Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production.
The inhibitory receptor FcgammaRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgammaRIIb levels. Furthermore, FcgammaRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgammaRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b(NZW) independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b(NZW) in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b(NZW) allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b(NZW) does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgammaRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells.


Derivation of intermediate to silicic magma from the basalt analyzed at the Vega 2 landing site, Venus.
Geochemical modeling using the basalt composition analyzed at the Vega 2 landing site indicates that intermediate to silicic liquids can be generated by fractional crystallization and equilibrium partial melting. Fractional crystallization modeling using variable pressures (0.01 GPa to 0.5 GPa) and relative oxidation states (FMQ 0 and FMQ -1) of either a wet (H2O = 0.5 wt%) or dry (H2O = 0 wt%) parental magma can yield silicic (SiO2 > 60 wt%) compositions that are similar to terrestrial ferroan rhyolite. Hydrous (H2O = 0.5 wt%) partial melting can yield intermediate (trachyandesite to andesite) to silicic (trachydacite) compositions at all pressures but requires relatively high temperatures (≥ 950°C) to generate the initial melt at intermediate to low pressure whereas at high pressure (0.5 GPa) the first melts will be generated at much lower temperatures (< 800°C). Anhydrous partial melt modeling yielded mafic (basaltic andesite) and alkaline compositions (trachybasalt) but the temperature required to produce the first liquid is very high (≥ 1130°C). Consequently, anhydrous partial melting is an unlikely process to generate derivative liquids. The modeling results indicate that, under certain conditions, the Vega 2 composition can generate silicic liquids that produce granitic and rhyolitic rocks. The implication is that silicic igneous rocks may form a small but important component of the northeast Aphrodite Terra.


High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.
Germline mutations in the tumour suppressor gene CDKN2A occur in 5-20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. In a national program, carriers of p.Arg112dup mutation have been identified. The aim of this study was to assess cancer risks in p.Arg112dup carriers and their first degree relatives (FDRs) and second degree relatives (SDRs). In this prospective cohort study, cancer diagnoses in carriers (n=120), non-carriers (n=111), carriers' FDRs (n=275) and SDRs (n=321) and controls (n=3976) were obtained from the Swedish Cancer Registry. Relative risks (RRs) for cancers were calculated (number of cancers/person years). Two-sided 95% CIs were calculated for all RRs. In carriers prospective RR for non-melanoma cancers was 5.0 (95% CI 3.7 to 7.3), for pancreatic cancer 43.8 (95% CI 13.8 to 139.0), for cancers in upper digestive tissues 17.1 (95% CI 6.3 to 46.5), and in respiratory tissues 15.6 (5.4 to 46.0). In FDRs and SDRs RRs were significantly elevated for cancers in pancreas, respiratory and upper digestive tissues. In ever-smoking carriers compared with never-smoking carriers, the odds ratio (OR) of cancers in pancreas, respiratory or upper digestive tissues was 9.3 (95% CI 1.9 to 44.7). CDKN2A p.Arg112dup mutation carriers from melanoma-prone families and their FDRs and SDRs have elevated risk for pancreatic, lung, head and neck and gastro-oesophageal carcinomas. These cancers were mainly seen in ever-smoking carriers. Germline CDKN2A mutations may confer an increased sensitivity to carcinogens in tobacco smoke. CDKN2A mutation carriers should be counselled to abstain from smoking.


Red blood cells: why or why not?
It is commonly stated that, if hemoglobin were dissolved in the blood plasma rather than enclosed in corpuscles, the viscosity of the blood would be greatly increased. We found that when the corpuscles of dog or goat blood were disrupted with ultrasound, giving a solution with the same hemoglobin concentration, the relative viscosity was drastically reduced. It appears, therefore, that the existence of blood corpuscles does not contribute to a reduced viscosity of blood.


Optical aberrations and alignment of the eye with age.
We explored the relative changes in ocular, corneal, and internal aberrations associated with normal aging with special emphasis in the role of ocular alignment and lens shape factor in the balance of aberrations. Ocular and corneal aberrations together with the angle kappa were measured for a 5-mm pupil diameter in 46 eyes with low refractive errors and ages ranging between 20 and 77 years. The root mean square (RMS) of the higher order ocular and corneal aberrations increased with age at a rate of 0.0032 μm/year and 0.0015 μm/year, respectively. While in young eyes the partial compensation of aberrations by the internal surfaces was clear, no significant difference was found between corneal and ocular RMS in the older group. The ocular spherical aberration (0.0011 μm/year) and horizontal coma (0.0017 μm/year) increased moderately with age. This is not due to changes in the optical alignment, since angle kappa did not vary significantly with age. Age-related variations in the radii of curvature of the crystalline lens modify slightly its shape factor, reducing the compensation of lateral coma. This suggests that geometrical changes in the crystalline lens with age contribute to modify its aberration structure, reducing the compensation mechanism and explaining most of the measured increment of ocular aberrations with age.


Vaccine and immunotherapeutic interventions.
As we enter the fourth decade in HIV epidemic, advances in understanding HIV pathogenesis and development of potent and safer antiretroviral drugs have been spectacular. More than 30 antiviral drugs have been registered and the impact of combination antiviral therapy on morbidity and mortality has been dramatic. However, despite long-term virus suppression, HIV invariably rebounds after interruption of therapy. Long-term antiviral therapy does not cure HIV infection nor does it induce restoration/development of virus-specific immune responses capable of controlling HIV replication. Therefore, development of immune-based interventions is needed to restore effective defenses that can lead to HIV functional cure and ultimately eradication. Therapeutic vaccination and immune interventions that generate de-novo or that boost preexisting HIV-specific T-cell responses are being investigated as a potential means to achieve a 'functional HIV cure'. One major hurdle in the quest of an HIV cure is control and elimination of the HIV latent reservoir. Several immune interventions that target the latent reservoir have been tried in recent years. In parallel, several therapeutic vaccination strategies have been developed and tested in early clinical studies. Recent encouraging studies show for the first time that vaccination can have an impact on HIV load. This review summarizes the main immune interventions evaluated over the last years. Ways to improve them, as well as challenges in monitoring/evaluating effects of such strategies, are being discussed. In addition, clinical efficacy and potential clinical benefits of immunotherapeutic interventions are particularly difficult to measure. This review highlights current assays used and their shortcoming.


Career intentions of nursing students and new nurse graduates: a review of the literature.
This paper highlights findings from a literature search to examine the role of nursing education in preparing nurses to meet healthcare demands. The review focused on nursing students' perceptions of nursing and whether these views change during their nursing studies and impact workplace preferences. Nursing students often enter their program with preconceived ideas of where they want to work following graduation. Large urban hospitals were favored over community care because of the perceived opportunities for support. Of particular importance were the negative views relating to care of elderly patients. Unless attitudes are changed during their nursing studies, they may affect initial job selection. Implications for nursing education include provision of educational experiences that foster an optimistic career outlook in areas where there is a growing need for nursing services. More research is needed to determine how to enable appropriate learning experiences when there are limited resources and practice placements.


The Risk of Cancer in Patients With Psoriasis: A Population-Based Cohort Study in the Health Improvement Network.
The risk of cancer in patients with psoriasis remains a cause of special concern due to the chronic inflammatory nature of the disease, the use of immune-suppressive treatments and UV therapies, and the increased prevalence of comorbid, well-established risk factors for cancer, such as smoking and obesity, all of which may increase the risk of carcinogenesis. To compare the overall risk of cancer, and specific cancers of interest, in patients with psoriasis compared with patients without psoriasis. Population-based cohort study of patients ages 18 to 89 years with no medical history of human immunodeficiency virus, cancer, organ transplants, or hereditary disease (albinism and xeroderma pigmentosum), prior to the start date, conducted using The Health Improvement Network, a primary care medical records database in the United Kingdom. The data analyzed had been collected prospectively from 2002 through January 2014. The analysis was completed in August 2015. Patients with at least 1 diagnostic code for psoriasis were classified as having moderate-to-severe disease if they had been prescribed psoralen, methotrexate, cyclosporine, acitretin, adalimumab, etanercept, infliximab, or ustekinumab or phototherapy for psoriasis. Patients were classified as having mild disease if they never received treatment with any of these agents. Incident cancer diagnosis. A total of 937,716 control group patients without psoriasis, matched on date and practice visit, and 198,366 patients with psoriasis (186,076 with mild psoriasis and 12,290 with moderate-to-severe disease) were included in the analysis. The adjusted hazard ratios (aHRs) with 95% CIs for any incident cancer excluding nonmelanoma skin cancer (NMSC) were 1.06 (95% CI, 1.02-1.09), 1.06 (95% CI, 1.02-1.09), and 1.08 (95% CI, 0.96-1.22) in the overall, mild, and severe psoriasis group. The aHRs for incident lymphoma were 1.34 (95% CI, 1.18-1.51), 1.31 (95% CI, 1.15-1.49), and 1.89 (95% CI, 1.25-2.86); for NMSC, 1.12 (95% CI, 1.07-1.16), 1.09 (95% CI, 1.05-1.13), and 1.61 (95% CI, 1.42-1.84); and for lung cancer, 1.15 (95% CI, 1.03-1.27), 1.12 (95% CI, 1.01-1.25), and 1.62 (95% CI, 1.16-2.28) in the overall, mild, and severe psoriasis groups, respectively. No significant association was seen with cancer of the breast, colon, prostate, or leukemia. The association between psoriasis and cancer, albeit small, was present in our cohort of patients with psoriasis. This association was primarily driven by NMSC, lymphoma, and lung cancer.


