HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice.
Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression. AUY922 showed higher efficacy, compared to BIIB021, in enhancing myelin synthesis in dorsal root ganglion explant cultures from neuropathic mice. For in vivo testing, we randomly assigned 2-3 month old C22 and 6 week old Trembler J (TrJ) mice to receive two weekly injections of either vehicle or AUY922 (2 mg/kg). By the intraperitoneal (i.p.) route, the drug was well-tolerated by all mice over the 5 month long study, without influence on body weight or general grooming behavior. AUY922 improved the maintenance of myelinated nerves of both neuropathic models and attenuated the decline in rotarod performance and peak muscle force production in C22 mice. These studies highlight the significance of proteostasis in neuromuscular function and further validate the HSP90 pathway as a therapeutic target for hereditary neuropathies.


Sex risk behaviors of drug users: a dual site study of predictors over time.
Reducing sex risk behaviors among high-risk injection drug users (IDUs) and crack smokers is a continuing challenge for HIV prevention. Based on a longitudinal study of sexually active Puerto Rican IDUs and crack smokers in New York (n = 573) and Puerto Rico (n = 264), baseline predictors of changes in sex risk (number of unprotected sex acts) at 6- and 36-month follow-up interviews were examined. In New York, predictors of higher sex risk were being younger, having primary partners, having more other sex partners, never exchanging sex, having lower self-efficacy for reducing sex risk behaviors and being HIV-negative, and these predictors were significant at both postbaseline periods. In Puerto Rico, short-term predictors included being male, having primary partners, never exchanging sex, lower sex risk norms and lower self-efficacy. However, only having primary partners was significant in longer-term behaviors. Results indicated the need for enhancing self-efficacy and for developing risk reduction strategies related to community differences.


Comparing primary prevention with secondary prevention to explain decreasing coronary heart disease death rates in Ireland, 1985-2000.
To investigate whether primary prevention might be more favourable than secondary prevention (risk factor reduction in patients with coronary heart disease(CHD)). The cell-based IMPACT CHD mortality model was used to integrate data for Ireland describing CHD patient numbers, uptake of specific treatments, trends in major cardiovascular risk factors, and the mortality benefits of these specific risk factor changes in CHD patients and in healthy people without recognised CHD. Between 1985 and 2000, approximately 2,530 fewer deaths were attributable to reductions in the three major risk factors in Ireland. Overall smoking prevalence declined by 14% between 1985 and 2000, resulting in about 685 fewer deaths (minimum estimate 330, maximum estimate 1,285) attributable to smoking cessation: about 275 in healthy people and 410 in known CHD patients. Population total cholesterol concentrations fell by 4.6%, resulting in approximately 1,300 (minimum estimate 1,115, maximum estimate 1,660) fewer deaths attributable to dietary changes(1,185 in healthy people and 115 in CHD patients) plus 305 fewer deaths attributable to statin treatment (45 in people without CHD and 260 in CHD patients). Mean population diastolic blood pressure fell by 7.2%, resulting in approximately 170 (minimum estimate 105, maximum estimate 300) fewer deaths attributable to secular falls in blood pressure (140 in healthy people and 30 in CHD patients), plus approximately 70 fewer deaths attributable to antihypertensive treatments in people without CHD. Of all the deaths attributable to risk factor falls, some 1,715 (68%) occurred in people without recognized CHD and 815(32%) in CHD patients. Compared with secondary prevention, primary prevention achieved a two-fold larger reduction in CHD deaths. Future national CHD policies should therefore prioritize nationwide interventions to promote healthy diets and reduce smoking.


Computers, medical records, and the right to privacy.
Recent advances in computer technology permit the accumulation, analysis, and storage of an unlimited quantity of medical record information, thereby seriously compounding existing controversies surrounding patient confidentiality and privacy. This article surveys both benefits and problems arising from this increased availability of medical records. It examines legal and ethical dilemmas arising from the conflict between the usefulness of patients, in particular their right to privacy. The article suggests guidelines for insuring fair and balanced health information policies.


Carotid sinus baroreceptor reflex control of respiration.
We have studied the effect of the carotid sinus baroreceptor reflex on respiration in 10 vagotomized, spontaneously breathing, pentobarbital anesthetized dogs. The carotid body chemoreceptor reflex response was eliminated by surgically excluding the carotid bodies from the carotid sinus baroreceptor area. Steady state frequency, tidal volume, and minute ventilation were measured after 25 mm Hg step changes in intrasinus pressure between 50 and 200 mm Hg. Over this range, the step decreases in intrasinus pressure caused concomitant increases in mean arterial pressure from 86 to 182 mm Hg. All of the respiratory response curves were sigmoidal in shape. Decreasing intrasinus pressure from 200 to 50 mm Hg caused respiratory frequency to increase from 4.8 to 9.7/min, and tidal volume to decrease from 704 to 515 ml. The calculated total ventilation, however, increased from 3180 to 4530 ml/min. The time of inspiration decreased from 3.7 to 2.4 seconds, and the time of expiration decreased from 9.8 to 4.1 seconds. These ventilatory responses are shown to be baroreceptor reflex mediated, and not secondary to changes in arterial pressure. These findings indicate that not only does the carotid sinus baroreceptor reflex control arterial pressure, but it also simultaneously influences ventilation, through changes in both respiratory frequency and tidal volume.


Toward an integrative understanding of social behavior: new models and new opportunities.
Social interactions among conspecifics are a fundamental and adaptively significant component of the biology of numerous species. Such interactions give rise to group living as well as many of the complex forms of cooperation and conflict that occur within animal groups. Although previous conceptual models have focused on the ecological causes and fitness consequences of variation in social interactions, recent developments in endocrinology, neuroscience, and molecular genetics offer exciting opportunities to develop more integrated research programs that will facilitate new insights into the physiological causes and consequences of social variation. Here, we propose an integrative framework of social behavior that emphasizes relationships between ultimate-level function and proximate-level mechanism, thereby providing a foundation for exploring the full diversity of factors that underlie variation in social interactions, and ultimately sociality. In addition to identifying new model systems for the study of human psychopathologies, this framework provides a mechanistic basis for predicting how social behavior will change in response to environmental variation. We argue that the study of non-model organisms is essential for implementing this integrative model of social behavior because such species can be studied simultaneously in the lab and field, thereby allowing integration of rigorously controlled experimental manipulations with detailed observations of the ecological contexts in which interactions among conspecifics occur.


Intrinsic contracture of the hand: diagnosis and management.
Intrinsic contracture of the hand may result from trauma, spasticity, ischemia, rheumatologic disorders, or iatrogenic causes. In severe cases, the hand assumes a posture with hyperflexed metacarpophalangeal joints and hyperextended proximal interphalangeal joints as the contracted interossei and lumbrical muscles deform the natural cascade of the fingers. Considerable disability may result because weakness in grip strength, difficulty with grasping larger objects, and troubles with maintenance of hygiene commonly encumber patients. Generally, the diagnosis is made via history and physical examination, but adjunctive imaging, rheumatologic testing, and electromyography may aid in determining the underlying cause or assessing the severity. Nonsurgical management may be appropriate in mild cases and consists of occupational therapy, orthoses, and botulinum toxin injections. The options for surgical management are diverse and dictated by the cause and severity of contracture.


TGF-beta inhibits Fas-mediated apoptosis of a follicular dendritic cell line by down-regulating the expression of Fas and caspase-8: counteracting role of TGF-beta on TNF sensitization of Fas-mediated apoptosis.
Follicular dendritic cells (FDC) constitute the framework of germinal center (GC) in secondary lymphoid follicles, and the integrity of FDC networks is critically affected by cytokines present in the GC. We have previously shown that TNF promotes Fas-mediated apoptosis of HK cells, an established FDC-like cell line, by up-regulating Fas expression. However, in the developing GC, FDC death is not a hallmark of GC despite the presence of TNF and FasL. In this study, we report that TGF-beta inhibits Fas-mediated apoptosis of HK cells by down-regulating the expression of surface Fas and caspase-8. The inhibitory effect of TGF-beta can be observed when HK cells were simultaneously treated with TNF and TGF-beta, indicating that TGF-beta counteracts the effect of TNF in sensitizing cells to Fas-mediated apoptosis. Furthermore, the deprivation of TGF-beta by injecting neutralizing TGF-beta Abs to the SRBC-immunized mice resulted in the sporadic appearance of FDC undergoing apoptosis in the lymphoid follicles, suggesting that TGF-beta functions as a naturally occurring inhibitor that rescues FDCs which are predisposed to apoptosis. Our study documents a novel function of TGF-beta in the maintenance of FDC networks.


Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults.
An analysis was undertaken to determine the optimal cut-off separating an asthmatic from a normal response to a bronchial provocation challenge by exercise and the inhalation of methacholine or histamine in children and young adults. Data were extracted, after appropriate correction, from published studies available in Medline of large random populations that complied with preset criteria of suitability for analysis, and the distribution of bronchial reactivity in the healthy population for exercise and inhalation challenges were derived. Studies on the response to exercise and methacholine inhalation in 232 young asthmatics of varying severity were carried out by the authors and the distribution of bronchial reactivity of a young asthmatic population obtained. Comparisons of the sensitivity and specificity of the challenges were aided by the construction of receiver operating characteristic curves. The optimal cut-off point of the fall in forced expiratory volume in one second (FEV1) after exercise was 13%, with a sensitivity (power) of 63% and specificity of 94%. For inhalation challenges, the optimal cut-off point for the dose of methacholine or histamine causing a 20% fall in FEV1 was 6.6 micromol, with a sensitivity of 92% and a specificity of 89%. The cut-off values were not materially affected by the severity of the asthma and provide objective data with which to evaluate the results of bronchial provocation challenges in children and young adults.


Health-related quality of life and work productivity in UK patients with HER2-positive breast cancer: a cross-sectional study evaluating the relationships between disease and treatment stage.
The impact of different disease stages and treatment for human epidermal growth factor 2 positive (HER2-positive) breast cancer (BC) on work productivity and health-related quality of life (HRQoL) is poorly understood. This was a UK cross-sectional study of 299 adult patients with HER2-positive early or metastatic BC (NCT03099200). Productivity was assessed using the work productivity and activity impairment scale; HRQoL was measured using EuroQol-5 Dimensions-5 levels (EQ-5D-5L), and Functional Assessment of Cancer Therapy Breast (FACT-G and -B) instruments. Three balanced patient groups were recruited: (1) early BC on treatment post-surgery, (2) early BC after completion of adjuvant treatment, (3) during metastatic BC treatment. Between-group comparisons were performed using an analysis of variance. Group 1 comprised 89 patients, Group 2, 108 and Group 3, 102. Age, ethnicity and comorbidities were similar across groups. Patients in Group 3 reported more often being unable to work (significant Bonferroni adjusted p < 0.003). Proportions of employed patients were 50.6%, 50.9% and 27.5% in Groups 1, 2 and 3, respectively. For patients in part-time employment, the number of hours worked was significantly higher in Group 2 patients versus Group 3 (p = 0.002). Group 2 also had significantly lower levels of work absenteeism and overall work impairment compared with Group 1 (p < 0.001). Patients in Group 3 reported worse health utility scores (p ≤ 0.002), moderate or worse problems in the EQ-5D-5L self-care and usual activity domains (p ≤ 0.001), and lower HRQoL as assessed by FACT summary scores (p < 0.001 for FACT-B and -G) than Groups 1 and 2. Poorer HRQoL was significantly associated with higher work impairment (p < 0.001), with the strongest relationships being observed between activity impairment and HRQoL (Pearson's r: 0.67). Metastatic disease and treatment of HER2-positive BC adversely impacted on work productivity and HRQoL. The results of this study support the idea that being able to delay or prevent the metastatic recurrence of BC, for example by extending the time patients are in remission or at early stage of BC, has wider benefits in terms of patient productivity and HRQoL.


The cost of moving optimally: kinematic path selection.
It is currently unclear whether the brain plans movement kinematics explicitly or whether movement paths arise implicitly through optimization of a cost function that takes into account control and/or dynamic variables. Several cost functions are proposed in the literature that are very different in nature (e.g., control effort, torque change, and jerk), yet each can predict common movement characteristics. We set out to disentangle predictions of the different variables using a combination of modeling and empirical studies. Subjects performed goal-directed arm movements in a force field (FF) in combination with visual perturbations of seen hand position. This FF was designed to have distinct optimal movements for muscle-input and dynamic costs while leaving kinematic cost unchanged. Visual perturbations in turn changed the kinematic cost but left the dynamic and muscle-input costs unchanged. An optimally controlled, physiologically realistic arm model was used to predict movements under the various cost variables. Experimental results were not consistent with a cost function containing any of the control and dynamic costs investigated. Movement patterns of all experimental conditions were adequately predicted by a kinematic cost function comprising both visually and somatosensory perceived jerk. The present study provides clear behavioral evidence that the brain solves kinematic and mechanical redundancy in separate steps: in a first step, movement kinematics are planned; and in a second, separate step, muscle activation patterns are generated.


Raspberry ketone increases both lipolysis and fatty acid oxidation in 3T3-L1 adipocytes.
Raspberry ketone (RK) is a natural phenolic compound of the red raspberry. The dietary administration of RK to male mice has been reported to prevent high-fat diet-induced elevation in body weight and to increase lipolysis in white adipocytes. To elucidate a possible mechanism for the antiobesity action of RK, its effects on the expression and the secretion of adiponectin, lipolysis, and fatty acid oxidation in 3T3-L1 were investigated. Treatment with 10 µM of RK increased lipolysis significantly in differentiated 3T3-L1 cells. An immunoassay showed that RK increased both the expression and the secretion of adiponectin, an adipocytokine mainly expressed and secreted by adipose tissue. In addition, treatment with 10 µM of RK increased the fatty acid oxidation and suppressed lipid accumulation in 3T3-L1 adipocytes. These findings suggest that RK holds great promise as an herbal medicine since its biological activities alter the lipid metabolism in 3T3-L1 adipocytes.


Errors associated with the preparation of aseptic products in UK hospital pharmacies: lessons from the national aseptic error reporting scheme.
Pharmacy aseptic units prepare and supply injectables to minimise risks. The UK National Aseptic Error Reporting Scheme has been collecting data on pharmacy compounding errors, including near-misses, since 2003. The cumulative reports from January 2004 to December 2007, inclusive, were analysed. The different variables of product types, error types, staff making and detecting errors, stage errors detected, perceived contributory factors, and potential or actual outcomes were presented by cross-tabulation of data. A total of 4691 reports were submitted against an estimated 958 532 items made, returning 0.49% as the overall error rate. Most of the errors were detected before reaching patients, with only 24 detected during or after administration. The highest number of reports related to adult cytotoxic preparations (40%) and the most frequently recorded error was a labelling error (34.2%). Errors were mostly detected at first check in assembly area (46.6%). Individual staff error contributed most (78.1%) to overall errors, while errors with paediatric parenteral nutrition appeared to be blamed on low staff levels more than other products were. The majority of errors (68.6%) had no potential patient outcomes attached, while it appeared that paediatric cytotoxic products and paediatric parenteral nutrition were associated with greater levels of perceived patient harm. The majority of reports were related to near-misses, and this study highlights scope for examining current arrangements for checking and releasing products, certainly for paediatric cytotoxic and paediatric parenteral nutrition preparations within aseptic units, but in the context of resource and capacity constraints.


Porcine Cysticercosis: Possible Cross-Reactivity of Taenia hydatigena to GP50 Antigen in the Enzyme-Linked Immunoelectrotransfer Blot Assay.
The lentil lectin glycoprotein enzyme-linked immunoelectrotransfer blot (LLGP EITB, reported sensitivity 99% and specificity 100%) is used as a serologic marker of exposure to Taenia solium in pigs. However, only a limited number of parasites have been evaluated for cross reactivity. Pigs may host other related cestode infections, including Taenia hydatigena, which have not been formally evaluated for cross-reactions. We investigated a corral in Tumbes, Peru, a region where a cysticercosis elimination demonstration project was completed in 2012. In this corral, 14/19 (73.7%) 6-8-week-old piglets were reactive to GP50 on LLGP EITB, and all had circulating Taenia sp. antigens. From eight necropsied piglets; four were infected with T. hydatigena metacestodes whereas none had evidence of T. solium infection. Two resident dogs were subsequently confirmed to have T. hydatigena taeniasis. These results suggest GP50 cross-reactivity in T. hydatigena-infected pigs, although controlled experimental infection is needed to confirm this hypothesis.


Malaria morbidity and mortality following introduction of a universal policy of artemisinin-based treatment for malaria in Papua, Indonesia: A longitudinal surveillance study.
Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species. A prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013. In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species. Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria. The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre-policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of -12.9% (95% confidence interval [CI] -13.5% to -12.2%). There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = -0.21% [95% CI -0.34 to -0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = -0.05% [95% CI -0.20 to 0.09]). Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital. After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48-0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71-0.73]). The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy. In this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality. The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria. In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria.


