Is Chronic Dialysis the Right Hard Renal End Point To Evaluate Renoprotective Drug Effects?
RRT and doubling of serum creatinine are considered the objective hard end points in nephrology intervention trials. Because both are assumed to reflect changes in the filtration capacity of the kidney, drug effects, if present, are attributed to kidney protection. However, decisions to start RRT are not only on the basis of filtration capacity of the kidney, but also on other factors. We therefore compared the time to RRT with the time to a fixed eGFR threshold and assessed the effect of the renoprotective drug irbesartan on both components. Post hoc analysis of two clinical trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of End points in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial, in patients with type 2 diabetes and nephropathy. The time to a predefined eGFR level of 11 ml/min per 1.73 m2 (eGFR11), calculated by within-patient linear regression, was compared with the time to RRT or sustained serum creatinine ≥6 mg/dl. A large difference was observed in the median time to RRT (779 days) compared with eGFR11 (678 days; P=0.01). We also observed a large variation in the difference between the time to RRT and eGFR11. In IDNT, the hazard ratio for the effect of irbesartan on the serum creatinine ≥6.0 mg/dl end point was 0.60 (95% confidence interval, 0.39 to 0.91; P=0.02), whereas it was smaller for the RRT end point (hazard ratio, 0.78; 95% confidence interval, 0.58 to 1.07; P=0.12). This study shows a difference in the time to RRT and a fixed eGFR threshold, and shows that the effect of an angiotensin receptor blocker on a filtration-based end point versus RRT varies. This implies that evaluating renoprotective effects of drugs with a combined RRT and doubling of serum creatinine end point may result in evaluating other effects beyond renoprotection alone. Future trials should consider registering all parameters that lead to RRT decisions.


Investigation of a novel 3-fluid nozzle spray drying technology for the engineering of multifunctional layered microparticles.
To examine the potential of a novel 3-fluid nozzle spray drying technology to formulate differentiated layered microparticles (MPs) of diclofenac sodium (DFS)/ethyl cellulose (EC). DFS/EC MPs were formulated using the inner and/or outer nozzles of a novel 3-fluid nozzle and compared with MPs formed using conventional (2-fluid) spray drying. MPs were characterised for particle size and for morphology by TEM and SEM. Distribution of DFS and EC of MPs was analysed by FT-IR and DSC. A two-factor, three-level (3(2)) factorial design was applied to investigate the effect and interaction of total feed solid content (TSC) and feed flow rate (FFR) on MP size, D(50%) and D(90%), bulk density and MP yield. Interestingly, TEM demonstrated that MPs formed by 3-fluid nozzle spray drying showed a heterogeneous internal morphology consisting of a core and coat, characteristic of a microcapsule. In comparison, MPs from conventional spray drying showed a homogeneous internal morphology, characteristics of a matrix system. This differential distribution of DFS/EC was supported by FT-IR and DSC. Results of multiple linear regression analysis showed a linear relationship for the effect of TSC and FFR on all responses except for D(50%) where a quadratric model was valid. The effect of TSC/FFR on MP size and yield was similar to conventional spray drying. The novel 3-fluid nozzle spray drying offers a new method of designing layered microparticles or microcapsules which can have wide applications from drug stabilisation to controlled drug delivery and targeting.


A Microengineered Airway Lung Chip Models Key Features of Viral-induced Exacerbation of Asthma.
Viral-induced exacerbation of asthma remains a major cause of hospitalization and mortality. New human-relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks and to advance treatment development. Here, we describe a new human-relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway epithelium and neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a microengineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a T-helper cell type 2 asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce key features of viral-induced asthma exacerbation. We observed that the infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a T-helper cell type 2 microenvironment through exogenous IL-13 stimulation induced features of asthmatic airways, including goblet cell hyperplasia, reduction of cilia beating frequency, and endothelial activation, but did not alter rhinovirus infectivity or replication. High-resolution kinetic analysis of secreted inflammatory markers revealed that IL-13 treatment altered IL-6, IFN-λ1, and CXCL10 secretion in response to HRV16. Neutrophil transepithelial migration was greatest when viral infection was combined with IL-13 treatment, whereas treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. In conclusion, our microengineered Airway Lung-Chip provides a novel human-relevant platform for exploring the complex mechanisms underlying viral-induced asthma exacerbation. Our data suggest that IL-13 may impair the hosts' ability to mount an appropriate and coordinated immune response to rhinovirus infection. We also show that the Airway Lung-Chip can be used to assess the efficacy of modulators of the immune response.


Cerebrospinal fluid stasis and its clinical significance.
We hypothesize that stasis of the cerebrospinal fluid (CSF) occurs commonly and is detrimental to health. Physiologic factors affecting the normal circulation of CSF include cardiovascular, respiratory, and vasomotor influences. The CSF maintains the electrolytic environment of the central nervous system (CNS), influences systemic acid-base balance, serves as a medium for the supply of nutrients to neuronal and glial cells, functions as a lymphatic system for the CNS by removing the waste products of cellular metabolism, and transports hormones, neurotransmitters, releasing factors, and other neuropeptides throughout the CNS. Physiologic impedance or cessation of CSF flow may occur commonly in the absence of degenerative changes or pathology and may compromise the normal physiologic functions of the CSF. CSF appears to be particularly prone to stasis within the spinal canal. CSF stasis may be associated with adverse mechanical cord tension, vertebral subluxation syndrome, reduced cranial rhythmic impulse, and restricted respiratory function. Increased sympathetic tone, facilitated spinal segments, dural tension, and decreased CSF flow have been described as closely related aspects of an overall pattern of structural and energetic dysfunction in the axial skeleton and CNS. Therapies directed at affecting CSF flow include osteopathic care (especially cranial manipulation), craniosacral therapy, chiropractic adjustment of the spine and cranium, Network Care (formerly Network Chiropractic), massage therapy (including lymphatic drainage techniques), yoga, therapeutic breath-work, and cerebrospinal fluid technique. Further investigation into the nature and causation of CSF stasis, its potential effects upon human health, and effective therapies for its correction is warranted.


Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group.
To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes. This is a descriptive study evaluating the data collected prospectively in the Children's Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children's hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks' gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010-July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge. High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%. Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.


Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells.
Natural killer (NK) cells are innate lymphocytes postulated to mediate resistance against primary haematopoietic but not solid tumor malignancies. Cancer stem cells (CSCs) are a small subset of malignant cells with stem-like properties which are resistant to chemo- and radiotherapies and are able to repopulate a tumor after cytoreductive treatments. We observed increased frequencies of stem-like tumor cells after irradiation, with increased expression of stress ligands on surviving stem-like cells. Ex vivo NK cells activated by low dose IL2 in vitro and IL15 in vivo displayed an increased ability to target solid tumor stem-like cells both in vitro and in vivo after irradiation. Mechanistically, both upregulation of stress-related ligands on the stem-like cells as well as debulking of non-stem populations contributed to these effects as determined by data from cell lines, primary tumor samples, and most relevant patient derived specimens. In addition, pretreatment of tumor-bearing mice with local radiation prior to NK transfer resulted in significantly longer survival indicating that radiation therapy in conjunction with NK cell adoptive immunotherapy targeting stem-like cancer cells may offer a promising novel radio-immunotherapy approach in the clinic.


Small bowel metastasis from pancreatic cancer in a long-term survival patient with synchronous advanced malignant pleural mesothelioma: A case report and literature review.
Diffuse malignant pleural mesothelioma (MPM) is an aggressive tumor that originates from the surface of the pleura. Approximately 70% of cases are associated with chronic asbestos exposure. MPM is regarded as an incurable disease, with a median survival of ~2 years following intensive multimodality treatment. Pancreatic cancer is a malignancy also associated with a poor prognosis, with only 2% of patients surviving for 5 years. The majority of patients with pancreatic cancer are diagnosed with an advanced stage of disease and experience a poor response to therapy. The development of synchronous MPM and other types of cancer is rare. The present study describes a patient with synchronous, biphasic MPM and pancreatic adenocarcinoma, who was treated with a multimodal therapeutic approach with stereotactic body radiation therapy. Due to a suspected diagnosis of 'acute abdomen', an emergency small intestine resection was performed and a subsequent diagnosis of moderately-differentiated adenocarcinoma was confirmed. During a further immunohistochemical examination, pathologists determined that the small bowel metastasis descended from pancreatic cancer. The onset of bowel metastasis is an event rarely associated with MPM, and has not been previously described in the literature for cases of pancreatic cancer. Therefore, to the best of our knowledge, the present study describes the first case of intestinal metastasis from pancreatic cancer in a long-term survival patient with biphasic MPM.


