A systematic review of oxymorphone in the management of chronic pain.
Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has recently been launched. The aim of this review was to assess the effectiveness of oxymorphone as an analgesic in chronic pain. A systematic search for published studies of oral oxymorphone in the management of chronic pain was conducted. The studies were evaluated for their internal validity according to standard criteria. They were also evaluated for their external validity and research ethic aspects. A meta-analysis was performed to examine the effect of oxymorphone compared with placebo. Nine studies were evaluated; three were excluded because of low quality. Six controlled studies (duration 2-12 weeks) included a total of 1489 subjects suffering from chronic low back pain, chronic pain from osteoarthritis, and chronic cancer pain. Three of the studies were of high quality and three of medium quality. External validity was assessed to be high, medium, and low (in one, three, and two studies, respectively). The meta-analysis suggests that daily doses of 40-100mg are superior to placebo; however, the estimate (reduction of pain intensity compared with placebo) of the treatment effect is imprecise (95% confidence interval -17.08, -8.69). Limited evidence suggests that oxymorphone is effective for pain control in patients with cancer. No significant differences between oxymorphone and oxycodone at equipotent doses were found. In conclusion, oxymorphone is superior to placebo. There is no evidence that the efficacy of oxymorphone differs from other opioids.


Role of FAAH-like anandamide transporter in anandamide inactivation.
The endocannabinoid system modulates numerous physiological processes including nociception and reproduction. Anandamide (AEA) is an endocannabinoid that is inactivated by cellular uptake followed by intracellular hydrolysis by fatty acid amide hydrolase (FAAH). Recently, FAAH-like anandamide transporter (FLAT), a truncated and catalytically-inactive variant of FAAH, was proposed to function as an intracellular AEA carrier and mediate its delivery to FAAH for hydrolysis. Pharmacological inhibition of FLAT potentiated AEA signaling and produced antinociceptive effects. Given that endocannabinoids produce analgesia through central and peripheral mechanisms, the goal of the current work was to examine the expression of FLAT in the central and peripheral nervous systems. In contrast to the original report characterizing FLAT, expression of FLAT was not observed in any of the tissues examined. To investigate the role of FLAT as a putative AEA binding protein, FLAT was generated from FAAH using polymerase chain reaction and further analyzed. Despite its low cellular expression, FLAT displayed residual catalytic activity that was sensitive to FAAH inhibitors and abolished following mutation of its catalytic serine. Overexpression of FLAT potentiated AEA cellular uptake and this appeared to be dependent upon its catalytic activity. Immunofluorescence revealed that FLAT localizes primarily to intracellular membranes and does not contact the plasma membrane, suggesting that its capability to potentiate AEA uptake may stem from its enzymatic rather than transport activity. Collectively, our data demonstrate that FLAT does not serve as a global intracellular AEA carrier, although a role in mediating localized AEA inactivation in mammalian tissues cannot be ruled out.


Stimulating basic reading processes using auditory discrimination in depth.
Recent research indicates that a major cause of reading (decoding) disabilities lies in an inability to manipulate speech at its phonemic (phonological) level. The Auditory Discrimination in Depth Program (ADD Program), stimulates basic phonological awareness and has been used extensively at The Reading Foundation in Calgary, Alberta. Here we present pre- and post-test data from 281 clients (ranging from school-age through adulthood) seen over a two-year period; post-test data was collected after 80 hours of ADD instruction. To assess whether significant gains had been achieved, an analysis of covariance was performed, covarying for age and initial vocabulary scores. After 80 hours of intensive instruction, highly significant gains (p<.001) were evident on measures of phonological awareness, sound/symbol connections, word identification, spelling, and decoding in context. In addition to the treatment effect, age and vocabulary had some influence on some of the variables. The data was also analyzed to determine whether the results went beyond a "group effect" only. A total of 229 cases were tabulated for gains or losses on the word attack subtest and on the reading and spelling subtests of the WRAT-R. Results indicate that the remediation was effective for all subjects, though gains on spelling tended to be less than on the two reading scores.


Positional adaptation reveals multiple chromatic mechanisms in human vision.
Precortical color vision is mediated by three independent opponent or cardinal mechanisms that linearly combine receptoral outputs to form L/M, S/(L+M), and L+M channels. However, data from a variety of psychophysical and physiological experiments indicate that chromatic processing undergoes a reorganization away from the basic opponent model. Frequently, this post-opponent reorganization is viewed in terms of the generation of multiple "higher order" chromatic mechanisms, tuned to a wide variety of axes in color space. Moreover, adaptation experiments have revealed that the synthesis of these mechanisms occurs at a level in the cortex following the binocular integration of the inputs from each eye. Here we report results from an experiment in which the influence of chromatic adaptation on the perceived visual location of a test stimulus was explored using a Vernier alignment task. The results indicate that not only is positional information processed independently within the L/M, S/(L+M), and L+M channels, but that when adapting and test stimuli are extended to non-cardinal axes, the existence of multiple chromatically tuned mechanisms is revealed. Most importantly, the effects of chromatic adaptation on this task exhibit little interocular transfer and have rapid decay rates, consistent with chromatic as opposed to contrast adaptation. These findings suggest that the reorganization of chromatic processing may take place earlier in the visual pathway than previously thought.


Eph receptors are involved in the activity-dependent synaptic wiring in the mouse cerebellar cortex.
Eph receptor tyrosine kinases are involved in many cellular processes. In the developing brain, they act as migratory and cell adhesive cues while in the adult brain they regulate dendritic spine plasticity. Here we show a new role for Eph receptor signalling in the cerebellar cortex. Cerebellar Purkinje cells are innervated by two different excitatory inputs. The climbing fibres contact the proximal dendritic domain of Purkinje cells, where synapse and spine density is low; the parallel fibres contact the distal dendritic domain, where synapse and spine density is high. Interestingly, Purkinje cells have the intrinsic ability to generate a high number of spines over their entire dendritic arborisations, which can be innervated by the parallel fibres. However, the climbing fibre input continuously exerts an activity-dependent repression on parallel fibre synapses, thus confining them to the distal Purkinje cell dendritic domain. Such repression persists after Eph receptor activation, but is overridden by Eph receptor inhibition with EphA4/Fc in neonatal cultured cerebellar slices as well as mature acute cerebellar slices, following in vivo infusion of the EphA4/Fc inhibitor and in EphB receptor-deficient mice. When electrical activity is blocked in vivo by tetrodotoxin leading to a high spine density in Purkinje cell proximal dendrites, stimulation of Eph receptor activation recapitulates the spine repressive effects of climbing fibres. These results suggest that Eph receptor signalling mediates the repression of spine proliferation induced by climbing fibre activity in Purkinje cell proximal dendrites. Such repression is necessary to maintain the correct architecture of the cerebellar cortex.


Conflicting selection pressures on synonymous codon use in yeast suggest selection on mRNA secondary structures.
Eukaryotic mRNAs often contain secondary structures in their untranslated regions that are involved in expression regulation. Whether secondary structures in the protein coding regions are of functional importance remains unclear: laboratory studies suggest stable secondary structures within the protein coding sequence interfere with translation, while several bioinformatic studies indicate stable mRNA structures are more frequent than expected. In contrast to several studies testing for unexpected structural stabilities, I directly compare the selective constraint of sites that differ in their structural importance. I.e. for each nucleotide, I identify whether it is paired with another nucleotide, or unpaired, in the predicted secondary structure. I assume paired sites are more important for the predicted secondary structure than unpaired sites. I look at protein coding yeast sequences and use optimal codons and synonymous substitutions to test for structural constraints. As expected under selection for secondary structures, paired sites experience higher constraint than unpaired sites, i.e. significantly lower numbers of conserved optimal codons and consistently lower numbers of synonymous substitutions. This is true for structures predicted by different algorithms. The results of this study are consistent with purifying selection on mRNA secondary structures in yeast protein coding sequences and suggest their biological importance. One should be aware, however, that accuracy of structure prediction is unknown for mRNAs and interrelated selective forces may contribute as well. Note that if selection pressures alternative to translational selection affect synonymous (and optimal) codon use, this may lead to under- or over-estimates of selective strength on optimal codon use depending on strength and direction of translational selection.


