Functional Recovery in Critically Ill Children, the "WeeCover" Multicenter Study.
To evaluate functional outcomes and evaluate predictors of an unfavorable functional outcome in children following a critical illness. Prospective observational longitudinal cohort study. Two tertiary care, Canadian PICUs: McMaster Children's Hospital and London Health Sciences. Children 12 months to 17 years old, admitted to PICU for at least 48 hours with one or more organ dysfunction, were eligible. Patients not expected to survive, direct transfers from neonatal ICU and patients in whom long-term follow-up would not be able to be conducted, were excluded. None. The primary endpoint was functional outcome up to 6 months post PICU discharge, measured using the Pediatric Evaluation of Disabilities Inventory Computer Adaptive Test. Secondary outcomes included predictors of unfavorable functional outcome, caregiver stress, health-related quality-of-life, and clinical outcomes such as mortality, length of stay, and PICU-acquired complications. One hundred eighty-two patients were enrolled; 78 children (43.6%) had functional limitations at baseline and 143 (81.5%) experienced functional deterioration following critical illness. Ninety-two (67.1%) demonstrated some functional recovery by 6 months. Higher baseline function and a neurologic insult at PICU admission were the most significant predictors of functional deterioration. Higher baseline function and increasing age were associated with slower functional recovery. Different factors affect the domains of functioning differently. Preexisting comorbidities and iatrogenic PICU-acquired morbidities were associated with persistent requirement for caregiver support (responsibility function) at 6 months. The degree of functional deterioration after critical illness was a significant predictor of increased hospital length of stay. This study provides new information regarding functional outcomes and the factors that influence meaningful aspects of functioning in critically ill children. Identifying patients at greatest risk and modifiable targets for improvement in PICU care guides us in developing strategies to improve functional outcomes and tailor to the rehabilitation needs of these patients and their families.


Effectiveness of Polypill for Prevention of Cardiovascular Disease (PolyPars): Protocol of a Randomized Controlled Trial.
Cardiovascular diseases (CVDs) are the leading cause of death in Iran. A fixed-dose combination therapy (polypill) was proposed as a cost-effective strategy for CVD prevention, especially in lower-resource settings. We conducted the PolyPars trial to assess the effectiveness and safety of polypill for prevention of CVD. The PolyPars trial is a pragmatic cluster randomized controlled trial nested within the Pars Cohort Study. Participants were randomized to an intervention arm and a control arm. Participants in the control arm received minimal non-pharmacological care, while those in the intervention arm received polypill in addition to minimal care. The polypill comprises hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg, and either enalapril 5 mg or valsartan 40 mg. The primary outcome of the study is defined as the first occurrence of acute coronary syndrome (non-fatal myocardial infarction and unstable angina), fatal myocardial infarction, sudden cardiac death, new-onset heart failure, coronary artery revascularization procedures, transient ischemic attack, cerebrovascular accidents (fatal or non-fatal), and hospitalization due to any of the mentioned conditions. The secondary outcomes of the study include adverse events, compliance, non-cardiovascular mortality, changes in blood pressure, fasting blood sugar, and lipids after five years of follow-up. From December 2014 to December 2015, 4415 participants (91 clusters) were recruited. Of those, 2200 were in the polypill arm and 2215 in the minimal care arm. The study is ongoing. This trial was registered with ClinicalTrials.gov number NCT03459560. Polypill may be effective for primary prevention of CVDs in developing countries.


BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer.
This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC). We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively. We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation-positive patients versus 12% of BRAF mutation-negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively. Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC.


Human-animal interactions and safety during dairy cattle handling--Comparing moving cows to milking and hoof trimming.
Cattle handling is a dangerous activity on dairy farms, and cows are a major cause of injuries to livestock handlers. Even if dairy cows are generally tranquil and docile, when situations occur that they perceive or remember as aversive, they may become agitated and hazardous to handle. This study aimed to compare human-animal interactions, cow behavior, and handler safety when moving cows to daily milking and moving cows to more rarely occurring and possibly aversive hoof trimming. These processes were observed on 12 Swedish commercial dairy farms. The study included behavioral observations of handler and cows and cow heart rate recordings, as well as recording frequencies of situations and incidents related to an increased injury risk to the handler. At milking, cows were quite easily moved using few interactions. As expected, the cows showed no behavioral signs of stress, fear, or resistance and their heart rate only rose slightly from the baseline (i.e., the average heart rate during an undisturbed period before handling). Moving cows to hoof trimming involved more forceful and gentle interactions compared with moving cows to milking. Furthermore, the cows showed much higher frequencies of behaviors indicative of aversion and fear (e.g., freezing, balking, and resistance), as well as a higher increase in heart rate. The risk of injury to which handlers were exposed also increased when moving cows to hoof trimming rather than to routine milking. Some interactions (such as forceful tactile interactions with an object and pulling a neck strap or halter) appeared to be related to potentially dangerous incidents where the handler was being kicked, head-butted, or run over by a cow. In conclusion, moving cows to hoof trimming resulted in higher frequencies of behaviors indicating fear, more forceful interactions, and increased injury risks to the handler than moving cows to milking. Improving potentially stressful handling procedures (e.g., by better animal handling practices and preparation of cows to cope with such procedures) can increase handler safety, animal welfare, ease of handling, and efficiency.


Radiogenomic Analysis Demonstrates Associations between (18)F-Fluoro-2-Deoxyglucose PET, Prognosis, and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.
Purpose To investigate whether non-small cell lung cancer (NSCLC) tumors that express high normalized maximum standardized uptake value (SUVmax) are associated with a more epithelial-mesenchymal transition (EMT)-like phenotype. Materials and Methods In this institutional review board-approved study, a public NSCLC data set that contained fluorine 18 ((18)F) fluoro-2-deoxyglucose positron emission tomography (PET) and messenger RNA expression profile data (n = 26) was obtained, and patients were categorized on the basis of measured normalized SUVmax values. Significance analysis of microarrays was then used to create a radiogenomic signature. The prognostic ability of this signature was assessed in a second independent data set that consisted of clinical and messenger RNA expression data (n = 166). Signature concordance with EMT was evaluated by means of validation in a publicly available cell line data set. Finally, by establishing an in vitro EMT lung cancer cell line model, an attempt was made to substantiate the radiogenomic signature with quantitative polymerase chain reaction, and functional assays were performed, including Western blot, cell migration, glucose transporter, and hexokinase assays (paired t test), as well as pharmacologic assays against chemotherapeutic agents (half-maximal effective concentration). Results Differential expression analysis yielded a 14-gene radiogenomic signature (P < .05, false discovery rate [FDR] < 0.20), which was confirmed to have differences in disease-specific survival (log-rank test, P = .01). This signature also significantly overlapped with published EMT cell line gene expression data (P < .05, FDR < 0.20). Finally, an EMT cell line model was established, and cells that had undergone EMT differentially expressed this signature and had significantly different EMT protein expression (P < .05, FDR < 0.20), cell migration, glucose uptake, and hexokinase activity (paired t test, P < .05). Cells that had undergone EMT also had enhanced chemotherapeutic resistance, with a higher half-maximal effective concentration than that of cells that had not undergone EMT (P < .05). Conclusion Integrative radiogenomic analysis demonstrates an association between increased normalized (18)F fluoro-2-deoxyglucose PET SUVmax, outcome, and EMT in NSCLC. (©) RSNA, 2016 Online supplemental material is available for this article.


Rough parameter dependence in climate models and the role of Ruelle-Pollicott resonances.
Despite the importance of uncertainties encountered in climate model simulations, the fundamental mechanisms at the origin of sensitive behavior of long-term model statistics remain unclear. Variability of turbulent flows in the atmosphere and oceans exhibits recurrent large-scale patterns. These patterns, while evolving irregularly in time, manifest characteristic frequencies across a large range of time scales, from intraseasonal through interdecadal. Based on modern spectral theory of chaotic and dissipative dynamical systems, the associated low-frequency variability may be formulated in terms of Ruelle-Pollicott (RP) resonances. RP resonances encode information on the nonlinear dynamics of the system, and an approach for estimating them--as filtered through an observable of the system--is proposed. This approach relies on an appropriate Markov representation of the dynamics associated with a given observable. It is shown that, within this representation, the spectral gap--defined as the distance between the subdominant RP resonance and the unit circle--plays a major role in the roughness of parameter dependences. The model statistics are the most sensitive for the smallest spectral gaps; such small gaps turn out to correspond to regimes where the low-frequency variability is more pronounced, whereas autocorrelations decay more slowly. The present approach is applied to analyze the rough parameter dependence encountered in key statistics of an El-Niño-Southern Oscillation model of intermediate complexity. Theoretical arguments, however, strongly suggest that such links between model sensitivity and the decay of correlation properties are not limited to this particular model and could hold much more generally.


