Revealing the structure of pharmacobehavioral space through motion sequencing.
Understanding how genes, drugs and neural circuits influence behavior requires the ability to effectively organize information about similarities and differences within complex behavioral datasets. Motion Sequencing (MoSeq) is an ethologically inspired behavioral analysis method that identifies modular components of three-dimensional mouse body language called 'syllables'. Here, we show that MoSeq effectively parses behavioral differences and captures similarities elicited by a panel of neuroactive and psychoactive drugs administered to a cohort of nearly 700 mice. MoSeq identifies syllables that are characteristic of individual drugs, a finding we leverage to reveal specific on- and off-target effects of both established and candidate therapeutics in a mouse model of autism spectrum disorder. These results demonstrate that MoSeq can meaningfully organize large-scale behavioral data, illustrate the power of a fundamentally modular description of behavior and suggest that behavioral syllables represent a new class of druggable target.


Thirty down, only ten to go?! Awareness and influence of a 10-year time frame in TTO.
Time trade-off (TTO) exercises typically present respondents with a limited time horizon, for example 10 years, thus implicitly considerably reducing remaining life expectancy for the average respondent. It is unclear how this affects health state valuations. The aim of the study is to investigate how awareness of the reduced life span implied by a 10-year TTO affects health state valuations, using an experimental design. Two Web-based questionnaires (Q1 and Q2) were administered in a sample representative of the Dutch population. Both questionnaires contained three 10-year TTO exercises valuing three distinct health states, specified using the EQ-5D. Q1 used a TTO instruction not explicitly emphasizing the fact that remaining life expectancy was reduced to 10 years, while in Q2 respondents were explicitly made aware of this fact by emphasizing their implied age of death. Respondents answering Q1 were asked retrospectively whether they had been aware of their reduced life span due to the 10-year TTO. In total, 656 respondents completed the questionnaires (Q1: 339 and Q2: 317). The average age of the respondents was 43 years and 51 % of respondents were male. The average numbers of years traded off for the respondents of Q1 were for TTO1 0.443, TTO2 0.552, and TTO3 2.083 years. For the respondents of Q2, these averages were lower, i.e., TTO1 0.401 (p = 0.085 vs. Q1), TTO2: 0.546 (p = 0.036 vs. Q1), and TTO3: 1.467 years (p = 0.000 vs. Q1). Fifty-seven percent of respondents in Q1 confirmed that they were aware of the reduced life span. This spontaneous awareness had a limited and mixed influence on results. The generalized negative binomial regression analysis, explaining the time traded off showed that age, subjective life expectancy, and questionnaire Q2 (vs. Q1) were negatively associated with the years traded off, whereas education and worse health states in the TTO exercise had a significant positive impact on the years traded off. The probit model investigating the impact on the willingness to trade showed that age (-), education (+), subjective life expectancy (-), questionnaire Q2 versus Q1 (-), the interaction between Q2 and male gender (+), and worse health states in the TTO exercise (+) had a significant impact on the willingness to trade. These findings emphasize the importance of expected and implied life expectancy in TTOs.


Expression of voltage-gated sodium channel alpha subunit in human ovarian cancer.
Voltage-gated sodium channels (VGSC) play important roles in the development and progression of many cancers. We report the possible roles of VGSC in human ovarian cancer. Relative mRNA expression levels of Nav1.1, Nav1.3, Nav1.4 and Nav1.5, analyzed by RT-PCR, were significantly higher in ovarian cancers cells compared with normal ovarian tissues; relative mRNA expression levels of Nav1.2, Nav1.4, Nav1.5 and Nav1.7 were significantly increased in highly metastatic ovarian cancer cells (Caov-3 and SKOV-3) compared with low-metastatic ovarian cancer cells (Anglne). Treatment of 30 microM tetrodotoxin reduced by 50-60% migration and invasion of Caov-3 and SKOV-3 without affecting proliferation. Real-time PCR, Western blot analysis and immunohistochemistry assays revealed that functional expression levels of Nav1.5 might be correlated with the grade and metastasis of ovarian cancer. Our findings suggested that abnormal expression of Nav1.5 could be an integral component of the metastatic process in human ovarian cancer and might serve as a therapeutic target in ovarian cancer treatment.


Honey and Chamomile Activate Keratinocyte Antioxidative Responses via the KEAP1/NRF2 System.
The stratum corneum protects against the entry of pathogens, allergens, and irritants while preventing dehydration. The Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) system maintains skin barrier homeostasis. Aggregated evidence suggests that NRF2-mediated antioxidative response is hardwired into the stratified squamous epithelia. Honey and chamomile have long been regarded as natural antioxidants. Nonetheless, it is still unclear whether they activate the KEAP1/NRF2 system in the epidermis and could promote epidermal barrier recovery. To address the abovementioned issue, we explored the antioxidative property of honey/chamomile extract by using non-cell-based KEAP1-inhibition assay and cultured human epidermal keratinocytes. Herein we report that the extract inhibited KEAP1-NRF2 interaction and induced keratinocyte production of antioxidant small proline-rich protein. Our results may offer an opportunity to develop cosmetic products that boost NRF2-mediated antioxidative/antiaging, epidermis-intrinsic bio-responses.


Risk factors for recurrent nonsyncopal falls. A prospective study.
Falls are a major threat to the health of older persons. We evaluated potential risk factors for falls in 325 community-dwelling persons aged 60 years or older who had fallen during the previous year, then followed up weekly for 1 year to ascertain nonsyncopal falls and their consequences. Risk factors for having a single fall were few and relatively weak, but multiple falls were more predictable. In multivariate analyses, we found increased odds of two or more falls for persons who had difficulty standing up from a chair, difficulty performing a tandem walk, arthritis, Parkinson's disease, three or more falls during the previous year, and a fall with injury during the previous year, and for whites. The proportion of subjects with two or more falls per year increased from 0.10 for those with none or one of these risk factors to 0.69 for those with four or more risk factors. Among older persons with a history of a recent fall, the risk of multiple nonsyncopal falls can be predicted from a few simple questions and examinations.


Depression of ventilatory responses to hypoxia and hypercapnia after pentamorphone.
Pentamorphone is a novel, potent opiate with rapid onset and short duration of action that has been reported to produce analgesia with limited depression of ventilation. We quantified the effects of pentamorphone (0.08, 0.24, and 0.60 micrograms/kg, IV) on ventilatory responses to hypercapnia and hypoxia in 12 healthy volunteers. Normoxic hypercapnia and isocapnic hypoxia were induced through a rebreathing method. During each test we recorded ventilation (VE), end tidal carbon dioxide tension (PETCO2), and arterial oxygen saturation (SO2) using a pulse oximeter. Using linear regression analysis of the relationships between VE and PCO2 during hypercapnia and VE and SO2 during hypoxia, we determined the slope (slope CO2) and intercept (V55), both at PCO2 55 mm Hg, and the slope (slope O2) and intercept (V80) at SO2 80%. Pentamorphone produced dose-related reductions in the ventilatory responses to both hypercapnia and hypoxia. Maximal depression occurred 15 min after injection of pentamorphone with all doses; the highest dose (0.60 micrograms/kg) produced 48% and 53% reductions in slope CO2 and V55, and 42% and 22% reductions in slope O2 and V80, respectively, relative to parallel saline controls. The respiratory depressant actions of pentamorphone were short-lived, as all parameters returned to baseline levels within 45 min. Testing was continued for 180 min after injection, but no delayed ventilatory effects were detected, and minimal side effects were reported, even at the highest dose. The findings confirm previous reports that pentamorphone has limited ventilatory depressant effects in humans in doses that (in other studies) have been associated with clinically effective analgesia.


Kinetic studies on the electron-transfer reaction between cytochrome c3 and flavodoxin from Desulfovibrio vulgaris strain Hildenborough.
The kinetic properties of the electron-transfer process between reduced Desulfovibrio vulgaris cytochrome c3 and D. vulgaris flavodoxin have been studied by anaerobic stopped-flow techniques. Anaerobic titrations of reduced cytochrome c3 with oxidized flavodoxin show a stoichiometry of 4 mol of flavodoxin required to oxidize the tetraheme cytochrome. Flavodoxin neutral semiquinone and oxidized cytochrome c3 are the only observable products of the reaction. At pH 7.5, the four-electron-transfer reaction is biphasic. Both the rapid and the slow phases exhibit limiting rates as the flavodoxin concentration is increased with respective rates of 73.4 and 18.5 s-1 and respective Kd values of 65.9 +/- 9.4 microM and 54.5 +/- 13 microM. A biphasic electron-transfer rate is observed when the ionic strength is increased to 100 mM KCl; however, the observed rate is no longer saturable, and relative second-order rate constants of 5.3 x 10(5) and 8.5 x 10(4) M-1 s-1 are calculated. The magnitude of the rapid phase of electron transfer diminishes with the level of heme reduction when varying reduced levels of the cytochrome are mixed with oxidized flavodoxin. No rapid phase is observed when 0.66e(-)-reduced cytochrome c3 reacts with an approximately 25-fold molar excess of flavodoxin. At pH 6.0, the electron-transfer reaction is monophasic with a limiting rate of 42 +/- 1.4 s-1 and a Kd value of approximately 8 microM. Increasing the ionic strength of the pH 6.0 solution to 100 microM KCl results in a biphasic reaction with relative second-order rate constants of 5.3 x 10(5) and 1.1 x 10(4) M-1 s-1. Azotobacter vinelandii flavodoxin reacts with reduced D. vulgaris cytochrome c3 in a slow, monophasic manner with limiting rate of electron transfer of 1.2 +/- 0.06 s-1 and a Kd value of 80.9 +/- 10.7 microM. These results are discussed in terms of two equilibrium conformational states for the cytochrome which are dependent on the pH of the medium and the level of heme reduction [Catarino et al. (1991) Eur. J. Biochem. 207, 1107-1113].