The effects of public and private health care expenditure on health status in sub-Saharan Africa: new evidence from panel data analysis.
Health care expenditure has been low over the years in developing regions of the world. A majority of countries in these regions, especially sub-Saharan Africa (SSA), rely on donor grants and loans to finance health care. Such expenditures are not only unsustainable but also inadequate considering the enormous health care burden in the region. The objectives of this study are to determine the effect of health care expenditure on population health status and to examine the effect by public and private expenditure sources. The study used panel data from 1995 to 2010 covering 44 countries in SSA. Fixed and random effects panel data regression models were fitted to determine the effects of health care expenditure on health outcomes. The results show that health care expenditure significantly influences health status through improving life expectancy at birth, reducing death and infant mortality rates. Both public and private health care spending showed strong positive association with health status even though public health care spending had relatively higher impact. The findings imply that health care expenditure remains a crucial component of health status improvement in sub-Saharan African countries. Increasing health care expenditure will be a significant step in achieving the Millennium Development Goals. Further, policy makers need to establish effective public-private partnership in allocating health care expenditures.


Stages of change: A qualitative study on the implementation of a perinatal audit programme in South Africa.
Audit and feedback is an established strategy for improving maternal, neonatal and child health. The Perinatal Problem Identification Programme (PPIP), implemented in South African public hospitals in the late 1990s, measures perinatal mortality rates and identifies avoidable factors associated with each death. The aim of this study was to elucidate the processes involved in the implementation and sustainability of this programme. Clinicians' experiences of the implementation and maintenance of PPIP were explored qualitatively in two workshop sessions. An analytical framework comprising six stages of change, divided into three phases, was used: pre-implementation (create awareness, commit to implementation); implementation (prepare to implement, implement) and institutionalisation (integrate into routine practice, sustain new practices). Four essential factors emerged as important for the successful implementation and sustainability of an audit system throughout the different stages of change: 1) drivers (agents of change) and team work, 2) clinical outreach visits and supervisory activities, 3) institutional perinatal review and feedback meetings, and 4) communication and networking between health system levels, health care facilities and different role-players.During the pre-implementation phase high perinatal mortality rates highlighted the problem and indicated the need to implement an audit programme (stage 1). Commitment to implementing the programme was achieved by obtaining buy-in from management, administration and health care practitioners (stage 2).Preparations in the implementation phase included the procurement and installation of software and training in its use (stage 3). Implementation began with the collection of data, followed by feedback at perinatal review meetings (stage 4).The institutionalisation phase was reached when the results of the audit were integrated into routine practice (stage 5) and when data collection had been sustained for a longer period (stage 6). Insights into the factors necessary for the successful implementation and maintenance of an audit programme and the process of change involved may also be transferable to similar low- and middle-income public health settings where the reduction of the neonatal mortality rate is a key objective in reaching Millennium Development Goal 4. A tool for reflecting on the implementation and maintenance of an audit programme is also proposed.


Definitive radiation therapy for cervical cancer: Non-white race and public insurance are risk factors for delayed completion, a pilot study.
This is a pilot study to assess whether racial disparities exist in time to initiation and completion of external beam pelvic radiation therapy and brachytherapy in cervical cancers treated with definitive chemoradiation. A retrospective analysis was conducted on all cervical cancer patients treated with definitive radiotherapy between 2006 and 2016 at a single institution. Patient demographics including age, race, insurance status and stage at diagnosis were obtained. Analyses were performed according to the following definitions of wait times: interval from pathologic diagnosis of cervical cancer to (Siegel et al., 2016) initiation of radiation therapy, (Yoo et al., 2017) completion of external beam radiation therapy and (DeSantis et al., 2016) completion of external beam radiation therapy plus brachytherapy if indicated. Of 50 women, 21 self-identified as white, 25 as black and 4 as Hispanic. Due to small numbers, Hispanic women were included with black women as a non-white group. The average age was 52 years for women in this cohort. Mean days to initiation of radiation therapy were 41.8 days: 33.7 days among white patients versus 47.8 days for non-white patients (p-value 0.101). Mean days from diagnosis to completion of external beam pelvic radiation therapy were 81.3 days: 70.9 days among white patients versus 88.9 days among non-white patients (p-value 0.006). Non-white patients were more likely to have public insurance, which was also associated with a longer time to completion of radiation treatment. We conclude that non-white patients experienced delays to completing external beam radiation therapy, which was no longer present after adjusting for insurance status.


gamma-Glutamyltransferase predicts cardiovascular death among Japanese women.
The clinical importance of gamma-glutamyltransferase (GGT) has recently been debated. Although some studies have suggested that the relationship between GGT and cardiovascular disease (CVD) mortality is independent of alcohol consumption, to our knowledge no studies have reported the relationship between GGT and CVD mortality in never-drinker subgroups. Since Japanese women are known to have a lower prevalence of alcohol consumption, we examined whether GGT predicts CVD mortality in never-drinkers. We followed 2724 Japanese men and 4122 Japanese women without prior CVD or liver dysfunction for 9.6 years and observed 83 and 82 CVD deaths, respectively. Current alcohol drinkers comprised 59% of men and 7% of women. Among women, the multiple adjusted hazard ratio (HR) for CVD mortality compared with the reference group (GGT: 1-12 U/L) was 2.88 (95% confidence interval (CI), 1.14-7.28) for the elevated group (GGT>or=50 U/L). This positive relationship was unchanged in the never-drinkers subgroup (HR for log-transformed continuous GGT, 1.62 (95% CI, 1.11-2.37)). No significant relationships were observed in men. GGT displays a strong positive association with CVD mortality among Japanese women, for whom the prevalence of ever-drinkers is very low. Exploring the significance and biological mechanisms of GGT might provide useful insights into CVD prevention.


Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review.
To review systematically the neurodevelopmental characteristics of individuals with sex chromosome trisomies (SCTs). A bibliographic search identified English-language articles on SCTs. The focus was on studies unbiased by clinical referral, with power of at least 0.69 to detect an effect size of 1.0. We identified 35 articles on five neonatally identified samples that had adequate power for our review. An additional 11 studies were included where cases had been identified for reasons other than neurodevelopmental concerns. Individuals with an additional X chromosome had mean IQs that were within broadly normal limits but lower than the respective comparison groups, with verbal IQ most affected. Cognitive outcomes were poorest for females with XXX. Males with XYY had normal-range IQs, but all three SCT groups (XXX, XXY, and XYY) had marked difficulties in speech and language, motor skills, and educational achievement. Nevertheless, most adults with SCTs lived independently. Less evidence was available for brain structure and for attention, social, and psychiatric outcomes. Within each group there was much variation. Individuals with SCTs are at risk of cognitive and behavioural difficulties. However, the evidence base is slender, and further research is needed to ascertain the nature, severity, and causes of these difficulties in unselected samples.


Composition of pluralistic health systems: how much can we learn from household surveys? An exploration in Cambodia.
In spite of all efforts to build national health services, health systems of many low-income countries are today highly pluralistic. Households use a vast range of public and private health care providers, many of whom are not controlled by national health authorities. Experts have called on Ministries of Health to re-establish themselves as stewards of the entire health system. Modern stewardship will require national and decentralized health authorities to have an overall view of their pluralistic health system, especially of the components outside the public sector. Little guidance has been provided so far on how to develop such a view. In this paper, we explore whether household surveys could be a source of information. The study builds on secondary data analysis of a household survey carried out in three health districts in rural Cambodia and of two national surveys. Cambodia is indeed an interesting case, as massive efforts by donors in favour of the public sector go hand in hand with a dominant role of the private sector in the provision of health care services. The study confirms that the health care sector in Cambodia is now highly pluralistic, and that the great majority of health seeking behaviour takes place outside the public health system. Our analysis of the survey also shows that the disaffection of the population with public health facilities varies across places, socio-economic groups and health problems. We illustrate how such knowledge could allow stewards to better identify challenges for existing or future health policies. We argue that a whole research programme on the composition of pluralistic health systems still needs to be developed. We identify some challenges and opportunities.


Pursuing the impossible: an interview with Tim Hunt.
Tim Hunt took an undergraduate degree in Natural Sciences at Cambridge in 1964, and his PhD and subsequent work focussed on the control of protein synthesis until 1982, when his adventitious discovery of the central cell cycle regulator cyclin, while he was teaching at the Marine Biological Laboratory in Woods Hole, redirected him to the study of cell cycle regulation. From 1990 to his retirement Tim worked in the Clare Hall Laboratories of Cancer Research UK. He shared the Nobel Prize in Physiology and Medicine with Lee Hartwell and Paul Nurse in 2001, and talked to us about the series of coincidences that led him to the prizewinning discovery.


Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria.
Eight patients with a homogeneous syndrome of progressive symmetric spinobulbar spasticity were studied. Clinical features were limited to those associated with dysfunction of the descending motor tracts and included spastic quadriparesis, pseudobulbar affect, spastic dysarthria, hyper-reflexia and bilateral Babinski signs. Lower motor neuron findings were absent and higher cognitive function preserved. Median age of onset was 50.5 yrs and median disease duration was 19 yrs. Neuropathologic features (including morphometric analysis) in the single autopsied case confirmed the selective involvement of the motor cortex. There was complete absence of Betz cells from layer 5 of the precentral cortex and the remaining pyramidal cells were significantly smaller than those seen in normal controls. Magnetic resonance imaging (MRI) revealed atrophy of the precentral gyrus and positron emission tomography (PET) scans showed diminished glucose [18F]fluorodeoxyglucose uptake in the pericentral cortex. Magnetic motor cortex stimulation revealed markedly prolonged central motor conduction times. The literature is reviewed and diagnostic criteria for primary lateral sclerosis based on clinical, laboratory and imaging features are proposed.


Temozolomide: a novel oral alkylating agent.
Temozolomide is an imidazotetrazine with a mechanism of action and efficacy similar to dacarbazine (DTIC). However, it differs from DTIC in that it can be taken orally, degrades spontaneously to an active metabolite and penetrates the blood-brain barrier. It is well tolerated, making it a suitable candidate for combination chemotherapy. Trials to date have focussed on its activity in advanced metastatic melanoma and high-grade malignant glioma. Investigations into other indications, in particular solid tumors with central nervous system metastases, are ongoing. Studies of new drug schedules and of drugs to ameliorate temozolomide resistance offer the prospect of increased efficacy.


A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles.
Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after. The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.


Physiological and therapeutical roles of ginger and turmeric on endocrine functions.
The natural product ginger (Zingiber officinale) has active constituents gingerol, Shogaol and Zerumbone, while turmeric (Curcuma longa) contains three active major curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. They have the same scientific classification and are reported to have anti-inflammatory and many therapeutic effects. This article reviews the physiological and therapeutic effects of ginger and turmeric on some endocrine gland functions, and signal pathways involved to mediate their actions. With some systems and adipose tissue, ginger and turmeric exert their actions through some/all of the following signals or molecular mechanisms: (1) through reduction of high levels of some hormones (as: T4, leptin) or interaction with hormone receptors; (2) by inhibition of cytokines/adipokine expression; (3) acting as a potent inhibitor of reactive oxygen species (ROS)-generating enzymes, which play an essential role between inflammation and progression of diseases; (4) mediation of their effects through the inhibition of signaling transcription factors; and/or (5) decrease the proliferative potent by down-regulation of antiapoptotic genes, which may suppress tumor promotion by blocking signal transduction pathways in the target cells. These multiple mechanisms of protection against inflammation and oxidative damage make ginger and curcumin particularly promising natural agents in fighting the ravages of aging and degenerative diseases, and need to be paid more attention by studies.


A Novel Approach to Proactive Primary Care-Based Case Finding and Multidisciplinary Management of Falls, Syncope, and Dizziness in a One-Stop Service: Preliminary Results.
National and international evidence and guidelines on falls prevention and management in community-dwelling elderly adults recommend that falls services should be multifactorial and their interventions multicomponent. The way that individuals are identified as having had or being at risk of falls in order to take advantage of such services is far less clear. A novel multidisciplinary, multifactorial falls, syncope, and dizziness service model was designed with enhanced case ascertainment through proactive, primary care-based screening (of individual case notes of individuals aged ≥60) for individual fall risk factors. The service model identified 4,039 individuals, of whom 2,232 had significant gait and balance abnormalities according to senior physiotherapist assessment. Significant numbers of individuals with new diagnoses ranging from cognitive impairment to Parkinson's disease to urgent indications for a pacemaker were discovered. More than 600 individuals were found who were at high risk of osteoporosis according to World Health Association Fracture Risk Assessment Tool score, 179 with benign positional paroxysmal vertigo and 50 with atrial fibrillation. Through such screening and this approach, Comprehensive Geriatric Assessment Plus (Plus falls, syncope and dizziness expertise), unmet need was targeted on a scale far outside the numbers seen in clinical trials. Further work is needed to determine whether this approach translates into fewer falls and decreases in syncope and dizziness.


The effects of heat treatment on physical properties and surface roughness of red-bud maple (Acer trautvetteri Medw.) wood.
Heat treatment is often used to improve the dimensional stability of wood. In this study, the effects of heat treatment on physical properties and surface roughness of red-bud maple (Acer trautvetteri Medw.) wood were examined. Samples obtained from Düzce Forest Enterprises, Turkey, were subjected to heat treatment at varying temperatures and durations. The physical properties of heat-treated samples were compared against controls in order to determine their; oven-dry density, air-dry density, and swelling properties. A stylus method was employed to evaluate the surface characteristics of the samples. Roughness measurements, using the stylus method, were made in the direction perpendicular to the fiber. Three main roughness parameters; mean arithmetic deviation of profile (Ra), mean peak-to-valley height (Rz), and maximum roughness (Rmax) obtained from the surface of wood, were used to evaluate the effect of heat treatment on the surface characteristics of the specimens. Significant differences were determined (p>0.05) between surface roughness parameters (Ra, Rz, Rmax) at three different temperatures and three periods of heat treatment. The results showed that the values of density, swelling and surface roughness decreased with increasing temperature treatment and treatment times. Red-bud maple wood could be utilized successfully by applying proper heat treatment techniques without any losses in investigated parameters. This is vital in areas, such as window frames, where working stability and surface smoothness are important factors.


Genetic evidence that heparin-like glycosaminoglycans are involved in wingless signaling.
We have identified the Drosophila UDP-glucose dehydrogenase gene as being involved in wingless signaling. Mutations in this gene, called kiwi, generate a phenotype identical to that of wingless. UDP-glucose dehydrogenase is required for the biosynthesis of UDP-glucuronate, which in turn is utilized in the biosynthesis of glycosaminoglycans. By rescuing the kiwi phenotype with both UDP-glucuronate and the glycosaminoglycan heparan sulfate, we show that kiwi function in the embryo is crucial for the production of heparan sulfate in the extracellular matrix. Further, injection of heparin degrading enzyme, heparinase (and not chondroitin, dermatan or hyaluronic acid degrading enzyme) into wild-type embryos leads to the degradation of heparin-like glycosaminoglycans and a 'wingless-like' cuticular phenotype. Our study thus provides the first genetic evidence for the involvement of heparin-like glycosaminoglycans in signal transduction.


In situ observation of the surface processes involved in dissolution from the cleavage surface of calcite in aqueous solution using combined scanning electrochemical-atomic force microscopy (SECM-AFM).
The surface processes involved in the initial stages of the proton-assisted dissolution of the calcite single crystal cleavage plane (1014) have been identified using a combined scanning electro-chemical-atomic force microscope (SECM-AFM). This instrument employs a platinum-coated AFM probe, which functions as an electrode as well as a high-resolution topographical sensor. Dissolution in this arrangement is effected by the local electrogeneration of protons, produced by oxidation of water at the probe electrode. By careful control of the applied potential, it is possible to vary the magnitude of the electrogenerated flux of protons from the probe towards the calcite surface. Crucially, by generating a small proton flux for short time periods (0.5 s) it is possible to observe and monitor the initial sites in the dissolution process. Topographical images were recorded in the same area of the surface both prior to and after inducing dissolution, as a function of the proton flux. At low proton fluxes, of the order of 1 nmol cm-2s-1 or less, the surface was observed to dissolve by the nucleation of monolayer deep pits, with densities of about 10(8) cm-2. These pits are likely to be formed at point vacancies or atomic (impurity, for example) defects in the crystal lattice. As the proton flux was increased (over two orders of magnitude), these same etch pits were found to open into wider macro-pits, with an outline morphology that reflected the crystallographic orientation of the surface. At the highest proton fluxes, dissolution from macroscopic step edges became significant.


Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5'-flanking region.
The apolipoprotein(a) (apo[a]) gene encodes a protein component of lipoprotein(a) [Lp(a)] whose plasma levels vary widely among individuals. Hyper-Lp(a)-emia constitutes a risk factor for thromboembolic disease. We previously subclassified the apo(a) gene into four allelic types (A-D) by polymorphisms in the 5'-flanking region. To elucidate whether these polymorphisms affect the expression of apo(a), we measured plasma Lp(a) concentrations in vivo by ELISA and examined expression of the gene by an in vitro assay using its 5'-flanking region. Homozygotes of type C had significantly higher Lp(a) levels than those of type D. The relative expression of type C was also about three times higher than that of type D, which was consistent with the in vivo results. Deletion analysis revealed that the substitution of C by T (+93) led to negative regulation in expression of the gene, while the change of G to A (+121) led to positive regulation. These results indicate that the polymorphisms in the 5'-flanking region of the apo(a) gene affect the efficiency of its expression and, in part, play a role in regulating plasma Lp(a) levels.


