Balneotherapy in rheumatoid arthritis-a systematic review.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent inflammation of synovial joints with pain, often leading to joint destruction and disability, and despite intensive research, the cause of RA remains unknown. Balneotherapy-also called mineral baths or spa therapy-uses different types of mineral water compositions like sulphur, radon, carbon dioxin, etc. The role of balneotherapy is on debate; Sukenik wrote that the sulphur mineral water has special proprieties to rheumatologic diseases, including in the course of active inflammatory phases in RA. The aim of this review is to summarize the available evidence on the effects of balneotherapy on patients with rheumatoid arthritis. We have made a systematic search of the articles published from 1980 to 2014 on this topic in PubMed, Scopus, CRD, PEDro, Web of Science and Embase databases. We have followed the method set by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). These that have compared balneotherapy with other therapeutic modalities or with no intervention were considered. The inclusion criteria of these papers were randomized control trial (RCT); languages: English, French, Spanish, Italian and Portuguese; evaluation of efficacy (analysis of outcomes); use of natural mineral water baths; and participants with RA. A total of eight articles documenting RCTs were found and included for full review and critical appraisal involving a total of 496 patients. The studies selected highlighted an important improvement and statistically significant in several clinical parameters, in spite of their heterogeneity between the various studies. One study emphasized an important improvement on functional capacity up to 6 months of follow-up (FU). Some of the studies (std.) reveal an improvement on morning stiffness (5 std.), number of active joints (3 std.), Ritchie index (2 std.) and activities of daily living (2 std.) up to 3 months of FU. Three studies reveal the improvement on handgrip strength up to 1 month of FU. About pain (VAS), the three studies which evaluated this parameter were inconclusive about real significant improvement. Our tables summarize the published papers about this topic. Different authors emphasize the same problems: methodologies differing from study to study, treatment modalities, outcomes and their analysis. On the one hand, it is particularly difficult to have homogeneity on this population in all the parameters (patient's clinical heterogeneity, diverse clinical course of the disease, variety of the drugs), and on the other hand, natural mineral water composition is always unique with potential specific biological effects. This comprehensive review has revealed that there are very few published studies about the use of natural mineral water in RA. International multicentre studies, using the same methodologies, could be achieved by carrying the scientific arguments to support our clinical practice.


Binge pattern of alcohol consumption during pregnancy and childhood mental health outcomes: longitudinal population-based study.
Patterns of alcohol consumption during pregnancy such as episodes of binge drinking may be as important as average levels of consumption in conferring risk for later childhood mental health and learning problems. However, it can be difficult to distinguish risk resulting from episodic or regular background levels of drinking. This large study investigates whether patterns of alcohol consumption are independently associated with child mental health and cognitive outcomes, whether there are gender differences in risk, and whether occasional episodes of higher levels of drinking carry any risk in the absence of regular daily drinking during pregnancy. This prospective, population-based study used data from the Avon Longitudinal Study of Parents and Children. We investigated the relationships between a binge pattern of alcohol use (consumption of > or =4 drinks in a day) in the second and third trimesters of pregnancy and childhood mental health problems at 47 and 81 months of age (n = 6355 and 5599, respectively). In a subgroup, we also investigated these relationships with child IQ at 49 months of age (n = 924). fter controlling for a range of prenatal and postnatal factors, any episodes of consuming > or =4 drinks in a day were independently associated with higher risks for mental health problems (especially hyperactivity/inattention) in girls at the age of 47 months and in both genders at 81 months. There was no association with IQ scores at 49 months after adjustment for confounders. The consumption of > or =4 drinks in a day continued to carry risk for mental health problems (especially hyperactivity/inattention) in the absence of regular daily drinking. The consumption of > or =4 drinks in a day on an occasional basis during pregnancy may increase risk for child mental health problems in the absence of moderate daily levels of drinking. The main risks seem to relate to hyperactivity and inattention problems.


Temporal profile of the renal transcriptome of HIV-1 transgenic mice during disease progression.
Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets.


Metal-semiconductor transition like behavior of naphthalene-doped single wall carbon nanotube bundles.
Naphthalene (N) or naphthalene-derivative (ND) adsorption-treatment evidently varies the electrical conductivity of single wall carbon nanotube (SWCNT) bundles over a wide temperature range due to a charge-transfer interaction. The adsorption treatment of SWCNTs with dinitronaphthalene molecules enhances the electrical conductivity of the SWCNT bundles by 50 times. The temperature dependence of the electrical conductivity of N- or ND-adsorbed SWCNT bundles having a superlattice structure suggests metal-semiconductor transition like behavior near 260 K. The ND-adsorbed SWCNT gives a maximum in the logarithm of electrical conductivity vs. T(-1) plot, which may occur after the change to a metallic state and be associated with a partial unravelling of the SWCNT bundle due to an evoked librational motion of the moieties of ND with elevation of the temperature.


[Comparison and evaluation of Lowenstein-Jensen medium and 2% Ogawa medium for the diagnosis of tuberculosis].
Accurate diagnosis of tuberculosis is based on the detection of the bacilli in the clinical specimen. The growth of mycobacteria in laboratory media is regarded as the gold standard for diagnosis and use of two different cultivation media, one of them being a liquid one, is recommended. In this study, the diagnostic values of egg-based Lowenstein-Jensen (LJ) medium used extensively all over the world and Ogawa (2%) medium were compared. A total of 7912 pulmonary and extrapulmonary clinical samples which belonged to 3311 patients with suspected tuberculosis, were enrolled in the National Tuberculosis Reference Laboratory in Refik Saydam National Public Health Agency during 2.5 years (January 2006- June 2008). The samples were processed by modified Petroff method (4% NaOH) for homogenization-decontamination-concentration on the same day and inoculated on two Ogawa and two LJ media. The cultures were incubated at 35-37°C for eight weeks and were controlled on the third day of incubation in terms of contamination. If no contamination were detected, the cultures were incubated for a total of eight weeks with regular weekly controls. The colonies detected in culture media were identified by biochemical tests, including paranitrobenzoic acid (PNB), niacin accumulation and nitrate reduction tests. Those identified as Mycobacterium tuberculosis complex were reported as positive. The rates of contamination was 3.1% for Ogawa medium and 4% for LJ medium. Culture results were found positive for 248 patients (7.5%). While 210 of these were positive by both of the media, 20 (8.1%) patients were detected positive only by LJ and 18 (7.3%) only by Ogawa medium. The sensitivity of LJ medium was 92.7% (230/248) and of Ogawa medium was 91.9% (228/248). When LJ medium was taken as the reference method, the sensitivity, specificity, positive and negative predictive values of Ogawa medium were 91.3%, 99.4%, 92.1% and 99.4%, respectively. It was concluded that, when low price and low contamination rates were taken into consideration, Ogawa medium, used together with a liquid medium + LJ medium, would increase the yield of mycobacteria from single samples (cerebrospinal fluid, biopsy, pus, etc.) sent to the laboratories.


Comparison of methods of DNA extraction from stream sediments.
In Upper Three Runs Creek (Aiken, S.C.) and many other environments, less than 1% of bacteria visible microscopically can be cultured. Exploitation of molecular biology techniques has led to development of new methods, such as extraction of nucleic acids from soils or sediments, to study the dominant, nonculturable bacteria. The purpose of this study was to compare three published methods of DNA extraction that fall into two general categories: those in which cells are lysed in sediments (the Ogram and Tsai and methods [A. Ogram, G. S. Sayler, and T. Barkay, J. Microbiol. Methods 7:57-66, 1987; Y. L. Tsai and B. H. Olson, Appl. Environ. Microbiol. 57:1070-1074, 1991]) and those in which cells are removed from sediments prior to lysis (the Jacobsen method [C. S. Jacobsen and O. S. Rasmussen; Appl. Environ. Microbiol. 58:2458-2462, 1992]). DNA yield varied with extraction method; the Ogram method had a significantly higher yield than the other methods. However, DNA extracted via the Ogram method was badly sheared and contained a smaller proportion of eubacterial DNA. The Tsai method was less time consuming than the other methods, but DNA samples were of lower purity. If DNA purity is of paramount concern (as would be the case if PCR was to be performed) and quantity is not important, the Jacobsen method is recommended because of the low concentration of contaminants. If DNA is to be used directly in DNA-DNA hybridizations, the Ogram method is recommended since it gives maximal yields.(ABSTRACT TRUNCATED AT 250 WORDS)


Blood NfL: A biomarker for disease severity and progression in Parkinson disease.
To examine whether plasma neurofilament light chain (NfL) levels were associated with motor and cognitive progression in Parkinson disease (PD). This prospective follow-up study enrolled 178 participants, including 116 with PD, 22 with multiple system atrophy (MSA), and 40 healthy controls. We measured plasma NfL levels with electrochemiluminescence immunoassay. Patients with PD received evaluations of motor and cognition at baseline and at a mean follow-up interval of 3 years. Changes in the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score and Mini-Mental State Examination score were used to assess motor and cognition progression. Plasma NfL levels were significantly higher in the MSA group than in the PD and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/mL, respectively, p < 0.001). In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001). NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95% confidence interval 0.46-0.56, p < 0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline motor or cognitive status showed that higher baseline NfL levels were associated with higher risks for either motor or cognition progression (p = 0.029 and p = 0.015, respectively). Plasma NfL levels correlated with disease severity and progression in terms of both motor and cognitive functions in PD. This study provides Class III evidence that plasma NfL level distinguishes PD from MSA and is a surrogate biomarker for PD progression.