A molecular assessment of phylogenetic relationships and lineage accumulation rates within the family Salamandridae (Amphibia, Caudata).
We examine phylogenetic relationships among salamanders of the family Salamandridae using approximately 2700 bases of new mtDNA sequence data (the tRNALeu, ND1, tRNAIle, tRNAGln, tRNAMet, ND2, tRNATrp, tRNAAla, tRNAAsn, tRNACys, tRNATyr, and COI genes and the origin for light-strand replication) collected from 96 individuals representing 61 of the 66 recognized salamandrid species and outgroups. Phylogenetic analyses using maximum parsimony and Bayesian analysis are performed on the new data alone and combined with previously reported sequences from other parts of the mitochondrial genome. The basal phylogenetic split is a polytomy of lineages ancestral to (1) the Italian newt Salamandrina terdigitata, (2) a strongly supported clade comprising the "true" salamanders (genera Chioglossa, Mertensiella, Lyciasalamandra, and Salamandra), and (3) a strongly supported clade comprising all newts except S. terdigitata. Strongly supported clades within the true salamanders include monophyly of each genus and grouping Chioglossa and Mertensiella as the sister taxon to a clade comprising Lyciasalamandra and Salamandra. Among newts, genera Echinotriton, Pleurodeles, and Tylototriton form a strongly supported clade whose sister taxon comprises the genera Calotriton, Cynops, Euproctus, Neurergus, Notophthalmus, Pachytriton, Paramesotriton, Taricha, and Triturus. Our results strongly support monophyly of all polytypic newt genera except Paramesotriton and Triturus, which appear paraphyletic, and Calotriton, for which only one of the two species is sampled. Other well-supported clades within newts include (1) Asian genera Cynops, Pachytriton, and Paramesotriton, (2) North American genera Notophthalmus and Taricha, (3) the Triturus vulgaris species group, and (4) the Triturus cristatus species group; some additional groupings appear strong in Bayesian but not parsimony analyses. Rates of lineage accumulation through time are evaluated using this nearly comprehensive sampling of salamandrid species-level lineages. Rate of lineage accumulation appears constant throughout salamandrid evolutionary history with no obvious fluctuations associated with origins of morphological or ecological novelties.


Allicin improves cardiac function by protecting against apoptosis in rat model of myocardial infarction.
To study the effects of allicin on cardiac function and underlying mechanism in rat model of myocardial infarction (MI). Ninety-four Wistar rats were randomly assigned to 6 groups (n=14-16 per group): sham control group [underwent thoracotomy without left anterior descending (LAD) occlusion and only received an injection of the same amount of citrate buffer], MI control group (subjected to LAD occlusion and only received an injection of same amount of citrate buffer), positive control group (subjected to LAD occlusion and received an injection of diltiazem hydrochloride at the dose of 1.5 mg/kg), and MI + allicin groups (subjected to LAD occlusion and received an injection of allicin at the doses of 1.2, 1.8, and 3.6 mg/kg). All of the drugs were administered intraperitoneally daily for 21 days. The infarct area was measured by myocardial staining. Hematoxylin-eosin staining was used to observe the pathological changes. Cardiac function parameters were assessed by echocardiography. The myocardial apoptotic index was estimated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The expression of Bax and Bcl-2 were detected by quantificational real-time polymerase chain reaction and Western blot. Treatment with allicin could attenuate the myocardial infarct area (P<0.05) and relieve the changes of the myocardium. The left ventricular anterior wall diastolic and systolic thicknesses were increased in the allicin-treated groups (P<0.05), while there was no signifificant difference in the left ventricular posterior wall diastolic and systolic thickness (P>0.05). The left ventricular internal diameter in systole, ejection fraction, fractional shortening, and stroke volume were dramatically elevated in allicin-treated rats (P<0.05). Allicin dose-dependently reduced creatine kinase and lactate dehydrogenase levels (P<0.05). The myocardial apoptotic index was also markedly lowered, and Bax expression was signifificantly decreased, whereas Bcl-2 expression exhibited an opposite trend in allicin-treated rats (P<0.05). Allicin appears to exert a cardioprotective effect that may be linked to blocking Bcl-2/Bax signaling pathway-denpendent apoptosis, further improving cardiac function.


The emergence of international food safety standards and guidelines: understanding the current landscape through a historical approach.
Following the Second World War, the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) teamed up to construct an International Codex Alimentarius (or 'food code') which emerged in 1963. The Codex Committee on Food Hygiene (CCFH) was charged with the task of developing microbial hygiene standards, although it found itself embroiled in debate with the WHO over the nature these standards should take. The WHO was increasingly relying upon the input of biometricians and especially the International Commission on Microbial Specifications for Foods (ICMSF) which had developed statistical sampling plans for determining the microbial counts in the final end products. The CCFH, however, was initially more focused on a qualitative approach which looked at the entire food production system and developed codes of practice as well as more descriptive end-product specifications which the WHO argued were 'not scientifically correct'. Drawing upon historical archival material (correspondence and reports) from the WHO and FAO, this article examines this debate over microbial hygiene standards and suggests that there are many lessons from history which could shed light upon current debates and efforts in international food safety management systems and approaches.


A Sensor System for Detecting and Localizing Partial Discharges in Power Transformers with Improved Immunity to Interferences.
The paper reports on the solution, principles, and application results related to a system for diagnosing main transformers in power plants via the radiofrequency method. The subject of the diagnostics is the occurrence of partial discharge activity in transformers. The technical solution of the system is characterized in the introductory section of the article. There then follows a description of the operating principle and the implemented novel advanced methods for signal detection and source localization. The results obtained from practical application of the system within the diagnostics of high-power transformers are presented as well. Because ambient electromagnetic disturbance was recognized as a major issue during the system development, novel detection methods were proposed, implemented, and verified. The principal approach utilizes an external radiofrequency sensor to detect outer impulse disturbance and to eliminate disturbance-triggered acquisitions, and it also ensures direct real-time visualization of the desired impulse signals. The ability of weak signal detection was verified via artificial impulse signal injection into the transformer. The developed detection methods were completed with localization techniques for signal source estimation. The desired impulse signal was detected and localized during full operation of the main transformer, despite the presence of strong electromagnetic interference.


Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial.
This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).


High job demands and lack of time: a future challenge in occupational therapy.
The aim of this study was to identify work-related stress factors that contributed to work-related stress among Swedish occupational therapists and to investigate the association between work-related stress, demographic factors, and perceived overall stress. A postal questionnaire and a letter of invitation were sent to 807 Swedish occupational therapists, selected at random and representing 10% of occupational therapists working in Sweden. The response rate was 59%. A stress index presenting 49 stress factors graded on a scale from 1 (indicating no source of stress) to 6 (definitely a source of stress) was included. In addition, the level of perceived overall stress during the last two weeks was scored on a rating scale with the end points 0 (no stress) and 10 (extreme stress). The main findings indicated that lack of resources and lack of time were the main stressors. "Working at a superficial level due to lack of time" was the only variable associated with high overall stress when both work-related and personal factors were included. Professional identity and clarity concerning the role were graded low with regard to stress. Work-related stress is just one aspect of the overall stress experienced but knowledge about its consequences highlights the importance of further studies.


Egg consumption and mortality from colon and rectal cancers: an ecological study.
The relation between egg consumption and mortality from colon and rectal cancers remains unclear and was investigated in this study. Colon and rectal cancer mortality data, mostly around 1993-94 and egg consumption data in nine time periods (1964-94) in 34 countries were derived from World Health Organization and Food and Agriculture Organization, respectively. Egg consumption was significantly and positively correlated with mortality from colon and rectal cancers in both sexes in most of the nine time periods. The correlations were generally stronger for colon cancer (r = 0.39 to 0.63 in men and r = 0.33 to 0.65 in women) than for rectal cancer (r = 0.18 to 0.49 in men and r = 0.08 to 0.45 in women). After adjustment for confounding factors, egg consumption was still significantly and positively associated with mortality from colon cancer in the earliest five time periods (1964-84) (P = 0.046 to 0.017 in men and P = 0.034 to 0.014 in women) and rectal cancer in the latest five time periods except for the last time period (1982-91) (P = 0.046 to 0.024 in men and P = 0.045 to 0.026 in women). This study suggested that egg consumption was associated with an increased risk of colon and rectal cancers at the population level


Immunotherapy of cancer with dendritic-cell-based vaccines.
Animal studies have shown that vaccination with genetically modified tumor cells or with dendritic cells (DC) pulsed with tumor antigens are potent strategies to elicit protective immunity in tumor-bearing animals, more potent than "conventional" strategies that have been tested in clinical settings with limited success. While both vaccination strategies are forms of cell therapy requiring complex and costly ex vivo manipulations of the patient's cells, current protocols using dendritic cells are considerably simpler and would be more widely available. Vaccination with defined tumor antigens presented by DC has obvious appeal. However, in view of the expected emergence of antigen-loss variants as well as natural immunovariation, effective vaccine formulations must contain mixtures of commonly, if not universally, expressed tumor antigens. When, or even if, such common tumor antigens will be identified cannot be, predicted, however. Thus, for the foreseeable future, vaccination with total-tumor-derived material as source of tumor antigens may be preferable to using defined tumor antigens. Vaccination with undefined tumor-derived antigens will be limited, however, by the availability of sufficient tumor tissue for antigen preparation. Because the mRNA content of single cells can be amplified, tumor mRNA, or corresponding cDNA libraries, offer an unlimited source of tumor antigens. DC transfected with tumor RNA were shown to engender potent antitumor immunity in animal studies. Thus, immunotherapy using autologous DC loaded with unfractionated tumor-derived antigens in the form of RNA emerges as a potentially powerful and broadly useful vaccination strategy for cancer patients.


