Increased cerebrovascular resistance after retrograde cerebral perfusion: a Doppler study.
Deep hypothermic circulatory arrest (DHCA) with retrograde cerebral perfusion (RCP) under high central venous pressure (CVP) is often used in aortic arch surgery under cardiopulmonary bypass (CPB). We hypothesized that DHCA with RCP under high CVP causes cerebral vascular compression because of increased perivascular pressure due to extravasation of fluid into intracranial tissue. In a retrospective study, we evaluated the pulsatility index (PI) and resistance index (RI) of the internal carotid arteries (ICA) and external carotid arteries (ECA) before and after CPB in 15 patients who underwent DHCA/RCP (group 1) and 17 patients who underwent regular CPB without DHCA/RCP (group 2). Both indices are known to reflect vascular resistance distal to the measurement point. The PI and RI of the ICA increased significantly after the procedure in group 1 but did not change in group 2. The PI and RI of the ECA did not change in either group. In group 1, the rate of increase in PI and RI correlated with the duration of RCP, which was significantly higher in patients who had postoperative delirium than in patients who did not experience postoperative delirium. As increases in PI/RI after DHCA/RCP occurred only in the ICA, we concluded that the changes were due to compression of vessels as a result of increased perivascular pressure. The greater increase in the PI/RI in patients who experienced postoperative delirium indicates that increased perivascular pressure plays a role in the occurrence of postoperative delirium after DHCA/RCP.


Towards a sexual ethics of rights and responsibilities.
Sexual rights as human rights encompass individual freedoms and social entitlements. Both depend for their realisation on equally important social responsibilities on the part of individuals, couples, families, other social institutions, and the State. The principle that all persons must understand their own sexual rights and responsibilities and respect the equal rights of others - particularly those of their sexual partners - informs our interpretation of the ethical basis of sexual behaviours. We propose a conceptual framework for defining a sexual ethics of equal rights and responsibilities pertaining to five dimensions of sexual behaviour: 1) sexual relationships and the right to choose one's partner; 2) sexual expression and the right to seek pleasure; 3) sexual consequences and the right to cooperation from one's partner; 4) sexual harm and the right to protection; and 5) sexual health and the right to information, education and health services. We suggest that the ethical principles presented here pertaining to sexual partnerships should be incorporated into sexuality education, sexual and reproductive health services, and social policies aimed at promoting the health and rights of all persons regardless of gender, marital status, sexual orientation, religion, ethnicity and other personal or group identities.


Antimicrobial resistance: a complex issue.
The discovery of antibiotics represented a turning point in human history. However, by the late 1950s infections that were difficult to treat, involving resistant bacteria, were being reported. Nowadays, multiresistant strains have become a major concern for public and animal health. Antimicrobial resistance is a complex issue, linked to the ability of bacteria to adapt quickly to their environment. Antibiotics, and antimicrobial-resistant bacteria and determinants, existed before the discovery and use of antibiotics by humans. Resistance to antimicrobial agents is a tool that allows bacteria to survive in the environment, and to develop. Resistance genes can be transferred between bacteria by horizontal transfer involving three mechanisms: conjugation, transduction and transformation. Resistant bacteria can emerge in any location when the appropriate conditions develop. Antibiotics represent a powerful selector for antimicrobial resistance in bacteria. Reducing the use of antimicrobial drugs is one way to control antimicrobial resistance; however, a full set of measures needs to be implemented to achieve this aim.


The heat-shock protein-70-induced renoprotective effect is partially mediated by CD4+ CD25+ Foxp3 + regulatory T cells in ischemia/reperfusion-induced acute kidney injury.
Recent reports suggest the presence of heat-shock protein (HSP)-reactive T cells with a regulatory phenotype in various inflammatory diseases. To test whether HSP exerts renoprotective effects through regulatory T cells (Tregs), ischemia/reperfusion injury was done with or without heat preconditioning in mice. Splenocytes from heat-preconditioned mice had Treg expansion and a reduced proliferative response upon mitogenic stimulus. T cells from heat-preconditioned mice failed to reconstitute postischemic injury when adoptively transferred to T cell-deficient nu/nu mice in contrast to those from control mice. Tregs were also increased in heat-preconditioned ischemic kidneys. Depleting Tregs before heat preconditioning abolished the renoprotective effect, while adoptive transfer of these cells back into Treg-depleted mice partially restored the beneficial effect of heat preconditioning. Inhibition of HSP70 by quercetin suppressed Treg expansion, as well as renoprotective effects. Transferring Tregs in quercetin-treated heat-preconditioned mice partially restored the beneficial effect of heat preconditioning. The specificity of immune cell HSP70 in renoprotection was confirmed by partial restoration of kidney injury when T cells from HSP70-deficient heat preconditioned mice were adoptively transferred to nu/nu mice. Thus, the renoprotective effect of HSP70 may be partially mediated by a direct immunomodulatory effect through Tregs. Better understanding of immunomodulatory mechanisms of various stress proteins might facilitate discovery of new preventive strategies in acute kidney injury.


Sporotrichoid lymphocutaneous infections: etiology, diagnosis and therapy.
Sporotrichoid lymphocutaneous infection is an uncommon syndrome that is often misdiagnosed and improperly treated. Of the several hundred cases seen each year in the United States, the majority are caused by Sporothrix schenckii, Nocardia brasiliensis, Mycobacterium marinum or Leishmania brasiliensis. The "sporotrichoid" disease begins at a site of distal inoculation and leads to the development of nodular lymphangitis. Systemic symptoms are characteristically absent. By recognizing the distinct pattern of nodular lymphangitis and focusing on the diverse but limited etiologies, the physician can obtain the appropriate histologic and microbiologic studies and start targeted antimicrobial therapy. Therapy is generally continued for two to three months after the resolution of cutaneous disease.


Early lunar magnetism.
It is uncertain whether the Moon ever formed a metallic core or generated a core dynamo. The lunar crust and returned samples are magnetized, but the source of this magnetization could be meteoroid impacts rather than a dynamo. Here, we report magnetic measurements and 40Ar/39Ar thermochronological calculations for the oldest known unshocked lunar rock, troctolite 76535. These data imply that there was a long-lived field on the Moon of at least 1 microtesla approximately 4.2 billion years ago. The early age, substantial intensity, and long lifetime of this field support the hypothesis of an ancient lunar core dynamo.


EVAR: critical applied aortic morphology relevant to type-II endoleaks following device enhancement in patients with abdominal aortic aneurysms.
Endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) is an established alternative option to conventional surgery for AAA, provided optimal anatomical morphology of the aneurysm sac, neck and outflow exists. In most documented series of EVAR, type-II endoleak occurrence is a universal procedural drawback. This is referred to as the Achilles heel of EVAR. This morphological study, addressing predominantly non-aneurysmal aortic anatomy, reveals the dyssynchronous origins of the renal ostia, ectopia of the superior mesenteric artery and median sacral artery, variations in the length of the infrarenal abdominal aorta, multiple mainstem renal arteries, and the presence of accessory renal arteries (in 13% of cadavers). Such potential vascular anomalies need careful consideration pre-operatively prior to EVAR. In a prospective, clinical study of EVAR in 163 patients over 60 months, using four different aortic stent devices, we demonstrated an intraprocedural type-II endoleak rate, before exclusion, of 3% (5/163). Most were related to patent lumbar arteries. An active policy of intraprocedural aneurysm pressure sac measurement and angiography was used to demonstrate type-I and type-II endoleaks, focusing on the applied anatomy of aortic side branches and variations. Selective intraprocedural coil embolisation and thrombin injection into the sac was utilised to thrombose persisting and large lumbar arteries that predisposed to retroleaks. We recorded a low incidence of persisting type-II endoleaks using this proactive treatment strategy by addressing variant aortic morphology and patent lumbar arteries during EVAR. One aneurysm-related death (0.6%) was observed due to late rupture after EVAR, and a single intraprocedural death was related to unpredictable aneurysm rupture. In conclusion, comprehensive anatomical knowledge of the abdominal aorta and its main collateral side branches, including variations, is a fundamental prerequisite if satisfactory and predictable results are to be achieved after EVAR, especially regarding prevention, diagnosis and treatment of type-II endoleaks. Intraprocedural aneurysm sac pressure monitoring, coil embolisation and the use of injection of thrombin into the aneurysm sac of selected patients is useful in reducing the incidence of post-EVAR type-II persisting endoleaks.