The relationship between the therapeutic alliance and treatment outcome in two distinct psychotherapies for chronic depression.
This study tested whether the quality of the patient-rated working alliance, measured early in treatment, predicted subsequent symptom reduction in chronically depressed patients. Secondarily, the study assessed whether the relationship between early alliance and response to treatment differed between patients receiving cognitive behavioral analysis system of psychotherapy (CBASP) vs. brief supportive psychotherapy (BSP). 395 adults (57% female; Mage = 46; 91% Caucasian) who met criteria for chronic depression and did not fully remit during a 12-week algorithm-based, open-label pharmacotherapy trial were randomized to receive either 16-20 sessions of CBASP or BSP in addition to continued, algorithm-based antidepressant medication. Of these, 224 patients completed the Working Alliance Inventory-Short Form at Weeks 2 or 4 of treatment. Blind raters assessed depressive symptoms at 2-week intervals across treatment using the Hamilton Rating Scale for Depression. Linear mixed models tested the association between early alliance and subsequent symptom ratings while accounting for early symptom change. A more positive early working alliance was associated with lower subsequent symptom ratings in both the CBASP and BSP, F(1, 1236) = 62.48, p < .001. In addition, the interaction between alliance and psychotherapy type was significant, such that alliance quality was more strongly associated with symptom ratings among those in the CBASP treatment group, F(1, 1234) = 8.31, p = .004. The results support the role of the therapeutic alliance as a predictor of outcome across dissimilar treatments for chronic depression. Contrary to expectations, the therapeutic alliance was more strongly related to outcome in CBASP, the more directive of the 2 therapies.


A 3-week dietary safety study of octenyl succinic anhydride (OSA)-modified starch in neonatal farm piglets.
Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2 days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20 g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20 g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth.


The European Stroke Organisation Guidelines: a standard operating procedure.
In 2008, the recently founded European Stroke Organisation published its guidelines for the management of ischemic stroke and transient ischemic attack. This highly cited document was translated in several languages and was updated in 2009. Since then, the European Stroke Organisation has published guidelines for the management of intracranial aneurysms and subarachnoidal hemorrhage, for the establishment of stroke units and stroke centers, and recently for the management of intracerebral hemorrhage. In recent years, the methodology for the development of guidelines has evolved significantly. To keep pace with this progress and driven by the strong determination of the European Stroke Organisation to further promote stroke management, education, and research, the European Stroke Organisation decided to delineate a detailed standard operating procedure for its guidelines. There are two important cornerstones in this standard operating procedure: The first is the implementation of the Grading of Recommendations Assessment, Development, and Evaluation methodology for the development of its Guideline Documents. The second one is the decision of the European Stroke Organisation to move from the classical model of a single Guideline Document about a major topic (e.g. management of ischemic stroke) to focused modules (i.e. subdivisions of a major topic). This will enable the European Stroke Organisation to react faster when new developments in a specific stroke field occur and update its recommendations on the related module rather swiftly; with the previous approach of a single large Guideline Document, its entire revision had to be completed before an updated publication, delaying the production of up-to-date guidelines. After discussion within the European Stroke Organisation Guidelines Committee and significant input from European Stroke Organisation members as well as methodologists and analysts, this document presents the official standard operating procedure for the development of the Guideline Documents of the European Stroke Organisation.


Survival of eight LLIN brands 6, 12, 24 and 36 months after a mass distribution campaign in rural and urban settings in Senegal.
Long lasting insecticidal nets (LLIN) are one of the core components of global malaria prevention and control. The lifespan of LLIN varies widely depending on the population or environment, and randomized studies are required to compare LLIN inaccording to arbitrary thresholds households under different field conditions. This study investigated survival of different LLIN brands in Senegal. Ten thousand six hundred eight LLINs were distributed in five regions, each stratified by rural and urban setting. As part of the longitudinal follow-up, 2222 nets were randomly sampled and monitored from 6 to 36 months. Using random effects for households, Bayesian models were used to estimate independent survival by net type (Interceptor®, Life Net®, MAGNet™, Netprotect®, Olyset® Net, PermaNet® 2.0 R, PermaNet® 2.0 C, Yorkool® LN) and by area (rural/urban). In addition to survival, median survival time and attrition of each LLIN brand was determined. Attrition was defined as nets that were missing because they were reported given away, destroyed and thrown away, or repurposed. Three net types had a proportion of survival above 80% after 24 months: Interceptor®87.8% (95% CI 80-93.4); conical PermaNet® 2.0 86.9% (95% CI 79.3-92.4) and Life Net® 85.6% (95% CI 75-93). At 36 months, conical PermaNet® 2.0 maintained a good survival rate, 79.5% (95% CI 65.9-88.8). The attrition due to redistributed nets showed that the two conical net types (PermaNet® 2.0 and Interceptor®) were more often retained by households and their median retention time was well above 3 years (median survival time = 3.5 years for PermaNet® 2.0 and median survival time = 4 years for Interceptor®). Despite this good retention, Interceptor® had weak physical integrity and its median survival due to wear and tear was below 3 years (median survival time = 2.4 years). The odds ratio of survival was 2.5 times higher in rural settings than in urban settings (OR 2.5; 95% CI 1.7-3.7). Differences in survival among LLIN may be driven by brand, shape or environmental setting. In this study in Senegal, conical PermaNet® 2.0 were retained in households while rectangular PermaNet® 2.0 had lower retention, suggesting that net shape may play a role in retention and should be further investigated. Distribution of preferred LLIN shape, accompanied by good communication on care and repair, could lead to increased effective lifespan, and allow for longer intervals between universal coverage campaigns.


Zika Virus Outbreak, Barbados, 2015-2016.
Barbados is a Caribbean island country of approximately 285,000 people, with a thriving tourism industry. In 2015, Zika spread rapidly throughout the Americas, and its proliferation through the Caribbean islands followed suit. Barbados reported its first confirmed autochthonous Zika transmission to the Pan American Health Organization in January 2016, a month before the global public health emergency was declared. After detection of suspected Zika cases on Barbados in 2015, 926 individuals were described as suspected cases, and 147 laboratory-confirmed cases were reported through December 2016, the end of the most recent epidemiological year. In this short report, we describe the epidemiological characteristics of 926 clinical case records that were originally suspected as cases of Zika, and which were subsequently sent for testing and confirmation; 147 were found positive for Zika, using reverse transcription-polymerase chain reaction methods, another 276 tested negative, and the remaining 503 were either pending results or still in the suspected category. Women were represented at about twice the rate of men in case records where gender was reported (71.9%), and confirmed cases (78.2%), and 19 of the confirmed positive cases were children under the age of 10.


Encoding of reward and space during a working memory task in the orbitofrontal cortex and anterior cingulate sulcus.
Several lines of research indicate that emotional and motivational information may be useful in guiding the allocation of attentional resources. Two areas of the frontal lobe that are particularly implicated in the encoding of motivational information are the orbital prefrontal cortex (PFo) and the dorsomedial region of prefrontal cortex, specifically the anterior cingulate sulcus (PFcs). However, it remains unclear whether these areas use this information to influence spatial attention. We used single-unit neurophysiology to examine whether, at the level of individual neurons, there was evidence for integration between reward information and spatial attention. We trained two subjects to perform a task that required them to attend to a spatial location across a delay under different expectancies of reward for correct performance. We balanced the order of presentation of spatial and reward information so we could assess the neuronal encoding of the two pieces of information independently and conjointly. We found little evidence for encoding of the spatial location in either PFo or PFcs. In contrast, both areas encoded the expected reward. Furthermore, PFo consistently encoded reward more quickly than PFcs, although reward encoding was subsequently more prevalent and stronger in PFcs. These results suggest a differential contribution of PFo and PFcs to reward encoding, with PFo potentially more important for initially determining the value of rewards predicted by sensory stimuli. They also suggest that neither PFo nor PFcs play a direct role in the control of spatial attention.


Risk of stroke in patients with newly diagnosed multiple myeloma: a retrospective cohort study.
Cerebrovascular events are a common complication among patients with cancer, increasing morbidity and mortality. However, the association between multiple myeloma and cerebrovascular events remains unclear. We therefore investigated multiple myeloma patients' risk factors for stroke to devise a better stroke-prevention strategy. This study includes consecutive patients 20 years and older who were newly diagnosed with symptomatic multiple myeloma at Taipei Veterans General Hospital, a tertiary medical center, between January 1, 2002 and December 31, 2014. The primary outcome was stroke development. Patients with head injuries, brain tumors, brain parenchymal invasions, or antecedent malignancies were excluded. Hazard ratios (HRs) of stroke risk factors for multiple myeloma patients were estimated by Cox proportional regression analysis. Overall, 395 patients with a median age of 70 years were investigated. In the median follow-up period of 18 months, cerebrovascular events occurred in 16 patients, including 10 ischemic strokes and 6 hemorrhagic strokes. The 5-year estimated cumulative incidence rate was 7.45%. In the multivariate analysis, the κ light chain isotype (adjusted HR, 8.37; 95% confidence interval [CI], 1.91-39.8), previous cerebrovascular accidents (adjusted HR, 5.16; 95% CI, 1.48-17.9), and serum creatinine > 2 mg/dL (adjusted HR, 4.21; 95% CI, 1.10-16.0) were identified as independent risk factors for stroke. Subgroup analysis showed that atrial fibrillation (adjusted HR, 8.07) and previous cerebrovascular accident (adjusted HR, 4.89) are significant risk factors for ischemic stroke. Serum creatinine > 2 mg/dL (adjusted HR, 30.6) and previous cerebrovascular accident (adjusted HR, 13.9) are significant for hemorrhagic stroke. Moreover, therapeutic strategies for multiple myeloma were not associated with stroke in our study. This study demonstrates that risk of stroke increases in myeloma patients with a κ light chain isotype, previous cerebrovascular events, and renal impairment. Further prospective clinical studies to clarify the relationship between multiple myeloma and stroke are warranted.


