Bilateral iatrogenic [corrected] maxillary fractures after dental treatment in two aged horses.
This clinical report describes two horses with bilateral maxillary fractures following dental treatment. The fractures occurred during dental treatment by a veterinarian, and both had rostral, transverse, and complete bilateral maxillary fractures with instability and minimal displacement. The fractures were repaired using bilateral intraoral wiring with the patients under general anesthesia. The postoperative period was without complications and the fractures healed as expected. Maxillary fractures during or after routine dental treatment are rare, but can occur, especially in older horses. Appropriate sedation and, if necessary, regional nerve blocks might reduce the risk of iatrogenic fractures of the maxilla. General anesthesia must be considered for tooth extraction in horses that are difficult to restrain.


Healthcare utilization, psychiatric medication and risk of rehospitalization in suicide-attempting patients with common mental disorders.
Common mental disorders are strong risk factors for suicide attempt. We compared common mental disorder patients with and without suicide attempt regarding health care utilization and psychiatric medication, assessed gender differences and identified how psychotropic medication of attempters is associated with subsequent rehospitalization. We used administrative claims data of 22,276 common mental disorder patients with inpatient care in Lower Austria between 1 January 2006 and 31 December 2011. Suicide attempters (cases, n = 615) and non-attempters (controls, n = 21,661) were compared regarding specific healthcare utilization by calculating mean differences of time-dependent contact probabilities and psychiatric medication (i.e. prescribed defined daily doses) ± 0.5 years around their suicide attempt (cases)/common mental disorder diagnosis (controls). Cluster analysis was used to group suicide attempters according to their psychiatric medication. The risk of rehospitalization 0.5-3 years after the attempt was calculated with regression analysis controlling for sex, age and morbidity-related factors. Contacts with general practitioners were lower for attempters than non-attempters (mean difference of contact probabilities over observation period, males = -0.05, 95% confidence interval = [-0.07, -0.03]; females: mean difference = -0.04, 95% confidence interval = [-0.05, -0.03]). Regarding psychiatrists, female attempters had markedly higher contact probabilities after the attempt compared to female non-attempters (mean difference = 0.02, 95% confidence interval = [0.007, 0.04]); male attempters had lower contact probabilities before the attempt compared to male non-attempters (mean difference = -0.01, 95% confidence interval = [-0.004, -0.02]). Attempters had higher dosages of psychiatric medication across the entire period. Antidepressant and antipsychotic medication peaked at the time of common mental disorder diagnosis/attempt. Benzodiazepine prescriptions were considerably higher for male attempters than their female counterparts and were constantly elevated for male attempters across the observation period. A cluster of attempters with long-term benzodiazepine prescriptions had an increased risk of rehospitalization (adjusted odds ratio = 2.4, 95% confidence interval = [1.1, 5.5]). Despite lower contact probabilities, common mental disorder patients with suicide attempt are prescribed more psychiatric medication, particularly benzodiazepines, with an elevated risk of rehospitalization. Strong sex differences were found.


Comparison of fondaparinux and enoxaparin in acute coronary syndromes.
The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding. We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months. The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P=0.13) and at the end of the study (1222 vs. 1308, P=0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P=0.02) and at 180 days (574 vs. 638, P=0.05). Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.).


Effects of Ibuprofen Compared to Other Premedication Drugs on the Risk and Intensity of Postendodontic Pain: A Systematic Review.
This systematic review aims to evaluate the effects of ibuprofen compared to other drugs on the risk and intensity of postoperative pain resulting from endodontic treatment in adult patients. A systematic search was carried out through Medline databases (Pubmed, Scopus, Web of Science, Cochrane, Lilacs, and BBO). There was no restriction on the publication year or idiom. The gray literature was explored. The Periodicos Capes Theses Databases and ProQuest Dissertations were also searched, as well as the unpublished and ongoing trials registry and the IADR abstracts (1990-2016). Solely randomized clinical trials that compared the risk or intensity of pain resulting from endodontic treatment in adult patients were included in this systematic review. The risk of bias of the articles was evaluated using the Cochrane Collaboration's tool. A random-effect meta-analysis was conducted for ibuprofen versus placebo and ibuprofen versus other drugs at 6, 8, and 24 hours. The GRADE approach was used to assess the quality of the evidence. A total of 1132 studies were identified, and only seven meet the eligibility criteria. No difference between the groups was detected in any of the meta-analysis. An exception was observed when one study was removed from the meta-analysis of pain intensity at 24 hours for ibuprofen versus placebo, favoring ibuprofen (SMD -0.67; 95% CI -1.05 to -0.17). The quality of evidence in all meta-analyses was graded as low or very low. Results of the present systematic review indicate that there is no clear evidence supporting that preoperative ibuprofen is better than other drugs in reducing the risk and intensity of postendodontic pain.


Air Pollution Is Associated With Ischemic Stroke via Cardiogenic Embolism.
The aim of the study was to assessed the impact of short-term exposure to air pollution on ischemic stroke subtype, while focusing on stroke caused via cardioembolism. From a nationwide, multicenter, prospective, stroke registry database, 13 535 patients with acute ischemic stroke hospitalized to 12 participating centers were enrolled in this study. Data on the hourly concentrations of particulate matter <10 μm, nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO) were collected from 181 nationwide air pollution surveillance stations. The average values of these air pollutants over the 7 days before stroke onset from nearest air quality monitoring station in each patient were used to determine association with stroke subtype. The primary outcome was stroke subtype, including large artery atherosclerosis, small-vessel occlusion, cardioembolism, and stroke of other or undetermined cause. Particulate matter <10 μm and SO2 concentrations were independently associated with an increased risk of cardioembolic stroke, as compared with large artery atherosclerosis and noncardioembolic stroke. In stratified analyses, the proportion of cases of cardioembolic stroke was positively correlated with the particulate matter <10 μm, NO2, and SO2 quintiles. Moreover, seasonal and geographic factors were related to an increased proportion of cardioembolic stroke, which may be attributed to the high levels of air pollution. Our findings suggest that the short-term exposure to air pollutants is associated with cardioembolic stroke, and greater care should be taken for those susceptible to cerebral embolism during peak pollution periods. Public and environmental health policies to reduce air pollution could help slow down global increasing trends of cardioembolic stroke.


The role of oxidative stress in the pathogenesis of diabetic vascular complications.
Oxidative stress has been paid increasing attention to as an important causative factor for diabetic vascular complications. Among possible various sources, accumulating evidence has indicated that NAD(P)H oxidase may be the most important source for reactive oxygen species production in diabetic vascular tissues. The mechanisms underlying activation and up-regulation of NAD(P)H oxidase has been supposed to be mediated by high glucose-induced protein kinase C (PKC) activation. In this review article, activation of local renin-angiotensin II system induced by chymase activation is also shown to amplify such a PKC-dependent activation of NAD(P)H oxidase. Additionally, human evidence showing the beneficial effect of antioxidants on diabetic vascular complications. Bilirubin has been recognized as a strong endogenous antioxidant. Here markedly lower prevalence of vascular complications is shown in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation. Lastly, statin, angiotensin II receptor blocker, chymase inhibitor, bilirubin and biliverdin, PKC β isoform inhibitor, and glucagon-like peptide-1 analog, are shown to serve as antioxidants and have some beneficial effect on diabetic vascular complications, via inhibiting PKC-NAD(P)H oxidase activation, supporting the notion that this mechanism may be an effective therapeutic target for preventing diabetic vascular complications.


Long-term enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer.
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and hypopigmentation of skin and hair. Low-phenylalanine diet therapy can prevent irreversible damage if instituted from birth. However, poor compliance with the strict lifelong dietary therapy leads to various neurologic and behavioral problems. To develop a safe and promising gene therapy method for PKU, we investigated whether a recombinant adeno-associated virus could be used as a PAH gene transfer vector to reduce the excessive phenylalanine level in the PKU mouse model. A recombinant adeno-associated virus vector encoding the human PAH gene (rAAV-hPAH), driven by EF1-alpha promoter, was infused into PAH-deficient mice, Pah(enu2), via the hepatic portal vein. Two weeks after injection, the plasma phenylalanine level dramatically decreased to 360 microM in male PKU mice, accompanied by the coat color changing to black. The mean plasma phenylalanine level of untreated PKU mice was 1800 microM. The PAH enzyme activities of treated mice increased to 10-17% of wild-type mice. No signs of liver toxicity were observed after gene transfer. The biochemical and phenotypic corrections were sustained for up to 25 wk (25-wk detection period). In contrast, the treatment was less effective in female PKU mice. These results indicate that recombinant adeno-associated virus vector-mediated gene therapy can be a useful therapeutic candidate for patients with PKU. Further studies are needed to clarify the differences in PKU pathogenesis in males and females, and to explore alternative administration routes besides hepatic portal vein injection.


Gender perspectives in medical education.
Medical students have to go through an incredibly vast number of voluminous textbooks in their undergraduate years. But most of us learn next to nothing about the intricacies of the social determinants of health and the larger socio-political-cultural spaces we will have to negotiate. Without any exposure to the larger patriarchal, economic and historical systems, which are bound to collide with our textbook learning, we will be highly unprepared to locate our own biomedical skills within the larger context. The objective of this article is to analyse the current level of gender sensitivity in the textbooks being used for undergraduate medical training, and the potential impact that this has on developing attitudes towards a gender and rights-based approach.