Motor programme activating therapy influences adaptive brain functions in multiple sclerosis: clinical and MRI study.
There is still little scientific evidence for the efficacy of neurofacilitation approaches and their possible influence on brain plasticity and adaptability. In this study, the outcome of a new kind of neurofacilitation approach, motor programme activating therapy (MPAT), was evaluated on the basis of a set of clinical functions and with MRI. Eighteen patients were examined four times with standardized clinical tests and diffusion tensor imaging to monitor changes without therapy, immediately after therapy and 1 month after therapy. Moreover, the strength of effective connectivity was analysed before and after therapy. Patients underwent a 1-h session of MPAT twice a week for 2 months. The data were analysed by nonparametric tests of association and were subsequently statistically evaluated. The therapy led to significant improvement in clinical functions, significant increment of fractional anisotropy and significant decrement of mean diffusivity, and decrement of effective connectivity at supplementary motor areas was observed immediately after the therapy. Changes in clinical functions and diffusion tensor images persisted 1 month after completing the programme. No statistically significant changes in clinical functions and no differences in MRI-diffusion tensor images were observed without physiotherapy. Positive immediate and long-term effects of MPAT on clinical and brain functions, as well as brain microstructure, were confirmed.


Genome-wide association studies and expression-based quantitative trait loci analyses reveal roles of HCT2 in caffeoylquinic acid biosynthesis and its regulation by defense-responsive transcription factors in Populus.
3-O-caffeoylquinic acid, also known as chlorogenic acid (CGA), functions as an intermediate in lignin biosynthesis in the phenylpropanoid pathway. It is widely distributed among numerous plant species and acts as an antioxidant in both plants and animals. Using GC-MS, we discovered consistent and extreme variation in CGA content across a population of 739 4-yr-old Populus trichocarpa accessions. We performed genome-wide association studies (GWAS) from 917 P. trichocarpa accessions and expression-based quantitative trait loci (eQTL) analyses to identify key regulators. The GWAS and eQTL analyses resolved an overlapped interval encompassing a hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyl transferase 2 (PtHCT2) that was significantly associated with CGA and partially characterized metabolite abundances. PtHCT2 leaf expression was significantly correlated with CGA abundance and it was regulated by cis-eQTLs containing W-box for WRKY binding. Among all nine PtHCT homologs, PtHCT2 is the only one that responds to infection by the fungal pathogen Sphaerulina musiva (a Populus pathogen). Validation using protoplast-based transient expression system suggests that PtHCT2 is regulated by the defense-responsive WRKY. These results are consistent with reports of CGA functioning as an antioxidant in response to biotic stress. This study provides insights into data-driven and omics-based inference of gene function in woody species.


Invited Review: The role of cow, pathogen, and treatment regimen in the therapeutic success of bovine Staphylococcus aureus mastitis.
Staphylococcus aureus is an important cause of udder infections in dairy herds. Both lactational and dry cow therapy are part of Staph. aureus control programs. Reported cure rates for Staph. aureus mastitis vary considerably. The probability of cure depends on cow, pathogen, and treatment factors. Cure rates decrease with increasing age of the cow, increasing somatic cell count, increasing duration of infection, increasing bacterial colony counts in milk before treatment, and increasing number of quarters infected. Staphylococcus aureus mastitis in hind quarters has a low cure rate compared with front quarters. Antimicrobial treatment of intramammary infections with penicillin-resistant Staph. aureus strains results in a lower cure rate for treatment with either beta-lactam or non-beta-lactam antibiotics. Other strain-specific factors may affect the probability of cure but routine diagnostic methods for use in bacteriology laboratories or veterinary practices are not yet available. The most important treatment factor affecting cure is treatment duration. Increased duration of treatment is associated with increased chance of cure. Economically, extended treatment is not always justified, even when indirect effects of treatment such as prevention of contagious transmission are taken into consideration. Usefulness of treatment trials could be improved by standardization of case definitions, consideration of host and strain factors, and sufficient statistical power. Treatment of young animals with penicillin-sensitive Staph. aureus infections is often justified based on bacteriological cure and economic outcome, whereas treatment of older animals, chronic infections, or penicillin-resistant isolates should be discouraged.


Updates in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for the ENT surgeon.
ENT involvement is common in ANCA-associated vasculitis (AAV), particularly in GPA and EGPA. Early recognition and treatment is important for good outcomes, yet evidence suggests that UK ENT surgeons may not consistently recognise the early features of AAV, despite a similar incidence to vestibular schwannoma. AAV is a rapidly advancing field, with significant developments in the understanding of its pathogenesis, classification and treatment over the past decade. Relevant vasculitis mimics are also discussed with a particular focus on the increasing prevalence of vasculitis mimics driven by an increase in recreational cocaine use, as well as the emergence and reclassification of several other vasculitis mimics in the head and neck. This article reviews key recent updates in the vasculitis literature, with a particular focus on those relevant to recognition and diagnosis of AAV for the ENT surgeon. Strengths and limitations of relevant diagnostic testing are discussed, and a method of evaluation of patients with features of AAV presenting to ENT services is outlined.


Racial-ethnic colorectal cancer survival disparities in the mountain west region: the case of Blacks compared to Whites.
Substantial disparities in colorectal cancer (CRC) survival among racial-ethnic groups, especially between Blacks and Whites, have been extensively documented in the Northeast, California and South of the United States. The purpose of this study was to ascertain the determinants of colorectal cancer racial-ethnic survival disparities in a state of the Mountain West region, Nevada. The study population consisted of a cohort of 12,181 men and women with a first primary invasive carcinoma in the colon and rectum diagnosed between 1995 and 2007, identified through the Nevada Central Cancer Registry and followed for vital status until 31 December 2007. Likelihood ratio chi-square statistics were used to compare the sociodemographic and clinical characteristics for race-ethnicity. Cox proportional regression modeling and partial likelihood tests were used to estimate the hazard ratios and assess interaction effects in CRC cause-specific death. Blacks and Hispanics were more likely to be diagnosed with distant stage disease, 22.4% and 21.5% respectively, compared to 17.9% in Whites. No difference was observed between racial-ethnic groups for diagnoses in regional stage. Univariate analysis yielded a 20.1% higher risk of CRC death for Blacks compared to Whites [95% CI = 1.05-1.37]. Adjustment for tumor stage, sex, age, diagnosis period, tumor sublocation, marital status, and economic status in the multivariate model showed a persistently increased risk of CRC death for Blacks (HR = 1.17, 95% CI = 1.02-1.33) in relation to Whites. Survival disparities persisted among Blacks in our study even after adjusting for common demographic and tumor factors. Further determinants of survival disparities between race/ethnicities, such as course of treatment, should be investigated. Additionally, more public health intervention programs should tailor CRC screening awareness towards minorities as well as ensuring equal access to health care and quality treatment.


Axonal outgrowth is associated with increased ERK 1/2 activation but decreased caspase 3 linked cell death in Schwann cells after immediate nerve repair in rats.
Extracellular-signal regulated kinase (ERK1/2) is activated by nerve damage and its activation precedes survival and proliferation of Schwann cells. In contrast, activation of caspase 3, a cysteine protease, is considered as a marker for apoptosis in Schwann cells. In the present study, axonal outgrowth, activation of ERK1/2 by phosphorylation (p-ERK 1/2 ) and immunoreactivity of cleaved caspase 3 were examined after immediate, delayed, or no repair of transected rat sciatic nerves. Axonal outgrowth, detected by neurofilament staining, was longer after immediate repair than after either the delayed or no repair conditions. Immediate repair also showed a higher expression of p-ERK 1/2 and a lower number of cleaved caspase 3 stained Schwann cells than after delayed nerve repair. If the transected nerve was not repaired a lower level of p-ERK 1/2 was found than in either the immediate or delayed repair conditions. Axonal outgrowth correlated to p-ERK 1/2, but not clearly with cleaved caspase 3. Contact with regenerating axons affected Schwann cells with respect to p-ERK 1/2 and cleaved caspase 3 after immediate nerve repair only. The decreased regenerative capacity that has historically been observed after delayed nerve repair may be related to impaired activation of Schwann cells and increased Schwann cell death. Outgrowing axons influence ERK 1/2 activation and apoptosis of Schwann cells.


Posterior glenohumeral thermal capsulorraphy, capsular imbrication and labral repair with complication of adhesive capsulitis: a modified rehabilitation approach.
Isolated atraumatic posterior glenohumeral instability is rare. Use of thermal capsulorraphy for glenohumeral instability is considered controversial. This case study describes a modified rehabilitation protocol for a patient who underwent a multistep arthroscopic procedure for isolated posterior glenohumeral instability with a postoperative complication of adhesive capsulitis. A 30-y-old man with a 15-y history of bilateral posterior glenohumeral instability related to generalized hypermobility underwent right-shoulder arthroscopy consisting of a combined posterior labral repair, capsular imbrication, and thermal capsulorraphy. A gunslinger orthosis was prescribed for 6 wk of immobilization. Adhesive capsulitis was diagnosed at the 5-wk postoperative visit and immobilization was discontinued. A modified treatment protocol was devised to address both the surgical procedures performed and the adhesive capsulitis. Residual symptoms resolved with release of an adhesion while stretching 10 months postoperatively. Scores of 5 shoulder-assessment tools improved from poor to excellent/good with subjective report of a very good outcome. The complication of adhesive capsulitis required an individualized treatment protocol. In contrast to the standard protocol, our modified approach allowed more time to be spent in each phase of the program, was aggressive with restoring range of motion (ROM) without excessively stressing the posterior capsule, and allowed the patient to progress to activities that were tolerated regardless of protocol phase. Shoulder stiffness or frank adhesive capsulitis after stabilization, as in this case, requires a more aggressive modification to prevent permanent ROM limitations. Conversely, patients with early rapid gains in ROM must be protected from overstretching the repaired tissue with a program that allows functional motion to be incorporated over a longer time frame. This study indicates the use of thermal capsulorraphy as a viable surgical modality when it is used judiciously with the proper postoperative restrictions and rehabilitation.


