The role of MHC I protein dynamics in tapasin and TAPBPR-assisted immunopeptidome editing.
Major Histocompatibility Complex class I (MHC I) molecules are highly polymorphic, with allotypes differing in peptide binding preferences, and in their dependence upon tapasin for optimal peptide selection. The tapasin dependence of MHC allotypes is inversely correlated with their self-editing ability, and underpinned by conformational plasticity. Recently, TAPBPR has been shown to enhance MHC I assembly via a chaperone-like function, and by editing the peptide repertoire of some MHC I allotypes. Structural analysis has shown TAPBPR binding changes the conformation and dynamics of MHC I, with MHC protein dynamics likely to determine the prevailing TAPBPR function: generically enhancing MHC I assembly by stabilising highly dynamic peptide-empty MHC I; and by editing the peptide repertoire of highly dynamic MHC I allotypes.


Cancer mortality among aircraft manufacturing workers: an extended follow-up.
Extended cancer follow-up among 77,943 aircraft workers. Comprehensive exposure information enabled detailed classification of trichloroethylene (TCE), perchloroethylene (PCE), mixed solvents, and chromates exposure among these workers. Exposure to TCE, PCE, mixed solvents or chromates was not associated with increased cancer risk overall or for most cancer sites. Elevated rates compared with the general population were seen for non-Hodgkin lymphoma for PCE exposure, and colon and testicular cancers and multiple myeloma for mixed solvents exposure. Internal cohort analyses, however, showed no significant trends of increasing risk for these cancers with increasing years of exposure to TCE, PCE or mixed solvents. This large, long-term cohort study with comprehensive exposure assessment found no consistent evidence of increased cancer risk overall or by site among aircraft workers, including those with long-term exposure to TCE, PCE, and mixed solvents.


Personal exposure monitoring wearing protocol compliance: an initial assessment of quantitative measurement.
Personal exposure sampling provides the most accurate and representative assessment of exposure to a pollutant, but only if measures are implemented to minimize exposure misclassification and reduce confounders that may cause misinterpretation of the collected data. Poor compliance with personal sampler wearing protocols can create positive or negative biases in the reported exposure concentrations, depending on proximity of the participant or the personal sampler to the pollutant source when the monitor was not worn as instructed. This paper presents an initial quantitative examination of personal exposure monitor wearing protocol compliance during a longitudinal particulate matter personal exposure monitoring study of senior citizens of compromise health in North Carolina. Wearing compliance varied between participants because of gender or employment status, but not longitudinally or between cohorts. A minimum waking wearing compliance threshold, 0.4 for this study of senior citizens, is suggested to define when personal exposure measurements are representative of a participant's exposure. The ability to define a minimum threshold indicates data weighting techniques may be used to estimate a participant's exposure assuming perfect protocol compliance.


A highly conserved 72,000 dalton centromeric antigen reactive with autoantibodies from patients with progressive systemic sclerosis.
An autoantibody reactive with a 72,000 dalton centromeric antigen was detected by immunoblotting with the use of a nuclear enriched HeLa cell preparation in 42 of 77 patients with progressive systemic sclerosis (PSS). Reactivity with the 72,000 dalton polypeptide was associated with anti-centromere autoantibodies (ACA) detected by immunofluorescence (IF), and the antigen was highly conserved, being present in both human cells and Leishmania tropica. Thirty-five (83%) of the 42 sera reactive with the 72,000 dalton polypeptide also reacted with a 19,500 dalton polypeptide, and antibodies eluted from both the 72,000 dalton and the 19,500 dalton polypeptides reacted with the centromere when retested by IF on intact HEp2 cells, demonstrating that both polypeptides are antigenic components of the centromere. Only one of the 42 sera had precipitating antibodies to the Scl-70 antigen detected by counterimmunoelectrophoresis, indicating that the 72,000 dalton polypeptide was not related to the previously described Scl-70 antigen. The other 35 of the 77 sera tested were negative for ACA, although all had ANA, with the main patterns of IF being fine speckling of the nucleus (18 sera) and homogeneous or speckled staining of the nucleolus (17 sera). Anti-Scl-70 antibodies were detected in 17 of these 35 patients, 15 (88%) of whom reacted with an 89,000 dalton polypeptide, one with a 140,000 dalton polypeptide, and one with a 74,000 dalton polypeptide. Ten of the 15 sera reacting with the 89,000 dalton polypeptide also reacted with a 74,000 dalton polypeptide, and 2-D gel analysis suggested a relationship between the two molecules. Clinically defined types of scleroderma tended to associate with antibodies to particular molecular antigenic specificities. Thirty-seven (88%) of the 42 patients reactive with the 72,000 dalton polypeptide had sclerodactyly and features of the CREST syndrome, whereas patients reactive with the 89,000 dalton polypeptide and with Scl-70 tended to have more extensive cutaneous and visceral involvement.


T cell activation and human immunodeficiency virus replication after influenza immunization of infected children.
T cell activation plays a major role in the ability of HIV to remain latent or to establish a productive infection. It has been hypothesized that vaccination-mediated immune stimulation can activate T cells and enhance HIV replication. Our study was designed to determine whether influenza immunization would induce T cell activation and increase HIV burdens in HIV-infected children. Blood samples from 16 HIV-infected children ages 6 months to 14 years were obtained immediately before and 2 and 6 to 8 weeks after the administration of influenza vaccine. The percentage of activated (CD25+) T cells was determined by flow cytometry, and HIV viral load was measured by quantitative cultures of peripheral blood mononuclear cells and plasma HIV RNA. The administration of influenza vaccine was associated with significant increases in HIV viral load in 5 of 16 children evaluated. These increases in HIV burden were transient, and in four of five patients the plasma HIV RNA copy number returned to baseline 6 to 8 weeks after immunization. There was no correlation between the patient's immunologic or clinical category according to the CDC classification and either the initial viral load or the likelihood of having a significant increase after immunization. Four of the five patients who experienced increases in viral load after influenza immunization were not receiving antiretroviral therapy. Our results emphasize the need for additional studies that examine the effect of routine immunizations on T cell activation and HIV replication in HIV-infected children.


Declines in both redundant and trace species characterize the latitudinal diversity gradient in tintinnid ciliates.
The latitudinal diversity gradient is a well-known biogeographic pattern. However, rarely considered is how a cline in species richness may be reflected in the characteristics of species assemblages. Fewer species may equal fewer distinct ecological types, or declines in redundancy (species functionally similar to one another) or fewer trace species, those occurring in very low concentrations. We focused on tintinnid ciliates of the microzooplankton in which the ciliate cell is housed inside a species-specific lorica or shell. The size of lorica oral aperture, the lorica oral diameter (LOD), is correlated with a preferred prey size and maximum growth rate. Consequently, species of a distinct LOD are distinct in key ecologic characteristics, whereas those of a similar LOD are functionally similar or redundant species. We sampled from East Sea/Sea of Japan to the High Arctic Sea. We determined abundance distributions of biological species and also ecological types by grouping species in LOD size-classes, sets of ecologically similar species. In lower latitudes there are more trace species, more size-classes and the dominant species are accompanied by many apparently ecologically similar species, presumably able to replace the dominant species, at least with regard to the size of prey exploited. Such redundancy appears to decline markedly with latitude in assemblages of tintinnid ciliates. Furthermore, the relatively small species pools of the northern high latitude assemblages suggest a low capacity to adapt to changing conditions.


A regional system for delivery of primary percutaneous coronary intervention in ST-elevation myocardial infarction: STEMI-St. Cloud.
Strategies of emergency care in the treatment of ST-segment elevation myocardial infarction (STEMI) have evolved rapidly over the past two decades to include primary percutaneous coronary intervention (PPCI) when possible. Most U.S.-based transfer programs still use complicated protocols that include fibrinolytic therapy often resulting in transfer delays, inappropriately applied therapy (wrong diagnosis) and bleeding and stroke complications. These protocols are often emphasized in low-volume centers. We implemented a program absent fibrinolytic therapy and applied it to a network of 25 participating hospitals over a 100-mile radius in central Minnesota. One-thousand consecutive patients ages 21 to 90 who presented within 12 hours of the onset of symptoms consistent with MI from April, 2004 to January, 2008 were included in this registry. Prior to transfer to the cardiac catheterization laboratory, patients received aspirin and heparin. Clopidogrel was added to the protocol in January, 2007. Glycoprotein (GP) IIb/IIIa inhibitors were typically utilized after diagnostic catheterization and prior to PPCI. Median door-to-balloon time was 56 minutes at the PCI Center and 110 minutes from referral sites (RS). Of the transfer patients, 71% underwent helicopter transfer. The success rate for PPCI was 99.4%. Despite inherent transfer delays, there was no difference in mortality between the PCI Center and RS. Overall mortality rates in-hospital, at 30 days, at 6 months, and 1 year were 2.1%, 2.9%, 3.8% and 4.5%, respectively, with follow up on 998 of 1,000 patients. In-hospital stroke, reinfarction and major bleeding were 0.7%, 2.0% and 2.7%, respectively. Despite increasing trends toward a pharmacoinvasive approach in transfer patients with STEMI, a protocol which stresses rapid transfer and PPCI results in excellent outcomes, with very low complication rates without fibrinolytic therapy.