Sorption and desorption of PVA-pyrene chains in and out of agarose Gel.
In situ steady-state fluorescence (SSF) measurement technique was applied to investigation of pyrene labeled Poly(vinyl alcohol) (PVA-Py) molecules diffusion in and out of agarose gels. Gel samples with four different concentration of agarose were prepared. PVA-Py was synthesized by "click" chemistry method and dissolved in water to use in diffusion experiments. The results were analyzed by using Fickian type diffusion model, and it was found that sorption and desorption processes of PVA-Py molecules in and out of agarose gel have two distinct regions for short and long diffusion times. Sorption and desorption coefficients were measured and it was seen that the diffusion rates were much larger at short times and at lower agarose concentrations.


Low-valent iron: an Fe(I) ate compound as a building block for a linear trinuclear Fe cluster.
A low-valent trinuclear iron complex with an unusual linear Fe(I)-Fe(II)-Fe(I) unit is presented. It is accessed in a rational approach using a salt metathesis reaction between a new anionic Fe(I) containing heterocycle and FeCl2. Its electronic structure was studied by single crystal XRD analysis, EPR and Mössbauer spectroscopy, and magnetic susceptibility measurements.


[Clinical and laryngoscopic findings in a Swiss Alpine goat with left grade 4 laryngeal hemiplegia].
This case report describes the diagnostic trial of an inspiratory wheeze in a 1.5-year-old Swiss Alpine goat. Left grade 4 laryngeal hemiplegia was diagnosed via laryngoscopy, whereas the severity of the hemiplegia was assessed according to the grading system used in horses. The results of clinical, radiographic, sonographic and endoscopic examinations as well as haematological, biochemical and serological analyses did not reveal the cause of the hemiplegia. Treatment with an antibiotic and vitamin B complex resulted in only slight improvement. A postmortem examination four months later revealed no gross lesions in the left laryngeal nerve, larynx and intrinsic laryngeal musculature. Histological examination of the nerve, arytenoid cartilage and intrinsic laryngeal musculature also showed no lesions. Therefore, the cause of the disease in this goat is suspected to be on the cellular or molecular level of the intrinsic laryngeal musculature.


Asymmetrizing an icosahedral virus capsid by hierarchical assembly of subunits with designed asymmetry.
Symmetrical protein complexes are ubiquitous in biology. Many have been re-engineered for chemical and medical applications. Viral capsids and their assembly are frequent platforms for these investigations. A means to create asymmetric capsids may expand applications. Here, starting with homodimeric Hepatitis B Virus capsid protein, we develop a heterodimer, design a hierarchical assembly pathway, and produce asymmetric capsids. In the heterodimer, the two halves have different growth potentials and assemble into hexamers. These preformed hexamers can nucleate co-assembly with other dimers, leading to Janus-like capsids with a small discrete hexamer patch. We can remove the patch specifically and observe asymmetric holey capsids by cryo-EM reconstruction. The resulting hole in the surface can be refilled with fluorescently labeled dimers to regenerate an intact capsid. In this study, we show how an asymmetric subunit can be used to generate an asymmetric particle, creating the potential for a capsid with different surface chemistries.


Association between recurrent aphthous stomatitis and Helicobacter pylori infection: a meta-analysis.
Several studies have shown the possible involvement of Helicobacter pylori infection in individuals with recurrent aphthous stomatitis (RAS), but the relationship remains controversial. This meta-analysis was performed to validate the association between RAS and H. pylori infection. The PubMed database was searched up to January 25, 2013 to select studies on the prevalence of H. pylori infection between RAS patients and control subjects. Studies were included if they evaluated and clearly defined exposure to RAS, reported the incidence of H. pylori infection, or provided data for their estimation. For subgroup analyses, studies were separated by region, publication year, and source of controls to screen the potential factors against the results. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Summary odds ratio (OR) estimates with 95 % confidence intervals (CIs) were calculated using the fixed-effects model. Seven case-control studies containing 339 cases and 271 controls were eventually selected for analysis. A total of 100 (29.50 %) RAS patients had H. pylori infection, which was significantly greater than the 54 (19.93 %) non-RAS controls with H. pylori infection (OR = 1.85, 95 % CI: 1.24-2.74, P = 0.002). This result persisted in a hospital-based control subgroup (OR = 2.72, 95 % CI: 1.57-4.72). Based on our meta-analysis, H. pylori infection is associated with an increased risk of RAS. The eradication of H. pylori in the stomach may promote relief of RAS symptoms and healing of oral ulcers, and even prevent the occurrence of RAS.


Interaction of ethanol and water with the {1014} surface of calcite.
Molecular dynamics simulations have been used to model the interaction between ethanol, water, and the {1014} surface of calcite. Our results demonstrate that a single ethanol molecule is able to form two interactions with the mineral surface (both Ca-O and O-H), resulting in a highly ordered, stable adsorption layer. In contrast, a single water molecule can only form one or other of these interactions and is thus less well bound, resulting in a more unstable adsorption layer. Consequently, when competitive adsorption is considered, ethanol dominates the adsorption layer that forms even when the starting configuration consists of a complete monolayer of water at the surface. The computational results are in good agreement with the results from atomic force microscopy experiments where it is observed that a layer of ethanol remains attached to the calcite surface, decreasing its ability to interact with water and for growth at the {1014} surface to occur. This observation, and its corresponding molecular explanation, may give some insight into the ability to control crystal form using mixtures of different organic solvents.


Skin colour and bilirubin in neonates.
The correlation between the yellow colour of the skin and serum bilirubin concentration, reserve albumin concentration, and pH was investigated in 76 icteric neonates. Significant linear correlation existed between yellow colour of the skin and serum bilirubin concentration, reciprocal of the reserve albumin concentration, and the squared hydrogen ion concentration. Furthermore, the basic yellowness of the skin at birth correlated linearily with the yellow colour of the skin measured when the child became jaundiced. The results support the proposed hypothesis that bilirubin is transferred from plasma to skin through two different mechanisms: (a) leakage of bilirubin-albumin complexes into extravascular spaces and (b) precipitation of bilirubin acid in phospholipid membranes. The latter mechanism suggests that measurement of the yellow colour of the skin may be a better predictor of brain damage than the serum bilirubin concentration and thus be of clinical utility. Measurement of the yellow colour of the skin as a method of obtaining serum bilirubin concentration is unreliable.


Paradoxical reduction in HDL-C with fenofibrate and thiazolidinedione therapy in type 2 diabetes: the ACCORD Lipid Trial.
To determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD). The ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4-8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as <25 mg/dL [0.647 mmol/L]) during the trial. Among ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P < 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization). Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.


Genome-wide association study of endo-parasite phenotypes using imputed whole-genome sequence data in dairy and beef cattle.
Quantitative genetic studies suggest the existence of variation at the genome level that affects the ability of cattle to resist to parasitic diseases. The objective of the current study was to identify regions of the bovine genome that are associated with resistance to endo-parasites. Individual cattle records were available for Fasciola hepatica-damaged liver from 18 abattoirs. Deregressed estimated breeding values (EBV) for F. hepatica-damaged liver were generated for genotyped animals with a record for F. hepatica-damaged liver and for genotyped sires with a least one progeny record for F. hepatica-damaged liver; 3702 animals were available. In addition, individual cow records for antibody response to F. hepatica on 6388 genotyped dairy cows, antibody response to Ostertagia ostertagi on 8334 genotyped dairy cows and antibody response to Neospora caninum on 4597 genotyped dairy cows were adjusted for non-genetic effects. Genotypes were imputed to whole-sequence; after edits, 14,190,141 single nucleotide polymorphisms (SNPs) and 16,603,644 SNPs were available for cattle with deregressed EBV for F. hepatica-damaged liver and cows with an antibody response to a parasitic disease, respectively. Association analyses were undertaken using linear regression on one SNP at a time, in which a genomic relationship matrix accounted for the relationships between animals. Genomic regions for F. hepatica-damaged liver were located on Bos taurus autosomes (BTA) 1, 8, 11, 16, 17 and 18; each region included at least one SNP with a p value lower than 10-6. Five SNPs were identified as significant (q value < 0.05) for antibody response to N. caninum and were located on BTA21 or 25. For antibody response to F. hepatica and O. ostertagi, six and nine quantitative trait loci (QTL) regions that included at least one SNP with a p value lower than 10-6 were identified, respectively. Gene set enrichment analysis revealed a significant association between functional annotations related to the olfactory system and QTL that were suggestively associated with endo-parasite phenotypes. A number of novel genomic regions were suggestively associated with endo-parasite phenotypes across the bovine genome and two genomic regions on BTA21 and 25 were associated with antibody response to N. caninum.