Acute off-target effects of neural circuit manipulations.
Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off-target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions.


Evolutionary pressures on simple sequence repeats in prokaryotic coding regions.
Simple sequence repeats (SSRs) are indel mutational hotspots in genomes. In prokaryotes, SSR loci can cause phase variation, a microbial survival strategy that relies on stochastic, reversible on-off switching of gene activity. By analyzing multiple strains of 42 fully sequenced prokaryotic species, we measure the relative variability and density distribution of SSRs in coding regions. We demonstrate that repeat type strongly influences indel mutation rates, and that the most mutable types are most strongly avoided across genomes. We thoroughly characterize SSR density and variability as a function of N→C position along protein sequences. Using codon-shuffling algorithms that preserve amino acid sequence, we assess evolutionary pressures on SSRs. We find that coding sequences suppress repeats in the middle of proteins, and enrich repeats near termini, yielding U-shaped SSR density curves. We show that for many species this characteristic shape can be attributed to purely biophysical constraints of protein structure. In multiple cases, however, particularly in certain pathogenic bacteria, we observe over enrichment of SSRs near protein N-termini significantly beyond expectation based on structural constraints. This increases the probability that frameshifts result in non-functional proteins, revealing that these species may evolutionarily tune SSR positions in coding regions to facilitate phase variation.


Bacterial agents causing gastroenteritis in various patient populations from South Florida.
A respective review was done on all stool specimens submitted for culture during an 18 month period at 5 hospitals in South Florida. The patient population seen at these hospitals was heterogeneous. All laboratories used a similar methodology for the isolation of enteric pathogens. The number of isolates from all institutions were as follows: (table; see text) The majority of Salmonella und Shigella isolates were from pediatric patients whereas Campylobacter was the major bacterial isolate in the adult population. Yersinia enterocolitica was an infrequent bacterial isolate and was only isolated from pediatric patients. No major outbreak of infection was detected. The distribution of Salmonella serotypes was in agreement with the serotype distribution reported in the United States. Approximately 58% of the isolates were serogroup B, 19% were serogroup C and 13% were serogroup D. Over two-thirds of the Shigella isolates were Shigella sonnei followed by S. flexneri, S. dysenteriae and S. boydii accounted for less than 3% of the isolates. Antibiotic resistance among Salmonella for ampicillin, tetracycline and chloramphenicol was 13%, 19% and 5%, respectively. Most resistant isolates were serogroup B. Overall, 40% of Shigella isolates were resistant to ampicillin, 15% resistant to tetracycline and 4% resistant to chloramphenicol.


Network estimation for censored time-to-event data for multiple events based on multivariate survival analysis.
In general survival analysis, multiple studies have considered a single failure time corresponding to the time to the event of interest or to the occurrence of multiple events under the assumption that each event is independent. However, in real-world events, one event may impact others. Essentially, the potential structure of the occurrence of multiple events can be observed in several survival datasets. The interrelations between the times to the occurrences of events are immensely challenging to analyze because of the presence of censoring. Censoring commonly arises in longitudinal studies in which some events are often not observed for some of the subjects within the duration of research. Although this problem presents the obstacle of distortion caused by censoring, the advanced multivariate survival analysis methods that handle multiple events with censoring make it possible to measure a bivariate probability density function for a pair of events. Considering this improvement, this paper proposes a method called censored network estimation to discover partially correlated relationships and construct the corresponding network composed of edges representing non-zero partial correlations on multiple censored events. To demonstrate its superior performance compared to conventional methods, the selecting power for the partially correlated events was evaluated in two types of networks with iterative simulation experiments. Additionally, the correlation structure was investigated on the electronic health records dataset of the times to the first diagnosis for newborn babies in South Korea. The results show significantly improved performance as compared to edge measurement with competitive methods and reliability in terms of the interrelations of real-life diseases.


Torticollis secondary to ocular pathology.
We report a series of 15 children, six male and nine female, of average age 20 months, seen at a paediatric orthopaedic clinic with torticollis. Orthopaedic examination revealed a normal range of neck movement in all cases but in seven there was palpable tightness in the absence of true shortening or contracture of the sternomastoid muscle. The patients were prospectively referred for ocular examination. In five of the 15 an ocular cause for the torticollis was detected with underaction of the superior oblique muscle in three, paresis of the lateral rectus muscle in one and nystagmus in one. Another two patients were found to have an abnormal ocular examination which was thought to be unrelated to their torticollis. Three of the patients with ocular torticollis required extra-ocular muscle surgery to abolish the head tilt and one of these had a tight sternomastoid muscle. Two of the non-ocular group had surgical release of the sternomastoid muscle; in the rest, the condition either resolved with physiotherapy or required no active treatment. We recommend that all patients with torticollis and no clear orthopaedic cause are referred for ocular assessment since it is not possible clinically to distinguish ocular from non-ocular causes.


What prompts help-seeking for cancer 'alarm' symptoms? A primary care based survey.
Encouraging prompt help-seeking for cancer symptoms can help shorten the patient interval and improve timely diagnosis. We explored factors associated with help-seeking in a primary care sample reporting 'alarm' symptoms. A questionnaire was mailed to 9771 adults (⩾ 50 years of age and no cancer diagnosis) and 3766 (39%) returned it. Our sample included 1732 adults reporting at least one cancer 'alarm' symptom; with a total of 2726 symptoms. Respondents completed questions relating to help-seeking, demographic and symptom characteristics (e.g., type, knowledge, concern, interference and attribution). Over a third of people who reported a cancer 'alarm' symptom in the past 3 months had not sought help from a doctor. An unexplained lump (odds ratio (OR) 2.46, 1.42-4.26) and persistent unexplained pain (OR 1.79, 1.19-2.69) were associated with increased likelihood of help-seeking. Symptom concern (OR 3.10, 2.19-4.39) and interference (OR 3.06, 2.15-4.36) were associated with an increased likelihood of seeking help independently of symptom type. People who were not working (OR 1.41, 1.09-1.83), were married/cohabiting rather than single (OR 1.38, 1.10-1.74) and were older (60-69 years) rather than younger (50-59 years; OR 1.33, 1.02-1.75) were more likely to have sought help. Our findings highlighted symptom type and symptom characteristics as key drivers of help-seeking. We also found that there may be specific demographic groups where encouraging help-seeking might be warranted.


Endocrine regulation of energy metabolism by the skeleton.
The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.


Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.
The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.


4-hydroxy tempo improves mitochondrial and neurobehavioral deficits in experimental model of Huntington's disease.
Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). To date, several free radical scavengers have been tested in experimental HD, but only a few have shown promise. Although most antioxidants rapidly reduce ROS but in the process they are oxidized, which limits their ability to protect. Therefore, in the present study we employed a potent recycling antioxidant, 4-hydroxy tempo (4-HT), because it can reinstate its reduced state even after its oxidation during scavenging of ROS. Female Wistar rats were administered 3-nitropropionic acid (3-NP) and/or 4-HT for 21 days, after which animals were subjected to biochemical and behavioral assessments. Our results showed that 4-HT treatment significantly attenuated the 3-NP induced decrease in the activities of mitochondrial electron transport chain enzymes. In addition, 4-HT administration restored the increased nitrite and lipid peroxidation levels. Apart from this, 4-HT also attenuated the 3-NP induced decrease in superoxide dismutase and catalase activities. Further, 4-HT administration resulted in significant improvement in 3-NP induced cognitive and motor impairments. Taken together, the results of the study demonstrate that 4-HT is beneficial in 3-NP induced model of HD and thus could be a potential therapeutic agent in management of this disease.


Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity.
P-type ATPases transport a wide array of ions, regulate diverse cellular processes, and are implicated in a number of human diseases. However, mechanisms that increase ion transport by these ubiquitous proteins are not known. SPCA1 is a P-type pump that transports Mn(2+) from the cytosol into the Golgi. We developed an intra-Golgi Mn(2+) sensor and used it to screen for mutations introduced in SPCA1, on the basis of its predicted structure, which could increase its Mn(2+) pumping activity. Remarkably, a point mutation (Q747A) predicted to increase the size of its ion permeation cavity enhanced the sensor response and a compensatory mutation restoring the cavity to its original size abolished this effect. In vivo and in vitro Mn(2+) transport assays confirmed the hyperactivity of SPCA1-Q747A. Furthermore, increasing Golgi Mn(2+) transport by expression of SPCA1-Q747A increased cell viability upon Mn(2+) exposure, supporting the therapeutic potential of increased Mn(2+) uptake by the Golgi in the management of Mn(2+)-induced neurotoxicity.


