Community efforts to expand dental services for low-income people.
Poor oral health among low-income people is gaining attention as a significant health care problem. Key barriers to dental services include low rates of dental insurance coverage, limited dental benefits available through public insurance programs, and a lack of dentists willing to serve low-income patients, according to findings from the Center for Studying Health System Change's (HSC) 2007 site visits to 12 nationally representative metropolitan communities. Communities are attempting to provide more dental services to low-income residents. Along with state efforts to increase dentists' participation in Medicaid and the State Children's Health Insurance Program (SCHIP), hospitals, community health centers, health departments, dental schools and others are working to expand dental services, with some focusing on basic preventive services and others pursuing more comprehensive dental care. Many community efforts rely on increasing the number of dental professionals available to treat low-income people. Without additional involvement from the dental community and state and federal policy makers, however, many low-income people likely will continue to lack access to dental care and suffer the consequences.


[Domestic violence against women and professional intervention in primary healthcare: an ethnographic study in Matinhos, Paraná State, Brazil].
Domestic violence has multiple repercussions on women's health and raises a challenging agenda for health professionals in Brazilian Unified National Health System (SUS). The aim of this study was to analyze how health professionals treat these women, problematizing the notion of acolhimento (receptiveness or openness to patients). A qualitative ethnographic research approach was used with health professionals from a primary care unit (PHU) in Matinhos, Paraná State, Brazil. The study revealed care that was focused on: (1) biologizing principles, with a focus on physical lesions and medicalization and (2) dialogue, active listening, psychosocial questions, and establishment of ties, especially featuring community health agents in this approach. The limited official local structure for handling domestic violence justifies treatment oriented by the grammar of acolhimento, recommended by the SUS, described in the literature, and verbalized in the PHU, but rarely problematized. This article thus proposed to contribute to this debate, not by establishing prescriptions for action, but by raising questions and mainly highlighting and translating the voices of those who deal with this challenge on a daily basis.


Clinical Challenges Associated with Universal Screening for Lynch Syndrome-Associated Endometrial Cancer.
Universal testing for Lynch syndrome is now a routine component of the diagnostic work-up of endometrial cancer patients. The purpose of this study was to identify prospectively the barriers to universal screening based on a tissue testing approach [microsatellite instability (MSI) analysis, IHC for DNA mismatch repair proteins, and MLH1 methylation analysis]. Endometrial carcinoma patients (n = 213) prospectively underwent microsatellite instability and IHC testing for expression of DNA mismatch repair (MMR) proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor MSI or immunohistochemical loss of MLH1 (and absent MLH1 methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor for consideration of germline testing. Six discordances (3.1% of tested cases) between IHC and MSI were identified. Half of these exhibited heterogeneous immunohistochemical loss of MLH1/PMS2 and were microsatellite stable (MSS). Of the remaining cases, one was MSS with immunohistochemical loss of MSH6, one was MSS with immunohistochemical loss of MLH1/PMS2 and absent MLH1 promoter methylation, and one was MSI-H with intact expression of DNA MMR proteins. Four patients had MSI-L tumors with intact immunohistochemical protein expression; the clinical significance of MSI-L in endometrial cancer is unclear. Eight patients did not have germline mutations despite tissue testing suggesting Lynch syndrome. Including cases with insufficient tissue for testing and patients declining tissue or germline testing, we encountered significant barriers to universal screening in 13.6% of screened patients (29/213) that preclude designation of a tumor as sporadic or hereditary. Cancer Prev Res; 10(2); 108-15. ©2016 AACR.


Heart healthy equals prostate healthy and statins, aspirin, and/or metformin (S.A.M.) are the ideal recommendations for prostate cancer prevention.
Cardiovascular disease (CVD) has been the number one cause of death in the U.S. for 114 of the last 115 years. Lifestyle factors that promote CVD also appear to increase prostate cancer risk and those that reduce CVD risk also appear to reduce the risk of prostate cancer. The largest randomized trials utilizing dietary supplements or pharmacologic agents for prostate cancer prevention (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) have also shed light on the problems and future solutions in this area. Dietary supplements that have not been found to be CVD protective, such as selenium and Vitamin E have not been found to be prostate protective. In addition, over exposure to specific anti-oxidants in nutritionally replete populations may be encouraging cancer growth. Future trials of dietary supplements to prevent prostate cancer could be problematic because by the time a definitive trial is initiated the participants will no longer be "deficient" in the nutrient being tested, which arguably occurred in the SELECT trial. It is also interesting that statins, aspirin, and/or metformin (S.A.M.) are 3 generic, low-cost, heart healthy agents derived from natural sources with separate mechanism of actions, which all appear to have the best benefit to risk ratio compared to any other agent available for prostate cancer prevention, especially aggressive disease, or as an ancillary agent (s) to conventional cancer treatment. It is time to focus on the forest over the trees and recommend proven CVD protective measures for men concerned about their risk of prostate cancer.


Regulation of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation.
The POU family transcription factor Brn-3a is required for the differentiation and survival of sensory neurones, and is phosphorylated in neuroblastoma cells following treatment with all-trans retinoic acid (RA). Mutation of serines-121 and -122 of Brn-3a to alanine blocks its phosphorylation and impairs RA-mediated neurite outgrowth. Here we show that this deficit in differentiation is mimicked by a single mutation at serine-122, and demonstrate a similar requirement for a second residue, threonine-39. Like Brn-3a, the neuropeptide Galanin has been implicated in the development of sensory neurones. We show that Brn-3a over-expression acts synergistically with RA treatment to up-regulate Galanin promoter activity; that the activity of the N-terminal transcriptional activation domain of Brn-3a is increased following RA treatment; and that both these effects require threonine-39 and serine-122. In addition, we demonstrate that the RA-mediated activation of Galanin promoter activity and Brn-3a N-terminal transcriptional activity are both blocked by pan-MEK inhibitors, and show that the expression of a constitutively-active mutant of MEK1, but not MEK5, is sufficient to increase Brn-3a activity. These results reveal an important role for the ERK1/2 pathway in Brn-3a regulation during RA-mediated neuronal differentiation and define the neuropeptide Galanin as a novel target of this transcription factor.


Effects of three interventions on the reading skills of children with reading disabilities in grade 2.
In a longitudinal intervention study, the effects of three intervention strategies on the reading skills of children with reading disabilities in Grade 2 were analyzed. The interventions consisted of computerized training programs: One bottom-up intervention aimed at improving word decoding skills and phonological abilities, the second intervention focused on top-down processing on the word and sentence levels, and the third was a combination of these two training programs (n = 25 in each group). In addition, there were two comparison groups, 25 children with reading disabilities who received ordinary special instruction and 30 age-matched typical readers. All reading disabled participants completed 25 training sessions with special education teachers. All groups improved their reading skills. The group who received combined training showed higher improvements than the ordinary special instruction group and the typical readers. Different cognitive variables were related to treatment gains for different groups. Thus, a treatment combining bottom-up and top-down aspects of reading was the most effective in general, but individual differences among children need to be considered.


Long-distance colonization and radiation in gekkonid lizards, Tarentola (Reptilia: Gekkonidae), revealed by mitochondrial DNA sequences.
Morphological systematics makes it clear that many non-volant animal groups have undergone extensive transmarine dispersal with subsequent radiation in new, often island, areas. However, details of such events are often lacking. Here we use partial DNA sequences derived from the mitochondrial cytochrome b and 12S rRNA genes (up to 684 and 320 bp, respectively) to trace migration and speciation in Tarentola geckos, a primarily North African clade which has invaded many of the warmer islands in the North Atlantic Ocean. There were four main invasions of archipelagos presumably by rafting. (i) The subgenus Neotarentola reached Cuba up to 23 million years (Myr) ago, apparently via the North Equatorial current, a journey of at least 6000 km. (ii) The subgenus Tarentola invaded the eastern Canary Islands relatively recently covering a minimum of 120 km. (iii) The subgenus Makariogecko got to Gran Canaria and the western Canary Islands 7-17.5 Myr ago, either directly from the mainland or via the Selvages or the archipelago of Madeira, an excursion of 200-1200 km. (iv) A single species of Makariogecko from Gomera or Tenerife in the western Canaries made the 1400 km journey to the Cape Verde Islands tip to 7 Myr ago by way of the south-running Canary current. Many journeys have also occurred within archipelagos, a minimum of five taking place in the Canaries and perhaps 16 in the Cape Verde Islands. Occupation of the Cape Verde archipelago first involved an island in the northern group, perhaps São Nicolau, with subsequent spread to its close neighbours. The eastern and southern islands were colonized from these northern islands, at least two invasions widely separated in time being involved. While there are just three allopatric species of Makariogecko in the Canaries, the single invader of the Cape Verde Islands radiated into five, most of the islands being inhabited by two of these which differ in size. While size difference may possibly be a product of character displacement in the northern islands, taxa of different sizes reached the southern islands independently.


