Prevalence of and risk factors for isolation of meticillin-resistant Staphylococcus spp. from dogs with pyoderma in northern California, USA.
Canine pyodermas associated with meticillin-resistant Staphylococcus spp. (MRS) have increased in prevalence over the past decade. To compare the prevalence of MRS isolation from dogs with superficial pyoderma at a primary care clinic (PCC) and those at a tertiary care facility (VMTH) in California, USA, and identify associated risk factors. Client-owned dogs from the VMTH (80 dogs) and the PCC (30 dogs). Aerobic bacterial culture and antibiotic susceptibility were performed on swab specimens collected from dogs, and meticillin resistance was determined using microdilution methods according to Clinical and Laboratory Standards Institute guidelines. A mecA gene PCR assay was used to confirm meticillin resistance when possible. Of 89 staphylococcal isolates from the VMTH, 34 (38.2%) were meticillin resistant. In 31 dogs, pyoderma persisted, and one or more follow-up isolates were obtained. The species isolated and drug susceptibility changed unpredictably during treatment. Of 33 PCC isolates, nine (27.3%) were meticillin resistant. Multiple drug resistance was identified in 41 of 53 (77.3%) MRS isolates from the VMTH and five of nine from the PCC. The sensitivity and specificity of PCR for the detection of meticillin resistance was 34 of 39 (87%) and 86 of 87 (99%), respectively. Risk factors for meticillin resistance for both sites were antibiotic treatment within the last year (P = 0.001), and for VMTH, hospitalization of dogs within the last year (P = 0.001). The prevalence of meticillin resistance was not different between VMTH and PCC isolates (P = 0.29). Previous antimicrobial therapy was an important risk factor for the isolation of MRS at both sites.


The association of discharge destination with 30-day rehospitalization rates among older adults receiving lumbar spinal fusion surgery.
As defined by Medicare (United States), post-acute rehabilitation services include care provided in inpatient rehabilitation units and facilities, skilled nursing facilities, long-term acute hospitals, and by home health services. We retrospectively evaluated the use of rehabilitation-based post-acute services among Medicare beneficiaries who were hospitalized for lumbar spinal fusion (ICD-9-CM procedure codes 81.04-81.08) in 2012-2014, examined the case-mix for those discharged to rehabilitation- and non-rehabilitation based services, and determined the association between these categories of discharge disposition and 30-day rehospitalization. The independent effect of rehabilitation-based discharge destination on 30-day readmissions was examined with a generalized linear mixed model, first adjusting for patient characteristics and then stratified by clusters that delineated more homogenous clinical profiles. Among 261,558 Medicare beneficiaries with lumbar spinal fusion surgery, 50.8% were discharged to a rehabilitation-based post-acute services. Patients discharged to rehabilitation-based services were older and had more comorbidities, and had longer hospital lengths of stays. After adjusting for patient and hospital characteristics, patients discharged to rehabilitation-based post-acute care had increased odds of 30-day rehospitalization than those without discharge to other destinations (OR 1.36; 95%CI = 1.31, 1.40). Analysis of patients by clinical profile clusters found similar results. Clinical profiles of Medicare beneficiaries who had lumbar spinal fusion surgery and were discharged to rehabilitation-based post-acute services included more comorbidities than those discharged to non-rehabilitation based settings. Controlling for these differences did not mediate the negative association between use of rehabilitation-based post-acute services and 30-day readmission.


Acoustoelasticity Analysis of Transient Waves for Non-Invasive In Vivo Assessment of Urinary Bladder.
A non-invasive method for measurement of the bladder wall nonlinear elastic behavior is presented. The method is based on acoustoelasticity modeling of the elasticity changes in bladder tissue modulus at different volumetric strain levels. At each volume, tissue strain is obtained from the real-time ultrasound images. Using acoustic radiation force, a transient Lamb wave is excited on the bladder wall and instantaneous modulus of shear elasticity is obtained from the 2-D Fourier analysis of the spatial-temporal dispersion maps. Measured elasticity and strain data are then used in an acoustoelasticity formulation to obtain the third order elastic coefficient, referred to as nonlinearity parameter A, and initial resting elasticity μ0. The method was tested in ex vivo porcine bladder samples (N = 9) before and after treatment with formalin. The estimated nonlinearity parameter, A, was significantly higher in the treated samples compared to intact (p < 0.00062). The proposed method was also applied on 16 patients with neurogenic bladders (10 compliant and 6 non-compliant subjects). The estimated nonlinearity parameter A was significantly higher in the non-compliant cases compared to the compliant (p < 0.0293). These preliminary results promise a new method for non-invasive evaluation of the bladder tissue nonlinearity which may serve as a new diagnostic and prognostic biomarker for management of the patients with neurogenic bladders.


Exercise or sports in midlife and healthy life expectancy: an ecological study in all prefectures in Japan.
With the increase of overall life expectancy in Japan, effective and beneficial lifestyle approaches and practices are crucial for individuals to have a long, productive and healthy life. Although previous studies suggest that exercise or sports, especially when performed with others, from midlife level have a positive impact on enhancing healthy life expectancy, there is paucity of information regarding these contexts and possible associations. The present study intends to clarify the relationship between engagement in exercise or sports among middle-aged persons and healthy life expectancy through an ecological study in all prefectures in Japan. We tabulated (1) the ratios of middle-aged individuals engaged in exercise or sports and (2) the different methods by which they are engaged in exercise or sports for each prefecture by using data from the 2005-2010 Longitudinal Survey of Middle-aged and Elderly Persons by the Ministry of Health, Labour and Welfare of Japan. Weighted multiple linear regression analyses were performed by sex, using healthy life expectancy in 2010 of each prefecture calculated by Hashimoto (2013) as a criterion variable; indices of (1) and (2) of each year as explanatory variables; and age, living conditions, employment, and chronic diseases as adjusted variables. For middle-aged males, the ratio of those engaged in exercise or sports in each year from 2005 to 2010 was positively correlated with healthy life expectancy; this relationship was found in the ratio of middle-aged engaging in exercise or sports "with families or friends". For females, such a relationship could only be found in the ratio of middle-aged females engaged in exercise or sports in 2008 and 2010, and those engaging in exercise or sports "with families or friends" in 2008. Prefectures with a higher ratio of middle-aged individuals engaging in exercise or sports, especially when done with families or friends, have longer healthy life expectancies. This was particularly evident for males. Thus, exercise or sports with families or friends in midlife seems to be more effective in promoting healthy life expectancy for males than females in Japan.


Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors.
Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ∼20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.


Maximum Insertion Torque, Stress, and Strain in Bone during Insertion of Three Dental Implants with Different Macroscopic Designs: A Dynamic Finite-Element Analysis.
Using finite element analysis, this study assesses maximum insertion torque, stress, and strain in bone during insertion of three dental implant types with different macroscopic designs. We model a bone block including cancellous and cortical bones and an osteotomy hole matching the size of the final implant drill. We then model three implants of the same length and diameter but with different thread and body designs. Model I has a conical body with greater apical region tapering and specifically designed threads, model II has wedge-shaped threads and a conical body, and model III is a conical implant with progressive threads. We place models into the bone block at 30 rounds/min and evaluate the implant insertion process in three equal phases of apical, middle, and coronal thirds. We record mean maximum von Mises stress, strain, and insertion torque at 10 points in each third of the osteotomy hole (total of 30 points). In all three implant models, increasing fixture insertion depth into the osteotomy hole results in augmented maximum von Mises stress, strain, and insertion torque in bone. Maximum values are recorded in model I, whereas minimum values are recorded in model III. The dental implant model with crestal microthread design shows maximum von Mises stress, strain, and insertion torque, whereas the model with progressive thread design and absence of coronal threads shows minimum stress, strain, and torque.


Salinity gradients shape the nitrifier community composition in Nanliu River Estuary sediments and the ecophysiology of comammox Nitrospira inopinata.
The recent discovery of complete ammonia oxidizers (comammox), which convert ammonia to nitrate in a single organism, revolutionized the conventional understanding that two types of nitrifying microorganisms have to be involved in the nitrification process for more than 100 years. However, how different types of nitrifiers in response to salinity change remains largely unclear. This study not only investigated nitrifier community (including ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB), comammox and nitrite-oxidizing Nitrospira) in the Nanliu estuary to find the ecological relationship between salinity and functional communities and also studied the physiology of a typical comammox Nitrospira inopinata in response to a salinity gradient. Based on sequences retrieved with four sets of functional gene primes, comammox Nitrospira was in general, mainly composed of clade A, with a clear separation of clade A1 subgroup in all samples and clade A2 subgroup in low salinity ones. As expected, group I.1b and group I.1a AOA dominated the AOA community in low- and high-salinity samples, respectively. Nitrosomonas-AOB were detected in all samples while Nitrosospira-AOB were mainly found in relatively high-salinity samples. Regarding general Nitrospira, lineages II and IV were the major groups in most of the samples, while lineage I Nitrospira was only detected in low-salinity samples. Furthermore, the comammox pure culture of N. inopinata showed an optimal salinity at 0.5‰ and ceased to grow at 12.8‰ for ammonia oxidation, but remained active for nitrite oxidation. These results show new evidence regarding niche specificity of different nitrifying microorganisms modulated mainly by salinity, and also a clear response by comammox N. inopinata to a wide range of simulated salinity levels.