Elastic to Plastic Deformation in Uniaxially Stressed Polylelectrolyte Multilayer Films.
Polyelectrolyte multilayer (PEM) are thin polymeric films produced by alternating adsorption of positively and negatively charged polyelectrolytes (PE) on a substrate. These films are considered drug delivery agents as well as coating material for implants, due to their antibiofouling and biologically benign properties. For these reasons the film mechanical properties as well as response to mechanical stress are important measurement parameters. Especially intriguing is the correlation of the mechanical properties of PEM on macroscopic level with the structure of PEM on molecular level, which is addressed here for the first time. This study investigates PEM from PDADMA/PSS produced by spraying technique with neutron and X-ray reflectometry. Reflectometry technique provides precise information on thickness and density (i.e., electron density or scattering length density, respectively), and, this way, allows to conclude on changes in film composition. Thus, neutron and X-ray reflectometry technique is suitable to investigate the overall and the internal transformations, which PEM films might undergo upon exposure to mechanical load. During uniaxial elongation two regimes of PEM-deformation can be observed: An elastic regime at small elongations (below ca. 0.2%), which is characterized by a reversible change of film thickness, and a plastic regime with a permanent change above this limit. Both regimes have in common, that the mechanical load induces an increase of the film thickness, which is accompanied by an uptake of water from the surrounding atmosphere. The strain causes a molecular rearrangement within the PEM-structure of stratified layers, which, even in elastic regime, is permanent, although the thickness change remains reversible.


Nicotine: alcohol reward interactions.
It is well established that the continued intake of drugs of abuse is reinforcing-that is repeated consumption increases preference. This has been shown in some studies to extend to other drugs of abuse; use of one increases preference for another. In particular, the present review deals with the interaction of nicotine and alcohol as it has been shown that smoking is a risk factor for alcoholism and alcohol use is a risk factor to become a smoker. The review discusses changes in the brain caused by chronic nicotine and chronic alcohol intake to approach the possible mechanisms by which one drug increases the preference for another. Chronic nicotine administration was shown to affect nicotine receptors in the brain, affecting not only receptor levels and distribution, but also receptor subunit composition, thus affecting affinity to nicotine. Other receptor systems are also affected among others catecholamine, glutamate, GABA levels and opiate and cannabinoid receptors. In addition to receptor systems and transmitters, there are endocrine, metabolic and neuropeptide changes as well induced by nicotine. Similarly chronic alcohol intake results in changes in the brain, in multiple receptors, transmitters and peptides as discussed in this overview and also illustrated in the tables. The changes are sex and age-dependent-some changes in males are different from those in females and in general adolescents are more sensitive to drug effects than adults. Although nicotine and alcohol interact-not all the changes induced by the combined intake of both are additive-some are opposing. These opposing effects include those on locomotion, acetylcholine metabolism, nicotine binding, opiate peptides, glutamate transporters and endocannabinoid content among others. The two compounds lower the negative withdrawal symptoms of each other which may contribute to the increase in preference, but the mechanism by which preference increases-most likely consists of multiple components that are not clear at the present time. As the details of induced changes of nicotine and alcohol differ, it is likely that the mechanisms of increasing nicotine preference may not be identical to that of increasing alcohol preference. Stimulation of preference of yet other drugs may again be different -representing one aspect of drug specificity of reward mechanisms.


Effect of statin treatment on vasospasm-related morbidity and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.
OBJECTIVE The efficacy of statin therapy in treating aneurysmal subarachnoid hemorrhage (SAH) remains controversial. In this meta-analysis, the authors investigated whether statin treatment significantly reduced the incidence of cerebral vasospasm and delayed neurological deficits, promoting a better outcome after aneurysmal SAH. METHODS A literature search of the PubMed, Ovid, and Cochrane Library databases was performed for randomized controlled trials (RCTs) and prospective cohort studies investigating the effect of statin treatment. The end points of cerebral vasospasm, delayed ischemic neurological deficit (DIND), delayed cerebral infarction, mortality, and favorable outcome were statistically analyzed. RESULTS Six RCTs and 2 prospective cohort studies met the eligibility criteria, and a total of 1461 patients were included. The meta-analysis demonstrated a significant decrease in the incidence of cerebral vasospasm (relative risk [RR] 0.76, 95% confidence interval [CI] 0.61-0.96) in patients treated with statins after aneurysmal SAH. However, no significant benefit was observed for DIND (RR 0.88, 95% CI 0.70-1.12), delayed cerebral infarction (RR 0.66, 95% CI 0.33-1.31), mortality (RR 0.69, 95% CI 0.39-1.24) or favorable outcome, according to assessment by the modified Rankin Scale or Glasgow Outcome Scale (RR 0.99, 95% CI 0.92-1.17). CONCLUSIONS Treatment with statins significantly decreased the occurrence of vasospasm after aneurysmal SAH. The incidence of DIND, delayed cerebral infarction, and mortality were not affected by statin treatment. Future research should focus on DIND and how statins influence DIND.


BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone.
Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists.


Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium-Induced Calcium Release Mechanism.
Free intracellular calcium ([Ca2+]i), in addition to being an important second messenger, is a key regulator of many cellular processes including cell membrane potential, proliferation, and apoptosis. In many cases, the mobilization of [Ca2+]i is controlled by intracellular store activation and calcium influx. We have investigated the effect of several ion channel modulators, which have been used to treat a range of human diseases, on [Ca2+]i release, by ratiometric calcium imaging. We show that six such modulators [amiodarone (Ami), dofetilide, furosemide (Fur), minoxidil (Min), loxapine (Lox), and Nicorandil] initiate release of [Ca2+]i in prostate and breast cancer cell lines, PC3 and MCF7, respectively. Whole-cell currents in PC3 cells were inhibited by the compounds tested in patch-clamp experiments in a concentration-dependent manner. In all cases [Ca2+]i was increased by modulator concentrations comparable to those used clinically. The increase in [Ca2+]i in response to Ami, Fur, Lox, and Min was reduced significantly (P < 0.01) when the external calcium was reduced to nM concentration by chelation with EGTA. The data suggest that many ion channel regulators mobilize [Ca2+]i We suggest a mechanism whereby calcium-induced calcium release is implicated; such a mechanism may be important for understanding the action of these compounds.


Vestibular migraine: An update on current understanding and future directions.
Vestibular migraine is among the most common causes of recurrent vertigo in the general population. Despite its prevalence and high impact on healthcare cost and utilization, it has remained an under-recognized condition with largely unknown pathophysiology. In the present article, we aim to provide an overview of the current understanding of vestibular migraine. We undertook a narrative literature review on the epidemiology, presentations, clinical and laboratory findings, pathophysiology, and treatments of vestibular migraine. Currently, the diagnosis of vestibular migraine relies solely on clinical symptoms since clinical tests of vestibular function are typically normal, or difficult to interpret based on inconsistent results reported in earlier studies. The challenges related to diagnosis of vestibular migraine lie in its relatively broad spectrum of manifestations, the absence of typical migraine headaches with vestibular symptoms, and its very recent definition as a distinct entity. Here, we highlight these challenges, discuss common vestibular symptoms and clinical presentations in vestibular migraine, and review the current aspects of its clinical diagnosis and evaluation. The concepts related to the pathophysiology and treatment of vestibular migraine are also discussed. Vestibular migraine is still underdiagnosed clinically. Future studies are needed to address the pathophysiological mechanisms and investigate effective treatment regimens.


Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.
Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.


Buffalograss germplasm resistance to Blissus occiduus (Hemiptera: Lygaeidae).
Plant germplasm collections may offer genetic variability useful in identifying insect resistance. The goal of this project was to evaluate buffalograss genotypes [Buchloë dactyloides (Nutt.) Engelm.] for resistance to the chinch bug, Blissus occiduus Barber (Hemiptera: Lygaeidae), and to relate resistance to ploidy level, chinch bug number, and pubescence. Forty-eight buffalograss genotypes from diverse geographic locations were evaluated in replicated studies under greenhouse conditions. Of the genotypes studied, four were highly resistant, 22 were moderately resistant, 19 were moderately susceptible, and three were highly susceptible to chinch bug damage. The mean number of chinch bugs was significantly different among the 48 genotypes. There was no significant correlation between chinch bug resistance and ploidy level or chinch bug resistance and pubescence. These results indicate the genetic source of resistance to chinch bugs exists in buffalograss germplasm. Highly resistant genotypes can be used in breeding programs to further improve buffalograss cultivars.


Sensitivity and Specificity of Computer-Based Neurocognitive Tests in Sport-Related Concussion: Findings from the NCAA-DoD CARE Consortium.
To optimally care for concussed individuals, a multi-dimensional approach is critical and a key component of this assessment in the athletic environment is computer-based neurocognitive testing. However, there continues to be concerns about the reliability and validity of these testing tools. The purpose of this study was to determine the sensitivity and specificity of three common computer-based neurocognitive tests (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT], CNS Vital Signs, and CogState Computerized Assessment Tool [CCAT]), to provide guidance on their clinical utility. This study analyzed assessments from a cohort of collegiate athletes and non-varsity cadets from the NCAA-DoD CARE Consortium. The data were collected from 2014-2018. Study participants were divided into two testing groups [concussed, n = 1414 (baseline/24-48 h) and healthy, n = 8305 (baseline/baseline)]. For each test type, change scores were calculated for the components of interest. Then, the Normative Change method, which used normative data published in a similar cohort, and the Reliable Change Index (RCI) method were used to determine if the change scores were significant. Using the Normative Change method, ImPACT performed best with an 87.5%-confidence interval and 1 number of components failed (NCF; sensitivity = 0.583, specificity = 0.625, F1 = 0.308). CNS Vital Signs performed best with a 90%-confidence interval and 1 NCF (sensitivity = 0.587, specificity = 0.532, F1 = 0.314). CCAT performed best when using a 75%-confidence interval and 2 NCF (sensitivity = 0.513, specificity = 0.715, F1 = 0.290). When using the RCI method, ImPACT performed best with an 87.5%-confidence interval and 1 NCF (sensitivity = 0.626, specificity = 0.559, F1 = 0.297). When considering all three computer-based neurocognitive tests, the overall low sensitivity and specificity results provide additional evidence for the use of a multi-dimensional assessment for concussion diagnosis, including symptom evaluation, postural control assessment, neuropsychological status, and other functional assessments.


Caenorhabditis elegans Show Preference for Stimulants and Potential as a Model Organism for Medications Screening.
The nematode Caenorhabditis elegans (C. elegans) is a popular invertebrate model organism to study neurobiological disease states. This is due in part to the intricate mapping of all neurons and synapses of the entire animal, the wide availability of mutant strains, and the genetic and molecular tools that can be used to manipulate the genome and gene expression. We have shown that, C. elegans develops a conditioned preference for cues that had previously been paired with either cocaine or methamphetamine exposure that is dependent on dopamine neurotransmission, similar to findings using place conditioning with rats and mice. In the current study, we show C. elegans also display a preference for, and self-exposure to, cocaine and nicotine. This substance of abuse (SOA) preference response can be selectively blocked by pretreatment with naltrexone and is consistent with the recent discovery of an opioid receptor system in C. elegans. In addition, pre-exposure to the smoking cessation treatment varenicline also inhibits self-exposure to nicotine. Exposure to concentrations of treatments that inhibit SOA preference/self-exposure did not induce any significant inhibition of locomotor activity or affect food or benzaldehyde chemotaxis. These data provide predictive validity for the development of high-throughput C. elegans behavioral medication screens. These screens could enable fast and accurate generation of data to identify compounds that may be effective in treating human addiction. The successful development and validation of such models would introduce powerful and novel tools in the search for new pharmacological treatments for substance use disorders, and provide a platform to study the mechanisms that underlie addictions.


'Who assisted with the delivery of (NAME)?' Issues in estimating skilled birth attendant coverage through population-based surveys and implications for improving global tracking.
The percentage of live births attended by a skilled birth attendant (SBA) is a key global indicator and proxy for monitoring progress in maternal and newborn health. Yet, the discrepancy between rising SBA coverage and non-commensurate declines in maternal and neonatal mortality in many low-income and middle-income countries has brought increasing attention to the challenge of what the indicator of SBA coverage actually measures, and whether the indicator can be improved. In response to the 2018 revised definition of SBA and the push for improved measurement of progress in maternal and newborn health, this paper examines the evidence on what women can tell us about who assisted them during childbirth and methodological issues in estimating SBA coverage via population-based surveys. We present analyses based on Demographic and Health Surveys and Multiple Indicator Cluster Surveys conducted since 2015 for 23 countries. Our findings show SBA coverage can be reasonably estimated from population-based surveys in settings of high coverage, though women have difficulty reporting specific cadres. We propose improvements in how skilled cadres are classified and documented, how linkages can be made to facility-based data to examine the enabling environment and further ways data can be disaggregated to understand the complexity of delivery care. We also reflect on the limitations of what SBA coverage reveals about the quality and circumstances of childbirth care. While improvements to the indicator are possible, we call for the use of multiple indicators to inform local efforts to improve the health of women and newborns.


A protocol for a systematic review of effective home support to people with dementia and their carers: components and impacts.
To review the evidence for home support approaches directed at tertiary prevention; ameliorating difficulties and enhancing well-being. With population ageing dementia represents a significant care challenge with 60% of people with dementia living at home. However, little is known about existing forms of home support and their relative effectiveness. A two-stage design: First, an overview of systematic reviews of psychosocial interventions for dementia to identify their components; second, a systematic review of the effectiveness of home support interventions to older people with dementia/their carers. We will search electronic databases using specific search terms with additional searches of other known studies. Data will be extracted by two reviewers according to pre-determined categories. An initial synthesis will elicit components of interventions from stage 1 and operationalize them in terms of specific techniques. These will then be used in synthesis of data in stage 2, to determine the extent to which each home support intervention relies on these components and distill evidence concerning outcomes. Studies from stage 2 are expected to be methodologically diverse; if so, a narrative approach to synthesis will be taken. Study findings will be explored with Patient, Public and Carer Involvement groups. The review seeks to develop a theory of home support: how and why interventions may work; in what contexts; and for whom. We will identify effective home support approaches, informing policy-makers and establishing how they might be experienced by people with dementia and their carers.