Telomeres and telomerase activity in scleractinian corals and Symbiodinium spp.
Telomeres are the repetitive sequences of DNA and associated proteins that cap the ends of eukaryotic chromosomes and play an essential role in maintaining chromosome stability. Compromised telomeres can lead to cell cycle arrest, senescence, apoptosis, or genetic instability, whereas maintenance of telomeres can endow cells with the capacity for indefinite self-renewal. Telomere integrity is maintained in most cells by the activity of telomerase, a ribonucleoprotein that can catalyze the addition of repeat sequences onto chromosome ends. Using the telomeric repeat amplification protocol (TRAP) assay, we detected telomerase activity in host nuclear extracts prepared from two scleractinian corals, Madracis auretenra and Madracis decactis, and also in cultured Symbiodinium, the symbiotic algae that live within corals. Sequencing the TRAP reaction products indicated that the telomeric DNA repeat sequence was TTAGGG for coral and TTTAGGG for Symbiodinium. Using this sequence information, we estimated telomere lengths by terminal restriction fragment (TRF) analysis to be greater than 19 kb for several species of coral and their associated Symbiodinium. Maintenance of coral telomeres by telomerase activity may be a mechanism that confers continuous growth and reproductive plasticity to these long-lived organisms.


The making of a chloroplast.
Since its endosymbiotic beginning, the chloroplast has become fully integrated into the biology of the host eukaryotic cell. The exchange of genetic information from the chloroplast to the nucleus has resulted in considerable co-ordination in the activities of these two organelles during all stages of plant development. Here, we give an overview of the mechanisms of light perception and the subsequent regulation of nuclear gene expression in the model plant Arabidopsis thaliana, and we cover the main events that take place when proplastids differentiate into chloroplasts. We also consider recent findings regarding signalling networks between the chloroplast and the nucleus during seedling development, and how these signals are modulated by light. In addition, we discuss the mechanisms through which chloroplasts develop in different cell types, namely cotyledons and the dimorphic chloroplasts of the C(4) plant maize. Finally, we discuss recent data that suggest the specific regulation of the light-dependent phases of photosynthesis, providing a means to optimize photosynthesis to varying light regimes.


Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus.
Among patients newly infected with hepatitis C virus (HCV), only 20-30% clear the infection spontaneously. In the remaining 70% the infection persists, causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. Retinoic acid inducible gene-I (RIG-I)-like helicases such as melanoma differentiation-associated gene 5 (MDA-5) are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analyzed 14 nonsynonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients who spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We found that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (odds ratio [OR]: 16.23; 95% confidence interval [CI]: 3.67-71.87; P = 1.1 × 10(-6) ). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection.


Antioxidant activity of a red lentil extract and its fractions.
Phenolic compounds were extracted from red lentil seeds using 80% (v/v) aqueous acetone. The crude extract was applied to a Sephadex LH-20 column. Fraction 1, consisting of sugars and low-molecular-weight phenolics, was eluted from the column by ethanol. Fraction 2, consisting of tannins, was obtained using acetone-water (1:1; v/v) as the mobile phase. Phenolic compounds present in the crude extract and its fractions demonstrated antioxidant and antiradical activities as revealed from studies using a beta-carotene-linoleate model system, the total antioxidant activity (TAA) method, the DPPH radical-scavenging activity assay, and a reducing power evaluation. Results of these assays showed the highest values when tannins (fraction 2) were tested. For instance, the TAA of the tannin fraction was 5.85 micromol Trolox eq./mg, whereas the crude extract and fraction 1 showed 0.68 and 0.33 micromol Trolox eq./mg, respectively. The content of total phenolics in fraction 2 was the highest (290 mg/g); the tannin content, determined using the vanillin method and expressed as absorbance units at 500 nm per 1 g, was 129. There were 24 compounds identified in the crude extract using an HPLC-ESI-MS method: quercetin diglycoside, catechin, digallate procyanidin, and p-hydroxybenzoic were the dominant phenolics in the extract.


Myristoylation of the fus1 protein is required for tumor suppression in human lung cancer cells.
FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region that is deleted in many cancers. Using surface-enhanced laser desorption/ionization mass spectrometric analysis on an anti-Fus1-antibody-capture ProteinChip array, we identified wild-type Fus1 as an N-myristoylated protein. N-myristoylation is a protein modification process in which a 14-carbon myristoyl group is cotranslationally and covalently added to the NH2-terminal glycine residue of the nascent polypeptide. Loss of expression or a defect of myristoylation of the Fus1 protein was observed in human primary lung cancer and cancer cell lines. A myristoylation-deficient mutant of the Fus1 protein abrogated its ability to inhibit tumor cell-induced clonogenicity in vitro, to induce apoptosis in lung tumor cells, and to suppress the growth of tumor xenografts and lung metastases in vivo and rendered it susceptible to rapid proteasome-dependent degradation. Our results show that myristoylation is required for Fus1-mediated tumor-suppressing activity and suggest a novel mechanism for the inactivation of tumor suppressors in lung cancer and a role for deficient posttranslational modification in tumor suppressor-gene-mediated carcinogenesis.


Effects of perceived racism and acculturation on hypertension in Native Hawaiians.
To examine the effects of perceived racism and acculturation on the hypertension status of Native Hawaiians. Cross-sectional data from 94 Native Hawaiian adults were obtained which included the following: 1) socio-demographic variables and self-reported hypertension status; 2) a 5-item Hawaiian cultural identity subscale (HCSS) and a 5-item American cultural identity subscale (ACSS); and 3) perceived racism based on a 6-item modified version of the 32-item Oppression Questionnaire (OQ). Based on logistic regression analysis, the ACSS scores and OQ scores had significant (p<.05) and independent effects on hypertension status, after considering the effects of age, sex, and education level, and HCSS scores. Of the variables examined, OQ scores had the greatest magnitude of effect on hypertension status. More perceived racism and a greater identification with the American mainstream culture were both, independently, related to self-reported hypertension in Native Hawaiians. These findings have important clinical and public health implications.


Optical Torques on Upconverting Particles for Intracellular Microrheometry.
Precise knowledge and control over the orientation of individual upconverting particles is extremely important for full exploiting their capabilities as multifunctional bioprobes for interdisciplinary applications. In this work, we report on how time-resolved, single particle polarized spectroscopy can be used to determine the orientation dynamics of a single upconverting particle when entering into an optical trap. Experimental results have unequivocally evidenced the existence of a unique stable configuration. Numerical simulations and simple numerical calculations have demonstrated that the dipole magnetic interactions between the upconverting particle and trapping radiation are the main mechanisms responsible of the optical torques that drive the upconverting particle to its stable orientation. Finally, how a proper analysis of the rotation dynamics of a single upconverting particle within an optical trap can provide valuable information about the properties of the medium in which it is suspended is demonstrated. A proof of concept is given in which the laser driven intracellular rotation of upconverting particles is used to successfully determine the intracellular dynamic viscosity by a passive and an active method.


Dementia-friendly communities: challenges and strategies for achieving stakeholder involvement.
Dementia-friendly communities (DFCs) are a UK policy initiative that aims to enable people with dementia to feel supported and included within their local community. Current approaches to DFC creation rely on stakeholder involvement, often requiring volunteer assistance. There is though a lack of evidence that examines the reality of achieving this. This paper critically assesses the challenges and strategies for achieving stakeholder involvement in DFCs. The evidence base is drawn from an inter-agency project funded by the National Health Service in the South of England where seven DFCs were developed by steering group partners and four part-time project workers (PWs). Data from the independent evaluation undertaken in the first year (2013-2014) of the project were analysed: 14 semi-structured interviews and a focus group examined PWs' experiences; while progress and key milestones are determined from monthly progress forms, good news stories, locality steering group minutes and press releases. Analysis was undertaken using a directed content analysis method, whereby data content for each locality was matched to the analytical framework that was drawn from Alzheimer's Society guidance. Challenges to achieving stakeholder involvement were identified as: establishing networks and including people representative of the local community; involving people affected by dementia; and gaining commitment from organisations. Strategies for achieving stakeholder involvement were recognised as: a sustainable approach; spreading the word; and sharing of ideas. By highlighting these challenges and the approaches that have been used within communities to overcome them, these findings form the foundation for the creation of DFC initiatives that will become embedded within communities. Stakeholder involvement is unpredictable and changeable; therefore, reliance on this approach questions the long-term sustainability of DFCs, and must be considered in future policies designed to enhance quality of life for people affected by dementia.


International harmonisation of regulatory requirements.
The International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) was formed in April 1996 and is a programme of collaboration between regulatory authorities and the animal health industries of three world regions: the European Union, Japan and the United States of America. Two other regions, Canada and Australia/New Zealand, have observer status. The principal goal of VICH is to harmonise technical data requirements of participating regulatory authorities before granting marketing authorisation or registration. VICH has finalised six guidelines on the technical requirements for marketing authorisation/registration of biological products. These guidelines have been fully implemented in the regions. Three more technical guidelines are under development by two expert working groups. VICH has also finalised a guideline which specifically deals with pharmacovigilance and veterinary medicinal products, including biological products. A further four guidelines relating to pharmacovigilance are under development by an expert working group.