Pharmacokinetic Analysis of a Novel Human EGFRvIII:CD3 Bispecific Antibody in Plasma and Whole Blood Using a High-Resolution Targeted Mass Spectrometry Approach.
Bispecific single chain antibody fragments (bi-scFv) represent an emerging class of biotherapeutics. We recently developed a fully human bi-scFv (EGFRvIII:CD3 bi-scFv) with the goal of redirecting CD3-expressing T cells to recognize and destroy malignant, EGFRvIII-expressing glioma. In mice, we showed that EGFRvIII:CD3 bi-scFv effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma. Here, we developed a targeted assay for pharmacokinetic (PK) analysis of EGFRvIII:CD3 bi-scFv, a necessary step in the drug development process. Using microflow liquid chromatography coupled to a high resolution parallel reaction monitoring mass spectrometry, and data analysis in Skyline, we developed a bottom-up proteomic assay for quantification of EGFRvIII:CD3 bi-scFv in both plasma and whole blood. Importantly, a protein calibrator, along with stable isotope-labeled EGFRvIII:CD3 bi-scFv protein, were used for absolute quantification. A PK analysis in a CD3 humanized mouse revealed that EGFRvIII:CD3 bi-scFv in plasma and whole blood has an initial half-life of ∼8 min and a terminal half-life of ∼2.5 h. Our results establish a sensitive, high-throughput assay for direct quantification of EGFRvIII:CD3 bi-scFv without the need for immunoaffinity enrichment. Moreover, these pharmacokinetic parameters will guide drug optimization and dosing regimens in future IND-enabling and phase I studies of EGFRvIII:CD3 bi-scFv.


A Novel, Web-Based Quality Improvement Platform to Address ACGME CLER Requirements.
In 2014, the Accreditation Council for Graduate Medical Education (ACGME) formally mandated trainee (resident and fellow) participation in health care quality improvement (QI) projects as one of the Clinical Learning Environment Review (CLER) Pathways to Excellence. Subsequent national reviews showed large variations in how QI education is conducted, as well as a significant mismatch between educational and organizational goals. We developed a web-based platform to engage trainees in QI that better aligned with best practice methodology and matched identified institutional priorities. A needs assessment survey was distributed to trainees to understand the obstacles to compliance with ACGME QI requirements. Based on the results, a web-based clearinghouse, called the QI Platform, was developed and launched in July 2016, and utilization was analyzed in February 2019. A total of 196 of 440 needs assessment surveys (45%) were completed. Themes extracted from surveys to identify barriers in QI participation included difficulties designing projects, lack of mentorship or expert support, and difficulty engaging an interprofessional team. Over 2.5 years, 151 projects were registered on the platform. Of these, 17 (11%) were collaborative entries. At the time of analysis, 166 of 437 trainees (38%) were listed as participants in active QI projects. A total of 22 projects were archived as complete, and 68 incomplete projects were reassigned to the "Ideas" section as works in progress after lead trainee graduation. An institutional QI Platform clearinghouse for GME QI projects was feasible to develop and maintain, and it appeared acceptable to most GME programs and trainees for recording and tracking QI projects, and linking these to hospital QI priorities.


The effects of long- or medium-chain fat diets on glucose tolerance and myocellular content of lipid intermediates in rats.
Accumulation of triacylglycerols (TAGs) and acylcarnitines in skeletal muscle upon high-fat (HF) feeding is the resultant of fatty acid uptake and oxidation and is associated with insulin resistance. As medium-chain fatty acids (MCFAs) are preferentially β-oxidized over long-chain fatty acids, we examined the effects of medium-chain TAGs (MCTs) and long-chain TAGs (LCTs) on muscle lipid storage and whole-body glucose tolerance. Rats fed a low-fat (LF), HFLCT, or an isocaloric HFMCT diet displayed a similar body weight gain over 8 weeks of treatment. Only HFLCT increased myocellular TAG (42.3 ± 4.9, 71.9 ± 6.7, and 48.5 ± 6.5 µmol/g for LF, HFLCT, and HFMCT, respectively, P < 0.05) and long-chain acylcarnitine content (P < 0.05). Neither HF diet increased myocellular diacylglycerol (DAG) content. Intraperitoneal (IP) glucose tolerance tests (1.5 g/kg) revealed a significantly decreased glucose tolerance in the HFMCT compared to the HFLCT-fed rats (802 ± 40, 772 ± 18, and 886 ± 18 area under the curve for LF, HFLCT, and HFMCT, respectively, P < 0.05). Finally, no differences in myocellular insulin signaling after bolus insulin injection (10 U/kg) were observed between LF, HFLCT, or HFMCT-fed rats. These results show that accumulation of TAGs and acylcarnitines in skeletal muscle in the absence of body weight gain do not impede myocellular insulin signaling or whole-body glucose intolerance.


Development of an Algorithm to Identify Cannabis Urine Drug Test Results within a Multi-Site Electronic Health Record System.
With the rapid changes in the legalization of cannabis in the U.S., there is an urgent need to understand clinical outcomes and processes of care among patients who use cannabis, particularly among patients with chronic pain who are high utilizers of cannabis. Electronic health records (EHRs) are a common and convenient mechanism for examining processes of care; however, there is not an indication for cannabis use that does not meet criteria for a diagnostic disorder. We used urine drug test (UDT) results identified through EHRs to identify patients with confirmed cannabis use. We developed and tested an algorithm to identify outcomes of UDT results for cannabis because there is wide variability in reporting methodology, including in multi-site health systems. Among all patients receiving care in the Department of Veterans Affairs (VA) who were prescribed long-term opioid therapy for chronic pain, we identified a random sample who completed UDT for cannabis. Through an iterative process, we developed an algorithm to identify UDT cannabis results. Manual review of EHR data was conducted to verify accuracy of UDT results. The final UDT algorithm correctly identified 99% of cannabis positive UDT results and 100% of cannabis negative UDT results among 200 randomly sampled patients. Study findings suggest a high degree of accuracy for using an algorithm to identify samples of patients with positive cannabis UDT results across multiple institutions with disparate UDT reporting practices. The methodology for testing this algorithm is feasible and may be applied to other multi-site health systems.


Electrolysis-driven bioremediation of crude oil-contaminated marine sediments.
Bioremediation is an effective technology to tackle crude oil spill disasters, which takes advantage of the capacity of naturally occurring microorganisms to degrade petroleum hydrocarbons under a range of environmental conditions. The enzymatic process of breaking down oil is usually more rapid in the presence of oxygen. However, in contaminated sediments, oxygen levels are typically too low to sustain the rapid and complete biodegradation of buried hydrocarbons. Here, we explored the possibility to electrochemically manipulate the redox potential of a crude oil-contaminated marine sediment in order to establish, in situ, conditions that are conducive to contaminants biodegradation by autochthonous microbial communities. The proposed approach is based on the exploitation of low-voltage (2V) seawater electrolysis to drive oxygen generation (while minimizing chlorine evolution) on Dimensionally Stable Anodes (DSA) placed within the contaminated sediment. Results, based on a laboratory scale setup with chronically polluted sediments spiked with crude oil, showed an increased redox potential and a decreased pH in the vicinity of the anode of 'electrified' treatments, consistent with the occurrence of oxygen generation. Accordingly, hydrocarbons biodegradation was substantially accelerated (up to 3-times) compared to 'non-electrified' controls, while sulfate reduction was severely inhibited. Intermittent application of electrolysis proved to be an effective strategy to minimize the energy requirements of the process, without adversely affecting degradation performance. Taken as a whole, this study suggests that electrolysis-driven bioremediation could be a sustainable technology for the management of contaminated sediments.


Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent.
We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.


Male demography in East Asia: a north-south contrast in human population expansion times.
The human population has increased greatly in size in the last 100,000 years, but the initial stimuli to growth, the times when expansion started, and their variation between different parts of the world are poorly understood. We have investigated male demography in East Asia, applying a Bayesian full-likelihood analysis to data from 988 men representing 27 populations from China, Mongolia, Korea, and Japan typed with 45 binary and 16 STR markers from the Y chromosome. According to our analysis, the northern populations examined all started to expand in number between 34 (18-68) and 22 (12-39) thousand years ago (KYA), before the last glacial maximum at 21-18 KYA, while the southern populations all started to expand between 18 (6-47) and 12 (1-45) KYA, but then grew faster. We suggest that the northern populations expanded earlier because they could exploit the abundant megafauna of the "Mammoth Steppe," while the southern populations could increase in number only when a warmer and more stable climate led to more plentiful plant resources such as tubers.


Preferences for Early Intervention Mental Health Services: A Discrete-Choice Conjoint Experiment.
Early intervention services (EISs) for mental illness may improve outcomes, although treatment engagement is often a problem. Incorporating patients' preferences in the design of interventions improves engagement. A discrete-choice conjoint experiment was conducted in Canada to identify EIS attributes that encourage treatment initiation. Sixteen four-level attributes were formalized into a conjoint survey, completed by patients, family members, and mental health professionals (N=562). Participants were asked which EIS option people with mental illness would contact. Latent-class analysis identified respondent classes characterized by shared preferences. Randomized first-choice simulations predicted which hypothetical options, based on attributes, would result in maximum utilization. Participants in the conventional-service class (N=241, 43%) predicted that individuals would contact traditional services (for example, hospital location and staffed by psychologists or psychiatrists). Membership was associated with being a patient or family member and being male. Participants in the convenient-service class (N=321, 57%) predicted that people would contact services promoting easy access (for example, self-referral and access from home). Membership was associated with being a professional. Both classes predicted that people would contact services that included short wait times, direct contact with professionals, patient autonomy, and psychological treatment information. The convenient-service class predicted that people would use an e-health model, whereas the conventional-service class predicted that people would use a primary care or clinic-hospital model. Provision of a range of services may maximize EIS use. Professionals may be more apt to adopt EISs in line with their beliefs regarding patient preferences. Considering several perspectives is important for service design.