Patients with chronic periodontitis present increased risk for osteoporosis: A population-based cohort study in Taiwan.
Chronic periodontitis is a bone destructive inflammatory disease with an adverse impact on general health and suggested underlying factors in common with osteoporosis. A few studies have examined the possible relationship between chronic periodontitis and osteoporosis; however, the results remain inconclusive. This longitudinal follow-up study investigated the possible risk of patients with chronic periodontitis to present osteoporosis by using a population-based national health insurance data set in Taiwan. A random sample consisting of 1 million individuals was collected from Taiwan's national health insurance data set. From the sample, a total of 29 463 patients with newly diagnosed periodontitis from 2002 to 2008 were recruited and compared with a matched cohort of 58 926 patients without periodontitis. All patients were tracked until an osteoporosis diagnosis, or death, until the end of 2011. Associated factors, such as gender, age and comorbidities were examined. Cox proportional-hazards regression was performed to examine the risk of osteoporosis for patients with or without periodontitis. Within the 6-year follow-up period, the incidence rates of osteoporosis in the periodontitis cohort and comparison group were 2.72 and 1.66 per 1000 person-years, respectively. Mild, moderate and severe periodontitis were found to have 1.56, 2.09 and 2.08 times the risk of osteoporosis respectively compared to patients without periodontitis. Log-rank analysis revealed that patients with periodontitis had significantly higher cumulative incidence rates of osteoporosis than the control group (P<.0001). This study found that patients with periodontitis had a higher risk of being diagnosed with osteoporosis.


Kidney paired donation: a plea for a Swiss National Programme.
Growing incidence of end-stage renal disease, shortage of kidneys from deceased donors and a better outcome for recipients of kidneys from living donor have led many centres worldwide to favour living donor kidney transplantation programmes. Although criteria for living donation have greatly evolved in recent years with acceptance of related and unrelated donors, an immunological incompatibility, either due to ABO incompatibility and/or to positive cross-match, between a living donor and the intended recipient, could impede up to 40% of such procedures. To avoid refusal of willing and healthy living donors, a number of strategies have emerged to overcome immunological incompatibilities. Kidney paired donation is the safest way for such patients to undergo kidney transplantation. Implemented with success in many countries either as national or multiple regional independent programmes, it could include simple exchanges between any number of incompatible pairs, incorporate compatible pairs and non-directed donors (NDDs) to start a chain of compatible transplantations, lead to acceptance of ABO-incompatible matching, and integrate desensitising protocols. Incorporating all variations of kidney paired donation, the Australian programme has been able to facilitate kidney transplantation in 49% of registered incompatible pairs. This review is a plea for implementing a national kidney paired donation programme in Switzerland.


Clinical validation of the quick dynamic insulin sensitivity test.
The quick dynamic insulin sensitivity test (DISTq) can yield an insulin sensitivity result immediately after a 30-min clinical protocol. The test uses intravenous boluses of 10 g glucose and 1 U insulin at t = 1 and 11 min, respectively, and measures glucose levels in samples taken at t = 0, 10, 20, and 30 min. The low clinical cost of the protocol is enabled via robust model formulation and a series of population-derived relationships that estimate insulin pharmacokinetics as a function of insulin sensitivity (SI). Fifty individuals underwent the gold standard euglycaemic clamp (EIC) and DISTq within an eight-day period. SI values from the EIC and two DISTq variants (four-sample DISTq and two-sample DISTq30) were compared with correlation, Bland-Altman and receiver operator curve analyses. DISTq and DISTq30 correlated well with the EIC [R = 0.76 and 0.75, and receiver operator curve c-index = 0.84 and 0.85, respectively]. The median differences between EIC and DISTq/DISTq30 SI values were 13% and 22%, respectively. The DISTq estimation method predicted individual insulin responses without specific insulin assays with relative accuracy and thus high equivalence to EIC SI values was achieved. DISTq produced very inexpensive, relatively accurate immediate results, and can thus enable a number of applications that are impossible with established SI tests.


CNS aquaporin-4 autoimmunity in children.
In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.


Complete genome sequence of Celeribacter marinus IMCC12053(T), the host strain of marine bacteriophage P12053L.
Isolated from coastal seawater from Yellow Sea of Korea, Celeribacter marinus IMCC12053 was used as the host bacterium for bacteriophage P12053L. Here we report the complete genome sequence of strain IMCC12053 for further study of the marine bacteriophage P12053L functional genes. Single molecule real-time technology (PacBio RSII) was used for the single circular chromosome that is 3,096,705 base pairs in length and the GC content is 56.24%. It contains 3155 ORFs with 45 tRNAs and 6 rRNAs genes. N(6)-methyladenosine patterns were also investigated for 32 unmethylated genes and intergenic regions that covered many regulators and phage genes as well as ribosomal RNA genes and tRNA genes. Cryptic N(4)-methylcytosine pattern was investigated to speculate GpC methylase activity throughout the genome. Comparative genomics with other Celeribacter genomes were carried out for polyaromatic hydrocarbon degradation, but there were no aromatic ring oxygenases in IMCC12053 when compared to Celeribacter indicus P73.


Violent death rates in the US compared to those of the other high-income countries, 2015.
Violence is a serious public health issue in the U.S. This research compares the US and other high-income countries in terms of violent death. We used data from the World Health Organization for populous, high-income countries. Data from CDC's WISQARS and WONDER systems were used to assess mortality data among US white and non-white populations and in low-, medium-, and high-gun states in 2015. Death rates per 100,000 populations were calculated overall, by age, and by sex. Poisson and negative binomial regression were used to test for significance. The homicide rate in the US was 7.5 times higher than the homicide rate in the other high-income countries combined, which was largely attributable to a firearm homicide rate that was 24.9 times higher. The overall firearm death rate was 11.4 times higher in the US than in other high-income countries. In this dataset, 83.7% of all firearm deaths, 91.6% of women killed by guns, and 96.7% of all children aged 0-4 years killed by guns were from the US. Firearm homicide rates were 36 times higher in high-gun US states and 13.5 times higher in low-gun US states than the firearm homicide rate in other high-income countries combined. The firearm homicide rate among the US white population was 12 times higher than the firearm homicide rate in other high-income countries. The US firearm death rate increased between 2003 and 2015 and decreased in other high-income countries. The US continues to be an outlier among high-income countries with respect to firearm deaths.


Nurses' behaviors and visual scanning patterns may reduce patient identification errors.
Patient identification (ID) errors occurring during the medication administration process can be fatal. The aim of this study is to determine whether differences in nurses' behaviors and visual scanning patterns during the medication administration process influence their capacities to identify patient ID errors. Nurse participants (n = 20) administered medications to 3 patients in a simulated clinical setting, with 1 patient having an embedded ID error. Error-identifying nurses tended to complete more process steps in a similar amount of time than non-error-identifying nurses and tended to scan information across artifacts (e.g., ID band, patient chart, medication label) rather than fixating on several pieces of information on a single artifact before fixating on another artifact. Non-error-indentifying nurses tended to increase their durations of off-topic conversations-a type of process interruption-over the course of the trials; the difference between groups was significant in the trial with the embedded ID error. Error-identifying nurses tended to have their most fixations in a row on the patient's chart, whereas non-error-identifying nurses did not tend to have a single artifact on which they consistently fixated. Finally, error-identifying nurses tended to have predictable eye fixation sequences across artifacts, whereas non-error-identifying nurses tended to have seemingly random eye fixation sequences. This finding has implications for nurse training and the design of tools and technologies that support nurses as they complete the medication administration process.


White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study.
White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.


Chromosomal localization of a new mouse lens opacity gene (lop18)
Examination of mouse strains with a slit lamp and indirect ophthalmoscopy revealed that strain CBA/CaGnLe has a white cataract obvious at weaning age. It soon progresses to a large white nuclear cataract with mild cortical changes. Crosses with C57BL/6J showed that this is inherited as a single recessive fully penetrant gene, which we have designated lop18 (lens opacity 18). Linkage analysis using visible marker T (brachyury), histocompatibility marker H2, and microsatellite markers D17Mit21, D17Mit28, D17Mit38, and D17Mit46 shows that the lop18 gene is located, approximately 16 cM from the centromere on mouse Chromosome 17. It is a likely candidate mutation for the alpha-crystallin (Crya1) gene.


Improving molecular testing and personalized medicine in non-small-cell lung cancer in Ontario.
Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.