Effect of transposon-induced motility mutations on colonization of the host light organ by Vibrio fischeri.
Vibrio fischeri is found both as a free-living bacterium in seawater and as the specific, mutualistic light organ symbiont of several fish and squid species. To identify those characteristics of symbiosis-competent strains that are required for successful colonization of the nascent light organ of juvenile Euprymna scolopes squids, we generated a mutant pool by using the transposon Mu dI 1681 and screened this pool for strains that were no longer motile. Eighteen independently isolated nonmotile mutants that were either flagellated or nonflagellated were obtained. In contrast to the parent strain, none of these nonmotile mutants was able to colonize the juvenile squid light organ. The flagellated nonmotile mutant strain NM200 possessed a bundle of sheathed polar flagella indistinguishable from that of the wild-type strain, indicating that the presence of flagella alone is not sufficient for colonization and that it is motility itself that is required for successful light organ colonization. This study identifies motility as the first required symbiotic phenotype of V. fischeri.


Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding.
The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity, as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions. Long-term cell proliferation studies at sub-cytotoxic doses with two representative acridones using the SKOV3 cell line, show that neither compound produces growth arrest, in contrast with the effects produced by the tri-substituted acridine compound BRACO-19. It is concluded that telomerase inhibitory activity is a necessary though by itself insufficient property in order for cellular growth arrest to occur at sub-toxic concentrations, and that tight quadruplex binding is also required.


Opium of the people? National identification predicts well-being over time.
Social group membership and its social-relational corollaries, for example, social contact, trust, and support, are prophylactic for health. Research has tended to focus on how direct social interactions between members of small-scale groups (i.e., a local sports team or community group) are conducive to positive health outcomes. The current study provides evidence from a longitudinal cross-cultural sample (N = 6,748; 18 countries/societies) that the prophylactic effect of group membership is not isolated to small-scale groups, and that members of groups do not have to directly interact, or in fact know of each other to benefit from membership. Our longitudinal analyses suggest that national identification (strength of association with the country/society of which one is a citizen) predicts lower anxiety and improved health; national identification was in fact almost as positively predictive of health status as anxiety was negatively predictive. The findings indicate that identification with large-scale groups, like small-scale groups, is palliative, and are discussed in terms of globalization and banal nationalism.


Tumor microenvironment-dependent 18F-FDG, 18F-fluorothymidine, and 18F-misonidazole uptake: a pilot study in mouse models of human non-small cell lung cancer.
(18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have demonstrated conclusive superiority. The aim of this study was to compare the intratumoral accumulation of (18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole and relate this to specific components of the tumor microenvironment in mouse models of human non-small cell lung cancer (NSCLC). We used NSCLC A549 and HTB177 cells to generate subcutaneous and peritoneal xenografts in nude mice. Animals were coinjected with a PET radiotracer, pimonidazole (hypoxia marker), and bromodeoxyuridine (proliferation marker) intravenously 1 h before animal euthanasia. Tumor perfusion was assessed by Hoechst 33342 injection, given 1 min before sacrifice. The intratumoral distribution of PET radiotracers was visualized by digital autoradiography and related to microscopic visualization of proliferation, hypoxia, perfusion, stroma, and necrosis. NSCLC xenografts had complex structures with intermingled regions of viable cancer cells, stroma, and necrosis. Cancer cells were either well oxygenated (staining negatively for pimonidazole) and highly proliferative (staining positively for bromodeoxyuridine) or hypoxic (pimonidazole-positive) and noncycling (little bromodeoxyuridine). Hypoxic cancer cells with a low proliferation rate had high(18)F-FDG and (18)F-misonidazole uptake but low (18)F-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of (18)F-fluorothymidine but low (18)F-FDG and(18)F-misonidazole. Tumor stroma and necrotic zones were always associated with low (18)F-FDG, (18)F-misonidazole, and (18)F-fluorothymidine activity. In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, (18)F-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas (18)F-misonidazole and (18)F-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. (18)F-FDG and (18)F-misonidazole display similar intratumoral distribution patterns, and both mutually exclude (18)F-fluorothymidine.


Combined antineoplastic and antiretroviral therapy for patients with Hodgkin's disease and human immunodeficiency virus infection. A prospective study of 17 patients. The Italian Cooperative Group on AIDS and Tumors (GICAT).
The optimal therapeutic approach for patients with Hodgkin's disease (HD) and human immunodeficiency virus (HIV) infection is unknown. In an attempt to improve the results obtained with standard chemotherapy and to decrease the occurrence of opportunistic infections (OI) during chemotherapy and follow-up observed in a previous experience, the authors designed a prospective combined antineoplastic and antiretroviral approach. Between March 1989 and March 1992, 17 consecutive previously untreated patients (median age, 30 years) with HD and HIV infection were enrolled. They had Stage III and IV or Stage I and II disease with adverse prognostic factors. The median CD4+ cell count was 184/microliters. Patients were stratified in two groups and treated accordingly. Group A was made up of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than 3 and without OI. These patients received epirubicin 70 mg/m2 intravenously on day 1, bleomycin 10 mg/m2 IV on day 1, and vinblastine 6 mg/m2 IV on day 1 (regimen EBV). Group B was made up of patients with PS of 3 or greater or previous OI who had received a 50% reduced dose of epirubicin and vinblastine and a full dose of bleomycin. Courses were repeated every 21 days for six cycles. Zidovudine was given at the dose of 500 mg/day from the beginning of chemotherapy in Group B and after the third cycle in Group A. Overall, 14 of 17 (82%) patients had an objective response and 9 of 17 (53%) achieved a complete remission (CR) of disease for a median duration of 20 months. Toxicity was moderate with Grade 3-4 leukopenia in eight patients and Grade 3 thrombocytopenia in one patient. Thirteen of 17 patients received zidovudine as planned with a median duration of 9 months. Only one patient had OI during or after chemotherapy (median follow-up, 11 months). No worsening of HIV markers during the combined therapy was seen, with the median CD4+ cell count before and after therapy being 184/microliters and 203/microliters, respectively. The median survival time was 11 months, with an actuarial survival rate of 48% at 36 months. The median survival time for the nine patients with CR has not been reached at the time of this analysis. These results revealed the feasibility and the activity of the combination of EBV regimen and zidovudine. Objective response rate seems similar to those previously observed in patients receiving standard chemotherapy, but only one patient had OI, and this compares favorably with the 16 OI observed in 28 patients treated with standard chemotherapy (6% versus 57%) in the authors' previous experience. Thus, it seems that the addition of antiretroviral therapy to the EBV regimen decreased the occurrence of OI during chemotherapy or follow-up.


The distribution of district-level leprosy incidence in India is geometric-stable, consistent with subcriticality.
Mathematical models predict that the community-level incidence of a controlled infectious disease across a region approaches a geometric distribution. This could hold over larger regions, if new cases remain proportional to existing cases. Leprosy has been disappearing for centuries, making an excellent candidate for testing this hypothesis. Here, we show the annual new case detection rate of leprosy in Indian districts to be consistent with a geometric distribution. For 2008-2013, goodness-of-fit testing was unable to exclude the geometric, and the shape parameter of the best fit negative binomial distribution was close to unity (0.95, 95% CI 0.87-1.03). Ramifications include that a district-level cross-sectional survey may reveal whether an infectious disease is headed towards elimination, that apparent outliers are expected and not necessarily representative of program failure, and that proportion 1/e of a small geographical unit may not meet a control threshold even when a larger area has.


[Turnover of chromatin-bound and membrane lipids in the liver and thymus of gamma-irradiated rats].
The turnover of nuclear and chromatin lipids from the liver and thymus of control and irradiated rats was studied by the incorporation of [14C]acetate. The chromatin-bound lipids were shown to possess a high metabolic activity which was especially well-pronounced in thymus cells. The higher specific radioactivity of the chromatin-bound lipids in comparison with that of intact nuclear lipids points to the structural uncoupling of chromatin lipids from other nuclear lipids.


Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in a β-thalassemia mouse model.
Thalassemias are a heterogeneous group of red blood cell disorders, considered a major cause of morbidity and mortality among genetic diseases. However, there is still no universally available cure for thalassemias. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoiesis. In β-thalassemia, β-globin synthesis is reduced causing α-globin accumulation. Unpaired globin chains, with heme attached to them, accumulate in thalassemic erythroblasts causing oxidative stress and the premature cell death. We hypothesize that in β-thalassemia heme oxygenase (HO) 1 could play a pathogenic role in the development of anemia and ineffective erythropoiesis. To test this hypothesis, we exploited a mouse model of β-thalassemia intermedia, Th3/+ We observed that HO inhibition using tin protoporphyrin IX (SnPP) decreased heme-iron recycling in the liver and ameliorated anemia in the Th3/+ mice. SnPP administration led to a decrease in erythropoietin and increase in hepcidin serum levels, changes that were accompanied by an alleviation of ineffective erythropoiesis in Th3/+ mice. Additionally, the bone marrow from Th3/+ mice treated with SnPP exhibited decreased heme catabolism and diminished iron release as well as reduced apoptosis. Our results indicate that the iron released from heme because of HO activity contributes to the pathophysiology of thalassemia. Therefore, new therapies that suppress heme catabolism may be beneficial in ameliorating the anemia and ineffective erythropoiesis in thalassemias.