Only six kingdoms of life.
There are many more phyla of microbes than of macro-organisms, but microbial biodiversity is poorly understood because most microbes are uncultured. Phylogenetic analysis of rDNA sequences cloned after PCR amplification of DNA extracted directly from environmental samples is a powerful way of exploring our degree of ignorance of major groups. As there are only five eukaryotic kingdoms, two claims using such methods for numerous novel 'kingdom-level' lineages among anaerobic eukaryotes would be remarkable, if true. By reanalysing those data with 167 known species (not merely 8-37), I identified relatives for all 8-10 'mysterious' lineages. All probably belong to one of five already recognized phyla (Amoebozoa, Cercozoa, Apusozoa, Myzozoa, Loukozoa) within the basal kingdom Protozoa, mostly in known classes, sometimes even in known orders, families or genera. This strengthens the idea that the ancestral eukaryote was a mitochondrial aerobe. Analogous claims of novel bacterial divisions or kingdoms may reflect the weak resolution and grossly non-clock-like evolution of ribosomal rRNA, not genuine phylum-level biological disparity. Critical interpretation of environmental DNA sequences suggests that our overall picture of microbial biodiversity at phylum or division level is already rather good and comprehensive and that there are no uncharacterized kingdoms of life. However, immense lower-level diversity remains to be mapped, as does the root of the tree of life.


Decline in Health-Related Quality of Life reported by more than half of those waiting for joint replacement surgery: a prospective cohort study.
In many healthcare systems, people with severe joint disease wait months to years for joint replacement surgery. There are little empirical data on the health consequences of this delay and it is unclear whether people with substantial morbidity at entry to the waiting list continue to deteriorate further while awaiting surgery. This study investigated changes in Health-Related Quality of Life (HRQoL), health status and psychological distress among people waiting for total hip (THR) and knee replacement (TKR) surgery at a major metropolitan Australian public hospital. 134 patients completed questionnaires including the Assessment of Quality of Life (AQoL) instrument, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kessler Psychological Distress Scale after entering an orthopaedic waiting list (baseline) and before surgery (preadmission). To quantify potential decline in wellbeing, we calculated the proportion of people experiencing clinically important deterioration using published guidelines and compared HRQoL and psychological distress outcomes with population norms. Most participants (69%) waited ≥6 months for surgery (median 286 days, IQR 169-375 days). Despite poor physical and psychological wellbeing at baseline, there was an overall deterioration in HRQoL during the waiting period (mean AQoL change -0.04, 95%CI -0.08 to -0.01), with 53% of participants experiencing decline in HRQoL (≥0.04 AQoL units). HRQoL prior to surgery remained substantially lower than Australian population norms (mean sample AQoL 0.37, 95%CI 0.33 to 0.42 vs mean population AQoL 0.83, 95%CI 0.82 to 0.84). Twenty-five per cent of participants showed decline in health status (≥9.6 WOMAC units) over the waiting period and prevalence of high psychological distress remained high at preadmission (RR 3.5, 95%CI 2.8 to 4.5). Most participants considered their pain (84%), fatigue (76%), quality of life (73%) and confidence in managing their health (55%) had worsened while waiting for surgery. Despite substantial initial morbidity, over half of the participants awaiting joint replacement experienced deterioration in HRQoL during the waiting period. These data provide much-needed evidence to guide health professionals and policymakers in the design of care pathways and resource allocation for people who require joint replacement surgery.


Benefits of Real-Time Continuous Glucose Monitoring in Pregnancy.
In recent years, continuous glucose monitoring (CGM) has become increasingly available with the introduction of devices that are specifically approved for use during pregnancy. Evidence in the form of randomized-controlled trials and cohort studies continues to build support for the use of CGM during pregnancy to improve measures of maternal glycemia as well as obstetric and neonatal outcomes. Based on data from the CGM in pregnant women with type 1 diabetes (CONCEPTT) trial alongside a Swedish cohort study of real-world outcomes of pregnant women with type 1 diabetes, the UK National Institute for Health and Clinical Excellence (NICE) guidelines now recommend that real-time CGM be offered to all pregnant women with type 1 diabetes. Based on these guidelines, all pregnant individuals in the United Kingdom with type 1 diabetes will receive government-funded real-time CGM for a 12-month duration. These guidelines are a game-changer and will continue to facilitate more widespread access to CGM use in the United Kingdom and beyond. This review describes the role of CGM in the management of diabetes in pregnancy, discusses contemporary maternal glucose levels and their relationship with outcomes in diabetes pregnancies, and examines the high-quality, randomized-controlled trial and the real-world clinical data evaluating the impact of CGM use.


Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.
A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer. We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events. The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. NCT02603341.


Postmortem protein degradation is a key contributor to fresh pork loin tenderness.
The objective of this study was to determine factors that influence tenderness independent of variation in pH, color, or marbling. To achieve the objective, 2 sample groups were chosen from a population of 159 pork loins aged 11 to 16 d. Predetermined ranges (ultimate pH, 5.54 to 5.86; marbling score, 1.0 to 3.0; percent total lipid, 1.61 to 3.37%) were defined for inclusion of individual loins in the study. The pork loins with the greatest ( = 12) and least ( = 12) Instron star probe values were assigned to 2 classification groups. The high star probe group had an average star probe that was 2.8 kg greater than the low star probe group (7.75 vs. 4.95 kg). Pork quality and sensory characteristics of pH, subjective and instrumental color values, cook loss, sensory tenderness, chewiness, juiciness, pork flavor, and off flavor were determined on fresh, never frozen pork chops. Lipid content, sarcomere length, myosin heavy-chain profile, and calpain autolysis were determined. Degradation of troponin-T, desmin, filamin, and titin were evaluated on the protein extracts from each sample. Pork loin pH, subjective color scores, Minolta L values, sarcomere length, and myosin heavy-chain composition were not different across groups. Chops from the low star probe group had a significantly greater marbling score (2.3 vs. 1.9) and lipid content (2.61 vs. 2.23%). Calpain-1 was completely autolyzed in both high and low star probe samples, demonstrating that calpain-1 potentially had been active in all samples. Low star probe whole-muscle protein extracts had more troponin-T ( < 0.01), desmin ( < 0.01), and filamin degradation ( < 0.01) than high star probe samples. Both classification groups showed degradation of titin. Remarkably, some high star probe samples still had observable intact bands of titin on SDS-PAGE gels. These results demonstrate that significant variation in instrumental tenderness is observed within a moderate pH range. Lipid content and proteolysis both appear to contribute to this variation.


A twist of nature--the significance of atropisomers in biological systems.
Recently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized.


Volume-controlled versus short drainage after inguinofemoral lymphadenectomy in vulvar cancer patients: A Dutch nationwide prospective study.
Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was <30ml/24h, except in the first 48h, and after a maximum of 28days (MAMBO-IA). In the second study, the drain was removed five days postoperatively regardless of production (MAMBO-IB). We assessed the complications within eight weeks after surgery using logistic regression to compare the incidence of one or more complications between the two drainage protocols, adjusting for possible confounders. We included 77 patients (139 groins) for volume-controlled drainage and 64 patients (112 groins) for short drainage. Volume-controlled drainage was associated with significant less lymphocele formation. Moreover, we found no difference in wound infection or primary wound breakdown. The estimated incidence of one or more complications was 46% per groin after volume-controlled drainage versus 75% after short drainage, (RD 29% (95% CI 8, 49) p=0.006). This prospective study shows that volume-controlled drainage is associated with significantly less complications compared to short drainage. We therefore recommend volume-controlled drainage after inguinofemoral lymphadenectomy in patients with vulvar squamous cell carcinoma.


The highly divergent Jekyll genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae.
Phylogenetically related groups of species contain lineage-specific genes that exhibit no sequence similarity to any genes outside the lineage. We describe here that the Jekyll gene, required for sexual reproduction, exists in two much diverged allelic variants, Jek1 and Jek3. Despite low similarity, the Jek1 and Jek3 proteins share identical signal peptides, conserved cysteine positions and direct repeats. The Jek1/Jek3 sequences are located at the same chromosomal locus and inherited in a monogenic Mendelian fashion. Jek3 has a similar expression as Jek1 and complements the Jek1 function in Jek1-deficient plants. Jek1 and Jek3 allelic variants were almost equally distributed in a collection of 485 wild and domesticated barley accessions. All domesticated barleys harboring the Jek1 allele belong to single haplotype J1-H1 indicating a genetic bottleneck during domestication. Domesticated barleys harboring the Jek3 allele consisted of three haplotypes. Jekyll-like sequences were found only in species of the closely related tribes Bromeae and Triticeae but not in other Poaceae. Non-invasive magnetic resonance imaging revealed intrinsic grain structure in Triticeae and Bromeae, associated with the Jekyll function. The emergence of Jekyll suggests its role in the separation of the Bromeae and Triticeae lineages within the Poaceae and identifies the Jekyll genes as lineage-specific.