Novel route to fatigue-resistant fully sintered ultrahigh molecular weight polyethylene for knee prosthesis.
The role of entanglements in obtaining a homogeneous product of ultrahigh molecular weight polyethylene (UHMW-PE) has been explored. Studies performed in this report show that a disentangled state before melting is a prerequisite to obtain homogeneous products of an intractable polymer like UHMW-PE. The disentangled state is obtained directly from the reactor by controlling the polymerization conditions or in the solid state when there is enhanced chain mobility along the c axis of a unit cell. The disentangled state is maintained in the melt over a period of time, invoking implications in polymer rheology. This approach is applicable to polymers in general. The homogeneous fully sintered UHMW-PE, obtained for the first time, shows a considerable decrease in oxygen permeability and an increase in toughness and fatigue resistance. Such homogeneous products of UHMW-PE are beneficial in highly demanding applications, especially in knee prosthesis, where the polymer is used as an inlay between the human bone and a metal or ceramic part, which slides against the polyethylene component during normal gait.


Kinetic Gait Analysis of Agility Dogs Entering the A-Frame.
The main purpose of this study was to investigate the effect of a decrease in the A-frame angle of incline on the vertical and cranio-caudal ground reaction forces observed in a homogeneous cohort of agility dogs during entrance and contact with the A-frame. A crossover study design was applied to eight large breed dogs to compare the vertical and cranio-caudal ground reaction forces entering the A-frame at three angles of incline: 40° (standard), 35° and 30°. The peak vertical force, passive impact peak, peak propulsive force, peak braking force, the time point (percentile) in the stance phase at which these events occurred and the proportion of time for limb contact spent in braking (% braking) and propulsion (% propulsion) were examined.The variables measured from three trials at each incline were evaluated for a significant effect of A-frame angle with height and velocity included as covariates. The peak propulsive force and the % propulsion were significantly higher at the 40° angle of incline compared with 30° (p = 0.013, p = 0.0165 respectively) and the % braking was significantly lower at the 40° angle of incline compared with 30° (p = 0.0165). There was no significant effect of A-frame angle on the vertical ground reaction forces measured. Compared with 30° incline, ascent up the A-frame at a 40° incline requires a higher propulsive force and extended time in propulsion to maintain forward movement and convert potential energy into forward kinetic energy.


Adjuvant activity of monophosphoryl lipid A for nasal and oral immunization with soluble or liposome-associated antigen.
The effectiveness of monophosphoryl lipid A (MPL) as a mucosal adjuvant was investigated following oral or intranasal (i.n.) administration of an aqueous adjuvant formulation of MPL (MPL-AF) added to soluble antigen or liposomal antigen or incorporated into liposomal antigen membranes. Groups of BALB/c female mice were immunized with 50 to 100 microg of free or liposomal Streptococcus mutans crude glucosyltransferase (C-GTF) with or without MPL-AF added to the vaccine or incorporated into the liposomal membrane. Plasma, saliva, vaginal wash, and fecal extract samples were collected biweekly following immunization and assessed for antigen-specific antibody activity by enzyme-linked immunosorbent assay (ELISA). Mice immunized by the i.n. route had higher levels of salivary, plasma, and vaginal immunoglobulin A (IgA) anti-C-GTF responses and higher levels of plasma IgG anti-C-GTF than the orally immunized groups. A second administration of the vaccine 14 weeks after the initial immunization resulted in an anamnestic response to C-GTF resulting in 10- and 100-fold increases in saliva and plasma IgA and plasma IgG, respectively (in the i.n. immunized groups). Mice receiving a second i.n. immunization with liposomal antigen and MPL-AF had higher salivary IgA anti-C-GTF responses than mice immunized with antigen plus MPL-AF or liposomal antigen (P < 0.05). Plasma IgG anti-C-GTF activity was highest in mice immunized by the i.n. route with antigen formulations containing MPL-AF (P < 0.05). These results demonstrate the effectiveness of MPL-AF as an adjuvant for potentiating mucosal and systemic immune responses to liposomal C-GTF following i.n. immunization.


Ethanol's effects on gait dynamics in mice investigated by ventral plane videography.
Performance of mice in motor function tests for ethanol sensitivity is often task dependent, not reflective of coordinated movement, and reported qualitatively. Therefore, we applied a new imaging technique to record and quantify coordinated gait dynamics in mice in response to ethanol. We applied ventral plane videography to record and report gait indices in mice walking on a transparent treadmill belt. We examined the effects of ethanol on gait in C57BL/6J (B6) and DBA/2J (D2) mice walking at a speed of 25 cm/sec. B6 and D2 are two inbred strains that are widely used to study the genetic influences of ethanol on motor function. Gait posture in D2 mice was less stable than in B6 mice. B6 mice always showed an alternate step sequence, whereas D2 mice sometimes showed cruciate and rotary step sequences. Ethanol in increasing doses increased stride frequency, decreased stride length, and increased stride length variability in D2 mice but not in B6 mice. The forelimb braking duration was significantly shortened and the hind limb propulsion duration was significantly prolonged with a high dose of ethanol in D2 mice but not in B6 mice. Differences in gait indices between the two strains of mice were more pronounced of the forelimbs with the highest dose of ethanol (2.75 g/kg). Our data suggest that the higher susceptibility of D2 compared with B6 mice to the effects of ethanol on motor function may be attributed to less stable basal gait characteristics that are perturbed by ethanol. The ability of this method to quantify step sequence patterns and gait indices of forelimb and hind limbs could provide new data regarding ethanol-induced motor incoordination.


Disaggregating Within- and Between-Person Effects of Social Identification on Subjective and Endocrinological Stress Reactions in a Real-Life Stress Situation.
Several experimental and cross-sectional studies have established the stress-buffering effect of social identification, yet few longitudinal studies have been conducted within this area of research. This study is the first to make use of a multilevel approach to disaggregate between- and within-person effects of social identification on subjective and endocrinological stress reactions. Specifically, we conducted a study with 85 prospective students during their 1-day aptitude test for a university sports program. Ad hoc groups were formed, in which students completed several tests in various disciplines together. At four points in time, salivary cortisol, subjective strain, and identification with their group were measured. Results of multilevel analyses show a significant within-person effect of social identification: The more students identified with their group, the less stress they experienced and the lower their cortisol response was. Between-person effects were not significant. Advantages of using multilevel approaches within this field of research are discussed.


Individual and geographic disparities in human papillomavirus types 16/18 in high-grade cervical lesions: Associations with race, ethnicity, and poverty.
Current vaccines protect against 2 human papillomavirus (HPV) types, HPV 16 and 18, which are associated with 70% of cervical cancers and 50% of high-grade cervical lesions. HPV type distribution was examined among women with high-grade lesions by individual and area-based measures of race, ethnicity, and poverty. This analysis included 832 women aged 18 to 39 years reported to a surveillance registry in Connecticut during 2008 to 2010. Diagnostic specimens were obtained for HPV DNA testing. Individual measures were obtained from surveillance reports, medical records, and patient interviews. Cases were geocoded to census tracts and linked to area-based measures of race, ethnicity, and poverty. Statistical analysis included use of generalized estimating equations. Overall, 44.8% of women had HPV 16/18. In a multivariate model controlled for confounding by age and diagnosis grade, black race (adjusted prevalence ratio [aPR] = 0.54, 95% confidence interval [CI] = 0.34-0.88), Hispanic ethnicity (aPR = 0.59, 95% CI = 0.40-0.88), and higher area-based poverty (aPR = 0.59, 95% CI = 0.40-0.87) were associated with a lower likelihood of HPV 16/18 positivity. Black and Hispanic women were less likely to have HPV 16/18 than white women across all levels of area-based measures. Black race, Hispanic ethnicity, and higher area-based poverty are salient predictors of lower HPV 16/18 positivity among women with high-grade cervical lesions. These data suggest that HPV vaccines might have lower impact among black and Hispanic women and those living in high poverty areas. These findings have implications for vaccine impact monitoring, vaccination programs, and new vaccine development.


Montmorency cherries reduce the oxidative stress and inflammatory responses to repeated days high-intensity stochastic cycling.
This investigation examined the impact of Montmorency tart cherry concentrate (MC) on physiological indices of oxidative stress, inflammation and muscle damage across 3 days simulated road cycle racing. Trained cyclists (n = 16) were divided into equal groups and consumed 30 mL of MC or placebo (PLA), twice per day for seven consecutive days. A simulated, high-intensity, stochastic road cycling trial, lasting 109 min, was completed on days 5, 6 and 7. Oxidative stress and inflammation were measured from blood samples collected at baseline and immediately pre- and post-trial on days 5, 6 and 7. Analyses for lipid hydroperoxides (LOOH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), interleukin-1-beta (IL-1-β), high-sensitivity C-reactive protein (hsCRP) and creatine kinase (CK) were conducted. LOOH (p < 0.01), IL-6 (p < 0.05) and hsCRP (p < 0.05) responses to trials were lower in the MC group versus PLA. No group or interaction effects were found for the other markers. The attenuated oxidative and inflammatory responses suggest MC may be efficacious in combating post-exercise oxidative and inflammatory cascades that can contribute to cellular disruption. Additionally, we demonstrate direct application for MC in repeated days cycling and conceivably other sporting scenario's where back-to-back performances are required.


100 Years of Mass Deworming Programmes: A Policy Perspective From the World Bank's Disease Control Priorities Analyses.
For more than 100 years, countries have used mass drug administration as a public health response to soil-transmitted helminth infection. The series of analyses published as Disease Control Priorities is the World Bank's vehicle for exploring the cost-effectiveness and value for money of public health interventions. The first edition was published in 1993 as a technical supplement to the World Bank's World Development Report Investing in Health where deworming was used as an illustrative example of value for money in treating diseases with relatively low morbidity but high prevalence. Over the second (2006) and now third (2017) editions deworming has been an increasingly persuasive example to use for this argument. The latest analyses recognize the negative impact of intestinal worm infection on human capital in poor communities and document a continuing decline in worm infection as a result of the combination of high levels of mass treatment and ongoing economic development trends in poor communities.