Screening of a Leptospira biflexa mutant library to identify genes involved in ethidium bromide tolerance.
Leptospira spp. are spirochete bacteria comprising both pathogenic and free-living species. The saprophyte L. biflexa is a model bacterium for studying leptospiral biology due to relative ease of culturing and genetic manipulation. In this study, we constructed a library of 4,996 random transposon mutants in L. biflexa. We screened the library for increased susceptibility to the DNA intercalating agent, ethidium bromide (EtBr), in order to identify genetic determinants that reduce L. biflexa susceptibility to antimicrobial agents. By phenotypic screening, using subinhibitory EtBr concentrations, we identified 29 genes that, when disrupted via transposon insertion, led to increased sensitivity of the bacteria to EtBr. At the functional level, these genes could be categorized by function as follows: regulation and signaling (n=11), transport (n=6), membrane structure (n=5), stress response (n=2), DNA damage repair (n=1), and other processes (n=3), while 1 gene had no predicted function. Genes involved in transport (including efflux pumps) and regulation (two-component systems, anti-sigma factor antagonists, etc.) were overrepresented, demonstrating that these genes are major contributors to EtBr tolerance. This finding suggests that transport genes which would prevent EtBr to enter the cell cytoplasm are critical for EtBr resistance. We identified genes required for the growth of L. biflexa in the presence of sublethal EtBr concentration and characterized their potential as antibiotic resistance determinants. This study will help to delineate mechanisms of adaptation to toxic compounds, as well as potential mechanisms of antibiotic resistance development in pathogenic L. interrogans.


Trans-generational effects on ageing in a wild bird population.
Ageing, long thought to be too infrequent to study effectively in natural populations, has recently been shown to be ubiquitous, even in the wild. A major challenge now is to explain variation in the rates of ageing within populations. Here, using 49 years of data from a population of great tits (Parus major), we show that offspring life-history trajectories vary with maternal age. Offspring hatched from older mothers perform better early in life, but suffer from an earlier onset, and stronger rate, of reproductive senescence later in life. Offspring reproductive lifespan is, however, unaffected by maternal age, and the different life-history trajectories result in a similar fitness payoff, measured as lifetime reproductive success. This study therefore identifies maternal age as a new factor underlying variation in rates of ageing, and, given the delayed trans-generational nature of this effect, poses the question as to proximate mechanisms linking age-effects across generations.


Pacemaker Dependency after Cardiac Surgery: A Systematic Review of Current Evidence.
Severe postoperative conduction disturbances requiring permanent pacemaker implantation frequently occur following cardiac surgery. Little is known about the long-term pacing requirements and risk factors for pacemaker dependency in this population. We performed a systematic review of the literature addressing rates and predictors of pacemaker dependency in patients requiring permanent pacemaker implantation after cardiac surgery. Using a comprehensive search of the Medline, Web of Science and EMBASE databases, studies were selected for review based on predetermined inclusion and exclusion criteria. A total of 8 studies addressing the endpoint of pacemaker-dependency were identified, while 3 studies were found that addressed the recovery of atrioventricular (AV) conduction endpoint. There were 10 unique studies with a total of 780 patients. Mean follow-up ranged from 6-72 months. Pacemaker dependency rates ranged from 32%-91% and recovery of AV conduction ranged from 16%-42%. There was significant heterogeneity with respect to the definition of pacemaker dependency. Several patient and procedure-specific variables were found to be independently associated with pacemaker dependency, but these were not consistent between studies. Pacemaker dependency following cardiac surgery occurs with variable frequency. While individual studies have identified various perioperative risk factors for pacemaker dependency and non-resolution of AV conduction disease, results have been inconsistent. Well-conducted studies using a uniform definition of pacemaker dependency might identify patients who will benefit most from early permanent pacemaker implantation after cardiac surgery.


Comparison of students' use and acceptance of emergency online learning due to COVID-19 in the USA, Mexico, Peru, and Turkey.
Due to the COVID-19 pandemic, and pursuant to the governments' order of citizens remaining at home, several countries were required to transition from face-to-face instruction to an online model to provide higher education to their students. While factors affecting the use of online learning are diverse and have been studied by models of use and acceptance of technology, this cross-sectional study explores the factors unique to the current emergency situation that influence students' use and acceptance of emergency online learning. Moreover, it proposes a model to predict a student's cognitive engagement in Mexico, Peru, Turkey, and the USA. This is a quantitative study with an exploratory and descriptive scope and cross-sectional design. Data was collected from 1009 students from the four countries, who completed surveys anonymously. The factors analyzed were attitude, affect, and motivation, perceived behavioral control (ease of use, self-efficacy, and accessibility), and cognitive engagement. The data was analyzed using descriptive, correlation, and regression analysis. The predictive model shows that students' attitude toward online learning impacts their cognitive engagement in Mexico, Peru, and the USA. Furthermore, self-efficacy is a significant moderator for cognitive engagement in all four countries. The model also shows that each country has different determinants for cognitive engagement. Understanding the factors that affect the use of emergency online learning is essential for the success and/or achievement of its maximum benefits in situations like a global pandemic. Limitations of this study have been identified as use of convenience sampling, and an inability to explore factors related to instruction and system attributes. Professors who did not teach online learning lacked knowledge about online educational strategies and used the technological resources that were immediately available to them. Therefore, research that explores the use of instructional strategies and the use of technological systems during emergency online learning is necessary. This study includes suggestions to incorporate open educational resources that use microlearning and emphasizes the importance of student self-efficacy; because it was predictor of cognitive engagement in all four countries. Faculty and higher education institutions can and should develop strategies to increase students' sense of self-efficacy.


Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference.
Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline.


A common cellular basis for muscle regeneration in arthropods and vertebrates.
Many animals are able to regenerate amputated or damaged body parts, but it is unclear whether different taxa rely on similar strategies. Planarians and vertebrates use different strategies, based on pluripotent versus committed progenitor cells, respectively, to replace missing tissues. In most animals, however, we lack the experimental tools needed to determine the origin of regenerated tissues. Here, we present a genetically tractable model for limb regeneration, the crustacean Parhyale hawaiensis. We demonstrate that regeneration in Parhyale involves lineage-committed progenitors, as in vertebrates. We discover Pax3/7-expressing muscle satellite cells, previously identified only in chordates, and show that these cells are a source of regenerating muscle in Parhyale. These similarities point to a common cellular basis of regeneration, dating back to the common ancestors of bilaterians.


Evaluation of histone deacetylases as drug targets in Huntington's disease models. Study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model.
The family of histone deacetylases (HDACs) has recently emerged as important drug targets for treatment of slow progressive neurodegenerative disorders, including Huntington's disease (HD). Broad pharmaceutical inhibition of HDACs has shown neuroprotective effects in various HD models. Here we examined the susceptibility of HDAC targets for drug treatment in affected brain areas during HD progression. We observed increased HDAC1 and decreased HDAC4, 5 and 6 levels, correlating with disease progression, in cortices and striata of HD R6/2 mice. However, there were no significant changes in HDAC protein levels, assessed in an age-dependent manner, in HD knock-in CAG140 mice and we did not observe significant changes in HDAC1 levels in human HD brains. We further assessed acetylation levels of α-tubulin, as a biomarker of HDAC6 activity, and found it unchanged in cortices from R6/2, knock-in, and human subjects at all disease stages. Inhibition of deacetylase activities was identical in cortical extracts from R6/2 and wild-type mice treated with a class II-selective HDAC inhibitor. Lastly, treatment with class I- and II-selective HDAC inhibitors showed similar responses in HD and wild-type rat striatal cells. In conclusion, our results show that class I and class II HDAC targets are present and accessible for chronic drug treatment during HD progression and provide impetus for therapeutic development of brain-permeable class- or isoform-selective inhibitors.


Habitat-related variation in reproductive endocrine condition in the coral reef damselfish Acanthochromis polyacanthus.
Spiny damselfish Acanthochromis polyacanthus are brood protectors with no larval dispersal stage, with the result that characteristics of local populations are likely to reflect local habitat conditions. In order to assess the possible effect of habitat on reproductive characteristics, spiny damselfish were captured by divers in 1999 and 2001 from reefs around Lizard Island in the northern section of Australia's Great Barrier Reef, chosen to represent a range of coral cover characteristics. Fish were bled underwater immediately after capture, then blood and fish were placed on ice at the end of the dive for transport to the laboratory where plasma was separated for subsequent measurement of testosterone (T) and 11-ketotestosterone (11KT) in males, and T and 17beta-estradiol (E2) in females. Ovaries from fish captured in 2001 were dispersed to isolate vitellogenic follicles, fecundity and follicle size were determined, then follicles were incubated in Leibowitz L15 medium alone or with human chorionic gonadotropin (hCG), to assess steroidogenic capacity. In 1999 there were significant site to site variations in plasma T and E2 levels in females, and in 2001, in E2 in females, and in T and 11KT in males. Highest hormone levels were recorded from sites of both low and high coral cover (a measure of presumptive habitat quality), but there was consistently low steroid production in fish from a site of high coral cover and fish density. An initial expectation that poor reproductive condition might be associated with degraded coral sites was not met. Vitellogenic follicles from fish captured in 2001 showed increased in vitro production of E2 and to a lesser extent, T, with increasing follicle size, and this was further augmented by treatment with hCG. Comparison of regression slopes of log E2 production versus follicle size showed that fish from sites where there were generally low levels of plasma steroids also had impaired in vitro steroidogenic capacity, and that this effect partially disappeared when follicles were stimulated with hCG. Reduced steroidogenic capacity was strongly associated with low fecundity, indicating that low in vitro and in vivo E2 production were reflected in reduced reproductive capacity. As the effect was most consistent at a site where fish density (and subsequent competition for planktonic food) was high, it is suggested that nutritional status associated with habitat characteristics may regulate reproductive endocrine condition in spiny damselfish. It is clear that local factors other than coral cover can generate site variation in reproductive performance.