Domino reaction of a gold catalyzed 5-endo-dig cyclization and a [3,3]-sigmatropic rearrangement towards polysubstituted pyrazoles.
Pyrazoles are important heterocyclic compounds with a broad range of biological activities. A new procedure toward tri- or tetrasubstituted pyrazoles has been developed, via a one-pot gold catalyzed synthesis from hydrazines with alkynyl aldehydes or ketones. The reaction proceeds through consecutive hydrazone formation, 5-endo-dig cyclization and an aza-Claisen rearrangement resulting in the desired polysubstitued pyrazoles.


Regular moist snuff dipping does not affect endurance exercise performance.
Physiological and medical effects of snuff have previously been obtained either in cross-sectional studies or after snuff administration to non-tobacco users. The effects of snuff cessation after several years of daily use are unknown. 24 participants with >2 years of daily snuff-use were tested before and after >6 weeks snuff cessation (SCG). A control group (CO) of 11 snuff users kept their normal habits. Resting heart rate (HR) and blood pressure (BP) were significantly lower in SCG after snuff cessation, and body mass was increased by 1.4 ± 1.7 kg. Total cholesterol increased from 4.12 ± 0.54 (95% CI 3.89-4.35) to 4.46 ± 0.70 (95% CI 4.16-4.75) mM L-1 in SCG, due to increased LDL, and this change was significantly different from CO. Resting values of HDL, C-reactive protein, and free fatty acids (FFA) remained unchanged in both groups. In SCG group, both HR and BP were reduced during a four-stage incremental cycling test (from 50 to 80% of VO2max) and a prolonged cycling test (60 min at 50% of VO2max). Oxygen uptake (VO2), respiratory exchange ratio, blood lactate (bLa) and blood glucose (bGlu) concentration, and rate of perceived exertion (RPE) were unchanged. In CO group, all measurements were unchanged. During the prolonged cycling test, FFA was reduced, but with no significant difference between groups. During the maximal treadmill running test peak values of VO2, pulmonary ventilation (VE), time to exhaustion and bLa were unchanged in both groups. In conclusion, endurance exercise performance (VO2max and maximal endurance time) does not seem to be affected by prolonged snuff use, while effects on cardiovascular risk factors are contradictory. HR and BP during rest and submaximal exercise are reduced after cessation of regular use of snuff. Evidently, the long-time adrenergic stress on circulation is reversible.


Fibroblasts in post-infarction inflammation and cardiac repair.
Fibroblasts are the predominant cell type in the cardiac interstitium. As the main matrix-producing cells in the adult mammalian heart, fibroblasts maintain the integrity of the extracellular matrix network, thus preserving geometry and function. Following myocardial infarction fibroblasts undergo dynamic phenotypic alterations and direct the reparative response. Due to their strategic location, cardiac fibroblasts serve as sentinel cells that sense injury and activate the inflammasome secreting cytokines and chemokines. During the proliferative phase of healing, infarct fibroblasts undergo myofibroblast transdifferentiation forming stress fibers and expressing contractile proteins (such as α-smooth muscle actin). Mechanical stress, transforming growth factor (TGF)-β/Smad3 signaling and alterations in the composition of the extracellular matrix induce acquisition of the myofibroblast phenotype. In the highly cellular and growth factor-rich environment of the infarct, activated myofibroblasts produce matrix proteins, proteases and their inhibitors regulating matrix metabolism. As the infarct matures, "stress-shielding" of myofibroblasts by the cross-linked matrix and growth factor withdrawal may induce quiescence and ultimately cause apoptotic death. Because of their critical role in post-infarction cardiac remodeling, fibroblasts are promising therapeutic targets following myocardial infarction. However, the complexity of fibroblast functions and the pathophysiologic heterogeneity of post-infarction remodeling in the clinical context discourage oversimplified approaches in clinical translation. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.


Survey shows that at least some physicians are not always open or honest with patients.
The Charter on Medical Professionalism, endorsed by more than 100 professional groups worldwide and the US Accreditation Council for Graduate Medical Education, requires openness and honesty in physicians' communication with patients. We present data from a 2009 survey of 1,891 practicing physicians nationwide assessing how widely physicians endorse and follow these principles in communicating with patients. The vast majority of physicians completely agreed that physicians should fully inform patients about the risks and benefits of interventions and should never disclose confidential information to unauthorized persons. Overall, approximately one-third of physicians did not completely agree with disclosing serious medical errors to patients, almost one-fifth did not completely agree that physicians should never tell a patient something untrue, and nearly two-fifths did not completely agree that they should disclose their financial relationships with drug and device companies to patients. Just over one-tenth said they had told patients something untrue in the previous year. Our findings raise concerns that some patients might not receive complete and accurate information from their physicians, and doubts about whether patient-centered care is broadly possible without more widespread physician endorsement of the core communication principles of openness and honesty with patients.


Cell cycle arrest of cdc mutants and specificity of the RAD9 checkpoint.
In eucaryotes a cell cycle control called a checkpoint ensures that mitosis occurs only after chromosomes are completely replicated and any damage is repaired. The function of this checkpoint in budding yeast requires the RAD9 gene. Here we examine the role of the RAD9 gene in the arrest of the 12 cell division cycle (cdc) mutants, temperature-sensitive lethal mutants that arrest in specific phases of the cell cycle at a restrictive temperature. We found that in four cdc mutants the cdc rad9 cells failed to arrest after a shift to the restrictive temperature, rather they continued cell division and died rapidly, whereas the cdc RAD cells arrested and remained viable. The cell cycle and genetic phenotypes of the 12 cdc RAD mutants indicate the function of the RAD9 checkpoint is phase-specific and signal-specific. First, the four cdc RAD mutants that required RAD9 each arrested in the late S/G2 phase after a shift to the restrictive temperature when DNA replication was complete or nearly complete, and second, each leaves DNA lesions when the CDC gene product is limiting for cell division. Three of the four CDC genes are known to encode DNA replication enzymes. We found that the RAD17 gene is also essential for the function of the RAD9 checkpoint because it is required for phase-specific arrest of the same four cdc mutants. We also show that both X- or UV-irradiated cells require the RAD9 and RAD17 genes for delay in the G2 phase. Together, these results indicate that the RAD9 checkpoint is apparently activated only by DNA lesions and arrests cell division only in the late S/G2 phase.


Idiopathic autoimmune hemolytic anemia due to lecithin overdose: a case report.
Idiopathic Autoimmune Hemolytic Anemia is a potentially fatal condition which requires prompt and potent treatment. Diagnosis of idiopathic autoimmune hemolytic anemia requires both serologic evidence of autoantibody presence and hemolysis. Although most of the times it is considered idiopathic, several underlying causes have been identified, like autoimmune and connective tissue diseases, viral infections, drugs or hyper function of the immune system. To our knowledge, this is the first case in the international literature describing lecithin-induced autoimmune hemolytic anemia. This case report is to highlight a rare but dangerous adverse reaction to overdose of lecithin. A 38 year old white female from Greece, presented to our emergency room with progressive fatigue over a period of ten days and icteric discoloration of her skin and conjunctiva. The patient had been taking lecithin supplements (1200 mg, 3 capsules a day) over a period of ten days for weight loss. She reports that the last 3 days, prior to the examination, she took 5 capsules/day, so that the supplement would take effect more rapidly. Her past medical, social and family history showed no disturbance. Relatives of the patient were requested to submit any blood-tests taken over a period of 20 days prior to the onset of symptoms caused by Lecithin. All tests proved that all functions were within normal scale. Her physical examination revealed pallor and jaundice without palpable hepatosplenomegaly. Blood biochemistry tests showed total bilirubin 7.5 mg/dl, with indirect bilirubin 6.4 mg/dl and complete blood count showed hemoglobin 7.6 g/dl with blood levels 21.4%. In every case of idiopathic autoimmune hemolytic anemia the administration of pharmaceutical substances should always be examined, except for the standard reasons that cause it. In this case the cause of hemolysis was attributed to the excessive intake of lecithin capsules for the loss of body weight. It is important that clinicians and immunologists are aware of this adverse effect.


Understanding ESL Teachers' Agency in Their Early Years of Professional Development: A Three-Layered Triadic Reciprocity Framework.
Drawing upon the Triadic Reciprocity Framework, this longitudinal qualitative multiple-case study examined how three Hong Kong secondary English as a second language (ESL) teachers exercised their teacher agency to take control of their teaching and professional development. More specifically, the study aimed at exploring how teachers' intentions and actions for the establishment of their professional identity were afforded and constrained by their workplaces. Findings reveal that these ESL teachers exercised different degrees of proactive, reactive, and passive agency. The four properties of human agency, i.e., intentionality, forethought, self-reactiveness, and self-reflectiveness, influenced the teachers' proactive, reactive, and passive agency when they responded to personal, behavioral, and environmental determinants. The findings shed light on a three-layered Triadic Reciprocity framework on teacher agency and contributes to a systematic and comprehensive discussion about the various internal and external factors that might exert influences on agency of early career teachers. This study offers pedagogical implications for school teachers, school leaders, and policy makers in Hong Kong and beyond.