Playing with a child with ADHD: a focus on the playmates.
Play is the context for acquiring social skills. While it is logical to suspect that the difficulties associated with ADHD would affect play, there is surprisingly little work in that area. Further, there is almost no previous research describing the playmates of children with ADHD. This study involved children with ADHD (n = 112) playing with a usual playmate (n = 112), and pairs of age-, ethnicity-, and sex-matched children (n = 126) playing together. In this paper, the authors interpret the data from the perspective of the playmates. The overall finding was that the play behavior of the playmates closely resembled that of the children with ADHD; it was characterized by low levels of empathy. A primary purpose of this paper is to explore possible explanations for this surprising finding. Two possible explanations are explored. First, children with ADHD are demanding playmates so that children who play with them mirror their negative behaviors. Second, although the playmates did not have ADHD, their play behaviors might reflect the known risk of negative behaviors reported amongst siblings and peers of children with ADHD. Evidence to support both explanations is presented and new lines of research are proposed to examine each possibility.


Dose-response relation between exercise duration and cognition.
The study aimed to provide evidence-based recommendations for the prescription of a single session of exercise to improve cognitive performance. In particular, the purpose was to determine the dose-response relation between exercise duration and cognitive performance for a moderate-intensity session of aerobic exercise. Twenty-six healthy young men participated in a reading control treatment and three exercise treatments presented in a random order. The exercise treatments were designed on the basis of the American College of Sports Medicine guidelines and consisted of a 5-min warm-up, a 5-min cooldown, and cycling at moderate intensity (approximately 65% HR reserve) for 10, 20, or 45 min. The Stroop test was administrated after completion of each assigned treatment. Exercise at moderate intensity for 20 min resulted in significantly better cognitive performance, as assessed by shorter response time and higher accuracy. This result was found regardless of the type of cognitive function assessed. In addition, a curvilinear dose-response relation between exercise duration and cognitive performance was observed. An exercise session consisting of a 5-min warm-up, 20 min of moderate-intensity exercise, and a 5-min cooldown improves cognition, whereas shorter or longer durations of moderate exercise have negligible benefits. This study provides the foundation for the prescription of a single session of moderate exercise to facilitate cognitive function in healthy younger adults.


New BMSC-Laden Gelatin Hydrogel Formed in Situ by Dual-Enzymatic Cross-Linking Accelerates Dermal Wound Healing.
In situ forming hydrogel shows enormous potential as a therapeutic implant or carrier in tissue repair and regeneration. It can perfectly seal or fill the defective tissue, consequently functioning as a cell/drug delivery vehicle. In this contribution, a new gelatin hydrogel with dual-enzymatic cross-linking of horseradish peroxidase (HRP) and galactose oxidase (GalOx) was developed, and the therapeutic effect of this hydrogel encapsulated with bone mesenchymal stem cells (BMSC) in dermal wound healing was investigated. This hydrogel possesses a quick gelation process within 5 min, a high water content, and a uniform three-dimensional (3D) porous network. The 3D cell culture study indicated that gelatin hydrogel matrix of HRP(5U):GalOx(1U) or HRP(2U):GalOx(1U) could provide a friendly 3D microenvironment for supporting the survival, proliferation, and spread of mouse bone mesenchymal stem cells (BMSC) with negligible cytotoxicity. Hematoxylin and eosin staining test suggested that this hydrogel has superior histocompatibility and minimized immune response in vivo. Furthermore, wound-healing studies on a C57 mouse model of excised wound demonstrated that BMSC-laden gelatin hydrogel could significantly accelerate the wound closure as compared to other groups. These data suggest that this dual-enzymatically cross-linked gelatin hydrogel loaded with BMSC has a great potential in wound healing and other tissue-regeneration applications.


A technique for accurately calibrating the motion of a phase mask used to inscribe complex fibre Bragg grating structures.
A technique is described for calibrating the amplitude of motion of a phase mask typically used for inscribing fibre Bragg grating (FBG) structures. The motion of the phase mask is detected using a simple Michelson interferometer that can be readily mounted onto an FBG writing system. The output of the interferometer provides a direct indication of the phase mask motion as a function of the true periodicity of the phase mask structure and so is ideally suited to inscription of apodised or phase shifted FBG structures. The technique can be automated and can achieve accuracies of +/-1 nm in approximately 1 minute.


Evolution of long-term coloration trends with biochemically unstable ingredients.
The evolutionarily persistent and widespread use of carotenoid pigments in animal coloration contrasts with their biochemical instability. Consequently, evolution of carotenoid-based displays should include mechanisms to accommodate or limit pigment degradation. In birds, this could involve two strategies: (i) evolution of a moult immediately prior to the mating season, enabling the use of particularly fast-degrading carotenoids and (ii) evolution of the ability to stabilize dietary carotenoids through metabolic modification or association with feather keratins. Here, we examine evolutionary lability and transitions between the two strategies across 126 species of birds. We report that species that express mostly unmodified, fast-degrading, carotenoids have pre-breeding moults, and a particularly short time between carotenoid deposition and the subsequent breeding season. Species that expressed mostly slow-degrading carotenoids in their plumage accomplished this through increased metabolic modification of dietary carotenoids, and the selective expression of these slow-degrading compounds. In these species, the timing of moult was not associated with carotenoid composition of plumage displays. Using repeated samples from individuals of one species, we found that metabolic modification of dietary carotenoids significantly slowed their degradation between moult and breeding season. Thus, the most complex and colourful ornamentation is likely the most biochemically stable in birds, and depends less on ecological factors, such as moult timing and migration tendency. We suggest that coevolution of metabolic modification, selective expression and biochemical stability of plumage carotenoids enables the use of unstable pigments in long-term evolutionary trends in plumage coloration.


A novel mouse model for multiple myeloma (MOPC315.BM) that allows noninvasive spatiotemporal detection of osteolytic disease.
Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10(4) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM.


Is there a role for digital rectal examination in the followup of patients after radical prostatectomy?
We determine the role of digital rectal examination in the followup of patients after radical prostatectomy. We retrospectively analyzed data on 501 consecutive patients who underwent radical retropubic prostatectomy between 1992 and 1998, and were followed at the University of Miami. Patients were evaluated at 3 to 6-month intervals after surgery with serum prostate specific antigen (PSA) and digital rectal examination. Biochemical recurrence was defined as PSA greater than 0.2 ng./ml. and increasing on at least 2 consecutive measurements. Local recurrence, detected by an abnormal digital rectal examination, was defined as an induration or nodularity in the prostatic fossa. Mean followup plus or minus standard deviation was 25.4+/-20.8 months. Disease recurred in 72 patients (14.4%) and was biochemical in all. An abnormal digital rectal examination was noted in 4 patients, none of whom had an undetectable PSA at the time of a palpable abnormality. Our results suggest that an abnormal digital rectal examination after radical prostatectomy is always associated with a detectable PSA, which implies that performing a digital rectal examination in the absence of a detectable PSA may not be necessary.


Visualising Spatio-Temporal Gaze Characteristics for Exploratory Data Analysis in Clinical Fetal Ultrasound Scans.
Visualising patterns in clinicians' eye movements while interpreting fetal ultrasound imaging videos is challenging. Across and within videos, there are differences in size an d position of Areas-of-Interest (AOIs) due to fetal position, movement and sonographer skill. Currently, AOIs are manually labelled or identified using eye-tracker manufacturer specifications which are not study specific. We propose using unsupervised clustering to identify meaningful AOIs and bi-contour plots to visualise spatio-temporal gaze characteristics. We use Hierarchical Density-Based Spatial Clustering of Applications with Noise (HDBSCAN) to identify the AOIs, and use their corresponding images to capture granular changes within each AOI. Then we visualise transitions within and between AOIs as read by the sonographer. We compare our method to a standardised eye-tracking manufacturer algorithm. Our method captures granular changes in gaze characteristics which are otherwise not shown. Our method is suitable for exploratory data analysis of eye-tracking data involving multiple participants and AOIs.


Risk of astrocytic brain tumors associated with occupational chemical exposures. A case-referent study.
A case-referent study was conducted on the risk of brain tumors among workers exposed to organic chemicals in petroleum refining and chemical manufacturing. Brain tumor cases in northern New Jersey, Philadelphia, and the Gulf Coast of Louisiana were identified from death certificates of a recent three-year period. The cases (N = 300) were white men aged greater than or equal to 30 years with a confirmed diagnosis of glioblastoma multiforme, astrocytoma, or a mixed glioma with astrocytic cells. The referents (N = 386) were white men who died from causes other than brain tumor, epilepsy, cerebrovascular disease, suicide, or homicide and were frequency-matched with the cases on age at death, year of death, and study area. Next-of-kin were interviewed for complete occupational histories. No statistically significantly elevated odds ratios (OR) were associated with employment in the chemical industry. The risk of astrocytic tumors was elevated among the subjects with production or maintenance jobs in petroleum refining (OR 1.7, 95% confidence interval 0.7-4.2); however, it decreased with duration employed. There were nonsignificant excess risks of astrocytic tumors among the men exposed to cutting fluids (OR 1.6) or organic solvents (OR 1.3), and also among the subjects exposed to lubricating oils (OR 1.4), organic solvents (OR 1.5), or cutting fluids (OR 1.8) for greater than or equal to 20 years.


Systemic administration of low-dose naltrexone increases bone mass due to blockade of opioid growth factor receptor signaling in mice osteoblasts.
Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice. We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses. Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group. Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.