Predicting the Academic Achievement of Deaf and Hard-of-Hearing Students From Individual, Household, Communication, and Educational Factors.
Research suggests that the academic achievement of deaf and hard-of-hearing (DHH) students is the result of a complex interplay of many factors. These factors include characteristics of the students (e.g., hearing thresholds, language fluencies, mode of communication, and communication functioning), characteristics of their family environments (e.g., parent education level, socioeconomic status), and experiences inside and outside school (e.g., school placement, having been retained at grade level). This paper examines the relative importance of such characteristics to U.S. DHH secondary students' academic achievement as indicated by the Woodcock-Johnson III subtests in passage comprehension, mathematics calculation, science, and social studies. Data were obtained for approximately 500 DHH secondary students who had attended regular secondary schools or state-sponsored special schools designed for DHH students. Across all subject areas, having attended regular secondary schools and having better spoken language were associated with higher test scores. Significant negative predictors of achievement varied by type of subtest but included having an additional diagnosis of a learning disability, having a mild hearing loss, and being African American or Hispanic. The findings have important implications for policy and practice in educating DHH students as well for interpreting previous research.


Alcohol use and HIV disease management: the impact of individual and partner-level alcohol use among HIV-positive men who have sex with men.
Alcohol use among HIV-positive (HIV+) individuals is associated with decreased adherence to antiretroviral therapy (ART) and consequently poorer HIV treatment outcomes. This study examined the independent association of individual and partner-level alcohol use with HIV disease management among men who have sex with men (MSM) in primary partnerships. In total, 356 HIV+ MSM and their male primary partners completed a baseline visit for a longitudinal study examining the role of couple-level factors in HIV treatment. The Alcohol Use Disorders Identification Test (AUDIT) was administered to assess the individual and the partner-level alcohol use. Primary outcome variables included self-reported ART adherence, ART adherence self-efficacy, and HIV viral load. Results demonstrated that abstainers, compared to hazardous drinkers, had higher self-efficacy to integrate and persevere in HIV treatment and a lower odds of having a detectable viral load. Participants with a partner-abstainer, versus a partner-hazardous drinker, had less self-efficacy to persevere in HIV treatment, a lower odds of 100% three-day adherence and a higher viral load. Together, these findings suggest that assessment and treatment of both the patient's and the patient's primary partner's pattern of alcohol consumption is warranted when attempting to optimize HIV care among MSM.


Aβ-amyloid and Tau Imaging in Dementia.
The introduction of in vivo imaging of Aβ-amyloid (Αβ) pathology more than a decade ago, transformed the assessment of Alzheimer disease (AD) allowing the evaluation of Aβ deposition over time by providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain to the extent that Aβ imaging has already been approved for clinical use and is being used for both patient recruitment and outcome measure in current anti-Αβ therapeutic trials. Aβ imaging studies have deepened our insight into Aβ deposition, showing that Aβ accumulation is a slow and protracted process extending for more than two decades before the onset of the clinical phenotype. Although cross-sectional evaluation of Αβ burden does not strongly correlate with cognitive impairment in AD, Αβ burden does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment subjects. These associations suggest that Αβ deposition is not a benign process. The recent addition of selective tau imaging will allow to elucidate if these effects are directly associated with Αβ deposition or if they are mediated, in toto or in parte, by tau as it spreads out of the mesial temporal lobe into neocortical association areas. The combination of Aβ and tau imaging studies would likely help elucidate the relationship or interplay between the two pathologic hallmarks of the disease. Longitudinal observations to assess their potential independent or synergistic, sequential or parallel effects on cognition, disease progression, and other disease-specific biomarkers of neurodegeneration would be required to further clarify the respective role of Αβ and tau deposition play in the course of AD.


The role of spirituality and religious coping in the quality of life of patients with advanced cancer receiving palliative radiation therapy.
National palliative care guidelines outline spiritual care as a domain of palliative care, yet patients' religiousness and/or spirituality (R/S) are underappreciated in the palliative oncology setting. Among patients with advanced cancer receiving palliative radiation therapy (RT), this study aims to characterize patient spirituality, religiousness, and religious coping; examine the relationships of these variables to quality of life (QOL); and assess patients' perceptions of spiritual care in the cancer care setting. This is a multisite, cross-sectional survey of 69 patients with advanced cancer (response rate = 73%) receiving palliative RT. Scripted interviews assessed patient spirituality, religiousness, religious coping, QOL (McGill QOL Questionnaire), and perceptions of the importance of attention to spiritual needs by health providers. Multivariable models assessed the relationships of patient spirituality and R/S coping to patient QOL, controlling for other significant predictors of QOL. Most participants (84%) indicated reliance on R/S beliefs to cope with cancer. Patient spirituality and religious coping were associated with improved QOL in multivariable analyses (β = 10.57, P < .001 and β = 1.28, P = .01, respectively). Most patients considered attention to spiritual concerns an important part of cancer care by physicians (87%) and nurses (85%). Limitations include a small sample size, a cross-sectional study design, and a limited proportion of nonwhite participants (15%) from one US region. Patients receiving palliative RT rely on R/S beliefs to cope with advanced cancer. Furthermore, spirituality and religious coping are contributors to better QOL. These findings highlight the importance of spiritual care in advanced cancer care.


Health workforce responses to global health initiatives funding: a comparison of Malawi and Zambia.
Shortages of health workers are obstacles to utilising global health initiative (GHI) funds effectively in Africa. This paper reports and analyses two countries' health workforce responses during a period of large increases in GHI funds. Health facility record reviews were conducted in 52 facilities in Malawi and 39 facilities in Zambia in 2006/07 and 2008; quarterly totals from the last quarter of 2005 to the first quarter of 2008 inclusive in Malawi; and annual totals for 2004 to 2007 inclusive in Zambia. Topic-guided interviews were conducted with facility and district managers in both countries, and with health workers in Malawi. Facility data confirm significant scale-up in HIV/AIDS service delivery in both countries. In Malawi, this was supported by a large increase in lower trained cadres and only a modest increase in clinical staff numbers. Routine outpatient workload fell in urban facilities, in rural health centres and in facilities not providing antiretroviral treatment (ART), while it increased at district hospitals and in facilities providing ART. In Zambia, total staff and clinical staff numbers stagnated between 2004 and 2007. In rural areas, outpatient workload, which was higher than at urban facilities, increased further. Key informants described the effects of increased workloads in both countries and attributed staff migration from public health facilities to non-government facilities in Zambia to PEPFAR. Malawi, which received large levels of GHI funding from only the Global Fund, managed to increase facility staff across all levels of the health system: urban, district and rural health facilities, supported by task-shifting to lower trained staff. The more complex GHI arena in Zambia, where both Global Fund and PEPFAR provided large levels of support, may have undermined a coordinated national workforce response to addressing health worker shortages, leading to a less effective response in rural areas.


Revealing hidden talents: The development, use, and benefit of VESPARCH.
School attainment tests and Cognitive Abilities Tests are used in the United Kingdom to set targets for educational outcome. Whilst these are good predictors, they depend not only on basic ability but also on learnt knowledge and skills, such as reading. VESPARCH is an online group test of verbal and spatial reasoning, which we propose gives a measure that more closely approximates to basic ability - fluid intelligence. The verbal test contains highly familiar words, does not require the child to read them, is untimed, and provides detailed feedback on five practice questions for each part of the test. The tests - one suitable and standardized for children aged 7-9 years and one for children aged 10-12 years - have good test-retest reliability and validity and conform to the Rasch model. Comparison of VESPARCH scores with school attainment measures allows identification of those students who are underachieving academically relative to their potential. The matched nature of the verbal and spatial tests allows reasoning ability in the two domains to be compared; those with much higher spatial scores might be expected to do well in STEM subjects. VESPARCH can be used alongside current school tests to ensure targeted teaching and encouragement for every child.


Functional recovery and blood pressure on acute post-stroke setting.
This study aims to evaluate the effects of blood pressure (BP) on functional recovery and length of stay (LOS) in post-stroke patients in an acute rehabilitation facility (ARF). A total of 116 ischemic stroke patients (60 males, 56 females; mean age 70.0±12.8 years; range, 37 to 93 years) who were admitted to the ARF between January 2012 and September 2012 were included. Daily BP measurements with mean systolic and diastolic BP values and Functional Independent Measure (FIM) scores at the time of admission and discharge were measured. The LOS and systolic and diastolic BP ranges were also recorded. There was no significant correlation between the BP and FIM scores. The mean diastolic BP was positively correlated with admission (rs=0.316, p=0.01) and discharge (rs=0.287, p=0.002), FIM scores, and FIM effectiveness (rs=0.185, p=0.047) and negatively correlated with age (r=-0.449, p<0.001) and LOS (rs=-0.189, p=0.042). The LOS in hospital was negatively correlated with FIM scores at admission (rs=-0.585, p<0.001) and discharge (rs=-0.352, p<0.001) and positively correlated with FIM score changes (rs=0.414, p<0.001). Our study results show that diastolic BP in the subacute phase of stroke does not have a major impact on the functional recovery and LOS in post-stroke patients. However, there is a significant correlation between diastolic BP values and FIM efficiency.