[Bipolar depression in the clinic of schizophrenia].
To confirm the existence of a special variant of schizophrenia with bipolar affective disorders. The group of patients (n=30) with schizophrenia and bipolar affective disorder (BAD) with the lack of expressed and persistent hallucinations and/or delusions was studied. Extremely low levels of family adaptation, the severity of negative symptoms and the degree of its impact on social and occupational functioning confirmed the diagnosis of schizophrenia. Material and methods. Psychopathological and psychometric methods were used. Bipolar depression was characterized by severity, atypical circadian rhythm, autochthonous asthenia, atypical symptoms, frequency of mixed depression, and accompanying comorbid symptoms as polymorphic phobias, symptoms of obsessive-compulsive disorders, and pathological body sensations (senestoalgia, senestopathy), subpsychotic episodes and the tendency to alcoholism. The results have shown that here is a need for the special variant of schizophrenia with bipolar affective disorders (outside BAD) in modern classifications of mental and behavioral disorders.


Large-Gap Quantum Spin Hall State and Temperature-Induced Lifshitz Transition in Bi4Br4.
Searching for quantum spin Hall insulators with large fully opened energy gap to overcome the thermal disturbance at room temperature has attracted tremendous attention because of the robustness of one-dimensional (1D) spin-momentum locked topological edge states in the practical applications of electronic devices and spintronics. Here, we report the investigation of topological nature of monolayer Bi4Br4 by the techniques of angle-resolved photoemission spectroscopy (ARPES) and scanning tunneling microscopy. The possible topological nontriviality of 1D edge state integrals within the large energy gap (∼0.2 eV) is revealed by the first-principle calculations. The ARPES measurements at different temperatures show a temperature-induced Lifshitz transition, corresponding to the resistivity anomaly evoked by the chemical potential shift. The connection between the emergency of superconductivity and the Lifshitz transition is discussed.


Force Shadows: An Online Method to Estimate and Distribute Vertical Ground Reaction Forces from Kinematic Data.
Kinetic models of human motion rely on boundary conditions which are defined by the interaction of the body with its environment. In the simplest case, this interaction is limited to the foot contact with the ground and is given by the so called ground reaction force (GRF). A major challenge in the reconstruction of GRF from kinematic data is the double support phase, referring to the state with multiple ground contacts. In this case, the GRF prediction is not well defined. In this work we present an approach to reconstruct and distribute vertical GRF (vGRF) to each foot separately, using only kinematic data. We propose the biomechanically inspired force shadow method (FSM) to obtain a unique solution for any contact phase, including double support, of an arbitrary motion. We create a kinematic based function, model an anatomical foot shape and mimic the effect of hip muscle activations. We compare our estimations with the measurements of a Zebris pressure plate and obtain correlations of 0.39≤r≤0.94 for double support motions and 0.83≤r≤0.87 for a walking motion. The presented data is based on inertial human motion capture, showing the applicability for scenarios outside the laboratory. The proposed approach has low computational complexity and allows for online vGRF estimation.


Assessing the quality of VA Human Research Protection Programs: VA vs. affiliated University Institutional Review Board.
We compared the Human Research Protection Program (HRPP) quality indicator data of the Department of Veterans Affairs (VA) facilities using their own VA institutional review boards (IRBs) with those using affiliated university IRBs. From a total of 25 performance metrics, 13 did not demonstrate statistically significant differences, while 12 reached statistically significance differences. Among the 12 with statistically significant differences, facilities using their own VA IRBs performed better on four of the metrics, while facilities using affiliate IRBs performed better on eight. However, the absolute difference was small (0.2-2.7%) in all instances, suggesting that they were of no practical significance. We conclude that it is acceptable for facilities to use their own VA IRBs or affiliated university IRBs as their IRBs of record.


How Evolving United States Payment Models Influence Primary Care and Its Impact on the Quadruple Aim.
Prior research has demonstrated the associations between a strong primary care foundation with improved Quadruple Aim outcomes. The prevailing fee-for-service payment system in the United States reinforces the volume of services over value-based care, thereby devaluing primary care, and obstructing the health care system from attaining the Quadruple Aim. By supporting a shift from volume-based to value-based payment models, the Medicare Access and Children's Health Insurance Program Reauthorization Act may help fortify the role of primary care. This narrative review proposes a taxonomy of the major health care payment models, reviewing their ability to uphold the functions of primary care, and their impacts across the Quadruple Aim. An Ovid MEDLINE search and expert opinion from members of the Family Medicine for America's Health payment and research tactic teams were used. Titles and abstracts were reviewed for relevance to the topic, and expert opinion further narrowed the literature for inclusion to timely and relevant articles. No payment model demonstrates consistent benefits across the Quadruple Aim across a limited evidence base. Several cross-cutting lessons from available payment models several recommendations for primary care payment models, including the following: implementing per member per month-based models, validating risk-adjustment tools, increasing investments in integrated behavioral health and social services, and connecting payments to patient-oriented and primary care-oriented metrics. Along with ongoing research in emerging payment models, data systems integrated across health care and social services settings using metrics that can capture the ideal functions of primary care will be critical to the development of future payment models that most optimally enhance the role of primary care in the United States. Although the ideal payment model for primary care remains to be determined, lessons learned from existing payment models can help guide the shift from volume-based to value-based care. To most effectively pay for primary care, future payment models should invest in a primary care infrastructure, one that supports team-based, community-oriented care, and measures the delivery of the functions of primary care.


Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.


Plasma-derived exosome-like vesicles are enriched in lyso-phospholipids and pass the blood-brain barrier.
Exosomes are vesicles involved in intercellular communication. Their membrane structure and core content is largely dependent on the cell of origin. Exosomes have been investigated both for their biological roles and their possible use as disease biomarkers and drug carriers. These potential technological applications require the rigorous characterization of exosomal blood brain barrier permeability and a description of their lipid bilayer composition. To achieve these goals, we have established a 3D static blood brain barrier system based on existing systems for liposomes and a complementary LC-MS/MS and 31P nuclear magnetic resonance methodology for the analysis of purified human plasma-derived exosome-like vesicles. Results show that the isolated vesicles pass the blood brain barrier and are taken up in endothelial cells. The compositional analysis revealed that the isolated vesicles are enriched in lyso phospholipids and do not contain phosphatidylserine. These findings deviate significantly from the composition of exosomes originating from cell culture, and may reflect active removal by macrophages that respond to exposed phosphahtidylserine.


Evaluation of patients with dry eye for presence of underlying Sjögren syndrome.
To evaluate the rate of Sjögren syndrome (SS) in a cohort of patients with dry eye syndrome. Medical records of patients with a primary diagnosis of dry eye syndrome (International Classification of Diseases [ICD] code 375.15 or 370.33) were reviewed retrospectively. Patients who had 2 or more visits to a single dry eye center during a 2-year period (January 2004 to January 2006) were considered. Two hundred twenty patients with dry eye syndrome were identified. A total of 57 patients (25.9%) had an underlying rheumatic condition: 25 patients (11.4%) had rheumatoid arthritis and 24 (10.9%) had primary Sjögren syndrome (PSS). Majority of the patients with rheumatoid arthritis (96%) carried the diagnosis at the time of presentation. Of all patients with PSS, only 33.3% (8/24) carried the diagnosis at the time of presentation. Fifty percent (12/24) were diagnosed as a result of the initial evaluation. Among those, only 66.6% (8/12) tested SSA (anti-Ro antibodies) or SSB (anti-La antibodies) positive. One third of patients (4/12) tested only antinuclear antibody positive at a titer of <1/320 and required minor salivary gland biopsy for definitive diagnosis. Additional 16.7% (4/24), who were initially serologically negative, eventually underwent minor salivary gland biopsy and became diagnosed with SS. PSS seems to be underdiagnosed in patients with dry eye syndrome and should be the focus of diagnostic evaluations. A minor salivary gland biopsy might be required for a definitive diagnosis in a significant proportion of the patients with SS.


Nitric oxide regulation of cyclic di-GMP synthesis and hydrolysis in Shewanella woodyi.
Although several reports have documented nitric oxide (NO) regulation of biofilm formation, the molecular basis of this phenomenon is unknown. In many bacteria, an H-NOX (heme-nitric oxide/oxygen-binding) gene is found near a diguanylate cyclase (DGC) gene. H-NOX domains are conserved hemoproteins that are known NO sensors. It is widely recognized that cyclic di-GMP (c-di-GMP) is a ubiquitous bacterial signaling molecule that regulates the transition between motility and biofilm. Therefore, NO may influence biofilm formation through H-NOX regulation of DGC, thus providing a molecular-level explanation for NO regulation of biofilm formation. This work demonstrates that, indeed, NO-bound H-NOX negatively affects biofilm formation by directly regulating c-di-GMP turnover in Shewanella woodyi strain MS32. Exposure of wild-type S. woodyi to a nanomolar level of NO resulted in the formation of thinner biofilms, and less intracellular c-di-GMP, than in the absence of NO. Also, a mutant strain in the gene encoding SwH-NOX showed a decreased level of biofilm formation (and a decreased amount of intracellular c-di-GMP) with no change observed upon NO addition. Furthermore, using purified proteins, it was demonstrated that SwH-NOX and SwDGC are binding partners. SwDGC is a dual-functioning DGC; it has diguanylate cyclase and phosphodiesterase activities. These data indicate that NO-bound SwH-NOX enhances c-di-GMP degradation, but not synthesis, by SwDGC. These results support the biofilm growth data and indicate that S. woodyi senses nanomolar NO with an H-NOX domain and that SwH-NOX regulates SwDGC activity, resulting in a reduction in c-di-GMP concentration and a decreased level of biofilm growth in the presence of NO. These data provide a detailed molecular mechanism for NO regulation of c-di-GMP signaling and biofilm formation.


