Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a significant prognostic factor affecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition by trafficking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance, gastrointestinal bleeding, ascites, inflammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively difficult to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids, antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional status, liver function, and hepatic encephalopathy in patients with end-stage liver failure.


Ontologies to improve chronic disease management research and quality improvement studies - a conceptual framework.
There is a growing burden of chronic non-communicable disease (CNCD). Managing CNCDs requires use of multiple sources of health and social care data, and information about coordination and outcomes. Many people with CNCDs have multimorbidity. Problems with data quality exacerbate challenges in measuring quality and health outcomes especially where there is multimorbidity. We have developed an ontological toolkit to support research and quality improvement studies in CNCDs using heterogeneous data, with diabetes mellitus as an exemplar. International experts held a workshop meeting, with follow up discussions and consensus building exercise. We generated conceptual statements about problems with a CNCD that ontologies might support, and a generic reference model. There were varying degrees of consensus. We propose a set of tools, and a four step method: (1) Identification and specification of data sources; (2) Conceptualisation of semantic meaning; (3) How available routine data can be used as a measure of the process or outcome of care; (4) Formalisation and validation of the final ontology.


The effectiveness of screening for diabetes and cardiovascular disease risk factors in a community pharmacy setting.
Risk factors for cardiovascular disease including diabetes have seen a large rise in prevalence in recent years. This has prompted interest in prevention through the identifying individuals at risk of both diabetes and cardiovascular disease and has seen increased investment in screening interventions taking place in primary care. Community pharmacies have become increasingly involved in the provision of such interventions and this systematic review and meta-analysis aims to gather and analyse the existing literature assessing community pharmacy based screening for risk factors for diabetes and those with a high cardiovascular disease risk. We conducted systematic searches of electronic databases using MeSH and free text terms from 1950 to March 2012. For our analysis two outcomes were assessed. They were the percentage of those screened who were referred for further assessment by primary care and the uptake of this referral. Sixteen studies fulfilled our inclusion criteria comprising 108,414 participants screened. There was significant heterogeneity for all included outcomes. Consequently we have not presented summary statistics and present forest plots with I2 and p values to describe heterogeneity. We found that all included studies suffered from high rates of attrition between pharmacy screening and follow up. We have also identified a strong trend towards higher rates for referral in more recent studies. Our results show that pharmacies are feasible sites for screening for diabetes and those at risk of cardiovascular disease. A significant number of previously unknown cases of cardiovascular disease risk factors such as hypertension, hypercholesterolemia and diabetes are identified, however a significant number of referred participants at high risk do not attend their practitioner for follow up. Research priorities should include methods of increasing uptake to follow up testing and early intervention, to maximise the efficacy of screening interventions based in community pharmacies.


Exaggerations and Caveats in Press Releases and Health-Related Science News.
Exaggerated or simplistic news is often blamed for adversely influencing public health. However, recent findings suggested many exaggerations were already present in university press releases, which scientists approve. Surprisingly, these exaggerations were not associated with more news coverage. Here we test whether these two controversial results also arise in press releases from prominent science and medical journals. We then investigate the influence of mitigating caveats in press releases, to test assumptions that caveats harm news interest or are ignored. Using quantitative content analysis, we analyzed press releases (N = 534) on biomedical and health-related science issued by leading peer-reviewed journals. We similarly analysed the associated peer-reviewed papers (N = 534) and news stories (N = 582). Main outcome measures were advice to readers and causal statements drawn from correlational research. Exaggerations in press releases predicted exaggerations in news (odds ratios 2.4 and 10.9, 95% CIs 1.3 to 4.5 and 3.9 to 30.1) but were not associated with increased news coverage, consistent with previous findings. Combining datasets from universities and journals (996 press releases, 1250 news), we found that when caveats appeared in press releases there was no reduction in journalistic uptake, but there was a clear increase in caveats in news (odds ratios 9.6 and 9.5 for caveats for advice and causal claims, CIs 4.1 to 24.3 and 6.0 to 15.2). The main study limitation is its retrospective correlational nature. For health and science news directly inspired by press releases, the main source of both exaggerations and caveats appears to be the press release itself. However we find no evidence that exaggerations increase, or caveats decrease, the likelihood of news coverage. These findings should be encouraging for press officers and scientists who wish to minimise exaggeration and include caveats in their press releases.


Blunt cerebrovascular injury practice management guidelines: the Eastern Association for the Surgery of Trauma.
Blunt injury to the carotid or vertebral vessels (blunt cerebrovascular injury [BCVI]) is diagnosed in approximately 1 of 1,000 (0.1%) patients hospitalized for trauma in the United States with the majority of these injuries diagnosed after the development of symptoms secondary to central nervous system ischemia, with a resultant neurologic morbidity of up to 80% and associated mortality of up to 40%. With screening, the incidence rises to 1% of all blunt trauma patients and as high as 2.7% in patients with an Injury Severity Score of >or=16. The Eastern Association for the Surgery of Trauma organization Practice Management Guidelines committee set out to develop an EBM guideline for the screening, diagnosis, and treatment of BCVI. A computerized search of the National Library of Medicine/National Institute of Health, Medline database was performed using citations from 1965 to 2005 inclusive. Titles and abstracts were reviewed to determine relevance, and isolated case reports, small case series, editorials, letters to the editor, and review articles were eliminated. The bibliographies of the resulting full-text articles were searched for other relevant citations, and these were obtained as needed. These papers were reviewed based on the following questions: 1. What patients are of high enough risk, so that diagnostic evaluation should be pursued for the screening and diagnosis of BCVI? 2. What is the appropriate modality for the screening and diagnosis of BCVI? 3. How should BCVI be treated? 4. If indicated, for how long should antithrombotic therapy be administered? 5. How should one monitor the response to therapy? One hundred seventy-nine articles were selected for review, and of these, 68 met inclusion criteria and are excerpted in the attached evidentiary table and used to make recommendations. The East Practice Management Guidelines Committee suggests guidelines that should be safe and efficacious for the screening, diagnosis, and treatment of BCVI. Risk factors for screening are identified (see ), screening modalities are reviewed indicating that although angiography remains the gold standard, multi-planar (>or==8 slice) CT angiography may be equivalent, and treatment algorithms are evaluated. It is noted that change in the diagnosis and management of this injury constellation is rapid due to technological advancement and the difficulties inherent in performing randomized prospective trials in this patient population.


Expression of L-histidine decarboxylase in granules of elicited mouse polymorphonuclear leukocytes.
Infiltrating polymorphonuclear leukocytes (PMN) in the peritoneal cavity were found to express L-histidine decarboxylase (HDC), the rate-limiting enzyme of histamine synthesis, in a csein-induced peritonitis model. Expression of HDC was detected in the elicited PMN, but not in the peripheral blood leukocytes. The peritoneal lavage fluids in this model were found to augment histamine synthesis in PMN isolated from the bone marrow. Rapid post-translational processing of HDC was observed in PMN, and the dominant form of HDC was the mature 53-kDa form, which was found to co-localize with a granule enzyme, matrix metalloproteinase-9 (MMP-9). Treatment of PMN with the phorbol ester PMA, which stimulates the release of MMP-9, did not liberate the granular HDC. Immunofluorescence studies using an anti-HDC antibody strongly suggested that HDC is bound to the cytosolic side of the granule membranes. These observations suggest that HDC is induced upon infiltration of PMN into the mouse peritoneal cavity and that histamine is synthesized by HDC attached to the granule membranes of PMN.


Politics, Power, Poverty and Global Health: Systems and Frames.
Striking disparities in access to healthcare and in health outcomes are major characteristics of health across the globe. This inequitable state of global health and how it could be improved has become a highly popularized field of academic study. In a series of articles in this journal the roles of power and politics in global health have been addressed in considerable detail. Three points are added here to this debate. The first is consideration of how the use of definitions and common terms, for example 'poverty eradication,' can mask full exposure of the extent of rectification required, with consequent failure to understand what poverty eradication should mean, how this could be achieved and that a new definition is called for. Secondly, a criticism is offered of how the term 'global health' is used in a restricted manner to describe activities that focus on an anthropocentric and biomedical conception of health across the world. It is proposed that the discourse on 'global health' should be extended beyond conventional boundaries towards an ecocentric conception of global/planetary health in an increasingly interdependent planet characterised by a multitude of interlinked crises. Finally, it is noted that the paucity of workable strategies towards achieving greater equity in sustainable global health is not so much due to lack of understanding of, or insight into, the invisible dimensions of power, but is rather the outcome of seeking solutions from within belief systems and cognitive biases that cannot offer solutions. Hence the need for a new framing perspective for global health that could reshape our thinking and actions.


Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).


COVID-19 stressors and health behaviors: A multilevel longitudinal study across 86 countries.
Anxiety associated with the COVID-19 pandemic and home confinement has been associated with adverse health behaviors, such as unhealthy eating, smoking, and drinking. However, most studies have been limited by regional sampling, which precludes the examination of behavioral consequences associated with the pandemic at a global level. Further, few studies operationalized pandemic-related stressors to enable the investigation of the impact of different types of stressors on health outcomes. This study examined the association between perceived risk of COVID-19 infection and economic burden of COVID-19 with health-promoting and health-damaging behaviors using data from the PsyCorona Study: an international, longitudinal online study of psychological and behavioral correlates of COVID-19. Analyses utilized data from 7,402 participants from 86 countries across three waves of assessment between May 16 and June 13, 2020. Participants completed self-report measures of COVID-19 infection risk, COVID-19-related economic burden, physical exercise, diet quality, cigarette smoking, sleep quality, and binge drinking. Multilevel structural equation modeling analyses showed that across three time points, perceived economic burden was associated with reduced diet quality and sleep quality, as well as increased smoking. Diet quality and sleep quality were lowest among respondents who perceived high COVID-19 infection risk combined with high economic burden. Neither binge drinking nor exercise were associated with perceived COVID-19 infection risk, economic burden, or their interaction. Findings point to the value of developing interventions to address COVID-related stressors, which have an impact on health behaviors that, in turn, may influence vulnerability to COVID-19 and other health outcomes.