Results and long-term patient satisfaction after gluteal augmentation with platelet-rich plasma-enriched autologous fat.
Buttock augmentation is gaining increasing popularity in aesthetic surgery. The relatively high incidence of complications after silicone implant placement lead to the increased use of lipofilling techniques, yielding variable results with respect to graft take rate and long-term stability. Platelet-rich plasma (PRP) has been shown to have beneficial effects on wound healing and angiogenesis in the past. Therefore, we aimed at investigating the long-term results and patient satisfaction after PRP-enriched lipofilling for buttock augmentation. Twenty-four bilateral gluteal augmentations with PRP-enriched autologous fat were performed. Additionally, contour shaping was achieved by liposuction of the adjacent zones. Post-operative results and complications were recorded, and satisfaction with buttock shape was estimated by a patient questionnaire. Mean follow-up time was 44 months, and mean amount of transferred fat was 481 cc for both sides. No seroma or hematoma formation, infection or liponecrosis were reported during the post-operative follow-up. Subjective patient satisfaction in general increased from preoperatively to 3 months postoperatively and declined only slightly in the long-term course. Satisfaction levels in general were specific for each patient. Patient recovery was quick, and the majority of patients returned to work within 10 days after surgery. PRP-enhanced lipofilling of the buttocks proved to be a safe procedure including a low complication rate and consistent results. However, subjective patient expectations have to be taken into account when choosing the indication. Further large volume studies are needed to elucidate the potential and benefit of PRP in this context. Level of Evidence: Level IV, therapeutic study.


The caregiving journey for family members of relatives with cancer: how do they cope?
Family caregivers need adequate support from healthcare professionals to complete the demands associated with caregiving with minimal impact on their own health and well-being. An optimal balance of provision of care between family and support services has not been achieved; therefore, this literature review investigates how family caregivers endure and cope with the challenges of caring for an adult relative with cancer. This review considered the characteristics of caregivers and their functioning, the external and internal supports that help them cope, the ongoing challenges as they journey along the caregiving trajectory, the personal costs of caregiving, and how caregivers cope with supporting their family members through to the end of their journeys. The literature provides an abundance of research on the numerous challenges encountered by families living with cancer; however, little research has been conducted on the coping strategies used by family caregivers at specific stages along the illness trajectory that either optimize or hinder personal recovery. Even less information is available on interventions nurses can introduce to ease the caregiving burden. Improving nurses' understanding of the stressors and unmet needs associated with caregiving is fundamental to the development of effective family-focused clinical interventions.


Promoter methylation of aminopeptidase N/CD13 in malignant melanoma.
Aminopeptidase N (APN)/CD13 as ubiquitously expressed membrane peptidase exerts important functions in diverse cellular processes, such as proliferation, migration and differentiation. Previously, a role of APN in the invasiveness of melanoma cells has been demonstrated, but the underlying molecular mechanisms controlling APN expression are not understood. The present study demonstrates that lack of APN expression in primary and established melanoma cells was directly associated with a high-grade DNA methylation status of the myeloid APN promoter. Demethylation by 5-aza-2'-desoxycytidine not only induced constitutive and cytokine-regulated APN protein expression but also resulted in an increased APN-dependent migration of melanoma cells. Furthermore, its heterogeneous expression was inversely correlated to the expression of melanocytic marker proteins in established as well as in short-term cultured human melanoma cells. Staining of tissue microarrays generated from a large series of melanoma samples and control tissues demonstrated a higher APN expression in primary melanoma lesions when compared with nevi and metastases, which was neither associated with clinico-pathological parameters nor with the patients' outcome. Thus, the heterogeneous APN expression pattern in melanoma cells is epigenetically controlled and directly associated with an altered migration capacity but not of clinical significance in our study group.


Long-Term Follow-Up of the Intergroup Exemestane Study.
Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.


The quaternary structure of amalgam, a Drosophila neuronal adhesion protein, explains its dual adhesion properties.
Amalgam (Ama) is a secreted neuronal adhesion protein that contains three tandem immunoglobulin domains. It has both homophilic and heterophilic cell adhesion properties, and is required for axon guidance and fasciculation during early stages of Drosophila development. Here, we report its biophysical characterization and use small-angle x-ray scattering to determine its low-resolution structure in solution. The biophysical studies revealed that Ama forms dimers in solution, and that its secondary and tertiary structures are typical for the immunoglobulin superfamily. Ab initio and rigid-body modeling by small-angle x-ray scattering revealed a distinct V-shaped dimer in which the two monomer chains are aligned parallel to each other, with the dimerization interface being formed by domain 1. These data provide a structural basis for the dual adhesion characteristics of Ama. Thus, the dimeric structure explains its homophilic adhesion properties. Its V shape suggests a mechanism for its interaction with its receptor, the single-pass transmembrane adhesion protein neurotactin, in which each "arm" of Ama binds to the extracellular domain of neurotactin, thus promoting its clustering on the outer face of the plasma membrane.


Ways of Hoping: Navigating the Paradox of Hope and Despair in Chronic Pain.
In this paper, we explore hope in the context of living with chronic pain. Individuals with chronic pain from temporomandibular disorder(s) were interviewed four to five times over the course of their 18-month participation in a clinical trial investigating the effectiveness of Traditional Chinese Medicine. We sought to understand shifts in participants' descriptions of expectations and hopefulness, particularly with regard to the work involved in counterbalancing positive thinking with buffers against disappointment. We found hope to be a dynamic and multifaceted mindset as distinct from being a single entity to be measured. Drawing upon Polanyi's concept of tacit knowing, we explore how different ways of hoping emerge and index one another in participant narratives. We offer a working typology of hope and raise as an issue the manner in which the paradox of hope--hoping enough to carry on while keeping hopes in check to avoid the ever-present possibility of despair--complicates simplistic notions of the relationship between positive thinking and the placebo response.


Red blood cell distribution in simplified capillary networks.
A detailed model of red blood cell (RBC) transport in a capillary network is an indispensable element of a comprehensive model for the supply of the human organism with oxygen and nutrients. In this paper, we introduce a two-phase model for the perfusion of a capillary network. This model accounts for the special role of RBCs, which have a strong influence on network dynamics. Analytical results and numerical simulations with a discrete model and a generic network topology indicate that there exists a local self-regulation mechanism for the flow rates and a global de-mixing process that leads to an inhomogeneous haematocrit distribution. Based on the results from the discrete model, we formulate an efficient algorithm suitable for computing the pressure and flow field as well as a continuous haematocrit distribution in large capillary networks at steady state.


Blood pressure self-monitoring in pregnancy: examining feasibility in a prospective cohort study.
Raised blood pressure (BP) affects approximately 10% of pregnancies worldwide, and a high proportion of affected women develop pre-eclampsia. This study aimed to evaluate the feasibility of self-monitoring of BP in pregnancy in women at higher risk of pre-eclampsia. This prospective cohort study of self-monitoring BP in pregnancy was carried out in two hospital trusts in Birmingham and Oxford and thirteen primary care practices in Oxfordshire. Eligible women were those defined by the UK National Institute for Health and Care Excellence (NICE) guidelines as at higher risk of pre-eclampsia. A total of 201 participants were recruited between 12 and 16 weeks of pregnancy and were asked to take two BP readings twice daily three times a week through their pregnancy. Primary outcomes were recruitment, retention and persistence of self-monitoring. Study recruitment and retention were analysed with descriptive statistics. Survival analysis was used to evaluate the persistence of self-monitoring and the performance of self-monitoring in the early detection of gestational hypertension, compared to clinic BP monitoring. Secondary outcomes were the mean clinic and self-monitored BP readings and the performance of self-monitoring in the detection of gestational hypertension and pre-eclampsia compared to clinic BP. Of 201 women recruited, 161 (80%) remained in the study at 36 weeks or to the end of their pregnancy, 162 (81%) provided any home readings suitable for analysis, 148 (74%) continued to self-monitor at 20 weeks and 107 (66%) at 36 weeks. Self-monitored readings were similar in value to contemporaneous matched clinic readings for both systolic and diastolic BP. Of the 23 who developed gestational hypertension or pre-eclampsia and self-monitored, 9 (39%) had a raised home BP prior to a raised clinic BP. Self-monitoring of BP in pregnancy is feasible and has potential to be useful in the early detection of gestational hypertensive disorders but maintaining self-monitoring throughout pregnancy requires support and probably enhanced training.


Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial.
Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. ClinicalTrials.gov Identifier: NCT01307579.


Neurotropic virus infections as the cause of immediate and delayed neuropathology.
A wide range of viruses from different virus families in different geographical areas, may cause immediate or delayed neuropathological changes and neurological manifestations in humans and animals. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the central nervous system, frequently leaving the patient or affected animal with a poor or fatal prognosis. Mechanisms that govern neuropathogenesis and immunopathogenesis of viral infections are highlighted, using examples of well-studied virus infections that are associated with these alterations in different populations throughout the world. A better understanding of the molecular, epidemiological and biological characteristics of these infections and in particular of mechanisms that underlie their clinical manifestations may be expected to provide tools for the development of more effective intervention strategies and treatment regimens.