Fast support vector data descriptions for novelty detection.
Support vector data description (SVDD) has become a very attractive kernel method due to its good results in many novelty detection problems. However, the decision function of SVDD is expressed in terms of the kernel expansion, which results in a run-time complexity linear in the number of support vectors. For applications where fast real-time response is needed, how to speed up the decision function is crucial. This paper aims at dealing with the issue of reducing the testing time complexity of SVDD. A method called fast SVDD (F-SVDD) is proposed. Unlike the traditional methods which all try to compress a kernel expansion into one with fewer terms, the proposed F-SVDD directly finds the preimage of a feature vector, and then uses a simple relationship between this feature vector and the SVDD sphere center to re-express the center with a single vector. The decision function of F-SVDD contains only one kernel term, and thus the decision boundary of F-SVDD is only spherical in the original space. Hence, the run-time complexity of the F-SVDD decision function is no longer linear in the support vectors, but is a constant, no matter how large the training set size is. In this paper, we also propose a novel direct preimage-finding method, which is noniterative and involves no free parameters. The unique preimage can be obtained in real time by the proposed direct method without taking trial-and-error. For demonstration, several real-world data sets and a large-scale data set, the extended MIT face data set, are used in experiments. In addition, a practical industry example regarding liquid crystal display micro-defect inspection is also used to compare the applicability of SVDD and our proposed F-SVDD when faced with mass data input. The results are very encouraging.


Establishing a Core Outcome Set for Autosomal Dominant Polycystic Kidney Disease: Report of the Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Consensus Workshop.
The omission of outcomes that are of relevance to patients, clinicians, and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision making. The Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on October 25, 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/caregivers and 47 health professionals (nephrologists, policy makers, industry, and researchers) attended the workshop. Four themes emerged: "Relevance of trajectory and impact of kidney function" included concerns about a patient's prognosis and uncertainty of when they may need to commence kidney replacement therapy and the lack of an early prognostic marker to inform long-term decisions; "Discerning and defining pain specific to ADPKD" highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management, and to have a validated measure for pain; "Highlighting ADPKD consequences" encompassed cyst-related complications and reflected patient's knowledge because of family history and the hereditary nature of ADPKD; and "Risk for life-threatening but rare consequences" such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease, and pain were established as the core outcomes for ADPKD.


Making a good decision: value from fit.
The classic answer to what makes a decision good concerns outcomes. A good decision has high outcome benefits (it is worthwhile) and low outcome costs (it is worth it). I propose that, independent of outcomes or value from worth, people experience a regulatory fit when they use goal pursuit means that fit their regulatory orientation, and this regulatory fit increases the value of what they are doing. The following postulates of this value from fit proposal are examined: (a) People will be more inclined toward goal means that have higher regulatory fit, (b) people's motivation during goal pursuit will be stronger when regulatory fit is higher, (c) people's (prospective) feelings about a choice they might make will be more positive for a desirable choice and more negative for an undesirable choice when regulatory fit is higher, (d) people's (retrospective) evaluations of past decisions or goal pursuits will be more positive when regulatory fit was higher, and (e) people will assign higher value to an object that was chosen with higher regulatory fit. Studies testing each of these postulates support the value-from-fit proposal. How value from fit can enhance or diminish the value of goal pursuits and the quality of life itself is discussed.


Mild, self-resolving acute leptospirosis in an HIV-infected patient in the Peruvian Amazon.
We report a case of acute, self-resolving leptospirosis presenting in a HIV-positive patient from the Peruvian Amazon. The patient presented with an undifferentiated acute febrile illness that resolved without treatment, diagnosed retrospectively as leptospirosis by serology and real-time polymerase chain reaction. Five months later, he was admitted because of a febrile illness with jaundice, hepatosplenomegaly, peripheral edema, and oral candidiasis. Because of the clinical suspicion of AIDS, stored sera of the previous admission were tested, and HIV seropositivity was confirmed, proving that the condition was present at the first admission. Acute leptospirosis in HIV coinfection is not inevitably severe, and there is probably a wide variation in clinical manifestations similar to what occurs in immuno-competent hosts.


Multiscale Modeling of Agglomerated Ceria Nanoparticles: Interface Stability and Oxygen Vacancy Formation.
The interface formation and its effect on redox processes in agglomerated ceria nanoparticles (NPs) have been investigated using a multiscale simulation approach with standard density functional theory (DFT), the self-consistent-charge density functional tight binding (SCC-DFTB) method, and a DFT-parameterized reactive force-field (ReaxFF). In particular, we have modeled Ce40O80 NP pairs, using SCC-DFTB and DFT, and longer chains and networks formed by Ce40O80 or Ce132O264 NPs, using ReaxFF molecular dynamics simulations. We find that the most stable {111}/{111} interface structure is coherent whereas the stable {100}/{100} structures can be either coherent or incoherent. The formation of {111}/{111} interfaces is found to have only a very small effect on the oxygen vacancy formation energy, E vac. The opposite holds true for {100}/{100} interfaces, which exhibit significantly lower E vac values than the bare surfaces, despite the fact that the interface formation eliminates reactive {100} facets. Our results pave the way for an increased understanding of ceria NP agglomeration.


Dating glacier ice of the last millennium by quantum technology.
Radiometric dating with 39Ar covers a unique time span and offers key advances in interpreting environmental archives of the last millennium. Although this tracer has been acknowledged for decades, studies so far have been limited by the low abundance and radioactivity, thus requiring huge sample sizes. Atom trap trace analysis, an application of techniques from quantum physics such as laser cooling and trapping, allows us to reduce the sample volume by several orders of magnitude compared with conventional techniques. Here we show that the adaptation of this method to 39Ar is now available for glaciological applications, by demonstrating the entire process chain for dating of alpine glacier ice by argon trap trace analysis (ArTTA). Ice blocks as small as a few kilograms are sufficient and have been obtained at two artificial glacier caves. Importantly, both sites offer direct access to the stratigraphy at the glacier base and validation against existing age constraints. The ice blocks obtained at Chli Titlis glacier at 3,030 m asl (Swiss Alps) have been dated by state-of-the-art microradiocarbon analysis in a previous study. The unique finding of a bark fragment and a larch needle within the ice of Schaufelferner glacier at 2,870 m asl (Stubai Alps, Austria) allows for conventional radiocarbon dating. At both sites the existing age information based on radiocarbon dating and visual stratigraphy corroborates the 39Ar ages. With our results, we establish argon trap trace analysis as the key to decipher so far untapped glacier archives of the last millennium.


Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials.
Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value.


(11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).
According to the latest revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) (NINCDS-ADRDA) diagnostic criteria for Alzheimer's disease dementia, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of imaging biomarkers. These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, the accuracy of biomarkers in the diagnosis of Alzheimer's disease dementia and other dementias has not yet been systematically evaluated. A formal systematic evaluation of the sensitivity, specificity, and other properties of positron emission tomography (PET) imaging with the (11)C-labelled Pittsburgh Compound-B ((11)C-PIB) ligand was performed. To determine the diagnostic accuracy of the (11)C- PIB-PET scan for detecting participants with MCI at baseline who will clinically convert to Alzheimer's disease dementia or other forms of dementia over a period of time. The most recent search for this review was performed on 12 January 2013. We searched MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science and Conference Proceedings (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We also requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies (managed by the Cochrane Renal Group).No language or date restrictions were applied to the electronic searches and methodological filters were not used so as to maximise sensitivity. We selected studies that had prospectively defined cohorts with any accepted definition of MCI with baseline (11)C-PIB-PET scan. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis for example NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. We screened all titles generated by electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. The identified full papers were assessed for eligibility and data were extracted to create two by two tables. Two independent assessors performed quality assessment using the QUADAS 2 tool. We used the hierarchical summary receiver operating characteristic (ROC) model to produce a summary ROC curve. Conversion from MCI to Alzheimer's disease dementia was evaluated in nine studies. The quality of the evidence was limited. Of the 274 participants included in the meta-analysis, 112 developed Alzheimer's dementia. Based on the nine included studies, the median proportion converting was 34%. The studies varied markedly in how the PIB scans were done and interpreted.The sensitivities were between 83% and 100% while the specificities were between 46% and 88%. Because of the variation in thresholds and measures of (11)C-PIB amyloid retention, we did not calculate summary sensitivity and specificity. Although subject to considerable uncertainty, to illustrate the potential strengths and weaknesses of (11)C-PIB-PET scans we estimated from the fitted summary ROC curve that the sensitivity was 96% (95% confidence interval (CI) 87 to 99) at the included study median specificity of 58%. This equated to a positive likelihood ratio of 2.3 and a negative likelihood ratio of 0.07. Assuming a typical conversion rate of MCI to Alzheimer's dementia of 34%, for every 100 PIB scans one person with a negative scan would progress and 28 with a positive scan would not actually progress to Alzheimer's dementia.There were limited data for formal investigation of heterogeneity. We performed two sensitivity analyses to assess the influence of type of reference standard and the use of a pre-specified threshold. There was no effect on our findings. Although the good sensitivity achieved in some included studies is promising for the value of (11)C-PIB-PET, given the heterogeneity in the conduct and interpretation of the test and the lack of defined thresholds for determination of test positivity, we cannot recommend its routine use in clinical practice.(11)C-PIB-PET biomarker is a high cost investigation, therefore it is important to clearly demonstrate its accuracy and standardise the process of the (11)C-PIB diagnostic modality prior to it being widely used.