The effectiveness of breath-holding to stabilize lung and pancreas tumors during radiosurgery.
To evaluate the effect of breath-holding on the short-term reproducibility and long-term variability of tumor position during image-guided radiosurgery. Thirteen patients have undergone single-fraction radiosurgery treatments during which the tumor was repeatedly imaged radiographically to observe its position. The imaging data were used to monitor the efficacy of breath-holding and to periodically readjust the alignment of the treatment beam with the tumor. These measurements have allowed the effects of breathing, heartbeat, patient movement, and instrumental uncertainties to be separately identified in the record of tumor position. During inspiration breath-holding, the lung tumor position was reproducible to within 1 mm, on average, in the direction of maximum displacement during regular breathing, and to within 1.8 mm in three dimensions overall. The pancreas tumor position in three dimensions was reproducible to within 2.5 mm on average. Some patients showed a slow, steady drift of tumor position during the extended sequence of breath-holds, which was compensated by periodic retargeting of the treatment beam. Breath-holding can allow the reduction of tumor motion dosimetry margins to 2 mm or less for lung cancer treatments, provided that the treatment system can detect and adapt to long-term variations in the mean tumor position during a lengthy treatment fraction.


Developmental protein kinase C hyper-activation results in microcephaly and behavioral abnormalities in zebrafish.
Susceptible genetic polymorphisms and altered expression levels of protein kinase C (PKC)-encoding genes suggest overactivation of PKC in autism spectrum disorder (ASD) development. To delineate the pathological role of PKC, we pharmacologically stimulated its activity during the early development of zebrafish. Results demonstrated that PKC hyper-activation perturbs zebrafish development and induces a long-lasting head size deficit. The anatomical and cellular analysis revealed reduced neural precursor proliferation and newborn neuron formation. β-Catenin that is essential for brain growth is dramatically degraded. Stabilization of β-catenin by gsk3β inhibition partially restores the head size deficit. In addition, the neuropathogenic effect of developmental PKC hyper-activation was further supported by the alterations in the behavioral domain including motor abnormalities, heightened stress reactivity and impaired habituation learning. Taken together, by causally connecting early-life PKC hyper-activation to these neuropathological traits and the impaired neurogenesis, these results suggest that PKC could be a critical pathway in ASD pathogenesis.


A European Multi Lake Survey dataset of environmental variables, phytoplankton pigments and cyanotoxins.
Under ongoing climate change and increasing anthropogenic activity, which continuously challenge ecosystem resilience, an in-depth understanding of ecological processes is urgently needed. Lakes, as providers of numerous ecosystem services, face multiple stressors that threaten their functioning. Harmful cyanobacterial blooms are a persistent problem resulting from nutrient pollution and climate-change induced stressors, like poor transparency, increased water temperature and enhanced stratification. Consistency in data collection and analysis methods is necessary to achieve fully comparable datasets and for statistical validity, avoiding issues linked to disparate data sources. The European Multi Lake Survey (EMLS) in summer 2015 was an initiative among scientists from 27 countries to collect and analyse lake physical, chemical and biological variables in a fully standardized manner. This database includes in-situ lake variables along with nutrient, pigment and cyanotoxin data of 369 lakes in Europe, which were centrally analysed in dedicated laboratories. Publishing the EMLS methods and dataset might inspire similar initiatives to study across large geographic areas that will contribute to better understanding lake responses in a changing environment.


Characterization and implications of solids associated with hydraulic fracturing flowback and produced water from the Duvernay Formation, Alberta, Canada.
Public concern is heightened around flowback and produced water (FPW) generated by the hydraulic fracturing process. FPW is a complex mix of organic and inorganic solutes derived from both the injected hydraulic fracturing fluid and interactions with the subsurface lithology. Few studies to date have systematically investigated the composition of FPW or its individual components. Here, we provide the first systematic characterization of the composition of the solids associated with FPW by analyzing samples from three wells drilled into the Duvernay Formation in Alberta, Canada. The FPW initially returned to the surface with high total dissolved solids (greater than 170 000 mg L-1) and enriched with Fe(ii), silica, sulfate, barium, and strontium. The solids form two distinct phases once the FPW reached the surface: (1) silica-enriched Fe(iii) oxyhydroxides, and (2) a barite-celestine solid solution. We hypothesize that the precipitation of the amorphous silica-enriched Fe(iii) oxyhydroxide is a two-step process, where first the silica precipitates as a function of the cooling of the FPW from elevated subsurface temperatures to ambient surface temperatures. Next, the silica acts as a template for the precipitation of Fe(iii) oxyhydroxide as the diffusion of oxygen into the subsurface causes oxidation of aqueous Fe(ii). The barite-celestine solid solution precipitates solely as a function of cooling. Elevated dissolved Fe concentrations in FPW and modeled saturation indices from five North American shale plays (Marcellus, Fayetteville, Barnett, Bakken, and Denver-Julesburg) indicate that solids similar to those found in Duvernay FPW, specifically Fe(iii) oxyhydroxides, barite and quartz, are likely to occur. With the solids known to carry a significant portion of FPW's toxicity and organic contaminant load, the development of new treatment technologies, such as the oxidation of the Fe(ii) in FPW, may increase FPW reuse and reduce the environmental risk posed by FPW.


Sub-optimal pain control in patients with rheumatic disease.
The visual analog scale (VAS) of pain is a ubiquitous clinical and research tool with widespread application in the rheumatic diseases. The objectives of this study were to assess if patients report pain differently to doctors or nurses, to determine reproducibility of this test for diagnosis, age, gender, and treatment, and to ascertain the level of pain in patients attending general rheumatology clinics. Using a standardized line of exactly 100 mm and instructions with identical wording, consecutive patients attending general rheumatology clinics were asked to score their perceived level of pain in the preceding week. Two assessments were carried out, one before and one after the clinic visit, and each patient was questioned by both a doctor and a nurse. Differences between the first and second VAS scores (VAS1 and VAS2) were recorded. One hundred and eight patients completed the study (69 female). VAS1 and VAS2 scores were administered by a similar number of doctors and nurses. There was no significant difference between mean VAS1 and VAS2 scores (41.1 vs. 41.4 mm, p = 0.78). VAS1 and VAS2 differed by <4 mm in 59% of patients. Age, gender, or diagnosis did not influence VAS1 or VAS2. Differences in scores were independent of which health professional administered the scale (p = 0.19). Patients taking painkillers had higher mean VAS scores (49 mm) compared with those not on analgesia (27 mm; p < 0.001). Anti-rheumatic treatment did not influence pain scores (p = 0.13). The VAS is a reliable and effective method of pain assessment. Results are independent of which health professional administers the scale. Patients with rheumatic disease report their pain similarly regardless of diagnosis. However, pain control is sub-optimal in patients taking analgesia. Specific assessment of pain is, thus, important in patients attending rheumatology clinics.


Carcass disposal: lessons from Great Britain following the foot and mouth disease outbreaks of 2001.
The foot and mouth disease (FMD) outbreak that occurred in the United Kingdom in 2001 was of an unprecedented scale and severity and presented a massive logistical challenge to Government. Over 6.5 million animals were slaughtered and disposed of, over 4 million as a direct result of disease and a further 2.5 million on welfare grounds. On-farm burial and on-farm burning were the principal routes for disposal at the commencement of the outbreak. On-farm burial was limited by legislation to protect groundwater supplies and pyre burning came increasingly under attack from local communities concerned about health risks from smoke and emissions. Burning also painted a vivid but distressing picture of the war against disease. Increasingly, rendering capacity made an important contribution to disposal. The peak of the outbreak could only be managed by the development of a new disposal route--mass burial in engineered sites and by using licensed landfill where available. During the course of the outbreak, a disposal hierarchy was developed to reflect environmental and public health concerns, namely: rendering and incineration ranked first, licensed landfill next, followed by burning with mass burial or on-farm burial as the least preferred options. However, the campaign against the disease could not have been won without the tactical use of mass burial in addition to all the other available disposal routes. The authors describe the development and deployment of the disposal routes used in the 2001 outbreak.


How (not) to protect genomic data privacy in a distributed network: using trail re-identification to evaluate and design anonymity protection systems.
The increasing integration of patient-specific genomic data into clinical practice and research raises serious privacy concerns. Various systems have been proposed that protect privacy by removing or encrypting explicitly identifying information, such as name or social security number, into pseudonyms. Though these systems claim to protect identity from being disclosed, they lack formal proofs. In this paper, we study the erosion of privacy when genomic data, either pseudonymous or data believed to be anonymous, are released into a distributed healthcare environment. Several algorithms are introduced, collectively called RE-Identification of Data In Trails (REIDIT), which link genomic data to named individuals in publicly available records by leveraging unique features in patient-location visit patterns. Algorithmic proofs of re-identification are developed and we demonstrate, with experiments on real-world data, that susceptibility to re-identification is neither trivial nor the result of bizarre isolated occurrences. We propose that such techniques can be applied as system tests of privacy protection capabilities.