Platelet-derived growth factor BB mediates the tropism of human mesenchymal stem cells for malignant gliomas.
Bone marrow-derived human mesenchymal stem cells (hMSCs) are capable of localizing to gliomas after systemic delivery and can be used in glioma therapy. However, the mechanism underlying the tropism of hMSCs for gliomas remains unclear. In vitro studies suggest that platelet-derived growth factor BB (PDGF-BB) may mediate this tropism. However, a causal role of PDGF-BB has not been demonstrated in vivo. Therefore, we tested the hypothesis that PDGF-BB mediates the attraction of hMSCs to gliomas in vitro and in vivo. U87 or LN229 glioma cells were transfected with plasmids encoding human PDGF-B. Stable transfected clones that secreted large amounts of PDFG-BB and clones that produced low levels of PDGF were chosen. In vitro migration of hMSCs toward PDGF-B or conditioned media from high- and low-secreting PDGF-B tumor cells was assessed using Matrigel invasion assays. For in vivo localization studies, hMSCs were tracked by bioluminescence imaging (BLI) after transduction with an adenovirus containing luciferase cDNA. In other studies, hMSCs were labeled with green fluorescent protein (gfp) and analyzed for intratumoral localization by immunohistochemistry. In vitro invasion assays showed that significantly more hMSCs migrated toward glioma cells engineered to secrete high levels of PDGF-BB compared with low-secreting gliomas. Anti-PDGF-BB-neutralizing antibody abrogated this increase in migration. Pretreatment of hMSCs with inhibitory antibodies against PDGF receptor-beta also reduced hMSC migration. To demonstrate that PDGF-BB mediates the localization of hMSCs in vivo, hMSCs-Ad-Luc were injected into the carotid artery of mice harboring orthotopic 7-day-old U87-PDGF-BB-high secreting or U87-PDGF-BB-low secreting xenografts and analyzed by BLI. Statistically significant increases in hMSCs were seen within PDGF-BB-high xenografts compared with PDGF-BB-low xenografts. To control for PDGF-BB-induced differences in tumor size and vascularity, gfp-labeled hMSCs were injected into the carotid arteries of animals harboring 4-day old PDGF-BB-high secreting xenografts or 7-day old PDGF-BB-low secreting xenografts. At these times tumors had similar size and vessel density. Statistically significant more hMSCs localized to PDGF-BB-high secreting xenografts compared with PDGF-BB-low secreting xenografts. Pretreatment of hMSCs with anti-PDGFR-beta-inhibitory antibodies decreased the localization of hMSCs in this intracranial model. PDGF-BB increases the attraction of hMSCs for gliomas in vitro and in vivo, and this tropism is mediated via PDGF-beta receptors on hMSCs. These findings can be exploited for advancing hMSC treatment.


Circulating antigen tests and urine reagent strips for diagnosis of active schistosomiasis in endemic areas.
Point-of-care (POC) tests for diagnosing schistosomiasis include tests based on circulating antigen detection and urine reagent strip tests. If they had sufficient diagnostic accuracy they could replace conventional microscopy as they provide a quicker answer and are easier to use. To summarise the diagnostic accuracy of: a) urine reagent strip tests in detecting active Schistosoma haematobium infection, with microscopy as the reference standard; and b) circulating antigen tests for detecting active Schistosoma infection in geographical regions endemic for Schistosoma mansoni or S. haematobium or both, with microscopy as the reference standard. We searched the electronic databases MEDLINE, EMBASE, BIOSIS, MEDION, and Health Technology Assessment (HTA) without language restriction up to 30 June 2014. We included studies that used microscopy as the reference standard: for S. haematobium, microscopy of urine prepared by filtration, centrifugation, or sedimentation methods; and for S. mansoni, microscopy of stool by Kato-Katz thick smear. We included studies on participants residing in endemic areas only. Two review authors independently extracted data, assessed quality of the data using QUADAS-2, and performed meta-analysis where appropriate. Using the variability of test thresholds, we used the hierarchical summary receiver operating characteristic (HSROC) model for all eligible tests (except the circulating cathodic antigen (CCA) POC for S. mansoni, where the bivariate random-effects model was more appropriate). We investigated heterogeneity, and carried out indirect comparisons where data were sufficient. Results for sensitivity and specificity are presented as percentages with 95% confidence intervals (CI). We included 90 studies; 88 from field settings in Africa. The median S. haematobium infection prevalence was 41% (range 1% to 89%) and 36% for S. mansoni (range 8% to 95%). Study design and conduct were poorly reported against current standards. Tests for S. haematobium Urine reagent test strips versus microscopyCompared to microscopy, the detection of microhaematuria on test strips had the highest sensitivity and specificity (sensitivity 75%, 95% CI 71% to 79%; specificity 87%, 95% CI 84% to 90%; 74 studies, 102,447 participants). For proteinuria, sensitivity was 61% and specificity was 82% (82,113 participants); and for leukocyturia, sensitivity was 58% and specificity 61% (1532 participants). However, the difference in overall test accuracy between the urine reagent strips for microhaematuria and proteinuria was not found to be different when we compared separate populations (P = 0.25), or when direct comparisons within the same individuals were performed (paired studies; P = 0.21).When tests were evaluated against the higher quality reference standard (when multiple samples were analysed), sensitivity was marginally lower for microhaematuria (71% vs 75%) and for proteinuria (49% vs 61%). The specificity of these tests was comparable. Antigen assayCompared to microscopy, the CCA test showed considerable heterogeneity; meta-analytic sensitivity estimate was 39%, 95% CI 6% to 73%; specificity 78%, 95% CI 55% to 100% (four studies, 901 participants). Tests for S. mansoni Compared to microscopy, the CCA test meta-analytic estimates for detecting S. mansoni at a single threshold of trace positive were: sensitivity 89% (95% CI 86% to 92%); and specificity 55% (95% CI 46% to 65%; 15 studies, 6091 participants) Against a higher quality reference standard, the sensitivity results were comparable (89% vs 88%) but specificity was higher (66% vs 55%). For the CAA test, sensitivity ranged from 47% to 94%, and specificity from 8% to 100% (4 studies, 1583 participants). Among the evaluated tests for S. haematobium infection, microhaematuria correctly detected the largest proportions of infections and non-infections identified by microscopy.The CCA POC test for S. mansoni detects a very large proportion of infections identified by microscopy, but it misclassifies a large proportion of microscopy negatives as positives in endemic areas with a moderate to high prevalence of infection, possibly because the test is potentially more sensitive than microscopy.


Sleep disturbances and their relationship to glucose tolerance in pregnancy.
To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes. Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT). Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = -0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2-7.4]), SS (2.4 [1.0-5.9]), SDB/SS (3.4 [1.3-8.7]), and frequent snoring (3.4 [1.3-8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers. Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.


Host-pathogen time series data in wildlife support a transmission function between density and frequency dependence.
A key aim in epidemiology is to understand how pathogens spread within their host populations. Central to this is an elucidation of a pathogen's transmission dynamics. Mathematical models have generally assumed that either contact rate between hosts is linearly related to host density (density-dependent) or that contact rate is independent of density (frequency-dependent), but attempts to confirm either these or alternative transmission functions have been rare. Here, we fit infection equations to 6 years of data on cowpox virus infection (a zoonotic pathogen) for 4 natural populations to investigate which of these transmission functions is best supported by the data. We utilize a simple reformulation of the traditional transmission equations that greatly aids the estimation of the relationship between density and host contact rate. Our results provide support for an infection rate that is a saturating function of host density. Moreover, we find strong support for seasonality in both the transmission coefficient and the relationship between host contact rate and host density, probably reflecting seasonal variations in social behavior and/or host susceptibility to infection. We find, too, that the identification of an appropriate loss term is a key component in inferring the transmission mechanism. Our study illustrates how time series data of the host-pathogen dynamics, especially of the number of susceptible individuals, can greatly facilitate the fitting of mechanistic disease models.


Further characterization of the platinum-reactive component of the alpha 2-macroglobulin-receptor recognition site.
alpha 2-Macroglobulin (alpha 2M)-methylamine that had been allowed to react with cis-dichlorodiammineplatinum(II) (cis-DDP) bound with greatly reduced affinity to specific alpha 2M receptors, as determined by macrophage binding studies in vitro and plasma-clearance experiments in vivo. Subsequent reaction with diethyl dithiocarbamate completely restored receptor recognition function. The optimal effect was obtained when the diethyl dithiocarbamate concentration was twice the total platinum concentration. alpha 2M-methylamine that was allowed to react with H2O2 competed less effectively for specific cell-surface binding sites, as demonstrated by studies both in vivo and in vitro. The apparent dissociation constant was increased nearly 7-fold by a 15 min exposure to H2O2. alpha 2M-methylamine was affected significantly less by the H2O2 exposure after pretreatment with cis-DDP. Amino acid analysis indicated that H2O2 treatment of alpha 2M modified 19 of the 25 methionine residues per alpha 2M subunit. Pretreatment with cis-DDP protected two to four of these methionine residues. The only other residue altered by H2O2 treatment of alpha 2M was histidine. A net decrease of two histidine residues per subunit was observed, but cis-DDP pretreatment did not alter this result. In order to rule out the slight possibility that histidine modification might account for the observed H2O2-induced loss in receptor recognition, diethyl pyrocarbonate was employed as a histidine-modifying reagent. This treatment modified 53 histidine residues in both native and fast-form alpha 2M. Fast-form alpha 2M was still recognized by the alpha 2M receptor, as determined by studies both in vivo and in vitro; however, a fraction of the modified protein now cleared via the acyl-low-density-lipoprotein receptor as well. Reaction of diethyl pyrocarbonate-treated alpha 2M with hydroxylamine reversed derivatization of 43 of the 53 histidine residues. Moreover, this treatment also resulted in an alpha 2M fast-form preparation that was recognized only by the alpha 2M receptor. It is concluded that cis-DDP and H2O2 modify a critical methionine residue in the primary sequence of the alpha 2M-receptor recognition site.


