[Use of a biological graft for subclavian-femoral bypassing in patients at operational-anaesthesiological risk].
Analysed herein are the results of an experimental study performed on 30 rabbits and a clinical study of treating a total of 60 patients presenting with critical ischaemia of lower limbs on the background of bilateral atherosclerotic lesions of the aortoiliac segment and running high operational-anaesthesiological risk. The animals were subdivided into three groups: an intact group consisting of 6 animals and two study groups comprising 12 rabbits each. In the first study group onto the wall of the abdominal aorta we implanted a synthetic polytetrafluoroethylene prosthesis, the second study group animals received biological graft "Kemangioprotez" from bovine internal thoracic arteries. The biological prosthesis on day three after implantation onto the arterial wall induced 3.2 times and on day seven 1.2 times more pronounced inflammatory reaction than the polytetrafluoroethylene prosthesis. 30 days after implantation of the synthetic graft the degree of repair connective-tissue processes in the arterial wall was 1.8-fold and 70 days after was 3.3-fold more pronounced than after implantation of the biological prosthesis at the same terms. In the connective-tissue capsule around the synthetic prosthesis predominated cellular elements while around the biological prosthesis - fibrous structures predominated. The patients were subdivided into 2 groups consisting of 30 patients each. In Group One patients the shunt used was a synthetic polytetrafluoroethylene prosthesis, in Group Two being a biological graft from bovine internal thoracic arteries. All patients suffered from severe concomitant diseases in the decompensation stage and a multi-level lesion of lower-limb arteries. Revascularization of the ischaemized extremity was carried out through the system of the deep femoral artery system. The use of a biological prosthesis made it possible in the immediate postoperative period to decrease the frequency of early postoperative complications by 13.3%, that of late graft thromboses by 30%, to prolong the average term of grafts functioning 1.8-fold, to increase the physical component of health by 12.8% and the mental one by 9.1%. For femorosubclavian shunting in high-risk patients it is appropriate to use a biological graft while establishing a distal anastomosis with the deep femoral artery.


Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials.
To investigate the frequency of breast-sparing treatment among breast cancer patients subsequently enrolled in national cooperative group studies of adjuvant chemotherapy. A data base was formed of 5,172 patients randomized onto two intergroup trials. Lumpectomy rates were analyzed within study-defined risk strata and across geographic regions. Significant predictors of lower lumpectomy usage were determined in multivariate analyses with variables that described patient and disease characteristics, systemic risk strata, geographic region, and socioeconomic indicators based on zip code of residence. Breast-conservation rates were 30% in the node-negative and 15% in the node-positive trials, with a wide geographic variation within each study (range, 14% to 49% and 9% to 31%, respectively). Lumpectomy use declined with increasing tumor size and did not exceed 40% even for tumors < or = 1 cm with negative nodes. With increasing risk of systemic relapse, frequency of lumpectomy declined (rates for five strata in order of increasing systemic risk: 41%, 33%, 24%, 18%, and 11%), even though these strata were not known at the time of the surgical decision. A logistic model confirmed the joint significance of geographic region and systemic risk. An exploratory model that adjusted for all important variables identified the following significant predictors of lower lumpectomy use: positive nodes; many positive nodes, increased systemic risk; tumor size > or = 2.0 cm; older age; South, Central or non-New England regions; and either lack of college degree or lower income levels. Breast-sparing therapy was used in the minority of women subsequently accrued to two national adjuvant breast cancer studies, even though this cohort and their referring surgeons represented a select population. Although multiple concrete factors were independent predictors of lower lumpectomy rates, prospective research is needed into how patients and their physicians approach the mastectomy versus lumpectomy decision.


Fruits and their impact on the gut microbiota, gut motility and constipation.
Fruits are the seed-bearing product of plants and have considerable nutritional importance in the human diet. The consumption of fruits is among the dietary strategies recommended for constipation due to its potential effects on the gut microbiota and gut motility. Dietary fiber from fruits has been the subject of research on the impact on gut microbiota, gut motility and constipation, however, fruits also contain other components that impact the intestinal luminal environment that may impact these outcomes including sorbitol and (poly)phenols. This review aims to explore the mechanisms of action and effectiveness of fruits and fruit products on the gut microbiota, gut motility and constipation, with a focus on fiber, sorbitol and (poly)phenols. In vitro, animal and human studies investigating the effects of fruits on gut motility and gut microbiota were sought through electronic database searches, hand searching and consulting with experts. Various fruits have been shown to modify the microbiota in human studies including blueberry powder (lactobacilli, bifidobacteria), prunes (bifidobacteria), kiwi fruit (Bacteroides, Faecalibacterium prausnitzii) and raisins (Ruminococcus, F. prausnitzii). Prunes, raisins and apple fiber isolate have been shown to increase fecal weight in humans, whilst kiwifruit to increase small bowel and fecal water content. Apple fiber isolate, kiwifruit, fig paste, and orange extract have been shown to reduce gut transit time, while prunes have not. There is limited evidence on which fruit components play a predominant role in regulating gut motility and constipation, or whether a synergy of multiple components is responsible for such effects.


Bee venom for the treatment of Parkinson's disease: How far is it possible?
Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta leading to depletion of striatal dopamine and motor symptoms as bradykinesia, resting tremors, rigidity, and postural instability. Current therapeutic strategies for PD are mainly symptomatic and may cause motor complications, such as motor fluctuations and dyskinesia. Therefore, alternative medicine may offer an effective adjuvant treatment for PD. Bee venom therapy (BVT) has long been used as a traditional therapy for several conditions, such as rheumatoid arthritis, asthma, and skin diseases. Experimental and clinical studies showed that BVT could be an effective adjuvant treatment for PD. Several mechanisms were suggested for these findings including the ability of BVT to attenuate neuroinflammation, inhibit apoptosis of dopaminergic neurons, protect against glutamate-induced neurotoxicity, and restore normal dopamine levels in the nigrostriatal pathway. In this article, we reviewed and summarized the literature regarding the potential of BVT for the treatment of PD.


The Anaplasma phagocytophilum effector AmpA hijacks host cell SUMOylation.
SUMOylation, the covalent attachment of a member of the small ubiquitin-like modifier (SUMO) family of proteins to lysines in target substrates, is an essential post-translational modification in eukaryotes. Microbial manipulation of SUMOylation recently emerged as a key virulence strategy for viruses and facultative intracellular bacteria, the latter of which have only been shown to deploy effectors that negatively regulate SUMOylation. Here, we demonstrate that the obligate intracellular bacterium, Anaplasma phagocytophilum, utilizes an effector, AmpA (A. phagocytophilum post-translationally modified protein A) that becomes SUMOylated in host cells and this is important for the pathogen's survival. We previously discovered that AmpA (formerly APH1387) localizes to the A. phagocytophilum-occupied vacuolar membrane (AVM). Algorithmic prediction analyses denoted AmpA as a candidate for SUMOylation. We verified this phenomenon using a SUMO affinity matrix to precipitate both native AmpA and ectopically expressed green fluorescent protein (GFP)-tagged AmpA. SUMOylation of AmpA was lysine dependent, as SUMO affinity beads failed to precipitate a GFP-AmpA protein when its lysine residues were substituted with arginine. Ectopically expressed and endogenous AmpA were poly-SUMOylated, which was consistent with the observation that AmpA colocalizes with SUMO2/3 at the AVM. Only late during the infection cycle did AmpA colocalize with SUMO1, which terminally caps poly-SUMO2/3 chains. AmpA was also detected in the cytosol of infected host cells, further supporting its secretion and likely participation in interactions that aid pathogen survival. Indeed, whereas siRNA-mediated knockdown of Ubc9 - a necessary enzyme for SUMOylation - slightly bolstered A. phagocytophilum infection, pharmacologically inhibiting SUMOylation in infected cells significantly reduced the bacterial load. Ectopically expressed GFP-AmpA served as a competitive agonist against native AmpA in infected cells, while lysine-deficient GFP-AmpA was less effective, implying that modification of AmpA lysines is important for infection. Collectively, these data show that AmpA becomes directly SUMOylated during infection, representing a novel tactic for A. phagocytophilum survival.