Sampling of urine for diagnosing urinary tract infection in general practice - First-void or mid-stream urine?
To study 1) whether the accuracy of point-of-care (POC) urine tests (dipstick, phase-contrast microscopy and culture) differs when performed on first-void urine (FVU) compared to mid-stream urine (MSU), and 2) if a delay of analysis up to four hours affects the accuracy of POC tests when performed on urine from symptomatic of urinary tract infection (UTI), non-pregnant women in general practice. Prospective diagnostic study using paired samples. Setting/Intervention: Three general practices in Copenhagen. Each woman delivered FVU and MSU samples from the same void. As a reference standard, 8 ml of MSU was sent for culture at the Microbiology Department. 117 women with one or more symptoms of UTI. Sensitivity, specificity and agreement with the reference standard of FVU and MSU with different time delays (zero vs. one vs. four hours) as compared to reference standard (MSU at time zero in boric acid tubes). All three POC tests performed on MSU were significantly more in agreement with the reference than when performed on FVU when analysis was done immediately. The error rate was 16% for MSU vs. 23% for FVU with POC culture, 27% vs. 40% with microscopy and 25% vs. 33% with dipstick testing. Delay of analysis up to four hours did not decrease agreement with the reference. Conclusion/Implication: MSU samples should be used in general practice for optimal accuracy of POC tests. Analysis can be delayed up to four hours. Key points Point-of-care tests (dipstick testing, microscopy and culture) for diagnosing urinary tract infection performed on mid-stream urine samples are significantly more accurate than when performed on first-void urine samples. Delay of analysis up to four hours did not decrease the accuracy of any of the point-of-care tests. Point-of-care culture was more accurate than dipstick and microscopy both when performed on mid-stream urine and first-void urine The main contaminant in first-void urine samples was Enterococci spp., which contributed to the majority of false positives.


Isolated osteoclasts resorb the organic and inorganic components of bone.
Osteoclasts are the principal resorptive cells of bone, yet their capacity to degrade collagen, the major organic component of bone matrix, remains unexplored. Accordingly, we have studied the bone resorptive activity of highly enriched populations of isolated chicken osteoclasts, using as substrate devitalized rat bone which had been labeled in vivo with L-[5-3H]proline or 45Ca, and bone-like matrix produced and mineralized in vitro by osteoblast-like rat osteosarcoma cells. When co-cultured with a radiolabeled substrate, osteoclast-mediated mineral mobilization reached a maximal rate within 2 h, whereas organic matrix degradation appeared more slowly, reaching maximal rate by 12-24 h. Thereafter, the rates of organic and inorganic matrix resorption were essentially linear and parallel for at least 6 d when excess substrate was available. Osteoclast-mediated degradation of bone collagen was confirmed by amino acid analysis. 39% of the solubilized tritium was recovered as trans-4-hydroxyproline, 47% as proline. 10,000 osteoclasts solubilized 70% of the total radioactivity and 65% of the [3H]-trans-4-hydroxyproline from 100 micrograms of 25-50 micron bone fragments within 5 d. Virtually all released tritium-labeled protein was of low molecular weight, 99% with Mr less than or equal to 10,000, and 65% with Mr less than or equal to 1,000. Moreover, when the 14% of resorbed [3H]proline-labeled peptides with Mr greater than or equal to 2,000 were examined for the presence of TCA and TCB, the characteristic initial products of mammalian collagenase activity, none was detected by SDS PAGE. In addition, osteoclast-conditioned medium had no collagenolytic activity, and exogenous TCA and TCB fragments were not degraded by osteoclasts. On the other hand, osteoclast lysates have collagenolytic enzyme activity in acidic but not in neutral buffer, with maximum activity at pH 4.0. These data indicate that osteoclasts have the capacity to resorb the organic phase of bone by a process localized to the osteoclast and its attachment site. This process appears to be independent of secretion of neutral collagenase and probably reflects acid protease activity.


Cardioprotection and natural polyphenols: an update of clinical and experimental studies.
Myocardial ischemia is the leading cause of death worldwide. Despite better outcomes with early coronary artery reperfusion strategies, morbidity and mortality remain significant. The principal myocardial hallmark of myocardial ischemia is cell death and the associated impairment of cardiac contractility. In this way, the use of extracts from medicinal plants versus synthetic drugs to mitigate post-ischemic damage constitutes an alternative. Despite their proven beneficial effects in cardiovascular disorders, the use of many plants is questioned. Our aim is to update the clinical and experimental studies about the actions of medicinal plants and polyphenol-enriched extracts against ischemia-reperfusion injury and the involved mechanisms. A review of the recent scientific literature (last ten years) on cardioprotective medicinal plants was developed using the following bibliographic databases: PubMed, Scopus, Web of Knowledge and Google Scholar. Herein, the clinical and experimental studies on medicinal plants and their phenolic compounds have been reviewed. The second part of this review was centered on the search for medicinal plant extracts and natural products isolated from them as potential cardioprotective agents. The botanical names of the cited plants have been authenticated by searching the Plant List and Royal Botanical Garden, Kew databases. The data collected show that treatment with natural products diminishes post-ischemic damage through an improvement of the mitochondrial functionality mainly mediated by enhanced nitric oxide bioavailability. Despite these results, further studies must be carried out to validate their use to prevent or mitigate ischemia-reperfusion injury in the clinical setting.


Use of a monoclonal antibody specific for wild-type yellow fever virus to identify a wild-type antigenic variant in 17D vaccine pools.
Monoclonal antibodies (MAbs) against the Asibi wild-type strain of yellow fever (YF) virus were prepared and characterized. One of the MAbs (designated MAb 117) was shown, by cross-immunofluorescence tests with flaviviruses, to be specific for wildtype YF virus. This MAb was used in indirect immunofluorescence tests to identify wild-type antigenic variants in several different YF vaccine pools. Simultaneously, a vaccine-specific MAb prepared previously (MAb 864) was used to identify YF strain 17D vaccine type variants in the wild-type Asibi virus preparation. One variant, isolated by plaque purification from a 17D vaccine pool, possessed the wild-type epitope and was neurovirulent in infant mice whereas other variants, lacking the wild-type epitope but with vaccine-specific epitopes (identified by MAb 411), were avirulent in infant mice. Avirulent variants were able to infect mice and induce antibody. Virus-specific antigen was still detected in the brains of these mice 4 weeks after inoculation, suggesting that persistent infections were developing. These results to the potential risk of selection of wild-type variants in YF vaccine preparations. They also point to the potential risk of selection of wild-type variants in YF vaccine preparations and re-emphasize the need for modernization of techniques and more effective control measures to be taken during the production of YF vaccine.


Suppressive effects of dietary high fluorine on the intestinal development in broilers.
Fluoride (F) is a well-recognized hazardous substance. Ingested F initially acts locally on the intestines. The small intestine plays a critical role in the digestion, absorption, and defense. In this study, therefore, we investigated the effects of fluorine on the intestinal development by light microscopy, transmission electron microscopy, and histochemistry. A total of 280 one-day-old avian broilers were randomly divided into four groups and fed on a corn-soybean basal diet as control diet (fluorine, 22.6 mg/kg) or the same basal diet supplemented with 400, 800, and 1,200 mg/kg fluorine (high fluorine groups I, II, and III) in the form of sodium fluoride for 42 days. The results showed that the intestinal gross, histological, and ultrastructural changes were observed in the high fluorine groups II and III. Meanwhile, the intestinal length, weight, viscera index, villus height, crypt depth, villus height to crypt depth ratio, diameter, muscle layer thickness, and goblet cell numbers were significantly lower (p < 0.01 or p < 0.05), and the intestinal diameter to villus height ratio was markedly higher (p < 0.01 or p < 0.05) in the high fluorine groups II and III than those in control group. In conclusion, dietary fluorine in the range of 800-1,200 mg/kg obviously altered the aforementioned parameters of the intestines, implying that the intestinal development was suppressed and the intestinal functions, such as digestion, absorption, defense, or osmoregulation were impaired in broilers.


Prostate cancer presenting as cervical lymphadenopathy.
Prostate cancer is the most common cancer in men in many Western countries and is the second-leading cause of cancer in men. More than 30% of men over the age of 50 will develop a malignant change in the prostate. Common sites of metastasis include bone and regional lymph nodes. This is a case report of prostate cancer in an elderly man presenting with cough and cervical lymphadenopathy. The lymph node cytology reported moderately differentiated adenocarcinoma, and immunohistochemistry of the biopsy specimen with PSA staining demonstrated the malignancy to be of prostatic origin. The patient responded dramatically to androgen blockade therapy. Clearing of chest infiltrates and regression in size of cervical lymph nodes were evident within 6 months. Prostate cancer should be considered as one of the differential diagnoses of generalized lymphadenopathy in males with adenocarcinoma of undetermined origin, even in the absence of lower urinary tract symptoms. Immunohistochemistry with PSA staining can confirm the diagnosis. Hormonal therapy is an effective treatment modality, even in patients with an advanced stage of disease.


A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis.
We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol. We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin. In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98-1.07, p=0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80-0.94, p = 0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77-0.99, p=0.038). The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol.


Liver Transplantation in the Obese Cirrhotic Patient.
Despite the rapidly increasing prevalence of obesity in the transplant population, the optimal management of obese liver transplant candidates remains undefined. Setting strict body mass index cutoffs for transplant candidacy remains controversial, with limited data to guide this practice. Body mass index is an imperfect measure of surgical risk in this population, partly due to volume overload and variable visceral adiposity. Weight loss before transplantation may be beneficial, but it remains important to avoid protein calorie malnutrition and sarcopenia. Intensive lifestyle modifications appear to be successful in achieving weight loss, though the durability of these interventions is not known. Pretransplant and intraoperative bariatric surgeries have been performed, but large randomized controlled trials are lacking. Traditional cardiovascular comorbidities are more prevalent in obese individuals and remain the basis for pretransplant cardiovascular evaluation and risk stratification. The recent US liver transplant experience demonstrates comparable patient and graft survival between obese and nonobese liver transplant recipients, but obesity presents important medical and surgical challenges during and after transplant. Specifically, obesity is associated with an increased incidence of wound infections, wound dehiscence, biliary complications and overall infection, and confers a higher risk of posttransplant obesity and metabolic syndrome-related complications. In this review, we examine current practices in the obese liver transplant population, offer recommendations based on the currently available data, and highlight areas where additional research is needed.