Boosting Cognition: Effects of Multiple-Session Transcranial Direct Current Stimulation on Working Memory.
Transcranial direct current stimulation (tDCS) is a promising tool for neurocognitive enhancement. Several studies have shown that just a single session of tDCS over the left dorsolateral pFC (lDLPFC) can improve the core cognitive function of working memory (WM) in healthy adults. Yet, recent studies combining multiple sessions of anodal tDCS over lDLPFC with verbal WM training did not observe additional benefits of tDCS in subsequent stimulation sessions nor transfer of benefits to novel WM tasks posttraining. Using an enhanced stimulation protocol as well as a design that included a baseline measure each day, the current study aimed to further investigate the effects of multiple sessions of tDCS on WM. Specifically, we investigated the effects of three subsequent days of stimulation with anodal (20 min, 1 mA) versus sham tDCS (1 min, 1 mA) over lDLPFC (with a right supraorbital reference) paired with a challenging verbal WM task. WM performance was measured with a verbal WM updating task (the letter n-back) in the stimulation sessions and several WM transfer tasks (different letter set n-back, spatial n-back, operation span) before and 2 days after stimulation. Anodal tDCS over lDLPFC enhanced WM performance in the first stimulation session, an effect that remained visible 24 hr later. However, no further gains of anodal tDCS were observed in the second and third stimulation sessions, nor did benefits transfer to other WM tasks at the group level. Yet, interestingly, post hoc individual difference analyses revealed that in the anodal stimulation group the extent of change in WM performance on the first day of stimulation predicted pre to post changes on both the verbal and the spatial transfer task. Notably, this relationship was not observed in the sham group. Performance of two individuals worsened during anodal stimulation and on the transfer tasks. Together, these findings suggest that repeated anodal tDCS over lDLPFC combined with a challenging WM task may be an effective method to enhance domain-independent WM functioning in some individuals, but not others, or can even impair WM. They thus call for a thorough investigation into individual differences in tDCS respondence as well as further research into the design of multisession tDCS protocols that may be optimal for boosting cognition across a wide range of individuals.


Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery.
The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data.


The development of grasping comprehension in infancy: covert shifts of attention caused by referential actions.
An eye tracking paradigm was used to investigate how infants' attention is modulated by observed goal-directed manual grasping actions. In Experiment 1, we presented 3-, 5-, and 7-month-old infants with a static picture of a grasping hand, followed by a target appearing at a location either congruent or incongruent with the grasping direction of the hand. The latency of infants gaze shift from the hand to the target was recorded and compared between congruent and incongruent trials. Results demonstrate a congruency effect from 5 months of age. A second experiment illustrated that the congruency effect of Experiment 1 does not extend to a visually similar mechanical claw (instead of the grasping hand). Together these two experiments describe the onset of covert attention shifts in response to manual actions and relate these findings to the onset of manual grasping.


Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairments in memory and cognition. Extracellular accumulation of soluble high-molecular-weight (HMW) Abeta oligomers has been proposed to be largely responsible for AD dementia and memory deficits in the Tg2576 mice, a model of AD. In this study, we found that a naturally derived grape seed polyphenolic extract can significantly inhibit amyloid beta-protein aggregation into high-molecular-weight oligomers in vitro. When orally administered to Tg2576 mice, this polyphenolic preparation significantly attenuates AD-type cognitive deterioration coincidentally with reduced HMW soluble oligomeric Abeta in the brain. Our study suggests that grape seed-derived polyphenolics may be useful agents to prevent or treat AD.


Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex.
A puzzling feature of the neocortex is the rich array of inhibitory interneurons. Multiple neuron recordings revealed numerous electrophysiological-anatomical subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons and three types of GABAergic synapses. The type of synapse used by each interneuron to influence its neighbors follows three functional organizing principles. These principles suggest that inhibitory synapses could shape the impact of different interneurons according to their specific spatiotemporal patterns of activity and that GABAergic interneuron and synapse diversity may enable combinatorial inhibitory effects in the neocortex.


Drug-induced expression of EpCAM contributes to therapy resistance in esophageal adenocarcinoma.
With a less than 5% overall survival rate, esophageal adenocarcinoma (EAC) is one of the leading causes of death in the United States. Epithelial cell adhesion molecule (EpCAM) is a cancer stem cell (CSC) marker that is expressed in various epithelial carcinomas, including EAC. Accumulating evidence indicates that CSC subpopulations can initiate cancer development and, in addition, drive metastasis, recurrence and drug resistance. It has also been reported that EpCAM up-regulation in EAC may lead to an aggressive behavior and, thus, an adverse clinical outcome. Here, we aimed to determine whether treatment with standard chemotherapeutic agents may induce EpCAM expression and, concomitantly, increases in malignant potential and drug resistance in EAC. EpCAM expression was assessed in 20 primary human EAC/adjacent normal tissues, as well as in a human EAC-derived cell line (OE-19), in a pre-malignant Barrett's Esophagus cell line (Bar-T) and in a benign esophageal cell line (HET 1-A), using immunohistochemistry, Western blotting and qRT-PCR, respectively. Drug-induced resistance was investigated in OE-19-derived spheres treated with (a combination of) adriamycin, cisplatin and 5-fluorouracil (ACF) using survival, adhesion and flow cytometric assays, respectively, and compared to drug resistance induced by standard chemotherapeutic agents (CTA). Finally, ACF treatment-surviving cells were evaluated for their tumor forming capacities both in vitro and in vivo using spheroid formation and xenograft assays, respectively. High EpCAM expression was observed in esophageal cancer tissues and esophageal cancer-derived cell lines, but not in adjacent benign esophageal epithelia and benign esophageal cell lines (HET 1-A and Bar-T). The OE-19 cell spheres were drug resistant and EpCAM expression was significantly induced in the OE-19 cell spheres compared to the non-sphere OE-19 cells. When OE-19 cell spheres were challenged with ACF, the EpCAM mRNA and protein levels were further up-regulated up to 48 h, whereas a decreased EpCAM expression was observed at 72 h. EpCAM down-regulation by RNA interference increased the ACF efficacy to kill OE-19 cells. Increased EpCAM expression coincided with the CSC marker CD90 and was associated with an aggressive growth pattern of OE-19 cell spheres in vivo. From our data we conclude that an ACF-induced increase in EpCAM expression reflects the selection of a CSC subpopulation that underlies tumor development and drug resistance in EAC.


Hydrogen-rich saline attenuated neuropathic pain by reducing oxidative stress.
Reactive oxygen species (ROS) are often associated with persistent pains such as neuropathic and inflammatory pain. Hydrogen gas can reduce ROS and alleviate cerebral, myocardial, and hepatic ischemia/reperfusion injuries. In the present study, we aim to investigate whether hydrogen-rich saline can reduce neuropathic pain in a rat model of chronic constriction injury (CCI). Thirty SD rats were randomly divided into three groups: sham group was administered sodium chloride by intrathecal injection (n=10); control groups underwent CCI surgery and were administered sodium chloride by intrathecal injection (n=10); vehicle group underwent CCI surgery and was administered hydrogen-rich saline by intrathecal injection (n=10). Drugs were administered in the dose of 100 ul/kg once a day at 0.5 hours before and 1-7 day after CCI surgery. The mechanical thresholds were tested at one day before and 3-14 day after CCI surgery. We found that hydrogen-rich saline significantly elevated the mechanical thresholds of neuropathic pain compared to vehicle (physiologic saline) control in CCI rats (p<0.05); it also decreased the levels of myeloperoxidase, maleic dialdehyde, and protein carbonyl in spinal cord by 7 days post-chronic constriction injury(p<0.05). In addition, hydrogen-rich saline also suppressed the expression of p38-mitogen-activated protein kinase (p38MAPK) and brain-derived neurotrophic factor (BDNF) in the spinal cord by 7 days post-chronic constriction injury (p<0.01, p<0.01, respectively), but had no effect on P2X4R (p>0.05), an ATP receptor. Intrathecal injection of hydrogen-rich saline can decrease oxidative stress and the expression of p38MAPK and BDNF that may contribute to the elevated threshold of neuropathic pain in rat CCI model. Le salin riche en hydrogène atténue la douleur névropathique en réduisant le stress oxydatif.


A retrospective analysis of 22 patients treated with percutaneous radiofrequency nerve ablation for prolonged moderate to severe heel pain associated with plantar fasciitis.
A retrospective study involving 22 patients (31 feet) with a history of prolonged moderate to severe heel pain associated with plantar fasciitis were examined to determine if ablation of the sensory branch of the medial calcaneal nerve would result in symptomatic relief. Participants in this study were given subjective questionnaires and visual analog scales in order to rate their symptoms before and after nerve ablation using radiofrequency energy. The results showed that the mean preintervention visual analog pain score was 8.12 +/- 1.61 (with 10 being the worst pain the patient could imagine), and this dropped to 3.26 +/- 1.97 after 1 week and 1.46 +/- 1.76 after 1 month, 1.96 +/- 1.98 at 3 months, and 2.07 +/- 2.06 at 6 months, and the improvement was statistically significant (P < .001) at each stage of follow-up. Furthermore, patients followed for up to 1 year showed no significant worsening of symptoms. Adverse events were limited to hematoma at the site of entry of the radiofrequency cannula. These findings support the conclusion that radiofrequency nerve ablation be considered an alternative to repetitive corticosteroid injections or open surgical intervention for the treatment of recalcitrant plantar heel pain. 4.