German Acupuncture Trials (GERAC) for chronic low back pain: randomized, multicenter, blinded, parallel-group trial with 3 groups.
To our knowledge, verum acupuncture has never been directly compared with sham acupuncture and guideline-based conventional therapy in patients with chronic low back pain. A patient- and observer-blinded randomized controlled trial conducted in Germany involving 340 outpatient practices, including 1162 patients aged 18 to 86 years (mean +/- SD age, 50 +/- 15 years) with a history of chronic low back pain for a mean of 8 years. Patients underwent ten 30-minute sessions, generally 2 sessions per week, of verum acupuncture (n = 387) according to principles of traditional Chinese medicine; sham acupuncture (n = 387) consisting of superficial needling at nonacupuncture points; or conventional therapy, a combination of drugs, physical therapy, and exercise (n = 388). Five additional sessions were offered to patients who had a partial response to treatment (10%-50% reduction in pain intensity). Primary outcome was response after 6 months, defined as 33% improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale questionnaire or 12% improvement or better on the back-specific Hanover Functional Ability Questionnaire. Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement. At 6 months, response rate was 47.6% in the verum acupuncture group, 44.2% in the sham acupuncture group, and 27.4% in the conventional therapy group. Differences among groups were as follows: verum vs sham, 3.4% (95% confidence interval, -3.7% to 10.3%; P = .39); verum vs conventional therapy, 20.2% (95% confidence interval, 13.4% to 26.7%; P < .001); and sham vs conventional therapy, 16.8% (95% confidence interval, 10.1% to 23.4%; P < .001. Low back pain improved after acupuncture treatment for at least 6 months. Effectiveness of acupuncture, either verum or sham, was almost twice that of conventional therapy.


The efficacy and safety of a nicotine conjugate vaccine (NicVAX®) or placebo co-administered with varenicline (Champix®) for smoking cessation: study protocol of a phase IIb, double blind, randomized, placebo controlled trial.
A potential new treatment in smoking cessation and relapse prevention is nicotine vaccination which is based on active immunization against the nicotine molecule. This immunization will elicit the immune system to produce nicotine-specific antibodies that sequester nicotine in the blood stream, after inhaling tobacco products. The resulting antibody-antigen is too large to cross the blood-brain barrier and is therefore postulated to attenuate the rewarding effect of nicotine by preventing the latter from reaching its receptors in the brain and causing the release of dopamine. The aim of this paper is to describe the design of a phase IIb, multi-center, double blind, randomized, placebo controlled trial to assess the efficacy of the nicotine vaccine NicVAX® co-administered with varenicline (Champix®) and intensive counseling as an aid in smoking cessation and relapse prevention. Two centers will include a total of 600 smokers who are motivated to quit smoking. At week -2 these smokers will be randomized, in a 1:1 ratio, to either 6 injections of NicVAX® or placebo, both co-administered with 12-weeks of varenicline treatment, starting at week 0. The target quit day will be set after 7 days of varenicline treatment at week 1. Smokers will be followed up for 54 weeks. The primary outcome is defined as biochemically validated prolonged smoking abstinence from week 9 to 52. Secondary outcomes include safety, immunogenicity, smoking abstinence from week 37 to 52, abstinence from week 9 to 24, abstinence in the subset of subjects with the highest antibody response, and lapse/relapse rate. This is the first study to assess the efficacy of a nicotine conjugate vaccine in combination with an evidence-based smoking cessation pharmacotherapy (varenicline) to quit smoking. Although NicVAX® is primarily designed as an aid to smoking cessation, our study is designed to explore its potential to maintain abstinence and prevent relapse. The results of this trial will give a unique insight in the potential of nicotine vaccination for relapse prevention. ClinicalTrials.gov: (NCT00995033).


Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer.
To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 μg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.


FOCuS: a metaheuristic algorithm for computing knockouts from genome-scale models for strain optimization.
Although handful tools are available for constraint-based flux analysis to generate knockout strains, most of these are either based on bilevel-MIP or its modifications. However, metaheuristic approaches that are known for their flexibility and scalability have been less studied. Moreover, in the existing tools, sectioning of search space to find optimal knocks has not been considered. Herein, a novel computational procedure, termed as FOCuS (Flower-pOllination coupled Clonal Selection algorithm), was developed to find the optimal reaction knockouts from a metabolic network to maximize the production of specific metabolites. FOCuS derives its benefits from nature-inspired flower pollination algorithm and artificial immune system-inspired clonal selection algorithm to converge to an optimal solution. To evaluate the performance of FOCuS, reported results obtained from both MIP and other metaheuristic-based tools were compared in selected case studies. The results demonstrated the robustness of FOCuS irrespective of the size of metabolic network and number of knockouts. Moreover, sectioning of search space coupled with pooling of priority reactions based on their contribution to objective function for generating smaller search space significantly reduced the computational time.


pH-controlled exponential and linear growing modes of layer-by-layer assemblies of star polyelectrolytes.
We report the unique layer-by-layer (LbL) assembly behavior of pH-sensitive star-shaped polyelectrolytes with both linear and exponential growth modes controlled by star architecture and assembly conditions. Cationic poly[2-(dimethylamino)ethyl methacrylate] and anionic poly(acrylic acid) stars were synthesized via "core-first" atom-transfer radical polymerization (ATRP) based on multifunctional initiators, in addition to their linear analogues. We demonstrated the LbL growth behavior as a function of deposition pH (ranging from 5 to 7), number of layers (up to 30 bilayers), and the method of assembly (dip- vs spin-assisted LbL). The spin-assisted LbL assembly makes it possible to render smoother and thinner LbL films with parameters controlled by the shear rate and pH conditions. In contrast, for dip-assisted LbL assembly, the pH-dependent exponential growth was observed for both linear and star polyelectrolytes. In the case of linear/linear pair, the exponential buildup was accompanied with a notable surface segregation which resulted in dramatic surface nonuniformity, "wormlike" heterogeneous morphology, and dramatic surface roughening. In contrast, star/linear and star/star LbL films showed very uniform and smooth surface morphology (roughness below 2.0 nm on the scale of 10 μm × 10 μm) with much larger thickness reaching up to 1.0 μm for 30 bilayers and rich optical interference effects. Star polyelectrolytes with partially screened charges and high mobility caused by compact branched architecture appear to facilitate fast diffusion and exponential buildup of LbL films. We suggest that the fast buildup prevents long-range lateral diffusion of polyelectrolyte star components, hinders large-scale microphase separation, and thus leads to unique thick, smooth, uniform, transparent, and colorful LbL films from star polyelectrolytes in contrast to mostly heterogeneous films from traditional linear counterparts.


[Impact of the use of point of care devices on the morbidity and the mortality of patients with oral anticoagulation].
The objective of this study is to evaluate the impact of International Normalized Ratio testing by point of care devices, on morbidity and mortality of patients treated with oral anticoagulants, in comparison with usual testing in laboratory.A systematic review of literature is performed. Data from selected trials are summarized in a global meta-analysis and also in subgroups meta-analysis, according to the fact that the user of POC device is the patient himself, with or without personal treatment adaptation, the general practitioner or a health professional in an anticoagulation clinic. Results of the global meta-analysis show a reduction of major thromboembolism and all causes mortality but not of major hemorrhage. Subgroup analysis shows that most favorable results are obtained when patient himself realizes the test and adapts the treatment. Results are compared with those of other published meta-analysis and the limits of results' validity are discussed.


TGF-β signaling regulates fibrotic expression and activity in carpal tunnel syndrome.
Fibrosis of the subsynovial connective tissue (SSCT) is a predominant feature of carpal tunnel syndrome (CTS). While the nature of CTS has been extensively studied, little is known about the etiology of this disease. We investigated SSCT tissue from patients with CTS and control subjects using fibrosis arrays and cell culture analysis. Twofold changes in fibrotic gene expression were found in multiple genes from patient SSCT using fibrosis arrays. This data was confirmed via qRT-PCR on a subset of genes; collagen I (Col1), collagen III (Col3), connective tissue growth factor (CTGF), transforming growth factor β (TGF-β), and SMAD3 (P < 0.05) which significantly corroborate the fold changes found in the fibrosis arrays. To further explore the nature of SSCT fibrosis, cells were isolated from patient and control tissue. Col1, Col3, TGF-β, and SMAD3 were highly expressed in patient SSCT fibroblasts as compared to control (P < 0.05). Further, fibrotic genes expression was decreased by inhibiting TGF-β receptor I (TβRI) activity (P < 0.05). TGF-β second messenger SMAD activity was significantly activated in SSCT fibroblasts from patients and this activation was abrogated by inhibiting TβRI signaling (P < 0.05). These findings suggest that blocking TGF-β signaling may be an important therapeutic approach to treating the underlying fibrosis of SSCT in CTS patients.


The economic value of an on-call neurosurgical resident physician.
The cost of training neurosurgical residents is especially high considering the duration of training and the technical nature of the specialty. Despite these costs, on-call residents are a source of significant economic value, through both indirectly and directly supervised activities. The authors sought to identify the economic value of on-call services provided by neurosurgical residents. A personal call log kept by a single junior neurosurgical resident over a 2-year period was used to obtain the total number of consultations, admissions, and procedures. Current Procedural Terminology (CPT) codes were used to estimate the resident's on-call economic value. A single on-call neurosurgical resident at the authors' institution produced 8172 work relative value units (wRVUs) over the study period from indirectly and directly supervised activities. Indirectly supervised procedures produced 7052 wRVUs, and directly supervised activities using the CPT modifier 80 yielded an additional 1120 wRVUs. Using the assistant surgeon billing rate for directly supervised activities and the Medical Group Management Association nationwide median neurosurgery reimbursement rate, the on-call activities of a single resident generated a theoretical billing value of $689,514 over the 2-year period, or $344,757 annually. As a program, the on-call residents collectively produced 39,550 wRVUs over the study period, or 19,775 wRVUs annually, which equates to potential reimbursements of $1,668,386 annually. Neurosurgery residents at the authors' institution theoretically produce enough economic value exclusively from on-call activities to far exceed the cost of their education. This information could be used to more precisely estimate the true overall cost of neurosurgical training and determine future graduate medical education funding.


Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy.
The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.


Pathobiology of chemotherapy-induced hair loss.
Hair loss can be a psychologically devastating adverse effect of chemotherapy, but satisfactory management strategies for chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-effect. We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.


The initial effects of a Mulligan's mobilization with movement technique on dorsiflexion and pain in subacute ankle sprains.
Physiotherapists frequently use manipulative therapy techniques to treat dysfunction and pain resulting from ankle sprain. This study investigated whether a Mulligan's mobilization with movement (MWM) technique improves talocrural dorsiflexion, a major impairment following ankle sprain, and relieves pain in subacute populations. Fourteen subjects with subacute grade II lateral ankle sprains served as their own control in a repeated measures, double-blind randomized controlled trial that measured the initial effects of the MWM treatment on weight bearing dorsiflexion and pressure and thermal pain threshold. The subacute ankle sprain group studied displayed deficits in dorsiflexion and local pressure pain threshold in the symptomatic ankle. Significant improvements in dorsiflexion occurred initially post-MWM ( F(2,26) = 7.82, P = 0.002 ), but no significant changes in pressure or thermal pain threshold were observed after the treatment condition. Results indicate that the MWM treatment for ankle dorsiflexion has a mechanical rather than hypoalgesic effect in subacute ankle sprains. The mechanism by which this occurs requires investigation if we are to better understand the role of manipulative therapy in ankle sprain management.


Perceptions of a 24-hour visiting policy in the intensive care unit.
To examine perceptions by intensive care unit (ICU) workers of unrestricted visitation, to measure visiting times, and to determine prevalence of symptoms of anxiety and depression in family members. Observational, prospective, single-center cohort. Medical-surgical ICU in a 460-bed tertiary-care hospital. Two hundred nine consecutive patients hospitalized >3 days were studied over the first 5 ICU days. None. Characteristics of patients (n = 209), families (n = 149), and ICU workers (n = 43) were collected. ICU workers reported their perceptions of unrestricted visitation, and family members completed the Hospital Anxiety and Depression Scale. Daily severity scores (Simplified Acute Physiology Score II and Logistic Organ Failure) and a workload score (Nine Equivalents of Nursing Manpower) were computed. Maximum median visit length was 120 mins per patient per day and occurred on days 4 and 5. No correlations were found among severity of illness, workload, and visit length. For 115 patients, both nurse and physician questionnaires were available; although several differences were noted, neither nurses nor physicians perceived open visitation as disrupting patient care. The median rating for delay in organizing care was "never" for physicians and "occasionally" for nurses. Nurses perceived more disorganization of care than physicians (p = .008). Compared with nurses, the physicians reported greater family trust (p = .0023), more family stress (p = .047), and greater unease when examining the patient (p = .02). The Hospital Anxiety and Depression Scale indicated symptoms of anxiety in 73 (49%) family members and depression in 44 (29.5%). The 24-hr visitation policy was perceived favorably by families. It induced only moderate discomfort among ICU workers, due to the potential for care interruption, in particular for nurses.


Effect of step width manipulation on tibial stress during running.
Narrow step width has been linked to variables associated with tibial stress fracture. The purpose of this study was to evaluate the effect of step width on bone stresses using a standardized model of the tibia. 15 runners ran at their preferred 5k running velocity in three running conditions, preferred step width (PSW) and PSW±5% of leg length. 10 successful trials of force and 3-D motion data were collected. A combination of inverse dynamics, musculoskeletal modeling and beam theory was used to estimate stresses applied to the tibia using subject-specific anthropometrics and motion data. The tibia was modeled as a hollow ellipse. Multivariate analysis revealed that tibial stresses at the distal 1/3 of the tibia differed with step width manipulation (p=0.002). Compression on the posterior and medial aspect of the tibia was inversely related to step width such that as step width increased, compression on the surface of tibia decreased (linear trend p=0.036 and 0.003). Similarly, tension on the anterior surface of the tibia decreased as step width increased (linear trend p=0.029). Widening step width linearly reduced shear stress at all 4 sites (p<0.001 for all). The data from this study suggests that stresses experienced by the tibia during running were influenced by step width when using a standardized model of the tibia. Wider step widths were generally associated with reduced loading of the tibia and may benefit runners at risk of or experiencing stress injury at the tibia, especially if they present with a crossover running style.


Class I- and class II-reactive TCRs coexpressed on CD4+ T cells both trigger CD4/CD8-shared and CD4-unique functions.
CD4+ and CD8+ T cells emerge from thymic selection expressing a TCR restricted by MHC class II (TCRII) and MHC class I (TCRI), and upon Ag stimulation develop respectively into Th and CTL effector cells. The influence of thymic differentiation and antigenic stimulation on the determination of T cell functions was studied, with CD4+ T cells expressing a transgenic TCRI that reacts with the class I alloantigen H-2K(b) in a CD8-independent fashion. Such T cells additionally express a TCR, probably TCRII, in which the transgenic TCR beta-chain is associated with endogenously rearranged TCR alpha-chains. Upon in vitro stimulation with H-2K(b)-expressing cells, both CD8+ and CD4+ transgenic TCR+ T cells developed into CTL capable of killing Ag-expressing target cells through a perforin-dependent mechanism, and secreted IL-2 and IFN-gamma. Fas ligand-dependent killing could also be induced in both CD8+ and CD4+ in vitro stimulated T cells. The capacity to secrete IL-4 was restricted to the CD4+ T cells, however, suggesting that both CD8/CD4-shared and CD4-unique programs can be elicited by stimulation of CD4 T cells through a TCRI. Acquisition of CTL function was also induced upon class II alloantigen stimulation through the endogenously rearranged TCRII, which represents a polyclonal set of TCRs. IL-2, IFN-gamma, and after restimulation, IL-4, were also produced. Thus: 1) events associated with intrathymic selection influence the gene program activated in response to the same TCRI/APC interaction; and 2) CD4+ T cells expressing a TCRI and a TCRII can activate the same gene program after engagement of either one of these TCRs.


The importance of medical education in the changing field of pain medicine.
Suffering chronic pain is a global epidemic that requires a closer look on how we are educating trainees to become more effective in pain management. The vast majority of medical professionals will encounter treatment of pain throughout their career. Our current system for educating these medical professionals is flawed in a number of ways. Improving pain education will narrow the gap between over and under treatment of acute and chronic pain. Reviews have demonstrated dissatisfaction among practitioners throughout the world on how pain education is currently conducted. Changing the educational process will require support from several areas: medical educators, clinicians, policymakers, administrators and several other organizations.


A Rasch measure of young children's temperament (Negative Emotionality) in Hong Kong.
An aspect of child behavior and temperament, called Negative Emotionality in the literature, is very important to teachers of very young children. The Children's Behavior Questionnaire, initially designed by Rothbart, Ahadi, Hershey and Fisher (2001) for use in western countries, was modified in line with Rasch measurement theory, revised for suitability with Hong Kong preschool children, and conceptually ordered from easy to hard along a continuum of attitude/behavior for negative emotionality, before data collection. Three ordered scoring categories (never or rarely scored 1, on some occasions scored 2, and on many occasions scored 3) were used. Data were collected from preschool teachers for N = 628 preschool children from 32 schools in Hong Kong and analyzed with the 2010 Rasch unidimensional measurement model computer program (RUMM2030). The item-trait interaction probability is 0.05 (2 = 101.88, df = 80) which indicates that there is reasonable agreement about the different difficulties of the items along the scale for all the children. Results and implications are discussed, and revisions for the scale suggested.


Endoplasmic reticulum stress and hypertension - a new paradigm?
Hypertension occurs in approximately 30% of individuals in Western populations and is known to be a major cause of stroke, heart failure, and myocardial infarction. Despite this, the molecular etiology of hypertension remains poorly understood. In this issue of the JCI, Young et al. show that endoplasmic reticulum (ER) stress is an essential signaling event for angiotensin II-induced hypertension in cells of the central nervous system. This provides new insight into the molecular mechanisms that drive hypertension and suggests a potential target for future therapy.


An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C.
Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.


Open-channel, water-in-oil emulsification in paper-based microfluidic devices.
Open-channel microfluidic devices have shown great potential in achieving a high degree of fluid control, at relatively low-cost, while enabling the opportunity for rapid fabrication. However, thus far, work in open channel microfluidics has largely focused on controlling the flow of water or other aqueous solutions. In this work we present new open channel microfluidic devices based on surfaces with patterned wettabilty that are capable of controlling the flow of virtually all high and low surface tension liquids. The fabricated open channel devices are capable of constraining a variety of low surface tension oils at high enough flow rates to enable, for the first time, water-in-oil microfluidic emulsification in an open channel device. By changing the flow rates for both the aqueous (dispersed) and organic (continuous) phases, we show that it is possible to vary the size of the emulsified droplets produced in the open channel device. Finally, we utilized the fabricated devices to synthesize relatively monodisperse, hydrogel microparticles that could incorporate a drug molecule. We also investigated the drug release characteristics of the fabricated particles.