Tobacco smoking and solid fuels for cooking and risk of liver cancer: A prospective cohort study of 0.5 million Chinese adults.
Previous research found tobacco smoking and solid fuel use for cooking to increase the risk of chronic liver disease mortality, but previous cohort studies have not investigated their independent and joint associations with liver cancer incidence in contemporary China. The China Kadoorie Biobank (CKB) study recruited 0.5 million adults aged 30 to 79 years from 10 areas across China during 2004 to 2008. Participants reported detailed smoking and fuel use information at baseline. After an 11.1-year median follow-up via electronic record linkage, we recorded 2997 liver cancer cases. Overall, 29.4% participants were current smokers. Among those who cooked at least once per month, 48.8% always used solid fuels (ie, coal or wood) for cooking. Tobacco smoking and solid fuel use for cooking were independently associated with increased risks of liver cancer, with hazard ratios (95% confidence intervals [CIs]) of 1.28 (1.15-1.42) and 1.25 (1.03-1.52), respectively. The more cigarettes consumed each day, the earlier the age of starting smoking or the longer duration of solid fuels exposure, the higher the risk (Ptrend < .001, =.001, =.018, respectively). Compared with never smokers who had always used clean fuels (ie, gas or electricity), ever-smokers who had always used solid fuels for cooking had a 67% (95% CIs: 1.29-2.17) higher risk. Among Chinese adults, tobacco smoking and solid fuel use for cooking were independently associated with higher risk of liver cancer incidence. Stronger association was observed with higher number of daily cigarette consumption, the earlier age of starting smoking and longer duration of solid fuel use.


CD44 is prognostic for overall survival in the NCI randomized trial on breast conservation with 25 year follow-up.
CD44 is a transmembrane glycoprotein involved in numerous cellular functions, including cell adhesion and extracellular matrix interactions. It is known to be functionally diverse, with alternative splice variants increasingly implicated as a marker for tumor-initiating stem cells associated with poor prognosis. Here, we evaluate CD44 as a potential marker of long-term breast cancer outcomes. Tissue specimens from patients treated on the National Cancer Institute 79-C-0111 randomized trial of breast conservation versus mastectomy between 1979 and 1987 were collected, and immunohistochemistry was performed using the standard isoform of CD44. Specimens were correlated with patient characteristics and outcomes. Survival analysis was performed using the log rank test. Fifty-one patients had evaluable tumor sections and available long-term clinical follow up data at a median follow up of 25.7 years. Significant predictors of OS were tumor size (median OFS 25.4 years for ≤2 cm vs. 7.5 years for >2 cm, p = 0.001), nodal status (median OS 17.2 years for node-negative patients vs. 6.7 years for node positive patients, p = 0.017), and CD44 expression (median OS 18.9 years for CD44 positive patients vs. 8.6 years for CD44 negative patients, p = 0.049). There was a trend toward increased PFS for patients with CD44 positive tumors (median PFS 17.9 vs. 4.3 years, p = 0.17), but this did not reach statistical significance. These findings illustrate the potential utility of CD44 as a prognostic marker for early stage breast cancer. Subgroup analysis in patients with lymph node involvement revealed CD44 positivity to be most strongly associated with increased survival, suggesting a potential role of CD44 in decision making for axillary management. As there is increasing interest in CD44 as a therapeutic target in ongoing clinical trials, the results of this study suggest additional investigation regarding the role CD44 in breast cancer is warranted.


Economies of scale in federally-funded state-organized public health programs: results from the National Breast and Cervical Cancer Early Detection Programs.
This study investigates the existence of economies of scale in the provision of breast and cervical cancer screening and diagnostic services by state National Breast and Cervical Cancer Early Detection Program (NBCCEDP) grantees. A translog cost function is estimated as a system with input factor share equations. The estimated cost function is then used to determine output levels for which average costs are decreasing (i.e., economies of scale exist). Data were collected from all state NBCCEDP programs and District of Columbia for program years 2006-2007, 2008-2009 and 2009-2010 (N = 147). Costs included all programmatic and in-kind contributions from federal and non-federal sources, allocated to breast and cervical cancer screening activities. Output was measured by women served, women screened and cancers detected, separately by breast and cervical services for each measure. Inputs included labor, rent and utilities, clinical services, and quasi-fixed factors (e.g., percent of women eligible for screening by the NBCCEDP). 144 out of 147 program-years demonstrated significant economies of scale for women served and women screened; 136 out of 145 program-years displayed significant economies of scale for cancers detected. The cost data were self-reported by the NBCCEDP State programs. Quasi-fixed inputs were allowed to affect costs but not economies of scale or the share equations. The main analysis accounted for clustering of observations within State programs, but it did not make full use of the panel data. The average cost of providing breast and cervical cancer screening services decreases as the number of women screened and served increases.


Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation.
Here, we investigated the anticancer effect of Rhus coriaria on three breast cancer cell lines. We demonstrated that Rhus coriaria ethanolic extract (RCE) inhibits the proliferation of these cell lines in a time- and concentration-dependent manner. RCE induced senescence and cell cycle arrest at G1 phase. These changes were concomitant with upregulation of p21, downregulation of cyclin D1, p27, PCNA, c-myc, phospho-RB and expression of senescence-associated β-galactosidase activity. No proliferative recovery was detected after RCE removal. Annexin V staining and PARP cleavage analysis revealed a minimal induction of apoptosis in MDA-MB-231 cells. Electron microscopy revealed the presence of autophagic vacuoles in RCE-treated cells. Interestingly, blocking autophagy by 3-methyladenine (3-MA) or chloroquine (CQ) reduced RCE-induced cell death and senescence. RCE was also found to activate p38 and ERK1/2 signaling pathways which coincided with induction of autophagy. Furthermore, we found that while both autophagy inhibitors abolished p38 phosphorylation, only CQ led to significant decrease in pERK1/2. Finally, RCE induced DNA damage and reduced mutant p53, two events that preceded autophagy. Our findings provide strong evidence that R. coriaria possesses strong anti-breast cancer activity through induction of senescence and autophagic cell death, making it a promising alternative or adjunct therapeutic candidate against breast cancer.


[Clinical review of 105 cases of adrenal tumor, with special reference to incidental tumor].
We reviewed 105 patients with adrenal tumor diagnosed at our institute from January 1984 to December 1993. In 74 patients tumors were symptomatically diagnosed (the symptomatic group), while in the remaining 31 patients tumors were incidentally detected (the incidental group). In 5 cases of the incidental group, tumors were found at a routine health examination, whereas in the remaining 26 cases tumors were found during the examination or treatment for unrelated diseases. On both the incidental group and symptomatic group, higher right-to-left side ratio was noted in the laterality of tumors detected by ultrasound scanning. The size of tumors in the incidental group was significantly larger than that in the symptomatic group, but there was no significant difference in size between the tumors detected by ultrasound and those detected by CT scan in either the symptomatic group or in the incidental group. In the symptomatic group 71 patients (95.9%) were found to have functioning tumor, where the most common diagnosis was primary aldosteronism (44 cases), and 68 of the 71 patients received adrenalectomy. While in the incidental group 12 patients (38.7%) were found to have functioning tumor, where the most common diagnosis was pheochromocytoma (7 cases), followed by Cushing's syndrome (3 cases) including one case with so-called pre-Cushing's syndrome, and all of the 12 patients received adrenalectomy. Of 16 primary incidental adrenal tumors which did not have any hormonal functions, 5 tumors larger than 30 mm in diameter were resected and the remaining 11 tumors were followed up without operation. Since the incidence of incidental adrenal tumor may increase in the future, careful diagnosis and decision of indication for surgery are required.


Multimodality treatment of pancreatic cancer with liver metastases using chemotherapy, radiation therapy, and/or Chinese herbal medicine.
To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM). From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed. Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors. Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.