The influence of electrically conductive and non-conductive nanocomposite scaffolds on the maturation and excitability of engineered cardiac tissues.
Utilization of electrically conductive nanomaterials for developing nanocomposite scaffolds has been at the center of attention for engineering functional cardiac tissues. The primary motive in the use of conductive nanomaterials has been to develop biomimetic scaffolds to recapitulate the extracellular matrix (ECM) of the native heart and to promote cardiac tissue maturity, excitability and electrical signal propagation. Alternatively, it is well accepted that the inclusion of nanomaterials also alters the stiffness and nano-scale topography of the scaffolds. However, what is missing in the literature is that to what extent the sole presence of nanomaterials within a scaffold, regardless of their conductivity, influences the maturation and excitability of engineered cardiac tissues. To address this knowledge gap, we developed four different classes of gelatin methacrylate (GelMA) hydrogels, with varied concentrations, embedded electrically conductive gold nanorods (GNRs) and non-conductive silica nanomaterials (SNPs), to assess the influence of matrix stiffness and the presence of nanomaterials on cardiac cell adhesion, protein expression (i.e. maturation), and tissue-level excitability. Our results demonstrated that either embedding nanomaterials (i.e. GNRs and SNPs) or increasing the matrix stiffness significantly promoted cellular retention and the expression of cardiac-specific markers, including sarcomeric α-actinin (SAC), cardiac troponin I (cTnI) and connexin43 (Cx43) gap junctions. Notably, excitation voltage thresholds at a high frequency (i.e. 2 Hz and higher), in both coupled and uncoupled gap junctions induced by heptanol, were lower for scaffolds embedded conductive GNRs or non-conductive SNPs, independent of matrix stiffness. Overall, our findings demonstrated that the sole presence of nanomaterials within the scaffolding matrix had a more pronounced influence as compared to the scaffold stiffness on the cell-cell coupling, maturation and excitability of engineered cardiac tissues.


Varicella vaccination and ischemic stroke in children: is there an association?
Ischemic stroke is a known complication of varicella disease. Although there have been case reports of ischemic stroke after varicella vaccination, the existence and magnitude of any vaccine-associated risk has not been determined. OBJECTIVE. The purpose of this work was to determine whether varicella vaccination is associated with an increased risk of ischemic stroke and encephalitis in children within 12 months after vaccination. We conducted a retrospective cohort study based on computerized data from children 11 months through 17 years old enrolled for > or =12 months in the Vaccine Safety DataLink from 1991 through 2004. International Classification of Disease codes identified cases of ischemic stroke (433-436, 437.1, 437.4, 437.6, 437.8-437.9) and encephalitis (052.0, 323.5, 323.8-9). Cox regression was used to model the risk in the 12 months after vaccination relative to all other person-time. Covariates included calendar time, gender, and stroke risk factors (eg, sickle cell disease). Varicella vaccine was administered to 35.3% of the 3.2 million children in the cohort. There were 203 new inpatient ischemic stroke diagnoses, including 8 that occurred within 12 months after vaccination; there was no temporal clustering. The adjusted stroke hazard ratio was not elevated during any of the time periods in the 12 months after vaccination. Stroke was strongly associated with known risk factors such as sickle cell disease and cardiac disease. None of the 243 encephalitis cases occurred during the first 30 days after vaccination, and there was no association between encephalitis and varicella vaccination at any time in the 12 months after vaccination. Our retrospective cohort study of >3 million children found no association between varicella vaccine and ischemic stroke.


Surface acoustic waves for on-demand production of picoliter droplets and particle encapsulation.
Microscopic water-in-oil droplets are a versatile chemical and biological platform whose dimensions result in short reaction times and require minuscule amounts of reagent. Methods exist for the production of droplets, though the vast majority are only able to do so in continuous flows, restricting the ability to independently control reactions of individual droplets, a prerequisite for programmable digital microfluidics. Here we present a novel method to produce individual picoliter-scale droplets on-demand using surface acoustic waves (SAW). Acoustic forces arising from SAW act on the oil-water interface, creating a droplet whose volume is defined by the applied power, duration of the force and system geometry. Additionally, this method is able to pre-concentrate particles simultaneously with droplet production, meaning that particles and cells, even if in a dilute mixture, can be easily encapsulated. Our method is expected to be applicable to high-throughput screening, bioreactor creation and other microfluidic processes.


Microbial evolution of sulphate reduction when lateral gene transfer is geographically restricted.
Lateral gene transfer (LGT) is an important mechanism by which micro-organisms acquire new functions. This process has been suggested to be central to prokaryotic evolution in various environments. However, the influence of geographical constraints on the evolution of laterally acquired genes in microbial metabolic evolution is not yet well understood. In this study, the influence of geographical isolation on the evolution of laterally acquired dissimilatory sulphite reductase (dsr) gene sequences in the sulphate-reducing micro-organisms (SRM) was investigated. Sequences on four continental blocks related to SRM known to have received dsr by LGT were analysed using standard phylogenetic and multidimensional statistical methods. Sequences related to lineages with large genetic diversity correlated positively with habitat divergence. Those affiliated to Thermodesulfobacterium indicated strong biogeographical delineation; hydrothermal-vent sequences clustered independently from hot-spring sequences. Some of the hydrothermal-vent and hot-spring sequences suggested to have been acquired from a common ancestral source may have diverged upon isolation within distinct habitats. In contrast, analysis of some Desulfotomaculum sequences indicated they could have been transferred from different ancestral sources but converged upon isolation within the same niche. These results hint that, after lateral acquisition of dsr genes, barriers to gene flow probably play a strong role in their subsequent evolution.


Bacterial transformation: ComFA is a DNA-dependent ATPase that forms complexes with ComFC and DprA.
Pneumococcal natural transformation contributes to genomic plasticity, antibiotic resistance development and vaccine escape. Streptococcus pneumoniae, like many other naturally transformable species, has evolved sophisticated protein machinery for the binding and uptake of DNA. Two proteins encoded by the comF operon, ComFA and ComFC, are involved in transformation but their exact molecular roles remain unknown. In this study, we provide experimental evidence that ComFA binds to single stranded DNA (ssDNA) and has ssDNA-dependent ATPase activity. We show that both ComFA and ComFC are essential for the transformation process in pneumococci. Moreover, we show that these proteins interact with each other and with other proteins involved in homologous recombination, such as DprA, thus placing the ComFA-ComFC duo at the interface between DNA uptake and DNA recombination during transformation.


The women radium dial painters as experimental subjects (1920-1990) or what counts as human experimentation.
The case of women radium dial painters - women who tipped their brushes while painting the dials of watches and instruments with radioactive paint - has been extensively discussed in the medical and historical literature. Their painful and abhorrent deaths have occupied the interest of physicians, lawyers, politicians, military agencies, and the public. Hardly any discussion has concerned, however, the use of those women as experimental subjects in a number of epidemiological studies that took place from 1920 to 1990. This article addresses the neglected issue of human experimentation in relation to the radium dial painters. Although women's medical examinations have been classified as simple, routine measurements of radiation burden on the body and presented as a great offer to humanity, for more than fifty years those women had been repeatedly used as experimental subjects without proper consent. I argue that through this case it becomes obvious that the issue of defining what counts as human experimentation shifts from an epistemological to a serious ethical and political question, concerning the making of scientific knowledge while issues of gender related to this process are also discussed.


Interventions to Support Adherence to Oral Anticancer Medications: Systematic Review and Meta-Analysis.
This systematic review compared the efficacy of interventions to usual care on adherence to oral anticancer regimens. Embase®, PubMed®, and CINAHL® were searched for eligible comparative studies published between January 2000 and May 2021. Outcomes of interest included adherence, cancer-related morbidity, quality of life, patient satisfaction, and other patient-specific outcomes. Reviewers assessed risk of bias using the Cochrane Risk of Bias 2 tool and Risk of Bias in Nonrandomized Studies of Interventions. Certainty of evidence was assessed using the GRADE framework. Risk assessment, ongoing or periodic assessment, proactive follow-up, motivational interviewing, or structured programs may improve adherence. Education or coaching interventions may improve or have little to no effect on adherence. Technological interventions may improve adherence, but interactive compared to noninteractive technology may have little to no effect. As more cancer treatments move to oral formulations, work remains to identify the most effective interventions to support people receiving oral anticancer regimens.