ICU Nurses' Perceived Barriers to Effective Enteral Nutrition Practices: A Multicenter Survey Study.
Critically ill patients are hypermetabolic and have increased energy requirements, making nutritional support a vital intervention. In the Intensive Care Units, enteral nutrition is based on opinions rather than evidence-based practices. Therefore, there is a need to identify the barriers to evidence based practice protocols for enteral feeding of patients in Jordanian ICUs. To explore Jordanian ICU nurses' perceived barriers for enteral nutrition that hinders them from utilizing the recommended EN guidelines. A descriptive cross-sectional design was utilized using self-administered questionnaire. A total of 131 nurses participated from different hospitals representing different healthcare sectors in Jordan. The five barriers subscales' means were almost equal ranging from 4.04 (Delivery of EN to the Patient) to 4.33 (ICU Resources) (out of 7). The most important barrier was "Not enough nursing staff to deliver adequate nutrition" (M=4.80, SD=1.81, 60%), followed by "Fear of adverse events due to aggressively feeding patients" (M= 4.59, SD=1.50, 56%). Although no significant differences in the mean barrier score were revealed, minimal significant differences were revealed that were distributed among different barrier subscales. Participants moderately perceived barriers with more focus on insufficient resources in ICU and among healthcare providers. Such barriers are modifiable and manageable, making their identification and management crucial for optimal patient care. This study confirms that enteral nutrition is a multidisciplinary responsibility.


The importance of discreet use of the diaphragm to Zimbabwean women and their partners.
We conducted a 6-month acceptability study of diaphragms as a potential HIV/STI prevention method among Zimbabwean women. We examined partner involvement in diaphragm use, and importance of discreet use (use without partner awareness). Of the 181 women who completed the study, 45% said discreet use was "very or extremely important" and in multivariate logistic regression, women were more likely to value discretion if their partners: had other partners; drank alcohol; or were believed to prefer condoms to diaphragms. Qualitative data confirmed these findings. Both women and their partners reported that diaphragms can be used discreetly and saw this as advantageous, for both sexual pleasure and female control. However, many were concerned that use without partner approval could lead to marital problems. Discreet use should be considered in development of barrier methods and in diaphragm promotion, if proven effective against HIV/STI.


Antimycobacterial potential of the juniper berry essential oil in tap water.
Mycobacterium avium complex-related diseases are often associated with poorly maintained hot water systems. This calls for the development of new control strategies. The aim of this study was to investigate the activity of essential oils (EOs) from the Mediterranean plants, common juniper, immortelle, sage, lavandin, laurel, and white cedar against Mycobacterium avium ssp. avium, Mycobacterium intracellulare, and Mycobacterium gordonae in culturing broth and freshwater as their most common habitat. To do that, we developed a new method of water microdilution to determine their minimal effective concentrations (MEC). The most active EO was the one from the common juniper with the MEC of 1.6 mg mL-1. Gas chromatography / mass spectrometry the juniper EO identified monoterpenes (70.54 %) and sesquiterpenes (25.9 %) as dominant component groups. The main monoterpene hydrocarbons were α-pinene, sabinene, and β-pinene. The juniper EO significantly reduced the cell viability of M. intracellulare and M. gordonae at MEC, and of M. avium at 2xMEC. Microscopic analysis confirmed its inhibitory effect by revealing significant morphological changes in the cell membrane and cytoplasm of all three bacteria. The mode of action of the juniper EO on the cell membrane was confirmed by a marked leakage of intracellular material. Juniper EO has a great practical potential as a complementary or alternative water disinfectant in hot water systems such as baths, swimming pools, spa pools, hot tubs, or even foot baths/whirlpools.


Assessment of vascularity in breast carcinoma by computer-assisted video analysis (CAVA) and its association with axillary lymph node status.
Case-control methodology was used to evaluate the significance of vascularity in small breast carcinomas with regard to the presence or absence of axillary lymph node metastases. Vascularity was assessed in 32 axillary node positive primary breast tumours (LN+ve) less than 2 cm in size and compared with 56 control axillary node negative primary tumours (LN-ve), which were matched for histological type and grade and tumour size. This study design employed computer-assisted video analysis (CAVA) to assess the total blood vessel perimeter (BVP), total blood vessel area (BVA), and total blood vessel density (BVD) throughout a tissue section that encompassed an entire cross section of the tumour and its immediate periphery. The BVA and BVD in these tumours were not significantly different between LN+ve and LN-ve groups. The LN-ve carcinomas had, on average, a significantly (P<0.05) higher total BVP (3355 microm/mm2) than LN+ve tumours (2771 microm/mm2). 'Hot spot' areas were also independently assessed by two pathologists and the same areas measured by CAVA. A strong correlation (P<0.001) between the two methods of assessment of BVD of the neovascular 'hot spots' was found; however, no association with axillary lymph node metastasis was found using either method of assessment. In conclusion, vascularity assessed by either blood vessel density or blood vessel size in primary invasive breast cancers less than 2 cm in diameter showed no association with axillary lymph node metastasis; in fact a negative association was found with total BVP of whole tumour sections and BVD in 'hot spots' using CAVA. Further, this study has established a computer-assisted method of quantifying vascularity in solid neoplasms and is a positive step towards a standardised approach to this diverse and methodologically variable area.


Correlative infrared nanospectroscopic and nanomechanical imaging of block copolymer microdomains.
Intermolecular interactions and nanoscale phase separation govern the properties of many molecular soft-matter systems. Here, we combine infrared vibrational scattering scanning near-field optical microscopy (IR s-SNOM) with force-distance spectroscopy for simultaneous characterization of both nanoscale optical and nanomechanical molecular properties through hybrid imaging. The resulting multichannel images and correlative analysis of chemical composition, spectral IR line shape, modulus, adhesion, deformation, and dissipation acquired for a thin film of a nanophase separated block copolymer (PS-b-PMMA) reveal complex structural variations, in particular at domain interfaces, not resolved in any individual signal channel alone. These variations suggest that regions of multicomponent chemical composition, such as the interfacial mixing regions between microdomains, are correlated with high spatial heterogeneity in nanoscale material properties.


Temporal trends in area socioeconomic disparities in breast-cancer incidence and mortality, 1988-2005.
Since an overarching goal of Healthy People 2010 was to eliminate health disparities, we determined temporal trends in socioeconomic disparities in five breast-cancer indicators (in situ, stage I, lymph-node positive, and locally advanced breast-cancer incidence, and breast-cancer mortality) by county socioeconomic deprivation using 1988-2005 population-based breast-cancer data. Using 1988-2005 data from women aged 40 and older from 200 counties in the Surveillance, Epidemiology, and End Results program, we examined trends in temporal disparities in the five breast-cancer indicators across quartiles of county socioeconomic deprivation. County-level trends were summarized using the estimated annual percentage change. Observed county rates were smoothed using Bayesian hierarchical spatiotemporal methods to calculate measures of absolute and relative disparity (using absolute and relative concentration indices) and their changes over time. Large increases in in situ breast cancer rates since 1988 were observed for each of the deprivation quartiles. Absolute and relative disparity both increased over time, suggesting increasing disparities across levels of county deprivation. Absolute and relative concentration indices were near zero for the other four breast-cancer indicators, suggesting no disparities among the four quartiles of county deprivation during 1988-2005. Efforts to target counties aimed at increasing breast-cancer screening based on their level of deprivation will not likely be beneficial.


Benthic protists and fungi of Mediterranean deep hypsersaline anoxic basin redoxcline sediments.
Some of the most extreme marine habitats known are the Mediterranean deep hypersaline anoxic basins (DHABs; water depth ∼3500 m). Brines of DHABs are nearly saturated with salt, leading many to suspect they are uninhabitable for eukaryotes. While diverse bacterial and protistan communities are reported from some DHAB water-column haloclines and brines, the existence and activity of benthic DHAB protists have rarely been explored. Here, we report findings regarding protists and fungi recovered from sediments of three DHAB (Discovery, Urania, L' Atalante) haloclines, and compare these to communities from sediments underlying normoxic waters of typical Mediterranean salinity. Halocline sediments, where the redoxcline impinges the seafloor, were studied from all three DHABs. Microscopic cell counts suggested that halocline sediments supported denser protist populations than those in adjacent control sediments. Pyrosequencing analysis based on ribosomal RNA detected eukaryotic ribotypes in the halocline sediments from each of the three DHABs, most of which were fungi. Sequences affiliated with Ustilaginomycotina Basidiomycota were the most abundant eukaryotic signatures detected. Benthic communities in these DHABs appeared to differ, as expected, due to differing brine chemistries. Microscopy indicated that only a low proportion of protists appeared to bear associated putative symbionts. In a considerable number of cases, when prokaryotes were associated with a protist, DAPI staining did not reveal presence of any nuclei, suggesting that at least some protists were carcasses inhabited by prokaryotic scavengers.