A biomimetic approach to C-nor-D-homo-steroids.
A biomimetic three-step transformation of classical "6-6-6-5"-steroids into their C-nor-D-homo-counterparts gives an easy and fast access to this highly important substructure of natural products, as it is found in cyclopamine, and nakiterpiosin. A novel reagent combination allows for the rearrangement even of 17-keto steroids with high endoselectivity. In several examples the broadness of this strategy is outlined.


Standing alone when life takes an unexpected turn: being a midlife next of kin of a relative who has suffered a myocardial infarction.
Suffering a myocardial infarction (MI) is a life-threatening event that impacts not only on the individual concerned but also on the next of kin. However, there seems to be a paucity of naturalistic inquiries that focus specifically on midlife next of kin and their experience of being close to a relative who has suffered an MI. This study aims to elucidate the experience of being a midlife next of kin of a relative who has suffered a myocardial infarction. Nine women and four men in midlife participated in the focused interviews, which were conducted and analysed during 2010/2011 using Lindseths and Norbergs' description of the phenomenological hermeneutical method. Four themes - Solely responsible, Lurking unease, Left out of the picture and Life on hold - formed the basis of the core theme Standing alone when life takes an unexpected turn. The core theme was interpreted as a central phenomenon encompassing the experience of being solely responsible for the well-being of their relative and the family, thus putting their own life on hold. The core theme also reflected the next of kin's experience of being left out of the picture when it came to the relative's care before and after the MI. The next of kin's negative feelings of standing alone were further intensified by their experience of being left out of the picture by the healthcare professionals concerning their relative's care. As a cardiac nurse, it would seem essential to have knowledge about the experiences of next of kin in connection with a relative's MI event. Such knowledge can facilitate the planning and organisation of nursing care and at the same time address the next of kin's role in the recovery and rehabilitation process.


Nephroprotective activity of virgin coconut oil on diclofenac-induced oxidative nephrotoxicity is associated with antioxidant and anti-inflammatory effects in rats.
Diclofenac is a non-steroidal anti-inflammatory drug linked with considerable organ toxicity caused via increased generation of reactive oxygen species. We evaluated whether the antioxidant effect of virgin coconut oil (VCO) could prevent diclofenac-induced oxidative nephrotoxicity in rats. Randomized rats were pre-supplemented orally with VCO (5 or 10 ml/kg body weight) from day 1 to 24, and injected with normal saline or diclofenac (100 mg/kg) from day 22 to day 24 intraperitoneally. Diclofenac significantly (p<0.05) increased serum urea and creatinine levels. Renal tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) levels markedly (p<0.05) increased, whereas renal glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) activities considerably (p<0.05) decreased compared to normal control. Histopathological alterations were caused by diclofenac. However, treatment with oral VCO for 21 days prior to diclofenac administration, attenuated histological renal damage, and restored antioxidant enzyme activities and TNF-α levels in kidney. These findings revealed that VCO has potential benefits to prevent diclofenac-induced nephrotoxic damage.


Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience.
Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol. Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)). Patients without disease progression then received gemcitabine twice weekly (50 mg/m(2) daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability. Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001). The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation.


Frequency and correlation of lip prints, fingerprints and ABO blood groups in population of Sriganganagar District, Rajasthan.
To investigate the frequency and uniqueness of different lip print patterns, fingerprint patterns in relation to gender and ABO Rh blood groups among a semi-urban population of Sriganganagar, Rajasthan. The study was conducted on 1200 healthy volunteers aged 18-30 years. The cheiloscopic and dermatographic data of each subject were obtained and were analysed according to the Suzuki and Tsuchihashi and Henry systems of classification, respectively. Two forensic experts analyzed the patterns independently. The ABO Rh blood group was also recorded for each subject. The Chi square statistical analysis was done and tests were considered significant when p value <0.001 and Cohen kappa test was applied to analyze inter-observer reliability. The B+ blood group was noted as most common in both genders while least common were A- among males and AB- in females. Type II lip pattern was most predominant while the least common was Type I' in males and Type I' and Type V in females. The UL fingerprint pattern was the most common, while RL was least noted in both genders. All the fingerprint patterns showed correlation with different lip print patterns. A correlation was found between different blood groups and lip print patterns except Type I (vertical) lip pattern. A positive correlation was observed between all the blood groups and fingerprint patterns, except for RL pattern. There is an association between lip print patterns, fingerprint patterns and ABO blood groups in both the genders. Thus, correlating the uniqueness of these physical evidences sometimes helps the forensic team members in accurate personal identification or it can at least narrow the search for an individual where there are no possible data referring to the identity of the subject.


Indium lung--case reports and epidemiology.
The present review is aimed to introduce an new occupational lung disease, Indium Lung. We searched case reports and epidemiological studies concerning indium-related lung diseases and reviewed. Up to March, 2010, 7 cases of interstitial pneumonia in Japanese indium-exposed workers, two cases of pulmonary alveolar proteinosis (PAP) in US indium-exposed workers, one case of PAP in a Chinese indium-exposed worker, and 4 cross-sectional surveys in Japan had been published. All cases and epidemiological studies in Japan indicate that exposure to hardly soluble indium compounds causes interstitial as well as emphysematous lung damages, which we call "Indium Lung". Based on the epidemiological studies, the Japan Society for Occupational Health proposed 3 μg/l of indium in serum as an occupational exposure limit based on biological monitoring to prevent significant increase of KL-6. Long-term follow-up of currently and formerly indium-exposed workers is essential not only to clarify the natural history of indium lung but also to trace the incidence of lung cancer. It is also necessary to elucidate the mechanism of indium lung and difference in clinical manifestations between Japanese and US cases.


Impact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia (IRONIC study): study protocol of a retrospective multicentre international study.
Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe sepsis and death among neutropenic cancer patients. There has been a recent increase of multidrug-resistant PA (MDRPA) isolates that may determine a worse prognosis, particularly in immunosuppressed patients. The aim of this study is to establish the impact of antibiotic resistance on the outcome of neutropenic onco-haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA bacteraemia and mortality. This is a retrospective, observational, multicentre, international study. All episodes of PA bacteraemia occurring in neutropenic onco-haematological patients followed up at the participating centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA bacteraemia. The secondary end points will be to describe the following: the incidence and risk factors for multidrug-resistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with those produced by MDRPA), the efficacy of ceftolozane/tazobactam, the rates of persistent bacteraemia and bacteraemia relapse and the risk factors for very early (48 hours), early (7 days) and overall (30 days) case-fatality rates. The Clinical Research Ethics Committee of Bellvitge University Hospital approved the protocol of the study at the primary site. To protect personal privacy, identifying information of each patient in the electronic database will be encrypted. The processing of the patients' personal data collected in the study will comply with the Spanish Data Protection Act of 1998 and with the European Directive on the privacy of data. All data collected, stored and processed will be anonymised. Results will be reported at conferences and in peer-reviewed publications.


Ethnopharmacological survey of medicinal plants practiced by traditional healers and herbalists for treatment of some urological diseases in the West Bank/Palestine.
Throughout history, every civilization in the world used plants or their derivatives for treatment or prevention of diseases. In Palestine as in many other countries, herbal medicines are broadly used in the treatment of wide range of diseases including urological diseases. The main objective of this research is to study the use of herbal remedies by herbalists and traditional healers for treatment of various urological diseases in the West Bank regions of Palestine and to assess their efficacy and safety through the literature review of the most cited plants. The study included a survey part, plant identification and a review study. The first part was a cross-sectional descriptive study. Face to face questionnaires were distributed to 150 traditional healers and herbalist in all regions of the West Bank of Palestine. The literature review part was to assess the most cited plants for their efficacy and toxicity. One hundred forty four herbalists and traditional healers accepted to participate in this study which was conducted between March and April, 2016. The results showed that 57 plant species belonging to 30 families were used by herbalists and traditional healers for treatment of various urinary tract diseases in Palestine. Of these, Apiaceae family was the most prevalent. Paronychia argentea, Plantago ovata, Punica granatum, Taraxacum syriacum, Morus alba and Foeniculum vulgare were the most commonly used plant species in the treatment of kidney stones, while Capsella bursa-pastoris, Ammi visnaga and Ammi majus were the most recommended species for treatment of urinary tract infections and Portulaca oleracea used for renal failure. In addition Curcuma longa and Crocus sativus were used for enuresis while Juglans regia, Quercus infectoria, Sambucus ebulus and Zea mays were used for treatment symptoms of benign prostate hyperplasia. Fruits were the most common parts used, and a decoction was the most commonly used method of preparation. Through literature review, it was found that Paronychia argentea has a low hemolytic effect and contains oxalic acid and nitrate. Therefore, it could be harmful to renal failure patients, also Juglans regia, Quercus infectoria and, Sambucus ebulus are harmful plants and cannot be used for treatment of any disease. Our data provided that ethnopharmacological flora in the West Bank regions of Palestine can be quite wealthy and diverse in the treatments of urinary tract diseases. Clinical trials and pharmacological tests are required evaluate safety and efficacy of these herbal remedies.