Habitat, wildlife, and one health: Arcanobacterium pyogenes in Maryland and Upper Eastern Shore white-tailed deer populations.
Understanding the distribution of disease in wildlife is key to predicting the impact of emerging zoonotic one health concerns, especially for wildlife species with extensive human and livestock interfaces. The widespread distribution and complex interactions of white-tailed deer (Odocoileus virginianus) with humans suggest deer population health and management may have implications beyond stewardship of the animals. The intracranial abscessation suppurative meningitis (IASM) disease complex in deer has been linked to Arcanobacterium pyogenes, an under-diagnosed and often misdiagnosed organism considered commensal in domestic livestock but associated with serious disease in numerous species, including humans. Our study used standard bacterial culture techniques to assess A. pyogenes prevalence among male deer sampled across six physiogeographic regions in Maryland and male and female deer in the Upper Eastern Shore under Traditional Deer Management (TDM) and Quality Deer Management (QDM), a management protocol that alters population demographics in favor of older male deer. Samples were collected from antler pedicles for males, the top of the head where pedicles would be if present for females, or the whole dorsal frontal area of the head for neonates. We collected nasal samples from all animals by swabbing the nasopharyngeal membranes. A gram stain and catalase test were conducted, and aerobic bacteria were identified to genus and species when possible. We evaluated the effect of region on whether deer carried A. pyogenes using Pearson's chi-square test with Yates' continuity correction. For the white-tailed deer management study, we tested whether site, age class and sex predisposed animals to carrying A. pyogenes using binary logistic regression. A. pyogenes was detected on deer in three of the six regions studied, and was common in only one region, the Upper Eastern Shore. In the Upper Eastern Shore, 45% and 66% of antler and nasal swabs from deer were positive for A. pyogenes, respectively. On the Upper Eastern Shore, prevalence of A. pyogenes cultured from deer did not differ between management areas, and was abundant among both sexes and across all age classes. No A. pyogenes was cultured from a small sample of neonates. Our study indicates A. pyogenes may be carried widely among white-tailed deer regardless of sex or age class, but we found no evidence the pathogen is acquired in utero. The distribution of A. pyogenes across regions and concentration in a region with low livestock levels suggests the potential for localized endemicity of the organism and the possibility that deer may serve as a maintenance reservoir for an emerging one health concern.


Telecommunication devices use, screen time and sleep in adolescents.
To investigate the association between telecommunication and other screen devices use and subjective and objective sleep measures in adolescents at 17-18 years. Cross-sectional study on adolescents aged 17-18 years from a Spanish population-based birth cohort established in Menorca in 1997-1998. Information on devices use was collected using self-reported questionnaires. Mobile Phone Problematic Use Scale was used to assess mobile phone use dependency. Pittsburgh Sleep Quality Index was used to assess subjective sleep (n = 226). ActiGraph wGT3X-BT for 7 nights was used to assess objective sleep (n = 110). One or more cordless phone calls/week was associated with a lower sleep quality [Prevalence Ratio (PR) 1.30 (95%Confidence Interval (CI) 1.04; 1.62)]. Habitual and frequent problematic mobile phone use was associated with a lower sleep quality [PR 1.55 (95%CI 1.03; 2.33) and PR 1.67 (95%CI 1.09; 2.56), respectively]. Higher tablet use was associated with decreased sleep efficiency and increased minutes of wake time after sleep onset [β-1.15 (95%CI -1.99; -0.31) and β 7.00 (95%CI 2.40; 11.60) per increase of 10 min/day of use, respectively]. No associations were found between other devices and sleep measures. Frequency of cordless phone calls, mobile phone dependency, and tablet use were related to an increase of subjective and objective sleep problems in adolescents. These results seem to indicate that sleep displacement, mental arousal, and exposure to blue light screen emission might play a more important role on sleep than a high RF-EMF exposure to the brain. However, more studies are needed assessing personal RF-EMF levels to draw conclusions.


Electrochemical sensors based on molecularly imprinted polymers on Fe3O4/graphene modified by gold nanoparticles for highly selective and sensitive detection of trace ractopamine in water.
A novel molecular imprinting polymer (MIP)-based electrochemical senor, consisting of Fe3O4 nanobeads and gold nanoparticles on a reduced graphene oxide (RGO) substrate, was fabricated to detect ractopamine (RAC) in water using the reversible addition fragmentation chain transfer (RAFT) polymerization technique. The Au nanoparticles widely dispersed on RGO can significantly increase the response current for RAC detection in water, which is confirmed by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and theoretical calculations. By means of the differential pulse voltammetry technique, the as-prepared MIP-based electrode shows a dynamic linear range of 0.002 to 0.1 μM with a correlation coefficient of 0.992 and a remarkably low detection limit of 0.02 nM (S/N = 3). Additionally, the sensor exhibits high binding affinity and selectivity towards RAC with excellent reproducibility. Our study demonstrates the potential for the proposed electrochemical sensors in monitoring organic pollutants in water.


Towards the development of a biobased economy in Europe and India.
India has emerged as a key player with a high potential to develop a biomass and biobased economy due to its large geographic size and the massive amounts of agricultural and non agricultural biomass produced. India has joined hands with Europe to synchronize its efforts to create and facilitate the development of a biobased economy in this country. This paper aims to examine common research and development actions between the European Union (EU) and India to facilitate the development of these biobased economies. As a base, a thorough study has been performed considering the biomass potential and current status of the bioeconomy in both the EU and India based on the distillation of a series of 80 potential recommendations. The recommendations were grouped into four major categories: (1) biomass production, (2) by-products/waste, (3) biorefineries and (4) policy, market, and value-added products. A questionnaire was designed and distributed to key stakeholders belonging to: academia, industry, and policymakers in both India and the EU. A total of 231 responses were received and analyzed, based on the key recommendations made for the essential research and development topics that are of prime importance to develop biobased economies in both the EU and India. The findings of this study suggest recognizing the value-added contributions made by biobased products such as: food, feed, valuable materials and chemicals in both regions. It is important to reduce the overall process costs and minimize the environmental impacts of such a biobased economy.


Genome-wide gene expression profiling reveals aberrant MAPK and Wnt signaling pathways associated with early parthenogenesis.
Mammalian parthenogenesis could not survive but aborted during mid-gestation, presumably because of lack of paternal gene expression. To understand the molecular mechanisms underlying the failure of parthenogenesis at early stages of development, we performed global gene expression profiling and functional analysis of parthenogenetic blastocysts in comparison with those of blastocysts from normally fertilized embryos. Parthenogenetic blastocysts exhibited changes in the expression of 749 genes, of which 214 had lower expression and 535 showed higher expressions than fertilized embryos using a minimal 1.8-fold change as a cutoff. Genes important for placenta development were decreased in their expression in parthenote blastocysts. Some maternally expressed genes were up-regulated and paternal-related genes were down-regulated. Moreover, aberrantly increased Wnt signaling and reduced mitogen-activated protein kinase (MAPK) signaling were associated with early parthenogenesis. The protein level of extracellular signal-regulated kinase 2 (ERK2) was low in parthenogenetic blastocysts compared with that of fertilized blastocysts 120 h after fertilization. 6-Bromoindirubin-3'-oxime, a specific glycogen synthase kinase-3 (GSK-3) inhibitor, significantly decreased embryo hatching. The expression of several imprinted genes was altered in parthenote blastocysts. Gene expression also linked reduced expression of Xist to activation of X chromosome. Our findings suggest that failed X inactivation, aberrant imprinting, decreased ERK/MAPK signaling and possibly elevated Wnt signaling, and reduced expression of genes for placental development collectively may contribute to abnormal placenta formation and failed fetal development in parthenogenetic embryos.


Thyrotrophin stimulation of adenylate cyclase and iodine uptake in human differentiated thyroid cancer.
TSH stimulation of adenylate cyclase (AC) and iodine uptake was compared in 39 surgical specimens of primary tumours and/or lymph node metastases from 29 human differentiated thyroid carcinomas. TSH stimulation of AC was significantly lower (2.1 +/- 0.3 fold the basal level) in patients without in vivo 131I uptake than in patients with 131I uptake (4.7 +/- 0.8). A significant correlation between TSH responsiveness of AC and TSH stimulation of in vitro 125I uptake was found. There was also a relationship between 127I tissue content and AC responsiveness. Nevertheless analysis of individual data showed discrepancies in about one quarter of the cases. Thus the response of neoplastic cell membrane to TSH appears to be necessary for iodine metabolism, but it is not sufficient. Additional defects may in some cases explain the lack of either iodine uptake or organification. There is a general correlation between TSH stimulation of AC and histological type. However, data from papillary carcinomas with various degrees of uptake capacity show that TSH stimulation of AC correlates better with functional activity than with cell morphology or tissue architecture. Stimulation by GMP P(N)P was decreased in carcinomas, while NaF stimulation was not significantly different from normal. This suggests that alterations in thyroid cancer are more related to defects in the regulatory than in the catalytic subunit of AC.


[Contextual psychiatry: a re-evaluation focusing on family system therapy].
Mental health services are currently in a state of flux and psychiatry is being affected by cost-cutting measures and is seeking a new direction. In this article we advocate the re-evaluation of contextual psychiatry. We focus primarily on the position of caregivers in view of the Dutch government's political decision that mental health care problems should, if at all possible, be solved in the intimacy of the family, involving care givers and family members. This decision has put these people, who are already over-burdened, under extra pressure if they do not receive additional support. To analyse the causes of the restricted influence of systemic insights in psychiatry and to make recommendations regarding the need for the re-evaluation of contextual psychiatry, in order to further the dialogue between the triad professional, patient and caregiver. Our article consists of a qualitative review and our analysis, opinions and recommendations. Caregivers feel that they do not receive enough attention. Professionals feel uncomfortable in dialogues with patients and caregivers because of issues such as loyalty, divided allegiance and the need for privacy. There are sufficient arguments to support the integration of systemic therapy into general psychiatric practice. Caregivers are essential partners for supplying information and support during the process of change. They deserve to be supported so that they do not become even more over-burdened. We advocate the re-unification of psychiatry, family policy and family therapy, more collaboration between the Dutch Association of Psychiatry and the Dutch Association of Family therapy and the introduction of new sections into existing teaching courses.