Expression and regulation of the early auxin-responsive Aux/IAA genes during strawberry fruit development.
The plant hormone auxin transcriptionally activates Aux/IAA genes. Auxin plays an important role in regulating fruit growth and ripening of strawberry and Aux/IAA genes have been extensively studied in Arabidopsis, rice and tomato, but little information is available on strawberry fruit. In the present work, two full-length of early auxin-responsive Aux/IAA genes, termed FaAux/IAA1 and FaAux/IAA2 respectively, were isolated and characterized from strawberry fruit. Moreover, the expression profiles of two FaAux/IAA genes during fruit development, and the effect of naphthalene acetic acid (NAA) on their expressions of fruits at two different developmental stages were also investigated. The results showed that the levels of FaAux/IAA1 and FaAux/IAA2 transcripts were very high at early stage of fruit development, and decreased sharply at ripening stage (after white stage). In addition, NAA applied at the stage of large green and white fruit obviously increased the accumulations of FaAux/IAA1 and FaAux/IAA2 transcripts. These data suggested that the expressions of both FaAux/IAA1 and FaAux/IAA2 genes were likely to be involved in early fruit development, and the enhancement of FaAux/IAAs transcripts might be attributed at least or partially to auxin-induced fruit growth and delayed fruit ripening of strawberry.


Unprecedented regiochemical control in the formation of aryl[1,2-a]imidazopyridines from alkynyliodonium salts: mechanistic insights.
Aryl(alkynyl)iodonium salts have been demonstrated to be valuable precursors to a diverse range of heteroaromatic ring systems including aryl[1,2-a]imidazopyridines. Successful application, using the recently described aryl(alkynyl)iodonium trifluoroacetate salts, is described, highlighting for the first time that the regioselectivity of this process is both counter-ion and concentration dependent. Studies with a carbon-13 labelled substrate established that the reactions of alkynyliodonium salts are highly complex and that multiple mechanistic processes appear to be underway simultaneously.


Self-assembly of proglycinin and hybrid proglycinin synthesized in vitro from cDNA.
An in vitro system was developed that results in the self-assembly of subunit precursors into complexes that resemble those found naturally in the endoplasmic reticulum. Subunits of glycinin, the predominant seed protein of soybeans, were synthesized from modified cDNAs using a combination of the SP6 transcription and the rabbit reticulocyte translation systems. Subunits produced from plasmid constructions that encoded either Gy4 or Gy5 gene products, but modified such that their signal sequences were absent, self-assembled into trimers equivalent in size to those precursors found in the endoplasmic reticulum. In contrast, proteins synthesized in vitro from Gy4 constructs failed to self-assemble when the signal sequence was left intact (e.g., preproglycinin) or when the coding sequence was modified to remove 27 amino acids from an internal hydrophobic region, which is highly conserved among the glycinin subunits. Various hybrid subunits were also produced by trading portions of Gy4 and Gy5 cDNAs and all self-assembled in our system. The in vitro assembly system provides an opportunity to study the self-assembly of precursors and to probe for regions important for assembly. It will also be helpful in attempts to engineer beneficial nutritional changes into this important food protein.


Pressure driven flow of polymer solutions in nanoscale slit pores.
Polymer solutions subject to pressure driven flow and in nanoscale slit pores are systematically investigated using the dissipative particle dynamics approach. The authors investigated the effect of molecular weight, polymer concentration, and flow rate on the profiles across the channel of the fluid and polymer velocities, polymer density, and the three components of the polymers radius of gyration. They found that the mean streaming fluid velocity decreases as the polymer molecular weight and/or polymer concentration is increased, and that the deviation of the velocity profile from the parabolic profile is accentuated with increase in polymer molecular weight or concentration. They also found that the distribution of polymers conformation is highly anisotropic and nonuniform across the channel. The polymer density profile is also found to be nonuniform, exhibiting a local minimum in the center plane followed by two symmetric peaks. They found a migration of the polymer chains either from or toward the walls. For relatively long chains, as compared to the thickness of the slit, a migration toward the walls is observed. However, for relatively short chains, a migration away from the walls is observed.


Playing the blues, the greens and the reds with cellulose-based structural colours.
Structural vivid colours can arise from the interference of light reflected from structures exhibiting periodicity on scales in the range of visible wavelengths. This effect is observed with light reflected from cell-walls of some plants and exoskeletons of certain insects. Sometimes the colour sequence observed for these structures consists of nearly circular concentric rings that vary in colour from Red, Orange, Yellow, Green, Cyan to Blue, from the periphery to the centre, similarly to the colour scheme sequence observed for the rainbow (ROYGB). The sequence of colours has been found for solid films obtained from droplets of aqueous cellulose nanocrystals (CNCs) suspensions and attributed to a "coffee ring" effect. In this work, coloured lyotropic solutions and solid films obtained from a cellulose derivative in the presence of trifluoroacetic acid (TFA), which acts as a "reactive solvent", are revisited. The systems were investigated with spectroscopy, using circularly and linearly polarised light, coupled with a polarised optical microscope (POM) and scanning electron microscopy (SEM). The lyotropic cholesteric liquid crystalline solutions were confined in capillaries to simplify 1D molecular diffusion along the capillary where an unexpected sequence of the structural colours was observed. The development and reappearance of the sequence of vivid colours seem consistent with the reaction-diffusion of the "reactive solvent" in the presence of the cellulosic chains. The strong TFA acts as an auto-catalyst for the chemical reaction between TFA and the hydroxyl groups, existing along the cellulosic chain, and diffuses to the top and bottom along the capillaries, carrying dissolved cellulosic chains. Uncovering the precise mechanism of colour sequence and evolution over time in cellulosic lyotropic solutions has important implications for future optical/sensors applications and for the understanding of the development of cellulose-based structures in nature.


Association of Changes in Neighborhood-Level Racial Residential Segregation With Changes in Blood Pressure Among Black Adults: The CARDIA Study.
Despite cross-sectional evidence linking racial residential segregation to hypertension prevalence among non-Hispanic blacks, it remains unclear how changes in exposure to neighborhood segregation may be associated with changes in blood pressure. To examine the association of changes in neighborhood-level racial residential segregation with changes in systolic and diastolic blood pressure over a 25-year period. This observational study examined longitudinal data of 2280 black participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective investigation of adults aged 18 to 30 years who underwent baseline examinations in field centers in 4 US locations from March 25, 1985, to June 7, 1986, and then were re-examined for the next 25 years. Racial residential segregation was assessed using the Getis-Ord Gi* statistic, a measure of SD between the neighborhood's racial composition (ie, percentage of black residents) and the surrounding area's racial composition. Segregation was categorized as high (Gi* >1.96), medium (Gi* 0-1.96), and low (Gi* <0). Fixed-effects linear regression modeling was used to estimate the associations of within-person change in exposure to segregation and within-person change in blood pressure while tightly controlling for time-invariant confounders. Data analyses were performed between August 4, 2016, and February 9, 2017. Within-person changes in systolic and diastolic blood pressure across 6 examinations over 25 years. Of the 2280 participants at baseline, 974 (42.7%) were men and 1306 (57.3%) were women. Of these, 1861 (81.6%) were living in a high-segregation neighborhood; 278 (12.2%), a medium-segregation neighborhood; and 141 (6.2%), a low-segregation neighborhood. Systolic blood pressure increased by a mean of 0.16 (95% CI, 0.06-0.26) mm Hg with each 1-SD increase in segregation score after adjusting for interactions of time with age, sex, and field center. Of the 1861 participants (81.6%) who lived in high-segregation neighborhoods at baseline, reductions in exposure to segregation were associated with reductions in systolic blood pressure. Mean differences in systolic blood pressure were -1.33 (95% CI, -2.26 to -0.40) mm Hg when comparing high-segregation with medium-segregation neighborhoods and -1.19 (95% CI, -2.08 to -0.31) mm Hg when comparing high-segregation with low-segregation neighborhoods after adjustment for time and interactions of time with baseline age, sex, and field center. Changes in segregation were not associated with changes in diastolic blood pressure. Decreases in exposure to racial residential segregation are associated with reductions in systolic blood pressure. This study adds to the small but growing body of evidence that policies that reduce segregation may have meaningful health benefits.


Transmembrane signalling mechanisms regulating expression of cationic amino acid transporters and inducible nitric oxide synthase in rat vascular smooth muscle cells.
The signalling mechanisms involved in the induction of nitric oxide synthase and l-arginine transport were investigated in bacterial lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-stimulated rat cultured aortic smooth muscle cells (RASMCs). The expression profile of transcripts for cationic amino acid transporters (CATs) and their regulation by LPS and IFN-gamma were also examined. Control RASMCs expressed mRNA for CAT-1, CAT-2A and CAT-2B. Levels of all three transcripts were significantly elevated in activated cells. Stimulated CAT mRNA expression and l-arginine transport occurred independently of protein kinase C (PKC), protein tyrosine kinase (PTK) and p44/42 mitogen-activated kinases (MAPKs), but were inhibited by the p38 MAPK inhibitor SB203580, which at 3 microM caused maximum inhibition of both responses. Induction of NO synthesis was independent of p44/42 MAPK activation and only marginally dependent on PKC, but was attenuated markedly by the PTK inhibitors genistein and herbimycin A. SB203580 differentially regulated inducible NO synthase expression and NO production, potentiating both processes at low micromolar concentrations and inhibiting at concentrations of >/=1 microM. In conclusion, our results suggest that RASMCs constitutively express transcripts for CAT-1, CAT-2A and CAT-2B, and that expression of these transcripts is significantly enhanced by LPS and IFN-gamma. Moreover, stimulation of l-arginine transport and induction of NO synthesis by LPS and IFN-gamma appear to be under critical regulation by the p38 MAPK, since both processes were significantly modified by SB203580 at concentrations so far shown to have no effect on other signalling pathways. Thus, in RASMCs, the p38 MAPK cascade represents an important signalling mechanism, regulating both enhanced l-arginine transport and induced NO synthesis.