Novel exons and splice variants in the human antibody heavy chain identified by single cell and single molecule sequencing.
Antibody heavy chains contain a variable and a constant region. The constant region of the antibody heavy chain is encoded by multiple groups of exons which define the isotype and therefore many functional characteristics of the antibody. We performed both single B cell RNAseq and long read single molecule sequencing of antibody heavy chain transcripts and were able to identify novel exons for IGHA1 and IGHA2 as well as novel isoforms for IGHM antibody heavy chain.


Cloned mouse cells with natural killer function and cloned suppressor T cells express ultrastructural and biochemical features not shared by cloned inducer T cells.
We have examined the morphology, cytochemistry, and biochemistry of mouse leukocyte subsets by analyzing cloned leukocyte populations specialized to perform different immunologic functions. Cloned cells expressing high-affinity plasma membrane receptors for IgE and mediating natural killer (NK) lysis and cloned antigen-specific suppressor T cells contained prominent osmiophilic cytoplasmic granules similar by ultrastructure to those of mouse basophils. Both clones also incorporated 35SO4 into granule-associated sulfated glycosaminoglycans, expressed a characteristic ultrastructural pattern of nonspecific esterase activity, incorporated exogenous [3H]5-hydroxytryptamine, and contained cytoplasmic deposits of particulate glycogen. By contrast, cloned inducer T cells lacked cytoplasmic granules and glycogen, incorporated neither 35SO4 nor [3H]5-hydroxytryptamine, and differed from the other clones in pattern of nonspecific esterase activity. These findings establish that certain cloned cells with NK activity and cloned suppressor T cells express morphologic and biochemical characteristics heretofore associated with basophilic granulocytes. However, these clones differ in surface glycoprotein expression and immunologic function, and the full extent of the similarities and differences among these populations and basophils remains to be determined.


Cardiac and metabolic effects of hypothermia and inhaled hydrogen sulfide in anesthetized and ventilated mice.
To test the hypothesis whether inhaled hydrogen sulfide amplifies the effects of deliberate hypothermia during anesthesia and mechanical ventilation as hypothermia is used to provide organ protection after brain trauma or circulatory arrest. Awake mice inhaling hydrogen sulfide exhibit reduced energy expenditure, hypothermia, and bradycardia despite unchanged systolic heart function. In rodents, anesthesia alone causes decreased metabolic rate and thus hypothermia and bradycardia. Prospective, controlled, randomized study. University animal research laboratory. Male C57/B6 mice. After surgical instrumentation (central venous, left ventricular pressure-conductance catheters, ultrasound flow probes on the portal vein and superior mesenteric artery), normo- or hypothermic animals (core temperature = 38 degrees C and 27 degrees C) received either 100 ppm hydrogen sulfide or vehicle over 5 hrs (3 hrs hydrogen sulfide during normothermia). During normothermia, hydrogen sulfide had no hemodynamic or metabolic effect. With or without hydrogen sulfide, hypothermia decreased blood pressure, heart rate, and cardiac output, whereas stroke volume, ejection fraction, and end-diastolic pressure remained unaffected. Myocardial and hepatic oxidative deoxyribonucleic acid damage (comet assay) and endogenous glucose production (rate of appearance of 1,2,3,4,5,6-13C6-glucose) were similar in all groups. Hypothermia comparably decreased CO2 production with or without inhaled hydrogen sulfide. During hypothermia, inhaled hydrogen sulfide increased the glucose oxidation rate (derived from the expiratory 13CO2/12CO2 ratio). This shift toward preferential carbohydrate utilization coincided with a significantly attenuated responsiveness of hepatic mitochondrial respiration to stimulation with exogenous cytochrome-c-oxidase (high-resolution respirometry). In anesthetized and mechanically ventilated mice, inhaled hydrogen sulfide did not amplify the systemic hemodynamic and cardiac effects of hypothermia alone. The increased aerobic glucose oxidation together with the reduced responsiveness of cellular respiration to exogenous cytochrome-c stimulation suggest that, during hypothermia, inhaled hydrogen sulfide improved the yield of mitochondrial respiration, possibly via the maintenance of mitochondrial integrity. Hence, inhaled hydrogen sulfide may offer metabolic benefit during therapeutic hypothermia.


Leakless end-to-end transport of small molecules through micron-length DNA nanochannels.
Designed and engineered protein and DNA nanopores can be used to sense and characterize single molecules and control transmembrane transport of molecular species. However, designed biomolecular pores are less than 100 nm in length and are used primarily for transport across lipid membranes. Nanochannels that span longer distances could be used as conduits for molecules between nonadjacent compartments or cells. Here, we design micrometer-long, 7-nm-diameter DNA nanochannels that small molecules can traverse according to the laws of continuum diffusion. Binding DNA origami caps to channel ends eliminates transport and demonstrates that molecules diffuse from one channel end to the other rather than permeating through channel walls. These micrometer-length nanochannels can also grow, form interconnects, and interface with living cells. This work thus shows how to construct multifunctional, dynamic agents that control molecular transport, opening ways of studying intercellular signaling and modulating molecular transport between synthetic and living cells.


EEG Single-Trial Detection of Gait Speed Changes during Treadmill Walk.
In this study, we analyse the electroencephalography (EEG) signal associated with gait speed changes (i.e. acceleration or deceleration). For data acquisition, healthy subjects were asked to perform volitional speed changes between 0, 1, and 2 Km/h, during treadmill walk. Simultaneously, the treadmill controller modified the speed of the belt according to the subject's linear speed. A classifier is trained to distinguish between the EEG signal associated with constant speed gait and with gait speed changes, respectively. Results indicate that the classification performance is fair to good for the majority of the subjects, with accuracies always above chance level, in both batch and pseudo-online approaches. Feature visualisation and equivalent dipole localisation suggest that the information used by the classifier is associated with increased activity in parietal areas, where mu and beta rhythms are suppressed during gait speed changes. Specifically, the parietal cortex may be involved in motor planning and visuomotor transformations throughout the online gait adaptation, which is in agreement with previous research. The findings of this study may help to shed light on the cortical involvement in human gait control, and represent a step towards a BMI for applications in post-stroke gait rehabilitation.


Role of [Ca(2+)]i and F-actin on mesothelial barrier function.
The mesothelial layer acts as a biological barrier between the organ and the enveloping serous cavity and may have functions of transport, equilibrium maintenance, and protection. However, the role of the mesothelial cells in regulation of pleural permeability remains essentially undefined. The present study was designed to clarify the effects of bradykinin, histamine, and thrombin on permeability in pleural mesothelial cells. Rat pleural mesothelial cells were cultured in vitro, and the permeability of mesothelial monolayers was evaluated by transmesothelial albumin diffusion and electrical resistance measurements. Furthermore, the temporal relationship between changes in the levels of [Ca(2+)]i and the mesothelial permeability was examined. Bradykinin (10 μM), histamine (1 mM), and thrombin (10 U) caused albumin diffusion within 5 min. The electrical resistance of mesothelial monolayer began falling within 5 min of adding each agent. Time and concentration dependency of changes in electrical resistance were almost the same as that in albumin diffusion. Each agent also induced a biphasic elevation of [Ca(2+)]i in pleural mesothelial cells. The concentration-dependency of the [Ca(2+)]i responses were almost similar to that noted for each agent induced albumin diffusion and electrical resistance fall. The increase in permeability occurred with reorganization of F-actin cytoskeleton and increased actin polymerization. These results suggest that the Ca(2+)- dependency of increases induced by these agents in mesothelial permeability have been related to the regulatory role of Ca(2+) in the F-actin cytoskeletal reorganization in pleural mesothelial cells.


Direct measurements of collagen fiber recruitment in the posterior pole of the eye.
Collagen is the main load-bearing component of the peripapillary sclera (PPS) and lamina cribrosa (LC) in the eye. Whilst it has been shown that uncrimping and recruitment of the PPS and LC collagen fibers underlies the macro-scale nonlinear stiffening of both tissues with increased intraocular pressure (IOP), the uncrimping and recruitment as a function of local stretch have not been directly measured. This knowledge is crucial to understanding their functions in bearing loads and maintaining tissue integrity. In this project we measured local stretch-induced collagen fiber bundle uncrimping and recruitment curves of the PPS and LC. Thin coronal samples of PPS and LC of sheep eyes were mounted and stretched biaxially quasi-statically using a custom system. At each step, we imaged the PPS and LC with instant polarized light microscopy and quantified pixel-level (1.5 μm/pixel) collagen fiber orientations. We used digital image correlation to measure the local stretch and quantified collagen crimp by the circular standard deviation of fiber orientations, or waviness. Local stretch-recruitment curves of PPS and LC approximated sigmoid functions. PPS recruited more fibers than the LC at the low levels of stretch. At 10% stretch the curves crossed with 75% bundles recruited. The PPS had higher uncrimping rate and waviness remaining after recruitment than the LC: 0.9º vs. 0.6º and 3.1º vs. 2.7º. Altogether our findings support describing fiber recruitment of both PPS and LC with sigmoid curves, with the PPS recruiting faster and at lower stretch than the LC, consistent with a stiffer tissue. STATEMENT OF SIGNIFICANCE: Peripapillary sclera (PPS) and lamina cribrosa (LC) collagen recruitment behaviors are central to the nonlinear mechanical behavior of the posterior pole of the eye. How PPS and LC collagen fibers recruit under stretch is crucial to develop constitutive models of the tissues but remains unclear. We used image-based stretch testing to characterize PPS and LC collagen fiber bundle recruitment under local stretch. We found that fiber-level stretch-recruitment curves of PPS and LC approximated sigmoid functions. PPS recruited more fibers at a low stretch, but at 10% bundle stretch the two curves crossed with 75% bundles recruited. We also found that PPS and LC fibers had different uncrimping rates and non-zero waviness's when recruited.