Controversies in the surgical management of newly diagnosed and recurrent/residual thyroid cancer.
Thyroid surgery is the mainstay of treatment for thyroid cancer, but there are options for the surgical approach. There is a general agreement that the goal of thyroid cancer surgery is to remove evident disease, minimize treatment and disease-related morbidity, minimize the risk of recurrence and metastatic spread, and facilitate long-term follow-up. Within these parameters, however, there are a number of controversies regarding the extent of surgery. To minimize the risk of recurrence and to optimize the treatment of patients with thyroid cancer, a total thyroidectomy should be performed as the initial operation if the preoperative diagnosis is consistent with thyroid cancer. Macroscopic lymph node involvement does impact recurrence and may influence survival. Therefore, a preoperative ultrasound evaluation of the neck is essential before operative intervention. If pathologic nodes are identified in either the central or lateral neck they should be removed at the initial operation. The role of prophylactic central neck dissection remains controversial, and the risks of this procedure may outweigh the benefits. Therefore, we do not recommend the routine performance of a central neck dissection. Similar to the recent American Thyroid Association guidelines, we agree that their may be a subset of high-risk patients who may benefit from a prophylactic central neck dissection, but that population has yet to be defined. The extent of lateral dissection that is required is also debated as levels 1 and 5 lymph node involvement is uncommon with thyroid cancer. Recurrent disease can be challenging to remove, but several adjuncts are available to maximize the safety and efficacy of reoperation, making it the best option for patients with localized recurrences. Total thyroidectomy and neck dissection are very safe procedures when performed by experienced surgeons and can play an essential role in the management of patients with thyroid cancer.


Live born recipient of twin-twin transfusion syndrome with anomalous mitral arcade.
We present a case report of anomalous mitral arcade in a live born former recipient of twin-twin transfusion syndrome. At 33+0 week of gestation fetal ultrasound demonstrated that she had a large mitral insufficiency, decreased movement of the lateral cusp of the mitral valve and dilated left atrium. The twins were delivered by caesarean section at week 33+1 due to fetal distress. The former recipient twin developed decompensated heart failure during her first day of life and was transferred to a surgical paediatric heart centre. Her clinical condition rapidly deteriorated, and she died of congestive heart failure 3 days old. Prenatal signs of anomalous mitral arcade in a recipient of twin-twin transfusion syndrome should warrant preparation of a critically ill neonate, including parental counselling and in utero transfer to surgical paediatric heart centre. There is a surgical treatment option available for neonates, but the experience with this technique is still very limited with a high risk of morbidity and mortality.


Oxytocin, vasopressin and sociality.
The neurobiology of social behaviour is interwoven with autonomic, endocrine and other homoeostatic processes responsible for the adaptive functions of reproduction and survival. Young mammals are dependent on their mothers for nourishment, and the interaction between the mother and infant may be a physiological and neuroendocrine prototype for mammalian sociality. Although these adaptive functions of the mother-infant social behavioural dyad are obvious, adult social interactions, including social bonds, also are important to health and survival. Two neuropeptides, oxytocin (OXT) and arginine vasopressin (AVP), have been repeatedly implicated in mammalian social behaviours and emotional states that support sociality. Although best known for their roles in reproduction and homoeostasis, these peptides play a central role in the activation and expression of social behaviours and emotional states. Recent studies from our work with the prairie vole (Microtus ochrogaster), reviewed here, reveal a role for both OXT and AVP in behavioural and endocrine changes during social interactions, and also changes that are associated with the absence of social interactions (i.e. social isolation).


Presurgical determination of estrogen receptor status using immunocytochemically stained fine needle aspirate smears in patients with breast cancer.
We have developed an immunocytochemical staining procedure (ERICA) using a monoclonal antibody to the estrogen receptor (ER) to determine ER status from samples obtained by fine needle aspiration of primary and recurrent breast cancer tissue (cyto-ERICA). ER status was assessable on 214 of 246 smeared aspirates from breast cancer patients. In 143 (66.8%) assessable smears positive nuclear staining was observed but was completely absent in 71 (33.2%) cases. In 107 cases we were able to compare results with those obtained with the quantifiable dextrancoated charcoal (DCC) radioligand binding technique using surgically excised material. We observed qualitative agreement in 53 of 62 (85.5%) of primary specimens and 16 of 16 (100%) recurrent samples compared to the subsequent DCC result on the same sample. Aspirates obtained from new secondary deposits were also assessed and in 16 of 19 (84.2%) cases results agreed with that established previously by DCC on the primary breast tumor. In a further 6 of 10 (60%) cases the cyto-ERICA result obtained from recurrent samples qualitatively agreed with that determined by DCC on a previous recurrent lesion. A comparison of staining of aspirates was also made against frozen tissue sections stained with the monoclonal antibody (tissue-ERICA). Where comparison was made of primary tumor specimens agreement was observed in 40 of 45 (88.9%) of cases while specimens from secondary lesions agreed qualitatively in 14 of 17 (82.3%) of cases. In a small number of samples where tissue-ERICA was performed on an earlier lesion to that aspirated for cyto-ERICA an agreement of 4 of 5 (80%) was observed. This technique shows good sensitivity in demonstrating ER in aspirate specimens, should therefore permit us to determine ER status before surgery for primary breast cancer, and may also mean that surgery for recurrent disease to determine receptor status is no longer necessary.


The levels of processing effect under nitrogen narcosis.
Previous research has consistently demonstrated that inert gas (nitrogen) narcosis affects free recall but not recognition memory in the depth range of 30 to 50 meters of sea water (msw), possibly as a result of narcosis preventing processing when learned material is encoded. The aim of the current research was to test this hypothesis by applying a levels of processing approach to the measurement of free recall under narcosis. Experiment 1 investigated the effect of depth (0-2 msw vs. 37-39 msw) and level of processing (shallow vs. deep) on free recall memory performance in 67 divers. When age was included as a covariate, recall was significantly worse in deep water (i.e., under narcosis), compared to shallow water, and was significantly higher in the deep processing compared to shallow processing conditions in both depth conditions. Experiment 2 demonstrated that this effect was not simply due to the different underwater environments used for the depth conditions in Experiment 1. It was concluded memory performance can be altered by processing under narcosis and supports the contention that narcosis affects the encoding stage of memory as opposed to self-guided search (retrieval).


Interventions for prevention of type 2 diabetes in relatives: A systematic review.
The relatives and partners of people with type 2 diabetes are at increased risk of developing type 2 diabetes. This systematic review examines randomized controlled trials, written in English that tested an intervention, which aimed to modify behaviors known to delay or prevent type 2 diabetes, among the relatives or partners of people with type 2 diabetes. Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias. Seven studies met the inclusion criteria. The majority of studies were at low risk of bias. Six studies tested an intervention in first-degree relatives of people with type 2 diabetes and one in partners. Intervention components and intervention intensity across studies varied, with those targeting diet and physical activity reporting the most significant changes in primary outcomes. Only one study did not observe significant changes in primary outcomes. There were three main recruitment approaches: advertising in the community, recruiting people through their relatives with diabetes, or identifying people as high risk by screening of their own health care contacts. Some evidence was found for potentially successful interventions to prevent type 2 diabetes among the relatives and partners of people with type 2 diabetes, although finding simple and effective methods to identify and recruit them remains a challenge. Future studies should explore the effect of patients' perceptions on their family members' behavior and capitalize on family relationships in order to increase intervention effectiveness.


Membraneless nuclear organelles and the search for phases within phases.
Cells are segregated into two distinct compartment groups to optimize cellular function. The first is characterized by lipid membranes that encapsulate specific regions and regulate macromolecular flux. The second, known collectively as membraneless organelles (MLOs), lacks defining lipid membranes and exhibits self-organizing properties. MLOs are enriched with specific RNAs and proteins that catalyze essential cellular processes. A prominent sub-class of MLOs are known as nuclear bodies, which includes nucleoli, paraspeckles, and other droplets. These microenvironments contain specific RNAs, exhibit archetypal liquid-liquid phase separation characteristics, and harbor intrinsically disordered, multivalent hub proteins. We present an analysis of nuclear body protein disorder that suggests MLO proteomes are significantly more disordered than structured cellular features. We also outline common MLO ultrastructural features, exemplified by the three sub-compartments present inside the nucleolus. A core-shell configuration, or phase within a phase, is displayed by several nuclear bodies and may be functionally important. Finally, we summarize evidence indicating extensive RNA and protein sharing between distinct nuclear bodies, suggesting functional cooperation and similar nucleation principles. Considering the substantial accumulation of specific coding and noncoding RNA classes inside MLOs, evidence that RNA buffers specific phase transition events, and the absence of a clear correlation between total intrinsic protein disorder and MLO accumulation, we conclude that RNA biogenesis may play a key role in MLO formation, internal organization, and function. This article is categorized under: RNA Export and Localization > RNA Localization RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.


