components of the diffusion tensor and estimates the Euler angles, which relate the principal axis frame of the diffusion tensor to the molecular frame. The approximate values of the principal components are then used as starting points for an exact calculation by a downhill simplex search for the principal components of the tensor over a grid of the space of Euler angles relating the diffusion tensor frame to the molecular frame. The search space of Euler angles is restricted using the tensor orientations calculated using the approximate method. The utility of this approach is demonstrated using both simulated and experimental relaxation data. A quality factor that determines the extent of the agreement between the measured and predicted relaxation data is provided. This approach is then used to estimate the relative orientation of SH3 and SH2 domains in the SH(32) dual-domain construct of Abelson kinase complexed with a consolidated ligand.


Acclimation of Arabidopsis thaliana to the light environment: the role of photoreceptors.
The regulation by light of the composition of the photosynthetic apparatus was investigated in photomorphogenic mutants of Arabidopsis thaliana (L.) Heynh. cv. Landsberg erecta. Leaf chlorophyll, photosynthesis, photosystem II function, and ribulose-1, 5-bisphosphate carboxylase-oxygenase and photosystem II contents were determined for plants grown under high- or low-irradiance growth regimes. Although certain mutant lines had altered chloroplast composition compared to the wild type, all photoreceptor mutants tested were capable of light-dependent changes in chloroplast composition and photosynthetic function, indicating that photoreceptors do not play a central role in the regulation of acclimation at the level of the chloroplast. However, the clear acclimation defect in a det1 signal transduction mutant indicates that photoreceptor-controlled responses either share regulatory components with acclimation, or are important in the expression of components which in turn regulate acclimation. We suggest that the COP/DET/FUS regulatory cluster is a focus for multiple signal transduction pathways, including some of the metabolic signals which form the basis for the acclimatory response.


Pacemaker diagnostic diagrams.
Dual-chamber pacemakers interact with cardiac rhythms in complex ways. The resultant surface electrocardiograms (ECGs) are often very difficult to interpret. A simple and automatic diagnostic diagram is described that graphically illustrates pacemaker-heart interactions. Pacemaker operation is explained by a continuous series of lines and symbols that interconnect any sequence of paced and sensed events in both chambers. Fixed, programmable, and adaptive pacemaker timing intervals are all shown in a simple format. The pacemaker diagnostic diagram is plotted directly below the ECG to help users interpret the paced cardiac rhythm. The pacemaker diagnostic diagram is generated by software in a pacemaker programmer from: (1) telemetered real-time event markers; (2) fixed and programmable timing parameters (lower rate, AV interval, etc.); (3) pacemaker conditional logic. If this computer analysis of the telemetered event markers is not consistent with normal pacemaker operation, a specific error-message is printed. The pacemaker diagnostic diagram should be useful for instruction, pacemaker follow-up, and troubleshooting.


[Investigation on HPV DNA detection and genotyping practices used in French laboratories in 2009].
The French National reference Laboratory for Human papillomavirus (HPV) performed in 2009 a national study in order to review the methods used to detect and identify HR HPV genotypes in microbiology laboratories. Results from this study show a great diversity in volumes of samples treated in laboratories. Among clinical indications, the most frequent is a result of ASC-US at a Pap smear. This indication in the only one covered by the National Public Insurance System and is mostly performed in laboratories from private sector. Other indications mainly correspond to research programs and are performed in public Hospitals. This study allowed also to review the adequacy between the liquid based cytology samples and the assays used for direct detection of HR HPV or identification of the genotypes present in the sample. The right tests were not carried in the right solution storage according to the recommendations from different HPV testing assays. National recommendations should be elaborated in order to improve the performance of the test used.