The genome sequence of the Antarctic bullhead notothen reveals evolutionary adaptations to a cold environment.
Antarctic fish have adapted to the freezing waters of the Southern Ocean. Representative adaptations to this harsh environment include a constitutive heat shock response and the evolution of an antifreeze protein in the blood. Despite their adaptations to the cold, genome-wide studies have not yet been performed on these fish due to the lack of a sequenced genome. Notothenia coriiceps, the Antarctic bullhead notothen, is an endemic teleost fish with a circumpolar distribution and makes a good model to understand the genomic adaptations to constant sub-zero temperatures. We provide the draft genome sequence and annotation for N. coriiceps. Comparative genome-wide analysis with other fish genomes shows that mitochondrial proteins and hemoglobin evolved rapidly. Transcriptome analysis of thermal stress responses find alternative response mechanisms for evolution strategies in a cold environment. Loss of the phosphorylation-dependent sumoylation motif in heat shock factor 1 suggests that the heat shock response evolved into a simple and rapid phosphorylation-independent regulatory mechanism. Rapidly evolved hemoglobin and the induction of a heat shock response in the blood may support the efficient supply of oxygen to cold-adapted mitochondria. Our data and analysis suggest that evolutionary strategies in efficient aerobic cellular respiration are controlled by hemoglobin and mitochondrial proteins, which may be important for the adaptation of Antarctic fish to their environment. The use of genome data from the Antarctic endemic fish provides an invaluable resource providing evidence of evolutionary adaptation and can be applied to other studies of Antarctic fish.


Diagnosing Parkinson's disease using videotaped neurological examinations: validity and factors that contribute to incorrect diagnoses.
Field work is commonly required in movement disorders research. Sending neurologists into the field can be logistically challenging and costly. Alternatively, neurological examinations may be videotaped and reviewed later. There is little knowledge of the validity of the videotaped neurological examination in the diagnosis of Parkinson's disease (PD). We examined the validity of the videotaped Unified Parkinson's Disease Rating Scale (UPDRS) motor examination in the diagnosis of PD, and sought to determine which factors are associated with incorrect diagnoses. PD patients and controls were enrolled in a familial aggregation study between August of 1998 and June of 2000, and as part of that study each was examined by a physician who performed an in-person UPDRS motor examination. Each also underwent a second, videotaped UPDRS motor examination. Based on the review of this videotape, a neurologist, who was blinded to the previous clinical diagnosis, assigned a diagnosis of PD or normal. A total of 211 of 231 PD patients (sensitivity = 91.3%), and 170 of 172 controls (specificity = 98.8%) were correctly identified based on the videotape. True positives had a higher mean rest tremor score (1.7 vs. 0.3; P < 0.001), action tremor score (0.9 vs. 0.3; P < 0.001), bradykinesia score (11.2 vs. 7.4; P = 0.02), and disease of longer mean duration (8.9 vs. 5.8 years; P = 0.001) than false negatives. False negatives did not differ from true positives in terms of age, total dose of levodopa, Hoehn and Yahr score, or rigidity, gait and posture, or facial masking scores (each assessed during the in-person examination). The videotaped UPDRS motor examination is a useful means of diagnosing PD and provides an alternative approach for the diagnosis of PD in field studies. A limitation is that patients with milder PD of shorter duration may not be recognized as PD.


The Monitoring and Evaluation of a Multicountry Surveillance Study, the Severe Typhoid Fever in Africa Program.
There is limited information on the best practices for monitoring multicountry epidemiological studies. Here, we describe the monitoring and evaluation procedures created for the multicountry Severe Typhoid Fever in Africa (SETA) study. Elements from the US Food and Drug Administration (FDA) and European Centre for Disease Prevention and Control (ECDC) recommendations on monitoring clinical trials and data quality, respectively were applied in the development of the SETA monitoring plan. The SETA core activities as well as the key data and activities required for the delivery of SETA outcomes were identified. With this information, a list of key monitorable indicators was developed using on-site and centralized monitoring methods, and a dedicated monitoring team was formed. The core activities were monitored on-site in each country at least twice per year and the SETA databases were monitored centrally as a collaborative effort between the International Vaccine Institute and study sites. Monthly reports were generated for key indicators and used to guide risk-based monitoring specific for each country. Preliminary results show that monitoring activities have increased compliance with protocol and standard operating procedures. A reduction in blood culture contamination following monitoring field visits in two of the SETA countries are preliminary results of the impact of monitoring activities. Current monitoring recommendations applicable to clinical trials and routine surveillance systems can be adapted for monitoring epidemiological studies. Continued monitoring efforts ensure that the procedures are harmonized across sites. Flexibility, ongoing feedback, and team participation yield sustainable solutions.


Is it really organic?--multi-isotopic analysis as a tool to discriminate between organic and conventional plants.
Novel procedures for analytical authentication of organic plant products are urgently needed. Here we present the first study encompassing stable isotopes of hydrogen, carbon, nitrogen, oxygen, magnesium and sulphur as well as compound-specific nitrogen and oxygen isotope analysis of nitrate for discrimination of organically and conventionally grown plants. The study was based on wheat, barley, faba bean and potato produced in rigorously controlled long-term field trials comprising 144 experimental plots. Nitrogen isotope analysis revealed the use of animal manure, but was unable to discriminate between plants that were fertilised with synthetic nitrogen fertilisers or green manures from atmospheric nitrogen fixing legumes. This limitation was bypassed using oxygen isotope analysis of nitrate in potato tubers, while hydrogen isotope analysis allowed complete discrimination of organic and conventional wheat and barley grains. It is concluded, that multi-isotopic analysis has the potential to disclose fraudulent substitutions of organic with conventionally cultivated plants.


A Clinical Study Assessing the Influence of Anodized Titanium and Zirconium Dioxide Abutments and Peri-implant Soft Tissue Thickness on the Optical Outcome of Implant-Supported Lithium Disilicate Single Crowns.
To assess the influence of anodized titanium and zirconium dioxide abutments and peri-implant soft tissue thickness on the optical outcome of implant-supported lithium disilicate single crowns. Twenty patients with a missing maxillary single incisor, canine, or first premolar received an endosseous implant after a two-stage surgery protocol. After healing and soft tissue conditioning, peri-implant soft tissues were reproduced in the impression, and the thickness was measured. Customized abutments were made of titanium, gold-anodized titanium, pink-anodized titanium, and zirconium dioxide. The definitive prosthesis was a lithium disilicate crown stratified by feldsphatic porcelain. Customized abutments were screwed (35 Ncm), and the crown was temporarily placed on the abutment with a try-in paste. Color measurements were made using a spectrophotometer. CIELab color scale was employed following the formula: ΔE = (ΔL)² + (Δa) ² + (Δb) ². Data were analyzed using repeated-measures analysis of variance (ANOVA), Bonferroni and Pearson's correlation tests (α = .05). Abutment material type significantly affected the ΔE values at both the peri-implant soft tissue (P = .0001) and coronal level (P = .001). The lowest ΔE values were obtained with zirconia abutments at both soft tissue (6.06 ± 3.2) and coronal level (5.76 ± 2.9) compared with those of other abutments (soft tissue: 8.96 ± 3.1 to 11.56 ± 3.4; coronal: 8.66 ± 6.1 to 10.42 ± 6.3). Mean soft tissue thickness (1.63 ± 0.64 mm) affected the ΔE values at the peri-implant soft tissue level for only titanium and pink-anodized titanium abutments (P = .024 and P = .048, respectively). In all conditions, correlation coefficients between ΔE and the abutment materials were higher for titanium (r = -0.544; P = .024) and the least for zirconia (r = -0.313; P = .238) and gold-anodized titanium (r = -0.393; P = .119) abutments. All abutment types demonstrated noticeable color difference at both the soft tissue and coronal levels. Zirconia abutments showed the lowest ΔE values at both measurement zones. Soft tissue thickness did not affect the ΔE values at the peri-implant soft tissue level.


The flavonoid apigenin potentiates the growth inhibitory effects of gemcitabine and abrogates gemcitabine resistance in human pancreatic cancer cells.
The aim of the study was to evaluate the effect of combination therapy of apigenin and gemcitabine on cell proliferation, the cell cycle, and gemcitabine resistance in human pancreatic cancer cells. Cell counting was used to assess the effect of single-agent and combination treatment on the proliferation of CD18 and AsPC-1 pancreatic cancer cells. Flow cytometry was performed to assess the effect of combination treatment on cell cycle progression and induction of apoptosis. Western blot analysis was used to evaluate phosporylated AKT (pAkt) and cell cycle proteins. The effect of apigenin on gemcitabine-resistant AsPC-1 cells was assessed via thymidine incorporation. Apigenin in combination with gemcitabine inhibited pancreatic cancer cell proliferation more than either agent alone. Combination treatment induced both S and G2/M phase arrest and increased apoptosis. Apigenin down-regulated pAkt expression and abrogated gemcitabine-mediated pAkt induction. In gemcitabine-resistant AsPC-1 cells, apigenin significantly inhibited cell proliferation in a dose-dependent manner. Combination treatment with apigenin and gemcitabine inhibited pancreatic cancer cell growth via cell cycle arrest, down-regulation of the prosurvival factor pAkt, and induction of apoptosis. Combination therapy may prove useful for the treatment of pancreatic cancer.


Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis.
Various treatments of osteoarthritis (OA) have been described, including use of nutraceuticals. To review systematically the literature about the effects of nutraceuticals on clinical signs of pain or abnormal locomotion in horses, dogs, and cats, and to discuss methodological aspects of trials and systematic reviews. A systematic search of controlled trials evaluating the impact of nutraceuticals on OA in horses, dogs, and cats was performed, using Medline, CAB Abstracts, and Google Scholar. Scientific evidence was evaluated by means of criteria proposed by the Food and Drug Administration (FDA), and a scoring system adapted from both the CONsolidated Standards of Reporting Trials (CONSORT) statement and recommendations for assessing trials by the Center of Evidence Based Medicine of Oxford. Twenty-two papers were selected and reviewed, with 5 studies performed in horses, 16 in dogs, and 1 in cats. The strength of evidence was low for all nutraceuticals except for omega-3 fatty acid in dogs. There were limited numbers of rigorous randomized controlled trials and of participants in clinical trials. The evidence of efficacy of nutraceuticals is poor, with the exception of diets supplemented with omega-3 fatty acids in dogs. Greater access to systematic reviews must be part of the objectives of the veterinary science in the future. Their reporting would be improved by internationally agreed-upon criteria for standards and guidelines.


The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation.
Molecular cloning experiments have led to the identification and characterization of a family of five receptors for the melanocortin (melanotropic and adrenocorticotropic) peptides. The first two members of the family cloned were the well-characterized melanocyte-stimulating hormone receptor (MSH-R) and adrenocorticotropin receptor (ACTH-R). The three new melanocortin receptors have been termed the MC3-R, MC4-R, and MC5-R, according to the order of their discovery, and little is known at this point concerning their function. Agouti and extension are two genetic loci known to control the amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments. Chromosomal mapping demonstrated that the MSH-R, now termed MCI-R, mapped to extension. Extension was shown to encode the MCI-R, and mutations in the MCI-R are responsible for the different pigmentation phenotypes caused by this locus. Functional variants of the MCI-R, originally characterized in the mouse, have now also been identified in the guinea pig and cow. Dominant constitutive mutants of the MCI-R are responsible for causing dark black coat colors while recessive alleles result in yellow or red coat colors. Agouti, a secreted 108 amino acid peptide produced within the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production. Experiments demonstrate that agouti is a high-affinity antagonist, acting at the MCI-R to block alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. The MCI-R is thus a unique bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti, both contributing to the variability seen in mammalian coat colors. The variable tan and black coat color patterns seen in the German Shepherd, for example, can now be understood on the molecular level as the interaction of a number of extension and agouti alleles encoding variably functioning receptors and a differentially expressed antagonist of the receptor, respectively.


The Influence of In Vitro Gastrointestinal Digestion on the Anticancer Activity of Manuka Honey.
: Manuka honey (MH) is a natural food with many beneficial properties to human health, thanks to its high variety of bioactive compounds; however, little is known about its bioaccessibility. The aim of this study was to evaluate and compare the polyphenol compounds, the antioxidant capacity and the anticancer activity of MH subjected to an in vitro gastrointestinal digestion in human HCT-116 colon cancer cells. Raw MH and digested MH (DMH) were assessed for total polyphenols and flavonoids by spectrophotometric and HPLC-ESI-MS/MS analysis, and total antioxidant capacity (TAC) using different methods. Cell viability, intracellular ROS production, apoptosis, cell cycle and colony formation capacity were tested after treatment with MH or DMH. Results showed that total polyphenols, total flavonoids and TAC were significantly (p < 0.05) reduced after in vitro digestion. In addition, MH and DMH at 8, 16 and 24 mg/mL had similar effects in inducing intracellular ROS production and in inhibiting the colon formation ability; MH induced a more marked apoptosis compared to DMH, while cell cycle was blocked in S phase by MH and in Sub G1 phase by DMH. Our results increase knowledge of the effect of gastrointestinal digestion on the biological effect of honey against colorectal cancer.


Competing risk bias to explain the inverse relationship between smoking and malignant melanoma.
The relationship between smoking and melanoma remains unclear. Among the different results is the paradoxical finding that smoking was shown to be inversely associated with the risk of malignant melanoma in some large cohort and case-control studies, even after control for suspected confounding variables. Smoking is a known risk factor for many non-communicable diseases, including coronary heart disease, stroke, as well as other malignancies; it has been shown to be positively associated with other types of skin cancer, and there remains no clear biologic explanation for a possible protective effect on malignant melanoma. In this paper, we propose a plausible mechanism of bias from smoking-related competing risks that may explain or contribute to the inverse association between smoking and melanoma as spurious. Using directed acyclic graphs for formalization and visualization of assumptions, and Monte Carlo simulation techniques, we demonstrate how published inverse associations might be compatible with selection bias resulting from uncontrolled or unmeasured common causes of competing outcomes of smoking-related diseases and malignant melanoma. We present results from various scenarios assuming a true null as well as a true positive association between smoking and malignant melanoma. Under a true null assumption, we find inverse associations due to the biasing mechanism to be compatible with published results in the literature, especially after the addition of unmeasured confounding variables. This study could be seen as offering a cautionary note in the interpretation of published smoking-melanoma findings.


The nutritional phenotype in the age of metabolomics.
The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on disease/wellness and is the quantitative indication of the paths by which genes and environment exert their effects on health. Advances in technology and in fundamental biological knowledge make it possible to define and measure the nutritional phenotype accurately in a cross section of individuals with various states of health and disease. This growing base of data and knowledge could serve as a resource for all scientific disciplines involved in human health. Nutritional sciences should be a prime mover in making key decisions that include: what environmental inputs (in addition to diet) are needed; what genes/proteins/metabolites should be measured; what end-point phenotypes should be included; and what informatics tools are available to ask nutritionally relevant questions. Nutrition should be the major discipline establishing how the elements of the nutritional phenotype vary as a function of diet. Nutritional sciences should also be instrumental in linking the elements that are responsive to diet with the functional outcomes in organisms that derive from them. As the first step in this initiative, a prioritized list of genomic, proteomic, and metabolomic as well as functional and behavioral measures that defines a practically useful subset of the nutritional phenotype for use in clinical and epidemiological investigations must be developed. From this list, analytic platforms must then be identified that are capable of delivering highly quantitative data on these endpoints. This conceptualization of a nutritional phenotype provides a concrete form and substance to the recognized future of nutritional sciences as a field addressing diet, integrated metabolism, and health.


Influenza virus effects on cell membrane proteins.
During infection by influenza virus, viral proteins become firmly attached to (or part of) host cell plasma membrane, nuclear membranes, mitochondrial, and microsomal membranes. Purified virus particles contain less than I percent host cell protein. Virus envelope proteins completely replace host membrane proteins in those discrete spots on the plasma membrane from which progeny virions bud out.


Human mammary progenitor cell fate decisions are products of interactions with combinatorial microenvironments.
In adult tissues, multi-potent progenitor cells are some of the most primitive members of the developmental hierarchies that maintain homeostasis. That progenitors and their more mature progeny share identical genomes, suggests that fate decisions are directed by interactions with extrinsic soluble factors, ECM, and other cells, as well as physical properties of the ECM. To understand regulation of fate decisions, therefore, would require a means of understanding carefully choreographed combinatorial interactions. Here we used microenvironment protein microarrays to functionally identify combinations of cell-extrinsic mammary gland proteins and ECM molecules that imposed specific cell fates on bipotent human mammary progenitor cells. Micropatterned cell culture surfaces were fabricated to distinguish between the instructive effects of cell-cell versus cell-ECM interactions, as well as constellations of signaling molecules; and these were used in conjunction with physiologically relevant 3 dimensional human breast cultures. Both immortalized and primary human breast progenitors were analyzed. We report on the functional ability of those proteins of the mammary gland that maintain quiescence, maintain the progenitor state, and guide progenitor differentiation towards myoepithelial and luminal lineages.


Cysteine desulfurase activity indicates a role for NIFS in metallocluster biosynthesis.
Biological nitrogen fixation is catalyzed by nitrogenase, a complex metalloenzyme composed of two separately purifiable component proteins encoded by the structural genes nifH, nifD, and nifK. Deletion of the Azotobacter vinelandii nifS gene lowers the activities of both nitrogenase component proteins. Because both nitrogenase component proteins have metallocluster prosthetic groups that are composed of iron- and sulfur-containing cores, this result indicated that the nifS gene product could be involved in the mobilization of the iron or sulfur required for metallocluster formation. In the present work, it is shown that NIFS is a pyridoxal phosphate-containing homodimer that catalyzes the formation of L-alanine and elemental sulfur by using L-cysteine as substrate. NIFS activity is extremely sensitive to thiol-specific alkylating reagents, which indicates the participation of a cysteinyl thiolate at the active site. Based on these results we propose that an enzyme-bound cysteinyl persulfide that requires the release of the sulfur from the substrate L-cysteine for its formation ultimately provides the inorganic sulfide required for nitrogenase metallocluster formation. The recent discovery of nifS-like genes in non-nitrogen-fixing organisms also raises the possibility that the reaction catalyzed by NIFS represents a universal mechanism that involves pyridoxal phosphate chemistry, in the mobilization of the sulfur required for metallocluster formation.