Rules for modeling signal-transduction systems.
Formalized rules for protein-protein interactions have recently been introduced to represent the binding and enzymatic activities of proteins in cellular signaling. Rules encode an understanding of how a system works in terms of the biomolecules in the system and their possible states and interactions. A set of rules can be as easy to read as a diagrammatic interaction map, but unlike most such maps, rules have precise interpretations. Rules can be processed to automatically generate a mathematical or computational model for a system, which enables explanatory and predictive insights into the system's behavior. Rules are independent units of a model specification that facilitate model revision. Instead of changing a large number of equations or lines of code, as may be required in the case of a conventional mathematical model, a protein interaction can be introduced or modified simply by adding or changing a single rule that represents the interaction of interest. Rules can be defined and visualized by using graphs, so no specialized training in mathematics or computer science is necessary to create models or to take advantage of the representational precision of rules. Rules can be encoded in a machine-readable format to enable electronic storage and exchange of models, as well as basic knowledge about protein-protein interactions. Here, we review the motivation for rule-based modeling; applications of the approach; and issues that arise in model specification, simulation, and testing. We also discuss rule visualization and exchange and the software available for rule-based modeling.


The therapeutic potential of the endocannabinoid system for Alzheimer's disease.
Dementia currently affects over 35 million people worldwide. The most common form of dementia is Alzheimer's disease (AD). Currently, treatments for AD do not stop or reverse the progression of the disease and they are accompanied by side effects. The main features of AD pathology, treatment options currently available, the endocannabinoid system and its functionality in general and its role in AD pathology in detail will be outlined. A particular focus will be on the therapeutic potential of the phytocannabinoid cannabidiol. Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans.


Phase-demodulation error of a fiber-optic Fabry-Perot sensor with complex reflection coefficients.
The influence of reflector losses attracts little discussion in standard treatments of the Fabry-Perot interferometer yet may be an important factor contributing to errors in phase-stepped demodulation of fiber optic Fabry-Perot (FFP) sensors. We describe a general transfer function for FFP sensors with complex reflection coefficients and estimate systematic phase errors that arise when the asymmetry of the reflected fringe system is neglected, as is common in the literature. The measured asymmetric response of higher-finesse metal-dielectric FFP constructions corroborates a model that predicts systematic phase errors of 0.06 rad in three-step demodulation of a low-finesse FFP sensor (R = 0.05) with internal reflector losses of 25%.


Assessing the Immunosafety of Engineered Nanoparticles with a Novel in Vitro Model Based on Human Primary Monocytes.
The possibility that nanomaterials could perturb the normal course of an inflammatory response is a key issue when assessing nanoimmunosafety. The alteration of the normal progress of an inflammatory response may have pathological consequences, since inflammation is a major defensive mechanism and its efficiency maintains the body's health. The immunosafety of engineered nanoparticles at nontoxic concentrations was investigated with the use of a human primary monocyte-based in vitro system, which reproduces in a simplified fashion the full course of the physiological inflammatory response, from initiation and development to resolution. The kinetics of expression and production of inflammatory and anti-inflammatory cytokines and the proteomic profiles were used for describing the inflammatory defensive response. We assessed the ability of gold and silver nanoparticles to trigger inflammation and to interfere with the course of an ongoing defensive reaction. While neither nanoparticle type was able to directly activate monocytes, silver nanoparticles could exacerbate the inflammatory response of monocytes but did not interfere with the resolution of the inflammatory reaction. These findings support the use of human primary monocyte-based in vitro assays for realistically investigating the effects of engineered nanoparticles on human innate immune responses, in order to predict the immunological risk of nanomaterials and implement safe nanoparticle-based applications.


Translation and cross-cultural adaptation of the Chilean Version of the Voice Activity and Participation Profile - VAPP.
The present study aimed to obtain the cross-culturally-adapted Chilean version of the voice activity and participation profile - VAPP. The process began a with translation of the original English version of the VAPP instrument into Spanish, carried out by two bilingual speech-language pathologists (SLP), followed by a back-translation from a third SLP who was unbiased by the previous stages. A committee of 5 SLP with experience in the area of voice compared the original version, the back translation, and the translated version, seeking divergences and discrepancies between the three versions. A consensus was reached, and they renamed the protocol "Perfil de Participación y Actividad Vocal (PPAV-CL)", with 28 questions which were answered using a visual analog scale (VAS) of 100 millimeters in length. In the process of making the cross-cultural equivalence, the protocol was applied to 24 subjects with voice disorders. For each question, the option of "Not applicable" was added to the answer choices for identification of the questions not comprehended or not appropriate for the target population. None of the subjects under assessment had difficulty answering the questions, therefore it was unnecessary to modify the translation of any of them. The final version of the PPAV-CL shows the appropriate characteristics to be understood. The PPAV-CL instrument reflects the original English version in the number of questions and items. a cultural equivalence of the VAPP to Chilean Spanish was achieved. The validation of the PPAV-CL is currently underway.


ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients.
Healthcare-associated infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB) are a leading cause of morbidity and mortality worldwide. These evidence-based guidelines have been produced after a systematic review of published studies on infection prevention and control interventions aimed at reducing the transmission of MDR-GNB. The recommendations are stratified by type of infection prevention and control intervention and species of MDR-GNB and are presented in the form of 'basic' practices, recommended for all acute care facilities, and 'additional special approaches' to be considered when there is still clinical and/or epidemiological and/or molecular evidence of ongoing transmission, despite the application of the basic measures. The level of evidence for and strength of each recommendation, were defined according to the GRADE approach.


"What about diet?" A qualitative study of cancer survivors' views on diet and cancer and their sources of information.
Given the abundance of misreporting about diet and cancer in the media and online, cancer survivors are at risk of misinformation. The aim of this study was to explore cancer survivors' beliefs about diet quality and cancer, the impact on their behaviour and sources of information. Semi-structured interviews were conducted with adult cancer survivors in the United Kingdom who had been diagnosed with any cancer in adulthood and were not currently receiving treatment (n = 19). Interviews were analysed using Thematic Analysis. Emergent themes highlighted that participants were aware of diet affecting risk for the development of cancer, but were less clear about its role in recurrence. Nonetheless, their cancer diagnosis appeared to be a prompt for dietary change; predominantly to promote general health. Changes were generally consistent with healthy eating recommendations, although dietary supplements and other non-evidence-based actions were mentioned. Participants reported that they had not generally received professional advice about diet and were keen to know more, but were often unsure about information from other sources. The views of our participants suggest cancer survivors would welcome guidance from health professionals. Advice that provides clear recommendations, and which emphasises the benefits of healthy eating for overall well-being, may be particularly well-received.


Post-lactational mammary gland regression: molecular basis and implications for breast cancer.
During pregnancy, there is a massive increase in the number of luminal epithelial cells in the breast, which are destined to become the milk factories after birth. These cells are no longer required when the young are weaned, and are removed in a carefully orchestrated event called involution. In this process, the secretory epithelial cells die and are replaced by adipocytes, which redifferentiate as the epithelium is removed. It is essential that the gland is properly remodelled to a pre-pregnant state so that successful lactation can occur following a subsequent pregnancy. Furthermore, failure to remove unnecessary lactational alveoli during weaning could result in inflammation and tissue damage. Recently, it has been shown that components in the fatty stroma in involuting breast can promote metastasis. Thus, it is important to understand the molecular mechanisms that regulate involution, how these can fail, the consequences of the remodelling process, and how this knowledge can inform us about breast cancer. In this review, I discuss the roles of the JAK-STAT, NF-kappaB and other signalling pathways in the regulation of apoptosis and tissue remodelling during involution.