Impactibility Model for Population Health Management in High-Cost Elderly Heart Failure Patients: A Capture Method Using the ACG System.
The aim of the present study is to use the ACG (Adjusted Clinical Groups) System to create an impactibility model by identifying homogeneous clinical subgroups of patients with high risk of an adverse health outcome in a population of heart failure patients with complex health care needs (PCHCN). This method will allow policy makers to target and prioritize services for the highest risk PCHCN in the context of limited health care resources, by identifying relatively homogeneous groups of patients with similar comorbidities. Subjects classified in 2012 as PCHCN in a local health unit by the ACG System were linked with hospital discharge records in 2013. The authors applied the Apriori algorithm to identify the most common sets of the most predictive diseases for the following outcomes of interest: at least 1 admission and at least 1 preventable admission in the year. Predictive performance for the former outcome was compared between the impactability model with the available ACG's individual risk score. The Apriori algorithm also was applied to predict the latter outcome as an example of an event that a policy maker would be able to prevent. Evidence showed no statistically significant difference between the 2 methods. The present model also displayed evidence of good calibration. The Apriori algorithm was applied as an impactibility model, built based on the ACG System, that allowed the authors to obtain an "ACG-based group risk score" and use it to identify clinically homogeneous subgroups of PCHCN. This will help policy makers develop "tool kits" for homogeneous groups of patients that improve health outcomes.


Single Core Genome Sequencing for Detection of both Borrelia burgdorferi Sensu Lato and Relapsing Fever Borrelia Species.
Lyme disease, initially described as Lyme arthritis, was reported before nucleic-acid based detection technologies were available. The most widely used diagnostic tests for Lyme disease are based on the serologic detection of antibodies produced against antigens derived from a single strain of Borrelia burgdorferi. The poor diagnostic accuracy of serological tests early in the infection process has been noted most recently in the 2018 Report to Congress issued by the U.S. Department of Health and Human Services Tick-Borne Disease Working Group. Clinical Lyme disease may be caused by a diversity of borreliae, including those classified as relapsing fever species, in the United States and in Europe. It is widely accepted that antibiotic treatment of Lyme disease is most successful during this critical early stage of infection. While genomic sequencing is recognized as an irrefutable direct detection method for laboratory diagnosis of Lyme borreliosis, development of a molecular diagnostic tool for all clinical forms of borreliosis is challenging because a "core genome" shared by all pathogenic borreliae has not yet been identified. After a diligent search of the GenBank database, we identified two highly conserved segments of DNA sequence among the borrelial 16S rRNA genes. We further developed a pair of Borrelia genus-specific PCR primers for amplification of a segment of borrelial 16S rRNA gene as a "core genome" to be used as the template for routine Sanger sequencing-based metagenomic direct detection test. This study presented examples of base-calling DNA sequencing electropherograms routinely generated in a clinical diagnostic laboratory on DNA extracts of human blood specimens and ticks collected from human skin bites and from the environment. Since some of the tick samples tested were collected in Ireland, borrelial species or strains not known to exist in the United States were also detected by analysis of this 16S rRNA "core genome". We recommend that hospital laboratories located in Lyme disease endemic areas begin to use a "core genome" sequencing test to routinely diagnose spirochetemia caused by various species of borreliae for timely management of patients at the early stage of infection.


Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.
The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.


Signaling pathways activated by a protease allergen in basophils.
Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.


Ectopic Liver Tissue Formation in Rats with Induced Liver Fibrosis.
The possible alternative approach to whole-organ transplantation is a cell-based therapy, which can also be used as a "bridge" to liver transplantation. However, morphological and functional changes in the liver of patients suffering from chronic liver fibrosis and cirrhosis restrict the effectiveness of direct cell transplantation. Therefore, extra hepatic sites for cell transplantation, including the spleen, pancreas, peritoneal cavity, and subrenal capsule, could be a useful therapeutic approach for compensation of liver functions. However, a method of transplantation of hepatocytes into ectopic sites is needed to improve hepatocyte engraftment. Previously published data has demonstrated that mouse lymph nodes can support the engraftment and proliferation of hepatocytes as ES and rescue Fah mice from lethal liver failure. Thus, the aim of the study was to evaluate the engraftment of i.p. injected allogeneic hepatocytes into extra hepatic sites in albino rats with chemically induced liver fibrosis (LF). Albino rats were randomly divided into 4 groups: (1) intact group (n = 18); (2) rats with induced LF (n = 18); (3) rats with induced LF and transplanted with hepatocytes (n = 18); (4) as a control, rats were treated with cyclosporine A only (n = 18). In order to prevent an immune response, groups 2 and 3 were subjected to immunosuppression by cyclosporine A (25 mg/kg per day). LF was induced using N-nitrosodimethylamine (NDMA), i.p., 10 mg/kg, three times a week for 4 weeks and confirmed by histological analysis of the liver samples. Hepatocytes transplantation (HT) was performed two days after NDMA exposure cessation by i.p. injection of 5×106 freshly isolated allogeneic hepatocytes. Liver function was assessed by quantifying blood biochemical parameters (ALT, AST, GGT, total protein, bilirubin, and albumin) at 1 week, 1 month, and 2 months after hepatocytes transplantation (HT). To confirm a hepatocytes' engraftment, we conducted immunohistochemical staining against HepPar1. We observed a 30% mortality rate among rats with LF within 1 week after NDMA exposure cessation, while 100% of animals with HT survived. ALT, AST, and GGT activities and bilirubin levels were markedly elevated in blood samples of LF rats compared to the control animals. However, HT significantly improved ALT, AST, and GGT activity as well as bilirubin levels. We also observed decreased levels of total protein and albumin in the blood serum of rats with LF, while HT normalized these parameters. At the same time, we have not detected any statistical differences of the studied parameters in the group 4, which was treated with Cyclosporine A only, compared with the intact animals. HepPar1 immunohistochemical staining of the different tissue sections demonstrated the presence of engrafted hepatocytes, mainly within enlarged Peyer's patches (aggregated lymphoid nodules in the lowest portion of the small intestine). The results of our study provide evidence that HT improves animal survival and liver functions. One potential reason for these results is that ectopic hepatic mass inside the Peyer's patches can rescue rats from liver failure.


Re-emphasizing the importance of catheter-based angiography to differentiate polyarteritis nodosa from cutaneous arteritis: two case reports.
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis with a poor prognosis, characterized by inflammation and necrosis of medium-sized arteries. PAN patients can present with a wide range of systemic manifestations, whereas cutaneous arteritis (CA) is a restricted manifestation to skin of the disease with a more favorable prognosis. Thus, differentiation between PAN and CA is crucial. Here we present two cases that were initially diagnosed as CA due to the limited presence of systemic symptoms, but were finally diagnosed as PAN through catheter-based angiography. Although contrast-enhanced computed tomography and computed tomographic angiography are increasingly used to diagnose PAN, neither case had any abnormal findings on these examinations. Our cases therefore underscore that catheter-based angiography is critical for differentiation between PAN and CA, even in cases with limited systemic symptoms.


Density-based clustering of small peptide conformations sampled from a molecular dynamics simulation.
This study describes the application of a density-based algorithm to clustering small peptide conformations after a molecular dynamics simulation. We propose a clustering method for small peptide conformations that enables adjacent clusters to be separated more clearly on the basis of neighbor density. Neighbor density means the number of neighboring conformations, so if a conformation has too few neighboring conformations, then it is considered as noise or an outlier and is excluded from the list of cluster members. With this approach, we can easily identify clusters in which the members are densely crowded in the conformational space, and we can safely avoid misclustering individual clusters linked by noise or outliers. Consideration of neighbor density significantly improves the efficiency of clustering of small peptide conformations sampled from molecular dynamics simulations and can be used for predicting peptide structures.