Distinct cerebral pathways for object identity and number in human infants.
All humans, regardless of their culture and education, possess an intuitive understanding of number. Behavioural evidence suggests that numerical competence may be present early on in infancy. Here, we present brain-imaging evidence for distinct cerebral coding of number and object identity in 3-mo-old infants. We compared the visual event-related potentials evoked by unforeseen changes either in the identity of objects forming a set, or in the cardinal of this set. In adults and 4-y-old children, number sense relies on a dorsal system of bilateral intraparietal areas, different from the ventral occipitotemporal system sensitive to object identity. Scalp voltage topographies and cortical source modelling revealed a similar distinction in 3-mo-olds, with changes in object identity activating ventral temporal areas, whereas changes in number involved an additional right parietoprefrontal network. These results underscore the developmental continuity of number sense by pointing to early functional biases in brain organization that may channel subsequent learning to restricted brain areas.


Visual analysis of network traffic for resource planning, interactive monitoring, and interpretation of security threats.
The Internet has become a wild place: malicious code is spread on personal computers across the world, deploying botnets ready to attack the network infrastructure. The vast number of security incidents and other anomalies overwhelms attempts at manual analysis, especially when monitoring service provider backbone links. We present an approach to interactive visualization with a case study indicating that interactive visualization can be applied to gain more insight into these large data sets. We superimpose a hierarchy on IP address space, and study the suitability of Treemap variants for each hierarchy level. Because viewing the whole IP hierarchy at once is not practical for most tasks, we evaluate layout stability when eliding large parts of the hierarchy, while maintaining the visibility and ordering of the data of interest.


The landscape of accessible chromatin in quiescent cardiac fibroblasts and cardiac fibroblasts activated after myocardial infarction.
After myocardial infarction, the massive death of cardiomyocytes leads to cardiac fibroblast proliferation and myofibroblast differentiation, which contributes to the extracellular matrix remodelling of the infarcted myocardium. We recently found that myofibroblasts further differentiate into matrifibrocytes, a newly identified cardiac fibroblast differentiation state. Cardiac fibroblasts of different states have distinct gene expression profiles closely related to their functions. However, the mechanism responsible for the gene expression changes during these activation and differentiation events is still not clear. In this study, the gene expression profiling and genome-wide accessible chromatin mapping of mouse cardiac fibroblasts isolated from the uninjured myocardium and the infarct at multiple time points corresponding to different differentiation states were performed by RNA sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. ATAC-seq peaks were highly enriched in the promoter area and the distal area where the enhancers are located. A positive correlation was identified between the expression and promoter accessibility for many dynamically expressed genes, even though evidence showed that mechanisms independent of chromatin accessibility may also contribute to the gene expression changes in cardiac fibroblasts after MI. Moreover, motif enrichment analysis and gene regulatory network construction identified transcription factors that possibly contributed to the differential gene expression between cardiac fibroblasts of different states.


Strategic implementation and accountability: the case of the long-term care alliance.
A group of chief executives of long-term care homes formed an alliance in order to tap the resources residing within their management teams. Adopting a strategic implementation project based on a framework of accountability, the executives were able to better understand the uncertainties of the environment and potentially structure their strategic implementation to best use scarce resources. The framework of accountability allowed the homes to recognize the need for a strong business approach to long-term care. Communication improved throughout the organizations while systems and resources showed improved utilization. Quality became the driving force for all actions taken to move the organizations toward achieving their visions.


Population-based survey on disease insight, quality of life, and health-seeking behavior associated with female urinary incontinence.
To evaluate disease insight, personal distress, and healthcare-seeking behavior of women with urinary incontinence (UI) to improve women's health in Korea. In October 2012, 500 Korean women residing around Seoul, Incheon, and Gyeonggi-do were selected by random sampling for a population-based cross-sectional survey conducted by computer-aided telephone interview. Sixteen questions, which included information on demographic characteristics, information sources, disease insights, and general health-seeking behavior, were used for data collection. Among the responders, 23.8% experienced UI, the prevalence of which increased with increasing age; 83.3% knew about UI through the mass media out of 98.2% apprehended people. Regarding general awareness of UI, 77.2% understood that UI is caused by aging. A total of 48.7% of subjects experienced societal restrictions because of UI. Most women in in their 30s (25.6%) in the acquired UI information from the Internet, while those in their 50s and 60s (50-59 years, 51.1%; 60-64 years, 42.4%) learned about UI through friends. Among subjects who did not have UI, 89.37% intended to see a doctor or consult a professional if they developed UI (83.2%). Among those with UI, however, only 59.0% had talked about UI; 79.7% had talked with friends or associates, whereas only 23.2% had consulted a professional. Most respondents tended to obtain information on UI through the mass media. Subjects who did not have UI expressed their intention to consult a professional if they developed UI, while the percentage of subjects with UI who had consulted a professional was very low. Many women are ashamed of UI in Korea, which may be changed by providing efficient advertising with the right information and establishing a new perception of UI.


Are passive smoking, air pollution and obesity a greater mortality risk than major radiation incidents?
Following a nuclear incident, the communication and perception of radiation risk becomes a (perhaps the) major public health issue. In response to such incidents it is therefore crucial to communicate radiation health risks in the context of other more common environmental and lifestyle risk factors. This study compares the risk of mortality from past radiation exposures (to people who survived the Hiroshima and Nagasaki atomic bombs and those exposed after the Chernobyl accident) with risks arising from air pollution, obesity and passive and active smoking. A comparative assessment of mortality risks from ionising radiation was carried out by estimating radiation risks for realistic exposure scenarios and assessing those risks in comparison with risks from air pollution, obesity and passive and active smoking. The mortality risk to populations exposed to radiation from the Chernobyl accident may be no higher than that for other more common risk factors such as air pollution or passive smoking. Radiation exposures experienced by the most exposed group of survivors of Hiroshima and Nagasaki led to an average loss of life expectancy significantly lower than that caused by severe obesity or active smoking. Population-averaged risks from exposures following major radiation incidents are clearly significant, but may be no greater than those from other much more common environmental and lifestyle factors. This comparative analysis, whilst highlighting inevitable uncertainties in risk quantification and comparison, helps place the potential consequences of radiation exposures in the context of other public health risks.


Team leadership in the intensive care unit: the perspective of specialists.
To identify the behaviors senior physicians (e.g., specialists, staff attendings) report using to lead multidisciplinary teams in the intensive care unit. Semistructured interviews focusing on team leadership, crisis management, and development of an environment that enable effective team performance in the intensive care unit. Seven general intensive care units based in National Health Service hospitals in the United Kingdom. Twenty-five senior intensive care medicine physicians. Responses to a semistructured interview were transcribed and subjected to "content" analysis. The interview analysis focused on references to the "functional" behaviors used by leaders to manage team performance and the "team development behaviors" used to build the conditions that enable effective team performance. Seven of the interviews were coded by a second psychologist to measure inter-rater reliability. Inter-rater reliability (Cohen's κ) was acceptable for both scales (κ = 0.72 and κ = 0.75). In total, 702 functional leadership behaviors (behaviors for information gathering, planning and decision-making, managing team members) were coded as being used to manage the intensive care unit, along with 216 team development behaviors (for providing team direction and establishing team norms). These behaviors were grouped together in a theoretically driven framework of intensive care unit team leadership. Intensive care unit senior physicians report using a variety of leadership behaviors to ensure high levels of team performance. The data described in this study provide insight into the team leadership behaviors used by intensive care unit team leaders and have implications for the development of team leadership training and assessment tools.


Membrane fusion: caught in a trap.
SNAREs are small coiled-coil proteins required for specific membrane fusion events in eukaryotic cells. Recent evidence points to the existence of an inhibitory class of SNAREs, i-SNAREs, which prevent incorrect fusions from occurring, adding a further layer of regulation to the process of membrane docking and fusion.


Physical activity and FTO genotype by physical activity interactive influences on obesity.
Although the effect of the fat mass and obesity-associated (FTO) gene on adiposity is well established, there is a lack of evidence whether physical activity (PA) modifies the effect of FTO variants on obesity in Latino populations. Therefore, the purpose of this study was to examine PA influences and interactive effects between FTO variants and PA on measures of adiposity in Latinos. After controlling for age and sex, participants who did not engage in regular PA exhibited higher BMI, fat mass, HC, and WC with statistical significance (P < 0.001). Although significant associations between the three FTO genotypes and adiposity measures were found, none of the FTO genotype by PA interaction assessments revealed nominally significant associations. However, several of such interactive influences exhibited considerable trend towards association. These data suggest that adiposity measures are associated with PA and FTO variants in Latinos, but the impact of their interactive influences on these obesity measures appear to be minimal. Future studies with large sample sizes may help to determine whether individuals with specific FTO variants exhibit differential responses to PA interventions.