An official american thoracic society statement: work-exacerbated asthma.
Occupational exposures can contribute to the exacerbation as well as the onset of asthma. However, work-exacerbated asthma (WEA) has received less attention than occupational asthma (OA) that is caused by work. The purpose of this Statement is to summarize current knowledge about the descriptive epidemiology, clinical characteristics, and management and treatment of WEA; propose a case definition for WEA; and discuss needs for prevention and research. Information about WEA was identified primarily by systematic searches of the medical literature. Statements about prevention and research needs were reached by consensus. WEA is defined as the worsening of asthma due to conditions at work. WEA is common, with a median prevalence of 21.5% among adults with asthma. Different types of agents or conditions at work may exacerbate asthma. WEA cases with persistent work-related symptoms can have clinical characteristics (level of severity, medication needs) and adverse socioeconomic outcomes (unemployment, reduction in income) similar to those of OA cases. Compared with adults with asthma unrelated to work, WEA cases report more days with symptoms, seek more medical care, and have a lower quality of life. WEA should be considered in any patient with asthma that is getting worse or who has work-related symptoms. Management of WEA should focus on reducing work exposures and optimizing standard medical management, with a change in jobs only if these measures are not successful. WEA is a common and underrecognized adverse outcome resulting from conditions at work. Additional research is needed to improve the understanding of the risk factors for, and mechanisms and outcomes of, WEA, and to inform and evaluate preventive interventions.


The effect of fellow eye visual acuity on visual acuity of study eyes receiving ranibizumab for age-related macular degeneration.
To investigate whether extremes in visual acuity (very good or very poor) of the fellow eye (FE) influence visual acuity of the study eye in patients receiving intravitreal ranibizumab treatment for neovascular age-related macular degeneration. From 2 randomized, controlled, clinical trials (MARINA and ANCHOR), we performed a retrospective analysis of ranibizumab-treated patients who maintained stable FE visual acuity (±5 letters from baseline at each of Months 1, 4, 6, and 12), comparing patients with untreated FE visual acuity that was either 20/32 or better (very good) or 20/200 or worse (very poor). Visual acuity of the treated study eyes, which received monthly intravitreal ranibizumab (0.3 mg or 0.5 mg), was compared between the 2 FE cohorts at the Month 6 and Month 12 visits. A total of 145 patients were analyzed. In the cohort with very poor FE visual acuity (n = 55), there were 35 patients in MARINA and 20 patients in ANCHOR; in the cohort with very good FE visual acuity (n = 90), there were 52 patients in MARINA and 38 patients in ANCHOR.The mean (standard deviation) gain of the study eye visual acuity in the very good FE cohort was 10.3 (13.3) and 10.8 (13.7) letters at Months 6 and 12, respectively, compared with a lesser mean visual acuity gain of 4.6 (12.2) and 6.7 (11.7) letters at Months 6 and 12 in the very poor vision FE cohort. There was no statistically significant difference (adjusted) in the study eye visual acuity change between the 2 cohorts at either 6 months (P = 0.11) or 12 months (P = 0.26). This retrospective analysis of the MARINA and ANCHOR study data did not support the hypothesis that FE visual acuity plays a significant role in driving visual acuity of patients receiving monthly intravitreal ranibizumab injections for neovascular age-related macular degeneration. Visual acuity of the FE by itself is, therefore, not a useful parameter in predicting visual acuity in a majority of ranibizumab-treated patients.


Ethics in HTA: Examining the "Need for Expansion".
The article by Daniels and colleagues on expanding the scope of health technology assessment (HTA) to embrace ethical analysis has received endorsement and criticism from commentators in this journal. Referring to this debate, we examine in this article the extent and locus of ethical analysis in HTA processes. An expansion/no-expansion framing of HTA is, in our view, not very fruitful. We argue that meaningfulness and relevance to the needs of the population are what should determine the extent of ethics in HTA. Once 'relevance' is the guiding principle, engaging in ethical analysis becomes inevitable as values are all over the place in HTA, also in how assessors frame research questions. We also challenge dividing the locus of ethical analysis into assessment and appraisal as this would detach HTA from its purpose, ie, supporting legitimate decision-making. Ethical analysis should therefore be considered integral to the HTA process.


Laboratory Validation of Inertial Body Sensors to Detect Cigarette Smoking Arm Movements.
Cigarette smoking remains the leading cause of preventable death in the United States. Traditional in-clinic cessation interventions may fail to intervene and interrupt the rapid progression to relapse that typically occurs following a quit attempt. The ability to detect actual smoking behavior in real-time is a measurement challenge for health behavior research and intervention. The successful detection of real-time smoking through mobile health (mHealth) methodology has substantial implications for developing highly efficacious treatment interventions. The current study was aimed at further developing and testing the ability of inertial sensors to detect cigarette smoking arm movements among smokers. The current study involved four smokers who smoked six cigarettes each in a laboratory-based assessment. Participants were outfitted with four inertial body movement sensors on the arms, which were used to detect smoking events at two levels: the puff level and the cigarette level. Two different algorithms (Support Vector Machines (SVM) and Edge-Detection based learning) were trained to detect the features of arm movement sequences transmitted by the sensors that corresponded with each level. The results showed that performance of the SVM algorithm at the cigarette level exceeded detection at the individual puff level, with low rates of false positive puff detection. The current study is the second in a line of programmatic research demonstrating the proof-of-concept for sensor-based tracking of smoking, based on movements of the arm and wrist. This study demonstrates efficacy in a real-world clinical inpatient setting and is the first to provide a detection rate against direct observation, enabling calculation of true and false positive rates. The study results indicate that the approach performs very well with some participants, whereas some challenges remain with participants who generate more frequent non-smoking movements near the face. Future work may allow for tracking smoking in real-world environments, which would facilitate developing more effective, just-in-time smoking cessation interventions.


Genetic features associated with 18F-FDG uptake in intrahepatic cholangiocarcinoma.
In intrahepatic cholangiocarcinoma (iCCA), genetic characteristics on 18F-fluorodeoxyglucose (18F-FDG)-PET scans are not yet clarified. If specific genetic characteristics were found to be related to FDG uptake in iCCA, we can predict molecular features based on the FDG uptake patterns and to distinguish different types of treatments. In this purpose, we analyzed RNA sequencing in iCCA patients to evaluate gene expression signatures associated with FDG uptake patterns. We performed RNA sequencing of 22 cases iCCA who underwent preoperative 18F-FDG-PET, and analyzed the clinical and molecular features according to the maximum standard uptake value (SUVmax). Genes and biological pathway which are associated with SUVmax were analyzed. Patients with SUVmax higher than 9.0 (n = 9) had poorer disease-free survival than those with lower SUVmax (n = 13, P = 0.035). Genes related to glycolysis and gluconeogenesis, phosphorylation and cell cycle were significantly correlated with SUVmax (r ≥ 0.5). RRM2, which is related to the toxicity of Gemcitabine was positively correlated with SUVmax, and SLC27A2 which is associated with Cisplastin response was negatively correlated with SUVmax. According to the pathway analysis, cell cycle, cell division, hypoxia, inflammatory, and metabolism-related pathways were enriched in high SUVmax patients. The genomic features of gene expression and pathways can be predicted by FDG uptake features in iCCA. Patients with high FDG uptake have enriched cell cycle, metabolism and hypoxic pathways, which may lead to a more rational targeted treatment approach.


Lactobacillus rhamnosus colonisation antagonizes Candida albicans by forcing metabolic adaptations that compromise pathogenicity.
Intestinal microbiota dysbiosis can initiate overgrowth of commensal Candida species - a major predisposing factor for disseminated candidiasis. Commensal bacteria such as Lactobacillus rhamnosus can antagonize Candida albicans pathogenicity. Here, we investigate the interplay between C. albicans, L. rhamnosus, and intestinal epithelial cells by integrating transcriptional and metabolic profiling, and reverse genetics. Untargeted metabolomics and in silico modelling indicate that intestinal epithelial cells foster bacterial growth metabolically, leading to bacterial production of antivirulence compounds. In addition, bacterial growth modifies the metabolic environment, including removal of C. albicans' favoured nutrient sources. This is accompanied by transcriptional and metabolic changes in C. albicans, including altered expression of virulence-related genes. Our results indicate that intestinal colonization with bacteria can antagonize C. albicans by reshaping the metabolic environment, forcing metabolic adaptations that reduce fungal pathogenicity.


Symmetry, topology and the maximum number of mutually pairwise-touching infinite cylinders: configuration classification.
We provide a complete classification of possible configurations of mutually pairwise-touching infinite cylinders in Euclidian three-dimensional space. It turns out that there is a maximum number of such cylinders possible in three dimensions independently of the shape of the cylinder cross-sections. We give the explanation of the uniqueness of the non-trivial configuration of seven equal mutually touching round infinite cylinders found earlier. Some results obtained for the chirality matrix, which is equivalent to the Seidel adjacency matrix, may be found useful for the theory of graphs.