The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury.
Aspirin, Neem oil, valproic, adipic, benzoic, isovaleric, 3-mercaptopropionic and 4-pentenoic acids are implicated in the pathogenesis of Reye's syndrome, Jamaican vomiting sickness, and related chemical toxicities. These disorders are characterized by hyperammonemia, hypoglycemia, microvesicular steatosis and encephalopathy. The goal of this study was to determine whether chemicals implicated in Reye's-related disorders induce the mitochondrial permeability translation (MPT). The MPT is induced by opening of a high-conductance, cyclosporin-sensitive pore in the mitochondrial inner membrane, causing swelling, depolarization and uncoupling of oxidative phosphorylation. In freshly isolated rat liver mitochondria, unhydrolyzed aspirin (300 microM) did not induce the MPT in the presence of 50 microM CaCl2. Salicylate, the hydrolysis product of aspirin and its active metabolite, was much more potent causing dose-dependent onset of the MPT in a therapeutic range of concentrations (37.5-300 microM). Similarly, Neem oil and valproic, adipic, benzoic, isovaleric, 3-mercaptopropionic and 4-pentenoic acids induced onset of the MPT. In all cases, cyclosporin A (200 nM), a specific inhibitor of the permeability transition pore, blocked the MPT caused by these inducers. Induction of the MPT by these agents was not caused by mitochondrial depolarization because concentrations of valproic acid and salicylate inducing the MPT had little effect on mitochondrial delta psi. Moreover, equivalent uncoupling caused by 5 nM carbonyl cyanide p-trifluoromethoxyphenylhydrazone did not induce an MPT. These data suggest that induction of the MPT is a common pathophysiological mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities.


Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators.
Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.


[Production of porcine blastocysts expressed EGFP by handmade cloning].
Production of transgenic animals via somatic cell nuclear transfer (SCNT) has been widely used worldwide. However, the application of SCNT is impeded by overall high costs and low efficiency. Here, we reported a modification of the existing technology in order to overcome some of the disadvantages associated with SCNT. Firstly, a marker gene, enhanced green fluorescent gene (EGFP), was transfected into pig fetal fibroblast cells, and was subsequently screened by fluorescent expression to ensure donor cells expressing EGFP. Porcine embryos expressing EGFP were then produced by a method called handmade cloning (HMC), a simplified method for micromanipulation. To demonstrate the concept, we collected a total of 378 fresh swine oocytes, from which 266 with the nucleus removed, obtained a total of 127 viable recombinant oocytes after fusion with EGFP-expressing cells. In vitro incubation of the 127 recombinant oocytes for approximately 144 hours resulted in successful generation of 65 viable embryos, with an average success rate of 52.1±8.3%. Compared with the traditional SCNT, the method of HMC is not only easy to operate, but also increases the rate of recombinant embryo significantly. Furthermore, the modified method no longer relies on expensive instrument like micromanipulator, facilitating the industrialization of transgenic animal production.


The association of contraceptive methods and depression.
None of the contraceptive methods are fully side-effect free. One of the side effects that commonly causes discontinuation is mood changes and depression. The present study aimed to compare the depression between contraceptive methods including low-dose estrogen (LD) combined pills, condom and intrauterine devices (IUD). In a cross-sectional study, 216 women were selected through systematic random sampling from 10 health care center sin Isfahan in 2011. Beck Depression Inventory II was used and individual productivity characteristics were asked. Validity and reliability of Beck depression inventory have been repeatedly confirmed in Iran. Content validity the productivity characteristics questionnaire was confirmed and its reliability was measured through Cronbach's alpha correlation coefficient (calculated as 0.71). ANOVA, covariance analysis and logistic regression were used to analyze the data. Depression was observed in 47.8% of participants; however, there was no difference between mean score of depression in the users of three contraceptive methods. The findings of this study showed that depression is not correlated with family planning type and fear of depression should not be an obstacle to choose between these methods. Depression is a multifactor issue. This study showed that type of family planning method in itself cannot be the cause of depression and family planners and consultants should consider this.


Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ice.
The Arctic icescape is rapidly transforming from a thicker multiyear ice cover to a thinner and largely seasonal first-year ice cover with significant consequences for Arctic primary production. One critical challenge is to understand how productivity will change within the next decades. Recent studies have reported extensive phytoplankton blooms beneath ponded sea ice during summer, indicating that satellite-based Arctic annual primary production estimates may be significantly underestimated. Here we present a unique time-series of a phytoplankton spring bloom observed beneath snow-covered Arctic pack ice. The bloom, dominated by the haptophyte algae Phaeocystis pouchetii, caused near depletion of the surface nitrate inventory and a decline in dissolved inorganic carbon by 16 ± 6 g C m-2. Ocean circulation characteristics in the area indicated that the bloom developed in situ despite the snow-covered sea ice. Leads in the dynamic ice cover provided added sunlight necessary to initiate and sustain the bloom. Phytoplankton blooms beneath snow-covered ice might become more common and widespread in the future Arctic Ocean with frequent lead formation due to thinner and more dynamic sea ice despite projected increases in high-Arctic snowfall. This could alter productivity, marine food webs and carbon sequestration in the Arctic Ocean.


Strong coupling and long-range collective interactions in optomechanical arrays.
We investigate the collective optomechanics of an ensemble of scatterers inside a Fabry-Pérot resonator and identify an optimized configuration where the ensemble is transmissive, in contrast to the usual reflective optomechanics approach. In this configuration, the optomechanical coupling of a specific collective mechanical mode can be several orders of magnitude larger than the single-element case, and long-range interactions can be generated between the different elements since light permeates throughout the array. This new regime should realistically allow for achieving strong single-photon optomechanical coupling with massive resonators, realizing hybrid quantum interfaces, and exploiting collective long-range interactions in arrays of atoms or mechanical oscillators.


Endoscopic resection of sinonasal mucosal melanoma has comparable outcomes to open approaches.
Endoscopic endonasal resection (EER) of sinonasal mucosal melanoma (SMM) is a newer surgical alternative to traditional external and/or open resection (OR). Studies on long-term outcomes are necessary to validate EER for this aggressive sinonasal malignancy. To compare outcomes of EER versus OR in SMM. A case series of patients who underwent surgical resection of SMM at a tertiary-care institution (2000-2015) was studied retrospectively. Demographics, tumor site and stage, surgical approach, surgical margin status, local control, and survival were compared between those who underwent EER and OR. Twenty-two patients met inclusion criteria. Nine underwent EER and 13 underwent OR. The mean age in the EER and OR groups was similar, 78.7 and 72.3 years, respectively. Two-thirds of patients were women (EER, 66.7%; OR, 61.5%). The nasal cavity was the most common primary tumor site (EER, 77.8%; OR, 84.6%). The local tumor stage in both groups was similar, with the majority of cases being T4 (EER, 55.6%; OR, 61.5%; p = 0.99). Negative margins were achieved in all EERs and in 69.2% of ORs. Median follow-up was 25.0 months for the overall group (range, 1.7-172.9 months), 32.6 months (range, 3.4-58.7 months) for EER and 14.1 months (range, 1.7-172.9 months) for OR cohorts. The 5-year overall survival was statistically similar in both groups (EER, 53.3%; OR, 22.7%; p = 0.214) as was disease-free survival (EER, 55.6%; OR, 22.8%; p = 0.178). Local control, however, was significantly higher in the EER cohort (EER, 85.7%; OR, 37.6%; p = 0.026). In carefully selected patients with sinonasal melanoma, endoscopic surgery with an experienced team may offer comparable survival and improved local control over open surgery. Prospective, multicentered studies with larger cohorts are needed to validate these results.


Impact of health care organization on surgical lung cancer care.
Organization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging. General numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy. In 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands. Surgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge.


Genetic analysis of autoimmune type 1 diabetes mellitus in mice.
Two genes, Idd-3 and Idd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps of the mouse and human genomes, the homologue of Idd-3 may reside on human chromosomes 1 or 4 and Idd-4 on chromosome 17.