Oral immunization with recombinant lactobacillus plantarum induces a protective immune response in mice with Lyme disease.
Mucosal immunization is advantageous over other routes of antigen delivery because it can induce both mucosal and systemic immune responses. Our goal was to develop a mucosal delivery vehicle based on bacteria generally regarded as safe, such as Lactobacillus spp. In this study, we used the Lyme disease mouse model as a proof of concept. We demonstrate that an oral vaccine based on live recombinant Lactobacillus plantarum protects mice from tick-transmitted Borrelia burgdorferi infection. Our method of expressing vaccine antigens in L. plantarum induces both systemic and mucosal immunity after oral administration. This platform technology can be applied to design oral vaccine delivery vehicles against several microbial pathogens.


Evidence for functional and regulatory cross-talk between the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex and 2-oxoadipate dehydrogenase on the l-lysine, l-hydroxylysine and l-tryptophan degradation pathways from studies in vitro.
Herein are reported findings in vitro suggesting both functional and regulatory cross-talk between the human 2-oxoglutarate dehydrogenase complex (hOGDHc), a key regulatory enzyme within the tricarboxylic acid cycle (TCA cycle), and a novel 2-oxoadipate dehydrogenase complex (hOADHc) from the final degradation pathway of l-lysine, l-hydroxylysine and l-tryptophan. The following could be concluded from our studies by using hOGDHc and hOADHc assembled from their individually expressed components in vitro: (i) Different substrate preferences (kcat/Km) were displayed by the two complexes even though they share the same dihydrolipoyl succinyltransferase (hE2o) and dihydrolipoyl dehydrogenase (hE3) components; (ii) Different binding modes were in evidence for the binary hE1o-hE2o and hE1a-hE2o subcomplexes according to fluorescence titrations using site-specifically labeled hE2o-derived proteins; (iii) Similarly to hE1o, the hE1a also forms the ThDP-enamine radical from 2-oxoadipate (electron paramagnetic resonance detection) in the oxidative half reaction; (iv) Both complexes produced superoxide/H2O2 from O2 in the reductive half reaction suggesting that hE1o, and hE1a (within their complexes) could both be sources of reactive oxygen species generation in mitochondria from 2-oxoglutarate and 2-oxoadipate, respectively; (v) Based on our findings, we speculate that hE2o can serve as a trans-glutarylase, in addition to being a trans-succinylase, a role suggested by others; (vi) The glutaryl-CoA produced by hOADHc inhibits hE1o, as does succinyl-CoA, suggesting a regulatory cross-talk between the two complexes on the different metabolic pathways.


A Meta-Regression Analysis of the Effectiveness of Mosquito Nets for Malaria Control: The Value of Long-Lasting Insecticide Nets.
Long-lasting insecticidal nets (LLINs) have been widely used as an effective alternative to conventional insecticide-treated nets (ITNs) for over a decade. Due to the growing number of field trials and interventions reporting the effectiveness of LLINs in controlling malaria, there is a need to systematically review the literature on LLINs and ITNs to examine the relative effectiveness and characteristics of both insecticide nettings. A systematic review of over 2000 scholarly articles published since the year 2000 was conducted. The odds ratios (ORs) of insecticidal net effectiveness in reducing malaria were recorded. The final dataset included 26 articles for meta-regression analysis, with a sample size of 154 subgroup observations. While there is substantial heterogeneity in study characteristics and effect size, we found that the overall OR for reducing malaria by LLIN use was 0.44 (95% CI = 0.41-0.48, p < 0.01) indicating a risk reduction of 56%, while ITNs were slightly less effective with an OR of 0.59 (95% CI = 0.57-0.61, p <0.01). A meta-regression model confirms that LLINs are significantly more effective than ITNs in the prevention of malaria, when controlling for other covariates. For both types of nets, protective efficacy was greater in high transmission areas when nets were used for an extended period. However, cross-sectional studies may overestimate the effect of the nets. The results surprisingly suggest that nets are less effective in protecting children under the age of five, which may be due to differences in child behavior or inadequate coverage. Compared to a previous meta-analysis, insecticide-treated nets appear to have improved their efficacy despite the risks of insecticide resistance. These findings have practical implications for policymakers seeking effective malaria control strategies.


Epidemiological and molecular analysis of a waterborne outbreak of norovirus GII.4.
Contaminated water is one of the main sources of norovirus (NoV) gastroenteritis outbreaks globally. Waterborne NoV outbreaks are infrequently attributed to GII.4 NoV. In September 2009, a NoV outbreak affected a small school in Guangdong Province, China. Epidemiological investigations indicated that household use water, supplied by a well, was the probable source (relative risk 1·9). NoV nucleic acid material in concentrated well-water samples was detected using real-time RT-PCR. Nucleotide sequences of NoV extracted from diarrhoea and well-water specimens were identical and had the greatest sequence identity to corresponding sequences from the epidemic strain GII.4-2006b. Our report documents the first laboratory-confirmed waterborne outbreak caused by GII.4 NoV genotype in China. Our investigations indicate that well water, intended exclusively for household use but not for consumption, caused this outbreak. The results of this report serve as a reminder that private well water intended for household use should be tested for NoV.


Clinical Significance of Shared T Cell Epitope Analysis in Early De Novo Donor-Specific Anti-HLA Antibody Production After Kidney Transplantation and Comparison With Shared B cell Epitope Analysis.
In pre-sensitizing events, immunological memory is mainly created via indirect allorecognition where CD4+ T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+ T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+ memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using an in silico assay, an alternative to estimate donor-reactive CD4+ memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+ memory T cells. De novo DSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+ memory T cells may help predict the risk of early de novo DSA formation after kidney transplantation.


Health. Care. Anywhere. Today.
What if clinical quality medical equipment were available to every consumer in a form factor that was inexpensive, accurate, and easy to use? What if this equipment provided information that previously was un-measurable or very difficult to measure? What if the physiological state of individuals, at resolutions measured in thousandths of a second instead of in visits per year, could be measured easily, making it possible to ascertain caloric intake and expenditure, patterns of sleep, contextual activities such as working-out and driving, even parameters of mental state and health. What aspect of healthcare would not change? We present a system that is available today that enables this vision. This award-winning multi-channel wearable physiological monitor has enabled the collection of more than 90 million minutes of data in natural settings from thousands of subjects engaged in diverse activities. Data modeling efforts are resulting in applications that present meaningful and actionable information in real-time to users and their designated collaborators (physicians, family members, counselors, coaches, etc.) We describe the SenseWear system, its design, and a summary of validation studies, current commercial applications, and ongoing research. This discussion will show how the convergence of design for wearability, advances in machine learning, and improvements in wireless technology will manifest the future of health care as personal, ubiquitous, and collaborative.


Fast magnetic resonance imaging with contrast for soft tissue sarcoma viability.
Because dynamic (fast) contrast-enhanced magnetic resonance imaging with its temporal resolution allows evaluation of contrast kinetics of soft tissue sarcomas, its efficacy for defining viable tumor in these neoplasms was studied for three applications: biopsy localization, chemotherapeutic response, and differentiation between recurrence and inflammation after treatment. After conventional T1-weighted and T2-weighted magnetic resonance sequences to localize the lesion, patients had dynamic contrast-enhanced magnetic resonance imaging with fast and ultrafast sequences and postprocessing techniques (subtraction, time-intensity curves, and parametric color-encoding). In 10 of 40 patients, dynamic imaging more precisely defined the most malignant foci of tumor for biopsy than conventional magnetic resonance imaging. After chemotherapy, dynamic imaging distinguished 11 good responders from 21 poor responders. In followup of 196 patients, dynamic imaging detected 42 early enhancing recurrences and excluded recurrent tumor in six late enhancing pseudotumors. Dynamic imaging can differentiate viable tumor from nonviable tumor and inflammation by showing two temporally different phases of contrast enhancement: an early phase correlative with viable tumor at histologic examination, and a late phase when all tissues enhance simultaneously and may be indistinguishable. By showing tumor viability, dynamic contrast-enhanced magnetic resonance imaging can help define biopsy sites, chemotherapeutic response, and presence or absence of recurrences and therefore affect the initial evaluation, treatment, and followup of patients with soft tissue sarcomas.


Activity of PLCε contributes to chemotaxis of fibroblasts towards PDGF.
Cell chemotaxis, such as migration of fibroblasts towards growth factors during development and wound healing, requires precise spatial coordination of signalling events. Phosphoinositides and signalling enzymes involved in their generation and hydrolysis have been implicated in regulation of chemotaxis; however, the role and importance of specific components remain poorly understood. Here, we demonstrate that phospholipase C epsilon (PLCε) contributes to fibroblast chemotaxis towards platelet-derived growth factor (PDGF-BB). Using PLCe1 null fibroblasts we show that cells deficient in PLCε have greatly reduced directionality towards PDGF-BB without detrimental effect on their basal ability to migrate. Furthermore, we show that in intact fibroblasts, signalling events, such as activation of Rac, are spatially compromised by the absence of PLCε that affects the ability of cells to enlarge their protrusions in the direction of the chemoattractant. By further application of live cell imaging and the use of FRET-based biosensors, we show that generation of Ins(1,4,5)P(3) and recruitment of PLCε are most pronounced in protrusions responding to the PDGF-BB gradient. Furthermore, the phospholipase C activity of PLCε is critical for its role in chemotaxis, consistent with the importance of Ins(1,4,5)P(3) generation and sustained calcium responses in this process. As PLCε has extensive signalling connectivity, using transgenic fibroblasts we ruled out its activation by direct binding to Ras or Rap GTPases, and suggest instead new unexpected links for PLCε in the context of chemotaxis.