MIANN models in medicinal, physical and organic chemistry.
Reducing costs in terms of time, animal sacrifice, and material resources with computational methods has become a promising goal in Medicinal, Biological, Physical and Organic Chemistry. There are many computational techniques that can be used in this sense. In any case, almost all these methods focus on few fundamental aspects including: type (1) methods to quantify the molecular structure, type (2) methods to link the structure with the biological activity, and others. In particular, MARCH-INSIDE (MI), acronym for Markov Chain Invariants for Networks Simulation and Design, is a well-known method for QSAR analysis useful in step (1). In addition, the bio-inspired Artificial-Intelligence (AI) algorithms called Artificial Neural Networks (ANNs) are among the most powerful type (2) methods. We can combine MI with ANNs in order to seek QSAR models, a strategy which is called herein MIANN (MI & ANN models). One of the first applications of the MIANN strategy was in the development of new QSAR models for drug discovery. MIANN strategy has been expanded to the QSAR study of proteins, protein-drug interactions, and protein-protein interaction networks. In this paper, we review for the first time many interesting aspects of the MIANN strategy including theoretical basis, implementation in web servers, and examples of applications in Medicinal and Biological chemistry. We also report new applications of the MIANN strategy in Medicinal chemistry and the first examples in Physical and Organic Chemistry, as well. In so doing, we developed new MIANN models for several self-assembly physicochemical properties of surfactants and large reaction networks in organic synthesis. In some of the new examples we also present experimental results which were not published up to date.


Dynamic visual acuity of normal subjects during vertical optotype and head motion.
To characterize the effect of passive vertical head motion on dynamic visual acuity of young, normally sighted subjects wearing telescopic spectacles, and to relate this to the velocity of images on the retina. Static visual acuity was measured without motion. Dynamic visual acuity was measured during vertical, sinusoidal motion of either optotypes or of a servo-driven rotating chair in which subjects were seated. Dynamic visual acuity for head motion was measured unaided, as well as with 1.9X, 4X, and 6X telescopic spectacles. Vertical eye movements were recorded using magnetic search coils. During optotype motion, acuity declined with increasing velocity to a minimum of approximately 20/200 at 100 degrees/sec. Pursuit gain (eye velocity/optotype velocity) for moving optotypes was low except for optotype velocities of 20 degrees/sec of less. Dynamic visual acuity without telescopic spectacles was not sensitive to head motion. Static visual acuity improved with increasing telescopic spectacle power, but dynamic visual acuity became progressively impaired by head motion as telescopic spectacle power was increased. Compared with static visual acuity, head motion with peak velocity of 40 degrees/sec reduced acuity two-fold for 1.9X telescopic spectacles, fourfold for 4X telescopic spectacles, and eightfold for 6X telescopic spectacles. Visual vestibulo-ocular reflex gain with telescopic spectacles increased to values markedly above 1.0, but was always less than telescopic spectacle magnification. There was visual tolerance of slip velocities of 2 degrees/sec or less, above which acuity declined in proportion to the 0.6 power of retinal slip velocity. Above 2 degrees/sec, retinal slip velocity accounted for 95% of the variance in dynamic visual acuity. These results confirm that acuity is sensitive to retinal image motion in the vertical direction, and extend this finding to indicate that sensitivity of acuity to vertical head motion during wearing of telescopic spectacles is attributable to retinal image slip velocity.


Reduced set averaging of face identity in children and adolescents with autism.
Individuals with autism have difficulty abstracting and updating average representations from their diet of faces. These averages function as perceptual norms for coding faces, and poorly calibrated norms may contribute to face recognition difficulties in autism. Another kind of average, known as an ensemble representation, can be abstracted from briefly glimpsed sets of faces. Here we show for the first time that children and adolescents with autism also have difficulty abstracting ensemble representations from sets of faces. On each trial, participants saw a study set of four identities and then indicated whether a test face was present. The test face could be a set average or a set identity, from either the study set or another set. Recognition of set averages was reduced in participants with autism, relative to age- and ability-matched typically developing participants. This difference, which actually represents more accurate responding, indicates weaker set averaging and thus weaker ensemble representations of face identity in autism. Our finding adds to the growing evidence for atypical abstraction of average face representations from experience in autism. Weak ensemble representations may have negative consequences for face processing in autism, given the importance of ensemble representations in dealing with processing capacity limitations.


Blurred boundaries: the therapeutics and politics of medical marijuana.
For 5 millennia, Cannabis sativa has been used throughout the world medically, recreationally, and spiritually. From the mid-19th century to the 1930s, American physicians prescribed it for a plethora of indications, until the federal government started imposing restrictions on its use, culminating in 1970 with the US Congress classifying it as a Schedule I substance, illegal, and without medical value. Simultaneous with this prohibition, marijuana became the United States' most widely used illicit recreational drug, a substance generally regarded as pleasurable and relaxing without the addictive dangers of opioids or stimulants. Meanwhile, cannabis never lost its cachet in alternative medicine circles, going mainstream in 1995 when California became the first of 16 states to date to legalize its medical use, despite the federal ban. Little about cannabis is straightforward. Its main active ingredient, δ-9-tetrahydrocannabinol, was not isolated until 1964, and not until the 1990s were the far-reaching modulatory activities of the endocannabinoid system in the human body appreciated. This system's elucidation raises the possibility of many promising pharmaceutical applications, even as draconian federal restrictions that hamstring research show no signs of softening. Recreational use continues unabated, despite growing evidence of marijuana's addictive potential, particularly in the young, and its propensity for inducing and exacerbating psychotic illness in the susceptible. Public approval drives medical marijuana legalization efforts without the scientific data normally required to justify a new medication's introduction. This article explores each of these controversies, with the intent of educating physicians to decide for themselves whether marijuana is panacea, scourge, or both. PubMed searches were conducted using the following keywords: medical marijuana, medical cannabis, endocannabinoid system, CB1 receptors, CB2 receptors, THC, cannabidiol, nabilone, dronabinol, nabiximols, rimonabant, marijuana legislation, marijuana abuse, marijuana dependence, and marijuana and schizophrenia. Bibliographies were hand searched for additional references relevant to clarifying the relationships between medical and recreational marijuana use and abuse.


Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates.
Zaire ebolavirus is the causative agent of the current outbreak of hemorrhagic fever disease in West Africa. Previously, we showed that a whole Ebola virus (EBOV) vaccine based on a replication-defective EBOV (EBOVΔVP30) protects immunized mice and guinea pigs against lethal challenge with rodent-adapted EBOV. Here, we demonstrate that EBOVΔVP30 protects nonhuman primates against lethal infection with EBOV. Although EBOVΔVP30 is replication-incompetent, we additionally inactivated the vaccine with hydrogen peroxide; the chemically inactivated vaccine remained antigenic and protective in nonhuman primates. EBOVΔVP30 thus represents a safe, efficacious, whole-EBOV vaccine candidate that differs from other EBOV vaccine platforms in that it presents all viral proteins and the viral RNA to the host immune system, which might contribute to protective immune responses.


On the Nature of Tintinnid Loricae (Ciliophora: Spirotricha: Tintinnina): a Histochemical, Enzymatic, EDX, and High-resolution TEM Study.
Tintinnids (Ciliophora: Spirotricha: Tintinnina) are occasionally the dominant ciliates in the marine plankton. The tintinnid loricae are minute artworks fascinating scientists for more than 230 years, but their chemical composition remained unclear, viz., chitinous or proteinaceous substances were discussed. Since sedimenting loricae contribute to the flux of elements and organic compounds in the oceans, knowledge about their nature is necessary in assessing their ecological role. Previous techniques and new methods, e.g. enzymatic digestion and high-resolution transmission electron microscopy, are applied in the present study. A chitinous nature of the loricae is rejected by the Van-Wisselingh test and failure of chitinase digestion. Only proteins might show a resistance against strong hot bases (KOH at 160°C for ~ 40 min. in tintinnid loricae) similar to that of chitin. Actually, the presence of nitrogen in the EDX analyses and the digestion of at least some loricae by proteinase K strongly indicate a proteinaceous nature. Furthermore, the crystal lattice revealed by high-resolution TEM in Eutintinnus loricae is similar to the proteinaceous surface layer (S-layer) of archaea, and the striation recognizable in transverse sections of Eutintinnus loricae has a periodicity resembling that of the crystalline proteins in the extruded trichocysts of Paramecium and Frontonia. The proteolytic resistance of some loricae does not reject the idea of a proteinaceous nature, as proteins in S-layers of some archaea and in most naturally occurring prions show comparable reactions. The data from the present study and the literature indicate proteins in the loricae of thirteen genera. Differences in the proteolytic resistance and staining properties between genera and congeners are probably due to deviations in the protein composition and the additional substances, e.g. lipids, carbohydrates. At the present state of knowledge, correlations between lorica structure, wall texture, ultrastructure of the lorica forming granules, and the histochemical and enzymatic findings are not evident. Therefore, further studies are required to estimate the taxonomic significance of these features and the ecological role of sedimenting loricae.