Harnessing genetic diversity in Saccharomyces cerevisiae for fermentation of xylose in hydrolysates of alkaline hydrogen peroxide-pretreated biomass.
The fermentation of lignocellulose-derived sugars, particularly xylose, into ethanol by the yeast Saccharomyces cerevisiae is known to be inhibited by compounds produced during feedstock pretreatment. We devised a strategy that combined chemical profiling of pretreated feedstocks, high-throughput phenotyping of genetically diverse S. cerevisiae strains isolated from a range of ecological niches, and directed engineering and evolution against identified inhibitors to produce strains with improved fermentation properties. We identified and quantified for the first time the major inhibitory compounds in alkaline hydrogen peroxide (AHP)-pretreated lignocellulosic hydrolysates, including Na(+), acetate, and p-coumaric (pCA) and ferulic (FA) acids. By phenotyping these yeast strains for their abilities to grow in the presence of these AHP inhibitors, one heterozygous diploid strain tolerant to all four inhibitors was selected, engineered for xylose metabolism, and then allowed to evolve on xylose with increasing amounts of pCA and FA. After only 149 generations, one evolved isolate, GLBRCY87, exhibited faster xylose uptake rates in both laboratory media and AHP switchgrass hydrolysate than its ancestral GLBRCY73 strain and completely converted 115 g/liter of total sugars in undetoxified AHP hydrolysate into more than 40 g/liter ethanol. Strikingly, genome sequencing revealed that during the evolution from GLBRCY73, the GLBRCY87 strain acquired the conversion of heterozygous to homozygous alleles in chromosome VII and amplification of chromosome XIV. Our approach highlights that simultaneous selection on xylose and pCA or FA with a wild S. cerevisiae strain containing inherent tolerance to AHP pretreatment inhibitors has potential for rapid evolution of robust properties in lignocellulosic biofuel production.


Human liver lauric acid hydroxylase activities.
Nine male and five female human liver microsomal sample were examined for laurate 11- and 12-hydroxylase activities. The mean specific activities for the 11- and 12-hydroxylation reactions were 0.78 +/- 0.33 and 1.07 +/- 0.12 nmol/min/mg protein, respectively. Antibody inhibition experiments, using a polyclonal antibody to a cytochrome P450 (P450) isolated from diethylhexyl phthalate-treated rats, which recognizes forms P4504A1, P4504A2, and P4504A3 of the rate, inhibited the 12-hydroxylase activity by 65%, but did not affect 11-hydroxylase activity. Western-blot analyses of the 14 human liver microsomal samples identified one major protein band at 52 kDa that comigrated with human form 4A11. A correlation coefficient of only 0.19 was calculated when comparing laurate 12-hydroxylase activities and the densitometric values of the immunochemically reactive protein bands in the human liver microsomal samples, which strongly suggests that additional P450 forms also support the 12-hydroxylation of lauric acid. Laurate 11-hydroxylase activity was inhibited by diethyldithiocarbamate, an inhibitor of P4502E1-mediated reactions, and by chlorzoxazone, a P4502E1 substrate. A comparison of laurate 11-hydroxylase activities with densitometric values of the P4502E1 protein bands indicated a strong correlation existed (0.82). An analysis of microsomal samples containing expressed human forms P4501A2, P4502A6, P4502C8, P4502C9, P4502D6, P4502E1, and P4503A4 showed that only form P4502E1 supported the 11-hydroxylation reaction.


Do-not-intubate orders in patients with acute respiratory failure: a systematic review and meta-analysis.
To assess the rates and variability of do-not-intubate orders in patients with acute respiratory failure. We conducted a systematic review of observational studies that enrolled adult patients with acute respiratory failure requiring noninvasive ventilation or high-flow nasal cannula oxygen from inception to 2019. Twenty-six studies evaluating 10,755 patients were included. The overall pooled rate of do-not-intubate orders was 27%. The pooled rate of do-not-intubate orders in studies from North America was 14% (range 9-22%), from Europe was 28% (range 13-58%), and from Asia was 38% (range 9-83%), p = 0.001. Do-not-intubate rates were higher in studies with higher patient age and in studies where do-not-intubate decisions were made without reported patient/family input. There were no significant differences in do-not-intubate orders according to illness severity, observed mortality, malignancy comorbidity, or methodological quality. Rates of do-not-intubate orders increased over time from 9% in 2000-2004 to 32% in 2015-2019. Only 12 studies (46%) reported information about do-not-intubate decision-making processes. Only 4 studies (15%) also reported rates of do-not-resuscitate. One in four patients with acute respiratory failure (who receive noninvasive ventilation or high-flow nasal cannula oxygen) has a do-not-intubate order. The rate of do-not-intubate orders has increased over time. There is high inter-study variability in do-not-intubate rates-even when accounting for age and illness severity. There is high variability in patient/family involvement in do-not-intubate decision making processes. Few studies reported differences in rates of do-not-resuscitate and do-not-intubate-even though recovery is very different for acute respiratory failure and cardiac arrest.


Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.
The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.


A review of family donor constructs: current research and future directions.
This review addresses research on gamete donors, recipients, and offspring and demonstrates that the foci on all three within the triad are largely directed at disclosure or anonymity; and each in turn centers on the perceived importance of the genetic link. The importance attached to genetics has led some countries to review the ethics of anonymous gamete donation (e.g. New Zealand's 'open system' of information sharing) and has led other countries (Sweden, Austria, Victoria, Australia; the Netherlands, the UK) to change their laws allowing donor gamete offspring the right to obtain identifying information about their genetic parent. This review demonstrates that genealogical inconsistencies between and within members of the triad are common regardless of legislation. A discussion of future trends and concerns, relating to the use of gamete donation and the effects legislation is likely to have on the donor triads in the UK following 2005, is provided. The review also addresses the importance of testing theoretical models within future research, and argues this would lead to a better understanding of the underlying problems encountered at a psychosocial level, such as continued preference for anonymity in donors and denial in large numbers of users of the involvement of a donor in conception. Lack of disclosure effectively prevents true implementation of legislation; if a child is not informed, it is the result of donated gametes, it cannot take up the legally available option of finding out identifiable information about their genetic parent(s).


TAT-HSP70 Attenuates Experimental Lung Injury.
Sepsis, a poorly understood syndrome of disordered inflammation, is the leading cause of death in critically ill patients. Lung injury, in the form of acute respiratory distress syndrome (ARDS), is the most common form of organ injury in sepsis. The heat shock response, during which heat shock proteins (HSPs) are expressed, is an endogenous mechanism to protect cells from injury. We have found that the abundance of pulmonary HSP70 is not increased after cecal ligation and double puncture (CLP) in a rat model of sepsis-induced ARDS. Using the HIV-1 trans-activator of transcription (TAT) cell-penetrating protein, we enhanced HSP70 protein abundance in the lung. We found that intratracheal administration of HSP70 using the TAT methodology, just after CLP (CLP-TAT-HSP70), when compared with treatment with phosphate buffered saline (CLP-phosphate buffered saline), significantly increased HSP70 abundance in the lung 24 and 48 h after surgery. Treatment of septic rats with TAT-HSP70 increased HSP70 abundance in histologically normal and abnormal lung regions. In addition, TAT-HSP70 treatment significantly decreased the levels of macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractant 1 24 h after CLP. The TAT-HSP70 treatment reduced myeloperoxidase abundance 48 h after CLP and attenuated histological evidence of inflammation at both 24 and 48 h. Administration of TAT-HSP70 also improved 48-h survival in this rat model of sepsis. Thus, intratracheal administration of TAT-HSP70 increased HSP70 abundance in the lung and attenuated the lung injury. Enhancing pulmonary HSP70 using TAT is a novel potential therapeutic strategy for the treatment of ARDS that will be explored further.