Neopterin and interleukin-6 as predictors of recurrent atrial fibrillation.
Available evidence suggests that inflammation may be associated with atrial fibrillation (AF). This prospective and observational study aimed to assess whether plasma neopterin (NPT) and interleukin-6 (IL-6) levels before and after electrical cardioversion (CV) predict AF recurrence. The study was designed as a prospective observational trial. Blood samples were collected (24 hours before, 24 h after CV, and 7 days after CV) in 60 patients with a dual-chamber pacemakar and preserved left ventricular systolic function who underwent successful CV of persistent AF. All significant parameters associated with AF recurrence lasting ≥30 min and detected by pacemaker data logs were evaluated in multivariate logistic regression analysis. Echocardiography was performed 7 days after CV in patients with sinus rhythm. The control group included 17 subjects without AF. The analysis included 51 patients who remained in sinus rhythm 7 days after CV. During 12 months of follow-up, AF recurred in 46 patients. Baseline IL-6 levels did not differ between the two groups, but baseline NPT levels were higher in the study group than in the control group (19±7 vs. 11±5 nmol/mL, p<0.001). NPT levels of ≥14.6 nmol/L at baseline and ≥13.3 nmol/L 7 days after CV separated the patients with AF recurrence from those without arrhythmia after CV. Only left atrial emptying fraction <38% was an independent predictor of AF recurrence (p=0.03), whereas NPT levels of ≥13.3 nmol/L 7 days after CV showed borderline statistical significance (p=0.07). Increased NPT level was observed in patients with persistent AF. Neither baseline IL-6 and NPT levels nor their changes within 7 days after CV were predictive of AF recurrence. Further studies are needed to establish the prognostic significance of NPT in patients with AF.


Ifosfamide metabolites CAA, 4-OH-Ifo and Ifo-mustard reduce apical phosphate transport by changing NaPi-IIa in OK cells.
Renal Fanconi syndrome occurs in about 1-5% of all children treated with Ifosfamide (Ifo) and impairment of renal phosphate reabsorption in about 20-30% of them. Pathophysiological mechanisms of Ifo-induced nephropathy are ill defined. The aim has been to investigate whether Ifo metabolites affect the type IIa sodium-dependent phosphate transporter (NaPi-IIa) in viable opossum kidney cells. Ifo did not influence viability of cells or NaPi-IIa-mediated transport up to 1 mM/24 h. Incubation of confluent cells with chloroacetaldehyde (CAA) and 4-hydroperoxyIfosfamide (4-OH-Ifo) led to cell death by necrosis in a concentration-dependent manner. At low concentrations (50-100 microM/24 h), cell viability was normal but apical phosphate transport, NaPi-IIa protein, and -mRNA expression were significantly reduced. Coincubation with sodium-2-mercaptoethanesulfonate (MESNA) prevented the inhibitory action of CAA but not of 4-OH-Ifo; DiMESNA had no effect. Incubation with Ifosfamide-mustard (Ifo-mustard) did alter cell viability at concentrations above 500 microM/24 h. At lower concentrations (50-100 microM/24 h), it led to significant reduction in phosphate transport, NaPi-IIa protein, and mRNA expression. MESNA did not block these effects. The effect of Ifo-mustard was due to internalization of NaPi-IIa. Cyclophosphamide-mustard (CyP-mustard) did not have any influence on cell survival up to 1000 microM, but the inhibitory effect on phosphate transport and on NaPi-IIa protein was the same as found after Ifo-mustard. In conclusion, CAA, 4-OH-Ifo, and Ifo- and CyP-mustard are able to inhibit sodium-dependent phosphate cotransport in viable opossum kidney cells. The Ifo-mustard effect took place via internalization and reduction of de novo synthesis of NaPi-IIa. Therefore, it is possible that Ifo-mustard plays an important role in pathogenesis of Ifo-induced nephropathy.


New insights into nucleolar structure and function.
The nucleolus is a non-membrane-bound nuclear organelle found in all eukaryotes. It is the quintessential 'RNA-seeded' nuclear body, forming around specific chromosomal features called nucleolar organizing regions that contain arrays of ribosomal DNA. Assembly is triggered by activation of RNA polymerase I-mediated transcription and regulated in mammalian cells in a cell cycle-dependent manner. Although the nucleolus is best known for its role in coordinating ribosome biogenesis, biochemical and proteomic analyses have revealed a much wider functional complexity than previously appreciated, including roles in cell cycle regulation, DNA damage sensing and repair, pre-mRNA processing, telomere metabolism, processing of non-coding RNAs, and coordination of the cellular response to various stresses. Despite these advances, much remains to be learned about the full range of biological processes that occur within, or involve, this organelle and how its assembly/disassembly and functional reorganization in response to various stimuli are regulated. Here, we review the impact of recent studies that provide major insights into these fundamental questions, and we highlight the therapeutic potential of targeting nucleolar pathways.


Non-immune binding of human IgG to M-related proteins confers resistance to phagocytosis of group A streptococci in blood.
The non-immune binding of immunoglobulins by bacteria is thought to contribute to the pathogenesis of infections. M-related proteins (Mrp) are group A streptococcal (GAS) receptors for immunoglobulins, but it is not known if this binding has any impact on virulence. To further investigate the binding of immunoglobulins to Mrp, we engineered mutants of an M type 4 strain of GAS by inactivating the genes for mrp, emm, enn, sof, and sfbX and tested these mutants in IgG-binding assays. Inactivation of mrp dramatically decreased the binding of human IgG, whereas inactivation of emm, enn, sof, and sfbx had only minor effects, indicating that Mrp is a major IgG-binding protein. Binding of human immunoglobulins to a purified, recombinant form of Mrp indicated that it selectively binds to the Fc domain of human IgG, but not IgA or IgM and that it preferentially bound subclasses IgG₁>IgG₄>IgG₂>IgG₃. Recombinant proteins encompassing different regions of Mrp were engineered and used to map its IgG-binding domain to its A-repeat region and a recombinant protein with 3 A-repeats was a better inhibitor of IgG binding than one with a single A-repeat. A GAS mutant expressing Mrp with an in-frame deletion of DNA encoding the A-repeats had a dramatically reduced ability to bind human IgG and to grow in human blood. Mrp exhibited host specificity in binding IgG; human IgG was the best inhibitor of the binding of IgG followed by pig, horse, monkey, and rabbit IgG. IgG from goat, mouse, rat, cow, donkey, chicken, and guinea pig were poor inhibitors of binding. These findings indicate that Mrp preferentially binds human IgG and that this binding contributes to the ability of GAS to resist phagocytosis and may be a factor in the restriction of GAS infections to the human host.


Dispersed crude oil amplifies germ cell apoptosis in Caenorhabditis elegans, followed a CEP-1-dependent pathway.
The Deepwater Horizon oil spill is among the most severe environmental disasters in US history. The extent of crude oil released and the subsequent dispersant used for cleanup was unprecedented. The dispersed crude oil represents a unique form of environmental contaminant that warrants investigations of its environmental and human health impacts. Lines of evidence have demonstrated that dispersed oil affects reproduction in various organisms, in a more potent manner than oil- and dispersant-only exposures. However, the action mechanism of dispersed oil remains largely unknown. In this study, we utilized the model organism Caenorhabditis elegans to investigate impacts of dispersed oil exposure on sex cell apoptosis and related gene expressions. Worms were exposed to different diluted levels of crude oil-dispersant (oil-dis) mixtures (20:1, v/v; at 500×, 2,000×, and 5,000× dilutions). The dispersed crude oil significantly increases the number of apoptotic germ cells in treated worms when compared with control at all exposure levels (p < 0.05). Genes involved in the apoptosis pathway were dysregulated, which include ced-13, ced-3, ced-4, ced-9, cep-1, dpl-1, efl-1, efl-2, egl-1, egl-38, lin-35, pax-2, and sir-2.1. Many aberrant expressed genes encoding for core components in apoptosis machinery (cep-1/p53, ced-13/BH3, ced-9/Bcl-2, ced-4/Apaf-1, and ced-3/caspase) displayed consistent expression patterns across all exposure levels. Significantly ced-3/caspase was upregulated at all dispersed oil-treated groups, consistent with the observed apoptosis phenotype. Given cep-1/p53 was activated at all dispersed oil treatments and the germ cell apoptosis was suppressed in the CEP-1 loss of function mutant, the increased apoptosis is likely CEP-1 dependent. In addition, the anti-apoptotic ced-9/Bcl-2 was activated in response to the increase in cell death. This study provides a mechanism understanding of dispersed crude oil-induced reproductive toxicity.


Update on the role of angiotensin in the pathophysiology of coronary atherothrombosis.
Coronary atherothrombosis due to atherosclerotic plaque rupture or erosion is frequently associated with acute coronary syndromes (ACS). Significant efforts have been made to elucidate the pathophysiological mechanisms underlying acute coronary events. This narrative review is based on the material searched for and obtained via PubMed up to August 2014. The search terms we used were as follows: 'angiotensin, acute coronary syndromes, acute myocardial infarction' in combination with 'atherosclerosis, vulnerability, clinical trial, ACE inhibitors, inflammation'. Among several regulatory components, the renin-angiotensin system (RAS) was shown as a key pathway modulating coronary atherosclerotic plaque vulnerability. Indeed, these molecules are involved in all stages of atherogenesis. Classically, the RAS is composed by a series of enzymatic reactions leading to the angiotensin (Ang) II generation and activity. However, the knowledge of RAS has expanded and become more complex. The discovery of novel components and their functions has revealed additional pathways that contribute to or counterbalance the actions of Ang II. In this review, we discussed on recent findings concerning the role of different angiotensin peptides in the pathophysiology of ACS and coronary atherothrombosis, exploring the link between these molecules and atherosclerotic plaque vulnerability. Treatments selectively targeting angiotensins (including Mas and AT2 agonists, ACE2 recombinant, or Ang-(1-7) and almandine in oral formulations) have been tested in animal studies or in small human subgroups, expanding the perspective in the ACS prevention. These novel strategies, especially in the counter-regulatory axis ACE2/Ang-(1-7)/Mas, might be promising to reduce plaque vulnerability and inflammation.