The contribution of spatial analysis to understanding HIV/TB mortality in children: a structural equation modelling approach.
South Africa accounts for more than a sixth of the global population of people infected with HIV and TB, ranking her highest in HIV/TB co-infection worldwide. Remote areas often bear the greatest burden of morbidity and mortality, yet there are spatial differences within rural settings. The primary aim was to investigate HIV/TB mortality determinants and their spatial distribution in the rural Agincourt sub-district for children aged 1-5 years in 2004. Our secondary aim was to model how the associated factors were interrelated as either underlying or proximate factors of child mortality using pathway analysis based on a Mosley-Chen conceptual framework. We conducted a secondary data analysis based on cross-sectional data collected in 2004 from the Agincourt sub-district in rural northeast South Africa. Child HIV/TB death was the outcome measure derived from physician assessed verbal autopsy. Modelling used multiple logit regression models with and without spatial household random effects. Structural equation models were used in modelling the complex relationships between multiple exposures and the outcome (child HIV/TB mortality) as relayed on a conceptual framework. Fifty-four of 6,692 children aged 1-5 years died of HIV/TB, from a total of 5,084 households. Maternal death had the greatest effect on child HIV/TB mortality (adjusted odds ratio=4.00; 95% confidence interval=1.01-15.80). A protective effect was found in households with better socio-economic status and when the child was older. Spatial models disclosed that the areas which experienced the greatest child HIV/TB mortality were those without any health facility. Low socio-economic status and maternal deaths impacted indirectly and directly on child mortality, respectively. These factors are major concerns locally and should be used in formulating interventions to reduce child mortality. Spatial prediction maps can guide policy makers to target interventions where they are most needed.


Perfusion MR imaging detection of carcinoma arising from preexisting salivary gland pleomorphic adenoma by computer-assisted analysis of time-signal intensity maps.
Tumor perfusion can be evaluated by analyzing the time-signal intensity curve (TIC) after dynamic contrast-enhanced (DCE) MR imaging. Accordingly, TIC profiles are characteristic of some benign and malignant salivary gland tumors. A carcinoma ex pleomorphic adenoma (CXPA) arises from a long-standing pleomorphic adenoma (PA) and has a distinctive prognostic risk depending on the tumor growth potential such as invasion beyond the preexisting capsule. Differentiating CXPA from PA can be very challenging. In this study, we have attempted to discriminate CXPA from PA based on a two-dimensional TIC mapping algorithm. TIC mapping analysis was performed on 8 patients with CXPA and 20 patients with PA after dynamic contrast-enhanced (DCE) MR imaging using a 1.5-T MR system. The TIC profiles obtained were automatically categorized into 5 types based on the enhancement ratio, maximum time, and washout ratio (Type 1 TIC with flat profile, Type 2 TIC with slow uptake, Type 3 TIC with rapid uptake and a low washout ratio, Type 4 TIC with rapid uptake and a high washout ratio, and Type 5 TIC not otherwise specific). The percentage tumor areas with each of the 5 TIC types were compared between CXPAs and PAs. Stepwise differentiation and cluster analysis using multiple TIC cut-off thresholds distinguished CXPAs from PAs with 75% sensitivity, 95% specificity, 86% accuracy, and 86% positive and 90% negative predictive values, when tumors with ≤1.1% Type 1 and ≥15% Type 4, or those with ≤1.1% Type 1, ≥78.1% Type 2, ≥16.1% Type 3, and <15% Type 4, or those with >1.1% Type 1, ≥78.1% Type 2, and ≥16.1% Type 3 areas were diagnosed as CXPAs. The overall TIC profiles predicted some aggressive CXPA growth patterns. These results suggest that stepwise differentiation based on TIC mapping is helpful in differentiating CXPAs from PAs.


Prevalence of occult hepatitis B virus infection in adults: a systematic review and meta-analysis.
Despite growing concerns about transmissibility and clinical impact, occult hepatitis B virus (HBV) infection has received little attention in the hepatitis elimination agenda. We aimed to estimate the prevalence of occult HBV infection at a global and regional scale and in specific populations. For this systematic review and meta-analysis, we searched the MEDLINE, Embase, Global Health, and Web of Science databases for articles published in any language between Jan 1, 2010, and Aug 14, 2019. We included original articles and conference abstracts of any study design that reported the proportion of HBsAg-negative adults (aged ≥18 years) who are positive for HBV DNA (ie, people with occult HBV infection). The prevalence of occult HBV infection was pooled, using the DerSimonian-Laird random-effects model, in the general population and specific groups defined by the type of study participants (blood donors; other low-risk populations; high-risk populations; and people with advanced chronic liver disease), and stratified by HBV endemicity in each country. We also assessed the performance of anti-HBc as an alternative biomarker to detect occult HBV infection. The study was registered with PROSPERO, CRD42019115490. 305 of 3962 articles were eligible, allowing a meta-analysis of 140 521 993 individuals tested for HBV DNA. Overall, only two studies evaluated occult HBV infection in the general population, precluding unbiased global and regional estimates of occult HBV infection prevalence. In blood donors, occult HBV infection prevalence mirrored HBV endemicity: 0·06% (95% CI 0·00-0·26) in low-endemicity countries, 0·12% (0·04-0·23) in intermediate-endemicity countries, and 0·98% (0·44-1·72), in high-endemicity countries (p=0·0012). In high-risk groups, occult HBV infection prevalence was substantial, irrespective of endemicity: 5·5% (95% CI 2·9-8·7) in low-endemicity countries, 5·2% (2·5-8·6) in intermediate-endemicity countries, and 12·0% (3·4-24·7) in high-endemicity countries. The pooled sensitivity of anti-HBc to identify occult HBV infection was 77% (95% CI 62-88) and its specificity was 76% (68-83). A substantial proportion of people carry occult HBV infection, especially among high-risk groups across the globe and people living in highly endemic countries. Occult HBV infection should be part of the global viral hepatitis elimination strategy. None.


Plasmodium infection and its risk factors in eastern Uganda.
Malaria is a leading cause of disease burden in Uganda, although surprisingly few contemporary, age-stratified data exist on malaria epidemiology in the country. This report presents results from a total population survey of malaria infection and intervention coverage in a rural area of eastern Uganda, with a specific focus on how risk factors differ between demographic groups in this population. In 2008, a cross-sectional survey was conducted in four contiguous villages in Mulanda, sub-county in Tororo district, eastern Uganda, to investigate the epidemiology and risk factors of Plasmodium species infection. All permanent residents were invited to participate, with blood smears collected from 1,844 individuals aged between six months and 88 years (representing 78% of the population). Demographic, household and socio-economic characteristics were combined with environmental data using a Geographical Information System. Hierarchical models were used to explore patterns of malaria infection and identify individual, household and environmental risk factors. Overall, 709 individuals were infected with Plasmodium, with prevalence highest among 5-9 year olds (63.5%). Thin films from a random sample of 20% of parasite positive participants showed that 94.0% of infections were Plasmodium falciparum and 6.0% were P. malariae; no other species or mixed infections were seen. In total, 68% of households owned at least one mosquito although only 27% of school-aged children reported sleeping under a net the previous night. In multivariate analysis, infection risk was highest amongst children aged 5-9 years and remained high in older children. Risk of infection was lower for those that reported sleeping under a bed net the previous night and living more than 750 m from a rice-growing area. After accounting for clustering within compounds, there was no evidence for an association between infection prevalence and socio-economic status, and no evidence for spatial clustering. These findings demonstrate that mosquito net usage remains inadequate and is strongly associated with risk of malaria among school-aged children. Infection risk amongst adults is influenced by proximity to potential mosquito breeding grounds. Taken together, these findings emphasize the importance of increasing net coverage, especially among school-aged children.


Uniform asymptotic approximation of diffusion to a small target: Generalized reaction models.
The diffusion of a reactant to a binding target plays a key role in many biological processes. The reaction radius at which the reactant and target may interact is often a small parameter relative to the diameter of the domain in which the reactant diffuses. We develop uniform in time asymptotic expansions in the reaction radius of the full solution to the corresponding diffusion equations for two separate reactant-target interaction mechanisms: the Doi or volume reactivity model and the Smoluchowski-Collins-Kimball partial-absorption surface reactivity model. In the former, the reactant and target react with a fixed probability per unit time when within a specified separation. In the latter, upon reaching a fixed separation, they probabilistically react or the reactant reflects away from the target. Expansions of the solution to each model are constructed by projecting out the contribution of the first eigenvalue and eigenfunction to the solution of the diffusion equation and then developing matched asymptotic expansions in Laplace-transform space. Our approach offers an equivalent, but alternative, method to the pseudopotential approach we previously employed [Isaacson and Newby, Phys. Rev. E 88, 012820 (2013)PLEEE81539-375510.1103/PhysRevE.88.012820] for the simpler Smoluchowski pure-absorption reaction mechanism. We find that the resulting asymptotic expansions of the diffusion equation solutions are identical with the exception of one parameter: the diffusion-limited reaction rates of the Doi and partial-absorption models. This demonstrates that for biological systems in which the reaction radius is a small parameter, properly calibrated Doi and partial-absorption models may be functionally equivalent.


Multistability property in cardiac ionic models of mammalian and human ventricular cells.
The underlying mechanisms of irregular cardiac rhythms are still poorly understood. Many experimental and modeling studies are aimed at identifying factors which cause cardiac arrhythmias. However, a lack of understanding of heart rhythm dynamical properties makes it difficult to uncover precise mechanisms of electrical instabilities, and hence to predict the onset of heart rhythm disorders. We review and compare the existing methods of studying cardiac dynamics, including restitution protocol (S1-S2), dynamic restitution protocol and multistability test protocol (S1-CI-S2). We focus on cardiac cell dynamics to elucidate regularities of heart rhythm. We demonstrate the advantages of our newly proposed systematic approach of analysis of cardiac cell dynamics using mammalian Luo Rudy 1991 and human ventricular Ten Tusscher 2006 single cell models under healthy and diseased conditions such as altered K(+) or Ca(2+) related currents. We investigate the role of ionic properties and the shape of an action potential on the nonlinear dynamics of electrical processes in periodically stimulated cardiac cells. We show the existence of multistability property for human ventricular cells. Moreover, the multistability is proposed to be an intrinsic property of cardiac cells, and is also suggested to be one of the mechanisms which could underlie the sudden triggering of life-threatening ventricular arrhythmias in the human heart.


Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice.
A recombinant protein corresponding to the Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) and synthetic 15-mer peptides of the whole MOG molecule with eight amino acid overlaps were screened for their ability to induce experimental allergic encephalomyelitis (EAE) in Biozzi AB/H (H-2dq1) and SJL (H-2S) mice. Clinical and histologic evidence of EAE developed after sensitization with the recombinant MOG protein in both AB/H and SJL mice. In AB/H mice at least three MOG epitopes within residues 1-22, 43-57, and 134-148 induced clinical and histologic EAE, whereas only the sequence 92-106 was encephalitogenic in SJL mice. Histologically, the inflammatory response in the central nervous system consisted of perivascular accumulations of CD5+ T cells and F4/80+ macrophage/microglia cells equally distributed in the brain and spinal cord. The subpial/meningeal infiltration, characteristic of mouse EAE induced with spinal cord homogenate, was only observed in cases of severe clinical disease in SJL mice in which the cellular infiltrates predominated in the spinal cord. In spite of the presence of histologic lesions in AB/H mice immunized with MOG, clinical disease either rapidly resolved or was clinically silent. In contrast to immunization of SJL mice with recombinant MOG, sensitization to MOG 92-106 induced severe clinical paralysis. After recovery these animals relapsed and exhibited demyelinated lesions. This study is the first to describe encephalitogenic epitopes of MOG that induce both clinical and histologic signs of EAE in mice. These and previous findings implicating MOG as a target Ag for Ab-mediated attack in EAE suggest that such autoreactivity to MOG may be significant in the development of human demyelinating diseases such as multiple sclerosis.


Effects of single administration of diethylstilbestrol on murine langerhans cells.
Diethylstilbestrol (DES) is a synthetic compound with potent estrogenic actions useful in the treatment of prostate carcinoma despite the fact that it can also induce some forms of neoplasia. Both effects are thought to be related to its estrogenic actions and very little attention has been focused on the possible effect of DES on the immune response. Skin is the largest organ of the body and constitutes the first line of defense against xenobiotics. The Skin Immune System (SIS) has become the center of attention of research for the development of new therapeutic approaches for neoplasic diseases. Langerhans cells (LC), as an element of SIS, are "professional" antigen presenting cells resident in the skin that participate in the immune response associated with tolerance and acquired immunity to antigens. Hence in this work we studied the effect of DES on LC of murine skin as a model to analyze the possible effect of DES on the immune response. Male CD-1 mice (20 to 35 g body weight) were treated topically (TO) or subcutaneously (SC) with DES (10 and 100 mg/kg, dissolved in ethanol) and sacrificed at 12, 84 and 228 hr. LC were quantified in the ear skin of mice using both an enzymatic histochemical technique to demonstrate ATP-ase activity; and an indirect immunohistochemical assay for detecting class II molecules of the major histocompatibility complex (MHC-II). DES induced a significant time- and dose- dependent reduction in the number of LC (P < 0.05). Data presented here suggest that estrogens may exert a modulatory action on LC.


Connective tissue and its growth factor CTGF distinguish the morphometric and molecular remodeling of the bladder in a model of neurogenic bladder.
We previously reported that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), develop profound urinary bladder dysfunction. Because neurogenic bladder in MS patients causes marked bladder remodeling, we next examined morphometric and molecular alterations of the bladder in EAE mice. EAE was created in female SJL/J mice by immunization with the p139-151 encephalitogenic peptide of myelin proteolipid protein in complete Freund's adjuvant, along with intraperitoneal injections of Bordetella pertussis toxin. Seventy days after immunization, mice were scored for the level of neurological impairment and then killed. Spinal cord sections were assessed for demyelination, inflammation, and T cell infiltration; the composition of the bladder tissue was measured quantitatively; and gene expression of markers of tissue remodeling and fibrosis was assessed. A significant increase in the bladder weight-to-body weight ratio was observed with increasing neurological impairment, and morphometric analysis showed marked bladder remodeling with increased luminal area and tissue hypertrophy. Despite increased amounts of all tissue components (urothelium, smooth muscle, and connective tissue), the ratio of connective tissue to muscle increased significantly in EAE mice compared with control mice. Marked increases in mRNA expression of collagen type I α(2), tropoelastin, transforming growth factor-β3, and connective tissue growth factor (CTGF) were observed in EAE mice, as were decreased levels of mRNAs for smooth muscle myosin heavy chain, nerve growth factors, and muscarinic and purinergic receptors. Our results suggest that bladder remodeling corresponding to EAE severity may be due to enhanced expression of CTGF and increased growth of connective tissue.


Cardamonin attenuates hyperalgesia and allodynia in a mouse model of chronic constriction injury-induced neuropathic pain: Possible involvement of the opioid system.
Neuropathic pain arises from the injury of nervous system. The condition is extremely difficult to be treated due to the ineffectiveness and presence of various adverse effects of the currently available drugs. In the present study, we investigated the antiallodynic and antihyperlagesic properties of cardamonin, a naturally occurring chalcone in chronic constriction injury (CCI)-induced neuropathic pain mice model. Our findings showed that single and repeated dose of intra-peritoneal administration of cardamonin (3, 10, 30mg/kg) significantly inhibited (P<0.001) the chronic constriction injury-induced neuropathic pain using the Hargreaves plantar test, Randall-Selitto analgesiometer test, dynamic plantar anesthesiometer test and the cold plate test in comparison with the positive control drug used (amitriptyline hydrochloride, 20mg/kg, i.p.). Pre-treatment with naloxone hydrochloride (1mg/kg, i.p.) and naloxone methiodide (1mg/kg, s.c) significantly reversed the antiallodynic and antihyperalgesic effects of cardamonin in dynamic plantar anesthesiometer test and Hargreaves plantar test, respectively. In conclusion, the current findings demonstrated novel antiallodynic and antihyperalgesic effects of cardamonin through the activation of the opioidergic system both peripherally and centrally and may prove to be a potent lead compound for the development of neuropathic pain drugs in the future.


Differences in the Reporting of Racial and Socioeconomic Disparities among Three Large National Databases for Breast Reconstruction.
Research derived from large-volume databases plays an increasing role in the development of clinical guidelines and health policy. In breast cancer research, the Surveillance, Epidemiology and End Results, National Surgical Quality Improvement Program, and Nationwide Inpatient Sample databases are widely used. This study aims to compare the trends in immediate breast reconstruction and identify the drawbacks and benefits of each database. Patients with invasive breast cancer and ductal carcinoma in situ were identified from each database (2005-2012). Trends of immediate breast reconstruction over time were evaluated. Patient demographics and comorbidities were compared. Subgroup analysis of immediate breast reconstruction use per race was conducted. Within the three databases, 1.2 million patients were studied. Immediate breast reconstruction in invasive breast cancer patients increased significantly over time in all databases. A similar significant upward trend was seen in ductal carcinoma in situ patients. Significant differences in immediate breast reconstruction rates were seen among races; and the disparity differed among the three databases. Rates of comorbidities were similar among the three databases. There has been a significant increase in immediate breast reconstruction; however, the extent of the reporting of overall immediate breast reconstruction rates and of racial disparities differs significantly among databases. The Nationwide Inpatient Sample and the National Surgical Quality Improvement Program report similar findings, with the Surveillance, Epidemiology and End Results database reporting results significantly lower in several categories. These findings suggest that use of the Surveillance, Epidemiology and End Results database may not be universally generalizable to the entire U.S.


Development and validation of a web-based questionnaire to identify environmental risk factors for inflammatory bowel disease: the Groningen IBD Environmental Questionnaire (GIEQ).
In the complex etiology of inflammatory bowel disease (IBD), the exposome is a major contributor. Though many environmental exposures have been identified, quality of evidence varies greatly and overall evidence for the exposome is inconclusive. A universal, precise, and reproducible measurement tool is needed to study the exposome in IBD. We built the web-based Groningen IBD Environmental Questionnaire (GIEQ), an extensive and structured questionnaire measuring potentially involved environmental exposures, consisting of 848 items, subdivided into 15 categories. For validation, 76 IBD patients completed the GIEQ twice (2-month interval). Cohen's kappa and correlation coefficients were used to compare both fills. Internal consistency was evaluated using Cronbach's alpha tests. Proportional bias was examined using Bland-Altman plots. In general, we obtained a mean kappa coefficient of 0.78 (standard deviation 0.17) for categorical questions and a mean intraclass correlation coefficient of 0.88 (0.15) for numeric questions. Cronbach's alpha ranged from 0.64 to 1.0 with a mean of 0.79 (0.14). Bland-Altman plots showed proportional bias only for current physical activity score. The GIEQ is a reliable measurement tool to study the exposome in IBD, enabling consistent measurement of an extended number of environmental factors and their interactions. Use of the GIEQ across IBD cohorts will lead to more standardized, generalizable, and comparable results. Also, the GIEQ can be used for calculation of an exposome risk score, applicable for secondary prevention by identifying high-risk patients as well as to analyze interactions between the exposome and other aspects of IBD etiology.