Medical universities educational and research online services: benchmarking universities' website towards e-government.
Websites as one of the initial steps towards an e-government adoption do facilitate delivery of online and customer-oriented services. In this study we intended to investigate the role of the websites of medical universities in providing educational and research services following the E-government maturity model in the Iranian universities. This descriptive and cross- sectional study was conducted through content analysis and benchmarking the websites in 2012. The research population included the entire medical university website (37). Delivery of educational and research services through these university websites including information, interaction, transaction, and Integration were investigated using a checklist. The data were then analyzed by means of descriptive statistics and using SPSS software. Level of educational and research services by websites of the medical universities type I and II was evaluated medium as 1.99 and 1.89, respectively. All the universities gained a mean score of 1 out of 3 in terms of integration of educational and research services. Results of the study indicated that Iranian universities have passed information and interaction stages, but they have not made much progress in transaction and integration stages. Failure to adapt to e-government in Iranian medical universities in which limiting factors such as users' e-literacy, access to the internet and ICT infrastructure are not so crucial as in other organizations, suggest that e-government realization goes beyond technical challenges.


Immunomodulatory effects of Hedysarum polybotrys extract in mice macrophages, splenocytes and leucopenia.
Astragali Radix (Huang-Qi) is a popular herbal medicine commonly used as a constituent in tonic herbal preparations. Hedysarum polybotrys Handel-Mazzetti is one species used of Astragali Radix. In this study, the immunomodulatory properties of H. polybotrys were explored by LPS-activated and SNP-treated RAW 264.7 cells and splenocytes and, daunoblastina-induced leucopenia BALB/c mice. Formononetin was used as the bioactive marker to monitor the quality of the H. polybotrys extracts. H. polybotrys was extracted with hot-water and methanol, and MeOH extract partitioned with H2O (M-H) and ethyl acetate (M-EA) to yield four different fractions. M-EA had the highest formononetin and total proanthocyanidin content and showed stronger inhibitory effects on the production and expression of NO, PGE2, iNOS and COX-2 in LPS-activated RAW 264.7 cells and splenocytes than the other fractions. In addition, M-EA significantly stimulated the proliferation of LPS-activated RAW 264.7 cells and splenocytes, enhanced NO radicals scavenging and attenuated NO-induced cytotoxicity. Furthermore, M-EA also significantly increased the rate of recovery of white blood cells level in daunoblastina-induced leucopenia mice. These evidences suggest that this traditional Qi-tonifying herb has potential effects in clinical conditions when immune-enhancing and anti-inflammatory effect is desired.


Bromism from excessive cola consumption.
Bromism is an unusual occurrence. Historically bromism has been known to occur with chronic ingestion of bromide salts used as sleep medications. In this case, excessive consumption of a cola with brominated vegetable oil caused a severe case of bromism. The patient presented with headache, fatigue, ataxia, and memory loss which progressed over 30 days. He consumed 2 to 4 L of cola containing brominated vegetable oil on a daily basis before presenting with these symptoms. His significantly elevated serum chloride, as measured by ion specific methods, and negative anion gaps were overlooked during a prior hospitalization and emergency department visits. A focal neurologic finding of right eyelid ptosis led to an extensive evaluation for a central nervous system lesion. The patient continued to deteriorate, until he was no longer able to walk. A diagnosis of severe bromism was eventually made and his serum bromide was confirmed at 3180 mg/L (39.8 mmol/L). Despite saline loading the patient failed to improve but subsequent hemodialysis dramatically cleared his clinical condition, and reduced his serum bromide levels. The unilateral eyelid ptosis, a rarely reported finding in bromism, also resolved with hemodialysis. A negative anion gap or an elevated serum chloride should prompt an evaluation for bromism. In this case hemodialysis dramatically improved the patient's clinical condition and reduced the half-life of bromide to 1.38 h.


Spanning four mechanistic regions of intramolecular proton-coupled electron transfer in a Ru(bpy)3(2+)-tyrosine complex.
Proton-coupled electron transfer (PCET) from tyrosine (TyrOH) to a covalently linked [Ru(bpy)(3)](2+) photosensitizer in aqueous media has been systematically reinvestigated by laser flash-quench kinetics as a model system for PCET in radical enzymes and in photochemical energy conversion. Previous kinetic studies on Ru-TyrOH molecules (Sjödin et al. J. Am. Chem. Soc. 2000, 122, 3932; Irebo et al. J. Am. Chem. Soc. 2007, 129, 15462) have established two mechanisms. Concerted electron-proton (CEP) transfer has been observed when pH < pK(a)(TyrOH), which is pH-dependent but not first-order in [OH(-)] and not dependent on the buffer concentration when it is sufficiently low (less than ca. 5 mM). In addition, the pH-independent rate constant for electron transfer from tyrosine phenolate (TyrO(-)) was reported at pH >10. Here we compare the PCET rates and kinetic isotope effects (k(H)/k(D)) of four Ru-TyrOH molecules with varying Ru(III/II) oxidant strengths over a pH range of 1-12.5. On the basis of these data, two additional mechanistic regimes were observed and identified through analysis of kinetic competition and kinetic isotope effects (KIE): (i) a mechanism dominating at low pH assigned to a stepwise electron-first PCET and (ii) a stepwise proton-first PCET with OH(-) as proton acceptor that dominates around pH = 10. The effect of solution pH and electrochemical potential of the Ru(III/II) oxidant on the competition between the different mechanisms is discussed. The systems investigated may serve as models for the mechanistic diversity of PCET reactions in general with water (H(2)O, OH(-)) as primary proton acceptor.


Nonsurgical Management of Early-onset Scoliosis.
Early-onset scoliosis is potentially fatal if left untreated. Although surgical management with growing instrumentation may be necessary, this is not a panacea and is associated with high complication rates. Recent evidence has demonstrated that nonsurgical treatment can be an effective early management strategy in delaying or even precluding the need for surgery, especially surgery with growing instrumentation. The goal of both nonsurgical and surgical management is to control or correct the spinal curve to allow appropriate pulmonary development while delaying definitive fusion until an appropriate skeletal age. Although more commonly used to delay surgery, serial cast correction using the Cotrel and Morel elongation-derotation-flexion technique may result in complete correction in patients with infantile idiopathic scoliosis and smaller curve magnitudes.


The enfacement illusion boosts facial mimicry.
Facial mimicry, the automatic imitation of another person's emotion, is a mechanism underlying emotion recognition and emotional contagion, a phylogenetically conserved form of empathy that precedes later developing empathic skills. We tested the possibility to increase facial mimicry by blurring self-other distinction via the enfacement illusion. To do so we delivered synchronous, versus asynchronous, visuo-tactile interpersonal multisensory stimulation on the observer and expresser's faces and then recorded surface facial EMG while participants observed videos of happy and sad facial expressions displayed by the expresser. Our results show that synchronous visuo-tactile stimulation can indeed enhance facial mimicry and that this depends on participants' baseline tendency to mimic.. Our findings could set the basis for developing novel interventions for conditions characterized by reduced empathic and emotion recognition skills, including autism and schizophrenia.


Role of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications.
Iron is one of the essential minerals that are required for a variety of molecules to maintain their normal structures and functions and for cells to live, grow, and proliferate. The homeostasis of iron results from a tightly coordinated regulation by different proteins involved in uptake, excretion and intracellular storage/trafficking. Although it is essential, iron can also be toxic once in excess amounts. Through Fenton reaction, iron as a transit mineral can generate various reactive oxygen or nitrogen species; therefore, abnormal metabolism of iron can lead to several chronic pathogenesis. Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks of insulin resistance and diabetes, but also causes cardiovascular diseases in non-diabetic and diabetic subjects. Temporal iron deficiency was found to sensitize insulin action, but chronic iron deficiency with anemia can accelerate the development of cardiovascular diseases in non-diabetic and diabetic patients. In this review, therefore, we will first outline iron homeostasis, function, and toxicity, and then mainly summarize the data regarding the roles of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications, as well as the possible links of iron to diabetes and diabetic complications. In the end, the possible therapy using iron chelators for diabetes and diabetic complications will also be discussed.


Effect of financial incentives on delivery of alcohol screening and brief intervention (ASBI) in primary care: longitudinal study.
Alcohol screening and brief intervention (ASBI) is effective but underprovided in primary care. Financial incentives may help address this. This study assesses the impact of a local pay-for-performance programme on delivery of ASBI in UK primary care. Longitudinal study using data from 30 general practices in north-west London from 2008 to 2011 with logistic regression to examine disparities in ASBI delivery. Of 211 834 registered patients, 45 040 were targeted by the incentive (cardiovascular conditions or high risk; mental health conditions), of whom 65.7% were screened (up from a baseline of 4.8%, P < 0.001), compared with 14.7% of non-targeted patients (P < 0.001). Screening rates were lower after adjustment in younger patients, White patients, less deprived areas and in patients with mental health conditions (P < 0.05). Of those screened, 11.5% were positive and 88.6% received BI. Men and White patients were significantly more likely to screen positive. Women and younger patients were less likely to receive BI. 30.1% of patients re-screened were now negative. However, patients with mental health conditions were less likely to re-screen negative than those with cardiovascular conditions. Financial incentives appear to be effective in increasing delivery of ASBI in primary care and may reduce hazardous and harmful drinking in some patients. The findings support universal rather than targeted screening.