A novel prospective three-dimensional analysis of nasolabial fold augmentation.
There are many products approved for aesthetic soft tissue augmentation. Despite this abundance, there is limited objective data regarding safety, longevity, and complication rates. Instead, most reports rely on subjective measures to report volume changes and outcomes, making product comparison difficult. The authors developed and validated a mathematical model to prospectively calculate and analyze three-dimensional (3D) volumetric changes associated with nasolabial fold augmentation based on human acellular dermis. Seven consecutive patients were included in this prospective review. The patients underwent nasolabial fold treatment with BellaDerm (Musculoskeletal Transplant Foundation, Edison, NJ), administered by a single surgeon. 3D photographs were obtained and analyzed with a novel mathematical model to determine absolute volumetric changes and objective longevity. Mean preoperative nasolabial fold volume was 0.17 mL. The mean one-, three-, and six-month postoperative fill volumes were 0.35, 0.19, and 0.07 mL, respectively. Fill volumes and contour changes returned to baseline by 24 weeks postoperatively in the majority of patients. The mathematical model utilized in this study provided prospective and objective data regarding longevity and volumetric changes associated with nasolabial fold augmentation. The analysis demonstrated minimal objective filler permanence beyond six months, with peak volume enhancement between one and three months. Adoption of objective 3D mathematical metrics into the assessment of soft tissue filler outcomes is critical to obtaining more accurate product-to-product comparisons.


Seafood intake and the development of obesity, insulin resistance and type 2 diabetes.
We provide an overview of studies on seafood intake in relation to obesity, insulin resistance and type 2 diabetes. Overweight and obesity development is for most individuals the result of years of positive energy balance. Evidence from intervention trials and animal studies suggests that frequent intake of lean seafood, as compared with intake of terrestrial meats, reduces energy intake by 4-9 %, sufficient to prevent a positive energy balance and obesity. At equal energy intake, lean seafood reduces fasting and postprandial risk markers of insulin resistance, and improves insulin sensitivity in insulin-resistant adults. Energy restriction combined with intake of lean and fatty seafood seems to increase weight loss. Marine n-3 PUFA are probably of importance through n-3 PUFA-derived lipid mediators such as endocannabinoids and oxylipins, but other constituents of seafood such as the fish protein per se, trace elements or vitamins also seem to play a largely neglected role. A high intake of fatty seafood increases circulating levels of the insulin-sensitising hormone adiponectin. As compared with a high meat intake, high intake of seafood has been reported to reduce plasma levels of the hepatic acute-phase protein C-reactive protein level in some, but not all studies. More studies are needed to confirm the dietary effects on energy intake, obesity and insulin resistance. Future studies should be designed to elucidate the potential contribution of trace elements, vitamins and undesirables present in seafood, and we argue that stratification into responders and non-responders in randomised controlled trials may improve the understanding of health effects from intake of seafood.


Contrast gain control in mouse auditory cortex.
The neocortex is thought to employ a number of canonical computations, but little is known about whether these computations rely on shared mechanisms across different neural populations. In recent years, the mouse has emerged as a powerful model organism for the dissection of the circuits and mechanisms underlying various aspects of neural processing and therefore provides an important avenue for research into putative canonical computations. One such computation is contrast gain control, the systematic adjustment of neural gain in accordance with the contrast of sensory input, which helps to construct neural representations that are robust to the presence of background stimuli. Here, we characterized contrast gain control in the mouse auditory cortex. We performed laminar extracellular recordings in the auditory cortex of the anesthetized mouse while varying the contrast of the sensory input. We observed that an increase in stimulus contrast resulted in a compensatory reduction in the gain of neural responses, leading to representations in the mouse auditory cortex that are largely contrast invariant. Contrast gain control was present in all cortical layers but was found to be strongest in deep layers, indicating that intracortical mechanisms may contribute to these gain changes. These results lay a foundation for investigations into the mechanisms underlying contrast adaptation in the mouse auditory cortex. NEW & NOTEWORTHY We investigated whether contrast gain control, the systematic reduction in neural gain in response to an increase in sensory contrast, exists in the mouse auditory cortex. We performed extracellular recordings in the mouse auditory cortex while presenting sensory stimuli with varying contrasts and found this form of processing was widespread. This finding provides evidence that contrast gain control may represent a canonical cortical computation and lays a foundation for investigations into the underlying mechanisms.


HER2 (c-erbB-2) oncoprotein expression in colorectal adenocarcinoma: an immunohistological study using three different antibodies.
Paraffin wax sections of 70 surgically resected colorectal adenocarcinomas were examined for the overexpression of HER2/c-erbB-2 oncoprotein using three different specific antibodies and the avidin-biotin immunoperoxidase technique. The patients included 38 men and 32 women aged between 47 and 80 years. The tumours were derived from various parts of the large intestinal tract, and represented all three stages of Dukes' classification and the three histological grades of differentiation. Many tumour sections also included adjacent normal or transitional mucosa. Eight tubular adenomas found in the colectomy specimens in association with some carcinomas were also examined. No positive membrane staining was seen in any of the 70 carcinomas, four adenomas, two hyperplastic polyps, nor in the adjacent normal or transitional mucosa. It is suggested that the overexpression of c-erbB-2 gene product is unlikely to be as common and as pronounced in colorectal adenocarcinoma as it is in ductal carcinoma of the breast.


Clinical practice guideline: red blood cell transfusion in adult trauma and critical care.
To develop a clinical practice guideline for red blood cell transfusion in adult trauma and critical care. Meetings, teleconferences and electronic-based communication to achieve grading of the published evidence, discussion and consensus among the entire committee members. This practice management guideline was developed by a joint taskforce of EAST (Eastern Association for Surgery of Trauma) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM). We performed a comprehensive literature review of the topic and graded the evidence using scientific assessment methods employed by the Canadian and U.S. Preventive Task Force (Grading of Evidence, Class I, II, III; Grading of Recommendations, Level I, II, III). A list of guideline recommendations was compiled by the members of the guidelines committees for the two societies. Following an extensive review process by external reviewers, the final guideline manuscript was reviewed and approved by the EAST Board of Directors, the Board of Regents of the ACCM and the Council of SCCM. Key recommendations are listed by category, including (A) Indications for RBC transfusion in the general critically ill patient; (B) RBC transfusion in sepsis; (C) RBC transfusion in patients at risk for or with acute lung injury and acute respiratory distress syndrome; (D) RBC transfusion in patients with neurologic injury and diseases; (E) RBC transfusion risks; (F) Alternatives to RBC transfusion; and (G) Strategies to reduce RBC transfusion. Evidence-based recommendations regarding the use of RBC transfusion in adult trauma and critical care will provide important information to critical care practitioners.


Genetic heterogeneity and population structure in eastern India: red cell enzyme variability in ten Assamese populations.
This paper is a part of the genetic study of the people of Assam (eastern India), initiated by the Anthropometry and Human Genetics Unit, Indian Statistical Institute, Calcutta, India, and the Dept. of Human Biology/Physical Anthropology, University of Bremen, W. Germany. The results of 1. allele distribution of five red cell enzyme polymorphisms in ten Assamese populations, 2. heterogeneity of allele frequencies and extent of gene differentiation among these populations, and 3. standard genetic distances are presented here. A total of 1024 blood samples was screened for aP, E D, AK, ADA and LDH enzyme systems for Brahmins, Kalitas, Kaibartas, Rajbanshis, Muslims, Ahoms, Chutiyas, Kacharis, Karbis (Mikirs) and Sonowals, of which the latter three are tribes. The gene diversity (FST) is smallest (0.0035) for pa and highest (0.1604) for HbE. The total FST value (0.0399 +/- 0.0141) appears to be statistically significant. From distance analysis two major clusters with sub-clusters in each are visible, which are in conformity with the ethnohistory of these populations.


The 'morbid anatomy' of the human genome: tracing the observational and representational approaches of postwar genetics and biomedicine the William Bynum Prize Essay.
This paper explores evolving conceptions and depictions of the human genome among human and medical geneticists during the postwar period. Historians of science and medicine have shown significant interest in the use of informational approaches in postwar genetics, which treat the genome as an expansive digital data set composed of three billion DNA nucleotides. Since the 1950s, however, geneticists have largely interacted with the human genome at the microscopically visible level of chromosomes. Mindful of this, I examine the observational and representational approaches of postwar human and medical genetics. During the 1970s and 1980s, the genome increasingly came to be understood as, at once, a discrete part of the human anatomy and a standardised scientific object. This paper explores the role of influential medical geneticists in recasting the human genome as being a visible, tangible, and legible entity, which was highly relevant to traditional medical thinking and practice. I demonstrate how the human genome was established as an object amenable to laboratory and clinical research, and argue that the observational and representational approaches of postwar medical genetics reflect, more broadly, the interdisciplinary efforts underlying the development of contemporary biomedicine.