Photonic band gaps induced by submicron acoustic plate waves in dielectric slab waveguides.
We generate photonic bandgaps (PBGs) in dielectric slab waveguides by exciting their acoustic plate eigenmodes of submicron wavelength. We investigate the optical forbidden bands below the light line where the slab interfaces and index of refraction are periodically modulated by the acoustic fields. Results show that multiple scattering through the enhanced periodic acousto-optic (AO) interaction opens Bragg PBGs. A tunable bandgap width and transmittance are achieved. Transmitted optical waves are found to incur strong nonlinear modulation through AO interaction by a multiphonon exchange mechanism. The applications include tunable optomechanical and AO devices.


An Update on Vitamin D and Disease Activity in Multiple Sclerosis.
Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism, yet have additional roles in immune and central nervous system cell homeostasis. Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing-remitting multiple sclerosis (RRMS), and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy. The results of the first large randomized clinical trials (RCTs), the SOLAR and CHOLINE studies, have now been published. The SOLAR study compared 14,000 IU of vitamin D3 (cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D3 100,000 IU every other week with placebo for 96 weeks in 129 randomized patients. All patients in both studies also used interferon-β-1a. None of the studies met their primary endpoints, which were no evidence of disease activity (NEDA-3) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks in CHOLINE. Both studies did, however, suggest modest effects on secondary endpoints. Thus, vitamin D reduced the number of new or enlarging lesions and new T2 lesions in SOLAR, and the annualized relapse rate and number of new T1 lesions, volume of hypointense T1 lesions, and disability progression in the 90 patients who completed 96 weeks' follow-up in CHOLINE. We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts. This contrasts the observation studies, where each 25 nmol/l increase in 25-hydroxyvitamin D levels were associated with 14-34% reduced relapse risk and 15-50% reduced risk of new lesions on magnetic resonnance imaging. This discrepancy may have several explanations, including confounding and reverse causality in the observational studies. The power calculations of the RCTs have been based on the observational studies, and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation. Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies, current evidence still support that people with MS should avoid vitamin D insufficiency, and preferentially aim for vitamin D levels around 100 nmol/L or somewhat higher.


Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo.
Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients' quality of life and is a major health problem worldwide. The above-mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease-modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.


[Evaluation of a public health program on early HIV diagnosis with quick test].
The use of HIV planned and structured, community-based rapid tests is one of the main strategies for the early detection of HIV infection. The objective of the study was to assess the HIV early diagnosis programme with rapid test in the Region of Murcia. Descriptive analysis of the programme users' epidemiological data during the years 2016 to 2018. Variables related to sociodemographic characteristics, risk exposure, history of HIV test performance and its result were analyzed. All analyzes were performed with statistical software IBM SPSS25 and Microsoft Excel version 2013. Frequencies were calculated in absolute values and the variables of interest were crosshead. There were 1,023 people tested, of which 74% performed risky sexual practices in the last 12 months, both homosexual (50%) and heterosexual (45%), with an age between 18 and 40 years. 18.2% of the users were foreigners and 61.9% had been previously tested. Among the participants in the programme the percentage of reactive tests was 2.1% and the contribution to the diagnosis of new HIV cases in the Region was 4.3%. The results of the study show that the community-based programme is an effective tool for the diagnosis of HIV infection in vulnerable groups. In addition, several opportunities for improvement were identified in the process assessment, such as accessibility to the program and the collection of information.


Low-dose aspirin for preventing recurrent venous thromboembolism.
Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events. In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).


The reliability and validity of the Korean version of the Epworth sleepiness scale.
The Epworth sleepiness scale (ESS) is widely used to measure the subject's average sleep propensity across those different situations in daily life, particularly in patients with sleep-disordered breathing. The purposes of this study were to test the hypothesis that the Korean version of the ESS (KESS) is valid and evaluate its usefulness. We developed the KESS, which involved translating into Korean and then translating back into English to check its accuracy. A total of 273 participants (181 obstructive sleep apnea (OSA)-37 mild, 61 moderate, 83 severe, 32 simple snoring and 60 normal) were included in this study. All subjects completed the overnight polysomnograph and 53 of the total subjects were randomly selected for a retest with the questionnaire approximately 2∼4 weeks later. The associations between KESS and the degree of OSA were examined through ANCOVA, adjusted for age, sex and BMI. The total score and each item's score of KESS in patients with OSA were significantly higher than subjects with normal controls (p < 0.01). As the severity of OSA increased, the KESS showed significantly increasing patterns (p for trend <0.01). The KESS in patient groups showed good internal consistency (Cronbach's α = 0.90) and test-retest reliability (r = 0.78 to 0.93). The KESS is a reliable and valid tool for screening patients with daytime sleepiness in Korea.


Cognitive mechanisms and motor control during a saccadic eye movement task: evidence from quantitative electroencephalography.
The saccadic movement is an important behavioral measure used to investigate several cognitive processes, including attention and sensorimotor integration. The present study aimed at investigating changes in beta coherence over frontal, motor, occipital, and parietal cortices during the performance of two different conditions of a prosacadic paradigm. The conditions involved a different pattern of stimulus presentation: a fixed and random stimulus presentation. Twelve healthy volunteers (three male, mean age of 26.25 (SD=4.13) performed the task, while their brain activity pattern was recorded using quantitative electroencephalography. The results showed an interaction between factors condition and moment for the pair of electrode C3/C4. We observed a main effect for moment to CZ/C4, FZ/F3, and P3/PZ. We also found a main effect for condition to FZ/F4, P3/P4, and O1/O2. Our results demonstrated an important role of the inter-connection of the two hemispheres in visual search and movement preparation. The study demonstrates an automation of action and reduction of the focus of attention during the task. We also found that the inter-hemispheric beta coherence plays an important role in the differentiation of the two conditions, and that beta in the right frontal cortex is able to differentiate the conditions, demonstrating a greater involvement of procedural memory in fixed condition. Our results suggest a neuronal specialization in the execution of prosacadic paradigm involving motor task sequence.


Fasting insulin in relation to subsequent blood pressure changes and hypertension in women.
The role of hyperinsulinemia in the development of hypertension is not well understood, particularly insofar as both conditions relate to obesity. The present analysis examines the hypothesis that hyperinsulinemia, independent of obesity, precedes hypertension and natural blood pressure increases in women. The subjects were 50-year-old women from a prospective population study in Gothenburg, Sweden. Fasting insulin levels were determined at baseline (1968-1969) and were evaluated in relation to subsequent hypertension. Blood pressures were measured at the initial physical examination and at the 6- and 12-year follow-up examinations. The first analysis presented here (n = 278) identified incident cases of hypertension during the 12-year follow-up period, whereas the second analysis (n = 219) examined continuous changes in blood pressure. In both analyses, degree, type, and changes in obesity were considered as possible confounding factors. High fasting insulin values were predictive of subsequent incidence of hypertension over the 12-year follow-up period. Subjects with insulin values above the 75th percentile experienced three times more hypertension than did those below the 25th percentile. There was also a significant association between insulin at baseline and increases in diastolic (but not systolic) blood pressure. The positive relations between fasting insulin, on one hand, and diastolic blood pressure changes and hypertension, on the other, could not be explained by confounding effects of body mass index, waist/hip ratio, or weight gain. These findings are consistent with the hypothesis that fasting insulin levels may be one predisposing factor in the etiology of hypertension.


Health benefits of algal polysaccharides in human nutrition.
The interest in functional food, both freshwater and marine algal products with their possible promotional health effects, increases also in regions where algae are considered as rather exotic food. Increased attention about algae as an abundant source of many nutrients and dietary fiber from the nutrition point of view, as well as from the scientific approaches to explore new nutraceuticals and pharmaceuticals, is based on the presence of many bioactive compounds including polysaccharides extracted from algal matter. Diverse chemical composition of dietary fiber polysaccharides is responsible for their different physicochemical properties, such as their ability to be fermented by the human colonic microbiota resulted in health benefit effects. Fundamental seaweed polysaccharides are presented by alginates, agars, carrageenans, ulvanes, and fucoidans, which are widely used in the food and pharmaceutical industry and also in other branches of industry. Moreover, freshwater algae and seaweed polysaccharides have emerged as an important source of bioactive natural compounds which are responsible for their possible physiological effects. Especially, sulfate polysaccharides exhibit immunomodulatory, antitumor, antithrombotic, anticoagulant, anti-mutagenic, anti-inflammatory, antimicrobial, and antiviral activities including anti-HIV infection, herpes, and hepatitis viruses. Generally, biological activity of sulfate polysaccharides is related to their different composition and mainly to the extent of the sulfation of their molecules. Significant attention has been recently focused on the use of both freshwater algae and seaweed for developing functional food by reason of a great variety of nutrients that are essential for human health.