The Association Between HbA1c and Time in Hypoglycemia During CGM and Self-Monitoring of Blood Glucose in People With Type 1 Diabetes and Multiple Daily Insulin Injections: A Randomized Clinical Trial (GOLD-4).
According to recent guidelines, individuals with type 1 diabetes should spend <4.0% of time per day with glucose levels <3.9 mmol/L (<70 mg/dL) and <1.0% per day with glucose levels <3.0 mmol/L (<54 mg/dL). In the GOLD randomized crossover trial, 161 individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) were randomized to continuous glucose monitoring (CGM) or conventional therapy with self-monitoring of blood glucose (SMBG) and evaluated over 16 months. We estimated the association between time spent in hypoglycemia and various mean glucose and HbA1c levels. Time spent in hypoglycemia (<3.9 mmol/L and <3.0 mmol/L) increased significantly with lower mean HbA1c and mean glucose levels during both CGM and conventional therapy. During CGM, 24 (57.1%) individuals with HbA1c <7.5% (<58 mmol/mol) had <1.0% time spent in hypoglycemia <3.0 mmol/L and 23 (54.8%) had <4.0% time spent in hypoglycemia <3.9 mmol/L. During CGM, mean time spent in hypoglycemia for individuals with mean HbA1c 7.0% (52 mmol/mol) was estimated to be 5.4% for <3.9 mmol/L and 1.5% for <3.0 mmol/L. The corresponding values during SMBG were 9.2% and 3.5%, respectively. Individuals with mean glucose levels of 8 mmol/L spent 4.9% units more time with glucose levels <3.9 mmol/L and 2.8% units more time <3.0 mmol/L during SMBG compared with CGM. Reaching current targets for time in hypoglycemia while at the same time reaching HbA1c targets is challenging for patients with type 1 diabetes treated with MDI both with CGM and SMBG monitoring. However, CGM is associated with considerably less time in hypoglycemia than SMBG at a broad range of HbA1c levels and is crucial for patients with MDI treatment if they are to have a chance to approach hypoglycemia targets.


RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex.
For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2∼Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaborates with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING-E2∼Ub catalytic modules such as APC11-UBCH10∼Ub collide with distally tethered disordered substrates remains poorly understood. We report structural mechanisms of UBCH10 recruitment to APC(CDH1) and substrate ubiquitination. Unexpectedly, in addition to binding APC11's RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APC(CDH1)-UBCH10∼Ub-substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin-RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin-RING-E2 interactions establish APC's specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. We propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3-E2∼Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation.


Proximal visceral endoderm and extraembryonic ectoderm regulate the formation of primordial germ cell precursors.
The extraembryonic tissues, visceral endoderm (VE) and extraembryonic ectoderm (ExE) are known to be important for the induction of primordial germ cells (PGCs) in mice via activation of the bone morphogenetic protein (BMP) signalling pathway. We investigated whether the VE and ExE have a direct role in the specification of PGCs, or in an earlier event, namely the induction of the PGC precursors in the proximal posterior epiblast cells. We cultured embryonic day (E) 5.75 to E7.0 mouse embryos in an explant-assay with or without extraembryonic tissues. The reconstituted pieces of embryonic and extraembryonic tissues were assessed for the formation of both PGC precursors and specified PGCs. For this, Blimp1:gfp and Stella:gfp transgenic mouse lines were used to distinguish between PGC precursors and specified PGC, respectively. We observed that the VE regulates formation of an appropriate number of PGC precursors between E6.25-E7.25, but it is not essential for the subsequent specification of PGCs from the precursor cells. Furthermore, we show that the ExE has a different role from that of the VE, which is to restrict localization of PGC precursors to the posterior part of the embryo. We show that the VE and ExE have distinct roles in the induction of PGC precursors, namely the formation of a normal number of PGC precursors, and their appropriate localization during early development. However, these tissues do not have a direct role during the final stages of specification of the founder population of PGCs.


Creating a research culture in a palliative care service environment: a qualitative study of the evolution of staff attitudes to research during a large longitudinal controlled trial (ISRCTN81117481).
This study investigated the impact of a three-year randomized control trial of different models of service provision on palliative care staff associated with the hospice where the trial was being conducted. Eleven open access de-identified qualitative focus groups were held over a period of three years: three months into the trial, one year after its inception, and at the end of the trial. Four staff groups were involved: inpatient hospice nurses, palliative care outreach nurses, medical palliative specialists, and administrative staff and social workers. Initially the impact of the trial produced high levels of staff stress which largely diminished over time, to be replaced by enthusiasm for the changes achieved and sadness that post trial the perceived benefits gained would be lost. When attempting to change a clinical culture to incorporate research, and in particular where increased staff workload is involved, highly interactive levels of communication and valuing of staff input are required to minimize the stress and burden of this imposition.


Species Distribution and Antimicrobial Profiles of Enterococcus spp. Isolates from Kenyan Small and Medium Enterprise Slaughterhouses.
The present study aimed at identifying and assessing antimicrobial resistance of Enterococcus spp. isolated from small and medium enterprise slaughterhouses in Kenya. In total, 67 isolates were recovered from 48 of 195 samples examined from beef carcasses, personnel, and cutting equipment in five small and medium enterprise slaughterhouses. The isolates were identified by using matrix-assisted laser desorption-ionization time of flight mass spectrometry and screened thereafter for their resistance against 12 antibiotics by using a disk diffusion assay. The isolates ( n = 67) included Enterococcus faecalis (41.8%), Enterococcus mundtii (17.9%), Enterococcus thailandicus (13.4%), Enterococcus faecium (9.0%), Enterococcus hirae (7.5%), Enterococcus casseliflavus (6.0%), and Enterococcus devriesei (4.5%). None of the isolates were resistant to ciprofloxacin, penicillin, ampicillin, vancomycin, nitrofurantoin, teicoplanin, linezolid, and levofloxacin. Resistance to rifampin (46.3%), erythromycin (23.9%), tetracycline (20.9%), and chloramphenicol (7.5%) was distributed among six of the seven species. All E. thailandicus were resistant to rifampin, erythromycin, and tetracycline. E. faecalis was resistant to rifampin (60.7%), tetracycline (17.9%), erythromycin (14.3%), and chloramphenicol (10.7%). Resistance to two or three antibiotics was observed in 26.9% of the enterococci isolates. The isolation of enterococci that are resistant to clinically relevant antibiotics, such as erythromycin, is of a serious concern given the role enterococci play in the transfer of antibiotic resistance genes.


Changes in leptin, plasminogen activator factor and oxidative stress in morbidly obese patients following open and laparoscopic Swedish adjustable gastric banding.
Oxidative stress is increased in obesity, leading to endothelial dysfunction, atherogenesis, and platelet aggregation. The purpose of this study was to determine the effects of weight loss after bariatric surgery on serum lipids, malondialdehyde (MDA, a marker of oxidative stress), oxidized low-density lipoprotein (oxLDL, which is increased in obesity and causes endothelial dysfunction), paraoxonase (PON-1, which inhibits lipid peroxidation), leptin and plasminogen activator inhibitor type-1 (PAI-1, which contributes to a thrombotic state). 40 morbidly obese patients had insertion of a Swedish adjustable gastric band (SAGB). A lipid profile, MDA, oxLDL, PON-1, leptin and PAI-1 levels were drawn before and 6 months after the operation. 20 patients underwent open (Group 1) and 20 laparoscopic (Group 2) SAGB, to compare the systemic inflammatory response of the two approaches. Patient demographics, indications for surgery, and postoperative results were no different between the groups. Postoperative BMI and concentrations of lipid, MDA, oxLDL, leptin and PAI-1 decreased significantly in both groups. PON-1 activity increased and was negatively correlated with BMI (r=-0.618, P< 0.01), MDA (r=-0.735, P<0.001), oxLDL (r=-0.701, P< 0.01), leptin (r=-0.626, P<0.01) and PAI-1 (r=-0.461, P<0.05). There was a correlation between BMI and MDA (r=0.790, P <0.001), and also leptin (r=0.900, P<0.001) and PAI-1 (r=0.888, P=0.001). There was no correlation between BMI and oxLDL. These findings support the hypothesis that in morbid obesity, weight loss after surgery has positive effects on fibrinolytic function, oxidative stress and antioxidant activity. Both operative approaches had similar effects in this study.


Coupled Turbidity and Spectroscopy Problems: A Simple Algorithm for Volumetric Analysis of Optically Thin or Dilute, In Vitro Bacterial Cultures in Various Media.
An approach binary spectronephelometry (BSN) to perform real-time simultaneous noninvasive in situ physical and chemical analysis of bacterial cultures in fluid media is described. We choose to characterize cultures of Escherichia coli (NC), Pseudomonas aeruginosa (PA), and Shewanella oneidensis (SO) in the specific case of complex media whose Raman spectrum cannot be unambiguously assigned. Nevertheless, organism number density and a measure of the chemical makeup of the fluid medium can be monitored noninvasively, simultaneously, and continuously, despite changing turbidity and medium chemistry. The method involves irradiating a culture in fluid medium in an appropriate vessel (in this case a standard 1 cm cuvette) using a near infrared laser and collecting all the backscattered light from the cuvette, i.e., the Rayleigh-Mie line and the inelastically emitted light which includes unresolved Raman scattered light and fluorescence. Complex "legacy" media contain materials of biological origin whose chemical composition cannot be fully delineated. We independently calibrate this approach to a commonly used reference, optical density at 600 nm (OD600) for characterizing the number density of organisms. We suggest that the total inelastically emitted light could be a measure of the chemical state of a biologically based medium, e.g., lysogeny broth (LB). This approach may be useful in a broad range of basic and applied studies and enterprises that utilize bacterial cultures in any medium or container that permits optical probing in the single scattering limit.