Distance-based assessment of the localization of functional annotations in 3D genome reconstructions.
Recent studies used the contact data or three-dimensional (3D) genome reconstructions from Hi-C (chromosome conformation capture with next-generation sequencing) to assess the co-localization of functional genomic annotations in the nucleus. These analyses dichotomized data point pairs belonging to a functional annotation as "close" or "far" based on some threshold and then tested for enrichment of "close" pairs. We propose an alternative approach that avoids dichotomization of the data and instead directly estimates the significance of distances within the 3D reconstruction. We applied this approach to 3D genome reconstructions for Plasmodium falciparum, the causative agent of malaria, and Saccharomyces cerevisiae and compared the results to previous approaches. We found significant 3D co-localization of centromeres, telomeres, virulence genes, and several sets of genes with developmentally regulated expression in P. falciparum; and significant 3D co-localization of centromeres and long terminal repeats in S. cerevisiae. Additionally, we tested the experimental observation that telomeres form three to seven clusters in P. falciparum and S. cerevisiae. Applying affinity propagation clustering to telomere coordinates in the 3D reconstructions yielded six telomere clusters for both organisms. Distance-based assessment replicated key findings, while avoiding dichotomization of the data (which previously yielded threshold-sensitive results).


All-optical Fresnel lens in coherent media: controlling image with image.
We theoretically explore an all-optical method for generating tunable diffractive Fresnel lenses in coherent media based on electromagnetically induced transparency. In this method, intensity-modulated images in coupling light fields can pattern the coherent media to induce the desired modulo-2π quadratic phase profiles for the lenses to diffract probe light fields. We characterize the focusing and imaging properties of the induced lenses. In particular, we show that the images in coupling fields can flexibly control the images in probe fields by diffraction, where large focal length tunability from 1 m to infinity and high output (∼ 88% diffraction efficiency) can be achieved. Additionally, we also find that the induced Fresnel lenses can be rapidly modulated with megahertz refresh rates using image-bearing square pulse trains in coupling fields. Our proposed lenses may find a wide range of applications for multimode all-optical signal processing in both the classical and quantum regimes.


[Comparability of various measurement methods in nasal provocation with allergens].
Defined criteria for nasal provocation exist only for the anterior Rhinomanometrie (aRM). During the last years there are other techniques for nasal provocation in use. In this study the new instruments were compared with the established aRM. We examined 14 patients with perennial rhinitis. All showed positive skin test and RAST against D. pteronyssinus. The controls were 13 atopic patients sensitized against pollen but not against D. pteronyssinus and 20 healthy volunteers. All subjects underwent nasal provocation with D. pteronyssinus. On the first day the provocation was unilateral. The instruments were the aRM, the Oscilloresistometry (ORM), the Peak Nasal Inspiratory Flowmeter (PNIF) and the Acoustic Rhinometry (Rhinoklack). On the second day the provocation was bilateral with ORM and PNIF. First we determined the limits for separation between a positive and negative nasal provocation test for the different instruments. Then we calculated the sensitivity and specificity for the instruments. By unilateral provocation there was a good sensitivity for all devices. The specificity was very good with the aRM, ORM and PNIF. In conclusion the PNIF is as good as the other instruments, but the Rhinoklack was less specific than the others.


Evaluation of the ultrasonographic features of salivary gland tumours.
to evaluate the value of the ultrasonographic features for differentiation between benign and malignant tumours of salivary glands. eighty-four cases of salivary gland tumours were analysed. Sixty-five cases were benign and 19 were malignant. All cases were confirmed by histopathological examination. The ultrasonographic features analysed included the shape of the tumour, the boundary echo, the internal echo and the posterior echo. Each feature was graded into three ranks. For statistical analysis, they were ranked respectively 1, 2 and 3. Another 28 cases of salivary gland tumours were analysed to verify the diagnostic accuracy of the ultrasonography. All data were analysed using SPSS 16.0 for windows. The Mann-Whitney U test, the receiver operating characteristic (ROC) curve and Fisher's discriminant test were performed. The differences between benign and malignant tumours were statistically significant in the shape of the tumour (P = 0.001), the boundary echo (P = 0.001) and the posterior echo (P = 0.000). However, the difference in the internal echo was not statistically significant (P > 0.05). The diagnostic accuracy, sensitivity and specificity were 82.1%, 63.2% and 87.7%, respectively, while the predicting diagnostic accuracy was 85.7%. the present study indicates that the shape of the tumour, the boundary echo and the posterior echo could be effective ultrasonographic criteria for differential diagnosis of benign tumours from malignant tumours in the salivary glands.


Education Outcomes in a Duty-Hour Flexibility Trial in Internal Medicine.
Concern persists that inflexible duty-hour rules in medical residency programs may adversely affect the training of physicians. We randomly assigned 63 internal medicine residency programs in the United States to be governed by standard duty-hour policies of the 2011 Accreditation Council for Graduate Medical Education (ACGME) or by more flexible policies that did not specify limits on shift length or mandatory time off between shifts. Measures of educational experience included observations of the activities of interns (first-year residents), surveys of trainees (both interns and residents) and faculty, and intern examination scores. There were no significant between-group differences in the mean percentages of time that interns spent in direct patient care and education nor in trainees' perceptions of an appropriate balance between clinical demands and education (primary outcome for trainee satisfaction with education; response rate, 91%) or in the assessments by program directors and faculty of whether trainees' workload exceeded their capacity (primary outcome for faculty satisfaction with education; response rate, 90%). Another survey of interns (response rate, 49%) revealed that those in flexible programs were more likely to report dissatisfaction with multiple aspects of training, including educational quality (odds ratio, 1.67; 95% confidence interval [CI], 1.02 to 2.73) and overall well-being (odds ratio, 2.47; 95% CI, 1.67 to 3.65). In contrast, directors of flexible programs were less likely to report dissatisfaction with multiple educational processes, including time for bedside teaching (response rate, 98%; odds ratio, 0.13; 95% CI, 0.03 to 0.49). Average scores (percent correct answers) on in-training examinations were 68.9% in flexible programs and 69.4% in standard programs; the difference did not meet the noninferiority margin of 2 percentage points (difference, -0.43; 95% CI, -2.38 to 1.52; P=0.06 for noninferiority). od Institute and the ACGME; iCOMPARE ClinicalTrials.gov number, NCT02274818 .). There was no significant difference in the proportion of time that medical interns spent on direct patient care and education between programs with standard duty-hour policies and programs with more flexible policies. Interns in flexible programs were less satisfied with their educational experience than were their peers in standard programs, but program directors were more satisfied. (Funded by the National Heart, Lung, and Blo


The incidence, characteristics and outcomes of pregnant women hospitalized with symptomatic and asymptomatic SARS-CoV-2 infection in the UK from March to September 2020: A national cohort study using the UK Obstetric Surveillance System (UKOSS).
There is a lack of population level data on risk factors, incidence and impact of SARS-CoV-2 infection in pregnant women and their babies. The primary aim of this study was to describe the incidence, characteristics and outcomes of hospitalized pregnant women with symptomatic and asymptomatic SARS-CoV-2 in the UK compared to pregnant women without SARS-CoV-2. We conducted a national, prospective cohort study of all hospitalized pregnant women with confirmed SARS-CoV-2 from 01/03/2020 to 31/08/2020 using the UK Obstetric Surveillance System. Incidence rates were estimated using national maternity data. Overall, 1148 hospitalized women had confirmed SARS-CoV-2 in pregnancy, 63% of which were symptomatic. The estimated incidence of hospitalization with symptomatic SARS-CoV-2 was 2.0 per 1000 maternities (95% CI 1.9-2.2) and for asymptomatic SARS-CoV-2 was 1.2 per 1000 maternities (95% CI 1.1-1.4). Compared to pregnant women without SARS-CoV-2, women hospitalized with symptomatic SARS-CoV-2 were more likely to be overweight or obese (adjusted OR 1.86, (95% CI 1.39-2.48) and aOR 2.07 (1.53-2.29)), to be of Black, Asian or Other minority ethnic group (aOR 6.24, (3.93-9.90), aOR 4.36, (3.19-5.95) and aOR 12.95, (4.93-34.01)), and to have a relevant medical comorbidity (aOR 1.83 (1.32-2.54)). Hospitalized pregnant women with symptomatic SARS-CoV-2 were more likely to be admitted to intensive care (aOR 57.67, (7.80-426.70)) but the absolute risk of poor outcomes was low. Cesarean births and neonatal unit admission were increased regardless of symptom status (symptomatic aOR 2.60, (1.97-3.42) and aOR 3.08, (1.99-4.77); asymptomatic aOR 2.02, (1.52-2.70) and aOR 1.84, (1.12-3.03)). The risks of stillbirth or neonatal death were not significantly increased, regardless of symptom status. We have identified factors that increase the risk of symptomatic and asymptomatic SARS-CoV-2 in pregnancy. Clinicians can be reassured that the majority of women do not experience severe complications of SARS-CoV-2 in pregnancy.