Family interaction styles of children with depressive disorders, schizophrenia-spectrum disorders, and normal controls.
Family interaction processes during a problem-solving task were examined in children with depressive disorders, children with schizophrenia-spectrum disorders, and a normal control group of community children screened for the absence of psychiatric disorder. Major findings were: a) children with depressive disorders were more likely than children with schizophrenia-spectrum disorders and children with no psychiatric disorder to direct guilt-inducing comments toward their parents; and b) parents of children with schizophrenia-spectrum disorders were more likely to direct harsh critical comments toward the child than were parents of depressed children or parents of normal controls. In addition, children's and mothers' use of benign criticism was linked, while children's harsh criticism was associated with intrusion from the father, and children's self-denigrating comments were related to specific paternal criticism. Implications of these results for understanding transactional processes associated with childhood-onset depressive and schizophrenia-spectrum disorders are discussed.


Complementary nontargeted and targeted mass spectrometry techniques to determine bioaccumulation of halogenated contaminants in freshwater species.
Assessing the toxicological significance of complex environmental mixtures is challenging due to the large number of unidentified contaminants. Nontargeted analytical techniques may serve to identify bioaccumulative contaminants within complex contaminant mixtures without the use of analytical standards. This study exposed three freshwater organisms (Lumbriculus variegatus, Hexagenia spp., and Pimephales promelas) to a highly contaminated soil collected from a recycling plant fire site. Biota extracts were analyzed by Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and mass defect filtering to identify bioaccumulative halogenated contaminants. Specific bioaccumulative isomers were identified by comprehensive two-dimensional gas chromatography high-resolution time-of-flight mass spectrometry (GCxGC-HRToF). Targeted analysis of mixed brominated/chlorinated dibenzo-p-dioxins and dibenzofurans (PXDD/PXDFs, X = Br and Cl) was performed by atmospheric pressure gas chromatography tandem mass spectrometry (APGC-MS/MS). Relative sediment and biota instrument responses were used to estimate biota-sediment accumulation factors (BSAFs). Bioaccumulating contaminants varied among species and included polychlorinated naphthalenes (PCNs), polychlorinated dibenzofurans (PCDFs), chlorinated and mixed brominated/chlorinated anthracenes/phenanthrenes, and pyrenes/fluoranthenes (Cl-PAHs and X-PAHs, X = Br and Cl), as well as PXDD/PXDFs. Bioaccumulation potential among isomers also varied. This study demonstrates how complementary high-resolution mass spectrometry techniques identify persistent and bioaccumulative contaminants (and specific isomers) of environmental concern.


Inhibition of aflatoxin B1-induced gamma-glutamyltranspeptidase positive (GGT+) hepatic preneoplastic foci and tumors by low protein diets: evidence that altered GGT+ foci indicate neoplastic potential.
Previous studies in this laboratory with young Fischer 344 male rats have shown that the post-initiation development of aflatoxin B1 (AFB1)-induced gamma-glutamyltranspeptidase positive (GGT+) hepatic foci was markedly inhibited by low protein feeding, even though the energy intake was greater. This dietary effect, however, did not necessarily apply to hepatic tumor development. Thus, the present investigation was undertaken to examine this dietary effect upon the development of hepatic tumors and, is so doing, to determine the correlation of foci development with tumor development. Following AFB1 dosing (15 daily doses of 0.3 mg/kg each), animals were fed diets containing 6, 14 or 22% casein (5.2, 12.2, 19.1% protein) for 6, 12, 40, 58 and 100 weeks. Foci at 12 weeks and tumors at 40, 58 and 100 weeks developed dose-dependently to protein intake. Foci development, tumor incidence, tumor size and the number of tumors per animal were markedly reduced while the time to tumor emergence was increased with low protein feeding. Non-hepatic tumor incidence also was lower in the animals fed the lowest protein diet. Foci development indices (foci number, per cent liver volume occupied) were highly correlated with tumor incidence at 58 and 100 weeks (r = 0.90-1.00). Tumor and foci inhibition occurred in spite of the greater energy intake.


Carboxyl-methylation of prenylated calmodulin CaM53 is required for efficient plasma membrane targeting of the protein.
Prenylation is necessary for association of the petunia calmodulin CaM53 with the plasma membrane. To determine whether post-prenylation processing of the protein was also required for plasma membrane targeting, we studied the subcellular localization of a GFP-labelled CaM53 reporter in yeast and plant cells. Blocking of carboxyl-methylation of prenylated proteins either by a specific inhibitor or in mutant yeast cells resulted in localization of green fluorescence to what appears to be the endomembrane system, in contrast with the plasma membrane localization observed in control cells. We show that a prenyl-cysteine methyltransferase (PCM) activity that carboxyl-methylates prenylated CaM53 also exists in plant cells, and that it is required for efficient plasma membrane targeting. We also report an Arabidopsis gene with homology to PCM and demonstrate that it encodes a protein with PCM activity that localizes to the endomembrane system of plant cells, similar to prenylated but unmethylated CaM53. Together, our data suggest that, following prenylation, CaM53 is probably associated with the endomembrane system, where a PCM activity methylates the prenylated protein prior to targeting it to its final destination in the plasma membrane.


HBPred: a tool to identify growth hormone-binding proteins.
Hormone-binding protein (HBP) is a kind of soluble carrier protein and can selectively and non-covalently interact with hormone. HBP plays an important role in life growth, but its function is still unclear. Correct recognition of HBPs is the first step to further study their function and understand their biological process. However, it is difficult to correctly recognize HBPs from more and more proteins through traditional biochemical experiments because of high experimental cost and long experimental period. To overcome these disadvantages, we designed a computational method for identifying HBPs accurately in the study. At first, we collected HBP data from UniProt to establish a high-quality benchmark dataset. Based on the dataset, the dipeptide composition was extracted from HBP residue sequences. In order to find out the optimal features to provide key clues for HBP identification, the analysis of various (ANOVA) was performed for feature ranking. The optimal features were selected through the incremental feature selection strategy. Subsequently, the features were inputted into support vector machine (SVM) for prediction model construction. Jackknife cross-validation results showed that 88.6% HBPs and 81.3% non-HBPs were correctly recognized, suggesting that our proposed model was powerful. This study provides a new strategy to identify HBPs. Moreover, based on the proposed model, we established a webserver called HBPred, which could be freely accessed at http://lin-group.cn/server/HBPred.


Improving dyadic coping in couples with a stress-oriented approach: a 2-year longitudinal study.
This study sought to assess the effectiveness of a marital distress prevention program for couples by examining how marital quality, especially marital competencies such as dyadic coping, could be improved by means of a prevention program focusing on the enhancement of coping resources (Couples Coping Enhancement Training). The study consisted of 59 couples in the intervention group and 59 couples in the matched comparison group. The results reveal that it is possible to improve marital quality, especially marital competencies, by means of one short-term intervention lasting 18 hr. However, the effects decreased after 2 years, raising the importance of booster sessions in helping to maintain effects over a longer period of time.


Patient-centred improvements in health-care built environments: perspectives and design indicators.
To explore patients' perceptions of health-care built environments, to assess how they perceived health-care built facilities and designs. To develop a set of patient-centred indicators by which to appraise future health-care designs. Qualitative and quantitative methodologies, including futures group conferencing, autophotographic study, novice-expert exchanges and a questionnaire survey of a representative sample of past patients. The research was carried out at Salford Royal Hospitals NHS Trust (SRHT), Greater Manchester, UK, selected for the study because of planned comprehensive redevelopment based on the new NHS vision for hospital care and service delivery for the 21st century. Participants included 35 patients who took part in an autophotographic study, eight focus groups engaged in futures conferencing, a sample of past inpatients from the previous 12 months that returned 785 completed postal questionnaires. The futures group provided suggestions for radical improvements which were categorized into transport issues; accessibility and mobility; ground and landscape designs; social and public spaces; homeliness and assurance; cultural diversity; safety and security; personal space and access to outside. Patients' autophotographic study centred on: the quality of the ward design, human interactions, the state and quality of personal space, and facilities for recreation and leisure. The novices' suggestions were organized into categories of elemental factors representing patient-friendly designs. Experts from the architectural and surveying professions and staff at SRHT in turn considered these categories and respective subsets of factors. They agreed with the novices in terms of the headings but differed in prioritizing the elemental factors. The questionnaire survey of past patients provided opinions about ward designs that varied according to where they stayed, single room, bay ward or long open ward. The main concerns were limitation of private space around the bed area, supportive of privacy and dignity, ward noise and other disturbances. Patients perceived sustainable health-care environments to be supportive of their health and recovery. The design indicators developed from their perspectives and from their considerations for improvements to the health-care built environment were based on their visions of the role of the health-care facilities. These were homely environments that supported normal lifestyle and family functioning and designs that were supportive of accessibility and travel movements through transitional spaces.