How does inhibition of the renin-angiotensin system affect the prognosis of advanced gastric cancer patients receiving platinum-based chemotherapy?.
The renin-angiotensin system (RAS) is related to the regulation of cell proliferation, angiogenesis, and tumor progression. We retrospectively analyzed the effect of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 63 patients with advanced gastric cancer (AGC) with platinum-based chemotherapy. All patients analyzed had received medications for hypertension at the diagnosis of AGC. Patients were divided into two groups: an ACEI/ARB group (n = 30) and a non-ACEI/ARB group (n = 33). Patient characteristics were not different between patients with and without ACEI/ARB. The response rate for all patients was 25.4% and the disease control rate was 77.8%. The median progression-free survival (PFS) for first-line chemotherapy was 5.5 months (95% CI 3.71-7.29) in the ACEI/ARB group and 4.3 months (95% CI 2.39-6.21) in the non-ACEI/ARB group (p = 0.506). There was a significant difference in overall survival (OS) in the ACEI/ARB group compared to the non-ACEI/ARB group (median OS: 8.2 vs. 13.9, p = 0.0095). In multivariate analysis, the use of ACEI/ARB was a significant independent prognostic factor for OS (p = 0.039) but not for PFS. ACEI/ARB in combination with standard chemotherapy might improve survival in patients with AGC and hypertension. These results support further investigation into the anticancer effects of ACEL/ARB.


Reexamining the Association of Body Mass Index With Overall Survival Outcomes After Liver Transplantation.
Several studies have shown that obese patients undergoing liver transplantation (LT) have an increased risk of mortality regardless of Model of End Stage Liver Disease (MELD) scores. The purpose of this study is to identify the range of body mass index (BMI) at LT associated with the lowest risks of posttransplant mortality by MELD category. A retrospective cohort of patients aged 18 years or older from the Organ Procurement and Transplantation Network database undergoing LT between February 27, 2002, and December 31, 2013, was identified and followed up through March 14, 2014. Patients' MELD score at the time of transplantation was categorized into 10 or lower (MELD1), 11 to 18 (MELD2), 19 to 24 (MELD3), and 25 or higher (MELD4). Multivariable adjusted Cox proportional hazard analyses were conducted. Among 48 226 patients in the analytic cohort (14.8% were in MELD1, 33.7% were in MELD2, 19.6% were in MELD3, and 32.0% were in MELD4), 25% died with mean follow-up of 1371 days. For MELD1, patient BMI ranging from 30 to 33 was associated with a better survival outcome than BMI less than 30 or 33 or greater; for MELD2, BMI ranging from 28 to 37 had a better survival outcome than BMI less than 28 or 37 or greater; for MELD3, the survival outcome improved with an increasing BMI; for MELD4, the survival outcome was not associated with patient BMI. This study provides evidence that obesity in LT patients is not necessarily associated with higher posttransplantation mortality and highlights the importance of the interaction between BMI and MELD category to determine their survival likelihood.


Supplementation trials with calcium citrate malate: evidence in favor of increasing the calcium RDA during childhood and adolescence.
The vast majority of peak adult bone mass is accumulated by the time longitudinal growth is complete. As peak bone mass is an important determinant of future fracture risk, the goal of the current calcium recommended dietary allowance during youth is to provide a calcium intake that allows individuals to reach their full genetic potential for acquiring skeletal mass. The advent of controlled trials of calcium supplementation and total body bone mass measurements in children and adolescents provide the first direct way of determining the amount of calcium necessary to achieve optimal skeletal accretion. These studies indicate that the current RDAs are insufficient to support optimal bone mass gain during growth and development. Based on the recent intervention trials, recommendations are made for an RDA of 1250 mg during childhood and 1450 mg during adolescence. These values are consistent with established calcium balance intake thresholds for growth during pre-adolescence and adolescence.


The molecular basis of herpesviruses as oncolytic agents.
Herpes simplex viruses (HSVs) have entered clinical trials as oncolytic agents. The following properties make them good candidates. It is a mild pathogen; drugs (Aciclovir) are available to control viral infection; the large genome is amenable to genetic engineering, they can be rendered cancer-specific by deletion of genes, envelope glycoproteins allow the insertion of heterologous ligands to achieve modification of the natural tropism. Genetically modified HSVs have been thoroughly tested in humans. New generation recombinants retargeted to cancer-specific heterologous receptors have been generated and are presently evaluated in pre-clinical settings. They will be reviewed along with the molecular bases of cancer specificity and the strategies for the enhancement of oncolytic potential of HSV recombinants.


Family Practitioners' Advice about Taking Time Off Work for Lower Respiratory Tract Infections: A Prospective Study in Twelve European Primary Care Networks.
Acute cough and lower respiratory tract infections (LRTIs) are one of the most important causes of lost working hours. to explore variation and predictors in family practitioners (FPs) advice to patients with LRTIs about taking time off work in different European countries. Prospective observational study in primary care networks in 12 countries, with multilevel mixed-effects binomial logistic regression. 324 FPs recruited 1616 employed adults who presented to primary care with LRTIs. The proportion of patients advised to take time off work varied from 7.6% in the Netherlands to 89.2% in Slovakia, and of these, 88.2% overall were advised to stay off work for seven days or less. None of Finnish or Dutch patients were advised to take more than 7 days off, in contrast to 35.5% of Polish and 27.0% of Slovak patients. The strongest predictors of FPs' advice about time off work were: patient symptoms interfering with normal activities (OR 4.43; P<0.001), fever (2.49; P<0.001), patients feeling generally unwell (2.21; P<0.001), antibiotic prescribing (1.51; P = 0.025) and auscultation abnormality (1.50; P = 0.029). Advice to take time off was not associated with patient reported recovery. There is large variation in FPs' advice given to patients with LRTIs in Europe about taking time off work, which is not explained by differences in patients' reported illness duration, but might be explained by differences in regulations around certification and sick pay. Evidence based guidance for advising patients about taking time off work for this common condition is needed.


Pharmacokinetic disposition of topical phosphodiesterase-4 inhibitor E6005 in patients with atopic dermatitis.
Background: A novel topical phosphodiesterase-4 inhibitor E6005 shows potential as effective treatment option for atopic dermatitis (AD); however, systemic exposure may cause potentially undesirable adverse reactions. In this study, we evaluated the relationship between the systemic exposure of E6005 and clinical parameters including skin condition and the incidence of AEs in patients with AD. Methods: The association analysis used the clinical data obtained in a previously conducted clinical study with topical E6005 in adult patients with AD. To estimate associations with drug exposure, generalized estimating equation logistic regression models were used, along with clinical data and plasma concentrations of M11, the major metabolite of E6005 (as an indicator for E6005 exposure). Results: The metabolite M11 was detected in 62 of 221 plasma samples from 72 subjects. From association analysis, SCORAD-A obtained prior to E6005 treatment was identified as the clinical parameter influenced to M11 detection with statistical significance (p = .003). M11 detection was not clearly associated with the incidence of adverse events occurred. Conclusion: Exposure to topical E6005 is associated with the eczema-associated area, however, that is not distinctly associated with its adverse drug reactions occurred after drug applications possibly due to E6005's characteristics of tissue distribution.


Nanoscale optical detector with single-photon and multiphoton sensitivity.
We present the first nanoscale (down to approximately 50 x 50 nm(2)) detector displaying single-photon sensitivity and a nanosecond response. This type of nanodetector can also be operated in multiphoton mode, where the detection threshold can be set at N = 1, 2, 3, or 4 photons, thus allowing the mapping of photon number statistics on the nanoscale. Its operation principle based on that of hot-spot formation in superconducting nanowires allies the temporal resolution and sensitivity of superconducting single-photon detectors with subwavelength resolution and photon number discrimination. Such detectors can be of great interest for the study of nanophotonic devices at low temperature.


Trace Elements Contamination and Human Health Risk Assessment in Drinking Water from the Agricultural and Pastoral Areas of Bay County, Xinjiang, China.
Tap water samples were collected from 180 families in four agricultural (KYR: Keyir, KRW: Kariwak, YTR: Yatur, DW: Dawanqi) and two pastoral areas (B: Bulong and Y: Yangchang) in Bay County, Xinjiang, China, and levels of seven trace elements (Cd, Cr, As Ni, Pb, Zn, Se) were analyzed using inductively-coupled plasma mass spectrometry (ICP-MS) to assess potential health risks. Remarkable spatial variations of contamination were observed. Overall, the health risk was more severe for carcinogenic versus non-carcinogenic pollutants due to heavy metal. The risk index was greater for children overall (Cr > As > Cd and Zn > Se for carcinogenic and non-carcinogenic elements, respectively). The total risk index was greater in agricultural areas (DW > KYR > YTR > KRW > B > Y). Total risk indices were greater where well water was the source versus fountain water; for the latter, the total health risk index was greater versus glacier water. Main health risk factors were Cr and As in DW, KYR, YTR, KRW, and B, and Zn, Cr, and As in the Y region. Overall, total trace element-induced health risk (including for DW adults) was higher than acceptable (10(-6)) and lower than priority risk levels (10(-4)) (KYR, YTR, KRW, Y, and B). For DW children, total health risk reached 1.08 × 10(-4), higher than acceptable and priority risk levels (10(-4)).


Impacts of climate change on precipitation and discharge extremes through the use of statistical downscaling approaches in a Mediterranean basin.
Mediterranean region is characterized by high precipitation variability often enhanced by orography, with strong seasonality and large inter-annual fluctuations, and by high heterogeneity of terrain and land surface properties. As a consequence, catchments in this area are often prone to the occurrence of hydrometeorological extremes, including storms, floods and flash-floods. A number of climate studies focused in the Mediterranean region predict that extreme events will occur with higher intensity and frequency, thus requiring further analyses to assess their effect at the land surface, particularly in small- and medium-sized watersheds. In this study, climate and hydrologic simulations produced within the Climate Induced Changes on the Hydrology of Mediterranean Basins (CLIMB) EU FP7 research project were used to analyze how precipitation extremes propagate into discharge extremes in the Rio Mannu basin (472.5km(2)), located in Sardinia, Italy. The basin hydrologic response to climate forcings in a reference (1971-2000) and a future (2041-2070) period was simulated through the combined use of a set of global and regional climate models, statistical downscaling techniques, and a process based distributed hydrologic model. We analyzed and compared the distribution of annual maxima extracted from hourly and daily precipitation and peak discharge time series, simulated by the hydrologic model under climate forcing. For this aim, yearly maxima were fit by the Generalized Extreme Value (GEV) distribution using a regional approach. Next, we discussed commonality and contrasting behaviors of precipitation and discharge maxima distributions to better understand how hydrological transformations impact propagation of extremes. Finally, we show how rainfall statistical downscaling algorithms produce more reliable forcings for hydrological models than coarse climate model outputs.