Simple improvements to classical bubble nucleation models.
We revisit classical nucleation theory (CNT) for the homogeneous bubble nucleation rate and improve the classical formula using a correct prefactor in the nucleation rate. Most of the previous theoretical studies have used the constant prefactor determined by the bubble growth due to the evaporation process from the bubble surface. However, the growth of bubbles is also regulated by the thermal conduction, the viscosity, and the inertia of liquid motion. These effects can decrease the prefactor significantly, especially when the liquid pressure is much smaller than the equilibrium one. The deviation in the nucleation rate between the improved formula and the CNT can be as large as several orders of magnitude. Our improved, accurate prefactor and recent advances in molecular dynamics simulations and laboratory experiments for argon bubble nucleation enable us to precisely constrain the free energy barrier for bubble nucleation. Assuming the correction to the CNT free energy is of the functional form suggested by Tolman, the precise evaluations of the free energy barriers suggest the Tolman length is ≃0.3σ independently of the temperature for argon bubble nucleation, where σ is the unit length of the Lennard-Jones potential. With this Tolman correction and our prefactor one gets accurate bubble nucleation rate predictions in the parameter range probed by current experiments and molecular dynamics simulations.


First Report of Anthracnose Caused by Colletotrichum gloeosporioides on Schefflera actinophylla in China.
In China, in mild to warm climates, Schefflera actinophylla is commonly grown as a decorative tree in gardens. When mature, it has bright red flowers in inflorescences with up to 20 racemes that develop in summer or early autumn. From 2008 to 2011, lesions were observed on young and mature leaves in several locations in Guangzhou, China. The first symptoms were circular, necrotic areas that usually developed into irregular, dry, brown to reddish brown or black spots. Spots often first appeared at or near the margins of leaves. Reproductive bodies of the pathogen appeared as black specks in leaf spots. Under a 10× magnification, black, needle-like fungal structures (setae) were observed in the centers of spots on the upper leaf surface. A fungus was isolated from the lesion and was identified as Colletotrichum gloeosporioides (Penz.) Penz. & Sacc. based on cultural characteristics and conidial morphology (1). The voucher isolates were deposited in the Institute of Plant Pathology, Zhongkai University of Agriculture and Engineering. C. gloeosporioides is a species complex (2) and there is a degree of unresolved aspects of taxonomy in this species complex. Cultures on potato dextrose agar (PDA) had aerial white mycelium that turned gray to grayish black after 10 days at 25°C and a 12-h photoperiod and produced salmon to orange conidial masses. Brown, 80 to 120 μm long setae were observed in the acervulus. Conidia 14.1 to 18.0 × 4.0 to 6.1 μm in size were hyaline, thin-walled, aseptate, granular inside, clavate to slightly navicular in shape with an obtuse apex and a truncate base. To identify the fungus, a 588-bp segment of the ITS1-5.8S-ITS2 rDNA region was amplified by PCR and sequenced. The DNA sequence was submitted to GenBank as KC207404. A BLAST search of the DNA sequence showed 99% identity with accessions AY266389.1, EF423519.1, and HM575258.1 of C. gloeosporioides. Pathogenicity tests were conducted under greenhouse conditions at 25 ± 2°C. A total of 15 leaves from three 1-year-old S. actinophylla plants were inoculated with mycelial PDA plugs that were placed on 0.5-cm2 leaf wounds and then wrapped with Parafilm. Control leaves were treated similarly except that they were inoculated with PDA plugs without the fungus. No symptoms developed on control leaves after 10 days. Foliar lesions on inoculated leaves closely resembled those observed in the field. C. gloeosporioides was reisolated consistently from inoculated leaves. Pathogenicity was also tested by spraying leaves of potted S. actinophylla plants about 30 cm in height with 10 ml of a conidial suspension (1 × 105 conidia/ml) prepared from 7-day-old PDA cultures grown at 25°C. Leaves sprayed with distilled water were used as controls. Three plants were inoculated in each of two experiments and were incubated at 25°C and 90% relative humidity in a growth chamber. Tiny brown spots started to develop on all inoculated leaves 5 days after inoculation and the progression of symptom development was similar to that observed in the field. Control leaves remained asymptomatic. C. gloeosporioides was reisolated from inoculated leaves. To my knowledge, this is the first report of C. gloeosporioides causing anthracnose on S. actinophylla in China. References: (1) B. C. Sutton. The genus Glomerella and its anamorph Colletotrichum. In: Colletotrichum Biology, Pathology and Control. CAB International, Wallingford, UK, 1992. (2) B. S. Weir et al. The Colletotrichum gloeosporioides species complex. Stud. Mycol. 73:115, 2012.


Closed-loop control of deep brain stimulation: a simulation study.
Deep brain stimulation (DBS) is an effective therapy to treat movement disorders including essential tremor, dystonia, and Parkinson's disease. Despite over a decade of clinical experience the mechanisms of DBS are still unclear, and this lack of understanding makes the selection of stimulation parameters quite challenging. The objective of this work was to develop a closed-loop control system that automatically adjusted the stimulation amplitude to reduce oscillatory neuronal activity, based on feedback of electrical signals recorded from the brain using the same electrode as implanted for stimulation. We simulated a population of 100 intrinsically active model neurons in the Vim thalamus, and the local field potentials (LFPs) generated by the population were used as the feedback (control) variable for closed loop control of DBS amplitude. Based on the correlation between the spectral content of the thalamic activity and tremor (Hua , 1998), (Lenz , 1988), we implemented an adaptive minimum variance controller to regulate the power spectrum of the simulated LFPs and restore the LFP power spectrum present under tremor conditions to a reference profile derived under tremor free conditions. The controller was based on a recursively identified autoregressive model (ARX) of the relationship between stimulation input and LFP output, and showed excellent performances in tracking the reference spectral features through selective changes in the theta (2-7 Hz), alpha (7-13 Hz), and beta (13-35 Hz) frequency ranges. Such changes reflected modifications in the firing patterns of the model neuronal population, and, differently from open-loop DBS, replaced the tremor-related pathological patterns with patterns similar to those simulated in tremor-free conditions. The closed-loop controller generated a LFP spectrum that approximated more closely the spectrum present in the tremor-free condition than did open loop fixed intensity stimulation and adapted to match the spectrum after a change in the neuronal oscillation frequency. This computational study suggests the feasibility of closed-loop control of DBS amplitude to regulate the spectrum of the local field potentials and thereby normalize the aberrant pattern of neuronal activity present in tremor.


Monitoring tissue engineering using magnetic resonance imaging.
Assessment of tissue regeneration is essential to optimize the stages of tissue engineering (cell proliferation, tissue development and implantation). Optical and X-ray imaging have been used in tissue engineering to provide useful information, but each has limitations: for example, poor depth penetration and radiation damage. Magnetic resonance imaging (MRI) largely overcomes these restrictions, exhibits high resolution (approximately 100 microm) and can be applied both in vitro and in vivo. Recently, MRI has been used in tissue engineering to generate spatial maps of tissue relaxation times (T(1), T(2)), water diffusion coefficients, and the stiffness (shear moduli) of developing engineered tissues. In addition, through the use of paramagnetic and superparamagnetic contrast agents, MRI can quantify cell death, assess inflammation, and visualize cell trafficking and gene expression. After tissue implantation MRI can be used to observe the integration of a tissue implant with the surrounding tissues, and to check for early signs of immune rejection. In this review, we describe and evaluate the growing role of MRI in the assessment of tissue engineered constructs. First, we briefly describe the underlying principles of MRI and the expected changes in relaxation times (T(1), T(2)) and the water diffusion coefficient that are the basis for MR contrast in developing tissues. Next, we describe how MRI can be applied to evaluate the tissue engineering of mesenchymal tissues (bone, cartilage, and fat). Finally, we outline how MRI can be used to monitor tissue structure, composition, and function to improve the entire tissue engineering process.


United States private-sector physicians and pharmaceutical contract research: a qualitative study.
There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities. We conducted a qualitative study in 2003-2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers. Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies. Please see later in the article for the Editors' Summary.


Endocytosis: relation to capping and cell locomotion.
Most mammalian cells, such as fibroblasts, continuously internalize part of their surface membrane by endocytosis, and then later return it to the cell surface. This cyclical process is initiated by coated pits in the plasma membrane. These pits collect specific receptors plus lipid for internalization, but exclude other proteins. On a motile cell, the sites of endocytosis (randomly located on the cell) and those of membrane return (located at the front of the cell) are not coincident. This causes a bulk flow of lipid plus receptors in the plasma membrane, away from the front of the cell. Large objects on the cell surface are swept to the rear of the cell by this flow, a process called capping. Cells may use this polarized endocytic cycle to move.


BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells.
Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails. An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain (BET) proteins, I-BET151, is known to counteract the induction of expression of inflammatory genes in macrophages. We have investigated the effects of I-BET151 on dendritic cell function, including expression of co-stimulatory molecules and cytokines, and capacity for T cell activation. Treatment of mouse bone marrow derived dendritic cells (BMDC) and human monocyte derived DCs (mdDC) with I-BET151 reduced LPS-induced expression of co-stimulatory molecules, as well as the production of multiple cyokines and chemokines. Most strikingly, secretion of IL-6, IL-12 and IL-10 was significantly reduced to 89.7%, 99.9% and 98.6% respectively of that produced by control cells. I-BET151-treated mdDC showed a reduced ability to stimulate proliferation of autologous Revaxis-specific T cells. Moreover, while I-BET151 treatment of BMDC did not affect their ability to polarise ovalbumin specific CD4+ CD62L+ naive T cells towards Th1, Th2, or Th17 phenotypes, an increase in Foxp3 expressing Tregs secreting higher IL-10 levels was observed. Suppression assays demonstrated that Tregs generated in response to I-BET151-treated BMDC displayed anti-proliferative capacity. Finally, evidence that I-BET151 treatment can ameliorate inflammation in vivo in a T cell dependent colitis model is shown. Overall, these results demonstrate marked effects of BET inhibition on DC maturation, reducing their capacity for pro-inflammatory cytokine secretion and T cell activation and enhancing the potential of DC to induce Foxp3 expressing Treg with suppressive properties.


Discrete linear canonical transform computation by adaptive method.
The linear canonical transform (LCT) describes the effect of quadratic phase systems on a wavefield and generalizes many optical transforms. In this paper, the computation method for the discrete LCT using the adaptive least-mean-square (LMS) algorithm is presented. The computation approaches of the block-based discrete LCT and the stream-based discrete LCT using the LMS algorithm are derived, and the implementation structures of these approaches by the adaptive filter system are considered. The proposed computation approaches have the inherent parallel structures which make them suitable for efficient VLSI implementations, and are robust to the propagation of possible errors in the computation process.


The computer-based anesthetic monitors: the Duke Automatic Monitoring Equipment (DAME) system and the microDAME.
From 1972 to 1983 the Duke University Department of Anesthesiology designed, built, and maintained most of its own operating room patient monitoring equipment. Construction of a new hospital facility in 1980 provided the opportunity to design and test a new computer-based system, the Duke Automatic Monitoring Equipment (DAME) System. The system consist of microcomputer-based instrumentation on monitoring carts, which communicate with a central minicomputer that allows selection of different software monitoring packages based on the needs of the patient. Multiple problems, including frequent total monitoring failures during surgery, plagued the DAME System in its first year of operation. Despite resolution of many of these problems, user acceptance was poor because of the large size and weight of the monitoring carts, the inadequate quality of displayed physiological waveforms, and inability to overcome the difficulties of the man-machine interface. Because the remaining problems could not be rectified with the existing monitoring carts, a new generation of monitors was designed. The smaller, multiprocessor microDAME was designed to be as automatic and user tolerant as possible. It would omit much of the flexibility that had proved undesirable in the DAME system. When the microDAME was nearly completed, however, departmental research in that area ceased. It remains for others to apply our experiences to further improve operating room patient monitors.


A novel hypothesis based on clinical, radiological, and histological data to explain the dentinogenesis imperfecta type II phenotype.
Purpose/Aim: The aim of this study was to explore whether dentinogenesis imperfecta (DGI)-related aberrations are detectable in odontogenic tissues. Materials and Methods: Morphological and histological analyses were carried out on 3 teeth (two maxillary 1st molars, one maxillary central incisor) extracted from a patient with DGI Type II. A maxillary 2nd molar teeth extracted from a healthy patient was used as control. A micro-computed tomographic (μCT) data-acquisition system was used to scan and reconstruct samples. Pentachrome and picrosirius red histologic stains were used to analyze odontogenic tissues and their collagenous matrices. Results: Our findings corroborate DGI effects on molar and incisor root elongation, and the hypo-mineralized state of DGI dentin. In addition to these findings, we discovered changes to the DGI pulp cavity: Reactionary dentin formation, which we theorize is exacerbated by the early loss of enamel, nearly obliterated an acellular but still-vascularized DGI pulp cavity. We also discovered an accumulation of lamellated cellular cementum at the root apices, which we hypothesize compensates for the severe and rapid attrition of the DGI tooth. Conclusions: Based on imaging and histological data, we propose a novel hypothesis to explain the complex dental phenotypes observed in patients with DGI Type II.


Acrylamide mitigation strategies: critical appraisal of the FoodDrinkEurope toolbox.
FoodDrinkEurope Federation recently released the latest version of the Acrylamide Toolbox to support manufacturers in acrylamide reduction activities giving indication about the possible mitigation strategies. The Toolbox is intended for small and medium size enterprises with limited R&D resources, however no comments about the pro and cons of the different measures were provided to advise the potential users. Experts of the field are aware that not all the strategies proposed have equal value in terms of efficacy and cost/benefit ratio. This consideration prompted us to provide a qualitative science-based ranking of the mitigation strategies proposed in the acrylamide Toolbox, focusing on bakery and fried potato products. Five authors from different geographical areas having a publication record on acrylamide mitigation strategies worked independently ranking the efficacy of the acrylamide mitigation strategies taking into account three key parameters: (i) reduction rate; (ii) side effects; and (iii) applicability and economic impact. On the basis of their own experience and considering selected literature of the last ten years, the authors scored for each key parameter the acrylamide mitigation strategies proposed in the Toolbox. As expected, all strategies selected in the Toolbox turned out to be useful, however, not at the same level. The use of enzyme asparaginase and the selection of low sugar varieties were considered the best mitigation strategies in bakery and in potato products, respectively. According to authors' opinion most of the other mitigation strategies, although effective, either have relevant side effects on the sensory profile of the products, or they are not easy to implement in industrial production. The final outcome was a science based commented ranking which can enrich the acrylamide Toolbox supporting individual manufacturer in taking the best actions to reduce the acrylamide content in their specific production context.


MRI characteristics of the substantia nigra in Parkinson's disease: a combined quantitative T1 and DTI study.
The substantia nigra contains dopaminergic cells that project to the striatum and are affected by the neurodegenerative process that appears in Parkinson's disease (PD). For accurate differential diagnosis and for disease monitoring the availability of a sensitive and non-invasive biomarker for Parkinson's disease would be essential. Although there has been notable progress in studying correlates of nigral degeneration by means of magnetic resonance imaging (MRI) in the past decade, MRI and analysis techniques that allow accurate high-resolution mapping of the SN within a clinically acceptable acquisition time are still elusive. The main purpose of the preliminary study was to evaluate the potential role of the driven equilibrium single pulse observation of T1 (DESPOT1) method for delineation of the SN and differentiation of PD patients from healthy control subjects (n=10 in each group). We also investigated whether additional measures that can be obtained with diffusion tensor imaging (DTI) can further improve the MRI-guided discrimination between PD patients and controls. Our results show that the DESPOT1 method allows for a clear visualisation of the SN as a whole. Volumetric comparisons between ten PD patients and ten healthy subjects revealed significantly smaller volumes in patients for both the left and the right sides when the whole SN was considered. Combining SN volumetry and its connectivity with the thalamus improved the classification sensitivity to 100% and specificity to 80% for PD (discriminant function analysis with leave-one-out cross validation). Combining DESPOT1 imaging and DTI could therefore serve as a diagnostic marker for idiopathic Parkinson's disease in the future.


From 'stepchild of primary healthcare' to priority programme: lessons for the implementation of the National Integrated School Health Policy in South Africa.
In this article, I explore the South African 2003 National School Health Policy (NSHP) and the revised 2012 Integrated School Health Policy (ISHP). I examine whether the shortcomings in the development, content and implementation of the 2003 NSHP, and the context in which it was implemented, have been addressed adequately in the 2012 ISHP. The shortcomings include poorly structured relationships among key policy actors; an absent policy translation process resulting in insufficient understanding and prioritisation of school health by district and facility managers; and poor support and training of nurses. Insufficient capacity and resources, compounded by inadequate referral service capacity, resulted in the inequitable coverage and quality of the service and caused nurses to refer to school health as 'the stepchild of primary healthcare'. The comparison of the 2003 and 2012 policies is guided by the policy analysis framework of the Walt and Gilson policy triangle, which considers the policy context, process of policy development, policy actors and the policy content as key dimensions to successful policy development and implementation. I draw on an evaluation of a six-year implementation period (2003 - 2009) of the 2003 NSHP, which revealed the implementation challenges with the related explanatory factors. I provide lessons from the evaluation of the 2003 NSHP, highlight the policy changes in the new 2012 ISHP and finally highlight key opportunities, and remaining challenges, for the implementation of the new 2012 ISHP.


Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study.
To examine the association between warfarin treatment and longitudinal outcomes after ischemic stroke in patients with atrial fibrillation in community practice. Observational study. Hospitals (n = 1487) participating in the Get With The Guidelines (GWTG)-Stroke program in the United States, from 2009 to 2011. 12,552 warfarin naive atrial fibrillation patients admitted to hospital for ischemic stroke and treated with warfarin compared with no oral anticoagulant at discharge, linked to Medicare claims for longitudinal outcomes. Major adverse cardiovascular events (MACE) and home time, a patient centered outcomes measure defined as the total number of days free from institutional care after discharge. A propensity score inverse probability weighting method was used to account for all differences in observed characteristics between treatment groups. Among 12,552 survivors of stroke, 11,039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke. Among ischemic stroke patients with atrial fibrillation, warfarin treatment was associated with improved long term clinical outcomes and more days at home. Clinical trial registration Clinical trials NCT02146274.