A Real-Time Electrical Load Forecasting in Jordan Using an Enhanced Evolutionary Feedforward Neural Network.
Power system planning and expansion start with forecasting the anticipated future load requirement. Load forecasting is essential for the engineering perspective and a financial perspective. It effectively plays a vital role in the conventional monopolistic operation and electrical utility planning to enhance power system operation, security, stability, minimization of operation cost, and zero emissions. Two Well-developed cases are discussed here to quantify the benefits of additional models, observation, resolution, data type, and how data are necessary for the perception and evolution of the electrical load forecasting in Jordan. Actual load data for more than a year is obtained from the leading electricity company in Jordan. These cases are based on total daily demand and hourly daily demand. This work's main aim is for easy and accurate computation of week ahead electrical system load forecasting based on Jordan's current load measurements. The uncertainties in forecasting have the potential to waste money and resources. This research proposes an optimized multi-layered feed-forward neural network using the recent Grey Wolf Optimizer (GWO). The problem of power forecasting is formulated as a minimization problem. The experimental results are compared with popular optimization methods and show that the proposed method provides very competitive forecasting results.


Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress.
Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.


Vibro-acoustography imaging of permanent prostate brachytherapy seeds in an excised human prostate--preliminary results and technical feasibility.
The objective in this work is to investigate the feasibility of using a new imaging tool called vibro-acoustography (VA) as a means of permanent prostate brachytherapy (PPB) seed localization to facilitate post-implant dosimetry (PID). Twelve OncoSeed (standard) and eleven EchoSeed (echogenic) dummy seeds were implanted in a human cadaver prostate. Seventeen seeds remained after radical retropubic prostatectomy. VA imaging was conducted on the prostate that was cast in a gel phantom and placed in a tank of degassed water. 2-D magnitude and phase VA image slices were obtained at different depths within the prostate showing location and orientation of the seeds. VA demonstrates that twelve of seventeen (71%) seeds implanted were visible in the VA image, and the remainder were obscured by intra-prostatic calcifications. Moreover, it is shown here that VA is capable of imaging and locating PPB seeds within the prostate independent of seed orientation, and the resulting images are speckle free. The results presented in this research show that VA allows seed detection within a human prostate regardless of their orientation, as well as imaging intra-prostatic calcifications.


Role of cereal type and processing in whole grain in vivo protection from oxidative stress.
The reduced risk of chronic diseases related to whole grain consumption is in part attributed to their high antioxidant content. Many studies have been performed on the in vitro antioxidant capacity of cereals, but in vivo studies are necessary. We have evaluated and compared the effect of whole grain durum wheat bread and whole grain Kamut khorasan bread on the oxidative status in rats. Two different bread-making processes were used for whole grain Kamut khorasan, sourdough and baker's yeast. After 7 weeks on the experimental diets rats were divided into two subgroups, one receiving an oxidative stress by doxorubicin injection. Our results evidenced both wheat durum and Kamut khorasan as good sources of antioxidants, and a lower oxidative state in rats fed the cereal-based diets. Furthermore, Kamut khorasan bread fed animals had a better response to stress than wheat durum fed, especially when a sourdough bread was supplied. Although further studies are needed, data herein reported suggest whole grains, particularly whole ancient grains, as a safe and convenient way of increasing antioxidant protection.


Hypothalamic paraventricular nucleus differentially supports lumbar and renal sympathetic outflow in water-deprived rats.
The present study sought to determine whether the hypothalamic paraventricular nucleus (PVN) contributes in a time-dependent manner to the differential patterning of lumbar and renal sympathetic nerve activity (SNA) in water-deprived rats. Mean arterial blood pressure (MAP) and both lumbar SNA (LSNA) and renal SNA (RSNA) were recorded simultaneously in control, 24 and 48 h water-deprived rats, and the PVN was inhibited bilaterally with microinjection of the GABA(A) agonist muscimol (100 pmol in 100 nl per side). Inhibition of the PVN significantly decreased RSNA in 48 h water-deprived rats but not in 24 h water-deprived or control rats (48 h, -17 +/- 4%; 24 h, -2 +/- 5%; control, 4 +/- 6%; P < 0.05). In addition, injection of muscimol significantly decreased LSNA in 48 and 24 h water-deprived rats but not in control rats (48 h, -41 +/- 4%; 24 h, -14 +/- 6%; control, -3 +/- 2%; P < 0.05). Interestingly, the decrease in LSNA was significantly greater than the decrease in RSNA of 24 and 48 h water-deprived rats (P < 0.05). Inhibition of the PVN also significantly decreased MAP to a greater extent in 48 and 24 h water-deprived rats compared to control rats (48 h, -34 +/- 5 mmHg; 24 h, -26 +/- 4 mmHg; control, -15 +/- 3 mmHg; P < 0.05). When 48 h water-deprived rats were acutely rehydrated by giving access to tap water 2 h before experiments, inhibition of the PVN with muscimol did not alter LSNA (-12 +/- 8%) or RSNA (7 +/- 4%) but did produce a small decrease in MAP (-15 +/- 4 mmHg) that was not different from control rats. In a parallel set of experiments, acute rehydration of 48 h water-deprived rats significantly attenuated the increased Fos immunoreactivity in PVN neurones that project to the spinal cord or rostral ventrolateral medulla. Collectively, the present findings suggest that PVN autonomic neurones are synaptically influenced during water deprivation, and that these neurones differentially contribute to LSNA and RSNA in water-deprived rats.


Catalyst nano-particle size dependence of the Fischer-Tropsch reaction.
Computational catalytic studies indicate that the elementary reactions that constitute the Fischer-Tropsch reaction strongly dependent on the structure of the catalyst reaction center. Recent experimental evidence is available that, for metallic Fischer-Tropsch catalysts such as Co or Ru, the very small metallic particles show altered catalytic performance. To distinguish between changes in the relative concentration of reaction centres, changes in chemical reactivity, or rate controlling steps, transient SSITKA data are extremely useful. Here, we present kinetics simulations to extract molecular kinetic information from SSITKA data. We have applied such simulations to interpret published experimental SSITKA data on nano-particle size dependent Fischer-Tropsch (FT) kinetics. The FT catalytic cycle consists of four essential reaction steps. Their relative size determines activity as well as selectivity. The simulated SSITKA indicate three different regimes with different kinetic behaviour, where the two fundamental regimes to distinguish are the monomer-formation-limited and the chain-growth-limited regime. Particle size changes shift kinetics from one to the other regime. We note different effects of supports and choice of metal composition on changes in elementary rates or the relative number of reactive centres when the particle size is decreased in the nanometre regime.


Injection prevalence and risks among male ethnic minority drug users in Northern Thailand.
Thailand's rate of HIV due to drug use is increasing, and nearly one-half of clients at a drug treatment centre in the north are from marginalized ethnic minority groups. We describe and compare socio-demographics, drug use, and sexual practices across ethnic minority people presenting for treatment at the Northern Drug Treatment Center, Mae Rim, Thailand. A prevalence study was conducted between February 1999 and January 2000. Trained interviewers administered a baseline questionnaire to 1,865 people admitted to the Northern Drug Dependence Treatment Center. Ethnic minority (Karen, Akha, Hmong, Lisu, and Lahu) males were included in this analysis (n = 629). Between 7% and 28% of each minority group had ever injected drugs (p = 0.002). Ninety-five per cent of men ever injecting had used heroin. Younger age, speaking Thai language, having a job with higher contact with Thais, and prior drug detoxification were significantly associated with injection in multivariate analysis, while Hmong and Lisu ethnicity were protective. Using occupation and language as proxies, contact with Thais and concomitant acculturation may be a risk for injection among this population. The inadvertent consequences of acculturation as it relates to injection and HIV risk must be addressed.


A review of prostate-specific antigen screening prevalence and risk perceptions for first-degree relatives of men with prostate cancer.
First-degree relatives of men with prostate cancer have a higher risk of being diagnosed with prostate cancer than men without a family history. The present review examines the prevalence and predictors of testing in first-degree relatives, perceptions of risk, prostate cancer knowledge and psychological consequences of screening. Medline, PsycInfo and Cinahl databases were searched for articles examining risk perceptions or screening practices of first-degree relatives of men with prostate cancer for the period of 1990 to August 2007. Eighteen studies were eligible for inclusion. First-degree relatives participated in prostate-specific antigen (PSA) testing more and perceived their risk of prostate cancer to be higher than men without a family history. Family history factors (e.g. being an unaffected son rather than an unaffected brother) were consistent predictors of PSA testing. Studies were characterized by sampling biases and a lack of longitudinal assessments. Prospective, longitudinal assessments with well-validated and comprehensive measures are needed to identify factors that cue the uptake of screening and from this develop an evidence base for decision support. Men with a family history may benefit from targeted communication about the risks and benefits of prostate cancer testing that responds to the implications of their heightened risk.