Natriuretic peptide receptor-3 gene (NPR3): nonsynonymous polymorphism results in significant reduction in protein expression because of accelerated degradation.
BACKGROUND- The primary role of natriuretic peptide receptor-3 (NPR3) or NPR-C is in the clearance of natriuretic peptides that play an important role in modulating intravascular volume and vascular tone. Genetic variation in NPR3 has been associated with variation in blood pressure and obesity. Despite the importance of NPR3, sequence variation in the gene has not been addressed using DNA from different ethnic populations. We set out to identify and functionally characterize genetic variation in NPR3 in 3 ethnic groups. METHODS AND RESULTS- DNA samples from 96 European American, 96 African American, and 96 Han Chinese American healthy subjects were used to resequence NPR3 exons, splice junctions, and flanking regions. We identified 105 polymorphisms, 50 of which were novel, including 8 nonsynonymous single-nucleotide polymorphisms, 7 were novel. Expression constructs were created for the nonsynonymous single-nucleotide polymorphisms. HEK293 cells were transfected with constructs for wild type and variant allozymes; and recombinant proteins were measured by quantitative Western blot analysis. The most significant change in NPR3 protein was observed for the Arg146 variant allozyme, with 20% of wild-type protein, primarily because of autophagy-dependent degradation. NPR3 structural modeling confirmed that the Arg146 variant protein was not compatible with wild-type conformation and could result in protein misfolding or instability. CONCLUSIONS- Multiple novel NPR3 genetic polymorphisms were identified in 3 ethnic groups. The Arg146 allozyme displayed a significant decrease in protein quantity because of degradation mediated predominantly by autophagy. This genetic variation could have a significant effect on the metabolism of natriuretic peptides with potential clinical implications.


Regional distributions of overall dentists and institutional dentists in Taiwan in 2019.
Taiwan is facing a huge urban-rural gap in the human resources of dentists between cities and counties. Although the postgraduate year training program for dentists (PGYD) was implemented in Taiwan in 2010, the uneven distribution of dentists is still a serious problem. The purpose of this study was to evaluate the distributions of overall dentists and dental training institutions and their dentists (so-called institutional dentists) in each city and county in 2019 to further analyze the regional distributions of overall dentists and institutional dentists in Taiwan. This study collected the numbers of dentists, dental training institutions, and institutional dentists in each city and county in 2019 for evaluating the regional distributions of dentists and institutional dentists in Taiwan. The numbers of dentists and institutional dentists in municipalities were significantly higher than those in non-municipalities in Taiwan, respectively. The coefficient of variation was greatest for dentists in the single-system institutions (1.72) and program-management institutions (1.87). The coefficients of correlation between the dentist index and institutional dentist index were R2 = 0.9805 (P < 0.001) for municipalities, R2 = 0.4523 (P < 0.01) for non-municipalities, and R2 = 0.7691 (P < 0.001) for nationwide. The dentist manpower and dental training institutions are concentrated in municipalities of Taiwan. The quantitative and qualitative improvement of collaborating institutions in the PGYD system may have an influence on the distribution of new-entry dentists and contribute to establishment of an effective regional dental health care service.


Nod1 and Nod2 induce CCL5/RANTES through the NF-kappaB pathway.
The Nod-like receptor proteins Nod1 and Nod2 participate in innate immune responses against bacteria through intracellular detection of peptidoglycan, a component of bacterial cell wall. Recent evidence has demonstrated that Nod1 stimulates the release of chemokines that attract neutrophils at the site of infection, such as CXCL8/IL-8 in humans, and CXCL1/keratinocyte-derived chemokine and CXCL2/MIP-2 in mice. We aimed to determine whether Nod proteins could trigger the release of CCL5/RANTES, a chemokine known to attract a number of immune cells, but not neutrophils. Our results demonstrate that activation of both Nod1 and Nod2 results in substantial secretion of CCL5 by murine macrophages. Moreover, in vivo, the intraperitoneal injection of murine Nod1 or Nod2 agonists resulted in a rapid secretion of CCL5 into the bloodstream. We also observed that Nod-dependent secretion of CCL5 did not correlate with the induction of the interferon-beta pathway, a major signaling cascade for the activation of CCL5 by viruses. In contrast, we identified a key role of the NF-kappaB pathway in Nod-dependent stimulation of the CCL5 promoter. Together, these results identify a novel target downstream of Nod1 and Nod2, which is likely to play a key role in orchestrating the global Nod-dependent immune defense during bacterial infections.


Pristine mangrove creek waters are a sink of nitrous oxide.
Nitrous oxide (N2O) is an important greenhouse gas, but large uncertainties remain in global budgets. Mangroves are thought to be a source of N2O to the atmosphere in spite of the limited available data. Here we report high resolution time series observations in pristine Australian mangroves along a broad latitudinal gradient to assess the potential role of mangroves in global N2O budgets. Surprisingly, five out of six creeks were under-saturated in dissolved N2O, demonstrating mangrove creek waters were a sink for atmospheric N2O. Air-water flux estimates showed an uptake of 1.52 ± 0.17 μmol m(-2) d(-1), while an independent mass balance revealed an average sink of 1.05 ± 0.59 μmol m(-2) d(-1). If these results can be upscaled to the global mangrove area, the N2O sink (~2.0 × 10(8) mol yr(-1)) would offset ~6% of the estimated global riverine N2O source. Our observations contrast previous estimates based on soil fluxes or mangrove waters influenced by upstream freshwater inputs. We suggest that the lack of available nitrogen in pristine mangroves favours N2O consumption. Widespread and growing coastal eutrophication may change mangrove waters from a sink to a source of N2O to the atmosphere, representing a positive feedback to climate change.


Preparatory trunk motion accompanies rapid upper limb movement.
Evaluation of trunk movements, trunk muscle activation, intra-abdominal pressure and displacement of centres of pressure and mass was undertaken to determine whether trunk orientation is a controlled variable prior to and during rapid bilateral movement of the upper limbs. Standing subjects performed rapid bilateral symmetrical upper limb movements in three directions (flexion, abduction and extension). The results indicated a small (0.4-3.3 degrees) but consistent initial angular displacement between the segments of the trunk in a direction opposite to that produced by the reactive moments resulting from limb movement. Phasic activation of superficial trunk muscles was consistent with this pattern of preparatory motion and with the direction of motion of the centre of mass. In contrast, activation of the deep abdominal muscles was independent of the direction of limb motion, suggesting a non-direction specific contribution to spinal stability. The results support the opinion that feedforward postural responses result in trunk movements, and that orientation of the trunk and centre of mass are both controlled variables in relation to rapid limb movements.


High-Temperature Cross-Linking of Carbon Nanotube Multi-Yarn Using Polyvinylpyrrolidone as a Binding Agent.
Carbon nanotube (CNT) multi-yarn was cross-linked together at elevated temperatures using a poly- mer, with the intent of improving their strength and electrical conductivity. They were functionalized using an acid treatment and immersed in a bath of different concentrations (0.5%, 0.1%, and 0.2%) of polyvinylpyrrolidone (PVP). Then they were placed in an oven at various temperatures (180 °C, 200 °C, and 220 °C) in order to cause cross-linking among the carbon nanotube yarns. The phys- ical, chemical, electrical, and mechanical properties of the cross-linked yarns were investigated. The yarns cross-linked at higher temperatures and greater concentrations of PVP had a greater increase in linear mass density, indicating that the cross-linking process had worked as expected. Yarns that were cross-linked at lower temperatures had greater tensile strength and better spe- cific electrical conductivity. Those that were treated with a greater concentration of polymer had a greater ultimate tensile strength. All these results are encouraging first step, but still need further development if CNT yarn is to replace copper wire.


Sex differences in circumstances and consequences of outdoor and indoor falls in older adults in the MOBILIZE Boston cohort study.
Despite extensive research on risk factors associated with falling in older adults, and current fall prevention interventions focusing on modifiable risk factors, there is a lack of detailed accounts of sex differences in risk factors, circumstances and consequences of falls in the literature. We examined the circumstances, consequences and resulting injuries of indoor and outdoor falls according to sex in a population study of older adults. Men and women 65 years and older (N = 743) were followed for fall events from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston prospective cohort study. Baseline measurements were collected by comprehensive clinical assessments, home visits and questionnaires. During the follow-up (median = 2.9 years), participants recorded daily fall occurrences on a monthly calendar, and fall circumstances were determined by a telephone interview. Falls were categorized by activity and place of falling. Circumstance-specific annualized fall rates were calculated and compared between men and women using negative binomial regression models. Women had lower rates of outdoor falls overall (Crude Rate Ratio (RR): 0.72, 95% Confidence Interval (CI): 0.56-0.92), in locations of recreation (RR: 0.34, 95% CI: 0.17-0.70), during vigorous activity (RR: 0.38, 95% CI: 0.18-0.81) and on snowy or icy surfaces (RR: 0.55, 95% CI: 0.36-0.86) compared to men. Women and men did not differ significantly in their rates of falls outdoors on sidewalks, streets, and curbs, and during walking. Compared to men, women had greater fall rates in the kitchen (RR: 1.88, 95% CI: 1.04-3.40) and while performing household activities (RR: 3.68, 95% CI: 1.50-8.98). The injurious outdoor fall rates were equivalent in both sexes. Women's overall rate of injurious indoor falls was nearly twice that of men's (RR: 1.98, 95% CI: 1.44-2.72), especially in the kitchen (RR: 6.83, 95% CI: 2.05-22.79), their own home (RR: 1.84, 95% CI: 1.30-2.59) and another residential home (RR: 4.65, 95% CI: 1.05-20.66) or other buildings (RR: 2.29, 95% CI: 1.18-4.44). Significant sex differences exist in the circumstances and injury potential when older adults fall indoors and outdoors, highlighting a need for focused prevention strategies for men and women.