Identifying patients' support needs following critical illness: a scoping review of the qualitative literature.
Intensive care survivors suffer chronic and potentially life-changing physical, psychosocial and cognitive sequelae, and supporting recovery is an international priority. As survivors' transition from the intensive care unit to home, their support needs develop and change. In this scoping review, we categorised patients' support needs using House's Social Support Needs framework (informational, emotional, instrumental, appraisal) and mapped these against the Timing it Right framework reflecting the patient's transition from intensive care (event/diagnosis) to ward (stabilisation/preparation) and discharge home (implementation/adaptation). We searched electronic databases from 2000 to 2017 for qualitative research studies reporting adult critical care survivors' experiences of care. Two reviewers independently screened, extracted and coded data. Data were analysed using a thematic framework approach. From 3035 references, we included 32 studies involving 702 patients. Studies were conducted in UK and Europe (n = 17, 53%), Canada and the USA (n = 6, 19%), Australasia (n = 6, 19%), Hong Kong (n = 1, 3%), Jordan (n = 1, 3%) and multi-country (n = 1, 3%). Across the recovery trajectory, informational, emotional, instrumental, appraisal and spiritual support needs were evident, and the nature and intensity of need differed when mapped against the Timing it Right framework. Informational needs changed from needing basic facts about admission, to detail about progress and treatments and coping with long-term sequelae. The nature of emotional needs changed from needing to cope with confusion, anxiety and comfort, to a need for security and family presence, coping with flashbacks, and needing counselling and community support. Early instrumental needs ranged from managing sleep, fatigue, pain and needing nursing care and transitioned to needing physical and cognitive ability support, strength training and personal hygiene; and at home, regaining independence, strength and return to work. Appraisal needs related to obtaining feedback on progress, and after discharge, needing reassurance from others who had been through the ICU experience. This review is the first to identify the change in social support needs among intensive care survivors as they transition from intensive care to the home environment. An understanding of needs at different transition periods would help inform health service provision and support for survivors.


Identification of tetratricopeptide repeat 1 as an adaptor protein that interacts with heterotrimeric G proteins and the small GTPase Ras.
The biological functions of heterotrimeric G proteins and small GTPases are modulated by both extracellular stimuli and intracellular regulatory proteins. Using Saccharomyces cerevisiae two-hybrid screening, we identified tetratricopeptide repeat 1 (TPR1), a 292-amino-acid protein with three TPR motifs, as a Galpha16-binding protein. The interaction was confirmed both in vitro and in transfected mammalian cells, where TPR1 also binds to several other Galpha proteins. TPR1 was found to interact with Ha-Ras preferentially in its active form. Overexpression of TPR1 promotes accumulation of active Ras. TPR1 was found to compete with the Ras-binding domain (RBD) of Raf-1 for binding to the active Ras, suggesting that it may also compete with Ras GTPase-activating protein, thus contributing to the accumulation of GTP-bound Ras. Expression of Galpha16 strongly enhances the interaction between TPR1 and Ras. Removal of the TPR1 N-terminal 112 residues abolishes potentiation by Galpha16 while maintaining the interaction with Galpha16 and the ability to discriminate active Ras from wild-type Ras. We have also observed that LGN, a Galphai-interacting protein with seven TPR motifs, binds Ha-Ras. Thus, TPR1 is a novel adaptor protein for Ras and selected Galpha proteins that may be involved in protein-protein interaction relating to G-protein signaling.


Effects of physical activity calorie equivalent food labelling to reduce food selection and consumption: systematic review and meta-analysis of randomised controlled studies.
There is limited evidence that nutritional labelling on food/drinks is changing eating behaviours. Physical activity calorie equivalent (PACE) food labelling aims to provide the public with information about the amount of physical activity required to expend the number of kilocalories in food/drinks (eg, calories in this pizza requires 45 min of running to burn), to encourage healthier food choices and reduce disease. We aimed to systematically search for randomised controlled trials and experimental studies of the effects of PACE food labelling on the selection, purchase or consumption of food/drinks. PACE food labelling was compared with any other type of food labelling or no labelling (comparator). Reports were identified by searching electronic databases, websites and social media platforms. Inverse variance meta-analysis was used to summarise evidence. Weighted mean differences (WMD) and 95% CIs were used to describe between-group differences using a random effects model. 15 studies were eligible for inclusion. When PACE labelling was displayed on food/drinks and menus, significantly fewer calories were selected, relative to comparator labelling (WMD=-64.9 kcal, 95% CI -103.2 to -26.6, p=0.009, n=4606). Presenting participants with PACE food labelling results in the consumption of significantly fewer calories (WMD=-80.4 kcal, 95% CI-136.7 to -24.2, p=0.005, n=486) relative to comparator food labelling. Based on current evidence PACE food labelling may reduce the number of kilocalories selected from menus and decrease the number of kilocalories/grams of food consumed by the public, compared with other types of food labelling/no labelling. CRD42018088567.


Electron injection dynamics in high-potential porphyrin photoanodes.
There is a growing need to utilize carbon neutral energy sources, and it is well known that solar energy can easily satisfy all of humanity's requirements. In order to make solar energy a viable alternative to fossil fuels, the problem of intermittency must be solved. Batteries and supercapacitors are an area of active research, but they currently have relatively low energy-to-mass storage capacity. An alternative and very promising possibility is to store energy in chemical bonds, or make a solar fuel. The process of making solar fuel is not new, since photosynthesis has been occurring on earth for about 3 billion years. In order to produce any fuel, protons and electrons must be harvested from a species in its oxidized form. Photosynthesis uses the only viable source of electrons and protons on the scale needed for global energy demands: water. Because artificial photosynthesis is a lofty goal, water oxidation, which is a crucial step in the process, has been the initial focus. This Account provides an overview of how terahertz spectroscopy is used to study electron injection, highlights trends from previously published reports, and concludes with a future outlook. It begins by exploring similarities and differences between dye-sensitized solar cells (DSSCs) for producing electricity and a putative device for splitting water and producing a solar fuel. It then identifies two important problems encountered when adapting DSSC technology to water oxidation-improper energy matching between sensitizer energy levels with the potential for water oxidation and the instability of common anchoring groups in water-and discusses steps to address them. Emphasis is placed on electron injection from sensitizers to metal oxides because this process is the initial step in charge transport. Both the rate and efficiency of electron injection are analyzed on a sub-picosecond time scale using time-resolved terahertz spectroscopy (TRTS). Bio-inspired pentafluorophenyl porphyrins are promising sensitizers because their high reduction potentials are compatible with the energy requirements of water oxidation. TRTS of free-base and metalated pentafluorophenyl porphyrins reveal inefficient electron injection into TiO2 nanoparticles but more efficient electron injection into SnO2 nanoparticles. With SnO2, injection time scales depend strongly on the identity of the central substituent and are affected by competition with excited-state deactivation processes. Heavy or paramagnetic metal ions increase the electron injection time scale by roughly one order of magnitude relative to free-base or Zn(2+) porphyrins due to the possibility of electron injection from longer-lived, lower-lying triplet states. Furthermore, electron injection efficiency loosely correlates with DSSC performance. The carboxylate anchoring group is commonly used to bind DSSC sensitizers to metal oxide surfaces but typically is not stable under the aqueous and oxidative conditions required for water oxidation. Electron injection efficiency of several water-stable alternatives, including phosphonic acid, hydroxamic acid, acetylacetone, and boronic acid, were evaluated using TRTS, and hydroxamate was found to perform as well as the carboxylate. The next challenge is incorporating a water oxidation catalyst into the design. An early example, in which an Ir-based precatalyst is cosensitized with a fluorinated porphyrin, reveals decreased electron injection efficiency despite an increase in photocurrent. Future research will seek to better understand and address these difficulties.


Inhibition of pannexin-1 channel activity by adiponectin in podocytes: Role of acid ceramidase activation.
The pannexin-1 (Panx1) channel has been reported to mediate the release of ATP that is involved in local tissue inflammation, obesity, and many chronic degenerative diseases. It remains unknown whether Panx1 is present in podocytes and whether this channel in podocytes mediates ATP release leading to glomerular inflammation or fibrosis. To answer these questions, we first characterized the expression of Panx channels in podocytes. Among the three known pannexins, Panx1 was the most enriched in podocytes, either cultured or native in mouse glomeruli. Using a Port-a-Patch planar patch-clamp system, we recorded a large voltage-gated outward current through podocyte membrane under the Cs+in/Na+out gradient. Substitution of gluconate or aspartate for chloride in the bath solution blocked voltage-gated outward currents and shifted the reversal potential of Panx1 currents to the right, indicating the anion permeability of this channel. Pharmacologically, the recorded voltage-gated outward currents were substantially attenuated by specific Panx1 channel inhibitors. Given the anti-inflammatory and intracellular ATP restorative effects of adiponectin, we tested whether this adipokine inhibits Panx1 channel activity to block ATP release. Adiponectin blocked Panx1 channel activity in podocytes. Mechanistically, inhibition of acid ceramidase (AC) remarkably enhanced Panx1 channel activity under control conditions and prevented the inhibition of Panx1 channel by adiponectin. Correspondingly, intracellular addition of AC products, sphingosine or sphingosine-1-phosphate (S1P), blocked Panx1 channel activity, while elevation of intracellular ceramide had no effect on Panx1 channel activity. These results suggest that adiponectin inhibits Panx1 channel activity in podocytes through activation of AC and associated elevation of intracellular S1P.