Traceless Immobilization of Analytes for High-Throughput Experiments with SAMDI Mass Spectrometry.
Label-free assays, and particularly those based on the combination of mass spectroscopy with surface chemistries, enable high-throughput experiments of a broad range of reactions. However, these methods can still require the incorporation of functional groups that allow immobilization of reactants and products to surfaces prior to analysis. In this paper, we report a traceless method for attaching molecules to a self-assembled monolayer for matrix-assisted laser desorption and ionization (SAMDI) mass spectrometry. This method uses monolayers that are functionalized with a 3-trifluoromethyl-3-phenyl-diazirine group that liberates nitrogen when irradiated and gives a carbene that inserts into a wide range of bonds to covalently immobilize molecules. Analysis of the monolayer with SAMDI then reveals peaks for each of the adducts formed from molecules in the sample. This method is applied to characterize a P450 drug metabolizing enzyme and to monitor a Suzuki-Miyaura coupling chemical reaction and is important because modification of the substrates with a functional group would alter their activities. This method will be important for high-throughput experiments in many areas, including reaction discovery and optimization.


Incidence of IBS in a cohort of people with asthma.
We conducted a study to examine the relation of asthma and its treatment to irritable bowel syndrome (IBS). We identified cohorts of members with and without asthma from January 1996 though June 2002 and calculated rates of IBS in both cohorts. In a nested case-control study, we calculated odds ratios for oral steroid dispensing before IBS onset. To address differential IBS detection, we conducted a quantitative sensitivity analysis. We identified 91,237 people with asthma and sample of 24,518 people without asthma. There was a 20% increase in the incidence of IBS among people with asthma (standardized morbidity ratio = 1.2; 95% CI, 1.0-1.5), and no association between oral steroids and IBS among people with asthma (OR = 1.0; 95% CI, 0.9-1.1.) Misclassification of IBS would have biased the rate ratio toward the null. We observed a small increase in IBS among people with asthma, and no association between oral steroids and IBS onset among asthma patients.


Polymorphism of HLA class II genes in Berbers from Southern Tunisia.
In this study, the HLA-DRB1 and -DQB1 molecular diversity of two Berber-speaking populations of Southern Tunisia was analysed. Genetic comparisons indicate that both populations exhibit peculiar profiles for HLA-DRB1, as they diverge significantly from most other North Africans, while being highly diversified. At the opposite, they are much less differentiated from neighbouring populations according to the HLA-DQB1 polymorphism. Overall, the HLA class II genetic structure of Arab and Berber-speaking populations from Tunisia, and of North Africa as a whole, is complex and cannot be simply explained by geographic or linguistic differentiations. The present North African genetic pool has probably been shaped by both genetic drift and the contribution of genetically heterogeneous populations during the history of settlement of North Africa.


The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.
The effects of MK-801 [( +]-5-methyl-10,11-dihydro-5H-di-benzo[a, d]cyclohepten-5,10-imine) on peripheral and central nicotinic receptors were studied using electrophysiological and biochemical techniques. MK-801 depressed the peak amplitude and accelerated the decay of end-plate currents. The drug (1-10 microM) decreased the frequency of activation of acetylcholine (ACh)-induced single-channel currents in addition to shortening the mean open and burst times of channels activated by either ACh or (+)anatoxin-a (AnTX). MK-801 (10-40 microM) depressed the single potentials and trains of ACh and AnTX-induced potentials in chronically denervated rat soleus muscles. MK-801 blocked the twitch responses (20-100 microM) of both frog sartorius and rat diaphragm muscles evoked by stimulation of their respective nerves. Also this drug (less than 1 microM) decreased the frequency of channels activated by AnTX or ACh in outside-out patch membranes of rat retinal ganglion cells with minimal changes in the channel open time. MK-801 (10-25 microM) depressed (-)nicotine-evoked gamma-amino[2,3-3H]butyric acid release from rat hippocampal synaptosomes; however, it failed to affect the binding of [3H](-)nicotine to brain membranes and also failed to interfere with the binding of [125I]alpha-bungarotoxin to either frog muscle or Torpedo membranes. On the other hand, MK-801 inhibited the binding of [3H]perhydrohistrionicotoxin to Torpedo membranes and such an effect was more pronounced in the presence of carbamylcholine. Neither AnTX nor any other nicotinic agonist increased the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor ion channel complex. The actions of MK-801 were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors. These results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801.


mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels.
Complementary DNAs (cDNAs) from mSlo, a gene encoding calcium-activated potassium channels, were isolated from mouse brain and skeletal muscle, sequenced, and expressed in Xenopus oocytes. The mSlo-encoded channel resembled "maxi" or BK (high conductance) channel types; single channel conductance was 272 picosiemens with symmetrical potassium concentrations. Whole cell and single channel currents were blocked by charybdotoxin, iberiotoxin, and tetraethylammonium ion. A large number of variant mSlo cDNAs were isolated, indicating that several diverse mammalian BK channel types are produced by a single gene.


Salt Intake and All-Cause Mortality in Hemodialysis Patients.
Although some clinical practice guidelines regarding hemodialysis recommend salt restriction, few studies have examined the association between salt intake and clinical outcomes in hemodialysis patients. This study aimed to clarify the association between salt intake and mortality in hemodialysis patients. This retrospective cohort study was based on the Japanese Society for Dialysis Therapy renal data registry database (2008) and included 88,115 adult patients who had received hemodialysis for at least 2 years. Estimated salt intake was the main predictor and was calculated from intra-dialytic weight loss and pre- and post-dialysis serum sodium levels. Nonlinear logistic regression was used to determine the association between salt intake and mortality, adjusting for potential confounders. The outcomes considered were all-cause mortality and cardiovascular death at 1 year. The median (25-75th percentile) salt intake at baseline was 6.4 (4.6-8.3) g/day. At 1 year, all-cause mortality occurred in 1,845 (2.1%) patients, including 807 cardiovascular deaths. The low salt intake group (< 6 g/day) demonstrated the highest all-cause mortality and cardiovascular deaths. No association was observed between high salt intake, all-cause mortality and cardiovascular deaths. The lowest risk for all-cause mortality and cardiovascular death occurred among patients with an estimated salt intake of 9 g/day. Low salt intake, but not high salt intake, was associated with all-cause and cardiovascular mortality in Japanese hemodialysis patients. Further studies to justify including a lower limit of salt intake for hemodialysis patients are suggested.


Ill-health reported by schoolchildren during questionnaire surveys in Ghana, Mozambique and Tanzania.
Insufficient attention has been paid to the health problems of school-age children in sub-Saharan Africa. A questionnaire administered to schoolchildren about their ill-health has been developed to identify schools in which urinary schistosomiasis occurs. The data collected during the interviews can also be used to assess other common health problems. To analyse data collected during health questionnaires in schools to assess how schoolchildren perceive their own health, and to compare the findings between three countries in sub-Saharan Africa. Questionnaires asking about recent health problems were administered by teachers to schoolchildren in 120 primary schools in Mozambique, 52 primary schools in Tanzania and 298 primary schools in Ghana. A total of 67 002 children aged 8-15 years took part. Of the 10 health problems asked about in all questionnaires, the average number reported by each child was 3.9 in Ghana, 3.4 in Mozambique and 3.1 in Tanzania. The distributions of the prevalence of each condition among schools were similar and the prevalence of all conditions showed a similar ranking. For most conditions a greater percentage of girls than boys reported each health problem. Schoolchildren in Ghana, Mozambique and Tanzania do not perceive themselves to be healthy. The pattern of reported health problems was similar in each country. School health questionnaires are worthy of further study and validation.


The pH-dependence and group modification of beta-lactamase I.
The pH-dependence of the kinetic parameters for the hydrolysis of the beta-lactam ring by beta-lactamase I (penicillinase, EC 188.8.131.52) was studied. Benzylpenicillin and ampicillin (6-[D(-)-alpha-aminophenylacetamido]penicillanic acid) were used. Both kcat. and kcat./Km for both substrates gave bell-shaped plots of parameter versus pH. The pH-dependence of kcat./Km for the two substrates gave the same value (8.6) for the higher apparent pK, and so this value may characterize a group on the free enzyme; the lower apparent pK values were about 5(4.85 for benzylpenicillin, 5.4 for ampicillin). For benzylpenicillin both kcat. and kcat./Km depended on pH in exactly the same way. The value of Km for benzylpenicillin was thus independent of pH, suggesting that ionization of the enzyme's catalytically important groups does not affect binding of this substrate. The pH-dependence of kcat. for ampicillin differed, however, presumably because of the polar group in the side chain. The hypothesis that the pK5 group is a carboxyl group was tested. Three reagents that normally react preferentially with carboxyl groups inactivated the enzyme: the reagents were Woodward's reagent K, a water-soluble carbodi-imide, and triethyloxonium fluoroborate. These findings tend to support the idea that a carboxylate group plays a part in the action of beta-lactamase I.