A Path Analysis of Self-determination and Resiliency for Consumers Living with Mental Illness.
Over the last three decades, resilience has become a key area in mental health research, practice and policy, due to its potential to positively impact on wellbeing and quality of life. Research findings have identified that resilience positively correlates with an individual's subjective sense of well-being and decreased mental health problems. Given the potential benefits of resilience for those living with mental illness, research should examine ways in which these individuals can increase their resilience levels. One such method of examining resilience in people living with mental illness is through a motivational lens. Using Self-Determination Theory (SDT) lens, this study examined the potential of a proposed model for understanding the correlation and influence of motivational constructs on the resilience of people with a lived experience of mental illness. Results illustrated a goodness-of-fit for the proposed model. Results can be used to illustrate the importance of motivation and self-determination for people living with mental illness.


Efficient herpes simplex virus type 1 (HSV-1) capsid formation directed by the varicella-zoster virus scaffolding protein requires the carboxy-terminal sequences from the HSV-1 homologue.
The scaffolding protein and associated protease of the human herpesvirus varicella-zoster virus (VZV), encoded by genes 33.5 and 33 respectively, were synthesized in insect cells using a baculovirus expression system. The expressed 33.5 product formed numerous long, flexible, hollow rods, and in this respect different from the herpes simplex virus type 1 (HSV-1) homologue which forms large aggregates consisting mainly of fibrous material interspersed with scaffold-like particles. Removal of 27 amino acids from the carboxy terminus of the VZV scaffolding protein by the gene 33 protease or expression of the cleaved product did not result in any discernible change in the morphology of the scaffolding protein. Again, this was in marked contrast to the situation in HSV-1 where removal of the 25 carboxy-terminal amino acids from the scaffolding protein by the associated protease or expression of VP22a results in the formation of large numbers of scaffold-like particles. Despite these differences, when cells were multiply infected with baculoviruses expressing the HSV-1 capsid shell proteins and the VZV scaffolding protein complete capsids were observed, suggesting that the VZV protein could act as a scaffold for the assembly of the HSV-1 capsid shell. The efficiency of capsid assembly was increased substantially by exchanging the 23 carboxy-terminal amino acids of the VZV scaffolding protein for the corresponding 22 carboxy-terminal amino acids of the HSV-1 homologue, supporting previous work which showed that this region was critical for the formation of intact capsids.


Modulation transfer function and quantum efficiency correlation at long wavelengths (greater than 800 nm) in linear charge coupled imagers.
The spectral modulation transfer function (MTF) of several architecturally identical commercial linear silicon charge coupled imagers (CCIs) was measured and compared to an MTF theory that included the effects of detector aperture and lateral diffusion in one dimension. A successful match between experimental data and theory was possible for proper choices of the detector aperture function and minority carrier lifetime. Long-wave (> 800-nm) MTF and spectral quantum efficiency (QE) data were very well correlated over the set of CCIs that were measured, indicating the key role of carrier lifetime (or equivalently carrier diffusion length) in determining both characteristics. This correlation was verified by exercising the MTF and QE models, tailored for the CCIs devices, with carrier lifetime as one of the free parameters.


Congenital lung lesions: classification and concordance of radiological appearance and surgical pathology.
Congenital lung lesions are diagnosed antenatally in the majority of cases. Postnatal management includes chest radiography and CT-scanning, followed by either surgical resection or CT surveillance. Pre-operatively, lesions are often "labelled" as CCAM (and the Stocker classification incorrectly applied), sequestration, or lobar emphysema, and their frequent "hybrid" nature sometimes missed. The aim of our study was to correlate antenatal and postnatal radiological diagnoses and classification of congenital lung lesions with surgical and pathological outcome. Twenty-six consecutive cases of antenatally-diagnosed cystic lung lesions managed at our centre between January 2003 and April 2007 were reviewed. Diagnoses were: cystic adenomatoid malformations (CCAM) in 13 cases (50.0%), three bronchopulmonary sequestrations (11.5%), "hybrid" lesions in eight cases (30.8%), one isolated lobar emphysema (3.8%) and a normal lung segment with anomalous systemic supply (3.8%). Overall concordance rate between prenatal ultrasound and resection pathology was 61.5%, whereas CT findings correlated with pathology in 65.4% of cases. Incorrect radiological classification resulted in one morbidity, when an attempted thoracoscopic resection of a presumed CCAM had to be converted to an open procedure due to bleeding from an unsuspected anomalous vessel. The common embryological origin of these lesions, and the need for standardisation of reporting is discussed. We propose that lesions should be classified anatomically according to their nature, arterial supply and venous drainage in order to reduce discrepancies between radiological, intra-operative and pathological reporting.


The safety and efficacy of spinal anesthesia for surgery in infants: the Vermont Infant Spinal Registry.
Studies with modest numbers of patients have suggested that spinal anesthesia in infants is associated with a very infrequent incidence of complications, such as hypoxemia, bradycardia, and postoperative apnea. Although spinal anesthesia would seem to be a logical alternative to general anesthesia for many surgical procedures, it remains an underutilized technique. Since 1978, clinical data concerning all infants undergoing spinal anesthesia at the University of Vermont have been prospectively recorded. In all, 1554 patients have been studied. Anesthesia was performed by anesthesia trainees and attending anesthesiologists. The success rate for LP was 97.4%. An adequate level of spinal anesthesia was achieved in 95.4% of cases. The average time required to induce spinal anesthesia was 10 min. Oxygen hemoglobin desaturation to <90% was observed in 10 patients. Bradycardia (heart rate <100 bpm) occurred in 24 patients (1.6%). This study confirms the infrequent incidence of complications associated with spinal anesthesia in infants. Spinal anesthesia can be performed safely, efficiently, and with the expectation of a high degree of success. Spinal anesthesia should be strongly considered as an alternative to general anesthesia for lower abdominal and lower extremity surgery in infants.


Kinetics of Na+ and K+ transport in red blood cells of Dahl rats. Effects of age and salt.
Blood pressure response to chronic high salt intake and kinetics of red blood cell Na+ and K+ (Rb+) transport were studied in salt-sensitive (DS) and salt-resistant (DR) Dahl rats fed a high salt diet (8% NaCl) for 7 weeks from the fifth (young), 12th (adult), or 23rd (old) week of age. The kinetics of ouabain-sensitive Rb+ uptake and Na+ extrusion were determined in Na+ media as a function of both intracellular Na+ (Na+i, 2-8 mmol/l cells) and extracellular Rb+ (Rb+o). In addition, the kinetics of furosemide-sensitive Rb+ uptake (related to Rb+o) and the magnitude of the Na+ and Rb+ leaks were assessed. High salt induced hypertension in young and adult but not in old DS rats although red blood cell Na+ was slightly increased in all age groups of DS rats fed a high salt diet. The kinetic parameters of the Na(+)-K+ pump were similar in DS and DR rats fed a low salt diet. Ouabain-sensitive transport rates were not suppressed in erythrocytes of salt hypertensive Dahl rats. Maximal velocities of the Na(+)-K+ pump (related to Na+i) decreased significantly with age in all groups except in DS rats fed a high salt diet. This was compensated by an age-dependent increase in the affinity for Na+i so that no substantial differences in transport rates between young and old rats were seen at physiological cell Na+ and plasma K+ levels.(ABSTRACT TRUNCATED AT 250 WORDS)


[Perceptions of dentistry teachers in the teaching and learning process].
The didactic-pedagogical training of the university professor and of the quality of higher education must be revised due to the demands of the dynamic society and to the implementation of national curricular guidelines. Within this context, it was analyzed the perceptions of dentistry undergraduate of Universidade Estadual de Londrina teachers about the role of the teacher in the teaching and learning process. A qualitative research was carried out and data were collected through semi-structured interviews. Results showed that the teacher plays an essential role in the teaching and learning process, being the sole provider of knowledge. Teaching and learning strategies are based on oral transmission. Most part of the teachers got their didactic-pedagogical education from postgraduate Courses (Master's and/or PhD), that do not qualify teachers adequately for their teaching career. The teachers are not formally prepared for their teaching careers. In conclusion, findings from this study must be revised both regarding the training and the didactic-pedagogical upgrading in search of a general, humanist, critical and reflexive formation of the student.


Toward more accurate use of the Beck Depression Inventory with chronic back pain patients.
To improve the accuracy of the Beck Depression Inventory (BDI) in assessing depression in chronic back pain (CBP) patients, the pattern of depression symptomatology was evaluated. Analyses of BDI data obtained from nondepressed and depressed CBP patients were conducted to identify the major factors that differentiated among the patient groups. CBP patients were recruited from a tertiary rehabilitation center. One hundred one nondepressed and 99 depressed CBP patients from the tertiary treatment center. Analyses of the BDI data revealed a general factor of depression severity that excluded items reflecting weight loss, sleep disturbance, and work inhibition. In addition, these analyses yielded a second factor reflecting somatic concerns and disability. Weight loss, sleep disturbance, and work inhibition failed to differentiate the depressed from the nondepressed CBP subjects, suggesting that these symptoms have poor diagnostic potential for CBP patients. This study demonstrated that the BDI can be used to generate important information about the severity of interference posed by pain on the functioning of an individual, while allowing for an independent evaluation of subjective indices of depression and somatic disturbances that need to be attended to by clinicians.