Has the Rajiv Aarogyasri Community Health Insurance Scheme of Andhra Pradesh Addressed the Educational Divide in Accessing Health Care?
Equity of access to healthcare remains a major challenge with families continuing to face financial and non-financial barriers to services. Lack of education has been shown to be a key risk factor for 'catastrophic' health expenditure (CHE), in many countries including India. Consequently, ways to address the education divide need to be explored. We aimed to assess whether the innovative state-funded Rajiv Aarogyasri Community Health Insurance Scheme of Andhra Pradesh state launched in 2007, has achieved equity of access to hospital inpatient care among households with varying levels of education. We used the National Sample Survey Organization 2004 survey as our baseline and the same survey design to collect post-intervention data from 8623 households in the state in 2012. Two outcomes, hospitalisation and CHE for inpatient care, were estimated using education as a measure of socio-economic status and transforming levels of education into ridit scores. We derived relative indices of inequality by regressing the outcome measures on education, transformed as a ridit score, using logistic regression models with appropriate weights and accounting for the complex survey design. Between 2004 and 2012, there was a 39% reduction in the likelihood of the most educated person being hospitalised compared to the least educated, with reductions observed in all households as well as those that had used the Aarogyasri. For CHE the inequality disappeared in 2012 in both groups. Sub-group analyses by economic status, social groups and rural-urban residence showed a decrease in relative indices of inequality in most groups. Nevertheless, inequalities in hospitalisation and CHE persisted across most groups. During the time of the Aarogyasri scheme implementation inequalities in access to hospital care were substantially reduced but not eliminated across the education divide. Universal access to education and schemes such as Aarogyasri have the synergistic potential to achieve equity of access to healthcare.


A longitudinal moderated mediation model of nonsuicidal self-injury among adolescents.
This study tested a longitudinal moderated mediation model of the engagement in non suicidal self-injury (NSSI) based on Nock's (2009) integrated theoretical model of the development of NSSI. We assessed general predisposing factors (i.e. borderline personality disorder features), precipitating factors (i.e. negative emotions), and NSSI-specific vulnerability factors (i.e. behavioral impulsivity and self-criticism) among 3,600 Chinese secondary school adolescents (56.6 % females, aged between 12 and 18 years). Assessments were conducted for three times, 6 months apart. Results supported the longitudinal mediation model, such that negative emotions mediated the relation of borderline personality disorder features to NSSI. The moderating effects of behavioral impulsivity and self-criticism were both significant, indicating that adolescents with higher levels of both variables were more likely to engage in NSSI. Moreover, behavioral impulsivity made additional contribution to the prediction of future NSSI above and beyond the effects of other risk factors. Findings of this study may help to elucidate the diverse roles of different types of risk factors in the engagement in NSSI, and may also shed new light on our understanding about the nature of this behavior.


Strategies for increasing the efficiency of heterojunction organic solar cells: material selection and device architecture.
Thin-film blends or bilayers of donor- and acceptor-type organic semiconductors form the core of heterojunction organic photovoltaic cells. Researchers measure the quality of photovoltaic cells based on their power conversion efficiency, the ratio of the electrical power that can be generated versus the power of incident solar radiation. The efficiency of organic solar cells has increased steadily in the last decade, currently reaching up to 6%. Understanding and combating the various loss mechanisms that occur in processes from optical excitation to charge collection should lead to efficiencies on the order of 10% in the near future. In organic heterojunction solar cells, the generation of photocurrent is a cascade of four steps: generation of excitons (electrically neutral bound electron-hole pairs) by photon absorption, diffusion of excitons to the heterojunction, dissociation of the excitons into free charge carriers, and transport of these carriers to the contacts. In this Account, we review our recent contributions to the understanding of the mechanisms that govern these steps. Starting from archetype donor-acceptor systems of planar small-molecule heterojunctions and solution-processed bulk heterojunctions, we outline our search for alternative materials and device architectures. We show that non-planar phthalocynanines have appealing absorption characteristics but also have reduced charge carrier transport. As a result, the donor layer needs to be ultrathin, and all layers of the device have to be tuned to account for optical interference effects. Using these optimization techniques, we illustrate cells with 3.1% efficiency for the non-planar chloroboron subphthalocyanine donor. Molecules offering a better compromise between absorption and carrier mobility should allow for further improvements. We also propose a method for increasing the exciton diffusion length by converting singlet excitons into long-lived triplets. By doping a polymer with a phosphorescent molecule, we demonstrate an increase in the exciton diffusion length of a polymer from 4 to 9 nm. If researchers can identify suitable phosphorescent dopants, this method could be employed with other materials. The carrier transport from the junction to the contacts is markedly different for a bulk heterojunction cell than for planar junction cells. Unlike for bulk heterojunction cells, the open-circuit voltage of planar-junction cells is independent of the contact work functions, as a consequence of the balance of drift and diffusion currents in these systems. This understanding helps to guide the development of new materials (particularly donor materials) that can further boost the efficiency of single-junction cells to 10%. With multijunction architectures, we expect that efficiencies of 12-16% could be attained, at which point organic photovoltaic cells could become an important renewable energy source.


Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions.
Glycoprotein hormones influence the development and function of the ovary, testis and thyroid by binding to specific high-affinity receptors. The extracellular domains of these receptors are members of the leucine-rich repeat (LRR) protein superfamily and are responsible for the high-affinity binding. The crystal structure of a glycoprotein hormone, namely human choriogonadotropin (hCG), is known, but neither the receptor structure, mode of hormone binding, nor mechanism for activation, have been established. Despite very low sequence similarity between exon-demarcated LRRs in the receptors and the LRRs of porcine ribonuclease inhibitor (RI), the secondary structures for the two repeat sets are found to be alike Constraints on curvature and beta-barrel geometry from the sequence pattern for repeated beta alpha units suggest that the receptors contain three-dimensional structures similar to that of RI. With the RI crystal structure as a template, models were constructed for exons 2-8 of the receptors. The model for this portion of the choriogonadotropin receptor is complementary in shape and electrostatic characteristics to the surface of hCG at an identified focus of hormone-receptor interaction. The predicted models for the structures and mode of hormone binding of the glycoprotein hormone receptors are to a large extent consistent with currently available biochemical and mutational data. Repeated sequences in beta-barrel proteins are shown to have general implications for constraints on structure. Averaging techniques used here to recognize the structural motif in these receptors should also apply to other proteins with repeated sequences.


Obstructive sleep apnea syndrome as an uncommon cause of fibromyalgia: a case report.
Fibromyalgia syndrome (FMS) is characterized by chronic widespread musculoskeletal pain, stiffness and tenderness at multiple points. Sleep disturbances are common in FMS and patients usually complain about nonrestorative sleep. Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive pharyngeal collapse during sleep. Recurrent arousals from sleep occurs to restore pharyngeal patency in OSAS and this results in increased sympathetic activity and fragmentation of sleep. Sleep disturbances may lead to musculoskeletal pain and some studies suggest a relation between OSAS and FMS. Since OSAS is strongly associated with increased risk of myocardial infarction, cerebrovascular accidents and congestive heart failure, its diagnosis and treatment are of particular importance. Herein we present a female patient with diagnosis of FMS for 10 years who had complaints of morning fatigue, restless sleep, sleepiness during day and snoring besides musculoskeletal symptoms. Severe OSAS was diagnosed after polysomnographic analysis and FMS symptoms were totally improved with nasal continuous positive airway pressure treatment.