Validation of the protective effects of Lonicera japonica polysaccharide on lipopolysaccharide-induced learning and memory impairments via regulation of autophagy based on network pharmacology.
Learning and memory impairments are important indexes in assessing Alzheimer's disease (AD). Lonicera japonica (L. japonica), a traditional Chinese herbal medicine, inhibits inflammation, but its role in neuroprotection is unclear. Polysaccharide is the main active ingredient in L. japonica. Here, we aimed to validate the effects of L. japonica polysaccharide (LJP) on lipopolysaccharide (LPS)-induced cognitive impairment and the underlying mechanism. The Chinese medicine system pharmacology database and analysis platform was used to predict the target of L. japonica; the GeneCards system was used to predict the AD target. We also performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Experiments were performed after bioinformatic analysis for verification. A chronic learning and memory impairment model was established by a single administration of LPS. Learning and memory abilities of Kunming mice were examined after 7 days of induction. The protective effects of LJP on LPS-induced impairment were investigated. Neuronal damage was observed by Nissl staining. Key proteins involved in the autophagy pathway were examined. Bioinformatic analysis showed that there were 151 genes in the intersection of the target and ADrelated genes, and KEGG analysis suggested that these genes may act via multiple pathways. LPS-induced changes in learning and memory in mice were significantly attenuated by LJP. Nissl staining revealed that the neurons in the control group were lost and cellular arrangement was disrupted. LJP alleviated the pathological changes in the neurons of mice. The autophagy pathway was selected to verify the mechanism. ATG5, Beclin 1, Vps34, and LC3 II expression in the LPS group was significantly increased, and it was further increased in the LJP group. LJP improved behavioral changes and neuronal loss associated with LPS-induced learning and memory impairments. The underlying mechanism may be related to the regulation of the autophagy pathways.


Ultrasound propagation in trabecular bone: a numerical study of the influence of microcracks.
The accumulation of microdamage in trabecular bone tissue is suspected of being a predictive indicator of osteoporosis diagnosis. To quantify this microdamage, the Dynamic AcoustoElastic Testing (DAET) method measures the Time Of Flight (TOF) and amplitude variations of transmitted ultrasound (US) pulses, while the bone sample is submitted to a low frequency sinusoidal hydrostatic pressure (opening/closing of microcracks). However, DAET is both sensitive to viscoelastic properties changes and microcracks density. To verify the microcracks density contribution on DAET results, a numerical approach is proposed. Multliple configurations of microdamaged trabecular bone-tissue-like mesh have been simulated. A 2D pseudo-spectral time domain numerical model was then developed to simulate linear wave propagation in heterogeneous solids. The influence of the microcracks number and orientation on the US TOF was particularly investigated. Results are discussed and compared with experimental data obtained from DAET measurements in trabecular bone samples.


Evaluation of sympathetic nerve terminals with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron emission tomography.
The goal of the present study was to directly compare the new radiopharmaceutical agent [(11)C]epinephrine (EPI) with [(11)C]hydroxyephedrine (HED) through the use of PET. Seven healthy volunteers and 10 patients were investigated after heart transplantation. PET images of both tracers were of excellent quality in the volunteers. Values for radiolabeled metabolites (measured in percent of blood activity) at 5, 20, and 60 minutes after injection were approximately 35%, approximately 82%, and approximately 86% for EPI and approximately 13%, approximately 47%, and approximately 78% for HED, respectively. At 35 minutes, metabolite-corrected mean myocardial retention fraction of EPI (0. 235+/-0.022 min(-1)) was significantly greater (P<0.01) than that of HED (0.142+/-0.012 min(-1)). Corrected tracer retention fractions of both EPI and HED were significantly reduced in transplant recipients (0.055+/-0.004 min(-1), P<0.0001; and 0.050+/-0.006 min(-1), P<0. 0001, respectively) compared with volunteers. Normalization of retention fractions of patients with transplantation within 1 year to volunteers resulted in a value (ratio expressed in percent) of 20. 6+/-1.8% for EPI, significantly (P<0.03) smaller than 27.8+/-0.8% for HED. In patients with transplantation later than 1 year, the values were 26.0+/-2.9% for EPI compared with 44.2+/-5.6% for HED (P<0.014). Both tracers showed high selectivity for neuronal uptake in the heart, with a significant reduction in tracer retention in transplant recipients compared with volunteers. Compared with HED, EPI showed greater retention in volunteers and a lower retention ratio in transplant recipients, suggesting that EPI may be the superior tracer with higher sensitivity to neuronal abnormalities. Because EPI reflects neuronal uptake, metabolism, and storage, it may be more suitable for the study of neuronal integrity than HED, which primarily traces uptake-1 capacity.


Group versus individual family planning counseling in Ghana: a randomized, noninferiority trial.
Group, rather than individual, family planning counseling has the potential to increase family planning knowledge and use through more efficient use of limited human resources. A randomized, noninferiority study design was utilized to identify whether group family planning counseling is as effective as individual family planning counseling in Ghana. Female gynecology patients were enrolled from two teaching hospitals in Ghana in June and July 2008. Patients were randomized to receive either group or individual family planning counseling. The primary outcome in this study was change in modern contraceptive method knowledge. Changes in family planning use intention before and after the intervention and intended method type were also explored. Comparisons between the two study arms suggest that randomization was successful. The difference in change in modern contraceptive methods known from baseline to follow-up between the two study arms (group-individual), adjusted for study site, was -0.21, (95% confidence interval: -0.53 to 0.12) suggesting no difference between the two arms. Group family planning counseling was as effective as individual family planning counseling in increasing modern contraceptive knowledge among female gynecology patients in Ghana.


Solid/trabecular subtype of papillary thyroid carcinoma on cytology with focal differentiated high-grade thyroid carcinoma on histology: a cyto-histologic correlation.
Solid/trabecular subtype of papillary thyroid carcinoma (S/T PTC) is a rare entity that has been shown to have higher tumour recurrence and mortality rates. A definite diagnosis on fine needle aspiration cytology is often not easy. Rather, this entity may be misdiagnosed in cytology due to a lack of widespread features of classic PTC. We present a case of S/T PTC in a 61-year-old female, showing a focus on differentiated high-grade thyroid carcinoma (DHGTC) on histology. We discuss cytological features with the histologic correlation of S/T PTC and briefly discuss the newly introduced entity, DHGTC.


A chemical probe unravels the reactive proteome of health-associated catechols.
Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as anticancer activity and neuroprotection. However, the molecular mode of action behind these properties is poorly understood. Here, we apply a mass spectrometry-based competitive chemical proteomics approach to elucidate the target scope of catechol-containing bioactive molecules from diverse foods and drugs. Inspired by the protein reactivity of catecholamine neurotransmitters, we designed and synthesised a broadly reactive minimalist catechol chemical probe based on dopamine. Initial labelling experiments in live human cells demonstrated broad protein binding by the probe, which was largely outcompeted by its parent compound dopamine. Next, we investigated the competition profile of a selection of biologically relevant catechol-containing substances. With this approach, we characterised the protein reactivity and the target scope of dopamine and ten biologically relevant catechols. Strikingly, proteins associated with the endoplasmic reticulum (ER) were among the main targets. ER stress assays in the presence of reactive catechols revealed an activation of the unfolded protein response (UPR). The UPR is highly relevant in oncology and cellular resilience, which may provide an explanation of the health-promoting effects attributed to many catechol-containing natural products.


The role of wax and sterol esters of meibomian secretions in chronic blepharitis.
We analyzed the fatty wax esters and sterol esters found in the expressed lipid secretions of six patients from each of six clinical groups of chronic blepharitis, plus eight normal controls. Using gas liquid chromatography (GLC), 12 peaks corresponding to equivalent chain lengths (ECL) of 33.6, 35.4, 36.1, 37.3, 38.2, 39.2, 40.1, 41.2, 42.1, 43.2, 44.9 and 45.7 were found in the fatty wax esters and five peaks corresponding to ECL 19.1, 20.0, 21.1, 22.0 and 23.2 were found in the sterol esters. The clinical groups showed significant differences in several of these components. Sterol and wax esters represent the largest fraction of the total meibomian lipid secretion. The finding that the blepharitic groups exhibit biochemical differences in the distribution of these esters indicates that the esters may play a role in the disease process, perhaps by providing a preferential substrate for normal flora which we have shown to have lipolytic capabilities. The resultant de-esterification could alter the tear film and contribute to ocular irritation. In addition, the differences seen in the composition of the ester fraction of the meibomian secretion could lead to differences in melting point, which, in turn, could affect viscosity and surface tension of the tear film, leading to changes in breakup time and to secretion stagnation within glands.


[Changes in molecular forms of sex hormone binding globulin during menstrual cycle and menopause].
Sex hormone binding globulin (SHBG) is a glycoprotein that transports mainly androgens and estrogens regulating the amount of free and bound hormone which in turn plays a role in the metabolic balance. It is also known that estrogens increase the hepatic production of SHBG which circulates in various molecular forms containing different amounts of sialic acid as the main component of carbohydrates. In the present work we studied physiological variations of molecular forms of SHBG during the normal menstrual cycle and the menopause. During the follicular phase the form 54 KD was the predominant variant, in the periovulatory period was isomers 90 KD, and during the luteal phase corresponded to both 54 and 90 KD. In the menopause dimeric form of 90 KD corresponded to the major proportion and was present a higher molecular forms of 115-135 KD. Following estrogen therapy the chromatographic profile changed as to that observed during the menstrual cycle. Important changes in the proportion of sialic acid were observed in each of the phases of menstrual cycle and following estrogen replacement. And increase in the amount of sialic acid corresponded to higher estrogen concentrations. It is concluded that SHBG concentrations varies during the menstrual cycle according the estrogen levels which in addition regulates the proportion of molecular forms and sialic acid containt.