Ponsin interacts with Nck adapter proteins: implications for a role in cytoskeletal remodelling during differentiation of skeletal muscle cells.
Skeletal muscle differentiation is a complex process: It is characterised by changes in gene expression and protein composition. Simultaneously, a dramatic remodelling of the cytoskeleton and associated cell-matrix contacts, the costameres, occurs. The expression and localisation of the protein ponsin at cell-matrix contacts marks the establishment of costameres. In this report we show that skeletal muscle cells are characterised by a novel ponsin isoform, which contains a large insertion in its carboxy-terminus. This skeletal muscle-specific module binds the adapter proteins Nck1 and Nck2, and increased co-localisation of ponsin with Nck2 is observed at remodelling cell-matrix contacts of differentiating skeletal muscle cells. Since this ponsin insertion can be phosphorylated, it may adjust the interaction affinity with Nck adapter proteins. The novel ponsin isoform and its interaction with Nck1/2 provide exciting insight into the convergence of signalling pathways at the costameres, and its crucial role for skeletal muscle differentiation and re-generation.


Macrophage Activation Syndrome in a Case of Myasthenia Gravis with Concurrent Cytomegalovirus Infection.
Macrophage activation syndrome (MAS) or reactive hemophagocytic lymphohistiocytosis (HLH) refers to a set of clinical symptoms caused by the excessive activation and proliferation of macrophages. It was linked with autoimmune disease such as systemic-onset juvenile rheumatoid arthritis, systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis, etc. Herein we report a case of myasthenia gravis (MG) with concurrent cytomegalovirus (CMV) infection developed MAS. A 31-year-old female with history of MG for 2 years under stable control with azathioprine and prednisolone. She presented with persistent high fever for 2 weeks after an upper respiratory infection. Lab data revealed pancytopenia, elevated triglyceride, ferritin and C-reactive protein (CRP). A bone marrow aspiration confirmed hemophagocytosis. Investigation for occult infection revealed her plasma was positive for CMV IgG and IgM, and high for CMV viral load. She was then treated with 5 sessions of plasmapheresis and pulse steroid. Azathioprine was discontinued and replaced with cyclosporine. Gancylovir was given for her concurrent CMV infection. After 2 weeks of treatment, her fever gradually subsided, and her blood cell count, hepatobiliary enzymes, ferritin and CRP have returned to normal range. She was discharged in good recovery. MAS is a rare complication of systemic autoimmune disease with poor prognosis, which may be precipitated by concurrent infection. Early recognition of this syndrome and prompt immune modulation therapy is crucial for successful treatment.


A fuzzy, nonparametric segmentation framework for DTI and MRI analysis: with applications to DTI-tract extraction.
This paper presents a novel fuzzy-segmentation method for diffusion tensor (DT) and magnetic resonance (MR) images. Typical fuzzy-segmentation schemes, e.g., those based on fuzzy C means (FCM), incorporate Gaussian class models that are inherently biased towards ellipsoidal clusters characterized by a mean element and a covariance matrix. Tensors in fiber bundles, however, inherently lie on specific manifolds in Riemannian spaces. Unlike FCM-based schemes, the proposed method represents these manifolds using nonparametric data-driven statistical models. The paper describes a statistically-sound (consistent) technique for nonparametric modeling in Riemannian DT spaces. The proposed method produces an optimal fuzzy segmentation by maximizing a novel information-theoretic energy in a Markov-random-field framework. Results on synthetic and real, DT and MR images, show that the proposed method provides information about the uncertainties in the segmentation decisions, which stem from imaging artifacts including noise, partial voluming, and inhomogeneity. By enhancing the nonparametric model to capture the spatial continuity and structure of the fiber bundle, we exploit the framework to extract the cingulum fiber bundle. Typical tractography methods for tract delineation, incorporating thresholds on fractional anisotropy and fiber curvature to terminate tracking, can face serious problems arising from partial voluming and noise. For these reasons, tractography often fails to extract thin tracts with sharp changes in orientation, such as the cingulum. The results demonstrate that the proposed method extracts this structure significantly more accurately as compared to tractography.


Quantitative determination by real-time PCR of four vaginal Lactobacillus species, Gardnerella vaginalis and Atopobium vaginae indicates an inverse relationship between L. gasseri and L. iners.
Most studies of the vaginal microflora have been based on culture or on qualitative molecular techniques. Here we applied existing real-time PCR formats for Lactobacillus crispatus, L. gasseri and Gardnerella vaginalis and developed new formats for Atopobium vaginae, L. iners and L. jensenii to obtain a quantitative non culture-based determination of these species in 71 vaginal samples from 32 pregnant and 28 non-pregnant women aged between 18 and 45 years. The 71 vaginal microflora samples of these women were categorized, using the Ison and Hay criteria, as refined by Verhelst et al. (2005), as follows: grade Ia: 8 samples, grade Iab: 10, grade Ib: 13, grade I-like: 10, grade II: 11, grade III: 12 and grade IV: 7.L. crispatus was found in all but 5 samples and was the most frequent Lactobacillus species detected. A significantly lower concentration of L. crispatus was found in grades II (p < 0.0001) and III (p = 0.002) compared to grade I. L. jensenii was found in all grades but showed higher concentration in grade Iab than in grade Ia (p = 0.024). A. vaginae and G. vaginalis were present in high concentrations in grade III, with log10 median concentrations (log10 MC), respectively of 9.0 and 9.2 cells/ml. Twenty (38.5%) of the 52 G. vaginalis positive samples were also positive for A. vaginae. In grade II we found almost no L. iners (log10 MC: 0/ml) but a high concentration of L. gasseri (log10 MC: 8.7/ml). By contrast, in grade III we found a high concentration of L. iners (log10 MC: 8.3/ml) and a low concentration of L. gasseri (log10 MC: 0/ml). These results show a negative association between L. gasseri and L. iners (r = -0.397, p = 0.001) and between L. gasseri and A. vaginae (r = -0.408, p < 0.0001). In our study we found a clear negative association between L. iners and L. gasseri and between A. vaginae and L. gasseri. Our results do not provide support for the generally held proposition that grade II is an intermediate stage between grades I and III, because L. gasseri, abundant in grade II is not predominant in grade III, whereas L. iners, abundant in grade III is present only in low numbers in grade II samples.


BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice.
We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15-20% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.


Engineering competing nonlinearities.
Weak modulation of a quasi-phase-matching (QPM) grating opens possibilities for engineering both the average quadratic nonlinearity and the incoherent average cubic nonlinearity induced by QPM. The relative strength of the average quadratic and effective (intrinsic plus induced) cubic nonlinearity is studied for LiNbO(3) . We show how the induced average cubic nonlinearity can be engineered to dominate the intrinsic material cubic nonlinearity and how doing so will allow the intensity at which the quadratic and cubic nonlinearities balance and thus compete to be decreased to a few gigawatts per square centimeter.


Gene therapy of chronic granulomatous disease: the engraftment dilemma.
The potential of gene therapy as a curative treatment for monogenetic disorders has been clearly demonstrated in a series of recent Phase I/II clinical trials. Among primary immunodeficiencies, gene transfer into hematopoietic stem (HSC)/progenitor cells has resulted in the long-term correction of immune and metabolic defects in treated patients. In most cases, successes were augmented by a recognized biological selection for successfully treated cells in vivo, perhaps even to some extent at the HSC level. In contrast, similar achievements have not turned into reality for immunodeficiencies in which gene-transduced cells lack selective advantages in vivo. This is the case for chronic granulomatous disease (CGD), a primary immunodeficiency, characterized by deficient antimicrobial activity in phagocytic cells. Several attempts to correct CGD by gene transfer in combination with bone marrow conditioning have resulted in low-level long-term engraftment and transient clinical benefits despite high levels of gene marking and high numbers of reinfused cells. This review summarizes the data from clinical trials for CGD and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD.


Projection of mesothelioma mortality in Britain using Bayesian methods.
Mesothelioma mortality has increased more than ten-fold over the past 40 years in Great Britain, with >1700 male deaths recorded in the British mesothelioma register in 2006. Annual mesothelioma deaths now account for >1% of all cancer deaths. A Poisson regression model based on a previous work by Hodgson et al has been fitted, which has allowed informed statistical inferences about model parameters and predictions of future mesothelioma mortality to be made. In the Poisson regression model, the mesothelioma risk of an individual depends on the average collective asbestos dose for the individual in a given year and an age-specific exposure potential. The model has been fitted to the data within a Bayesian framework using the Metropolis-Hastings algorithm, a Markov Chain Monte Carlo technique, providing credible intervals for model parameters as well as prediction intervals for the number of future cases of mortality. Males were most likely to have been exposed to asbestos between the ages of 30 and 49 years, with the peak year of asbestos exposure estimated to be 1963. The estimated number of background cases was 1.08 cases per million population. Mortality among males is predicted to peak at approximately 2040 deaths in the year 2016, with a rapid decline thereafter. Approximately 91,000 deaths are predicted to occur from 1968 to 2050 with around 61,000 of these occurring from 2007 onwards.