Plasma parathyroid hormone is associated with vascular dementia and cerebral hyperintensities in two community-based cohorts.
In diseases with increased PTH such as hyperparathyroidism and chronic renal failure, dementia is common. Little is known of PTH and dementia in the community. We sought to investigate relations between PTH, clinical dementia and cerebral micro-vascular disease. The Uppsala Longitudinal Study Of Adult Men (ULSAM) was prospective, baseline, 1991-1995; followup, 15.8 years. The Prospective Investigation Of The Vasculature In Uppsala Seniors (PIVUS) was cross-sectional, baseline, 2001. Both settings were community based. PARTICIPANTS AND MAIN OUTCOME MEASURE: In the ULSAM study of 998 men (age 71) the association between PTH and dementia was investigated. In the PIVUS study of 406 men and women (age 70) the relation between PTH and magnetic resonance imaging signs of cerebral small vascular disease was investigated. During followup, 56 individuals were diagnosed with vascular, 91 with Alzheimer's, and 59 with other dementias. In Cox-regression analyses, higher PTH was associated with vascular dementia (hazard ratio per 1 SD increase of PTH, 1.41; P < .01), but not with other dementias. The top tertile of PTH accounted for 18.5% of the population-attributable risk for vascular dementia, exceeding all other risk factors. In linear regression analysis in PIVUS, PTH was associated with increasing white matter hyperintensities (WMHI), reflecting increasing burden of cerebral small vessel disease (1 SD PTH increase, 0.31 higher category of WMHI; P = .016). All models were adjusted for vascular risk factors and mineral metabolism. In two community-based samples, PTH predicted clinically diagnosed vascular dementia as well as neuroimaging indices of cerebral small vessel disease. Our data suggest a role for PTH in the development of vascular dementia.


An inhibition of the hypothalamic somatostatinergic tone is not the cause of the enhanced growth hormone response to growth hormone-releasing hormone in patients with liver cirrhosis.
Animal models of liver cirrhosis (LC) display a reduced hypothalamic somatostatinergic tone. To test whether a similar mechanism could explain the enhanced Growth Hormone (GH) secretory response to GH-Releasing Hormone (GHRH), which is seen in human LC, we studied the effect of the cholinesterase inhibitor pyridostigmine (PD), which is able to reduce the release of hypothalamic somatostatin (SS), on the GHRH-stimulated GH secretion. We considered that if PD were unable to increase GH secretion, this would constitute evidence of an already inhibited endogenous somatostatinergic tone. If proved, this in turn could explain the enhanced GH response to GHRH seen in LC. Ten LC patients and nine controls were given GHRH (100 microg, intravenously), or PD (120 mg, orally) plus GHRH. After GHRH alone, the GH peak was four times higher in LC than in controls (40.85+/-15.7 ng/ml in LC and 9.35+/-2.5 ng/ml in controls). In LC, PD administration markedly increased the GH response to GHRH (GH peak: 98.0+/-19.7 ng/ml; +240% vs. GHRH alone). The ability of PD to increase the GH response in patients with LC suggests that in this condition the enhanced GH response to GHRH is not due to a completely inhibited endogenous somatostatinergic tone. SS appears instead to maintain its modulator role on GH secretion in human LC, in contrast with what observed in animal models.


Differential redistribution of lectin receptor classes on clonal rat myotubes and myoblasts.
To evaluate the relative mobilities of cell surface glycoconjugates during myogenesis we have studied the redistribution of fluorescein-conjugated plant lectins on L6 rat myogenic cells. Previous experiments had demonstrated that the receptors for the lectins soybean agglutinin (SBA), wheat germ agglutinin, concanavalin A and Lens culinaris agglutinin all were relatively uniformly distributed on both myoblasts and myotubes, and that SBA receptors were capable of rapid redistribution on myotubes but not myoblasts at 4 degrees C (Sawyer & Akeson, 1983). Here we show that when SBA-labelled myoblasts are incubated at 37 degrees C, or for extended times at 4 degrees C, the lectin aggregates as on myotubes. So it appears that SBA-binding components show a quantitative rather than qualitative change in their mobility during L6 differentiation. In addition, the redistribution of the three other lectins on myoblasts and myotubes was either less prominent (i.e. showing fewer apparent surface clusters) or occurred less rapidly than with SBA. None of these three lectins showed striking differences in mobility between myoblasts and myotubes. Thus, it appears that SBA binds to a subset of surface glycoconjugates that is relatively highly mobile, and that this mobility is specifically enhanced with differentiation.


Towards a clinical application of freeze-dried squalene-based nanomedicines.
Squalene-adenosine (SQAd) nanoparticles (NPs) were found to display promising pharmacological activity similar to many other nanomedicines, but their long-term stability was still limited, and their preparation required specific know-how and material. These drawbacks represented important restrictions for their potential use in the clinic. Freeze-drying nanoparticles is commonly presented as a solution to allow colloidal stability, but this process needs to be adapted to each nanoformulation. Hence, we aimed at developing a specific protocol for freeze-drying SQAd NPs while preserving their structural features. NPs were lyophilised, resuspended and analysed by dynamic light scattering, atomic force microscopy and small-angle scattering. Among four different cryoprotectants, trehalose was found to be the most efficient in preserving NPs physico-chemical characteristics. Interestingly, we identified residual ethanol in NP suspensions as a key parameter which could severely affect the freeze-drying outcome, leading to NPs aggregation. Long-term stability was also assessed. No significant change in size distribution or zeta potential could be detected after three-month storage at 4 °C. Finally, freeze-dried NPs innocuity was checked in vitro on cultured hepatocytes and in vivo on mice. In conclusion, optimisation of freeze-drying conditions resulted in safe lyophilised SQAd NPs that can be easily stored, shipped and simply reconstituted into an injectable form.


Is the Sensorimotor Cortex Relevant for Speech Perception and Understanding? An Integrative Review.
In the neuroscience of language, phonemes are frequently described as multimodal units whose neuronal representations are distributed across perisylvian cortical regions, including auditory and sensorimotor areas. A different position views phonemes primarily as acoustic entities with posterior temporal localization, which are functionally independent from frontoparietal articulatory programs. To address this current controversy, we here discuss experimental results from functional magnetic resonance imaging (fMRI) as well as transcranial magnetic stimulation (TMS) studies. On first glance, a mixed picture emerges, with earlier research documenting neurofunctional distinctions between phonemes in both temporal and frontoparietal sensorimotor systems, but some recent work seemingly failing to replicate the latter. Detailed analysis of methodological differences between studies reveals that the way experiments are set up explains whether sensorimotor cortex maps phonological information during speech perception or not. In particular, acoustic noise during the experiment and 'motor noise' caused by button press tasks work against the frontoparietal manifestation of phonemes. We highlight recent studies using sparse imaging and passive speech perception tasks along with multivariate pattern analysis (MVPA) and especially representational similarity analysis (RSA), which succeeded in separating acoustic-phonological from general-acoustic processes and in mapping specific phonological information on temporal and frontoparietal regions. The question about a causal role of sensorimotor cortex on speech perception and understanding is addressed by reviewing recent TMS studies. We conclude that frontoparietal cortices, including ventral motor and somatosensory areas, reflect phonological information during speech perception and exert a causal influence on language understanding.


Combining Slaughterhouse Surveillance Data with Cattle Tracing Scheme and Environmental Data to Quantify Environmental Risk Factors for Liver Fluke in Cattle.
Liver fluke infection causes serious disease (fasciolosis) in cattle and sheep in many regions of the world, resulting in production losses and additional economic consequences due to condemnation of the liver at slaughter. Liver fluke depends on mud snails as an intermediate host and infect livestock when ingested through grazing. Therefore, environmental factors play important roles in infection risk and climate change is likely to modify this. Here, we demonstrate how slaughterhouse data can be integrated with other data, including animal movement and climate variables to identify environmental risk factors for liver fluke in cattle in Scotland. We fitted a generalized linear mixed model to the data, with exposure-weighted random and fixed effects, an approach which takes into account the amount of time cattle spent at different locations, exposed to different levels of risk. This enabled us to identify an increased risk of liver fluke with increased animal age, rainfall, and temperature and for farms located further to the West, in excess of the risk associated with a warmer, wetter climate. This model explained 45% of the variability in liver fluke between farms, suggesting that the unexplained 55% was due to factors not included in the model, such as differences in on-farm management and presence of wet habitats. This approach demonstrates the value of statistically integrating routinely recorded slaughterhouse data with other pre-existing data, creating a powerful approach to quantify disease risks in production animals. Furthermore, this approach can be used to better quantify the impact of projected climate change on liver fluke risk for future studies.


Histological analysis of benign breast imaging reporting and data system categories 4c and 5 breast lesions in imaging study.
The objective of this study was to analyze the histology of breast lesions categorized as Breast Imaging Reporting and Data System (BI-RADS) 4c or 5 breast lesions during the imaging evaluation, but diagnosed as benign during the histological evaluation. We retrospectively reviewed 71 breast lesions categorized as BI-RADS 4c or 5 during imaging study, but diagnosed as benign upon histological evaluation. Breast lesions were classified into six groups upon histological analysis: intraductal papilloma (18 cases), inflammatory group (15 cases), fibroepithelial tumor (14 cases), clustered microcalcification (10 cases), minimal histological alteration (10 cases), and adenosis (4 cases). Sclerosis and architectural complexity were associated with most of the biopsies that were morphologically similar to malignancy. Among 71 cases categorized as 4c or 5 during the imaging study, but diagnosed as benign upon histological examination, intraductal papilloma was the most frequently identified histological lesion. These 71 cases exhibited histological characteristics of sclerosis and/or complex/complicated features that should be histologically differentiated from malignancy during evaluation.