Neuroendocrine studies in hyperprolactinaemic male mice.
In several species, including man and the rat, hyperprolactinaemia is associated with suppression of gonadotrophin release and male sexual behaviour. However, in the hyperprolactinaemic male mouse, plasma LH and FSH levels and copulatory behaviour are increased rather than suppressed. In an attempt to identify mechanism(s) which may be responsible for these effects of hyperprolactinaemia in the mouse, we have examined the effects of two ectopic pituitary isografts on several indices of hypothalamic and pituitary function in adult DBA/2J males. Animals with pituitary grafts had markedly increased plasma concentrations of prolactin, LH and FSH and enlarged seminal vesicles, whereas testicular and pituitary weights were not affected. Content of LHRH receptors and activity of aromatase in the pituitary, as well as dopamine-beta-hydroxylase activity in the hypothalamus were nearly identical in pituitary-grafted and sham-operated males. Biosynthesis of dopamine and turnover of noradrenaline in the median eminence were significantly increased in grafted males. We suggest that the increase in the activity of hypothalamic noradrenergic neurones may mediate stimulatory action of hyperprolactinaemia on LH and FSH release in the mouse. Comparison of these results with those obtained previously in the rat suggests that species differences in the effects of prolactin on gonadotrophin release may be related to its divergent effects on noradrenaline turnover.


National maternal mortality ratio in Egypt halved between 1992-93 and 2000.
Two surveys of maternal mortality conducted in Egypt, in 1992-93 and in 2000, collected data from a representative sample of health bureaus covering all of Egypt, except for five frontier governorates which were covered only by the later survey, using the vital registration forms. The numbers of maternal deaths were determined and interviews conducted. The medical causes of death and avoidable factors were determined. Results showed that the maternal mortality ratio (MMR) had dropped by 52% within that period (from 174 to 84/100,000 live births). The National Maternal Mortality Survey in 1992-93 (NMMS) revealed that the metropolitan areas and Upper Egypt had a higher MMR than Lower Egypt. In response to these results, the Egyptian Ministry of Health and Population (MOHP) intensified the efforts of its Safe Motherhood programmes in Upper Egypt with the result that the regional situation had reversed in 2000. Consideration of the intermediate and outcome indicators suggests that the greatest effect of maternal health interventions was on the death-related avoidable factors "substandard care by health providers" and "delays in recognizing problems or seeking medical care". The enormous improvements in these areas are certainly due in part to extensive training, revised curricula, the publication of medical protocols and services standards, the upgrading of facilities, and successful community outreach programmes and media campaigns. The impact on the utilization of antenatal care (ANC) has been less successful. Other areas that remain problematic are inadequate supplies of blood, drugs and equipment. Although the number of maternal deaths linked to haemorrhage has been drastically reduced, it remains the primary cause. The drop in maternal mortality in the 1990s in response to Safe Motherhood programmes was impressive and the ability to tailor interventions based on the data from the NMMS of 1992-93 and 2000 was clearly demonstrated. To ensure the continuing availability of information to guide and evaluate programmes for reducing maternal mortality, an Egyptian national maternal mortality surveillance system is being developed.


Expression of the leukocyte common antigen CD45 by endothelium.
The CD45 family of Ag expressed by leukocytes play a key role in lymphocyte activation. In this study, we identify both a restricted pattern of expression of CD45 Ag by human endothelial cells and differences in m.w. of endothelial CD45 compared with lymphocyte CD45. Initially, immunoperoxidase staining of endothelial cells in culture revealed the presence of the CD45RO isoform provided the endothelial cells had been stimulated by IL-1 for several days. No other isoform of CD45 was detected by immunoperoxidase staining of endothelium. Leukocyte common antibodies, reputed to detect all isoforms of CD45, did not detect endothelial CD45RO. A polymerase chain reaction method was then used to demonstrate that the message for the CD45RO isoform was constitutively present, with increased levels after IL-1 stimulation. Western blot confirmed the presence of the RO isoform. No other CD45 isoform was detected, either by PCR amplification for message or by Western blot. There were clear differences between lymphocyte and endothelial CD45. The RO isoform expressed by endothelium has an estimated M(r) of 235,000 in contrast to lymphocyte RO that, on our gels, has an estimated M(r) of 190,000. Given the large surface area of endothelium (approximately 1 km2 in the human), the close apposition of lymphocytes and endothelium in immunologic tissues such as lymph nodes, and the pivotal role CD45 plays in activation, expression of CD45RO by endothelium may have important implications in lymphocyte-endothelial interactions. This is most likely to occur in endothelium after a few days of IL-1 stimulation, e.g., at sites of chronic inflammation, or in the draining lymph node of an inflammatory focus.


Composition of soluble misfolded superoxide dismutase-1 in murine models of amyotrophic lateral sclerosis.
A common cause of amyotrophic lateral sclerosis is mutations in superoxide dismutase-1, which provoke the disease by an unknown mechanism. We have previously found that soluble hydrophobic misfolded mutant human superoxide dismutase-1 species are enriched in the vulnerable spinal cords of transgenic model mice. The levels were broadly inversely correlated with life spans, suggesting involvement in the pathogenesis. Here, we used methods based on antihuman superoxide dismutase-1 peptide antibodies specific for misfolded species to explore the composition and amounts of soluble misfolded human superoxide dismutase-1 in tissue extracts. Mice expressing 5 different human superoxide dismutase-1 variants with widely variable structural characteristics were examined. The levels were generally higher in spinal cords than in other tissues. The major portion of misfolded superoxide dismutase-1 was shown to be monomers lacking the C57-C146 disulfide bond with large hydrodynamic volume, indicating a severely disordered structure. The remainder of the misfolded protein appeared to be non-covalently associated in 130- and 250-kDa complexes. The malleable monomers should be prone to aggregate and associate with other cellular components, and should be easily translocated between compartments. They may be the primary cause of toxicity in superoxide dismutase-1-induced amyotrophic lateral sclerosis.


PCR-based 'serotyping' of Legionella pneumophila.
Currently, several PCR assays based on 16S rRNA and virulence-associated genes are available for detection of Legionella pneumophila. So far, no genotyping method has been published that can discriminate between serogroups and monoclonal subgroups of the most common L. pneumophila serogroup 1. Our first approach was to analyse LPS-associated genes of seven L. pneumophila serogroup 1 strains, and we developed two PCR-based methods specific for serogroup 1. Specific DNA fragments could be amplified from all the serogroup 1 strains (n=43) including the strains from the American Type Culture Collection. In contrast, none of the strains from serogroups 2-15 (n=41) contained these specific gene regions. In a second approach, primers specific for the lag-1 gene, encoding an O-acetyltransferase, which is responsible for the presence of the LPS epitope recognized by mAb 3/1, were designed and tested for their ability to differentiate between mAb 3/1-positive and -negative strains. All mAb 3/1-positive strains (n=30) contained the lag-1 gene, but in turn 4 of 13 tested mAb 3/1-negative strains were also positive in the PCR. Thus, the discrimination between mAb 3/1-positive and mAb 3/1-negative subgroups could not be achieved for all strains. In a third approach, two intergenic regions expected to be specific for monoclonal subgroup Knoxville and closely related subgroups Benidorm/Bellingham were identified and used for selective genotyping. These intergenic regions could not only be amplified in every tested strain belonging to the subgroups Knoxville, Benidorm and Bellingham, but also in some strains of other unrelated subgroups. The two PCR approaches with primers specific for serogroup 1 genes definitely represent a valuable tool in outbreak investigations and for risk assessment. They also might be used for culture-independent diagnosis of legionellosis caused by L. pneumophila serogroup 1.