Murine cytotoxic T lymphocytes recognize an epitope in an EBNA-1 fragment, but fail to lyse EBNA-1-expressing mouse cells.
Major histocompatibility complex class I-restricted cytotoxic T lymphocytes (CTLs) specific for epitopes within eight of the nine Epstein Barr Virus (EBV)-encoded latency-associated proteins have been recovered from EBV-infected human subjects by restimulation of lymphocytes in vitro. However, human class I-restricted CTL responses capable of recognizing EBNA-1 expressing cells were not detected in these studies. We have raised a murine CTL line that recognizes an epitope within EBNA-1 by immunizing mice with a vaccinia virus encoding a COOH-terminal EBNA-1 fragment. This novel CTL line was used to investigate whether the epitope (positions 509-517 in EBNA-1, presented through Kd) was presented to CTL by mouse cells expressing full-length EBNA-1 or a deletion mutant of EBNA-1, lacking the Glycine-Alanine (Gly-Ala)-rich region. Cells expressing full-length EBNA-1 are not lysed by the CTL line, whereas cells expressing the Gly-Ala deletion mutant are recognized. These results suggest that epitopes from full-length EBNA-1 are poorly presented, and that the Gly-Ala-rich region is responsible for this phenomenon. The inefficient presentation of EBNA-1-derived epitopes may explain the absence or rarity of EBNA-1-specific CTLs in vivo, a strategy that may allow EBV to maintain persistence within the immunocompetent host without being eliminated by CTLs.


Evidence for the effect of learning on timing of reproduction in blue tits.
We experimentally show that in blue tits (Parus caeruleus) egg-laying date is causally linked to experience in the previous year. Females that received additional food in the nestling period in one year laid eggs later in the next year compared with the control birds, whatever the degree of synchronization with the natural food abundance in the previous year. As a result, they raised their brood much later than the peak period of nestling food availability in the next year. The response to experience is adaptive for blue tits, which live in heterogeneous habitats where the peak period of food varies, but once settled will breed at the same location for life.


Increased Susceptibility to Postoperative PCA Morphine-Induced Respiratory Depression in a Patient with an Undiagnosed Traumatic Porencephalic Cyst - A Case Report.
Patient-controlled analgesia with morphine is routinely used for postoperative pain management. Due to the safety profiles of the technique, which are patient/disease related or technique/equipment related, severe respiratory depression requiring opioid antagonists or airway management are uncommon. The case of a patient with right colon carcinoma who was operated on for hemicolectomy under general anaesthesia and who presented with apnoea, after postoperatively receiving an initial bolus of 1mg of morphine. A large post-traumatic porencephalic cyst of the left brain hemisphere, previously undiagnosed, was found on the computed tomography scan. We excluded human errors, technique and equipment factors, and the patient did not have any other predisposing conditions like sleep apnoea, obesity, recent head injury or concurrent use of other sedatives. Previously the patient had been entirely asymptomatic, and her increased susceptibility to respiratory depression was the only clinical manifestation of porencephaly. Adult acquired porencephaly is seldom reported in the literature, clinical manifestations depending on the location and size of the cyst. In the present reported case, increased susceptibility to low-dose opioids might be associated with the structural and functional reorganisation of the brain after head trauma with the occurrence of the porencephalic cyst of the brain.


Inhibitors of Bacillus subtilis DNA polymerase III. 6-(arylalkylamino)uracils and 6-anilinouracils.
6-(Benzylamino)uracils and substituted 6-anilinouracils have been found to be potent inhibitors of Bacillus subtilis DNA polymerase III by a mechanism identical with that of 6-(phenylhydrazino)uracils. Higher phenylalkylamino homologues are progressively weaker inhibitors of the enzyme. Examination of the effects of substituents on the activity of 6-(benzylamino)uracils against wild-type and mutant enzymes and preliminary results for 6-anilinouracils have permitted further dissection of the mechanism of inhibition. The experimental results indicate that (1) the polymerase inhibitor binding site is compact, accommodating only small alterations in the distance between the uracil and phenyl rings, (2) the phenyl ring, which provides the major contribution to inhibitor-enzyme binding, adopts a specific active conformation, and (3) an enzyme site which interacts with substituents in the phenyl ring forms a part of the active site of DNA polymerase III.


Expression of endoplasmic reticulum stress proteins is a candidate marker of brain metastasis in both ErbB-2+ and ErbB-2- primary breast tumors.
The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis.


Genetic regulation of plasma levels of vitamin K-dependent proteins involved in hematostatis: results from the GAIT Project. Genetic Analysis of Idiopathic Thrombophilia.
Vitamin K-dependent proteins play a critical role in hemostasis. We have analysed the genetic and environmental correlations between measures of several vitamin K-dependent proteins in 21 Spanish extended families, including 397 individuals. Plasma functional levels of factors II, VII, IX, X, protein C and functional protein S were assayed in an automated coagulometer. Antigenic levels of total and free protein S were measured using an ELISA method. A maximum likelihood-based covariance decomposition analysis was used to assess the heritability of each trait and the genetic and environmental correlations between all possible pairs. All of the plasma levels had a significant genetic component (heritability) ranging from 22% to 52% of the phenotypic variance. Among the 28 possible pairs of genetic correlations, 18 were significant at a level of p < 0.05 and six exhibited a p-value between 0.05 and 0.10. Positive environmental correlation was observed for 25 of the pairs (p < 0.05). We conclude that genetic effects account for a large proportion of the observed phenotypic variation in vitamin K-dependent proteins. Some of the genes appear to pleiotropically influence all of these traits, since most pairs of phenotypes exhibit significant genetic correlation. However, since these phenotypes show a high degree of environmental correlation, it is also likely that the same environmental factors influence them co-jointly.


Household resources as determinants of child mortality in Ghana.
Although the association between child mortality and socioeconomic status is well established, the role of household assets as predictors of child mortality, over and above other measures of socioeconomic status, is not well studied in developing nations. This study investigated the contribution of several household resources to child mortality, beyond the influence of maternal education as a measure of socioeconomic status. This secondary analysis used data from the 2007 Ghana Maternal Health Survey to explore the relationship of child mortality to household resources. The analysis of 7183 parous women aged 15-45 years examined household resources for their association with maternal reports of any child's death for children aged less than 5 years using a survey-weighted logistic regression model while controlling for sociodemographic and health covariates. The overall household resources index was significantly associated with the death of one or more child in the entire sample (adjusted odd ratios (OR)=0.95; 95% confidence interval (CI): 0.92, 0.98]. In stratified analysis, this finding held for women living in rural but not in urban areas. Having a refrigerator at the time of interview was associated with lower odds of reporting child mortality (OR=0.63; 95%CI: 0.48, 0.83). Having a kerosene lantern (OR=1.40; 95%CI: 1.06, 1.85) or flush toilet (OR=1.84; 95%CI: 1.23, 2.75) was associated with higher odds of reporting child mortality. Adjusted regression models showed only possession of a refrigerator retained significance. Possession of a refrigerator may play a role in child mortality. This finding may reflect unmeasured socioeconomic status or the importance of access to refrigeration in preventing diarrheal disease or other proximal causes of child mortality in sub-Saharan Africa.


Eating disorders "mental health literacy" in low risk, high risk and symptomatic women: implications for health promotion programs.
Attitudes and beliefs concerning the nature and treatment of bulimia nervosa (BN) were compared among young adult women at low risk of an eating disorder (n = 332), at high risk (n = 83), or already showing symptoms (n = 94). Participants completed a self-report questionnaire that included a measure of eating disorder symptoms. A vignette of a fictional person suffering from BN was presented, followed by a series of questions addressing the nature and treatment of the problem described. High-risk and symptomatic participants were more likely than low-risk participants to report that they would not approach anyone for advice or help, were they to have BN or a similar problem, because they would not want anyone to know. Symptomatic participants were more likely to believe that someone with BN would be discriminated against, more likely to consider bulimic behaviors to be acceptable, and more likely to view BN as being common among women in the community, than low-risk participants, participants in the high-risk group being intermediate on each of these questions. The findings suggest that the attitudes and beliefs of individuals with eating disorder symptoms differ systematically from those of individuals at high risk, but who do not yet have symptoms, and from those at low risk. They also indicate specific attitudes and beliefs that may need to be addressed in prevention and early intervention programs. The potential benefits of assessing individuals' attitudes and beliefs concerning the nature and treatment of eating-disordered behaviour and tailoring program content accordingly may be worthy of investigation.