Fertilization and development of mouse oocytes cryopreserved using a theoretically optimized protocol.
Rational design of a cryopreservation protocol was demonstrated by using theoretical models of the cryopreservation process to develop an optimal freezing protocol for mouse oocytes. A coupled mechanistic model of the processes of freeze-induced cell dehydration and intracellular ice formation was developed, and cryomicroscopical measurements of intracellular ice formation kinetics were used to determine biophysical parameters required by the model, and to test model predictions of the freezing behaviour of mouse oocytes. A simple phenomenological model for oocyte damage resulting from exposure to concentrated electrolyte and cryoprotectant solutions during cryopreservation was obtained by defining a cost function equal to the duration of the freezing protocol. A two-step freezing protocol was theoretically optimized by using a sequential simplex algorithm to minimize the cost function, subject to the constraint that the predicted probability of intracellular ice formation remain below 5%, yielding a putative optimum at the cooling rate B = 0.59 degrees C/min, and plunge temperature Tp = -67 degrees C. By systematically varying B and Tp about these values in experiments with mouse oocytes cryopreserved in 1.5 M dimethyl sulphoxide, the maximal recovery of intact oocytes with a normal morphology (82%) was obtained for B = 0.5 degrees C/min and Tp = -80 degrees C. Further evaluation of the fertilizability and developmental capacity of oocytes cryopreserved using the optimized protocol yielded cleavage to the 2-cell stage in 65% of oocytes inseminated, and blastocyst formation in 50% of these 2-cell embryos.


Massive localized lymphedema of the male external genitalia: a clinicopathologic study of 6 cases.
Massive localized lymphedema is a reactive pseudotumor strongly associated with obesity. The tumor most commonly presents as pendulous masses in the lower limbs with only 3 reported cases involving external male genitalia. In this study, we report an additional 6 cases localized to the external male genitalia. The cases were retrospectively identified from the surgical pathology database of the Johns Hopkins Hospital. All 6 patients were obese (5 presented with diffuse scrotal edema and 1 with a penile mass). In all cases, the clinical impression was of a benign chronic process developing over 3 months to 1 year. All 3 cases from outside institutions were referred with benign pathologic diagnoses. The lesions ranged in size from 4 to 55 cm. Microscopically, all cases exhibited stromal fibrosis and edema, multinucleated stromal cells, perivascular chronic inflammation, and lymphangiectasia. Entrapped fat was a minor feature and seen in only 3 cases. Variable hyperplasia and hypertrophy of dartos muscle were noted in 6 lesions. Three cases showed prominent microvascular proliferation around the edge of individual dartos muscle bundles. In summary, diagnosis of massive localized lymphedema requires appropriate correlation between clinical and microscopic findings. Lesions in the male external genitalia share many microscopic findings with massive localized lymphedema at other sites, although entrapped adipose tissue is not prominent. Additional, although not specific, findings include variably hyperplastic and hypertrophic dartos muscle and capillary neoangiogenesis at the interface between smooth muscle bundles and stroma.


Using GIS in ecological management: green assessment of the impacts of petroleum activities in the state of Texas.
Geo-information technologies are valuable tools for ecological assessment in stressed environments. Visualizing natural features prone to disasters from the oil sector spatially not only helps in focusing the scope of environmental management with records of changes in affected areas, but it also furnishes information on the pace at which resource extraction affects nature. Notwithstanding the recourse to ecosystem protection, geo-spatial analysis of the impacts remains sketchy. This paper uses GIS and descriptive statistics to assess the ecological impacts of petroleum extraction activities in Texas. While the focus ranges from issues to mitigation strategies, the results point to growth in indicators of ecosystem decline.


Access to the US Department of Veterans Affairs health system: self-reported barriers to care among returnees of Operations Enduring Freedom and Iraqi Freedom.
The U.S. Department of Veterans Affairs (VA) implemented the Polytrauma System of Care to meet the health care needs of military and veterans with multiple injuries returning from combat operations in Afghanistan and Iraq. Studies are needed to systematically assess barriers to use of comprehensive and exclusive VA healthcare services from the perspective of veterans with polytrauma and with other complex health outcomes following their service in Afghanistan and Iraq. These perspectives can inform policy with regard to the optimal delivery of care to returning veterans. We studied combat veterans (n = 359) from two polytrauma rehabilitation centers using structured clinical interviews and qualitative open-ended questions, augmented with data collected from electronic health records. Our outcomes included several measures of exclusive utilization of VA care with our primary exposure as reported access barriers to care. Nearly two thirds of the veterans reported one or more barriers to their exclusive use of VA healthcare services. These barriers predicted differences in exclusive use of VA healthcare services. Experiencing any barriers doubled the returnees' odds of not using VA exclusively, the geographic distance to VA barrier resulted in a 7 fold increase in the returnees odds of not using VA, and reporting a wait time barrier doubled the returnee's odds of not using VA. There were no striking differences in access barriers for veterans with polytrauma compared to other returning veterans, suggesting the barriers may be uniform barriers that predict differences in using the VA exclusively for health care. This study provides an initial description of utilization of VA polytrauma rehabilitation and other medical care for veteran returnees from all military services who were involved in combat operations in Afghanistan or Iraq. Our findings indicate that these veterans reported important stigmatization and barriers to receiving services exclusively from the VA, including mutable health delivery system factors.


A comparative case study of bowel cancer screening in the UK and Australia: evidence lost in translation?
(i) To document the current state of the English, Scottish, Welsh, Northern Irish and Australian bowel cancer screening programmes, according to seven key characteristics, and (ii) to explore the policy trade-offs resulting from inadequate funding. United Kingdom and Australia. A comparative case study design using document and key informant interview analysis. Data were collated for each national jurisdiction on seven key programme characteristics: screening frequency, population coverage, quality of test, programme model, quality of follow-up, quality of colonoscopy and quality of data collection. A list of optimal features for each of the seven characteristics was compiled, based on the FOBT screening literature and our detailed examination of each programme. Each country made different implementation choices or trade-offs intended to conserve costs and/or manage limited and expensive resources. The overall outcome of these trade-offs was probable lower programme effectiveness as a result of compromises such as reduced screening frequency, restricted target age range, the use of less accurate tests, the deliberate setting of low programme positivity rates or increased inconvenience to participants from re-testing. Insufficient funding has forced programme administrators to make trade-offs that may undermine the potential net population benefits achieved in randomized controlled trials. Such policy compromise contravenes the principle of evidence-based practice which is dependent on adequate funding being made available.


Outbreak of Salmonella Enteritidis linked to the consumption of frozen beefburgers received from a food bank and originating from Poland: northern France, December 2014 to April 2015.
A prolonged outbreak of Salmonella enterica serotype Enteritidis occurred in northern France between December 2014 and April 2015. Epidemiological investigations following the initial notification on 30 December 2014 of five cases of salmonellosis (two confirmed S. Enteritidis) in young children residing in the Somme department revealed that all cases frequented the same food bank A. Further epidemiological, microbiological and food trace-back investigations indicated frozen beefburgers as the source of the outbreak and the suspected lot originating from Poland was recalled on 22 January 2015. On 2 March 2015 a second notification of S. Enteritidis cases in the Somme reinitiated investigations that confirmed a link with food bank A and with consumption of frozen beefburgers from the same Polish producer. In the face of a possible persistent source of contamination, all frozen beefburgers distributed by food bank A and from the same origin were blocked on 3 March 2015. Microbiological analyses confirmed contamination by S. Enteritidis of frozen beefburgers from a second lot remaining in cases' homes. A second recall was initiated on 6 March 2015 and all frozen beefburgers from the Polish producer remain blocked after analyses identified additional contaminated lots over several months of production.