Validity of the Falls Risk for Older People in the Community (FROP-Com) tool to predict falls and fall injuries for older people presenting to the emergency department after falling.
The aims of this study were to (1) externally validate the accuracy of the Falls Risk for Older People in the Community (FROP-Com) falls risk assessment tool in predicting falls and (2) undertake initial validation of the accuracy of the FROP-Com to predict injurious falls (requiring medical attention) in people aged ≥ 60 years presenting to emergency departments (EDs) after falling. Two hundred and thirteen participants (mean age = 72.4 years; 59.2% women) were recruited (control group of a randomised controlled trial). A FROP-Com assessment was completed at a home visit within 2 weeks of ED discharge. Data on falls and injurious falls requiring medical attention were collected via monthly falls calendars for the next 12 months. Predictive accuracy was evaluated using sensitivity and specificity of a high-risk FROP-Com classification (score ≥ 19) in predicting a fall and injurious falls requiring medical attention. Fifty per cent of participants fell, with 60.4% of falls requiring medical attention. Thirty-two per cent were classified as high, 49% as moderate and 19% low falls risk. Low sensitivity was achieved for the FROP-Com high-risk classification for predicting falls (43.4%) and injurious falls (34.4%), although specificity was high (79.4% and 78.6%, respectively). Despite the FROP-Com's low predictive accuracy, the high fall rate and high falls risk of the sample suggest that older people who fall, present to ED and are discharged home are at high risk of future falls. In high-falls-risk populations such as in this study, the FROP-Com is not a valid tool for classifying risk of falls or injurious falls. Its potential value may instead be in identifying risk factors for falling to direct tailoring of falls prevention interventions to reduce future falls.


The neurobiology of tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) is a multiorgan genetic disease caused by inactivation of either the TSC1 or TSC2 genes. The disorder typically has profound neurologic involvement and often presents early in life with epilepsy, developmental delay, mental retardation, and autism. These features are generally accepted to result from structural brain abnormalities that are found in patients with TSC. Although much progress has recently been made in discerning the function(s) of the TSC genes, many questions remain as to the role of these genes in brain development and homeostasis. This review will summarize recent progress and suggest future avenues of basic science research.


The molecular basis for wine grape quality--a volatile subject.
Volatile organic compounds are important flavor components of finished wines. In addition to winemaking practices, which shape wine quality, cultivation of the grape berries in the vineyard each season affects the production of volatile organic compounds as well as other chemical components that ultimately contribute to our perception of flavor in finished wines. By studying how berry flavor components are determined by the interplay of vine genotypes, the environment, and cultivation practices at the molecular level, scientists will develop advanced tools and knowledge that will aid viticulturalists in consistently producing balanced, flavorful berries for wine production.


Induction and developmental expression of cytochrome P450IA1 messenger RNA in rat and human tissues: detection by the polymerase chain reaction.
The expression of cytochrome P450 genes directly within target cells is an important determinant of human susceptibility to cancers, birth defects, and other chemically initiated diseases. One pivotal gene, CYP1A1, codes for an inducible cytochrome P450 isozyme (P450IA1) responsible for the bioactivation of numerous carcinogenic polycyclic hydrocarbons and aromatic amines. In this study, we used the polymerase chain reaction (PCR) to amplify endogenous P450IA1 mRNA transcripts in a variety of human and rat tissues from different stages of development. The PCR approach greatly enhanced detection sensitivities over those previously achieved and permitted characterization of constitutive as well as induced P450IA1 mRNA expression patterns in specific cell types and organs and during early gestational stages. P450IA1 mRNAs are expressed constitutively in the rat as early as day 15 of fetal liver development and increased in level with increasing developmental age. Transplacental treatment of fetal rats with 3-methylcholanthrene resulted in marked increases in P450IA1 mRNA levels, and responsiveness to the inducer also increased in concordance with developmental age. Comparatively lower constitutive and induced levels of the mRNA were detected in rat lung and kidney, but no P450IA1 mRNA was detected in the rat testis. PCR results obtained from experiments with human tissue samples demonstrated the presence of P450IA1 transcripts in whole organs, in purified cell fractions (lymphocytes, macrophages), and in fetuses as early as day 45 of human gestation. Data from cell culture studies indicated markedly higher levels of P450IA1 PCR product in human pulmonary alveolar macrophages following treatment with the inducing agent beta-naphthoflavone. These results underscore the potential role of P450IA1 as a key determinant of individual susceptibility to tissue-specific and developmentally related cancers associated with certain environmental chemical exposures.


FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.


Functional comparison between the BuMA Supreme biodegradable polymer sirolimus-eluting stent and a durable polymer zotarolimus-eluting coronary stent using quantitative flow ratio: PIONEER QFR substudy.
Quantitative flow ratio (QFR) based on three-dimensional quantitative coronary angiography (3D-QCA) is a novel method to assess physiological functionality after treatment with stents. The current study aimed to evaluate the difference in physiological functionality nine months after implantation of a bioresorbable polymer-based sirolimus-eluting stent with an electrografting base layer (BuMA Supreme: B-SES) versus a durable polymer-based zotarolimus-eluting stent (Resolute: R-ZES). The current post hoc analysis was performed in the PIONEER randomised trial (1:1 randomisation to B-SES [83 patients/95 lesions] and R-ZES [87 patients/101 lesions]). QFR was measured in stented vessels in both arms at preprocedural, post-procedural and nine-month angiography without pharmacologically induced hyperaemia (contrast QFR). At nine months, both the values of QFR distal to the stent (B-SES: 0.89±0.10 vs. R-ZES: 0.89±0.11, p=0.97) and the number of vessels with QFR ≤0.8 were not significantly different between the two groups (11.0% vs. 12.8%, p=0.72), while the in-stent binary restenosis rate was also comparable (3.7% vs. 3.5%, p=1.00). QFR gradient across the device (∆QFR) at nine months was also similar between the groups (B-SES: 0.03±0.04 vs. R-ZES: 0.03±0.07, p=0.95). Quantitative flow assessment nine months after stenting did not differ between B-SES and R-ZES, despite a significant difference in in-stent late lumen loss.


On potential interactions between non-selective cation channel TRPM4 and sulfonylurea receptor SUR1.
The sulfonylurea receptor SUR1 associates with Kir6.2 or Kir6.1 to form K(ATP) channels, which link metabolism to excitability in multiple cell types. The strong physical coupling of SUR1 with Kir6 subunits appears exclusive, but recent studies argue that SUR1 also modulates TRPM4, a member of the transient receptor potential family of non-selective cation channels. It has been reported that, following stroke, brain, or spinal cord injury, SUR1 is increased in neurovascular cells at the site of injury. This is accompanied by up-regulation of a non-selective cation conductance with TRPM4-like properties and apparently sensitive to sulfonylureas, leading to the postulation that post-traumatic non-selective cation currents are determined by TRPM4/SUR1 channels. To investigate the mechanistic hypothesis for the coupling between TRPM4 and SUR1, we performed electrophysiological and FRET studies in COSm6 cells expressing TRPM4 channels with or without SUR1. TRPM4-mediated currents were Ca(2+)-activated, voltage-dependent, underwent desensitization, and were inhibited by ATP but were insensitive to glibenclamide and tolbutamide. These properties were not affected by cotransfection with SUR1. When the same SUR1 was cotransfected with Kir6.2, functional K(ATP) channels were formed. In cells cotransfected with Kir6.2, SUR1, and TRPM4, we measured K(ATP)-mediated K(+) currents and Ca(2+)-activated, sulfonylurea-insensitive Na(+) currents in the same patch, further showing that SUR1 controls K(ATP) channel activity but not TRPM4 channels. FRET signal between fluorophore-tagged TRPM4 subunits was similar to that between Kir6.2 and SUR1, whereas there was no detectable FRET efficiency between TRPM4 and SUR1. Our data suggest that functional or structural association of TRPM4 and SUR1 is unlikely.


Cognitive functioning in chronic fatigue syndrome: a meta-analysis.
Cognitive problems are commonly reported in persons with chronic fatigue syndrome (CFS) and are one of the most disabling symptoms of this condition. A number of cognitive deficits have been identified, although the findings are inconsistent and hindered by methodological differences. The current study therefore conducted a meta-analysis of research examining cognitive functioning in persons with CFS in order to identify the pattern and magnitude of any deficits that are associated with this condition. A comprehensive search of the PubMed and PsycINFO databases for studies that examined cognitive functioning in CFS between 1988 and 2008 identified 50 eligible studies. Weighted Cohen's d effect sizes, 95% confidence intervals and fail-safe Ns were calculated for each cognitive score. Evidence of cognitive deficits in persons with CFS was found primarily in the domains of attention, memory and reaction time. Deficits were not apparent on tests of fine motor speed, vocabulary, reasoning and global functioning. Persons with CFS demonstrate moderate to large impairments in simple and complex information processing speed and in tasks requiring working memory over a sustained period of time.