In vitro and in vivo trackable titanocene-based complexes using optical imaging or SPECT.
A novel Ti/111In-heterometallic radiotheranostic along with non-radioactive Ti/In, Ti/Lu, and Ti/Y analogues has been reported, thanks to the design of a challenging synthesis of the first titanocene-DOTA ligand. The corresponding titanocene-BODIPY complex was developed for in vitro tracking by optical imaging. The different complexes were characterized and their antiproliferative properties were evaluated on three cancer cell lines (A2780, B16F1, and PC3). As a proof of concept, initial studies in healthy mice were performed with a Ti/111In derivative to obtain information about its uptake, its biodistribution, and its excretion. Confocal microscopy experiments were performed with fluorescent complexes to track it in vitro.


Examining the Preliminary Efficacy of a Dating Violence Prevention Program for Hispanic Adolescents.
The purpose of this study is to evaluate the preliminary efficacy of a dating violence (DV) prevention program for Cuban American adolescents (JOVEN/YOUTH: Juntos Opuestos a la Violence Entre Novios/Together Against Dating Violence). A randomized-controlled experimental design with a delayed condition was used to evaluate the effects on DV victimization and perpetration (N = 82). Self-administrated assessments were completed at baseline, 1 week, 3 months, and 12 months after the intervention to assess for psychological victimization and perpetration and physical and sexual victimization and perpetration. Effect sizes were estimated, and generalized estimating equations were generated to test intervention effects over time and potential gender interactions. The intervention had medium to strong effects on DV victimization and perpetration for male participants but not for females. However, intervention effects were not statistically significant over time. More research is needed to enhance intervention effects of JOVEN on DV outcomes and to evaluate these effects among a larger and more diverse sample.


Casein kinase I-like protein kinases encoded by YCK1 and YCK2 are required for yeast morphogenesis.
Casein kinase I is an acidotropic protein kinase class that is widely distributed among eukaryotic cell types. In the yeast Saccharomyces cerevisiae, the casein kinase I isoform encoded by the gene pair YCK1 and YCK2 is a 60- to 62-kDa membrane-associated form. The Yck proteins perform functions essential for growth and division; either alone supports growth, but loss of function of both is lethal. We report here that casein kinase I-like activity is associated with a soluble Yck2-beta-galactosidase fusion protein in vitro and that thermolabile protein kinase activity is exhibited by a protein encoded by fusion of a temperature-sensitive yck2 allele with lacZ. Cells carrying the yck2-2ts allele arrest at restrictive temperature with multiple, elongated buds containing multiple nuclei. This phenotype suggests that the essential functions of the Yck proteins include roles in bud morphogenesis, possibly in control of cell growth polarity, and in cytokinesis or cell separation. Further, a genetic relationship between the yck2ts allele and deletion of CDC55 indicates that the function of Yck phosphorylation may be related to that of protein phosphatase 2A activity.


In vitro system for modeling influenza A virus resistance under drug pressure.
One of the biggest challenges in the effort to treat and contain influenza A virus infections is the emergence of resistance during treatment. It is well documented that resistance to amantadine arises rapidly during the course of treatment due to mutations in the gene coding for the M2 protein. To address this problem, it is critical to develop experimental systems that can accurately model the selection of resistance under drug pressure as seen in humans. We used the hollow-fiber infection model (HFIM) system to examine the effect of amantadine on the replication of influenza virus, A/Albany/1/98 (H3N2), grown in MDCK cells. At 24 and 48 h postinfection, virus replication was inhibited in a dose-dependent fashion. At 72 and 96 h postinfection, virus replication was no longer inhibited, suggesting the emergence of amantadine-resistant virus. Sequencing of the M2 gene revealed that mutations appeared at between 48 and 72 h of drug treatment and that the mutations were identical to those identified in the clinic for amantadine-resistant viruses (e.g., V27A, A30T, and S31N). Interestingly, we found that the type of mutation was strongly affected by the dose of the drug. The data suggest that the HFIM is a good model for influenza virus infection and resistance generation in humans. The HFIM has the advantage of being a highly controlled system where multiplicity parameters can be directly and accurately controlled and measured.


Functional and neural mechanisms of embodiment: importance of the vestibular system and the temporal parietal junction.
Embodiment, the sense of being localized within one's physical body, is a fundamental aspect of the self. Recent research shows that self and body processing as well as embodiment require distinct brain mechanisms. Here, we review recent clinical and neuroimaging research on multisensory perception and integration as well as mental imagery, pointing out their importance for the coding of embodiment at the temporo-parietal junction (TPJ). Special reference is given to vestibular mechanisms that are relevant for self and embodiment and to methods that interfere experimentally with normal embodiment. We conclude that multisensory and vestibular coding at the TPJ mediates humans' experience as being embodied and spatially situated, and argue that pathologies concerning the disembodied self, such as out-of-body experience or other autoscopic phenomena, are due to deficient multisensory integration at the TPJ.


The Australian Longitudinal Study on Women's Health: Using Focus Groups to Inform Recruitment.
Recruitment and retention of participants to large-scale, longitudinal studies can be a challenge, particularly when trying to target young women. Qualitative inquiries with members of the target population can prove valuable in assisting with the development of effective recruiting techniques. Researchers in the current study made use of focus group methodology to identify how to encourage young women aged 18-23 to participate in a national cohort online survey. Our objectives were to gain insight into how to encourage young women to participate in a large-scale, longitudinal health survey, as well as to evaluate the survey instrument and mode of administration. The Australian Longitudinal Study on Women's Health used focus group methodology to learn how to encourage young women to participate in a large-scale, longitudinal Web-based health survey and to evaluate the survey instrument and mode of administration. Nineteen groups, involving 75 women aged 18-23 years, were held in remote, regional, and urban areas of New South Wales and Queensland. Focus groups were held in 2 stages, with discussions lasting from 19 minutes to over 1 hour. The focus groups allowed concord to be reached regarding survey promotion using social media, why personal information was needed, strategies to ensure confidentiality, how best to ask sensitive questions, and survey design for ease of completion. Recruitment into the focus groups proved difficult: the groups varied in size between 1 and 8 participants, with the majority conducted with 2 participants. Intense recruitment efforts and variation in final focus group numbers highlights the "hard to reach" character of young women. However, the benefits of conducting focus group discussions as a preparatory stage to the recruitment of a large cohort for a longitudinal Web-based health survey were upheld.


Monte Carlo sampling for error propagation in linear regression and applications in isochron geochronology.
Geochronology is essential for understanding Earth's history. The availability of precise and accurate isotopic data is increasing; hence it is crucial to develop transparent and accessible data reduction techniques and tools to transform raw mass spectrometry data into robust chronological data. Here we present a Monte Carlo sampling approach to fully propagate uncertainties from linear regressions for isochron dating. Our new approach makes no prior assumption about the causes of variability in the derived chronological results and propagates uncertainties from both experimental measurements (analytical uncertainties) and underlying assumptions (model uncertainties) into the final age determination. Using synthetic examples, we find that although the estimates of the slope and y-intercept (hence age and initial isotopic ratios) are comparable between the Monte Carlo method and the benchmark "Isoplot" algorithm, uncertainties from the later could be underestimated by up to 60%, which are likely due to an incomplete propagation of model uncertainties. An additional advantage of the new method is its ability to integrate with geological information to yield refined chronological constraints. The new method presented here is specifically designed to fully propagate errors in geochronological applications involves linear regressions such as Rb-Sr, Sm-Nd, Re-Os, Pt-Os, Lu-Hf, U-Pb (with discordant points), Pb-Pb and Ar-Ar.