Use of a food frequency questionnaire to assess diets of Jamaican adults: validation and correlation with biomarkers.
Assessment of habitual diet is important in investigations of diet-disease relationships. Many epidemiological studies use the food frequency questionnaire (FFQ) to evaluate dietary intakes but few studies validate the instrument against biological markers. The aim of this study was to assess the validity and reproducibility of a previously validated 70-item food frequency questionnaire (FFQ) that was expanded to 120-items to assess diet-cancer relations. Relative validity of the FFQ was assessed against twelve 24-hour recalls administered over 12 months in 70 subjects. The FFQ was repeated after one year (FFQ2) to assess reproducibility. The validity of the FFQ was evaluated by comparing nutrient and food group intakes from 24-hour recalls with the first and second FFQ. In addition, FFQ validity for cholesterol and folate were determined through correlation with biomarkers (serum cholesterol, serum folate and whole blood folate) in 159 control subjects participating in a case-control prostate cancer study. Compared to recalls the FFQ tended to overestimate energy and carbohydrate intakes but gave no differences in intake for protein and fat. Quartile agreement for energy-adjusted nutrient intakes between FFQ2 and recalls ranged from 31.8%-77.3% for the lowest quartile and 20.8%-81.0% in the highest quartile. Gross misclassification of nutrients was low with the exceptions of protein, vitamin E and retinol and weighted kappa values ranged from 0.33 to 0.64 for other nutrients. Validity correlations for energy-adjusted nutrients (excluding retinol) were moderate to high (0.38-0.86). Correlation coefficients between multiple recalls and FFQ1 ranged from 0.27 (fruits) to 0.55 (red meat); the second FFQ gave somewhat higher coefficients (0.30 to 0.61). Reproducibility correlations for the nutrients ranged from 0.50 to 0.84.Calibration of the FFQ with biochemical markers showed modest correlations with serum cholesterol (0.24), serum folate (0.25) and whole blood folate (0.33) adjusted for age, energy, body mass index and smoking. The expanded FFQ had good relative validity for estimating food group and nutrient intakes (except retinol and vitamin E) and was a reliable measure of habitual intake. Associations with biomarkers were comparable to other studies.


Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects.
The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P5]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P5 on basic fibroblast growth factor (FGF-2)-induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(1,3,4,5,6)P5, a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies.


Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma.
Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N'-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. U251 human glioma cells (4×10(5)) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8-21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0-21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0-21 days treatment), tumor volume, tumor blood volume, permeability, extravascular and extracellular space volume, tumor cell proliferation, and cell migration were decreased compared with that of the vehicle-treated group. HET0016 is capable of controlling tumor growth and migration, but these effects are dependent on the timing of drug administration. The addition of HET0016 to vatalanib may attenuate the unwanted effect of vatalanib.


Immunogold labeling of Hrp pili of Pseudomonas syringae pv. tomato assembled in minimal medium and in planta.
Hypersensitive reaction and pathogenicity (hrp) genes are required for Pseudomonas syringae pv. tomato (Pst) DC3000 to cause disease in susceptible tomato and Arabidopsis thaliana plants and to elicit the hypersensitive response in resistant plants. The hrp genes encode a type III protein secretion system known as the Hrp system, which in Pst DC3000 secretes HrpA, HrpZ, HrpW, and AvrPto and assembles a surface appendage, named the Hrp pilus, in hrp-gene-inducing minimal medium. HrpA has been suggested to be the Hrp pilus structural protein on the basis of copurification and mutational analyses. In this study, we show that an antibody against HrpA efficiently labeled Hrp pili, whereas antibodies against HrpW and HrpZ did not. Immunogold labeling of bacteria-infected Arabidopsis thaliana leaf tissue with an Hrp pilus antibody revealed a characteristic lineup of gold particles around bacteria and/or at the bacterium-plant contact site. These results confirm that HrpA is the major structural protein of the Hrp pilus and provide evidence that Hrp pili are assembled in vitro and in planta.


Shared Care in Monitoring Stable Glaucoma Patients: A Randomized Controlled Trial.
Comparing the quality of care provided by a hospital-based shared care glaucoma follow-up unit with care as usual. This randomized controlled trial included stable glaucoma patients and patients at risk for developing glaucoma. Patients in the Usual Care group (n=410) were seen by glaucoma specialists. In the glaucoma follow-up unit group (n=405), patients visited the glaucoma follow-up unit twice followed by a visit to a glaucoma specialist. The main outcome measures were: compliance to the working protocol by glaucoma follow-up unit employees; difference in intraocular pressure between baseline and at ≥18 months; and patient satisfaction. Glaucoma follow-up unit employees closely adhered to the working protocol for the measurement of intraocular pressure, visual acuity and GDx (≥97.5% of all visits). Humphrey Field Analyzer examinations were not performed as frequently as prescribed by the working protocol, but more often than in the Usual Care group. In a small minority of patients that required back-referral, the protocol was disregarded, notably when criteria were only slightly exceeded. There was no statistically significant difference in changes in intraocular pressure between the 2 treatment groups (P=0.854). Patients were slightly more satisfied with the glaucoma follow-up unit employees than with the glaucoma specialists (scores: 8.56 vs. 8.40; P=0.006). In general, the hospital-based shared care glaucoma follow-up closely observed its working protocol and patients preferred it slightly over the usual care provided by medical doctors. The glaucoma follow-up unit operated satisfactorily and might serve as a model for shared care strategies elsewhere.


The developmental origin of heart size and shape differences in Astyanax mexicanus populations.
Regulation of heart size and shape is one of the least understood processes in developmental biology. We have for the first time analysed the hearts of Astyanax mexicanus and identified several differences in heart morphology between the surface (epigean morph) and cave-dwelling (troglomorph) morphs. Examination of the adult revealed that the troglomorph possesses a smaller heart with a rounder ventricle in comparison to the epigean morph. The size differences identified appear to arise early in development, as early as 24 h post-fertilisation (hpf), while shape differences begin to appear at 2 days post-fertilisation. The heart of the first-generation cross between the cave-dwelling and river-dwelling morph shows uncoupling of different phenotypes observed in the parental populations and indicates that the cardiac differences have become embedded in the genome during evolution. The differences in heart morphology are accompanied by functional changes between the two morphs, with the cave-dwelling morph exhibiting a slower heart rate than the river-dwelling morph. The identification of morphological and functional differences in the A. mexicanus heart could allow us to gain more insight into how such parameters are regulated during cardiac development, with potential relevance to cardiac pathologies in humans.


Evaluation of efficacy and tolerability of a fixed combination of dry extracts of thyme herb and primrose root in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled multicentre clinical trial.
The objective of the study was to assess the efficacy and tolerability of a fixed combination of dry extracts of thyme herb and primrose root (thyme-primrose combination) and matched placebo in patients suffering from acute bronchitis with productive cough. In a double-blind, placebo-controlled, multicentre Phase IV study, 361 outpatients with acute bronchitis and > or = 10 coughing fits during the day, onset of bronchial mucus production with impaired ability to cough up at a maximum of 2 days prior to recruitment, and a Bronchitis Severity Score (BSS) > or = 5 score points were randomly assigned to an 11-day treatment (1 tablet three times daily) with either thyme-primrose combination (Bronchipret TP FCT; N = 183) or placebo (N = 178). After the baseline examination (Visit 1 = Day 0), 2 control examinations were scheduled (Visit 2 = Day 4; Visit 3 = Day 10/end of treatment). The efficacy of the study treatment on acute bronchitis was evaluated by the patient's daily counting of coughing fits during the daytime (manual counter), assessment of acute bronchitis related symptoms and by the investigator's assessment of the most important symptoms of acute bronchitis using the BSS. Evaluation of tolerability was based upon adverse event (AE) monitoring, measurement of vital signs as well as the patient's and investigator's global judgement of tolerability at study end. Primary outcome was the change in frequency of coughing fits during daytime on days 7-9 according to patient's accurate daily recording with a manual counter and documentation in the diary. Treatment effects were analysed by analysis of variance (ANOVA) adjusted for centre effects. Due to significant deviation from the "preconditions" of the ANOVA, the Mann-Whitney-Wilcoxon test (stratified by centre) was carried out additionally. The mean reduction in coughing fits on days 7 to 9 relative to baseline (primary endpoint) was 67.1% under thyme-primrose combination compared to 51.3% under placebo (p < 0.0001). In the thyme-primrose combination group, a 50% reduction in coughing fits from baseline was reached about 2 days earlier compared to the placebo group. The symptoms of acute bronchitis (BSS) improved rapidly in both groups, but regression was faster and the responder rates compared to placebo were higher at Visit 2 (77.5% vs 60.1%; p = 0.0006) and Visit 3 (92.9% vs 75.8%; p < 0.0001) under the treatment of thyme-primrose combination. Treatment was well tolerated with no difference in the frequency or severity of AE between thyme-primrose combination and placebo groups. Severe or serious AE were not reported. Oral treatment of acute bronchitis with thyme-primrose combination for about 11 days was superior to placebo in terms of efficacy. The treatment was safe and well tolerated.


Accountable care for the poor and underserved: Minnesota's Hennepin Health model.
Hennepin Health provides integrated medical and social services to low-income Medicaid patients in a large county located in Minneapolis, Minnesota. Data sharing is critical to program operations along with care coordination provided by community health workers. Early evidence indicates fewer emergency department visits and increased use of outpatient primary care. By focusing on prevention, coordination, and team-based care, the county hopes to improve individuals' quality of life while reducing costs through better care management and reductions in emergency department use.


Fruit flies and the sperm proteome.
Sperm have been studied for their obvious role in fertilization and as a model system for cell-cell interactions and cell signaling. Despite its central and critical role in reproduction, we know surprisingly little about the overall molecular composition of sperm. Interest in sperm function has greatly intensified for two reasons: first, it is becoming increasingly apparent that human infertility can be traced to male factors, including alterations in sperm proteins, and second, there is increasing empirical evidence that sperm provide essential factors, both nucleic acid- and protein-based, to early zygote development possibly beyond their role in fertilization. At the molecular level, study of the sperm proteome has revealed a variety of genetic mechanisms involved in the organization and evolution of sperm form and function. These discoveries are being augmented and expanded by the application of proteomics that directly identifies protein constituents of sperm. In this article I argue that sperm are ideal candidate cell types for proteomic analyses and describe the current state of the field focussing on the recently described sperm proteome in the fruit fly Drosophila melanogaster.


Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients.
Eleven patients with asthma and aspirin hypersensitivity have been challenged with eight non-steroidal anti-inflammatory drugs. Each drug was given by mouth in at least three different doses and the patients' symptoms and peak expiratory flow (PEF) rates were observed over a three-hour period. Indomethacin 5 mg caused bronchoconstriction in all patients. Therapeutic doses of mefenamic or flufenamic acid caused bronchoconstriction in most patients. Phenylbutazone 200-400 mg induced a moderate fall in PEF. There were no reactions to therapeutic doses of salicylamide, paracetamol, benzydamine, and chloroquine. Microsomal prostaglandin synthetase, activity was inhibited by aspirin, indomethacin, mefenamic acid, flufenamic acid, and phenylbutazone. The other four drugs had no inhibitory effect. We suggest that precipitation of attacks in asthmatic patients hypersensitive to certain anti-inflammatory drugs is related to drug's ability to inhibit prostaglandin biosynthesis.


Quantitative SERS by hot spot normalization - surface enhanced Rayleigh band intensity as an alternative evaluation parameter for SERS substrate performance.
The performance of surface-enhanced Raman spectroscopy (SERS) substrates is typically evaluated by calculating an enhancement factor (EF). However, it is challenging to accurately calculate EF values since the calculation often requires the use of model analytes and requires assumptions about the number of analyte molecules within the laser excitation volume. Furthermore, the measured EF values are target analyte dependent and thus it is challenging to compare substrates with EF values obtained using different analytes. In this study, we propose an alternative evaluation parameter for SERS substrate performance that is based on the intensity of the surface plasmon enhanced Rayleigh band (IRayleigh) that originates from the amplified spontaneous emission (ASE) of the laser. Compared to the EF, IRayleigh reflects the enhancing capability of the substrate itself, is easy to measure without the use of any analytes, and is universally applicable for the comparison of SERS substrates. Six SERS substrates with different states (solid, suspended in liquid, and hydrogel), different plasmonic nanoparticle identities (silver and gold), as well as different nanoparticle sizes and shapes were used to support our hypothesis. The results show that there are excellent correlations between the measured SERS intensities and IRayleigh as well as between the SERS homogeneity and the variation of IRayleigh acquired with the six SERS substrates. These results suggest that IRayleigh can be used as an evaluation parameter for both SERS substrate efficiency and reproducibility.


Mutation load under vegetative reproduction and cytoplasmic inheritance.
For reasons that remain unclear, even multicellular organisms usually originate from a single cell. Here I consider the balance between deleterious mutations and selection against them in a population with obligate vegetative reproduction, when every offspring is initiated by more than one cell of a parent. The mutation load depends on the genomic deleterious mutation rate U, strictness of selection, number of cells which initiate an offspring n, and the relatedness among the initial cells. The load grows with increasing U, n and strictness of selection, and declines when an offspring is initiated by more closely related cells. If Un >> 1, the load under obligate vegetative reproduction may be substantially higher than under sexual or asexual reproduction, which may account for its rarity. In nature obligate vegetative reproduction seems to be more common and long term in taxa whose cytological features ensure a relatively low load under it. The same model also describes the mutation load under two other modes of inheritance: (1) uniparental transmission of organelles and (2) reproduction by division of multinuclear cells, where each daughter cell receives many nuclei. The load declines substantially when the deleterious mutation rate per organelle genome gets lower or when the number of nuclei in a cell sometimes drops. This may explain the small sizes of organelle genomes in sexual lineages and the presence of karyonic cycles in asexual unicellular multinuclear eukaryotes.


Resistance and renewal: health sector reform and Cambodia's national tuberculosis programme.
Following the destruction of Cambodia's health infrastructure during the Khmer Rouge period (1975-1979) and the subsequent decade of United Nations sanctions, international development assistance has focused on reconstructing the country's health system. The recognition of Cambodia's heavy burden of tuberculosis (TB) and the lapse of TB control strategies during the transition to democracy prompted the national tuberculosis programme's relaunch in the mid-1990s as WHO-backed health sector reforms were introduced. This paper examines the conflicts that arose between health reforms and TB control programmes due to their different operating paradigms. It also discusses how these tensions were resolved during introduction of the DOTS strategy for TB treatment.


Nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk among African Americans: a case-control study.
Genome-wide association studies of white persons with lung cancer have identified a region of extensive linkage disequilibrium on chromosome 15q25.1 that appears to be associated with both risk for lung cancer and smoking dependence. Because studying African American persons, who exhibit lower levels of linkage disequilibrium in this region, may identify additional loci that are associated with lung cancer, we genotyped 34 single-nucleotide polymorphisms (SNPs) in this region (including LOC123688, PSMA4, CHRNA5, CHRNA3, and CHRNB4 genes) in 467 African American patients with lung cancer and 388 frequency-matched African American control subjects. Associations of SNPs in LOC123688 (rs10519203; odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.25 to 2.05, P = .00016), CHRNA5 (rs2036527; OR = 1.67, 95% CI = 1.26 to 2.21, P = .00031), and CHRNA3 (rs1051730; OR = 1.81, 95% CI = 1.26 to 2.59, P = .00137) genes with lung cancer risk reached Bonferroni-corrected levels of statistical significance (all statistical tests were two-sided). Joint logistic regression analysis showed that rs684513 (OR = 0.47, 95% CI = 0.31 to 0.71, P = .0003) in CHRNA5 and rs8034191 (OR = 1.76, 95% CI = 1.23 to 2.52, P = .002) in LOC123688 were also associated with risk. The functional A variant of rs1696698 in CHRNA5 had the strongest association with lung cancer (OR = 1.98, 95% CI = 1.25 to 3.11, P = .003). These SNPs were primarily associated with increased risk for lung adenocarcinoma histology and were only weakly associated with smoking phenotypes. Thus, among African American persons, multiple loci in the region of chromosome 15q25.1 appear to be strongly associated with lung cancer risk.


In vivo ultrasonic attenuation slope estimates for detecting cervical ripening in rats: Preliminary results.
To effectively postpone preterm birth, cervical ripening needs to be detected and delayed. As the cervix ripens, the spacing between the collagen fibers increases and fills with water, hyaluronan, decorin, and enzymes suggesting that the ultrasonic attenuation of the cervix should decrease. The decrease in ultrasonic attenuation may be detectable, leading to an effective means of detecting cervical ripening. Herein, the traditional attenuation slope-estimation algorithm based on measuring the downshift in center frequency of the ultrasonic backscattered signal with propagation depth was modified and applied to the cervix of rats. The modified algorithm was verified using computer simulations and an ex vivo tissue sample before being evaluated in in vivo animal studies. Spherically-focused f/3 transducers with 33-MHz center frequencies and with 9-mm focal lengths were used in both the simulations and experiments. The accuracy was better than 15% in the simulations, and the attenuation slope of the cervix in the ex vivo experiment was 2.6+/-0.6 dB/cm-MHz, which is comparable to 2.5+/-0.4 dB/cm-MHz measured using a through-transmission insertion loss technique. For the in vivo experiments, a statistically significant effect of ultrasonic attenuation with gestational age was not observed. The large variances in the in vivo results were most likely due to the natural variation in attenuation for biological tissue between animals.


Mindfulness-Based Cognitive Therapy in Advanced Prostate Cancer: A Randomized Controlled Trial.
Purpose Advanced prostate cancer (PC) is associated with substantial psychosocial morbidity. We sought to determine whether mindfulness-based cognitive therapy (MBCT) reduces distress in men with advanced PC. Methods Men with advanced PC (proven metastatic and/or castration-resistant biochemical progression) were randomly assigned to an 8-week, group-based MBCT intervention delivered by telephone (n = 94) or to minimally enhanced usual care (n = 95). Primary intervention outcomes were psychological distress, cancer-specific distress, and prostate-specific antigen anxiety. Mindfulness skills were assessed as potential mediators of effect. Participants were assessed at baseline and were followed up at 3, 6, and 9 months. Main statistical analyses were conducted on the basis of intention to treat. Results Fourteen MBCT groups were conducted in the intervention arm. Facilitator adherence ratings were high (> 93%). Using random-effects mixed-regression models, intention-to-treat analyses indicated no significant changes in intervention outcomes or in engagement with mindfulness for men in MBCT compared with those receiving minimally enhanced usual care. Per-protocol analyses also found no differences between arms in outcomes or engagement, with the exception of the mindfulness skill of observing, which increased over time for men in MBCT compared with usual care ( P = .032). Conclusion MBCT in this format was not more effective than minimally enhanced usual care in reducing distress in men with advanced PC. Future intervention research for these men should consider approaches that map more closely to masculinity.