Efficacy and safety of re-treatment with the same artemisinin-based combination treatment (ACT) compared with an alternative ACT and quinine plus clindamycin after failure of first-line recommended ACT (QUINACT): a bicentre, open-label, phase 3, randomised controlled trial.
Quinine or alternative artemisinin-based combination treatment (ACT) is the recommended rescue treatment for uncomplicated malaria. However, patients are often re-treated with the same ACT though it is unclear whether this is the most suitable approach. We assessed the efficacy and safety of re-treating malaria patients with uncomplicated failures with the same ACT used for the primary episode, compared with other rescue treatments. This was a bicentre, open-label, randomised, three-arm phase 3 trial done in Lisungi health centre in DR Congo, and Kazo health centre in Uganda in 2012-14. Children aged 12-60 months with recurrent malaria infection after treatment with the first-line ACT were randomly assigned to either re-treatment with the same first-line ACT, an alternative ACT, which were given for 3 days, or quinine-clindamycin (QnC), which was given for 5-7 days, following a 2:2:1 ratio. Randomisation was done by computer-generated randomisation list in a block design by country. The three treatment groups were assumed to have equivalent efficacy above 90%. Both the research team and parents or guardians were aware of treatment allocation. The primary outcome was the proportion of patients with an adequate clinical and parasitological response (ACPR) at day 28, in the per-protocol population. This trial was registered under the numbers NCT01374581 in ClinicalTrials.gov and PACTR201203000351114 in the Pan African Clinical Trials Registry. From May 22, 2012, to Jan 31, 2014, 571 children were included in the trial. 240 children were randomly assigned to the re-treatment ACT group, 233 to the alternative ACT group, and 98 to the QnC group. 500 children were assessed for the primary outcome. 71 others were not included because they did not complete the follow-up or PCR genotyping result was not conclusive. The ACPR response was similar in the three groups: 91·4% (95% CI 87·5-95·2) for the re-treatment ACT, 91·3% (95% CI 87·4-95·1) for the alternative ACT, and 89·5% (95% CI 83·0-96·0) for QnC. The estimates for rates of malaria recrudescence in the three treatment groups were similar (log-rank test: χ2=0·22, p=0·894). Artemether-lumefantrine was better tolerated than QnC (p=0·0005) and artesunate-amodiaquine (p<0·0001) in the modified intention-to-treat analysis. No serious adverse events were observed. The most common adverse events reported in the re-treatment ACT group were anorexia (31 [13%] of 240 patients), asthenia (20 [8%]), coughing (16 [7%]), abnormal behaviour (13 [5%]), and diarrhoea (12 [5%]). Anorexia (13 [6%] of 233 patients) was the most frequently reported adverse event in the alternative ACT group. The most commonly reported adverse events in the QnC group were anorexia (12 [12%] of 98 patients), abnormal behaviour (6 [6%]), asthenia (6 [6%]), and pruritus (5 [5%]). Re-treatment with the same ACT shows similar efficacy as recommended rescue treatments and could be considered for rescue treatment for Plasmodium falciparum malaria. However, the effect of this approach on the selection of resistant strains should be monitored to ensure that re-treatment with the same ACT does not contribute to P falciparum resistance. Fonds Wetenschappelijk Onderzoek, Vlaamse Interuniversitaire Raad-Universitaire Ontwikkelings Samenwerking, European and Developing Countries Clinical Trials Partnership, and the Belgian Technical Cooperation-Programme d'Etudes et d'Expertises-in the Democratic Republic of Congo.


Selective induction of calcineurin activity and signaling by oligomeric amyloid beta.
Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Abeta) is a signature of AD, evidence suggests that the preplaque small oligomeric Abeta promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Abeta and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Abeta. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Abeta on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Abeta specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Abeta oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Abeta on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Abeta in the aging CNS.


Effect of age on forward and backward span tasks.
The central executive component of working memory has been argued to play an important role in the performance of span tasks, particularly backward span. Age-related decline in central executive function has also been reported, and yet there have been inconsistent findings to indicate that with increasing age, the discrepancy between forward and backward span increases. A secondary analysis of the Wechsler Memory Scale-Third Edition standardization sample (N = 1030) was performed to investigate this relationship. It was hypothesized on the basis of past research indicating an age-related decline in central executive performance, that backward digit and spatial span performance would decrease at a greater rate than forward span performance. However, the results indicated that the rate of age-related performance decline was equivalent for both measures. It is proposed that both forward and backward span tasks recruit central executive resources for successful task performance.


Salt Sensitivity of the Thermoresponsive Behavior of PNIPAAm Brushes.
We report investigations on the salt sensitivity of the thermoresponsive behavior of PNIPAAm brushes applying the quartz crystal microbalance coupled with spectroscopic ellipsometry technique. This approach enables a detailed study of the optical and mechanical behavior of the polymer coatings. Additional conclusions can be drawn from the difference between both techniques due to a difference in the contrast mechanism of both methods. A linear shift of the phase-transition temperature to lower temperatures with the addition of sodium chloride was found, similar to the behavior of free polymer chains in solution. The thermal hysteresis was found to be decreased by the addition of sodium chloride to the solution, hinting to the interaction of the ions with the amide groups of the polymer, whereby the formation of hydrogen bonds is hindered. The results of this study are of relevance to the application of PNIPAAm brushes in biological fluids and demonstrate the additional potential of the ion sensitivity besides the better known thermosensitivity.


Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation.
The monomeric small GTPase Rab27a is specifically localized on both secretory granules and lysosome-related organelles. Although natural mutations of the Rab27a gene in human Griscelli syndrome and in ashen mice cause partial albinism and immunodeficiency reflecting the dysfunction of lysosome-related organelles, phenotypes resulting from the defective exocytosis of secretory granules have not been reported. To explore the roles of Rab27a in secretory granules, we analyzed insulin secretion profiles in ashen mice. Ashen mice showed glucose intolerance after a glucose load without signs of insulin resistance in peripheral tissues or insulin deficiency in the pancreas. Insulin secretion from isolated islets was decreased specifically in response to high glucose concentrations but not other nonphysiological secretagogues such as high K+ concentrations, forskolin, or phorbol ester. Neither the intracellular Ca2+ concentration nor the dynamics of fusion pore opening after glucose stimulation were altered. There were, however, marked reductions in the exocytosis from insulin granules predocked on the plasma membrane and in the replenishment of docked granules during glucose stimulation. These results provide the first genetic evidence to our knowledge for the role of Rab27a in the exocytosis of secretory granules and suggest that the Rab27a/effector system mediates glucose-specific signals for the exocytosis of insulin granules in pancreatic beta cells.


Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.
Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.


Phytochrome B Mediates the Regulation of Chlorophyll Biosynthesis through Transcriptional Regulation of ChlH and GUN4 in Rice Seedlings.
Accurate regulation of chlorophyll synthesis is crucial for chloroplast formation during the greening process in angiosperms. In this study, we examined the role of phytochrome B (phyB) in the regulation of chlorophyll synthesis in rice seedlings (Oryza sativa L.) through the characterization of a pale-green phenotype observed in the phyB mutant grown under continuous red light (Rc) irradiation. Our results show that the Rc-induced chlorophyll accumulation can be divided into two components--a phyB-dependent and a phyB-independent component, and that the pale-green phenotype is caused by the absence of the phyB-dependent component. To elucidate the role of the missing component we established an Rc-induced greening experiment, the results of which revealed that several genes encoding proteins on the chlorophyll branch were repressed in the phyB mutant. Notable among them were ChlH and GUN4 genes, which encode subunit H and an activating factor of magnesium chelatase (Mg-chelatase), respectively, that were largely repressed in the mutant. Moreover, the kinetic profiles of chlorophyll precursors suggested that Mg-chelatase activity simultaneously decreased with the reduction in the transcript levels of ChlH and GUN4. These results suggest that phyB mediates the regulation of chlorophyll synthesis through transcriptional regulation of these two genes, whose products exert their action at the branching point of the chlorophyll biosynthesis pathway. Reduction of 5-aminolevulinic acid (5-ALA) synthesis could be detected in the mutant, but the kinetic profiles of chlorophyll precursors indicated that it was an event posterior to the reduction of the Mg-chelatase activity. It means that the repression of 5-ALA synthesis should not be a triggering event for the appearance of the pale-green phenotype. Instead, the repression of 5-ALA synthesis might be important for the subsequent stabilization of the pale-green phenotype for preventing excessive accumulation of hazardous chlorophyll precursors, which is an inevitable consequence of the reduction of Mg-chelatase activity.


Structure-Function Analysis in Patients With Intermediate Age-Related Macular Degeneration.
To examine the topographic correlation between retinal morphology and retinal sensitivity by mesopic and scotopic fundus-controlled perimetry (FCP) in eyes with intermediate AMD. Thirty-five eyes from 32 patients (mean age 70.9 years) and 29 age-matched controls prospectively underwent spectral-domain optical coherence tomography (SD-OCT) imaging. Mesopic (Goldman III, 200 ms, 4-2 strategy) and scotopic (Goldman V, 200 ms, 4-2 strategy) FCP with a 56-stimulus point grid was performed in AMD patients with the MP-1S. Thickness values of different retinal layers were measured at each stimulus point and compared, topographically corresponding to values in controls of similar age for pointwise structural-functional analysis. The overall mean sensitivity in patients was 16.9 ± 3.0 dB for mesopic and 14.0 ± 3.7 dB for scotopic testing. Within the central 4° of the macula, reduced mesopic and scotopic sensitivity values were found (P < 0.0001). These findings correlated to central increasing retinal pigment epithelium-drusen complex (RPEDC) thickness and central decreasing outer nuclear layer (ONL) and photoreceptor (PR)-segments thickness (P < 0.0001, respectively). Structure-function correlations revealed that a reduction of mesopic and scotopic sensitivity was associated with increasing thickness of the total retina and the RPEDC and a decrease of the ONL and the PR-segments (P < 0.001, respectively). Accumulation of sub-RPE material in patients with intermediate AMD is spatially associated to quantifiable structural alterations in various retinal layers and to corresponding retinal dysfunction. The topographic analysis of retinal thickness and retinal sensitivity will be helpful for a better understanding of the disease process and for the evaluation of new interventional approaches.