Effect of Palliative Care-Led Meetings for Families of Patients With Chronic Critical Illness: A Randomized Clinical Trial.
Family caregivers of patients with chronic critical illness experience significant psychological distress. To determine whether family informational and emotional support meetings led by palliative care clinicians improve family anxiety and depression. A multicenter randomized clinical trial conducted from October 2010 through November 2014 in 4 medical intensive care units (ICUs). Adult patients (aged ≥21 years) requiring 7 days of mechanical ventilation were randomized and their family surrogate decision makers were enrolled in the study. Observers were blinded to group allocation for the measurement of the primary outcomes. At least 2 structured family meetings led by palliative care specialists and provision of an informational brochure (intervention) compared with provision of an informational brochure and routine family meetings conducted by ICU teams (control). There were 130 patients with 184 family surrogate decision makers in the intervention group and 126 patients with 181 family surrogate decision makers in the control group. The primary outcome was Hospital Anxiety and Depression Scale symptom score (HADS; score range, 0 [best] to 42 [worst]; minimal clinically important difference, 1.5) obtained during 3-month follow-up interviews with the surrogate decision makers. Secondary outcomes included posttraumatic stress disorder experienced by the family and measured by the Impact of Events Scale-Revised (IES-R; total score range, 0 [best] to 88 [worst]), discussion of patient preferences, hospital length of stay, and 90-day survival. Among 365 family surrogate decision makers (mean age, 51 years; 71% female), 312 completed the study. At 3 months, there was no significant difference in anxiety and depression symptoms between surrogate decision makers in the intervention group and the control group (adjusted mean HADS score, 12.2 vs 11.4, respectively; between-group difference, 0.8 [95% CI, -0.9 to 2.6]; P = .34). Posttraumatic stress disorder symptoms were higher in the intervention group (adjusted mean IES-R score, 25.9) compared with the control group (adjusted mean IES-R score, 21.3) (between-group difference, 4.60 [95% CI, 0.01 to 9.10]; P = .0495). There was no difference between groups regarding the discussion of patient preferences (intervention, 75%; control, 83%; odds ratio, 0.63 [95% CI, 0.34 to 1.16; P = .14]). The median number of hospital days for patients in the intervention vs the control group (19 days vs 23 days, respectively; between-group difference, -4 days [95% CI, -6 to 3 days]; P = .51) and 90-day survival (hazard ratio, 0.95 [95% CI, 0.65 to 1.38], P = .96) were not significantly different. Among families of patients with chronic critical illness, the use of palliative care-led informational and emotional support meetings compared with usual care did not reduce anxiety or depression symptoms and may have increased posttraumatic stress disorder symptoms. These findings do not support routine or mandatory palliative care-led discussion of goals of care for all families of patients with chronic critical illness. clinicaltrials.gov Identifier: NCT01230099.


Variability and dilemmas in harm reduction for anabolic steroid users in the UK: a multi-area interview study.
The UK continues to experience a rise in the number of anabolic steroid-using clients attending harm reduction services such as needle and syringe programmes. The present study uses interviews conducted with harm reduction service providers as well as illicit users of anabolic steroids from different areas of England and Wales to explore harm reduction for this group of drug users, focussing on needle distribution policies and harm reduction interventions developed specifically for this population of drug users. The article addresses the complexity of harm reduction service delivery, highlighting different models of needle distribution, such as peer-led distribution networks, as well as interventions available in steroid clinics, including liver function testing of anabolic steroid users. Aside from providing insights into the function of interventions available to steroid users, along with principles adopted by service providers, the study found significant tensions and dilemmas in policy implementation due to differing perspectives between service providers and service users relating to practices, risks and effective interventions. The overarching finding of the study was the tremendous variability across harm reduction delivery sites in terms of available measures and mode of operation. Further research into the effectiveness of different policies directed towards people who use anabolic steroids is critical to the development of harm reduction.


The p40/ARPC1 subunit of Arp2/3 complex performs multiple essential roles in WASp-regulated actin nucleation.
The Arp2/3 complex is a conserved seven-subunit actin-nucleating machine activated by WASp (Wiskott Aldrich syndrome protein). Despite its central importance in a broad range of cellular processes, many critical aspects of the mechanism of the Arp2/3 complex have yet to be resolved. In particular, some of the individual subunits in the complex have not been assigned clear functional roles, including p40/ARPC1. Here, we dissected the structure and function of Saccharomyces cerevisiae p40/ARPC1, which is encoded by the essential ARC40 gene, by analyzing 39 integrated alleles that target its conserved surfaces. We identified three distinct sites on p40/ARPC1 required for function in vivo: one site contacts p19/ARPC4, one contacts p15/ARPC5, and one site resides in an extended structural "arm" of p40/ARPC1. Using a novel strategy, we purified the corresponding lethal mutant Arp2/3 complexes from yeast and compared their actin nucleation activities. Lethal mutations at the contact with p19/ARPC4 specifically impaired WASp-induced nucleation. In contrast, lethal mutations at the contact with p15/ARPC5 led to unregulated ("leaky") nucleation in the absence of WASp. Lethal mutations in the extended arm drastically reduced nucleation, and the same mutations disrupted the ability of the purified p40/ARPC1 arm domain to bind the VCA domain of WASp. Together, these data indicate that p40/ARPC1 performs at least three distinct, essential functions in regulating Arp2/3 complex-mediated actin assembly: 1) suppression of spontaneous nucleation by the Arp2/3 complex, which requires proper contacts with p15/ARPC5; 2) propagation of WASp activation signals via contacts with p19/ARPC2; and 3) direct facilitation of actin nucleation through interactions of the extended arm with the VCA domain of WASp.


Hip fracture rates in South Australia: into the next century.
Fractures of the femoral neck already represent a major public health problem in Australia. This situation is set to worsen as the population ages. The present study estimates the number of patients over 50 years of age with femoral neck fractures that is expected to impact on the South Australian healthcare service into the next century. Population projections from the Australian Bureau of Statistics 1996 census were combined with age- and gender-specific incidence rates for fractures of the femoral neck for persons over the age of 50 in South Australia. Projections for the expected number of hip fractures in this State were then calculated. Assuming there are no changes in the age- and gender-specific incidence of fracture rates, the number of fractures in South Australia is estimated to increase by approximately 66% by the year 2021 and 190% by 2051. Based on the population projections and the assumption that conditions contributing to hip fractures remain constant, the number of fractured neck of femurs will increase in far greater proportion than the overall population in the next century. The results of the present study indicate the serious implications for the South Australian healthcare system if there is no reduction in incidence rates.


Human iPSC-derived hepatocyte-like cells support Plasmodium liver-stage infection in vitro.
Malaria eradication is a major goal in public health but is challenged by relapsing malaria species, expanding drug resistance, and the influence of host genetics on antimalarial drug efficacy. To overcome these hurdles, it is imperative to establish in vitro assays of liver-stage malaria for drug testing. Induced pluripotent stem cells (iPSC) potentially allow the assessment of donor-specific drug responses, and iPSC-derived hepatocyte-like cells (iHLCs) can facilitate the study of host genetics on host-pathogen interactions and the discovery of novel targets for antimalarial drug development. We establish in vitro liver-stage malaria infections in iHLCs using P. berghei, P. yoelii, P. falciparum, and P. vivax and show that differentiating cells acquire permissiveness to malaria infection at the hepatoblast stage. We also characterize antimalarial drug metabolism capabilities of iHLCs using prototypical antimalarial drugs and demonstrate that chemical maturation of iHLCs can improve their potential for antimalarial drug testing applications.


Association between Dietary Patterns and Cardiovascular Risk Factors among Middle-Aged and Elderly Adults in Taiwan: A Population-Based Study from 2003 to 2012.
Cardiovascular disease (CVD) is one of the leading causes of mortality and loss of disability-adjusted life years in developed countries. This study derived a dietary pattern using an a priori method and additionally derived dietary patterns using a posteriori methods, and assessed the relationship with CVD risk factors in Taiwanese middle-aged and elderly adults. Cross-sectional analyses of 62,965 subjects aged 40 years and above from the Mei Jau (MJ) database collected between 2003 and 2012 in Taiwan. Diet was assessed using a 22 item semi-quantitative food frequency questionnaire. Using this information, three dietary patterns were generated. The a priori diet was labeled the Taiwanese dietary pattern and was derived using hypothesized effect of 22 food groups, while two a posteriori dietary patterns, "vegi-fruits" and "meat-processed", were derived using principal component analysis. The association between dietary patterns and a range of CVD risk factors (i.e. blood lipids, blood glucose and C-reactive protein) was evaluated using linear regression. The results showed that high intake (Q5, quintile 5) of Taiwanese diet was negatively associated with CVD risk factors at (p < 0.001, model 3), but not with triacylglycerol. In addition, high intake of vegi-fruit dietary pattern (Q5) was negatively associated with CVD risk factors (p < 0.001), but not with high-density lipoprotein, while high consumption of meat-processed dietary pattern (Q5) was positively associated with CVD risk factors (p < 0.001), but negatively related with triacylglycerol in Q3 level and no association with C-reactive protein. A negative association was observed between Taiwanese or vegi-fruit dietary patterns and CVD risk factors, while a positive association was found between meat-processed dietary pattern and CVD risk factors. The findings suggested that a diet rich in vegetables and fruits has a beneficial effect in the management of CVD risk factors.