Diagnosing occupational asthma: use of induced sputum.
The diagnosis of occupational asthma (OA) needs to be made with as much objective evidence as possible. If there is airway inflammation, measurement of this should be an asset. The objective of this study was to investigate whether there is an increase in induced sputum and blood eosinophils and eosinophil cationic protein (ECP) in OA after work exposure. Patients were assessed after a 2-4 week period at work and away from work with cell counts and ECP assays performed blind to the clinical data. They were considered to have OA if symptoms were worse at work and there was a fall in forced expiratory volume in one second (FEV1) > or =20% or in the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of four-fold or more compared with away from work. Patients whose symptoms were worse at work but had a change in FEV1 of <20% and in methacholine PC20 of less than four-fold were considered as controls. Sixteen patients were studied. Ten had OA and six were controls. Patients with OA had a significant increase in median (interquartile range) sputum eosinophils and ECP when at work compared with the periods out of work, 10.0 (17.05) versus 0.8 (1.6)% (p=0.007) and 3,840 (6,076) versus 116 (180) microg x L(-1) (p=0.01). They also had a higher blood eosinophil count, 0.3 (0.5) x 10(9) versus 0.2 (0.1) x 10(9) x L(-1) (p=0.013), and a trend towards higher serum ECP levels, 44.0 (20.0) versus 32.0 (18.5) microg x L(-1) (p=0.07). In conclusion, the proportion of eosinophils and levels of eosinophil cationic protein in sputum are particularly high at work in patients with occupational asthma, suggesting that the measurement of these factors can supplement other physiological outcomes in establishing the diagnosis of occupational asthma.


A relative shift in cloacal location repositions external genitalia in amniote evolution.
The move of vertebrates to a terrestrial lifestyle required major adaptations in their locomotory apparatus and reproductive organs. While the fin-to-limb transition has received considerable attention, little is known about the developmental and evolutionary origins of external genitalia. Similarities in gene expression have been interpreted as a potential evolutionary link between the limb and genitals; however, no underlying developmental mechanism has been identified. We re-examined this question using micro-computed tomography, lineage tracing in three amniote clades, and RNA-sequencing-based transcriptional profiling. Here we show that the developmental origin of external genitalia has shifted through evolution, and in some taxa limbs and genitals share a common primordium. In squamates, the genitalia develop directly from the budding hindlimbs, or the remnants thereof, whereas in mice the genital tubercle originates from the ventral and tail bud mesenchyme. The recruitment of different cell populations for genital outgrowth follows a change in the relative position of the cloaca, the genitalia organizing centre. Ectopic grafting of the cloaca demonstrates the conserved ability of different mesenchymal cells to respond to these genitalia-inducing signals. Our results support a limb-like developmental origin of external genitalia as the ancestral condition. Moreover, they suggest that a change in the relative position of the cloacal signalling centre during evolution has led to an altered developmental route for external genitalia in mammals, while preserving parts of the ancestral limb molecular circuitry owing to a common evolutionary origin.


The powerful combination of phage surface display of cDNA libraries and high throughput screening.
Phage surface display of cDNA libraries facilitates cloning, expression and rapid selection of functional gene products physically linked to their genetic information through gene product-ligand interactions. Efficient screening technologies based on selective enrichment of clones expressing desired gene products allows, within a short time, the isolation of all ligand-specific clones that are present in a library. Manual identification of clones by restriction analysis and random sequencing is unlike to be successful for the isolation of gene products derived from rare mRNA species resulting from selection of the libraries using polyvalent ligands like serum from patients. Here we describe rapid handling of large numbers of individual clones selected from molecular libraries displayed on phage surface using the power of robotics-based high throughput screening. The potential of the combination of cDNA-phage surface display, with selection for specific interactions by functional screening and robotic technology is illustrated by the isolation of more sequences potentially encoding IgE-binding proteins than postulated from Western blot analyses using extracts derived from raw material of complex allergenic sources. The subsequent application of functional enrichment and robotics-based screening will facilitate the rapid generation of information about the repertoire of protein structures involved in allergic diseases.


Vaginal versus Obstetric Infection Escherichia coli Isolates among Pregnant Women: Antimicrobial Resistance and Genetic Virulence Profile.
Vaginal Escherichia coli colonization is related to obstetric infections and the consequent development of infections in newborns. Ampicillin resistance among E. coli strains is increasing, which is the main choice for treating empirically many obstetric and neonatal infections. Vaginal E. coli strains are very similar to extraintestinal pathogenic E. coli with regards to the virulence factors and the belonging to phylogroup B2. We studied the antimicrobial resistance and the genetic virulence profile of 82 E. coli isolates from 638 vaginal samples and 63 isolated from endometrial aspirate, placental and amniotic fluid samples from pregnant women with obstetric infections. The prevalence of E. coli in the vaginal samples was 13%, which was significant among women with associated risk factors during pregnancy, especially premature preterm rupture of membranes (p<0.0001). Sixty-five percent of the strains were ampicillin-resistant. The E. coli isolates causing obstetric infections showed higher resistance levels than vaginal isolates, particularly for gentamicin (p = 0.001). The most prevalent virulence factor genes were those related to the iron uptake systems revealing clear targets for interventions. More than 50% of the isolates belonged to the virulent B2 group possessing the highest number of virulence factor genes. The ampicillin-resistant isolates had high number of virulence factors primarily related to pathogenicity islands, and the remarkable gentamicin resistance in E. coli isolates from women presenting obstetric infections, the choice of the most appropriate empiric treatment and clinical management of pregnant women and neonates should be carefully made. Taking into account host-susceptibility, the heterogeneity of E. coli due to evolution over time and the geographical area, characterization of E. coli isolates colonizing the vagina and causing obstetric infections in different regions may help to develop interventions and avoid the aetiological link between maternal carriage and obstetric and subsequent puerperal infections.


Early MinION™ nanopore single-molecule sequencing technology enables the characterization of hepatitis B virus genetic complexity in clinical samples.
Until recently, the method of choice to characterize viral diversity consisted in cloning PCR amplicons of full-length viral genomes and Sanger-sequencing of multiple clones. However, this is extremely laborious, time-consuming, and low-throughput. Next generation short-read sequencing appears also limited by its inability to directly sequence full-length viral genomes. The MinION™ device recently developed by Oxford Nanopore Technologies can be a promising alternative by applying long-read single-molecule sequencing directly to the overall amplified products generated in a PCR reaction. This new technology was evaluated by using hepatitis B virus (HBV) as a model. Several previously characterized HBV-infected clinical samples were investigated including recombinant virus, variants that harbored deletions and mixed population. Original MinION device was able to generate individual complete 3,200-nt HBV genome sequences and to identify recombinant variants. MinION was particularly efficient in detecting HBV genomes with multiple large in-frame deletions and spliced variants concomitantly with non-deleted parental genomes. However, an average-12% sequencing error rate per individual reads associated to a low throughput challenged single-nucleotide resolution, polymorphism calling and phasing mutations directly from the sequencing reads. Despite this high error rate, the pairwise identity of MinION HBV consensus genome was consistent with Sanger sequencing method. MinION being under continuous development, further studies are needed to evaluate its potential use for viral infection characterization.


Deciphering of the Genetic Control of Phenology, Yield, and Pellicle Color in Persian Walnut (Juglans regia L.).
Yield, nut quality, and ability to adapt to specific climate conditions, are all important factors to consider in the development and selection of new Persian walnut (Juglans regia L.) varieties. The genetic control of these traits is still unknown in walnut, limiting the accuracy and rapidity of releasing new cultivars for commercial use. We studied the genetic architecture of five traits crucial for either marketing (i.e., yield, lateral fruit-bearing, and pellicle color) or selection of individuals with specific phenology (i.e., leafing and harvest date). By combining over 30 years of phenotypic data with genetic profiles generated using the latest Axiom™ J. regia 700K SNP array, we were able to identify and confirm major loci for all these traits. In particular, we revealed that a genomic region at the beginning of Chr1 controls both leafing and harvest date in walnut, consistent with the observed strong phenotypical correlation between these traits, and including candidate genes involved in plant development, leaf formation, and cell division. In addition, a large genomic region on Chr11 that includes genes with a central role in flowering control and shoot meristem growth underlies both lateral fruit-bearing and yield in walnut. We observed a more complex genetic architecture for pellicle color, strongly influenced by the environment (h 2 = 0.43). We identified two marker-trait associations on Chr6 and 7 for pellicle color, where genes encoding a UDP-glycosyltransferase or involved in the response to oxidation were found. In conclusion, by combining classical quantitative trait loci (QTL) mapping and genome-wide association mapping, we deciphered, for the first time, the molecular pathways controlling walnut phenology, yield, lateral fruitfulness, and pellicle color. Our findings represent a further milestone in the transition from conventional to genome-assisted breeding in Persian walnut.