HoxB8 neutrophils replicate Fcγ receptor and integrin-induced neutrophil signaling and functions.
Neutrophils are short-lived, terminally differentiated leukocytes that form an essential part of host immunity and play a key role in acute and chronic inflammation. The analysis of these important cells is hindered by the fact that neutrophils are not amenable to culture, transfection, or transduction. Conditionally HoxB8-immortalized mouse hematopoietic progenitors are suitable for in vitro differentiation of a range of myeloid cells, including neutrophils. Integrins and FcγRs are cell surface receptors, the ligation of which is required for a range of neutrophil functions that are important in health and disease. We show here that HoxB8 neutrophils express major neutrophil integrins and FcγRs. They respond to FcγR and integrin stimulation in a manner that is comparable with primary neutrophils, in terms of intracellular signaling. HoxB8 neutrophils also perform a range of FcγR/integrin-dependent neutrophil functions, including, generation of reactive oxygen species, degranulation, and chemotaxis. Our findings suggest that HoxB8 neutrophils represent a faithful experimental model system for the analysis of Fc and integrin receptor-dependent neutrophil functions.


Development of bioadhesive transdermal bupivacaine gels for enhanced local anesthetic action.
Topical drug dosage forms such as ointments and creams can be easily removed through wetting, movement and contact. The new bioadhesive formulations with enhanced local anesthetic effects are needed for topical administration. The adhesive capacity of hydroxypropyl methylcellulose (HPMC) was determined by measuring the maximum detachment force and the adhesion work with an auto peeling tester. The release of drug from a HPMC gel was studied according to the drug concentration. Permeation study through the rat skin was performed at 37°C using phosphate buffer solution (pH = 7.4) as a receptor medium. To increase the skin permeation of bupivacaine from the HPMC gels, penetration enhancer such as the saturated and unsaturated fatty acids, the pyrrolidones, the propylene glycol derivatives, the glycerides, and the non-ionic surfactants were incorporated in the bupivacaine-HPMC gels. The local anesthetic effect of the formulated gel preparation was examined using a tail-flick analgesimeter. As the concentration of HPMC increased, the bioadhesive force and viscosity were increased. The rate of drug release was increased with increasing the drug concentration. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the most enhancing effects on drug permeation through the skin. In the rat tail flick test, the area under the efficacy curve of bupivacaine gel containing polyoxyethylene 2-oleyl ether and tetrahydrozoline showed a 2.36-fold increase in anesthetic activity compared to control gel without any additives. The bupivacaine gels containing both penetration enhancer and vasoconstrictor showed enhancement and prolonged efficacy compared to the control gel. To enhance the local anesthetic effects of bupivacaine, the transdermal bupivacaine gel formulation containing penetration enhancer and vasoconstrictor could be developed.


Corticosterone inhibits the lipid-mobilizing effects of oleoyl-estrone in adrenalectomized rats.
Oleoyl-estrone (OE) is an adipose-derived signal that decreases energy intake and body lipid, maintaining energy expenditure and glycemic homeostasis. Glucocorticoids protect body lipid and the metabolic status quo. We studied the combined effects of OE and corticosterone in adrenalectomized female rats: daily OE gavages (0 or 10 nmol/g) and slow-release corticosterone pellets at four doses (0, 0.5, 1.7, and 4.8 mg/d). Intact and sham-operated controls were also included. After 8 d, body composition and plasma metabolites and hormones were measured. OE induced a massive lipid mobilization (in parallel with decreased food intake and maintained energy expenditure). Corticosterone increased fat deposition and inhibited the OE-elicited mobilization of body energy, even at the lowest dose. OE enhanced the corticosterone-induced rise in plasma triacylglycerols, and corticosterone blocked the OE-induced decrease in leptin. High corticosterone and OE increased insulin resistance beyond the effects of corticosterone alone. The presence of corticosterone dramatically affected OE effects, reversing its decrease of body energy (lipid) content, with little or no change on food intake or energy expenditure. The maintenance of glycemia and increasing insulin in parallel to the dose of corticosterone indicate a decrease in insulin sensitivity, which is enhanced by OE. The reversal of OE effects on lipid handling, insulin resistance, can be the consequence of a corticosterone-induced OE resistance. Nevertheless, OE effects on cholesterol were largely unaffected. In conclusion, corticosterone administration effectively blocked OE effects on body lipid and energy balance as well as insulin sensitivity and glycemia.


Distribution and epidemiological characteristics of published individual patient data meta-analyses.
Individual patient data meta-analyses (IPDMAs) prevail as the gold standard in clinical evaluations. We investigated the distribution and epidemiological characteristics of published IPDMA articles. IPDMA articles were identified through comprehensive literature searches from PubMed, Embase, and Cochrane library. Two investigators independently conducted article identification, data classification and extraction. Data related to the article characteristics were collected and analyzed descriptively. A total of 829 IPDMA articles indexed until 9 August 2012 were identified. An average of 3.7 IPDMA articles was published per year. Malignant neoplasms (267 [32.2%]) and circulatory diseases (179 [21.6%]) were the most frequently occurring topics. On average, each IPDMA article included a median of 8 studies (Interquartile range, IQR 5 to 15) involving 2,563 patients (IQR 927 to 8,349). Among 829 IPDMA articles, 229 (27.6%) did not perform a systematic search to identify related studies. In total, 207 (25.0%) sought and included individual patient data (IPD) from the "grey literature". Only 496 (59.8%) successfully obtained IPD from all identified studies. The number of IPDMA articles exhibited an increasing trend over the past few years and mainly focused on cancer and circulatory diseases. Our data indicated that literature searches, including grey literature and data availability were inconsistent among different IPDMA articles. Possible biases may arise. Thus, decision makers should not uncritically accept all IPDMAs.


Safety and efficacy of large balloon sphincteroplasty in a third care hospital.
large balloon sphincteroplasty (LBS) associated with sphincterotomy (ES) has gained acceptance as a useful tool in extracting difficult bile duct stones. Our purpose was to evaluate the efficacy and safety of LBS with balloons > or = 10 mm in clinical practice setting. unicentre prospective study in a tertiary care hospital. All patients who underwent LBS associated with ES between July 2007 and March 2011 were included prospectively in a database recording clinical aspects, procedure data, outcome and complications.Success is the main outcome defined as complete stone removal documented by absence of any filling defect during a final occlusion cholangiogram and absence of clinical or radiological findings after the ERCP consistent with remaining stones. Complications as pancreatitis, cholangitis, post-ERCP bleeding, perforation and others were also measured. one hundred twenty procedures were made in 109 patients with balloons ranging from 10 to 20 mm. Success rate was 91% in the first attempt and 96.7% after two procedures. Mechanical lithotripsy was only needed in one case (0.8%). Complication rate was 4.2% due to five cases of post-ERCP bleeding in high risk patients. large balloon sphincteroplasty associated to sphincterotomy in clinical practice is a very effective and safe technique.


Consciousness and attention: on sufficiency and necessity.
Recent research has slowly corroded a belief that selective attention and consciousness are so tightly entangled that they cannot be individually examined. In this review, we summarize psychophysical and neurophysiological evidence for a dissociation between top-down attention and consciousness. The evidence includes recent findings that show subjects can attend to perceptually invisible objects. More contentious is the finding that subjects can become conscious of an isolated object, or the gist of the scene in the near absence of top-down attention; we critically re-examine the possibility of "complete" absence of top-down attention. We also cover the recent flurry of studies that utilized independent manipulation of attention and consciousness. These studies have shown paradoxical effects of attention, including examples where top-down attention and consciousness have opposing effects, leading us to strengthen and revise our previous views. Neuroimaging studies with EEG, MEG, and fMRI are uncovering the distinct neuronal correlates of selective attention and consciousness in dissociative paradigms. These findings point to a functional dissociation: attention as analyzer and consciousness as synthesizer. Separating the effects of selective visual attention from those of visual consciousness is of paramount importance to untangle the neural substrates of consciousness from those for attention.