Multi-model inference of non-random mating from an information theoretic approach.
Non-random mating has a significant impact on the evolution of organisms. Here, I developed a modelling framework for discrete traits (with any number of phenotypes) to explore different models connecting the non-random mating causes (mate competition and/or mate choice) and their consequences (sexual selection and/or assortative mating). I derived the formulaefor the maximum likelihood estimates of each model and used information criteria to perform multi-model inference. Simulation results showed a good performance of both model selection and parameter estimation. The methodology was applied to ecotypes data of the marine gastropod Littorina saxatilis from Galicia (Spain), to show that the mating pattern is better described by models with two parameters that involve both mate choice and competition, generating positive assortative mating plus female sexual selection. As far as I know, this is the first standardized methodology for model selection and multi-model inference of mating parameters for discrete traits. The advantages of this framework include the ability of setting up models from which the parameters connect causes, as mate competition and mate choice, with their outcome in the form of data patterns of sexual selection and assortative mating. For some models, the parameters may have a double effect i.e. they produce sexual selection and assortative mating, while for others there are separated parameters for one kind of pattern or another. From an empirical point of view, it is much easier to study patterns than processes and, for this reason, the causal mechanisms of sexual selection are not so well known as the patterns they produce. The goal of the present work is to propose a new tool that helps to distinguish among different alternative processes behind the observed mating pattern. The full methodology was implemented in a software called InfoMating (available at http://acraaj.webs6.uvigo.es/InfoMating/Infomating.htm).


Infectious human papillomavirus type 18 pseudovirions.
Human papillomavirus type 18 (HPV18) capsid proteins L1 and L2, synthesised in mammalian cells using recombinant vaccinia viral expression vectors, are transported to the nucleus and assembled into virus-like particles. When 293T cells, which express SV40 T antigen, were transfected with plasmid DNAs containing an SV40 origin of replication then infected with vaccinia viral vectors encoding L1 and L2, plasmid DNA was encapsidated into the particles. The DNAs ranged in size from 5.4 to 7.9 kb. By encapsidating plasmids containing either the beta-galactosidase gene or the puromycin-resistance gene, the pseudovirions were shown to be infectious in that they could transfer beta-galactosidase activity or confer resistance to puromycin to a number of cell types, indicating that the uptake and decapsidation of HPV particles are not the main determinants of cell type specificity of HPV. Episomal HPV16 DNA in a cervical keratinocyte line could also be encapsidated. Further investigation showed that DNA encapsidation is independent of HPV DNA sequences and of T antigen-mediated plasmid DNA replication. Instead, the minor capsid protein, L2, was found to be attached to plasmid mini-chromosomes extracted from these cells, suggesting a role for L2 in encapsidation. Consistent with this, the L1 protein alone was unable to encapsidate DNA, although it was able to form virus-like particles. The results suggest that intracellular episomal DNAs of suitable size can be encapsidated by the HPV18 L1 and L2 proteins without the need of any HPV packaging signal, and reintroduced into cells.


Prevalence of high-risk indications for influenza vaccine varies by age, race, and income.
Estimates of the proportions of the population who are at high risk of influenza complications because of prior health status or who are likely to have decreased vaccination response because of immunocompromising conditions would enhance public health planning and model-based projections. We estimate these proportions and how they vary by population subgroups using national data systems for 2006-2008. The proportion of individuals at increased risk of influenza complications because of health conditions varied 10-fold by age (4.2% of children <2 years to 47% of individuals >64 years). Age-specific prevalence differed substantially by gender, by racial/ethnic groups (with African Americans highest in all age groups) and by income. Individuals living in families with less than 200% of federal poverty level (FPL) were significantly more likely to have at least one of these health conditions, compared to individuals with 400% FPL or more (3-fold greater among <2 and 30% greater among >64 years). Among children, there were significantly elevated proportions in all regions compared to the West. The estimated prevalence of immunocompromising conditions ranged from 0.02% in young children to 6.14% older adults. However, national data on race/ethnicity and income are not available for most immunocompromising conditions, nor is it possible to fully identify the degree of overlap between persons with high-risk health conditions and with immunocompromising conditions. Modifications to current national data collection systems would enhance the value of these data for public health programs and influenza modeling.


An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations.
Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163-75. ©2018 AACR.


Avian hosts of St. Louis encephalitis virus in Pine Bluff, Arkansas, 1991.
An investigation of the extent of St. Louis encephalitis (SLE) virus activity in the avian population in Pine Bluff, Arkansas was conducted from August 30, 1991 through September 5, 1991, following an SLE epidemic that resulted in 25 human cases. A total of 363 birds of 33 species were captured with ground-level mist nets at four sites along the northern edge of the city. No viruses were isolated from the serum of these birds, but 91 birds (25%) of 11 species had detectable neutralizing antibody against the TBH-28 strain of SLE virus in the constant-virus, serum-dilution, plaque-reduction neutralization test in Vero cell culture. No antibody to eastern equine encephalitis virus was detected. The prevalence of antibody to SLE virus varied among the sites from 11% to 44%, but the prevalence at each site was influenced by the avian species composition. The two most abundant species captured in the city, the American robin (43%) and house sparrow (42%), also had the highest prevalence of antibody. Nine other bird species were serologically positive but at significantly lower rates than for the abundant species. The antibody prevalence was higher in immature birds (27%) than in adult birds (15%), but the antibody titers were higher in adult birds than in immature ones. The overall SLE antibody prevalence and the prevalence for house sparrows were significantly higher than the average prevalence for avian hosts studied during previous SLE epidemics. Therefore, house sparrows would be a good choice for a local sentinel species.


Investigating the Role of Working Memory in Speech-in-noise Identification for Listeners with Normal Hearing.
With the advent of cognitive hearing science, increased attention has been given to individual differences in cognitive functioning and their explanatory power in accounting for inter-listener variability in understanding speech in noise (SiN). The psychological construct that has received most interest is working memory (WM), representing the ability to simultaneously store and process information. Common lore and theoretical models assume that WM-based processes subtend speech processing in adverse perceptual conditions, such as those associated with hearing loss or background noise. Empirical evidence confirms the association between WM capacity (WMC) and SiN identification in older hearing-impaired listeners. To assess whether WMC also plays a role when listeners without hearing loss process speech in acoustically adverse conditions, we surveyed published and unpublished studies in which the Reading-Span test (a widely used measure of WMC) was administered in conjunction with a measure of SiN identification. The survey revealed little or no evidence for an association between WMC and SiN performance. We also analysed new data from 132 normal-hearing participants sampled from across the adult lifespan (18-91 years), for a relationship between Reading-Span scores and identification of matrix sentences in noise. Performance on both tasks declined with age, and correlated weakly even after controlling for the effects of age and audibility (r = 0.39, p ≤ 0.001, one-tailed). However, separate analyses for different age groups revealed that the correlation was only significant for middle-aged and older groups but not for the young (< 40 years) participants.


The use of a monitoring tool to assess counselling and HIV testing in the public health sector in Malawi.
Scaling up of counselling and HIV testing (VCT) services requires a system of regular monitoring and evaluation. AVCT monitoring tool was developed through a consultative process and used to assess counselling and HIV testing services in 16 government and mission hospitals in Malawi, which had started expanded HIV-TB activities in July 2003. The essential components of theVCT monitoring tool included assessments of: (i) the hospital VCT personnel, in particular the number of counsellors (full-time and part-time) and those trained in and performing whole blood rapid HIV testing; (ii) the hospital laboratory service, in particular the protocols for HIV testing; (iii) the number, structure and function of dedicated VCT rooms; (iv) registers for patients, clients and donors having HIV tests; and (v) the quality of VCT through structured interviews with HIV-positive patients with TB. The main findings were: 9644 patients and clients were HIV tested between July and September 2003; HIV testing protocols were not standardized and differed between hospitals; there was little in the way of external quality assurance and there were deficiencies in the counselling process. In each hospital, the mean time taken to obtain the data and complete theVCT monitoring tool was 3 h. TheVCT monitoring tool is straightforward to use, and the data collected should help to improve standardization, quality and future planning of VCT services in the country.


Differential Effects of Silibinin A on Mitochondrial Function in Neuronal PC12 and HepG2 Liver Cells.
The Mediterranean plant Silybum marianum L., commonly known as milk thistle, has been used for centuries to treat liver disorders. The flavonolignan silibinin represents a natural antioxidant and the main bioactive ingredient of silymarin (silybin), a standard extract of its seeds. Mitochondrial dysfunction and the associated generation of reactive oxygen/nitrogen species (ROS/RNS) are involved in the development of chronic liver and age-related neurodegenerative diseases. Silibinin A (SIL A) is one of two diastereomers found in silymarin and was used to evaluate the effects of silymarin on mitochondrial parameters including mitochondrial membrane potential and ATP production with and without sodium nitroprusside- (SNP-) induced nitrosative stress, oxidative phosphorylation, and citrate synthase activity in HepG2 and PC12 cells. Both cell lines were influenced by SIL A, but at different concentrations. SIL A significantly weakened nitrosative stress in both cell lines. Low concentrations not only maintained protective properties but also increased basal mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. However, these effects could not be associated with oxidative phosphorylation. On the other side, high concentrations of SIL A significantly decreased MMP and ATP levels. Although SIL A did not provide a general improvement of the mitochondrial function, our findings show that SIL A protects against SNP-induced nitrosative stress at the level of mitochondria making it potentially beneficial against neurological disorders.