Three weeks of eccentric training combined with overspeed exercises enhances power and running speed performance gains in trained athletes.
Eccentric and overspeed training modalities are effective in improving components of muscular power. Eccentric training induces specific training adaptations relating to muscular force, whereas overspeed stimuli target the velocity component of power expression. We aimed to compare the effects of traditional or eccentric training with volume-matched training that incorporated overspeed exercises. Twenty team-sport athletes performed 4 counterbalanced 3-week training blocks consecutively as part of a preseason training period: (1) traditional resistance training; (2) eccentric-only resistance training; (3) traditional resistance training with overspeed exercises; and (4) eccentric resistance training with overspeed exercises. The overspeed exercises performed were assisted countermovement jumps and downhill running. Improvements in bench press (15.0 ± 5.1 kg; effect size [ES]: 1.52), squat (19.5 ± 9.1 kg; ES: 1.12), and peak power in the countermovement jump (447 ± 248 W; ES: 0.94) were observed following the 12-week training period. Greater strength increases were observed as a result of the eccentric training modalities (ES: 0.72-1.09) with no effect of the overspeed stimuli on these measures (p > 0.05). Eccentric training with overspeed stimuli was more effective than traditional resistance training in increasing peak power in the countermovement jump (94 ± 55 W; ES: 0.95). Eccentric training induced no beneficial training response in maximal running speed (p > 0.05); however, the addition of overspeed exercises salvaged this relatively negative effect when compared with eccentric training alone (0.03 ± 0.01 seconds; ES: 1.33). These training results achieved in 3-week training blocks suggest that it is important to target-specific aspects of both force and movement velocity to enhance functional measures of power expression.


Indel detection from RNA-seq data: tool evaluation and strategies for accurate detection of actionable mutations.
Driver somatic mutations are a hallmark of a tumor that can be used for diagnosis and targeted therapy. Mutations are primarily detected from tumor DNA. As dynamic molecules of gene activities, transcriptome profiling by RNA sequence (RNA-seq) is becoming increasingly popular, which not only measures gene expression but also structural variations such as mutations and fusion transcripts. Although single-nucleotide variants (SNVs) can be easily identified from RNA-seq, intermediate long insertions/deletions (indels > 2 bases and less than sequence reads) cause significant challenges and are ignored by most RNA-seq analysis tools. This study evaluates commonly used RNA-seq analysis programs along with variant and somatic mutation callers in a series of data sets with simulated and known indels. The aim is to develop strategies for accurate indel detection. Our results show that the RNA-seq alignment is the most important step for indel identification and the evaluated programs have a wide range of sensitivity to map sequence reads with indels, from not at all to decently sensitive. The sensitivity is impacted by sequence read lengths. Most variant calling programs rely on hard evidence indels marked in the alignment and the programs with realignment may use soft-clipped reads for indel inferencing. Based on the observations, we have provided practical recommendations for indel detection when different RNA-seq aligners are used and demonstrated the best option with highly reliable results. With careful customization of bioinformatics algorithms, RNA-seq can be reliably used for both SNV and indel mutation detection that can be used for clinical decision-making.


Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel-Crafts alkylations.
The first immobilization of a MacMillan's first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a-c was tested in the asymmetric Friedel-Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.


Low-temperature deposition of BaCuSF, a visible through mid-infrared p-type transparent conductor.
Barium copper sulfur fluoride (BaCuSF) is a p-type transparent conductor (p-TC) that, when doped with potassium, exhibits exceptionally high conductivity. The results of a detailed optical and electronic characterization of BaCuSF thin films deposited at a substrate temperature of 100 °C are presented. X-ray diffractometry shows the presence of a cubic BaCuSF phase. Spectroscopic measurements demonstrate that the films transmit from the visible through the mid-infrared with a band gap of 1.8 eV. Hall measurements indicate that the material is a degenerate semiconductor. As deposited, the films exhibit conductivity at room temperature of approximately 260 S/cm - among the highest reported room temperature conductivities for p-TCs. After post-deposition treatment in water, their conductivity increases to as high as 800 S/cm, and their band gap is reduced to 1.5 eV. The potential for low temperature deposition of p-type films with high conductivity and optical transmittance makes BaCuSF promising for several applications including flexible electronics and photovoltaics.


Constriction of Retinal Venules to Endothelin-1: Obligatory Roles of ETA Receptors, Extracellular Calcium Entry, and Rho Kinase.
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in retinal venous pathologies such as diabetic retinopathy and retinal vein occlusion. However, underlying mechanisms contributing to venular constriction remain unknown. Thus, we examined the roles of ET-1 receptors, extracellular calcium (Ca2+), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) in ET-1-induced constriction of retinal venules. Porcine retinal venules were isolated and pressurized for vasoreactivity study using videomicroscopic techniques. Protein and mRNA were analyzed using molecular tools. Retinal venules developed basal tone and constricted concentration-dependently to ET-1. The ETA receptor (ETAR) antagonist BQ123 abolished venular constriction to ET-1, but ETB receptor (ETBR) antagonist BQ788 had no effect on vasoconstriction. The ETBR agonist sarafotoxin S6c did not elicit vasomotor activity. In the absence of extracellular Ca2+, venules lost basal tone and ET-1-induced constriction was nearly abolished. Although L-VOCC inhibitor nifedipine also reduced basal tone and blocked vasoconstriction to L-VOCC activator Bay K8644, constriction of venules to ET-1 remained. The ROCK inhibitor H-1152 but not PKC inhibitor Gö 6983 prevented ET-1-induced vasoconstriction. Protein and mRNA expressions of ETARs and ETBRs, along with ROCK1 and ROCK2 isoforms, were detected in retinal venules. Extracellular Ca2+ entry via L-VOCCs is essential for developing and maintaining basal tone of porcine retinal venules. ET-1 causes significant constriction of retinal venules by activating ETARs and extracellular Ca2+ entry independent of L-VOCCs. Activation of ROCK signaling, without involvement of PKC, appears to mediate venular constriction to ET-1 in the porcine retina.


The endocrine disruptor bisphenol A may play a role in the aetiopathogenesis of polycystic ovary syndrome in adolescent girls.
Experimental in vitro studies have shown that bisphenol A affects steroidogenesis, folliculogenesis and ovarian morphology. The aim of this study was to investigate the role of the endocrine disruptor bisphenol A in the aetiopathogenesis of polycystic ovary syndrome (PCOS) in adolescents and its relationship with metabolic parameters, insulin resistance and obesity in this population. A total of 112 girls with PCOS and 61 controls between 13 and 19 years of age were enrolled in the study. Serum bisphenol A levels were measured by high-pressure liquid chromatography. An oral glucose tolerance test was also performed. Adolescents with PCOS had markedly increased serum bisphenol A levels (mean: 1.1 ng/mL 95% CI: 1.0-1.2) than controls (mean: 0.8 ng/mL 95% CI: 0.6-0.9, p = 0.001). When we compared the subgroups according to obesity, the main factor determining the significant increase in bisphenol A was the presence of PCOS, but not obesity (p = 0.029). Bisphenol A was significantly correlated with total testosterone (r = 0.52), free testosterone (r = 0.44), dehydroepiandrosterone sulphate (r = 0.37) and Ferriman-Gallwey score (r = 0.43) (p < 0.05). Adolescents with PCOS had higher serum bisphenol A levels than controls, independent of obesity. Bisphenol A concentrations were significantly correlated with androgen levels, leading us to consider that bisphenol A might play a role in the aetiopathogenesis of PCOS in adolescents.


The unending deposit insurance mess.
The thrift institution deposit insurance mess is rooted in defects in political and bureaucratic accountability. Under existing incentives, covering up evidence of poor regulatory performance and relaxing binding capital requirements are rational governmental responses to widespread industry insolvency. Similarly, aggressive industry risk taking is a rational response by thrift managers to regulatory forbearances. Far from acknowledging these incentive defects, the Bush plan for cleaning up the mess adopts theories that spotlight other causes: specifically, poor thrift management and the deregulation of thrift institution activities and of deposit interest rates. To end the mess, politicians and regulators must jettison these comfortable theories and surrender discretion that permits them to finesse the need to budget for governmental financial commitments.


Seroepidemiology of chlamydial infections of wild ruminants in Spain.
Chlamydial infections were determined serologically among wild ruminants in the Nature Park of the Sierras de Cazorla, Segura y Las Villas (CNP; Spain). Sampling was done during the period from 1990-95. There were 1,244 blood samples collected, consisting of 490 from fallow deer (Dama dama), 343 from mouflon (Ovis mussimon), 283 from red deer (Cervus elaphus) and 128 from Spanish ibex (Capra pyrenaica). Specific complement-fixing antibodies of Chlamydia spp. were detected by means of microtechnique, using lipopolysaccharide antigen. The relationship of biological (species, sex, age), temporal (year) and territorial (central and peripheral areas) factors to seropositive prevalence was examined, and preliminary data were collected on whether or not sheep and goat herds grazing in the peripheral areas of the park also were infected with Chlamydia spp. Chlamydiosis was common in the four species of wild ruminants in the CNP in all the years studied. The prevalence of Chlamydia sp. in mouflon (37%) was significantly greater than in fallow deer (30%), and both had a significantly higher prevalence rate than Spanish ibex and red deer (both 24%). The four species of wild ruminants were similar in that they act as reservoirs of Chlamydia spp., although their receptivity may be different, and the infection can certainly be maintained among these animals by intra-group transmission. The differences in prevalences and geometric mean titers (GMT), both between the sexes (male versus female) and between different ages (adult versus juvenile), were insignificant in all four species. For all species of wild ruminants both prevalence rates and GMTs were greater in populations occupying the peripheral areas of the park than in those inhabiting the central area. Herds of sheep and goats had a high prevalence of chlamydiosis. Intertransmission of Chlamydia sp. between wild and domestic ruminants occurred through grazing on the same pastures. The highest mean prevalence (44%) of patent infections (CFT titers of > or =1:80) was detected in red deer, although this frequency was not significantly different from those observed in mouflon (39%), Spanish ibex (38%), and fallow deer (37%). The proportion of patent infection was higher in females than in males, and none of the juveniles (<2-yr-old) showed patent infections. The prevalence of predicted patent chlamydial infections was always higher in the peripheral areas of the park, although only among mouflon and fallow deer were the differences statistically significant.