Little effects on soil organic matter chemistry of density fractions after seven years of forest soil warming.
Rising temperatures enhance microbial decomposition of soil organic matter (SOM) and thereby increase the soil CO2 efflux. Elevated decomposition rates might differently affect distinct SOM pools, depending on their stability and accessibility. Soil fractions derived from density fractionation have been suggested to represent SOM pools with different turnover times and stability against microbial decomposition. To investigate the effect of soil warming on functionally different soil organic matter pools, we here investigated the chemical and isotopic composition of bulk soil and three density fractions (free particulate organic matter, fPOM; occluded particulate organic matter, oPOM; and mineral associated organic matter, MaOM) of a C-rich soil from a long-term warming experiment in a spruce forest in the Austrian Alps. At the time of sampling, the soil in this experiment had been warmed during the snow-free period for seven consecutive years. During that time no thermal adaptation of the microbial community could be identified and CO2 release from the soil continued to be elevated by the warming treatment. Our results, which included organic carbon content, total nitrogen content, δ13C, Δ14C, δ15N and the chemical composition, identified by pyrolysis-GC/MS, showed no significant differences in bulk soil between warming treatment and control. Surprisingly, the differences in the three density fractions were mostly small and the direction of warming induced change was variable with fraction and soil depth. Warming led to reduced N content in topsoil oPOM and subsoil fPOM and to reduced relative abundance of N-bearing compounds in subsoil MaOM. Further, warming increased the δ13C of MaOM at both sampling depths, reduced the relative abundance of carbohydrates while it increased the relative abundance of lignins in subsoil oPOM. As the size of the functionally different SOM pools did not significantly change, we assume that the few and small modifications in SOM chemistry result from an interplay of enhanced microbial decomposition of SOM and increased root litter input in the warmed plots. Overall, stable functional SOM pool sizes indicate that soil warming had similarly affected easily decomposable and stabilized SOM of this C-rich forest soil.


A dynamic model of the eye nystagmus response to high magnetic fields.
It was recently shown that high magnetic fields evoke nystagmus in human subjects with functioning vestibular systems. The proposed mechanism involves interaction between ionic currents in the endolymph of the vestibular labyrinth and the static magnetic field. This results in a Lorentz force that causes endolymph flow to deflect the cupulae of the semi-circular canals to evoke a vestibular-ocular reflex (VOR). This should be analogous to stimulation by angular acceleration or caloric irrigation. We made measurements of nystagmus slow-phase velocities in healthy adults experiencing variable magnetic field profiles of up to 7 T while supine on a bed that could be moved smoothly into the bore of an MRI machine. The horizontal slow-phase velocity data were reliably modelled by a linear transfer function incorporating a low-pass term and a high-pass adaptation term. The adaptation time constant was estimated at 39.3 s from long exposure trials. When constrained to this value, the low-pass time constant was estimated at 13.6 ± 3.6 s (to 95% confidence) from both short and long exposure trials. This confidence interval overlaps with values obtained previously using angular acceleration and caloric stimulation. Hence it is compatible with endolymph flow causing a cupular deflection and therefore supports the hypothesis that the Lorentz force is a likely transduction mechanism of the magnetic field-evoked VOR.


Technical note: Validation of 3D ultrasound for image registration during oncological liver surgery.
Registration of pre- and intraoperative images is a crucial step of surgical liver navigation, where rigid registration of vessel centerlines is currently commonly used. When using 3D ultrasound (US), accuracy during navigation might be influenced by the size of the intraoperative US volume, yet the relationship between registration accuracy and US volume size is understudied. In this study, we specify an optimal 3D US volume size for registration using varying volumes of liver vasculature. While previous studies measured accuracy at registered fiducials, in this work, accuracy is determined at the target lesion which is clinically the most relevant structure. Three-dimensional US volumes were acquired in 14 patients after laparotomy and liver mobilization. Manual segmentation of vasculature and centerline extraction was performed. Intraoperative and preoperative vasculature centerlines were registered with coherent point drift, using different sub-volumes (sphere with radius r = 30, 40, …, 120 mm). Accuracy was measured by fiducial registration error (FRE) between vessel centerlines and target registration error (TRE) at the center of the target lesion. The lowest FRE for vessel registration was reached with r = 50 mm (6.5 ± 2.5 mm), the highest with r = 120 mm (7.1 ± 2.1 mm). Clinical accuracy at the target lesion, resulted most accurate (TRE = 8.8 ± 5.0 mm) in sub-volumes with a radius of 50 mm. Smaller US sub-volumes resulted in lower average TREs when compared to larger US sub-volumes (Pearson's correlation coefficient R = 0.91, p < 0.001). Our results indicate that there is a linear correlation between US volume size and registration accuracy at the tumor. Volumes with radii of 50 mm around the target lesion yield higher accuracy (p < 0.05) (Trial number IRBd18032, 11 September 2018).


Mixed brain pathologies in dementia: the BrainNet Europe consortium experience.
Dementia results from heterogeneous diseases of the brain. Mixed disease forms are increasingly recognized. We performed a survey within brain banks of BrainNet Europe to estimate the proportion of mixed disease forms underlying dementia and age- and gender-specific influences. Data collected in 9 centres from 3,303 individuals were analysed. The proportion of patients with mixed diagnoses among all cases with Alzheimer disease (AD), vascular pathology (VP), argyrophilic grain dementia (AGD), and synucleinopathies, such as Lewy body dementia (LBD), Parkinson disease (PD) and synuclein pathology only in the amygdala, was 53.3%. Mixed pathology was more frequently reported with LBD, PD, AGD, and VP than with AD. The percentage of mixed diagnoses for AGD and VP significantly differed between centres. In patients younger than 75 years, synucleinopathies, and pure forms of AD, VP, and AGD were more frequent in men. Above 75 years of age, more women had pure AD and pure AGD. The most obvious neuropathological alteration should not terminate the diagnostic procedure since copathology is likely to be found. Neuropathological interpretation of AGD and VP has not been sufficiently established in a consensus. Pure forms of synucleinopathies are unlikely sole substrates for dementia.


Watching the clock: studying variation in rates of molecular evolution between species.
Evidence is accumulating that rates of molecular evolution vary substantially between species, and that this rate variation is partly determined by species characteristics. A better understanding of how and why rates of molecular evolution vary provides a window on evolutionary processes, and might facilitate improvements in DNA sequence analysis. Measuring rates of molecular evolution and identifying the correlates of rate variation present a unique set of challenges. We describe and compare recent methodological advances that have been proposed to deal with these challenges. We provide a guide to the theoretical basis and practical application of the methods, outline the types of data on which they can be used, and indicate the types of questions they can be used to ask.


Clumpak: a program for identifying clustering modes and packaging population structure inferences across K.
The identification of the genetic structure of populations from multilocus genotype data has become a central component of modern population-genetic data analysis. Application of model-based clustering programs often entails a number of steps, in which the user considers different modelling assumptions, compares results across different predetermined values of the number of assumed clusters (a parameter typically denoted K), examines multiple independent runs for each fixed value of K, and distinguishes among runs belonging to substantially distinct clustering solutions. Here, we present Clumpak (Cluster Markov Packager Across K), a method that automates the postprocessing of results of model-based population structure analyses. For analysing multiple independent runs at a single K value, Clumpak identifies sets of highly similar runs, separating distinct groups of runs that represent distinct modes in the space of possible solutions. This procedure, which generates a consensus solution for each distinct mode, is performed by the use of a Markov clustering algorithm that relies on a similarity matrix between replicate runs, as computed by the software Clumpp. Next, Clumpak identifies an optimal alignment of inferred clusters across different values of K, extending a similar approach implemented for a fixed K in Clumpp and simplifying the comparison of clustering results across different K values. Clumpak incorporates additional features, such as implementations of methods for choosing K and comparing solutions obtained by different programs, models, or data subsets. Clumpak, available at http://clumpak.tau.ac.il, simplifies the use of model-based analyses of population structure in population genetics and molecular ecology.


Lipases of Fonsecaea pedrosoi and Phialophora verrucosa.
Lipase activity was demonstrable titrimetrically in the culture filtrates of Fonsecaea pedrosoi and Phialophora verrucosa on the 6th day of incubation reaching a peak on the 15th and 12th days respectively for the two fungi. Purified lipases of F. pedrosoi and P. verrucosa, with specific activities of 36.0 and 39.4 fold increase respectively, were obtained by cold acetone extraction, gel filtration followed by ion exchange chromatography. The lipases had the same optimum pH (5.5) and temperature (35 degrees C). The molecular weights of the lipases of F. pedrosoi and P. verrucosa, estimated by gel filtration on Sephadex G-100, were 25,000 and 20,000, respectively and the enzymes showed broad substrate specificity. The possible role of lipase in the pathogenesis of infection caused by the fungi is discussed.


[Study of a population outbreak of hepatitis A. Effectiveness of vaccination as a control measure].
To describe an outbreak of hepatitis A in the city of Albacete (Spain) and to assess the effectiveness of the control measures implemented. When the outbreak was noted, definitions of a case were established. Clinical and epidemiological data were collected through a survey. The temporal-spatial distribution was identified through mapping and the epidemic curve. Health education and immunoglobulin (IG) administration were conducted as immediate prevention and control measures in the population at risk. From January 2005 to January 2006, 62 cases were reported. The most affected age groups were school children and young adults. Transmission was person to person. The epidemic curve was divided into two periods. Initial control measures consisted of hygiene measures and IG administration to contacts. In the second period, these measures were complemented with vaccination against hepatitis A in students of the school centers of the two neighborhoods initially involved. Due to public alarm and spread of the outbreak to adjacent neighborhoods, vaccination was extended to schools close to those where cases had been detected. No cases were notified after the last vaccination in January 2006. The use of vaccination after exposure to the hepatitis A virus in young adults and the school population seems to be an effective outbreak control measure.