Dengue in the Middle East and North Africa: A Systematic Review.
Dengue virus (DENV) infection is widespread and its disease burden has increased in past decades. However, little is known about the epidemiology of dengue in the Middle East and North Africa (MENA). Following Cochrane Collaboration guidelines and reporting our findings following PRISMA guidelines, we systematically reviewed available records across MENA describing dengue occurrence in humans (prevalence studies, incidence studies, and outbreak reports), occurrence of suitable vectors (Aedes aegypti and Aedes albopictus), and DENV vector infection rates. We identified 105 human prevalence measures in 13 of 24 MENA countries; 81 outbreaks reported from 9 countries from 1941-2015; and reports of Ae. aegypti and/or Ae. albopictus occurrence in 15 countries. The majority of seroprevalence studies were reported from the Red Sea region and Pakistan, with multiple studies indicating >20% DENV seroprevalence in general populations (median 25%, range 0-62%) in these subregions. Fifty percent of these studies were conducted prior to 1990. Multiple studies utilized assays susceptible to serologic cross-reactions and 5% of seroprevalence studies utilized viral neutralization testing. There was considerable heterogeneity in study design and outbreak reporting, as well as variability in subregional study coverage, study populations, and laboratory methods used for diagnosis. DENV seroprevalence in the MENA is high among some populations in the Red Sea region and Pakistan, while recent outbreaks in these subregions suggest increasing incidence of DENV which may be driven by a variety of ecologic and social factors. However, there is insufficient study coverage to draw conclusions about Aedes or DENV presence in multiple MENA countries. These findings illustrate the epidemiology of DENV in the MENA while revealing priorities for DENV surveillance and Aedes control.


[New approaches to the measurement of clinical competence].
A new phase in the development of an instrument designed for the measurement of clinical competence is presented. The instrument (exam type) was previously validated; we report its use in three generations of students of a specialization course in internal medicine: those recently admitted to the course (group I); those finishing their first training year (group II) and those finishing the second year (group III). In the exam 304 out of the 600 questions included were classified as "experimental" (dealing with knowledge in internal medicine) and the remaining 296 questions corresponded to "control" questions (dealing with knowledge in other specialties). The variables considered in the exam were: 1) global result; 2) usage of diagnostic indicators; 3) omission of necessary procedures without a iatrogenic effect; 4) commission of unnecessary procedures without a iatrogenic effect; 5) omission of necessary procedures with resulting iatrogenic consequences; 6) commission of unnecessary procedures with resulting iatrogenic consequences; 7) global omission (variables 3 and 5); 8) global commission (variables 4 and 6); 9) global iatrogenesis (variables 5 and 6); 10) knowledge in nosology. Scores obtained by the three groups on the experimental questions differed in accordance with the respective time of clinical experience (group I obtained the lowest scores, group II showed intermediate scores, and group III showed the highest scores). Analysis of variance was significant (p less than 0.05) in variables 1, 2, 6, 8 and 9. The scores obtained by the three groups on the control questions were similar. In conclusion, we believe that this instrument is capable of detecting learning dependent on the time of clinical experience.(ABSTRACT TRUNCATED AT 250 WORDS)


In situ modulation of gold nanorod's surface charge drives the growth of end-to-end assemblies from dimers to large networks that enhance single-molecule fluorescence by 10 000-fold.
End-to-end assemblies of anisotropic plasmonic nanostructures with small nanogaps are of great interest as they create strong hot spots for enhancing weak fluorescence and/or scattering of molecules. Here we report the growth of dithiol-linked end-to-end assemblies of gold nanorods from dimers to large networks containing thousands of individual nanorods, directed by in situ tuning of nanorod's surface charge. Surface charge was lowered to initiate the aggregation process but was subsequently increased to achieve slow tip-specific growth over seven days to form end-to-end networks of nanorods, which were stable in solution for over one month. Furthermore, we showed that these assemblies contained strong plasmonic hot spots which enhanced the fluorescence signal of a weak emitter by 104-fold. This enhancement is approximately 10-fold larger than that obtained using a single gold nanorod and is comparable to the largest enhancement obtained using more expensive lithographically made in-plane antenna arrays.


The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis.
Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1(G93A) NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1(G93A) NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1(G93A) motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1(G93A) , providing evidence that ER stress plays a major role in ALS.


The role of 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors.
In patients with suspected but yet not localized neuroendocrine tumors (NETs), early diagnosis or reliable exclusion is crucial for optimal individual prognosis and therapy. Despite recourse to several imaging modalities, the definite diagnosis of NET can be challenging. Therefore, we tested (68)Ga-DOTATATE PET/CT as a tool for improved diagnosis in a cohort of patients with suspected, nonlocalized NET. (68)Ga-DOTATATE PET/CT recordings were obtained in 104 consecutive patients meeting at least one of the following criteria: clinical suspicion of NET (n = 70), elevated blood levels of tumor markers (n = 49), and image-based suspicion of NET (n = 53). The presence of NET was validated by histopathology (n = 49) or clinical follow-up of 107 ± 59 wk (n = 55). In 36 of 104 patients (35%), NET was histologically verified, most frequently located in the small bowel (10/36), pancreas (8/36), lung (5/36), and stomach (2/36). Twelve patients had tumors of nonneuroendocrine origin, and 7 patients had benign tumors. (68)Ga-DOTATATE PET/CT identified NET in 29 of the 36 cases and excluded the presence of a NET in 61 of the 68 non-NET patients, indicating a sensitivity of 81% and specificity of 90%. The PET/CT gave a false-positive result in 7 patients and a false-negative in another 7 patients, indicating positive and negative predictive values of 81% and 90%, respectively, and an accuracy of 87%. Chromogranin A levels were significantly higher in both PET-positive patients (1,841 vs. 342 ng/mL; P < 0.05) and patients with verified NET (2,214 vs. 524 ng/mL; P < 0.05). In patients with suspected NETs due to clinical symptoms, elevated levels of tumor markers, or indeterminate tumors suggestive of NET, (68)Ga-DOTATATE PET/CT is highly accurate, thus supporting its use in clinical routine diagnostics.


Amitrole Translocation in Agropyron repens Increased by the Addition of Ammonium Thiocyanate.
The mechanism for the enhancement of amitrole activity on quackgrass (Agropyron repens) by the addition of ammonium thiocyanate was studied. Absorption and translocation of C(14)-amitrole after applications to foliage were determined by a direct count of the radioactivity in the wash solution and plant extracts. Regardless of the time of application, the addition of ammonium thiocyanate did not alter the amount of C(14)-amitrole absorbed. Ammonium thiocyanate (5000 parts per million) greatly increased the amount of carbon-14 translocated. This increase may account for the greater herbicidal effectiveness of the mixture of amitrole and ammonium thiocyanate.


Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease.
In recent years, control of neglected tropical diseases has been increasingly gaining momentum and interventions against schistosomiasis are being progressively scaled-up through expansion of donated praziquantel and preventive chemotherapy campaigns. However, the public health importance of female genital schistosomiasis is not fully recognised nor its control is adequately addressed. Taking a clinical and anatomopathological perspective, we evaluated the available literature to highlight the importance of female genital schistosomiasis and its connections with two sexually transmitted infections of global importance, Human Immunodeficiency Virus (HIV) and Human Papilloma Virus. Outside the long list of clinical descriptive reports beginning in 1899, there is presently a shocking gap in epidemiological assessment and a significant underestimation of the burden of FGS remains. The scarcity of integrated approaches to address female genital schistosomiasis calls for more concerted action in its detection, treatment and prevention alongside other concomitant women's health issues, otherwise female genital schistosomiasis will remain a neglected gynaecological disease.


Single-lumen endotracheal intubated anaesthesia for thoracoscopic sympathectomy--experience of 719 cases.
A total of 719 thoracoscopic sympathicotomies were performed at our hospital from October, 1989 to December, 1992. We have been practicing single-lumen endotracheal intubation for general anaesthesia in all of our cases. We will review our experience and discuss our anaesthetic technique and the intraoperative complications encountered as well as post-operative pain control. General anaesthesia with controlled manual ventilation assisted the surgeon well and created clear access for electro-cauterisation of the sympathetic chain. Thirty patients were randomly chosen for arterial blood gas analysis. There was no evidence of systemic hypoxaemia or clinically significant carbon dioxide retention throughout the surgery or afterwards in the recovery room. In our experience of 719 cases, single-lumen endotracheal intubated anaesthesia is safe and economic for thoracoscopic sympathicotomy.