Quantitative rainbow schlieren deflectometry.
In the rainbow schlieren apparatus, a continuously graded rainbow filter is placed in the back focal plane of the decollimating lens. Refractive-index gradients in the test section thus appear as gradations in huerather than irradiance. Asimple system is described wherein a conventional color CCD array and video digitizer are used to quantify accurately the color attributes of the resulting image, and hence the associated ray deflections. The present system provides a sensitivity comparable with that of conventional interferometry, while being simpler to implement and less sensitive to mechanical misalignment.


Forecasting the effectiveness of indoor residual spraying for reducing dengue burden.
Historically, mosquito control programs successfully helped contain malaria and yellow fever, but recent efforts have been unable to halt the spread of dengue, chikungunya, or Zika, all transmitted by Aedes mosquitoes. Using a dengue transmission model and results from indoor residual spraying (IRS) field experiments, we investigated how IRS-like campaign scenarios could effectively control dengue in an endemic setting. In our model, we found that high levels of household coverage (75% treated once per year), applied proactively before the typical dengue season could reduce symptomatic infections by 89.7% (median of 1000 simulations; interquartile range [IQR]:[83.0%, 94.8%]) in year one and 78.2% (IQR: [71.2%, 88.0%]) cumulatively over the first five years of an annual program. Lower coverage had correspondingly lower effectiveness, as did reactive campaigns. Though less effective than preventative campaigns, reactive and even post-epidemic interventions retain some effectiveness; these campaigns disrupt inter-seasonal transmission, highlighting an off-season control opportunity. Regardless, none of the campaign scenarios maintain their initial effectiveness beyond two seasons, instead stabilizing at much lower levels of benefit: in year 20, median effectiveness was only 27.3% (IQR: [-21.3%, 56.6%]). Furthermore, simply ceasing an initially successful program exposes a population with lowered herd immunity to the same historical threat, and we observed outbreaks more than four-fold larger than pre-intervention outbreaks. These results do not take into account evolving insecticide resistance, thus long-term effectiveness may be lower if new, efficacious insecticides are not developed. Using a detailed agent-based dengue transmission model for Yucatán State, Mexico, we predict that high coverage indoor residual spraying (IRS) interventions can largely eliminate transmission for a few years, when applied a few months before the typical seasonal epidemic peak. However, vector control succeeds by preventing infections, which precludes natural immunization. Thus, as a population benefits from mosquito control, it gradually loses naturally acquired herd immunity, and the control effectiveness declines; this occurs across all of our modeled scenarios, and is consistent with other empirical work. Long term control that maintains early effectiveness would require some combination of increasing investment, complementary interventions such as vaccination, and control programs across a broad region to diminish risk of importation.


Propagating depolarization in anisotropic human and canine cardiac muscle: apparent directional differences in membrane capacitance. A simplified model for selective directional effects of modifying the sodium conductance on Vmax, tau foot, and the propagation safety factor.
As yet there is no model or simulation that accounts for the anisotropic difference in the shape of the upstroke and safety factor of propagating cardiac action potentials: fast upstrokes occur with slow transverse propagation and slow upstrokes occur with fast longitudinal propagation. The purpose of this paper is to demonstrate, however, that a simplified cable model based on directional differences in the effective membrane capacitance predicts in detail the experimentally measured directionally dependent behavior of the upstroke in response to modification of the sodium conductance. Quinidine and lidocaine produced greater relative decreases in Vmax and conduction velocity with longitudinal propagation than with transverse propagation, as predicted on the basis that the shape differences should produce an anisotropic distribution in the membrane uptake of sodium channel binding drugs. The simulation predictions of the effects of positive shifts of the take-off potential due to premature action potentials were also confirmed experimentally: there was a greater relative decrease in conduction velocity, Vmax, and Vamp with a greater increase in tau foot during longitudinal propagation than with transverse propagation. The major anisotropic differences in shape occurred when the take-off potential approached the least negative value that produced a propagated response. The extensive experimental verification of the results of a simplified model based on directional differences of effective membrane capacitance, combined with directional differences in effective axial resistivity, provides an initial quantitative basis for the anisotropic behavior of propagating depolarization in response to modification of the sodium conductance in cardiac muscle.


Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation.
Perichondrium in fetal limb is composed of undifferentiated mesenchymal cells. However, the multipotency of cells in this region and the role of perichondrium in bone marrow formation are not well understood. In this report, we purified and characterized perichondrial cells using a monoclonal antibody against activated leukocyte cell adhesion molecule (ALCAM) and investigated the role of perichondrial cells in hematopoietic bone marrow formation. ALCAM is expressed on hematopoietic cells, endothelial cells, bone marrow stromal cells, and mesenchymal stem cells and mediates homophilic (ALCAM-ALCAM)/heterophilic (ALCAM-CD6) cell adhesion. Here we show by immunohistochemical staining that ALCAM is expressed in perichondrium. ALCAM+ perichondrial cells isolated by FACS exhibit the characteristics of mesenchymal stem cells. ALCAM+ cells can differentiate into osteoblasts, adipocytes, chondrocytes, and stromal cells, which can support osteoclastogenesis, hematopoiesis, and angiogenesis. Furthermore, the addition of ALCAM-Fc or CD6-Fc to the metatarsal culture, the invasion of the blood vessels to a cartilage was inhibited. Our findings indicate that ALCAM+ perichondrial cells participate in vascular invasion by recruiting osteoclasts and vessels. These findings suggest that perichondrium might serve as a stem cell reservoir and play an important role in the early development of a bone and bone marrow.


Ethnic differences in stillbirth and early neonatal mortality in The Netherlands.
Ethnic disparities in perinatal mortality are well known. This study aimed to explore the contribution of demographic, socioeconomic, health behavioural and pre-existent medical risk factors among different ethnic groups on fetal and early neonatal mortality. We assessed perinatal mortality from 24.0 weeks' gestation onwards in 554 234 singleton pregnancies of nulliparous women in the linked Netherlands Perinatal Registry over the period 2000-2006. Logistic regression modelling was used. Considerable ethnic differences in perinatal mortality exist especially in fetal mortality. Maternal age, socioeconomic status and pre-existent diseases could not explain these ethnic differences. Late booking visit could explain some differences. Compared with the Dutch, African women had an increased fetal mortality risk of OR 1.7 (95% CI 1.4 to 2.1); South Asian women, 1.8 (1.4 to 2.3); other non-Western women, 1.3 (1.1 to 1.6) and Turkish/Moroccan women, 1.3 (1.1 to 1.4). The risk on early neonatal mortality was only increased in other non-Western women, OR 1.3 (1.0 to 1.8). Ethnic differences were even present in the women without risk factors including preterm births. Mortality risk for East Asian and other Western women was lower or comparable with the Dutch. Important ethnic differences in fetal mortality exist, especially among women of African and South Asian origin. Ethnic minorities should be more acquainted with the significance of early start of prenatal care. Tailored prenatal care for women with African and South Asian origin seems necessary. More research on underlying cause of deaths is needed by ethnic group.


An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.
There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil with ∼3,600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole-resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode of action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Additional tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens.


Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. COALITION COVID-19 Brazil and EMS.


Device-guided breathing to lower blood pressure: case report and clinical overview.
The belief that breathing exercises may provide health benefits has been shared by many cultures for centuries. A case study illustrates one such FDA-approved intervention, its performance over time, and the day-to-day home blood pressure (BP) variation in response to treatment. The device used by this patient (which interactively entrains slowed and deep breathing) has been studied in 7 clinical trials. Routine use of the device (RESPeRATE, InterCure Inc., Fort Lee, New Jersey; www.resperate.com/MD) significantly lowered home and office BPs without adverse effects, when used alone, with lifestyle modifications, or adjunctively to antihypertensive drugs. The proposed physiological mechanism(s), the technology that guides slowed breathing, pooled clinical research outcomes, and recommendations regarding this modality in clinical practice are also reviewed. Device-guided paced breathing may offer an effective, simple, and new nonpharmacologic option for treating high BP without additional side effects, but like all lifestyle modifications, must be practiced consistently to provide benefits.