Examining the effectiveness of 2 solutions used to flush capped pediatric peripheral intravenous catheters.
An evidence-based study examined the effectiveness of 2 solutions, heparin and normal saline, when used to flush capped pediatric peripheral intravenous (CPP IV) catheters. This experimental study assessed patency, redness, swelling, clotting, bruising, leakage, and patient pain after each intervention/flush. Study participants included 62 children (32 heparin and 30 normal saline) who had CPP IV catheters using 20-, 22-, or 24-gauge catheters. No statistically significant differences were found in IV catheter patency between children in the normal saline group and children in the heparin group. A postimplementation follow-up study with 30 patients who received normal saline only as a flush experienced no patency issues.


Factors affecting the abundance of leaf-litter arthropods in unburned and thrice-burned seasonally-dry Amazonian forests.
Fire is frequently used as a land management tool for cattle ranching and annual crops in the Amazon. However, these maintenance fires often escape into surrounding forests, with potentially severe impacts for forest biodiversity. We examined the effect of experimental fires on leaf-litter arthropod abundance in a seasonally-dry forest in the Brazilian Amazon. The study plots (50 ha each) included a thrice-burned forest and an unburned control forest. Pitfall-trap samples were collected at 160 randomly selected points in both plots, with sampling stratified across four intra-annual replicates across the dry and wet seasons, corresponding to 6, 8, 10 and 12 months after the most recent fire. Arthropods were identified to the level of order (separating Formicidae). In order to better understand the processes that determine arthropod abundance in thrice-burned forests, we measured canopy openness, understory density and litter depth. All arthropod taxa were significantly affected by fire and season. In addition, the interactions between burn treatment and season were highly significant for all taxa but Isoptera. The burned plot was characterized by a more open canopy, lower understory density and shallower litter depth. Hierarchical partitioning revealed that canopy openness was the most important factor explaining arthropod order abundances in the thrice-burned plot, whereas all three environmental variables were significant in the unburned control plot. These results reveal the marked impact of recurrent wildfires and seasonality on litter arthropods in this transitional forest, and demonstrate the overwhelming importance of canopy-openness in driving post-fire arthropod abundance.


Abnormal levels of heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) in tumour tissue and blood samples from patients diagnosed with lung cancer.
Lung cancer is the second most common type of cancer in the world and is the most common cause of cancer-related death in both men and women. Research into causes, prevention and treatment of lung cancer is ongoing and much progress has been made recently in these areas, however survival rates have not significantly improved. Therefore, it is essential to develop biomarkers for early diagnosis of lung cancer, prediction of metastasis and evaluation of treatment efficiency, as well as using these molecules to provide some understanding about tumour biology and translate highly promising findings in basic science research to clinical application. In this investigation, two-dimensional difference gel electrophoresis and mass spectrometry were initially used to analyse conditioned media from a panel of lung cancer and normal bronchial epithelial cell lines. Significant proteins were identified with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), pyruvate kinase M2 isoform (PKM2), Hsc-70 interacting protein and lactate dehydrogenase A (LDHA) selected for analysis in serum from healthy individuals and lung cancer patients. hnRNPA2B1, PKM2 and LDHA were found to be statistically significant in all comparisons. Tissue analysis and knockdown of hnRNPA2B1 using siRNA subsequently demonstrated both the overexpression and potential role for this molecule in lung tumorigenesis. The data presented highlights a number of in vitro derived candidate biomarkers subsequently verified in patient samples and also provides some insight into their roles in the complex intracellular mechanisms associated with tumour progression.


Analysis of rat haunch odor using dynamic solvent effect and principal component analysis.
We used the dynamic solvent effect to sample rat haunch odor, which we then analyzed using principal component analysis. PCA, based on 22 volatile components, indicated that one axis clearly separated rat haunch odor samples according to sex and female reproductive condition (estrus and diestrus), explaining 79.5% of the variation in proportional peak area. We have therefore been able to separate odors along biologically meaningful lines.


Calcium transport by sarcoplasmic reticulum Ca-ATPase can be investigated on a solid-supported membrane.
Sarcoplasmic reticulum (SR) native vesicles incorporating Ca-ATPase are adsorbed on a solid-supported lipid membrane (SSM). Upon adsorption, the ion pumps are chemically activated by concentration jumps of ATP and the capacitive current transients generated by SR Ca-ATPase are measured under potentiostatic conditions. The Michaelis-Menten constant, K(M), for ATP is evaluated by varying the concentration of ATP in the activating solution. This preliminary result shows that ion transport by SR Ca-ATPase can be suitably investigated by a technique based on concentration jumps on an SSM.


Identification of novel DNA methylation markers in cervical cancer.
Testing for DNA methylation has potential in cancer screening. Most previous studies of DNA methylation in cervical cancer used a candidate gene approach. The aim our study was to identify novel genes that are methylated in cervical cancers and to test their potential in clinical applications. We did a differential methylation hybridization using a CpG island (CGI) microarray containing 8640 CGI tags to uncover methylated genes in squamous cell carcinomas (SCC) of the uterine cervix. Pooled DNA from cancer tissues and normal cervical swabs were used for comparison. Methylation-specific polymerase chain reaction, bisulfite sequencing and reverse transcription polymerase chain reaction were used to confirm the methylation status in cell lines, normal cervices (n = 45), low-grade lesions (n = 45), high-grade lesions (HSIL; n = 58) and invasive squamous cell carcinomas (SCC; n = 22 from swabs and n = 109 from tissues). Human papillomavirus (HPV) was detected using reverse line blots. We reported 6 genes (SOX1, PAX1, LMX1A, NKX6-1, WT1 and ONECUT1) more frequently methylated in SCC tissues (81.5, 94.4, 89.9, 80.4, 77.8 and 20.4%, respectively) than in their normal controls (2.2, 0, 6.7, 11.9, 11.1 and 0%, respectively; p < 0.0001). Parallel testing of HPV and PAX1 methylation in cervical swabs confers an improved sensitivity than HPV testing alone (80% vs. 66%) without compromising specificity (63% vs. 64%) for HSIL/SCC. Testing PAX1 methylation marker alone, the specificity for HSIL/SCC is 99%. The analysis of these novel DNA methylations may be a promising approach for the screening of cervical cancers.


The enteropathy of prostaglandin deficiency.
Small intestinal ulcers are frequent complications of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine. Eicosanoids and metabolites were measured by isotope dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR. We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P<0.006), and serum 12-HETE was 1.3% of controls (P<0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-alpha (cPLA2-alpha), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA2-alpha cDNA demonstrated two heterozygous nonsynonymous single-base-pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known single nucleotide polymorphism (SNP), Lys651Arg (K651R). Characterization of this cPLA2-alpha deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers.


Vitamin K and bone health.
Vitamin K has been purported to play an important role in bone health. It is required for the gamma-carboxylation of osteocalcin (the most abundant noncollagenous protein in bone), making osteocalcin functional. There are 2 main forms (vitamin K1 and vitamin K2), and they come from different sources and have different biological activities. Epidemiologic studies suggest a diet high in vitamin K is associated with a lower risk of hip fractures in aging men and women. However, randomized controlled trials of vitamin K1 or K2 supplementation in white populations did not increase bone mineral density at major skeletal sites. Supplementation with vitamin K1 and K2 may reduce the risk of fractures, but the trials that examined fractures as an outcome have methodological limitations. Large well-designed trials are needed to compare the efficacies of vitamin K1 and K2 on fractures. We conclude that currently there is not enough evidence to recommend the routine use of vitamin K supplements for the prevention of osteoporosis and fractures in postmenopausal women.


Remote ischemic preconditioning impairs ventricular function and increases infarct size after prolonged ischemia in the isolated neonatal rabbit heart.
Remote ischemic preconditioning (rIPC) reduces myocardial injury in adults and children undergoing cardiac surgery. We compared the effect of rIPC in adult and neonatal rabbits to investigate whether protection against ischemia-reperfusion injury can be achieved in the newborn heart by (1) in vivo rIPC and (2) dialysate from adult rabbits undergoing rIPC. Isolated hearts from newborn and adult rabbits were randomized into 3 subgroups (control, in vivo rIPC, and dialysate obtained from adult, remotely preconditioned rabbits). Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Left ventricular (LV) function was assessed using a balloon-tipped catheter, glycolytic flux by tracer kinetics, and infarct size by tetrazolium staining. Isolated hearts underwent stabilization while perfused with standard Krebs-Henseleit buffer (control and in vivo rIPC) or Krebs-Henseleit buffer with added dialysate, followed by global no-flow ischemia and reperfusion. Within the age groups, the baseline LV function was similar in all subgroups. In the adult rabbit hearts, rIPC and rIPC dialysate attenuated glycolytic flux and protected against ischemia-reperfusion injury, with better-preserved LV function compared with that of the controls. In contrast, in the neonatal hearts, the glycolytic flux was lower and LV function was better preserved in the controls than in the rIPC and dialysate groups. In the adult hearts, the infarct size was reduced in the rIPC and dialysate groups compared with that in the controls. In the neonatal hearts, the infarct size was smaller in the controls than in the rIPC and dialysate groups. Remote ischemic preconditioning does not protect against ischemia-reperfusion injury in isolated newborn rabbit hearts and might even cause deleterious effects. Similar adverse effects were induced by dialysate from remotely preconditioned adult rabbits.