Location of sternal fractures as a possible marker for associated injuries.
Introduction. Sternal fractures often occur together with serious and life-threatening additional injuries. This retrospective study was designed to assess concomitant injuries and develop a correlation between fracture location and the severity of injury. Methods. All patients (n = 58) diagnosed with a fracture of the sternum by means of a CT scan were analysed with respect to accident circumstances, fracture morphology and topography, associated injuries, and outcome. Results. Isolated sternal fractures occurred in 9%. In all other admissions, concomitant injuries were diagnosed: mainly rip fractures (64%), injury to the head (48%), the thoracic spine (38%), lumbar spine (27%), and cervical spine (22%). Predominant fracture location was the manubrium sterni. In these locations, the observed mean ISS was the highest. They were strongly associated with thoracic spine and other chest injuries. Furthermore, the incidence of head injuries was significantly higher. ICU admission was significantly higher in patients with manubrium sterni fractures. Conclusion. Sternal fractures are frequently associated with other injuries. It appears that the fracture location can provide important information regarding concomitant injuries. In particular, in fractures of manubrium sterni, the need for further detailed clinical and radiologic workup is necessary to detect the frequently associated injuries and reduce the increased mortality.


Noncoding SNPs influence a distinct phase of Polycomb silencing to destabilize long-term epigenetic memory at Arabidopsis FLC.
In Arabidopsis thaliana, the cold-induced epigenetic regulation of FLOWERING LOCUS C (FLC) involves distinct phases of Polycomb repressive complex 2 (PRC2) silencing. During cold, a PHD-PRC2 complex metastably and digitally nucleates H3K27me3 within FLC On return to warm, PHD-PRC2 spreads across the locus delivering H3K27me3 to maintain long-term silencing. Here, we studied natural variation in this process in Arabidopsis accessions, exploring Lov-1, which shows FLC reactivation on return to warm, a feature characteristic of FLC in perennial Brassicaceae This analysis identifies an additional phase in this Polycomb silencing mechanism downstream from H3K27me3 spreading. In this long-term silencing (perpetuated) phase, the PHD proteins are lost from the nucleation region and silencing is likely maintained by the read-write feedbacks associated with H3K27me3. A combination of noncoding SNPs in the nucleation region mediates instability in this long-term silencing phase with the result that Lov-1 FLC frequently digitally reactivates in individual cells, with a probability that diminishes with increasing cold duration. We propose that this decrease in reactivation probability is due to reduced DNA replication after flowering. Overall, this work defines an additional phase in the Polycomb mechanism instrumental in natural variation of silencing, and provides avenues to dissect broader evolutionary changes at FLC.


Will We Do If We Can? Habitual Qualitative and Quantitative Physical Activity in Multi-Morbid, Older Persons with Cognitive Impairment.
This study aimed to identify determinants of quantitative dimensions of physical activity (PA; duration, frequency, and intensity) in community-dwelling, multi-morbid, older persons with cognitive impairment (CI). In addition, qualitative and quantitative aspects of habitual PA have been described. Quantitative PA and qualitative gait characteristics while walking straight and while walking turns were documented by a validated, sensor-based activity monitor. Univariate and multiple linear regression analyses were performed to delineate associations of quantitative PA dimensions with qualitative characteristics of gait performance and further potential influencing factors (motor capacity measures, demographic, and health-related parameters). In 94 multi-morbid, older adults (82.3 ± 5.9 years) with CI (Mini-Mental State Examination score: 23.3 ± 2.4), analyses of quantitative and qualitative PA documented highly inactive behavior (89.6% inactivity) and a high incidence of gait deficits, respectively. The multiple regression models (adjusted R2 = 0.395-0.679, all p < 0.001) identified specific qualitative gait characteristics as independent determinants for all quantitative PA dimensions, whereas motor capacity was an independent determinant only for the PA dimension duration. Demographic and health-related parameters were not identified as independent determinants. High associations between innovative, qualitative, and established, quantitative PA performances may suggest gait quality as a potential target to increase quantity of PA in multi-morbid, older persons.


Ursodeoxycholic acid reduces lipid peroxidation and mucin secretagogue activity in gallbladder bile of patients with cholesterol gallstones.
Recently it has been postulated that gallbladder mucin hypersecretion observed in the pathogenesis of cholesterol gallstone disease may be induced by biliary lipid peroxidation. Ursodeoxycholic acid treatment reduces mucin concentration and the formation of cholesterol crystals in the gallbladder bile of patients with cholesterol gallstones and this effect might be mediated by a decrease of biliary lipid peroxidation. In a double-blind, placebo-controlled trial patients with symptomatic cholesterol gallstones received either ursodeoxycholic acid (750 mg daily) (n = 10) or placebo (n = 12) 10-12 days prior to cholecystectomy. As a marker for lipid peroxidation malondialdehyde was measured in bile together with mucin concentration. In addition, the mucin secretagogue activity of the individual bile samples was assessed in cultured dog gallbladder epithelial cells. Ursodeoxycholic acid therapy resulted in a significant reduction of lipid peroxidation in bile as determined by the biliary malondialdehyde concentration (1.36 +/- 0.28 vs. 2.05 +/- 0.38 micromol L(-1); P < 0.005) and the malondialdehyde (micromol L(-1))/total bile acid (mmol L(-1)) ratio (0.02 +/- 0.005 vs. 0.06 +/- 0.01; P < 0.001). Furthermore, a decrease in mucin concentrations (0.7 +/- 0.3 vs. 1.3 +/- 0.5 mg mL(-1); P < 0.005) and of the mucin secretagogue activity of gallbladder bile (0.9 +/- 0.2 vs. 2.2 +/- 0.3 times control; P < 0.001) was observed. The reduction of lipid peroxidation and mucin secretagogue activity of gallbladder bile induced by ursodeoxycholic acid treatment may contribute to the beneficial effects of this drug on gallbladder bile composition and symptoms in cholesterol gallstone patients.


The Criminal Narrative Experience of Psychopathic and Personality Disordered Offenders.
Given the challenges associated with psychopathic and personality disordered offenders, further insight is needed. One way of doing this is by looking at offending from the first-person perspective. The study investigated the criminal narrative experience (CNE) of this population during the commissioning of crimes. Twenty-two high-risk male offenders were recruited and a questionnaire design was used. The data were analysed using Smallest Space Analysis which revealed four themes consistent with Ioannou, Canter, and Youngs's CNE framework: depressed victim, distressed revenger, calm professional, and elated hero. Independent samples t tests explored whether personality disorders related to CNE themes, and Pearson's product-moment correlation was used to explore the relationship between psychopathy and the CNE themes. Borderline personality disorder identified with the depressed victim. Paranoid and schizoid personality disorders did not identify with the calm professional. There was no significant relationship between psychopathy and the CNE themes. The theoretical and practical implications are discussed.


The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics.
RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology.


Rhodium-catalyzed [3 + 2] annulation of indoles.
An effective Rh(2)(S-DOSP)(4)-catalyzed asymmetric cyclopentannulation of indolyl rings has been developed. Depending on the substitution pattern of the indole, two distinct regioisomeric products can be generated. These studies demonstrate that rhodium-catalyzed reactions of donor/acceptor carbenoids proceeding by means of zwitterionic intermediates can be carried out with very high asymmetric induction.


Occlusion of the HIV poly(A) site.
To investigate the selective use of poly(A) sites in the 3' long terminal repeat (LTR) but not the 5' LTR of retroviruses, we have studied the poly(A) site of the human immunodeficiency virus (HIV-1). Using hybrid HIV/alpha-globin gene constructs, we demonstrate that the HIV poly(A) site is inactive or occluded when adjacent to an active promoter, either the homologous HIV promoter or the alpha-globin gene promoter. Furthermore, this occlusion of the HIV poly(A) site occurs over a considerable distance of up to at least 500 bp. In contrast, two nonretroviral poly(A) sites [alpha-globin and a synthetic poly(A) site] are active when close to a promoter. We also show that a short fragment of approximately 60 nucleotides containing the HIV poly(A) site is fully active when placed at the 3' end of the human alpha-globin gene or within the rabbit beta-globin gene. This result rules out the requirement of more distant upstream elements for the activity of the HIV poly(A) site, as has been suggested for other viral poly(A) sites. Finally, we show that the GT-rich downstream region of the HIV poly(A) site confers poly(A) site occlusion properties on a synthetic poly(A) site. This result focuses attention on this more variable part of a poly(A) site in retroviruses as a possible general signal for poly(A) site occlusion.