Invited review: Use of meta-analysis in animal health and reproduction: methods and applications.
The objectives of this paper are to provide an introduction to meta-analysis and systematic review and to discuss the rationale for this type of research and other general considerations. We highlight methods used to produce a rigorous meta-analysis and discuss some aspects of interpretation of meta-analysis drawing on examples from the animal and veterinary science literature. Meta-analysis is a rapidly expanding area of research that has been relatively underutilized in animal and veterinary science. It is a quantitative, formal, epidemiological study design used to systematically assess previous research studies to derive conclusions about that body of research. Outcomes from a meta-analysis may include a more precise estimate of the effect of treatment or risk factor for disease, or other outcomes, than any individual study contributing to the pooled analysis. The examination of variability or heterogeneity in study results is also a critical outcome. The benefits of meta-analysis include a consolidated and quantitative review of a large, and often complex, sometimes apparently conflicting, body of literature. Meta-analytic methods place less emphasis on dichotomous outcomes from null hypothesis significance testing and greater emphasis on determining the magnitude and the precision of an effect of interest. A substantial benefit of meta-analysis is the potential to investigate new hypotheses using existing data, both through the development of a priori hypotheses and by examination of the heterogeneity in study responses. The specification of the outcome and hypotheses that are tested is critical to the conduct of meta-analyses, as is a sensitive literature search. A failure to identify the majority of existing studies can lead to erroneous conclusions; however, there are methods of examining data to identify the potential for studies to be missing; for example, by the use of funnel plots. Many of the statistical methods to conduct meta-analysis are widely used. Bayesian methods are well suited to meta-analysis. The post-hoc methods used to evaluate heterogeneity and publication bias, which include the I (2) statistic, L'Abbé plots, Galbraith plots, Rosenthal's N, and influential study analysis are exclusively used in meta-analysis. Examples where meta-analyses have been repeated in animal science or veterinary medicine show good consistency in estimates of effect. Findings of studies to date have provided new understandings of rumen modifiers, milk fever, parasite control, mastitis, somatotropin, and reproductive manipulations. Rigorously conducted meta-analyses are useful tools to improve animal well-being and productivity. The need to integrate findings from many studies ensures that meta-analytic research is desirable and the large body of research now generated makes the conduct of this research feasible.


What Proportion of Patients Meet the Criteria for Uncomplicated Sepsis in an Irish Emergency Department?
Emergency medicine plays a central role in the early recognition of patients presenting to hospital with sepsis. However, the epidemiology of sepsis in the Irish Emergency Department (ED) setting has not been described. The primary aim of this study was to determine the proportion of adult ED patients who meet the current criteria for uncomplicated sepsis. This cross-sectional study was performed in the ED of Beaumont Hospital, Dublin. The clinical records of all patients presenting to the ED over a four-week period were retrospectively screened to determine if they met the current Health Service Executive (HSE) criteria for uncomplicated sepsis. Overall, 3,585 adult patients attended the ED during the study period, with 152 patients meeting the criteria for uncomplicated sepsis. The proportion of ED patients who met the criteria for uncomplicated sepsis was 4.24% (95% CI 3.57-4.91%).


A common pathomechanism in GMAP-210- and LBR-related diseases.
Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.


Patient choice in the selection of hospitals by 9-1-1 emergency medical services providers in trauma systems.
Reasons for undertriage (transporting seriously injured patients to nontrauma centers) and the apparent lack of benefit of trauma centers among older adults remain unclear; understanding emergency medical services (EMS) provider reasons for selecting certain hospitals in trauma systems may provide insight to these issues. In this study, the authors evaluated reasons cited by EMS providers for selecting specific hospital destinations for injured patients, stratified by age, injury severity, field triage status, and prognosis. This was a retrospective cohort study of injured children and adults transported by 61 EMS agencies to 93 hospitals (trauma and nontrauma centers) in five regions of the western United States from 2006 through 2008. Hospital records were probabilistically linked to EMS records using trauma registries, state discharge data, and emergency department data. The seven standardized reasons cited by EMS providers for selecting hospital destinations included closest facility, ambulance diversion, physician choice, law enforcement choice, patient or family choice, specialty resource center, and other. "Serious injury" was defined as an Injury Severity Score (ISS) ≥ 16, and unadjusted in-hospital mortality was considered as a marker of prognosis. All analyses were stratified by age in 10-year increments, and descriptive statistics were used to characterize the findings. A total of 176,981 injured patients were evaluated and transported by EMS over the 3-year period, of whom 5,752 (3.3%) had ISS ≥ 16 and 2,773 (1.6%) died. Patient or family choice (50.6%), closest facility (20.7%), and specialty resource center (15.2%) were the most common reasons indicated by EMS providers for selecting destination hospitals; these frequencies varied substantially by patient age. The frequency of patient or family choice increased with increasing age, from 36.4% among 21- to 30-year-olds to 75.8% among those older than 90 years. This trend paralleled undertriage rates and persisted when restricted to patients with serious injuries. Older patients with the worst prognoses were preferentially transported to major trauma centers, a finding that was not explained by field triage protocols. Emergency medical services transport patterns among injured patients are not random, even after accounting for field triage protocols. The selection of hospitals appears to be heavily influenced by patient or family choice, which increases with patient age and involves inherent differences in patient prognosis.


Efficient generation of Rosa26 knock-in mice using CRISPR/Cas9 in C57BL/6 zygotes.
The CRISPR/Cas9 system is increasingly used for gene inactivation in mouse zygotes, but homology-directed mutagenesis and use of inbred embryos are less established. In particular, Rosa26 knock-in alleles for the insertion of transgenes in a genomic 'safe harbor' site, have not been produced. Here we applied CRISPR/Cas9 for the knock-in of 8-11 kb inserts into Rosa26 of C57BL/6 zygotes. We found that 10-20 % of live pups derived from microinjected zygotes were founder mutants, without apparent off-target effects, and up to 50 % knock-in embryos were recovered upon coinjection of Cas9 mRNA and protein. Using this approach, we established a new mouse line for the Cre/loxP-dependent expression of Cas9. Altogether, our protocols and resources support the fast and direct generation of new Rosa26 knock-in alleles and of Cas9-mediated in vivo gene editing in the widely used C57BL/6 inbred strain.


Gait performance is not influenced by working memory when walking at a self-selected pace.
Gait performance exhibits patterns within the stride-to-stride variability that can be indexed using detrended fluctuation analysis (DFA). Previous work employing DFA has shown that gait patterns can be influenced by constraints, such as natural aging or disease, and they are informative regarding a person's functional ability. Many activities of daily living require concurrent performance in the cognitive and gait domains; specifically working memory is commonly engaged while walking, which is considered dual-tasking. It is unknown if taxing working memory while walking influences gait performance as assessed by DFA. This study used a dual-tasking paradigm to determine if performance decrements are observed in gait or working memory when performed concurrently. Healthy young participants (N = 16) performed a working memory task (automated operation span task) and a gait task (walking at a self-selected speed on a treadmill) in single- and dual-task conditions. A second dual-task condition (reading while walking) was included to control for visual attention, but also introduced a task that taxed working memory over the long term. All trials involving gait lasted at least 10 min. Performance in the working memory task was indexed using five dependent variables (absolute score, partial score, speed error, accuracy error, and math error), while gait performance was indexed by quantifying the mean, standard deviation, and DFA α of the stride interval time series. Two multivariate analyses of variance (one for gait and one for working memory) were used to examine performance in the single- and dual-task conditions. No differences were observed in any of the gait or working memory dependent variables as a function of task condition. The results suggest the locomotor system is adaptive enough to complete a working memory task without compromising gait performance when walking at a self-selected pace.


YscN, the putative energizer of the Yersinia Yop secretion machinery.
Pathogenic yersiniae secrete a set of 11 antihost proteins called Yops. Yop secretion appears as the archetype of the type III secretion pathway. Several components of this machinery are encoded by the virA (lcrA) and virC (lcrC) loci of the 70-kb pYV plasmid. In this paper, we describe yscN, another gene involved in this pathway. It is the first gene of the virB locus. It encodes a 47.8-kDa protein similar to the catalytic subunits of F0F1 and related ATPases, as well as to products of other genes presumed to be involved in a type III secretion pathway. YscN contains the two consensus nucleotide-binding motifs (boxes A and B) described by Walker et al. (J. E. Walker, M. Saraste, M. J. Runswick, and N. J. Gay, EMBO J. 1:945-951, 1982). We engineered a pYV mutant encoding a modified YscN protein lacking box A. This mutant, impaired in Yop secretion, can be complemented in trans by a cloned yscN gene. We conclude that YscN is a component of the Yop secretion machinery using ATP. We hypothesize that it is either the energizer of this machinery or a part of it.


The anchoring effect-long-term dormancy and genetic population structure.
Understanding the genetic structure of populations is key to revealing past and present demographic and evolutionary processes in a species. In the past decade high genetic differentiation has been observed in many microbial species challenging the previous view of cosmopolitan distribution. Populations have displayed high genetic differentiation, even at small spatial scales, despite apparent high dispersal. Numerous species of microalgae have a life-history strategy that includes a long-term resting stage, which can accumulate in sediments and serve as refuge during adverse conditions. It is presently unclear how these seed banks affect the genetic structure of populations in aquatic environments. Here we provide a conceptual framework, using a simple model, to show that long-term resting stages have an anchoring effect on populations leading to increased genetic diversity and population differentiation in the presence of gene flow. The outcome that species with resting stages have a higher degree of genetic differentiation compared to species without, is supported by empirical data obtained from a systematic literature review. With this work we propose that seed banks in aquatic microalgae play an important role in the contradicting patterns of gene flow, and ultimately the adaptive potential and population dynamics in species with long-term resting stages.