An emerging HIV risk environment: a preliminary epidemiological profile of an MSM POZ Party in New York City.
To develop a preliminary epidemiological description of a men who have sex with men (MSM) "POZ Party," an emerging sex environment for HIV+ MSM. As part of a pilot study in New York City in 2003, data were collected using a brief, behavioural intercept survey at entry to POZ Party events. Domains include demographic characteristics, history of HIV infection, motivations for attending POZ parties, lifetime and recent exposure to drugs (including use during POZ Party events), and recent sexual practices (both within both POZ Party venues as well as in non-POZ Party venues). Predominantly white and over the age of 30, subjects in the sample include a broad range of years living with HIV infection. Motivations for using a POZ Party venue for sexual partnering include relief from burdens for serostatus disclosure, an interest in not infecting others, and opportunities for unprotected sexual exchange. High rates of unprotected sex with multiple partners are prevalent in the venue. Although the sample evidences high rates of lifetime exposure to illicit drugs, relatively little drug use was reported in these sexual environments. These reports are consistent with evidence from direct observation at the venues themselves, in which no drug use was apparent. Serosorting among HIV+ MSM may reduce new HIV infections, a stated interest of both POZ Party organisers and participants alike. However, high rates of unprotected anal intercourse within these venues signal continued risk for STIs. Additionally, unprotected sexual contact with HIV partners and status unknown partners outside POZ Party venues heightens concern for diffusion of HIV superinfection.


The Hispanic mortality advantage and ethnic misclassification on US death certificates.
We tested the data artifact hypothesis regarding the Hispanic mortality advantage by investigating whether and to what degree this advantage is explained by Hispanic origin misclassification on US death certificates. We used the National Longitudinal Mortality Study, which links Current Population Survey records to death certificates for 1979 through 1998, to estimate the sensitivity, specificity, and net ascertainment of Hispanic ethnicity on death certificates compared with survey classifications. Using national vital statistics mortality data, we estimated Hispanic age-specific and age-adjusted death rates, which were uncorrected and corrected for death certificate misclassification, and produced death rate ratios comparing the Hispanic with the non-Hispanic White population. Hispanic origin reporting on death certificates in the United States is reasonably good. The net ascertainment of Hispanic origin is just 5% higher on survey records than on death certificates. Corrected age-adjusted death rates for Hispanics are lower than those for the non-Hispanic White population by close to 20%. The Hispanic mortality paradox is not explained by an incongruence between ethnic classification in vital registration and population data systems.


Neurotensin, substance P, and insulin enhance cell migration.
Neurotensin, substance P, and insulin have been demonstrated to improve wound healing in vivo. However, the mechanism behind their effect is still not fully understood. This study investigates the effects leading to enhanced scratch closure by these peptides in vitro. The skin keratinocyte cell line, HaCaT, was used to test scratch closure effects of the peptides and alterations of cytokine levels. HUVEC cells were used to test the angiogenic effect of the peptides. Furthermore, clinical isolates of Staphylococcus lugdunensis were used to examine the potential antimicrobial activity of each peptide. Our results demonstrate that neurotensin, substance P, and insulin had significant migratory effects in scratch assays were neurotensin had the lowest effect. Furthermore, we investigated use of the peptides in combination. When substance P was used in combination with neurotensin, the cell migratory capacity was decreased, and the peptides showed a negative correlation (r = -0.298, P < .001). Neurotensin and insulin significantly increased levels of monocyte chemoattractant protein-1 (P < .001) secreted from white blood cells, whereas substance P showed a tendency. Interestingly, neurotensin increased the level of monocyte chemoattractant protein-1 significantly compared to substance P (P < .01). Additionally, the peptides decreased TNFα mRNA levels (P < .001) in HaCaT cells, whereas only neurotensin and insulin decreased IL-8 mRNA (P < .001) but had no significant effect on IL-6 mRNA levels. Surprisingly, substance P increased IL-6 mRNA 9-fold (P < .001). Furthermore, we demonstrate that the peptides increased angiogenesis in the HUVEC cells (P < .001). Finally, S. lugdunensis isolates were not susceptible to the peptides. We demonstrate that the peptides worked differently on HaCaT cells, but substance P acted differently than neurotensin on cytokine levels expression as well as on migration of HaCaT cells. On the contrary, neurotensin and insulin worked similarly. All of these aspects are crucial for proper wound healing, and the results suggest multiple mechanisms for wound-healing properties of these peptides.


An Ecological Momentary Assessment of Cigarette and Cigar Dual Use Among African American Young Adults.
The dual use of cigarettes and cigars among African American young adults is a significant public health issue. Patterns of and reasons for dual use are difficult to capture using traditional self-report methods. This study used ecological momentary assessment (EMA) to characterize patterns of dual smoking and examine the personal and environmental predictors of cigarette and cigar smoking among African American young adult dual users (ages 18-29) in real-time. For 14 days, 64 participants smoked ad libitum and were prompted four times daily to record their smoking, craving, emotions, social smoking, and environment via text message on their mobile phones. The odds of single product and dual use were examined using adjusted generalized estimating equations. Participants smoked an average of 7.9 cigarettes and 4.2 cigars per day. Cigarettes and cigars were smoked as frequently during periods of dual use as they were during periods of single product use. Cigarette craving was positively associated with cigarette-only smoking (OR: 1.07), whereas cigar craving was positively associated with cigar-only smoking (OR: 1.43) and dual use (OR: 1.08). Cigars had the greatest odds of dual use when with others (OR: 4.69) and in others' homes (OR: 4.33). Cigarettes had the greatest odds of being smoked while alone (OR: 1.57). EMA was useful for capturing variable smoking patterns and predictors. In this study population, cigarettes and cigars appeared to be smoked additively, and cigars smoked socially. These findings can inform future interventions addressing dual use in this high priority population. This is the first study to use EMA to examine naturalistic patterns and predictors of multiple tobacco use in real-time. African American young adults smoked cigarettes and cigars during periods of dual use as frequently as during periods of single product use. This suggests that most use was additive (one product smoked in addition to another) and less often as substitution (one product smoked instead of another). Social smoking and craving were strongly associated with cigar smoking in single and dual use periods. This study suggests the need for cessation messaging specifically targeted to reduce dual use in this population.


The dynamics in implantation for patients with clefts.
To investigate the stresses and strains of an endosseous dental implant in patients with different types of cleft palate in a finite element model. Seven three-dimensional (3D) maxillary models were designed on a personal computer according to computed tomography slice data obtained from seven dry skulls. Next, computer-aided modification was performed on each model to produce three other 3D models with different cleft patterns. Thus, four model types with different cleft patterns were designed and termed NORM (without cleft), ALVEOLAR (only alveolar cleft), PALATAL (only palatal cleft), and COMPLETE (complete cleft). An implant was embedded into the molar region of each model, and a 300-N vertical load and 50-N horizontal load were applied to simulate mastication. Under these conditions, the stresses occurring at the implant-bone interface were calculated by finite element analysis. Different stress patterns were observed between the models with a palatal cleft (PALATAL and COMPLETE) and those without palatal cleft (NORM and ALVEOLAR). Regarding vertical load application, greater stresses occurred in PALATAL and COMPLETE types than in NORM and ALVEOLAR types. On application of a horizontal load, though the stresses did not show quantitative difference, their vector patterns differed. In patients with palatal clefts, characteristic stress patterns occur on the bone-implant interface during mastication. This should be taken into consideration when performing an implant treatment in patients with clefts.


Continuing professional development and the charity paradigm: interrelated individual, collective and organisational issues about continuing professional development.
This paper aims to highlight some issues and tensions that currently challenge the profession, individual nurses and their employers when considering the need for continuing professional development. The Nursing and Midwifery Council states the professional requirements for continuing professional development. However the nature and type required seems to be determined by the individual on the one hand and the organisation on the other, rather than an integral part of professional activity within the context of work. This can lead to a mismatch between personal and organisational goals. Views emerged from participants in a previous case study that focused on learning through work, about support available to nurses for professional development. The perceptions of nurses and their managers about learning through work were explored, using semi structured interviews, picture mapping and structured interviews. The 'Charity Paradigm' is presented as an outcome of major issues within an organisation. It underpins negative perceptions of individuals about employer support of continuing professional development. It is suggested that there is a need for collaborative collective approaches to structured development in order to meet both individual and organisational needs. This is also advocated in order to achieve life long learning and transformational learning within an organisation. The tension between individual personal ambitions and employer demands can adversely affect the professional development of the practitioner and the organisation that employs them. The personal perspectives of nurses and managers about learning within their organisation are therefore important to acknowledge in terms of positive and negative influences. It is also necessary to recognise the contribution of the employer as well as the identifiable charitable contribution of individual practitioners and the input from external contributors to the organisation.