Does behavioural hypothermia promote post-exercise recovery in cold-submerged frogs?
At the low temperatures of the overwintering environment of the frog Rana temporaria, small changes in ambient temperature have large effects on metabolism and behaviour, especially since Q10 values are often greatly elevated in the cold. How the overwintering aquatic frog copes with variable thermal environments in terms of its overall activity metabolism and recovery from pursuit by predators is poorly understood, as is the role of behavioural thermoregulation in furthering recovery from intense activity. Exhaustive exercise was chosen as the method of evaluating activity capacity (defined by time to exhaustion, total distance swum and number of leg contractions before exhaustion) and was determined at 1.5 and 7 degreesC. Other cohorts of frogs were examined at both temperatures to determine the metabolic (acid-base, lactate, glucose, ATP and creatine phosphate) and respiratory responses to exercise in cold-submerged frogs. Finally, temperature preference before and after exercise was determined in a thermal gradient to define the importance of behavioural thermoregulation on the recovery rates of relevant metabolic and respiratory processes. Activity capacity was significantly reduced in frogs exercised at 1.5 versus 7 degreesC, although similar levels of tissue acid-base metabolites and lactate were reached. Blood pH, plasma PCO2 and lactate levels recovered more rapidly at 1.5 degreesC than at 7 degreesC; however, intracellular pH and the recovery of tissue metabolite levels were independent of temperature. Resting aerobic metabolic rates were strongly affected by temperature (Q10=3.82); however, rates determined immediately after exercise showed a reduced temperature sensitivity (Q10=1.67) and, therefore, a reduced factorial aerobic scope. Excess oxygen consumption recovered to resting values after 5-6.25 h, and 67 % recovery times tended to be slightly faster at the lower temperatures. Exercise in the cold, therefore, provided an immediately higher factorial scope, which could be involved in the faster rate of recovery of blood lactate levels in the colder frogs. In addition, exercise significantly lowered the preferred temperature of the frogs from 6.7 to 3.6 degreesC for nearly 7 h, after which they returned to their normal, unstressed preferred temperatures. Thus, a transient behavioural hypothermia in the skin-breathing, overwintering frog may be an important strategy for minimising post-exercise stress and maintaining aerobic metabolism during recovery from intense activity.


Localization and stimulation of chromatophore motoneurones in the brain of the squid, Lolliguncula brevis.
The relatively simple chromatophore system of the squid, Lolliguncula brevis, was studied with combined behavioural, morphological and electrophysiological methods in order to understand how the chromatophore patterns in the skin are organized at the level of the posterior chromatophore lobes (PCL). There are nine simple chromatic components of patterning in L. brevis. Retrograde transport of horseradish-peroxidase from chromatophores in the mantle skin established that the chromatophore motoneurones are located in the PCL. Focal threshold stimulation of the PCL in perfused, semi-intact preparations showed that the motor fields of individual chromatophore motoneurones are compact, including 2-60 chromatophores, generally of the same colour. Adjacent motoneurones in the lobe do not necessarily have adjacent motor fields in the skin.


Interaction between the Gly460Trp alpha-adducin gene variant and diuretics on the risk of myocardial infarction.
The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. The aim of the study was to determine whether the alpha-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the alpha-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). This study suggests that the alpha-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.


A meta-analysis of water quality and aquatic macrophyte responses in 18 lakes treated with lanthanum modified bentonite (Phoslock(®)).
Lanthanum (La) modified bentonite is being increasingly used as a geo-engineering tool for the control of phosphorus (P) release from lake bed sediments to overlying waters. However, little is known about its effectiveness in controlling P across a wide range of lake conditions or of its potential to promote rapid ecological recovery. We combined data from 18 treated lakes to examine the lake population responses in the 24 months following La-bentonite application (range of La-bentonite loads: 1.4-6.7 tonnes ha(-1)) in concentrations of surface water total phosphorus (TP; data available from 15 lakes), soluble reactive phosphorus (SRP; 14 lakes), and chlorophyll a (15 lakes), and in Secchi disk depths (15 lakes), aquatic macrophyte species numbers (6 lakes) and aquatic macrophyte maximum colonisation depths (4 lakes) across the treated lakes. Data availability varied across the lakes and variables, and in general monitoring was more frequent closer to the application dates. Median annual TP concentrations decreased significantly across the lakes, following the La-bentonite applications (from 0.08 mg L(-1) in the 24 months pre-application to 0.03 mg L(-1) in the 24 months post-application), particularly in autumn (0.08 mg L(-1) to 0.03 mg L(-1)) and winter (0.08 mg L(-1) to 0.02 mg L(-1)). Significant decreases in SRP concentrations over annual (0.019 mg L(-1) to 0.005 mg L(-1)), summer (0.018 mg L(-1) to 0.004 mg L(-1)), autumn (0.019 mg L(-1) to 0.005 mg L(-1)) and winter (0.033 mg L(-1) to 0.005 mg L(-1)) periods were also reported. P concentrations following La-bentonite application varied across the lakes and were correlated positively with dissolved organic carbon concentrations. Relatively weak, but significant responses were reported for summer chlorophyll a concentrations and Secchi disk depths following La-bentonite applications, the 75th percentile values decreasing from 119 μg L(-1) to 74 μg L(-1) and increasing from 398 cm to 506 cm, respectively. Aquatic macrophyte species numbers and maximum colonisation depths increased following La-bentonite application from a median of 5.5 species to 7.0 species and a median of 1.8 m to 2.5 m, respectively. The aquatic macrophyte responses varied significantly between lakes. La-bentonite application resulted in a general improvement in water quality leading to an improvement in the aquatic macrophyte community within 24 months. However, because, the responses were highly site-specific, we stress the need for comprehensive pre- and post-application assessments of processes driving ecological structure and function in candidate lakes to inform future use of this and similar products.


The occurrence and distribution of selected trace elements in the Upper Rio Grande and tributaries in Colorado and northern New Mexico.
Two sampling trips were undertaken in 1994 to determine the distribution of trace elements in the Upper Rio Grande and several of its tributaries. Water discharges decreased in the main stem of the Rio Grande from June to September, whereas dissolved concentrations of trace elements generally increased. This is attributed to dilution of base flow from snowmelt runoff in the June samples. Of the three major mining districts (Creede, Summitville, and Red River) in the Upper Rio Grande drainage basin, only the Creede District appears to impact the Rio Grande in a significant manner, with both waters and sediments having elevated concentrations of some trace elements considerably downriver. For example, dissolved zinc concentrations upriver of Willow Creek, which primarily drains the Creede District, were about 2-3 microg/L; immediately downstream of the Willow Creek confluence, concentrations were above 20 microg/L; and elevated concentrations occurred in the Rio Grande for the next 100 km. The Red River District does not significantly impact the Upper Rio Grande for most trace elements. Because of current water management practices, it is difficult to assess the impact of the Summitville District on the Upper Rio Grande. There are, however, large increases in many dissolved trace element concentrations as the Rio Grande passes through the San Luis Valley, coincident with elevated concentrations of those same trace elements in tributaries. Among these elements are As, B, Cr, Li, Mn, Mo, Ni, Sr, U, and V. None of the trace elements exceeded U.S. EPA primary drinking water standards in either survey, with the exception of cadmium in Willow Creek. Secondary drinking water standards were frequently violated, especially in tributaries draining areas where mining has occurred. Dissolved zinc (in Willow Creek in both June and September) was the only element that exceeded the EPA Water Quality Criteria for aquatic life of 120 microg/L.


Degradation of bisphenol A by Bacillus pumilus isolated from kimchi, a traditionally fermented food.
Novel bisphenol A (BPA)-degrading bacterial strains, designated as BP-2CK, BP-21DK, and BP-22DK, were isolated from kimchi, a traditionally fermented food. These isolates were identified as Bacillus pumilus and efficiently degraded BPA in a medium supplemented with nutrients such as peptone, beef extract, and yeast extract. Strains BP-2CK, BP-21DK, and BP-22DK successfully degraded 25, 25, and 50 ppm of BPA, respectively, and all strains exhibited BPA-degrading activity in the presence of 10% NaCl. Accumulation of the metabolites including 4-hydroxyacetophenone, one of the intermediates produced by the other BPA-degrading bacteria, was not observed in BPA degradation by the isolated strains. These results indicate that the isolated food-derived bacteria are applicable for the construction of efficient and safer systems for the removal of BPA.