A new structural protein for Newcastle disease virus.
Proteins induced in Newcastle disease virus (NDV)-infected chick embryo fibroblasts (CEF) and proteins incorporated into virions grown in ovo were analysed by modified versions of a two-dimensional polyacrylamide gel electrophoresis system. The following previously described NDV-induced proteins were detected and resolved from host proteins: L (mol. wt. approx. 200K), HN (75K), F0 (66K), F1 (56K), NP (55K) and M (39K). Two additional polypeptides, NAP (nucleocapsid-associated protein, mol. wt. 56K) and a 36K mol. wt. protein were induced in NDV-infected cells. NAP but not 36K was found in purified virions. Radioactive labelling studies with 3H-glucosamine and 32P-orthophosphate demonstrated that neither NAP nor 36K is glycosylated, but that both are phosphorylated. Variation in the isoelectric point and apparent mol. wt. of NAP among different strains was seen and exactly reproduced in both CEF and baby hamster kidney (BHK) cells. The synthesis of NDV-induced proteins including NAP and 36K was unaffected by actinomycin D, whereas the synthesis of host cell proteins was drastically reduced. These data are evidence that NAP and 36K are virus coded. Peptide analysis indicated that NAP, NP and F1 are unrelated polypeptides. The demonstration that NAP is virus coded, together with its phosphorylation and association with the nucleocapsid, suggest that NAP may be the NDV analogue of the P protein of Sendai virus.


Blood-based metabolic signatures in Alzheimer's disease.
Identification of blood-based metabolic changes might provide early and easy-to-obtain biomarkers. We included 127 Alzheimer's disease (AD) patients and 121 control subjects with cerebrospinal fluid biomarker-confirmed diagnosis (cutoff tau/amyloid β peptide 42: 0.52). Mass spectrometry platforms determined the concentrations of 53 amine compounds, 22 organic acid compounds, 120 lipid compounds, and 40 oxidative stress compounds. Multiple signatures were assessed: differential expression (nested linear models), classification (logistic regression), and regulatory (network extraction). Twenty-six metabolites were differentially expressed. Metabolites improved the classification performance of clinical variables from 74% to 79%. Network models identified five hubs of metabolic dysregulation: tyrosine, glycylglycine, glutamine, lysophosphatic acid C18:2, and platelet-activating factor C16:0. The metabolite network for apolipoprotein E (APOE) ε4 negative AD patients was less cohesive compared with the network for APOE ε4 positive AD patients. Multiple signatures point to various promising peripheral markers for further validation. The network differences in AD patients according to APOE genotype may reflect different pathways to AD.


Complete fourth metatarsal and arches in the foot of Australopithecus afarensis.
The transition to full-time terrestrial bipedality is a hallmark of human evolution. A key correlate of human bipedalism is the development of longitudinal and transverse arches of the foot that provide a rigid propulsive lever and critical shock absorption during striding bipedal gait. Evidence for arches in the earliest well-known Australopithecus species, A. afarensis, has long been debated. A complete fourth metatarsal of A. afarensis was recently discovered at Hadar, Ethiopia. It exhibits torsion of the head relative to the base, a direct correlate of a transverse arch in humans. The orientation of the proximal and distal ends of the bone reflects a longitudinal arch. Further, the deep, flat base and tarsal facets imply that its midfoot had no ape-like midtarsal break. These features show that the A. afarensis foot was functionally like that of modern humans and support the hypothesis that this species was a committed terrestrial biped.


Reconstructing the history of a fragmented and heavily exploited red deer population using ancient and contemporary DNA.
Red deer (Cervus elaphus) have been an important human resource for millennia, experiencing intensive human influence through habitat alterations, hunting and translocation of animals. In this study we investigate a time series of ancient and contemporary DNA from Norwegian red deer spanning about 7,000 years. Our main aim was to investigate how increasing agricultural land use, hunting pressure and possibly human mediated translocation of animals have affected the genetic diversity on a long-term scale. We obtained mtDNA (D-loop) sequences from 73 ancient specimens. These show higher genetic diversity in ancient compared to extant samples, with the highest diversity preceding the onset of agricultural intensification in the Early Iron Age. Using standard diversity indices, Bayesian skyline plot and approximate Bayesian computation, we detected a population reduction which was more prolonged than, but not as severe as, historic documents indicate. There are signs of substantial changes in haplotype frequencies primarily due to loss of haplotypes through genetic drift. There is no indication of human mediated translocations into the Norwegian population. All the Norwegian sequences show a western European origin, from which the Norwegian lineage diverged approximately 15,000 years ago. Our results provide direct insight into the effects of increasing habitat fragmentation and human hunting pressure on genetic diversity and structure of red deer populations. They also shed light on the northward post-glacial colonisation process of red deer in Europe and suggest increased precision in inferring past demographic events when including both ancient and contemporary DNA.


Noradrenaline increases high-frequency firing at the calyx of Held synapse during development by inhibiting glutamate release.
The mammalian auditory brain stem receives profuse adrenergic innervation, whose function is poorly understood. Here we investigate, during postnatal development, the effect of noradrenaline (NA) at the calyx of Held synapse in the rat medial nucleus of the trapezoid body (MNTB). We observed that NA inhibits the large glutamatergic EPSC, evoked by afferent fiber stimulation, in a dose-dependent manner. The inhibition was maximal (approximately 48%) at the concentration of 2 microM. It was antagonized by yohimbine and mimicked by the alpha2-adrenergic specific agonist UK14304. Both AMPA and NMDA receptor-mediated EPSCs were inhibited in parallel by NA, suggesting a presynaptic effect. Presynaptic recordings showed that NA inhibits the action potential (AP) generated Ca current by about 20%; however, NA did not significantly affect the presynaptic AP waveform. We thus conclude that the calyx of Held presynaptic terminal expresses alpha2-adrenergic receptors that inhibit its Ca current and thus glutamate release. Noradrenaline was effective in all cells tested from postnatal days 6 to 7 (P6-P7), and thereafter the number of responsive cells diminished, although half of the P14 cells tested still had EPSCs that were inhibited by NA. By contrast, activation by L-2-amino-5-phosphonovaleric acid-sensitive metabotropic glutamate receptors strongly inhibited the EPSCs of all cells tested from P6 to P14. The effect of NA on postsynaptic action potential firing was dependent on the stimulus frequency. At 10 Hz, NA had no effect on firing probability; however, NA helped MNTB cells fire more action potentials during a 100-Hz train of stimuli, even though it did not increase the steady-state depressed EPSC, because it produced a smaller N-methyl-D-aspartate (NMDA) receptor-activated depolarizing plateau. We therefore suggest that the reduction by NA of the first few EPSCs in a train leads to a smaller NMDA depolarizing plateau and thus to increased firing probability at 100 Hz in young synapses. Surprisingly, the inhibition of glutamate release by NA can thus actually increase the excitability of MNTB neurons during early postnatal development.


Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance.
Fluconazole-susceptible Candida albicans strains accumulated [3H]fluconazole at a rate of approximately 2 pmol/min per 10(9) cells. Fluconazole accumulation was not affected by the pretreatment of cells with sodium azide or with 2-deoxyglucose. The rate of fluconazole accumulation became saturated at high fluconazole concentrations and was not affected by the addition of ketoconazole, and there was no fluconazole accumulation in cells incubated at 4 degrees C. A fluconazole-resistant mutant of C. albicans SGY-243 was isolated following growth enrichment in fluconazole-containing medium. Cells of the mutant strain, designated FR2, showed a reduced rate of fluconazole accumulation compared with SGY-243 and were not resistant to other azole antifungal agents. The rates of fluconazole accumulation by C. albicans FR2 and the other azole-resistant strains, B59630, AD, and KB, were increased in the presence of sodium azide, suggesting that fluconazole resistance in these strains may be associated with an energy-dependent drug efflux. Fluconazole-resistant C. albicans strains all contained elevated amounts (2- to 17-fold) of mRNA encoding Cdr1, and an ATP-binding cassette-type transporter. In addition, C. albicans FR2 also contained increased amounts of mRNA encoding Benr, a major facilitator superfamily transporter. These results suggest that fluconazole enters C. albicans cells by facilitated diffusion and that fluconazole resistance may involve energy-dependent drug efflux associated with increased expression of Benr and/or Cdr1.


Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies.
Few data are available on the long-term immunologic response to antiretroviral therapy (ART) in resource-limited settings, where ART is being rapidly scaled up using a public health approach, with a limited repertoire of drugs. To describe immunologic response to ART among ART patients in a network of cohorts from sub-Saharan Africa, Latin America, and Asia. STUDY POPULATION/METHODS: Treatment-naive patients aged 15 and older from 27 treatment programs were eligible. Multilevel, linear mixed models were used to assess associations between predictor variables and CD4 cell count trajectories following ART initiation. Of 29 175 patients initiating ART, 8933 (31%) were excluded due to insufficient follow-up time and early lost to follow-up or death. The remaining 19 967 patients contributed 39 200 person-years on ART and 71 067 CD4 cell count measurements. The median baseline CD4 cell count was 114 cells/microl, with 35% having less than 100 cells/microl. Substantial intersite variation in baseline CD4 cell count was observed (range 61-181 cells/microl). Women had higher median baseline CD4 cell counts than men (121 vs. 104 cells/microl). The median CD4 cell count increased from 114 cells/microl at ART initiation to 230 [interquartile range (IQR) 144-338] at 6 months, 263 (IQR 175-376) at 1 year, 336 (IQR 224-472) at 2 years, 372 (IQR 242-537) at 3 years, 377 (IQR 221-561) at 4 years, and 395 (IQR 240-592) at 5 years. In multivariable models, baseline CD4 cell count was the most important determinant of subsequent CD4 cell count trajectories. These data demonstrate robust and sustained CD4 response to ART among patients remaining on therapy. Public health and programmatic interventions leading to earlier HIV diagnosis and initiation of ART could substantially improve patient outcomes in resource-limited settings.