Knowledge, attitude, and behavior of nurses toward delivery of Primary Oral Health Care in Dakshina Kannada, India.
Majority of young children in many countries do not visit dental clinics for examinations before the age of three though they frequently visit primary health care providers for routine medical check-ups. Nurses are easily accessible and are in frequent contact with waiting mothers and children for routine check-ups and this provides an opportunity to integrate oral health promotion and care into health care. The purpose of this study was thus to study the knowledge, attitude and behaviour towards oral health care among nurses. The study was a cross-sectional questionnaire survey. Total of 170 medical nurses working in the Institutional Hospital and who provided care for paediatric patients and pregnant mothers participated in the study. Chi-Square test was used to analyse the data using SPSS version 17.0 with a significance value of P < 0.05. All the nurses were aware that good oral health is important for overall health of the child. About 70% of the respondents had poor knowledge regarding dental caries. Good response was obtained regarding importance of oral hygiene maintenance for both the child and mother for prevention of caries. Majority of the nurses showed positive attitudes toward preventive OHC and the role of medical nurses. Routinely the nurses do not refer pregnant mothers and children for dental check up nor do they counsel them regarding oral hygiene and its importance. Appropriate training and encouragement for promotion of oral health and to provide suitable care for the prevention of dental diseases should be included in the curriculum of nurses training.


Transport of Calcareous Fragments by Reef Fishes.
The weight of sand, coral scrapings, algal fragments, and other calcareous materials which pass through the intestines of reef fishes was calculated on a hectare-per-year basis. It was found that browsing omnivorous reef fishes which rely, in part, on a plant diet ingested and redeposited at least 2300 kg of such material on a 1-hectare study reef near Bermuda. Reasons are presented why this estimate, certainly in order of magnitude, should be applicable to coral reefs in general.


Isometric knee-extension and knee-flexion torque production during early follicular and postovulatory phases in recreationally active women.
Acute decreases in strength have been associated with risky biomechanical strategies that might predispose one to injury. Whether acute changes in thigh muscle torque occur across the menstrual cycle remains equivocal. We compared maximal voluntary isometric contraction (MVIC) torque of the knee flexors and extensors between the early follicular (EF) and either the early luteal (EL) or midluteal (ML) phases, which were confirmed by serum hormone concentrations. We expected that MVIC torques would increase from the EF to the EL phase after estradiol peaked and before increased exposure to progesterone. Cohort study. Applied Neuromechanics Research Laboratory. Seventy-one recreationally active women (age range, 18-30 years). The MVICs were measured 1 day during menses and 1 day during the 8 days after ovulation. Participants were grouped by the hormone profile of their luteal test days as EL phase, ML phase, or anovulatory cycle. The MVIC torque of knee flexors and extensors (Nm/kg), estradiol (pg/mL), progesterone (ng/mL), and testosterone (ng/dL). We tested 29 women during their EL phases, 32 during their ML phases, and 10 during anovulatory cycles. Although we observed relatively large individual changes in sex hormone concentrations and MVIC torques across the 2 test sessions, we observed no difference in MVIC torque between test phases (F(1,68) = 1.17, P = .28) or among groups by test phase (F(2,68) = 0.31, P = .74). Thigh MVIC torque did not change from time of menses (when estradiol and progesterone were lowest) to time in the luteal phase after an unopposed estradiol rise or combined estradiol and progesterone rise. However, these findings were limited to MVIC torque production measured at 2 different times, and further research examining these relationships at multiple times and using other measures of neuromuscular function is needed.


Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.
Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.


Big Data in Transplantation Practice-the Devil Is in the Detail-Fontan-associated Liver Disease.
As a result of the Fontan procedure, the prognosis of congenital single-ventricle heart disease has improved, with many affected children surviving into adulthood. However, the unanticipated consequences of chronic exposure to Fontan hemodynamics have revealed a new set of secondary noncardiac complications. Fontan-associated liver disease (FALD) is characterized by progressive hepatic fibrosis in nearly all patients post-Fontan, with the potential to develop cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A lack of data regarding FALD-related prognosis makes consideration of indications for and timing of heart alone versus combined heart-liver transplantation challenging. A multidisciplinary group within the American Society for Transplantation analyzed several administrative datasets to study the epidemiology of FALD. This approach presented several obstacles, and efforts to characterize FALD were limited by a lack of Fontan- and FALD-specific diagnostic codes and an inability to follow individual patients through multiple health systems. Several ongoing Fontan registries were also reviewed but these do not adequately capture FALD-related variables. Such barriers highlight the need for large-scale data collection in patients post-Fontan to better understand and care for this complex population. This study emphasizes the challenges of studying emerging transplant-related diagnoses in existing datasets and the need for mechanisms to adapt registries to appropriately identify patients with rare or emerging conditions.


Deficits of knowledge versus executive control in semantic cognition: insights from cued naming.
Deficits of semantic cognition in semantic dementia and in aphasia consequent on CVA (stroke) are qualitatively different. Patients with semantic dementia are characterised by progressive degradation of central semantic representations, whereas multimodal semantic deficits in stroke aphasia reflect impairment of executive processes that help to direct and control semantic activation in a task-appropriate fashion [Jefferies, E., & Lambon Ralph, M. A. (2006). Semantic impairment in stroke aphasia vs. semantic dementia: A case-series comparison. Brain 129, 2132-2147]. We explored interactions between these two aspects of semantic cognition by examining the effects of cumulative phonemic cueing on picture naming in case series of these two types of patient. The stroke aphasic patients with multimodal semantic deficits cued very readily and demonstrated near-perfect name retrieval when cumulative phonemic cues reached or exceeded the target name's uniqueness point. Therefore, knowledge of the picture names was largely intact for the aphasic patients, but they were unable to retrieve this information without cues that helped to direct activation towards the target response. Equivalent phonemic cues engendered significant but much more limited benefit to the semantic dementia patients: their naming was still severely impaired even when most of the word had been provided. In contrast to the pattern in the stroke aphasia group, successful cueing was mainly confined to the more familiar un-named pictures. We propose that this limited cueing effect in semantic dementia follows from the fact that concepts deteriorate in a graded fashion [Rogers, T. T., Lambon Ralph, M. A., Garrard, P., Bozeat, S., McClelland, J. L., & Hodges, J. R., et al. (2004). The structure and deterioration of semantic memory: A neuropsychological and computational investigation. Psychological Review 111, 205-235]. For partially degraded items, the residual conceptual knowledge may be insufficient to drive speech production to completion but these items might reach threshold when they are bolstered by cues.


The relationship between transposable elements and ecological niches in the Greater Cape Floristic Region: A study on the genus Pteronia (Asteraceae).
Non-coding repetitive DNA (repeatome) is an active part of the nuclear genome, involved in its structure, evolution and function. It is dominated by transposable elements (TEs) and satellite DNA and is prone to the most rapid changes over time. The TEs activity presumably causes the global genome reorganization and may play an adaptive or regulatory role in response to environmental challenges. This assumption is applied here for the first time to plants from the Cape Floristic hotspot to determine whether changes in repetitive DNA are related to responses to a harsh, but extremely species-rich environment. The genus Pteronia (Asteraceae) serves as a suitable model group because it shows considerable variation in genome size at the diploid level and has high and nearly equal levels of endemism in the two main Cape biomes, Fynbos and Succulent Karoo. First, we constructed a phylogeny based on multiple low-copy genes that served as a phylogenetic framework for detecting quantitative and qualitative changes in the repeatome. Second, we performed a comparative analysis of the environments of two groups of Pteronia differing in their TEs bursts. Our results suggest that the environmental transition from the Succulent Karoo to the Fynbos is accompanied by TEs burst, which is likely also driving phylogenetic divergence. We thus hypothesize that analysis of rapidly evolving repeatome could serve as an important proxy for determining the molecular basis of lineage divergence in rapidly radiating groups.


Implication of neuropeptide-Y Y2 receptors in the effects of immune stress on emotional, locomotor and social behavior of mice.
Neuropeptide Y (NPY) is involved in the regulation of emotional behavior, and there is indirect evidence for a role of NPY in the cerebral responses to peripheral immune challenge. Since the NPY receptors involved in these reactions are not known, we investigated the effect of Escherichia coli lipopolysaccharide (LPS) on emotional, locomotor and social behavior, body temperature and circulating corticosterone in female Y2 (Y2-/-) and Y4 (Y4-/-) receptor knockout mice. LPS (0.1mg/kg injected IP 2.5h before testing) increased rectal temperature in control and Y4-/- mice to a larger degree than in Y2-/- animals. Both Y2-/- and Y4-/- mice exhibited reduced anxiety-related and depression-like behavior in the open field, elevated plus-maze and tail suspension test, respectively. While depression-like behavior was not changed by LPS, anxiety-related behavior was enhanced by LPS in Y2-/-, but not control and Y4-/- animals. Y2-/- mice were also particularly susceptible to the effect of LPS to attenuate locomotor behavior and social interaction with another mouse. The corticosterone response to LPS was blunted in Y2-/- mice which presented elevated levels of circulating corticosterone following vehicle treatment. These data show that Y2-/- mice are particularly sensitive to the effects of LPS-evoked immune stress to attenuate locomotion and social interaction and to increase anxiety-like behavior, while the LPS-induced rise of temperature and circulating corticosterone is suppressed by Y2 receptor knockout. Our observations attest to an important role of endogenous NPY acting via Y2 receptors in the cerebral response to peripheral immune challenge.