Functional connectivity alterations in a murine model of optic neuritis.
The basis for neuronal dysfunction following inflammatory demyelination of the central nervous system (CNS) remains poorly understood. We characterized the network response to white matter injury in the anterior visual pathway using an experimental model of optic neuritis (ON), as ON is often an early manifestation of immune-mediated CNS demyelination in multiple sclerosis (MS). Optical intrinsic signal imaging was performed before and after the induction of ON in mice to measure changes in cortical network functional connectivity. We observed a greater loss of connectivity between homotopic visual cortices in ON mice compared to controls. Further, decreases in homotopic visual cortex connectivity were associated with visual acuity loss in ON mice. These results demonstrate that network connectivity changes resulting from ON can be modeled in an experimental murine system. Future studies will identify the mechanisms that cause neuronal dysfunction due to white matter injury seen in MS.


Sedentary behavior, physical activity, and markers of health in older adults.
The purpose of this study was to examine the association between sedentary behavior (SB), cardiometabolic risk factors, and self-reported physical function by level of moderate-vigorous physical activity (MVPA). Cross-sectional analysis was completed on 1914 older adults age ≥ 65 yr from the 2003-2006 U.S. National Health and Nutrition Examination Survey. MVPA and SB were derived from ActiGraph accelerometers worn for 1 wk. MVPA was categorized as sufficient to meet the current U.S. guidelines (≥ 150 min · wk(-1)) or not; SB was split into quartiles. Various biomarkers were examined in laboratory analyses and physical exams, and the number of functional limitations was self-reported. Statistical interaction between SB and MVPA on the biomarker associations was the primary analysis, followed by an examination of their independent associations with relevant covariate adjustment. Average SB was 9.4 ± 2.3 h · d(-1) (mean ± SD), and approximately 35% were classified as sufficiently active. Overall, no significant meaningful statistical interactions were found between SB and MVPA for any of the outcomes; however, strong independent positive associations were found between SB and weight (P < 0.01), body mass index (P < 0.01), waist circumference (P < 0.01), C-reactive protein (P < 0.01), plasma glucose (P = 0.04), and number of functional limitations (P < 0.01) after adjustment for MVPA. Similarly, MVPA was negatively associated with weight (P = 0.01), body mass index (P < 0.01), waist circumference (P < 0.01), diastolic blood pressure (P = 0.04), C-reactive protein (P < 0.01), and number of functional limitations (P < 0.01) after adjustment for SB. The results suggest that sufficient MVPA did not ameliorate the negative associations between SB and cardiometabolic risk factors or functional limitations in the current sample and that there was independence on a multiplicative scale in their associations with the outcomes examined. Thus, older adults may benefit from the joint prescription to accumulate adequate MVPA and avoid prolonged sitting.


Association of conventional risk factors for cardiovascular disease with IMT in middle-aged and elderly Chinese.
To study the association between known risk factors for cardiovascular disease and intima-media thickness (IMT) in the carotid and popliteal arteries in middle-aged and elderly Chinese adults. 686 middle aged and elderly Chinese adults from the China Da Qing Diabetes Prevention Study who had full clinical, laboratory, ultrasound examination results were enrolled in the study. Common carotid artery (CCA) and popliteal artery (PA) IMT were obtained using high resolution ultrasound machine. Pearson's or Spearman's correlation analysis and logistic regression analysis were used to determine association between risk factors [age, gender, tobacco smoking, body mass index (BMI), diabetes mellitus (DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, glycosylated hemoglobin (HbA1c)] and CCA- or PA-IMT. The age range of the study population was 45-87 years, 384 of them (56 %) were women. The prevalence of high blood pressure and DM was 60.6 and 68.8 %, respectively. Participants in DM group tended to be older, had greater value for SBP, HbA1c and PA-IMT, but smaller value for DBP than those in control group. Smoke status, BMI, blood lipids and CCA-IMT were not statistically different between groups. Pearson's or Spearman's rank correlation analysis showed that CCA-IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. PA-IMT showed a positive correlation with age, gender and SBP. Univariate logistic regression analysis showed that elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA-IMT thickening, so was reduction of HDL-C. Risk factors that predicted significant thickening of PA-IMT were age, gender, tobacco smoking. After adjusted for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having DM) that predicted CCA-IMT thickening remained significant; however none of the risk factors predicted PA-IMT thickening after adjusted for age and gender. The current results provide evidence that CCA-IMT is a superior marker for atherosclerosis compared with PA-IMT. Aggressive control of SBP, HbA1c and proper control of weight may postpone thickening of CCA-IMT.


Putative zinc finger protein binding sites are over-represented in the boundaries of methylation-resistant CpG islands in the human genome.
Majority of CpG dinucleotides in mammalian genomes tend to undergo DNA methylation, but most CpG islands are resistant to such epigenetic modification. Understanding about mechanisms that may lead to the methylation resistance of CpG islands is still very poor. Using the genome-scale in vivo DNA methylation data from human brain, we investigated the flanking sequence features of methylation-resistant CpG islands, and discovered that there are several over-represented putative Transcription Factor Binding Sites (TFBSs) in methylation-resistant CpG islands, and a specific group of zinc finger protein binding sites are over-represented in boundary regions ( approximately 400 bp) flanking such CpG islands. About 77% of the over-represented putative TFBSs are conserved among human, mouse and rat. We also observed the enrichment of 4 histone methylations in methylation-resistant CpG islands or their boundaries. Our results suggest a possible mechanism that certain putative zinc finger protein binding sites over-represented in the boundary regions of the methylation-resistant CpG islands may block the spreading of methylation into these islands, and those TFBSs over-represented within the islands may both reinforce the methylation blocking and promote transcription. Some histone modifications may also enhance the immunity of the CpG islands against DNA methylation by augmenting these TFs' binding. We speculate that the dynamical equilibrium between methylation spreading and blocking is likely to be responsible for the establishment and maintenance of the relatively stable DNA methylation pattern in human somatic cells.


Influence of brain injury on early posttraumatic bone metabolism.
Various clinical studies and observations demonstrate enhanced osteogenesis in patients sustaining traumatic brain injury. It is presumed that the induction of this process starts early after trauma. The purpose of our study was to investigate humoral markers of bone metabolism during the early posttraumatic period, with special regard to traumatic brain injury. Serum concentrations of biochemical markers of bone metabolism (calcium, inorganic phosphorus, carboxyl-terminal propeptide of type 1 procollagen, pyridinoline cross-linked telopeptide domain of type 1 collagen, Ostase, osteocalcin, intact parathyroid hormone, and calcitonin) were measured in three different groups of 80 patients during the first posttraumatic week. Patients were categorized into three groups: group I, fractures only; group II, isolated traumatic brain injury; and group III, traumatic brain injury in combination with fractures. Osteocalcin levels were significantly lower in the presence of traumatic brain injury (p < .05). Elevated pyridinoline cross-linked telopeptide domain of type 1 collagen levels expressed enhanced bone resorption in all groups, but levels were significantly higher in the absence of traumatic brain injury (p < .05). Intact parathyroid hormone levels were significantly higher on days 0 and 1 in the combined presence of traumatic brain injury plus fractures. These results demonstrate an imbalance of bone formation and resorption parameters in patients with traumatic brain injury during the early posttraumatic period, suggesting a central regulation in bone formation. The lower levels of osteocalcin detected in this study may play an important role in patients with brain injury and the later development of posttraumatic heterotopic ossification.


Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair.
The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted cell-type lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.


Management strategies for gastroesophageal reflux disease.
In the treatment of gastroesophageal reflux disease (GERD), the most effective treatment option is the use of proton pump inhibitor (PPI), which minimizes the effect of gastric acid on the distal esophagus. Both the step-up and step-down treatment strategies have advantages and disadvantages. Most physicians would like to choose the step-down therapy rather than the step-up therapy. The 'No-step' PPI therapy (i.e. continuous PPI therapy) is another relevant option. After an initial remission, long-term PPI therapy is an appropriate form of maintenance therapy in many patients. As a treatment plan for non-erosive reflux disease, a standard dose of PPI for 4-8 weeks followed by either the step-down strategy or the on-demand treatment strategy is acceptable. When treating erosive esophagitis, PPI is better than H(2) receptor blockers in healing mucosal breaks and relieving symptoms. Long-term maintenance PPI therapy is reported to be very effective in maintaining the remission of reflux esophagitis for up to 5 years. On-demand PPI is also another good option for a maintenance therapy in erosive esophagitis. In Barrett's esophagus, symptoms seem to be well-controlled with PPIs. Unfortunately, however, PPIs have no effect on the shortening of Barrett's esophagus or in preventing the progression to dysplasia and adenocarcinoma. In summary, after reviewing existing guidelines a rather simple guideline on the management of GERD is suggested - PPI should be given for 4-8 weeks followed by either on-demand or maintenance PPI therapy according to the clinical severity.


Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.
Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.