Apoptosis in the in vivo mammalian forebrain.
Apoptosis is a word originally introduced by Kerr, Wyllie, and colleagues for a cell death process they defined in terms of its ultrastructural appearance in nonneuronal cells from various tissues. There are very few studies providing detailed ultrastructural criteria for recognizing neuronal apoptosis in the in vivo mammalian brain. In the absence of such criteria, the Kerr/Wyllie description pertaining to nonneuronal cells has served as a reference standard. However, contemporary neurobiologists typically rely on cell culture models for studying neuronal apoptosis, and these models are rarely validated ultrastructurally; rather they are assumed to be appropriate models based on unvalidated biochemical tests for apoptosis. Relying on evidence generated in such cell culture models or on nonspecific cytochemical tests applied to brain tissue, many authors have recently suggested that an apoptotic mechanism may mediate neuronal death in a wide variety of human neurodegenerative diseases. Whether the cell death process in neurodegenerative diseases meets ultrastructural criteria for apoptosis has been given very little consideration. Recently, several methods have been described for triggering extensive apoptotic neurodegeneration in the developing in vivo mammalian brain. These methods include head trauma or treatment with several types of drugs (NMDA antagonists, GABAA agonists, or ethanol). We have performed an ultrastructural analysis of the neuronal cell death process triggered in the cerebral cortex and thalamus by these several methods and compared it with physiological cell death (PCD), a prototypic example of neuronal apoptosis that occurs naturally in the developing brain. Our findings, which are reviewed herein, demonstrate that the types and sequence of changes induced by each of the above methods are identical to those that characterize PCD. This confirms that each of these methods produces bona fide in vivo apoptotic neurodegeneration, and it signifies that our description of this neuronal apoptotic process, which differs in some respects from the Kerr/Wyllie description of nonneuronal apoptosis, can serve as a useful reference standard for recognizing the characteristic changes that in vivo neurons undergo when they are dying by an apoptotic mechanism.


Spatiotemporal epidemiology, environmental correlates, and demography of malaria in Tak Province, Thailand (2012-2015).
Tak Province, at the Thai-Myanmar border, is one of three high malaria incidence areas in Thailand. This study aimed to describe and identify possible factors driving the spatiotemporal trends of disease incidence from 2012 to 2015. Climate variables and forest cover were correlated with malaria incidence using Pearson's r. Statistically significant clusters of high (hot spots) and low (cold spots) annual parasite incidence per 1000 population (API) were identified using Getis-Ord Gi* statistic. The total number of confirmed cases declined by 76% from 2012 to 2015 (Plasmodium falciparum by 81%, Plasmodium vivax by 73%). Incidence was highly seasonal with two main annual peaks. Most cases were male (62.75%), ≥ 15 years (56.07%), and of Myanmar (56.64%) or Thai (39.25%) nationality. Median temperature (1- and 2-month lags), average temperature (1- and 2-month lags) and average relative humidity (2- and 3-month lags) correlated positively with monthly total, P. falciparum and P. vivax API. Total rainfall in the same month correlated with API for total cases and P. vivax but not P. falciparum. At sub-district level, percentage forest cover had a low positive correlation with P. falciparum, P. vivax, and total API in most years. There was a decrease in API in most sub-districts for both P. falciparum and P. vivax. Sub-districts with the highest API were in the Tha Song Yang and Umphang Districts along the Thai-Myanmar border. Annual hot spots were mostly in the extreme north and south of the province. There has been a large decline in reported clinical malaria from 2012 to 2015 in Tak Province. API was correlated with monthly climate and annual forest cover but these did not account for the trends over time. Ongoing elimination interventions on one or both sides of the border are more likely to have been the cause but it was not possible to assess this due to a lack of suitable data. Two main hot spot areas were identified that could be targeted for intensified elimination activities.


Transferable Mechanisms of Quinolone Resistance from 1998 Onward.
While the description of resistance to quinolones is almost as old as these antimicrobial agents themselves, transferable mechanisms of quinolone resistance (TMQR) remained absent from the scenario for more than 36 years, appearing first as sporadic events and afterward as epidemics. In 1998, the first TMQR was soundly described, that is, QnrA. The presence of QnrA was almost anecdotal for years, but in the middle of the first decade of the 21st century, there was an explosion of TMQR descriptions, which definitively changed the epidemiology of quinolone resistance. Currently, 3 different clinically relevant mechanisms of quinolone resistance are encoded within mobile elements: (i) target protection, which is mediated by 7 different families of Qnr (QnrA, QnrB, QnrC, QnrD, QnrE, QnrS, and QnrVC), which overall account for more than 100 recognized alleles; (ii) antibiotic efflux, which is mediated by 2 main transferable efflux pumps (QepA and OqxAB), which together account for more than 30 alleles, and a series of other efflux pumps (e.g., QacBIII), which at present have been sporadically described; and (iii) antibiotic modification, which is mediated by the enzymes AAC(6')Ib-cr, from which different alleles have been claimed, as well as CrpP, a newly described phosphorylase.


Six year multicenter surveillance of invasive pneumococcal infections in children.
Monitor clinical and microbiologic features including antimicrobial susceptibility of invasive pneumococcal infections among children. A 6-year (September, 1993, through August, 1999) prospective surveillance study of all invasive pneumococcal infections in children. Infants and children cared for at eight children's hospitals in the United States with culture-proved invasive pneumococcal infection. During the 6-year period 2581 episodes of invasive pneumococcal infection occurred in 2498 children. Underlying conditions were present in 29% of the children. Of children without an underlying condition, 15% of the total infections occurred in those 25 to 60 months old. As the ages of the children advanced the proportion of cases classified as bacteremia declined, whereas the proportion classified as pneumonia increased. Also, as the ages of the children increased the proportion of isolates in serotypes/serogroups 1, 3 and 23 increased. whereas the proportion for serotype 14 diminished. During the 6 years of the study, there was a significant increase in the percentage of isolates intermediate or resistant to penicillin (P < 0.000001) or intermediate to ceftriaxone (P < 0.002). By the sixth year of the study, 37 and 11% of the isolates were nonsusceptible to penicillin or ceftriaxone, respectively. Antibiotic use in the 30 days before diagnosis of systemic pneumococcal infection occurred in 30 to 35% of the children for each of the 6 years. The overall case-fatality rate for children with systemic pneumococcal infection was 1.56%. Mortality was greatest in children >60 months old and in those with underlying conditions; mortality was not related to antibiotic susceptibility. The percentage of pneumococcal isolates recovered from children with systemic infection which were intermediate for penicillin or ceftriaxone or resistant to penicillin increased steadily during the 6-year period. There was also a trend toward increasing rates of resistance to ceftriaxone. The age and serogroup/serotype distributions of our patients support the recommendations to consider administration of the seven valent pneumococcal conjugate vaccine for all children 24 to 59 months old, with special consideration for selected groups.


Modification of fecal microbiota as a mediator of effective weight loss and metabolic benefits following bariatric surgery.
Bariatric surgery (primarily Laparoscopic Sleeve Gastrectomy [LSG] and Roux-en-Y Gastric Bypass [RYGB]) is an efficacious and durable therapeutic option for weight loss in obesity. The mechanisms that mediate weight loss following bariatric surgery remain incompletely understood. Pubmed search of published data on fecal microbiota, metabolic health, LSG, and RYGB. The fecal microbiome plays a key role in the establishment and maintenance of metabolic wellbeing, and may also contribute (through fecal dysbiosis) to metabolic dysfunction. LSG and RYGB both result in characteristic, procedure-specific changes to the fecal microbiota that may mediate at least some of the resultant weight-loss and metabolically beneficial effects, when applied to the management of obesity. The human fecal microbiome, containing around 100 trillion microbes, evolved over millions of years and interacts symbiotically with its human host. Rodent-based studies have provided insights into the complexities of the gut-microbiome-brain axis. This includes the important role of the gut microbiome in the mediation of normal immunological development, inflammatory pathways, metabolic functioning, hypothalamic appetite regulation, and the absorption of essential nutrients as by-products of bacterial metabolism. Fecal transformation is likely to provide an important therapeutic target for future prevention and management of obesity and metabolic dysfunction.


Histamine H(1) antagonist treatment with pyrilamine reduces nicotine self-administration in rats.
Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.


Effects of private and public health expenditure on health outcomes among countries with different health care systems: 2000 and 2014.
Background: In the recent decades, most studies have paid more attention to community expenditures in health sector and health outcomes. This study provides econometric evidence linking countries' health expenditures to 3 health outcomes: (1) infant mortality, (2) under 5 mortality and (3) life expectancy within 4 different health care systems. Methods: In this study, we used the econometric method to estimate the effect of health expenditure on health status. Panel data were collected and grouped for 25 countries according to the health care system over 15 years (2000-2015). The random effects model was selected over the fixed effects model based on the Hausman test to assess the effect of different factors on the 3 mentioned health outcomes. Results: A significant relationship was found between health expenditures and health indicators. The effect of private health expenditures on health outcomes in countries with mixed health financing system and traditional sickness fund insurance was higher than public expenditures. Also, after comparing the results between different health care systems, we found that the effect of health expenditure on the health outcome in countries with national health system (NHS) was more than other health care systems. Conclusion: To improve health status, health policymakers should focus on the factors that lie inside the health care system. Therefore, since private and public health expenditures have different effects on health outcomes in each health care system, countries should choose an optimal combination of private and public health expenditures.