Molecular analysis of laminin N-terminal domains mediating self-interactions.
The ability of laminins to self-polymerize is crucial for the formation of basement membranes. Development of this polymerized network has profound effects upon tissue architecture as well as on the intracellular organization and differentiation of neighboring cells. The laminin N-terminal (LN) domains have been shown to mediate this interaction and studies using proteolytic fragments derived from laminin-1 led to the theory that network assembly depends on the formation of a heterotrimeric complex between LN domains derived from alpha, beta, and gamma chains in different laminin molecules with homologous interactions being insignificant. The laminin family consists of 15 known isoforms formed from five alpha, three beta, and three gamma chains, of which some are truncated and lack the N-terminal LN domain. To address whether the model of heterotrimeric complex formation is applicable to laminin isoforms other than laminin-1, eight LN domains found in the laminin protein family were recombinantly expressed and tested in three different assays for homologous and heterologous interactions. The results showed that the lack of homologous interactions is an exception, with such interactions being seen for LN domains derived from all alpha chains and from the beta2 and beta3 subunits. The gamma chain-derived LN domains showed a far more limited binding repertoire, particularly in the case of the gamma3 chain, which is found present in a range of non-basement membrane locations. Further, whereas the interactions depended upon Ca2+ ions, with EDTA reversibly abrogating binding, EDTA-induced conformational changes were not reversible. Together these results demonstrate that the assembly model proposed on the basis of laminin-1 may be a simplification, with the assembly of naturally occurring laminin networks being far more complex and highly dependent upon which laminin isoforms are present.


ABHD11-AS1: An Emerging Long Non-Coding RNA (lncRNA) with Clinical Significance in Human Malignancies.
The aberrant expression of lncRNAs has been linked to the development and progression of different cancers. One such lncRNA is ABHD11 antisense RNA 1 (ABHD11-AS1), which has recently gained attention for its significant role in human malignancies. ABHD11-AS1 is highly expressed in gastric, lung, breast, colorectal, thyroid, pancreas, ovary, endometrium, cervix, and bladder cancers. Several reports highlighted the clinical significance of ABHD11-AS1 in prognosis, diagnosis, prediction of cancer progression stage, and treatment response. Significantly, the levels of ABHD11-AS1 in gastric juice had been exhibited as a clinical biomarker for the assessment of gastric cancer, while its serum levels have prognostic potential in thyroid cancers. The ABHD11-AS1 has been reported to exert oncogenic effects by sponging different microRNAs (miRNAs), altering signaling pathways such as PI3K/Akt, epigenetic mechanisms, and N6-methyladenosine (m6A) RNA modification. In contrast, the mouse homolog of AHD11-AS1 (Abhd11os) overexpression had exhibited neuroprotective effects against mutant huntingtin-induced toxicity. Considering the emerging research reports, the authors attempted in this first review on ABHD11-AS1 to summarize and highlight its oncogenic potential and clinical significance in different human cancers. Lastly, we underlined the necessity for future mechanistic studies to unravel the role of ABHD11-AS1 in tumor development, prognosis, progression, and targeted therapeutic approaches.


Cell therapy for disc degeneration--potentials and pitfalls.
Disc degeneration is considered a major source of pain in patients with chronic low back pain. Novel strategies to cure or decrease the symptoms and increase the patient's quality of life and function are under development. Until recently conservative treatment and fusion surgery were the main therapeutic options. Disc prostheses are undergoing clinical evaluation. The potential for cell transplantation to the intervertebral disc with mature autologous disc cells, chondrocytes, or stem cells is in early stages of investigation. Cell transplantation potentially can increase proteoglycan production and induce disc regeneration or slow down the degeneration process. In animal models, transplantation of autologous disc cells and chondrocytes (derived from costal cartilage) has been demonstrated to be feasible and may slow disc degeneration.


Pancreas transplantation at the University of Maryland.
1. The University of Maryland pancreas transplant program was initiated in July 1991. Through December 1996, 230 pancreas transplants were performed (145 SPK, 64 PAK, 21 PTA). Overall one-year patient and graft survival rates were 95.5% and 78.9%, respectively. 2. The majority of pancreases have been transplanted simultaneously with a kidney. The one-year patient, pancreas and kidney survival rates for SPK transplants were 95.5%, 91.9%, and 82.5%, respectively. 3. Pancreas alone (PA = PAK or PTA) transplants have represented an increasing proportion of the total in recent years. Although the results of PA were previously inferior to SPK transplants, recent developments have made the outcomes equivalent. The advent of FK and MMF have sharply reduced graft losses due to irreversible rejection. Percutaneous pancreas biopsy now provides a safe and effective means to diagnose acute rejection in a timely manner. Anticoagulation protocols have markedly reduced the risk of idiopathic postoperative graft thrombosis. The most recent series of 71 PA cases at our center had a one-year graft survival rate of 75.8% overall, and 88.2% for the 61 technically successful ones. 4. The most widely practiced pancreas transplant technique in the US today includes bladder drainage of exocrine secretions. This results in a high incidence of bladder complications, which can be avoided by enteric exocrine drainage. The most recent series of pancreas transplants at the University of Maryland have been enteric drained, encompassing about half of all cases. Adoption of this technique has eliminated bladder complications, and has not been associated with an increase in anastomotic leaks, infectious complications or graft loss. 5. Most pancreas transplants have had systemic venous drainage via the iliac vein. We recently adopted the portal venous drainage technique, since it eliminates the peripheral hyperinsulinemia associated with systemic drainage, and may therefore improve lipid metabolism and possibly reduce the risk of progression of atherosclerosis. Early results have been favorable. 6. At present the major determinant of pancreas transplant outcome is donor quality. We have emphasized the importance of using pancreases free of fatty or fibrotic transformation, which have been skillfully procured from young, stable, non-obese donors.


Unrecognised long-lasting tramadol-induced delirium in two elderly patients. A case report.
We present the cases of two elderly patients with intermittent long-term tramadol intake against chronic back pain. Over a period of more than two years they experienced fluctuating confusional states and cognitive deficits, reversible only after discontinuation of tramadol. According to the DSM IV-criteria, an unrecognised recurrent tramadol-induced delirium can be diagnosed in both cases. Although tramadol may represent a well established safe therapy for chronic non-malignant pain in the elderly, these cases demonstrate that it should be applied with caution even in healthy subjects.


Bromate ion formation in dark chlorination and ultraviolet/chlorination processes for bromide-containing water.
Bormate (BrO3(-)) is a carcinogenic chemical produced in ozonation or chlorination of bromide-containing water. Although its formation in seawater with or without sunlight has been previously investigated, the formation of bromate in dilute solutions, particularly raw water for water treatment plant, is unknown. In this article, the results of bench scale tests to measure the formation rates of bromate formation in dilute solutions, including de-ionized water and raw water from Yangtze River, were presented in dark chlorination and ultraviolet (UV)/chlorination processes. And the effects of initial pH, initial concentration of NaOCl, and UV light intensity on bromate formation in UV/chlorination of the diluted solutions were investigated. Detectable bromate was formed in dark chlorination of the two water samples with a relatively slow production rate. Under routine disinfecting conditions, the amount of formed bromate is not likely to exceed the national standards (10 microg/L). UV irradiation enhanced the decay of free chlorine, and, simultaneously, 6.6%--32% of Br was oxidized to BrO3(-). And the formation of bromate exhibited three stages: rapid stage, slow stage and plateau. Under the experimental conditions (pH = 4.41--11.07, Ccl2 = 1.23--4.50 mg/L), low pH and high chlorine concentration favored the generation of bromate. High light intensity promoted the production rate of bromate, but decreased its total generation amount due to acceleration of chlorine decomposition.


A variety of dicer substrates in human and C. elegans.
The endoribonuclease Dicer is known for its central role in the biogenesis of eukaryotic small RNAs/microRNAs. Despite its importance, Dicer target transcripts have not been directly mapped. Here, we apply biochemical methods to human cells and C. elegans and identify thousands of Dicer-binding sites. We find known and hundreds of additional miRNAs with high sensitivity and specificity. We also report structural RNAs, promoter RNAs, and mitochondrial transcripts as Dicer targets. Interestingly, most Dicer-binding sites reside on mRNAs/lncRNAs and are not significantly processed into small RNAs. These passive sites typically harbor small, Dicer-bound hairpins within intact transcripts and generally stabilize target expression. We show that passive sites can sequester Dicer and reduce microRNA expression. mRNAs with passive sites were in human and worm significantly associated with processing-body/granule function. Together, we provide the first transcriptome-wide map of Dicer targets and suggest conserved binding modes and functions outside of the miRNA pathway.


Routine use of auxiliary partial orthotopic liver transplantation for children with fulminant hepatic failure: Preliminary report.
Auxiliary partial orthotopic liver transplantation (APOLT) has been performed for both metabolic disorders and fulminant liver failure (FHF). When the native liver regenerates, the patients with FHF who undergo APOLT have a chance to withdraw immunosuppression. It may be most beneficial for children. This preliminary report describes our start to routinely offer APOLT as an option to standard OLT for children with FHF in 2005. Six children (ages 8 months to 8 years) received APOLT: 1 in 1996 and the others in 2005 and 2006. The donor ages ranged from 4 to 40 years. We used either a left lateral segment or a left lobe graft. The recipient left lobe, which was removed, showed submassive to massive necrosis at the time of transplantation. All children are alive and well. The first patient who received APOLT in 1996 is currently off immunosuppression with a fully recovered native liver; the grafted liver underwent complete atrophy. The 5 remaining subjects are receiving reduced levels of immunosuppression with close monitoring. Their serial liver biopsy specimens show slight to significant recovery. One developed hepatic artery thrombosis, requiring retransplantation. The native liver was retained at the time of retransplantation (redo APOLT). Other postoperative complications included a bile leak (n = 1), invasive mucomycosis of the arm (preexisting condition; n = 1), biliary stricture (n = 1), and acute cellular rejection (n = 3). Posttransplantation length of stay was 6 to 60 days (median, 15 days). In conclusion, APOLT can be safely performed in children with FHF displaying short-term outcomes comparable to standard transplantations.


Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis.
Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [18F]2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scans, might provide further insight. Our aim was to understand normal early tuberculosis resolution patterns on pulmonary PET-CT scans in treated patients with tuberculosis who were subsequently cured. In this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18-75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment. Among the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa. In participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and Mycobacterium tuberculosis viability within cavities might better explain treatment outcomes and why some patients are cured and others relapse. Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health. For the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.


Understanding, avoiding, and managing dermal filler complications.
BACKGROUND Dermal fillers are increasingly being utilized for multiple cosmetic dermatology indications. The appeal of these products can be partly attributed to their strong safety profiles. Nevertheless, complications can sometimes occur. OBJECTIVE To summarize the complications associated with each available dermal filling agent, strategies to avoid them, and management options if they do arise. METHODS AND MATERIALS Complications with dermal fillers reported in peer-reviewed publications, prescribing information, and recent presentations at professional meetings were reviewed. Recommendations for avoiding and managing complications are provided, based on the literature review and the author's experience. RESULTS Inappropriate placement or superficial placement is one of the most frequent reasons for patient dissatisfaction. Due to the reversibility of hyaluronic acid, complications from these fillers can be easily corrected. Sensitivity to any of the currently approved FDA products is quite rare and can usually be managed with anti-inflammatory agents. Infection is quite uncommon as well and can usually be managed with either antibiotics or antivirals depending on the clinical features. The most concerning complication is cutaneous necrosis, and a protocol to treat the full spectrum of this process is reviewed. CONCLUSIONS Complications with dermal fillers are infrequent, and strategies to minimize their incidence and impact are easily deployed. Familiarity with each family of soft-tissue augmentation products, potential complications, and their management will optimize the use of these agents.


Hepatic uptake and storage of warfarin. The relation with the target enzyme vitamin K 2,3-epoxide reductase.
The mechanisms of the reported dose-dependent warfarin pharmacokinetics were investigated using [14C]warfarin. When administered in microdoses (9 micrograms i.v.) to rats (male Wistars, 270-300 g), a steep distribution phase (T1/2 = 0.25 hr) was followed by a relatively slow beta-phase (T1/2 = 40 hr). The observed volume of distribution was 390 ml. This pharmacokinetic behavior contrasted highly with the one seen for higher (greater than 0.2 mg/kg) doses (unlabeled) warfarin; volume of distribution = 45 ml, T1/2 = 12.5 hr. If a "macrodose" (0.2 mg/kg) preceded (16 hr) the "microdose," "normal" pharmacokinetics were observed for the latter, suggesting a saturable "deep compartment." The administration of 4-hydroxycoumarins (i.e., acenocoumarol, phenprocoumon and warfarin) after the microdose of [14C]warfarin was in its beta-phase caused a rapid rise of plasma [14C]warfarin indicating [14C]warfarin to be displaced from the "deep compartment." The rate of appearance of [14C]warfarin was 0.3 hr-1 irrespective the 4-hydroxycoumarin used. The hepatic distribution of [14C]warfarin was investigated and the effect of a displacer thereupon. Fifty-three hours after the [14C]warfarin administration, the liver contained about 40% of the dose; 45% of it was bound to microsomes. The administration of acenocoumarol (0.2 mg/kg) at 48 hr, halved the liver content. [14C]warfarin was redistributed from microsomes (-65%) and from the 10,000 X g pellet (-65%) into the cytosol (+260%) and the plasma (+320%). Microsomal bound [14C]warfarin in vitro could not be washed out or be displaced unless dithiothreitol (50 mM) was included in the washing buffers.(ABSTRACT TRUNCATED AT 250 WORDS)


Multiphoton plasmon-resonance microscopy.
A novel method for detection of noble-metal nanoparticles by their nonlinear optical properties is presented and applied for specific labeling of cellular organelles. When illuminated by laser light in resonance with their plasmon frequency these nanoparticles generate an enhanced multiphoton signal. This enhanced signal is measured to obtain a depth-resolved image in a laser scanning microscope setup. Plasmon-resonance images of both live and fixed cells, showing specific labeling of cellular organelles and membranes, either by two-photon autofluorescence or by third-harmonic generation, are presented.


Low Ca2+ reperfusion and enhanced susceptibility of the postischemic heart to the calcium paradox.
This study was designed to define the effect of postischemic low Ca2+ perfusion on recovery of high-energy phosphates, intracellular pH, and contractile function in isolated rat hearts. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow creatine phosphate, adenosine triphosphate, intracellular inorganic phosphate, and intracellular pH during control perfusion (15 minutes), total ischemia (30 minutes), and reperfusion (30 minutes). In Group I the perfusate [Ca2+] was 1.3 mmol/l throughout the experiment, whereas in Group II the perfusate [Ca2+] was reduced to 0.05 mmol/l during the first 10 minutes of reperfusion. Hearts from Group III were not made ischemic but were subjected to 10 minutes of low Ca2+ perfusion followed by 20 minutes of normal Ca2+ perfusion. During low Ca2+ reperfusion (Group II) recovery of high-energy phosphates and pH was significantly better than in controls (Group I). However, after reexposure to normal Ca2+, metabolic recovery was largely abolished, coronary flow was suddenly impaired, and contracture developed without any rhythmic contractions. These observations indicated the occurrence of a calcium paradox rather than postponed ischemia-reperfusion damage. On the other hand, normoxic hearts (Group III) tolerated temporary perfusion with 0.05 mmol/l Ca2+ very well with respect to left ventricular developed pressure, coronary flow, and metabolic parameters. In conclusion, postischemic low Ca2+ (0.05 mmol/l) perfusion may reduce reperfusion damage, but at the same time ischemia appears to enhance the susceptibility of the heart to the calcium paradox.


Unique Trichomonas vaginalis gene sequences identified in multinational regions of Northwest China.
Trichomonas vaginalis (T. vaginalis) is a flagellated protozoan parasite that infects humans worldwide. This study determined the sequence of the 18S ribosomal RNA gene of T. vaginalis infecting both females and males in Xinjiang, China. Samples from 73 females and 28 males were collected and confirmed for infection with T. vaginalis, a total of 110 sequences were identified when the T. vaginalis 18S ribosomal RNA gene was sequenced. These sequences were used to prepare a phylogenetic network. The rooted network comprised three large clades and several independent branches. Most of the Xinjiang sequences were in one group. Preliminary results suggest that Xinjiang T. vaginalis isolates might be genetically unique, as indicated by the sequence of their 18S ribosomal RNA gene. Low migration rate of local people in this province may contribute to a genetic conservativeness of T. vaginalis. The unique genetic feature of our isolates may suggest a different clinical presentation of trichomoniasis, including metronidazole susceptibility, T. vaginalis virus or Mycoplasma co-infection characteristics. The transmission and evolution of Xinjiang T. vaginalis is of interest and should be studied further. More attention should be given to T. vaginalis infection in both females and males in Xinjiang.


Single-molecule localization super-resolution microscopy: deeper and faster.
For over a decade fluorescence microscopy has demonstrated the capacity to achieve single-molecule localization accuracies of a few nanometers, well below the ≈ 200 nm lateral and ≈ 500 nm axial resolution limit of conventional microscopy. Yet, only the recent development of new fluorescence labeling modalities, the increase in sensitivity of imaging hardware, and the creation of novel image analysis tools allow for the emergence of single-molecule-based super-resolution imaging techniques. Novel methods such as photoactivated localization microscopy and stochastic optical reconstruction microscopy can typically reach a tenfold increase in resolution compared to standard microscopy methods. Their implementation is relatively easy only requiring minimal changes to a conventional wide-field or total internal reflection fluorescence microscope. The recent translation of these two methods into commercial imaging systems has made them further accessible to researchers in biology. However, these methods are still evolving rapidly toward imaging live samples with high temporal resolution and depth. In this review, we recall the roots of single-molecule localization microscopy, summarize major recent developments, and offer perspective on potential applications.