[Prognostic factors in medullary breast cancer].
In 55 patients with medullary carcinoma of the breast follow-up data over an average period of 68.1 +/- 35.3 months were recorded. The histological slides of all tumors were retrospectively classified according to the same criteria. The parameters registered were: tumor-size, histological grading, receptor status, necrosis of tumor tissue, cellularity of the stroma, status of axillary nodes, reactive changes of axillary nodes and tumor invasion of lymphatic vessels. The importance of each parameter registered for disease-free survival and overall survival was calculated statistically using the log-rank-test. Of all parameters, only the nodal status of the axilla proved prognostically significant. Metastases of axillary nodes were demonstrable in only 31% of all MC. The incidence of nodal involvement proved to be less than in non medullary breast cancers. In 15 (27.3%) of the patients, progression of the tumor occurred. All women with distant metastases i.e. 12 (21.8%) died of the disease, whereas patients with only local recurrence of breast cancer are still alive. 72.7% of the patients showed relapse-free survival. Other parameters of proven prognostic value in breast cancers like receptor status and histological grading were of no relevance to the survival in MC. Prediction of prognosis depends on the correct classification of the tumor subgroup according to strict microscopical and macroscopical criteria.


Mapping of 5q35 chromosomal rearrangements within a genomically unstable region.
Recent molecular studies of breakpoints of recurrent chromosome rearrangements revealed the role of genomic architecture in their formation. In particular, segmental duplications representing blocks of >1 kb with >90% sequence homology were shown to mediate non-allelic homologous recombination (NAHR). However, the occurrence of the majority of newly detected submicroscopic imbalances cannot be explained by the presence of segmental duplications. Therefore, further studies are needed to investigate whether architectural features other than segmental duplications mediate these rearrangements. We analysed a series of patients with breakpoints clustering within chromosome band 5q35. Using high density arrays and subsequent quantitative polymerase chain reaction (qPCR), we characterised the breakpoints of four interstitial deletions (including one associated with an unbalanced paracentric inversion), a duplication and a familial reciprocal t(5;18)(q35;q22) translocation. Five of the breakpoints were located within an interval of approximately 265 kb encompassing the RANBP17 and TLX3 genes. This region is also targeted by the recurrent cryptic t(5;14)(q35;q32) translocation, which occurs in approximately 20% of childhood T cell acute lymphoblastic leukaemia (T-ALL). In silico analysis indicated the architectural features most likely to contribute to the genomic instability of this region, which was supported by our molecular data. Of further interest, in two patients and the familial translocation, the delineated breakpoint regions encompassed highly homologous LINEs (long interspersed nuclear elements), suggesting that NAHR between these LINEs may have mediated these rearrangements.


[Mathematical study of the sensitivity curves of Escherichia coli exposed to polymyxins].
The time killing curves of five strains of Escherichia coli (ATCC 25922, ATCC 29194, CIP 54125, CIP 54127, CIP 54117 (K 12)) exposed to five concentrations of polymyxin B are similar: latency phasis, two decreasing phasis and for the low polymyxin B concentrations growth phasis. In our experimental conditions, the Mg(+)+ and Ca(+)+ concentrations of the medium (Mueller-Hinton; medium A: Ca(+)+ = 9 mg/l, Mg(+)+ = 0.5 mg/l; medium B: Ca(+)+ = 35 mg/l, Mg(+)+ = 15.5 mg/l; medium C: Ca(+)+ = 60 mg/l, Mg(+)+ = 20 mg/l) have no time effect upon the killing curves. A decreasing biexponential model can be fitted to the data. Such a model is compatible with interaction between antibiotic and bacterium and can be formalized accorrding to the equation: T + ATB K1 in equilibrium of K2 T* - ATB K3----ATB + dead with ATB: Polymyxine B in excess, T: target bacterium and T*: modification target bacterium.


The role of methicillin-resistant Staphylococcus aureus in skin and soft tissue infections.
Methicillin-resistant Staphylococcus aureus (MRSA) has become a major public health issue worldwide over the last years. MRSA is frequently implicated in the development of skin and soft tissue infections, leading to significant increases in morbidity, mortality and overall healthcare costs. In order to face the threat of MRSA, major changes in clinical management of skin and soft tissue infections are required. The identification of populations at risk for the acquisition of infections due to MRSA, together with the improvement of the diagnostic techniques, is paramount. Moreover, a number of new antimicrobials with activity against MRSA have been recently developed and approved for the treatment of skin and soft tissue infections, however, the use of the new drugs in the wide clinical practice remains limited. We reviewed the current epidemiology of MRSA in skin and soft tissue infections, with particular focus on implications for clinical management. The potential role of new antibiotic options against MRSA infections is also discussed.


Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis.
Heterotrimeric G proteins couple external signals to the activation of intracellular signal transduction pathways. Agonist-stimulated guanine nucleotide exchange activity of G-protein-coupled receptors results in the exchange of G-protein-bound GDP to GTP and the dissociation and activation of the complex into Gα-GTP and a Gβγ dimer. In Dictyostelium, a basal chemotaxis pathway consisting of heterotrimeric and monomeric G proteins is sufficient for chemotaxis. Symmetry breaking and amplification of chemoattractant sensing occurs between heterotrimeric G protein signaling and Ras activation. In a pull-down screen coupled to mass spectrometry, with Gα proteins as bait, we have identified resistant to inhibitors of cholinesterase 8 (Ric8) as a nonreceptor guanine nucleotide exchange factor for Gα-protein. Ric8 is not essential for the initial activation of heterotrimeric G proteins or Ras by uniform chemoattractant; however, it amplifies Gα signaling, which is essential for Ras-mediated symmetry breaking during chemotaxis and development.


Neuroprotection and neurodegenerative disease.
This paper will focus on commonalities in the aetiology and pathology in five areas of neurological disease with illustrative examples of therapy. Possibilities of multimodal and neuroprotective therapies in human disease, employing currently available drugs and showing evidence of neuroprotective potential in animal models, are discussed. By definition, neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, its cells, structure and function. It is thought that there are many neurochemical modulators of nervous system damage. In epilepsy, excessive glutamate-mediated neurotransmission, impaired voltage sensitive sodium and calcium channel functioning, impaired GABA-mediated inhibition and alterations in acid base balance, when set in motion, may trigger a cascade of events leading to neuronal damage and cell death. Acute and chronic nervous system damage in response to an insult may lead to acute or delayed neuronal death, apoptotic cell death, neuronal degeneration, injury and loss, and gliosis. Cell death in the CNS following injury can occur in the manner of apoptosis, necrosis or hybrid forms. In general, NMDA receptor and non-NMDA receptor mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum. The effects of neuronal injury depend on factors including the degree of brain maturity or site of the lesion. There is some evidence supporting the hypothesis that neuroprotection may be a practical and achievable target using drugs already available, at present employed only for limited indications. Using these drugs early in the disease, may save decades of development of new drugs, which would require evaluation in animal studies, and human clinical trials. New drugs would also need to be shown to be safe and acceptable, physiologically not detrimental to humans and free from idiosyncratic adverse effects.


Suicide prevention as a community development process: understanding circumpolar youth suicide prevention through community level outcomes.
Community-based models have become increasingly prominent in prevention, and have special relevance for suicide prevention in circumpolar Indigenous communities. It follows that outcomes from circumpolar suicide prevention programs might be more completely understood at the community level. We present here a methodology for analysis at this level. This paper seeks to understand a cultural prevention program for rural Yup'ik youth in Alaska targeting suicide and co-occurring alcohol abuse as a community development process through changes at the community level. Quasi-experimental design with assessment at pre- and post-intervention or at 4 time points. The community development process for this project began in October 2004. The first program baseline assessment began in November 2006, prior to prevention activities with youth and parents, and the post-intervention assessment concluded in March 2008. Five key informants pre- and post-intervention completed a community readiness assessment, which is a structured procedure assessing a community's awareness of suicide as an issue and its, organizational readiness for prevention programming. Forty-three adult caregivers or sponsors of youth in the prevention program completed an assessment of behaviours that contributed to community protective factors from youth suicide and alcohol abuse at 4 time points before, during and after the intervention. The 54 youth who participated in the prevention program completed an assessment of community protective factors, also at 4 time points before, during and after the intervention. The community protective factors from suicide that were assessed included safety, enforcement of alcohol prohibitions, role models, support and opportunities for youth. Community readiness for the prevention efforts increased to new developmental stages of readiness post-intervention, and a trend in the data suggested community protective factors increased in the amount of protective behaviours performed by adults (slope estimate = 0.0162, 95% CI--0.0028-0.0351, d=.55) and in the perceptions of youth (slope estimate=0.0148, 95% CI--0.0004-0.0291, d=.45), in a dose response relationship to the number of prevention program sessions attended by adults and youth. Using data from a feasibility study, this paper demonstrates the feasibility and potential utility of methodological approaches that use community-level variables beyond individual level outcomes in circumpolar suicide prevention research.


[The effect of diet and exercise on the parameters of lipid metabolism in the patients with metabolic syndrome and impaired carbohydrate metabolism of various degrees].
The aim of our study was the investigation of the peculiarities of lipid metabolism in the patients with metabolic syndrome and impaired carbohydrate metabolism of various degrees after diet and moderate exercise. We selected 123 overweight patients from Imereti Region. Metabolic syndrome in patients was determined by World Health Organization -2002 classification. Total cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, very low density lipoprotein and atherogenic indices have been measured. Diet and exercise - changes in the life style decreases the risk of metabolic syndrome development and decrease fasting and postprandial glucose. It was also indicated that the parameters of lipid metabolism sharply improved by diet and exercise and the degree of improvement was practically identical in patients with diabetes mellitus type 2 and impaired glucose tolerance.