Identification of potential new protein vaccine candidates through pan-surfomic analysis of pneumococcal clinical isolates from adults.
Purified polysaccharide and conjugate vaccines are widely used for preventing infections in adults and in children against the Gram-positive bacterium Streptococcus pneumoniae, a pathogen responsible for high morbidity and mortality rates, especially in developing countries. However, these polysaccharide-based vaccines have some important limitations, such as being serotype-dependent, being subjected to losing efficacy because of serotype replacement and high manufacturing complexity and cost. It is expected that protein-based vaccines will overcome these issues by conferring a broad coverage independent of serotype and lowering production costs. In this study, we have applied the "shaving" proteomic approach, consisting of the LC/MS/MS analysis of peptides generated by protease treatment of live cells, to a collection of 16 pneumococcal clinical isolates from adults, representing the most prevalent strains circulating in Spain during the last years. The set of unique proteins identified in all the isolates, called "pan-surfome", consisted of 254 proteins, which included most of the protective protein antigens reported so far. In search of new candidates with vaccine potential, we identified 32 that were present in at least 50% of the clinical isolates analyzed. We selected four of them (Spr0012, Spr0328, Spr0561 and SP670_2141), whose protection capacity has not yet been tested, for assaying immunogenicity in human sera. All of them induced the production of IgM antibodies in infected patients, thus indicating that they could enter the pipeline for vaccine studies. The pan-surfomic approach shows its utility in the discovery of new proteins that can elicit protection against infectious microorganisms.


Bayesian analysis of diastolic blood pressure measurement.
A mathematical model is presented for measurements that include substantial fluctuation and error. Under the assumptions that the fluctuation-error variance is the same for all subjects, and that the distributions of fluctuation-error variance within subjects and "true" values of the measurements in the population are normal, Bayes' theorem produces a simple estimate of the "true" value of a measurement, and a standard error, conditional on a single observation. The model is easily extended to several observations. Methods for estimating the parameters of the model from a data set are presented, and applied to diastolic blood pressures of patients in the authors' primary care clinic. The test-retest reliability of a single blood pressure measurement for this population is 0.41. Because continuous measurements are often dichotomized into "normal" and "abnormal" ranges by a threshold criterion, the authors present formulas for the positive predictive value when a decision rule based on a given number of observations is used in a population with respect to a threshold criterion for the "true" values. For example, classifying their patients as hypertensive on the basis of the average of two readings exceeding 90 mm Hg diastolic pressure would have a positive predictive value of 52% for the "gold standard" of average diastolic pressure exceeding 90 mm Hg. Formulas to calculate the frequency with which patients will be classified "abnormal" by one decision rule but will be classified "normal" by later application of another rule are provided and used to "predict" the frequency with which this crossover phenomenon should have occurred in the enrollment phase of the Hypertension Detection and Follow-up Programs.(ABSTRACT TRUNCATED AT 250 WORDS)


Why cost-effectiveness should trump (clinical) effectiveness: the ethical economics of the South West quadrant.
In many health decision making situations there is a requirement that the effectiveness of interventions, usually their 'clinical' effectiveness, be established, as well as their cost-effectiveness. Often indeed this is effectively a prior requirement for their cost-effectiveness being investigated. If, however, one accepts the ethical argument for using a threshold incremental cost-effectiveness ratio (ICER) for interventions that are more effective but more costly (i.e. fall in the NE quadrant of the cost-effectiveness plane), one should apply the same decision rule in the SW quadrant, where the intervention is less effective but less costly. This implication is present in most standard treatments of cost-effectiveness analysis, including recent stochastic versions, and had gone relatively unquestioned within the discipline until the recent suggestion that the ICER threshold might be 'kinked'. A kinked threshold would, O'Brien et al. argue, better reflect the asymmetrical individual preferences found in empirical studies of consumer's willingness to pay and willingness to accept and justify different decision rules in the NE and SW quadrants. We reject the validity of such asymmetric preferences in the context of public health care decisions and consider and counter the two main 'ethical' objections that probably underlie the asymmetry in this case--the objection to 'taking away' and the objection to being required to undergo treatment that is less effective than no treatment at all.


A Pathovar of Xanthomonas oryzae Infecting Wild Grasses Provides Insight Into the Evolution of Pathogenicity in Rice Agroecosystems.
Xanthomonas oryzae (Xo) are globally important rice pathogens. Virulent lineages from Africa and Asia and less virulent strains from the United States have been well characterized. Xanthomonas campestris pv. leersiae (Xcl), first described in 1957, causes bacterial streak on the perennial grass, Leersia hexandra, and is a close relative of Xo. L. hexandra, a member of the Poaceae, is highly similar to rice phylogenetically, is globally ubiquitous around rice paddies, and is a reservoir of pathogenic Xo. We used long read, single molecule real time (SMRT) genome sequences of five strains of Xcl from Burkina Faso, China, Mali, and Uganda to determine the genetic relatedness of this organism with Xo. Novel transcription activator-like effectors (TALEs) were discovered in all five strains of Xcl. Predicted TALE target sequences were identified in the Leersia perrieri genome and compared to rice susceptibility gene homologs. Pathogenicity screening on L. hexandra and diverse rice cultivars confirmed that Xcl are able to colonize rice and produce weak but not progressive symptoms. Overall, based on average nucleotide identity (ANI), type III (T3) effector repertoires, and disease phenotype, we propose to rename Xcl to X. oryzae pv. leersiae (Xol) and use this parallel system to improve understanding of the evolution of bacterial pathogenicity in rice agroecosystems.


Roles of dioxins and heavy metals in cancer and neurological diseases using ROS-mediated mechanisms.
Oxidants have critical functions inside healthy and unhealthy cells. Deregulated cell cycle and apoptosis, both regulated by oxidative stress, have been described as hallmarks of mitotic (cancer) and postmitotic (neuronal) cells. This review provides an updated revision of the oxidant effects of some environmental contaminants such as dioxins and the heavy metals cadmium, cobalt, and copper. Dioxins exert their toxic actions by acting on phase I and phase II enzymes, such as cytochromes P450, superoxide dismutase, and glutathione peroxidase, promoting cell proliferation, growth arrest, and apoptosis, affecting cancer homeostasis and neuronal function. Heavy metals manifest cytotoxic effects in various cells and tissues, and tight regulation of metals is essential to the health of organisms. Cadmium modulates gene expression and signal transduction and reduces activities of proteins involved in antioxidant defense, interfering with DNA repair and modifying cancer development and brain function. Cobalt provokes generation of reactive oxygen species and DNA damage in cancer cells and brain tissues, altering proliferation and differentiation and causing apoptosis. Copper is a key metal in cell division processes in both normal and tumor cells. Copper also has been shown to have an important role in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.


The Protective Effect of a Unique Mix of Polyphenols and Micronutrients against Neurodegeneration Induced by an In Vitro Model of Parkinson's Disease.
Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5+, in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5+ causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5+ treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5+ mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect.


Subjective Memory Problems and Availability of Emotional Support.
This study examines (1) whether subjective memory problems (SMP) influence perceived emotional support from and frequency of contact with family and friends; and, (2) the extent to which this relationship is moderated by gender, education, and functional limitations. We use the 2014 wave of the Health and Retirement Study, a nationally representative panel survey of adults aged 51 and over in the United States. While SMP does not affect perceived emotional support for younger group (YG; aged 51-64), in older group (OG; aged 65+), SMP is associated with reduced perceived support from friends. Also, SMP is predictive of fewer writing-based contact with children and friends among OG but not among YG. Lastly, we find that the effect of SMP on support from children is contingent upon activity of daily living (YG) and gender (OG), while the effect of SMP on writing-based contact with both children and friends is contingent upon education (YG only).


Application of characteristic vector analysis to the spectral energy distribution of daylight and the spectral reflectance of american soils.
Measurements have been made of the spectral energy distribution of daylight (sunlight plus skylight) and skylight in the near-uv and visible region of the spectrum as a function of solar altitude for various atmospheric conditions as measured on planes of different orientation. A characteristic vector analysis was made of the digitized data. From these data, a variance-covariance matrix was computed for the daylight energy data and another for the skylight energy data. The four vectors were capable of accounting for 98.2% of the trace of the variance-covariance matrix for daylight and 99.4% for the skylight data. Spectral reflectances extending from 320 nm to 1000 nm have been obtained for 160 soil samples collected from thirty-six states. Measurements were made of both wet and dry samples, which vary widely in color and reflectance. An examination of the 160 sets of curves indicates that they can be classified into three general types with respect to their curve shapes. A characteristic vector analysis was made of the spectral reflectance data; it showed that by linear combinations of four vectors and the mean curve, each set of data could be reconstituted to a high degree of accuracy (99.9% of the trace). Empirical regression equations have been derived that relate spectral reflectance data at thirty-five wavelengths spaced at 20-nm increments to measurements made at only five specially selected wavelengths. To the extent that soils may be identified by their reflectance characteristics, this abridged technique seems to have sufficient accuracy for the 160 samples that have been measured.


Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis.
Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the aetiology of ALS have provided inconsistent results. If physical use of a limb were important in defining the site of onset, then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset ALS. ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively. 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The frequency of left handedness was commensurate with that found in the general population. These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness and reflected by the "split hand" phenomenon consistently observed in ALS.