DNA damage in human skin and the capacities of natural compounds to modulate the bystander signalling.
Human skin is a stratified organ frequently exposed to sun-generated ultraviolet radiation (UVR), which is considered one of the major factors responsible for DNA damage. Such damage can be direct, through interactions of DNA with UV photons, or indirect, mainly through enhanced production of reactive oxygen species that introduce oxidative changes to the DNA. Oxidative stress and DNA damage also associate with profound changes at the cellular and molecular level involving several cell cycle and signal transduction factors responsible for DNA repair or irreversible changes linked to ageing. Crucially, some of these factors constitute part of the signalling known for the induction of biological changes in non-irradiated, neighbouring cells and defined as the bystander effect. Network interactions with a number of natural compounds, based on their known activity towards these biomarkers in the skin, reveal the capacity to inhibit both the bystander signalling and cell cycle/DNA damage molecules while increasing expression of the anti-oxidant enzymes. Based on this information, we discuss the likely polypharmacology applications of the natural compounds and next-generation screening technologies in improving the anti-oxidant and DNA repair capacities of the skin.


Effect of solvent on radical cyclisation pathways: SRN1 vs. aryl-aryl bond forming mechanisms.
A recent paper identified a series of alternative cyclisation pathways of aryl radicals that resulted from electron transfer to various tethered haloarene-acetylarene substrates, in either benzene or DMSO as solvent. The electron transfer occurred from one of two enolates that were formed in the presence of KOtBu: either the enolate of the acetylarene, within the haloarene-acetylarene substrate, or the enolate 7 of the N,N'-dipropyl diketopiperazine (DKP) additive 6. This paper uses contemporary computational methods to determine the reaction pathways involved; depending on the substrate, the aryl radical underwent (i) SRN1 onto the enolate anion of the acetylarene, (ii) aryl-aryl bond formation, (iii) tandem hydrogen atom abstraction followed by SRN1 cyclisation and even (iv) ArC-N cleavage. The influence of the solvent was investigated. In this paper it is shown that the solvent influences which reactive species are present in the reaction mixture, and whether each species acts as an electron donor or an electron acceptor in the radical initiation or propagation steps. The main initiation step is a single electron transfer from the enolate anion 7 of the DKP additive in benzene, but in DMSO the initiation can occur from the enolate anion of the substrate itself. Using computational techniques a deeper understanding of the radical pathways involved has been obtained, which shows how we can use solvent to preferentially access products arising from either SRN1 or aryl-aryl bond formation pathways.


The epidemiology, genetics and future management of syndactyly.
Syndactyly is a condition well documented in current literature due to it being the most common congenital hand defect, with a large aesthetic and functional significance.There are currently nine types of phenotypically diverse non-syndromic syndactyly, an increase since the original classification by Temtamy and McKusick(1978). Non-syndromic syndactyly is inherited as an autosomal dominant trait, although the more severe presenting types and sub types appear to have autosomal recessive and in some cases X-linked hereditary.Gene research has found that these phenotypes appear to not only be one gene specific, although having individual localised loci, but dependant on a wide range of genes and subsequent signalling pathways involved in limb formation. The principal genes so far defined to be involved in congenital syndactyly concern mainly the Zone of Polarizing Activity and Shh pathway.Research into the individual phenotypes appears to complicate classification as new genes are found both linked, and not linked, to each malformation. Consequently anatomical, phenotypical and genotypical classifications can be used, but are variable in significance, depending on the audience.Currently, management is surgical, with a technique unchanged for several decades, although future development will hopefully bring alternatives in both earlier diagnosis and gene manipulation for therapy.


Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.
A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.


[Serum folate and vitamin B12 in older people: results from the Chilean National Health Survey 2009-2010].
Supraphysiological levels (SFL) of serum folate (SF) derived from flour fortification with folic acid (FA) could be risky among older adults with low vitamin B12 (B12) levels. To describe and analyze SF and B12 levels in older Chileans and to identify risk groups. Participants were 1.043 older people aged ≥ 65 years from the National Health Chilean Health Survey 2009-2010 (ChNHS 2009-10), a multistage stratified random sample, representative of the national population. SF (µg/L) and B12 (pg/ml) were determined in fasting samples by competitive chemoluminescence immunoassay. Mean, deciles and percentiles 5 and 95th were calculated. We defined SF categories: < 4.4 (deficit); 4.41-20 (normal) and SFL: 20.01-25.6; 25.6-29 and > 29 µg/L (80th percentile of the distribution) and vitamin B12 categories: ≤ 200 (deficit); 200.1-299.5 (marginal deficit) and > 299.5 (normal). Prevalence rates, multiple and logistic regression models were used and adjusted by sex and age, educational level and residence area. SF and B12 mean and 95th percentiles were 21.2 ± 0.56/38.6 µg/L and 348.4 ± 7.6/637(pg/ml) respectively. Forty nine percent of participants had SFL. Folate and B12 deficiency were present in 0.3 and 8.1% of participants, respectively. Men had significantly lower prevalence of SFL > 29 µg/L (OR adjusted odds ratio 0.47 95% confidence intervals: 0.26-0.84). B12 showed no significant variation by age and sex. The prevalence of SFL associated with B12 deficiency was 4.1%. No statistically significant association was observed between levels of folate and B12. Folate deficit is almost inexistent, but a significant percentage of participants had SFL suggesting the need for revising the current wheat flour fortification levels.


Fluid-Blood Level and Hematoma Expansion in a Cerebral Amyloid Angiopathy-Associated Intracerebral Hematoma.
BACKGROUND Cerebral amyloid angiopathy (CAA) results from progressive deposition of amyloid-ß in the walls of cortical and leptomeningeal vessels, leading to CAA-associated intracerebral hemorrhage (ICH). Hematoma expansion is a common early complication of spontaneous ICH, and is a strong independent predictor of poor outcome. However, there are limited reports of hematoma expansion related to CAA-associated ICH. Herein, we describe a novel case of hematoma expansion with a fluid-blood level in the cystic cavity of CAA-associated ICH. CASE REPORT A 76-year-old male was initially diagnosed with probable CAA according to the modified Boston criteria, and presented with lobar ICH in the left frontal lobe 4 months later. Admission computed tomography scans showed an ICH including a high-density hematoma within a cystic cavity, revealing a clearly lower-density fluid component. Serial computed tomography scans showed no evidence of an expansion of the high-density clot, but obvious expansion of the fluid component containing a fluid-blood level. We recognized a bleeding site with no enhancement on preoperative magnetic resonance imaging. Left frontal craniotomy revealed a liquefied hematoma, which was removed by suction. We subsequently evacuated the blood clot extending into the left frontal sulcus, and confirmed and cauterized the bleeding site, leading to successful hemostasis. CONCLUSIONS We report a CAA-associated ICH case showing hematoma expansion with a fluid-blood level. Intraparenchymal fluid-blood level suggests extravasation of blood into pre-existing cystic cavities because of hematoma liquefaction. Thus, fluid-blood levels are an important finding of hematoma expansion in acute CAA-associated ICH, and early treatment should be considered.


Evaluation of integrated control of three dog transmitted zoonoses: Rabies, visceral leishmaniasis and cystic echinococcosis, in Morocco.
The present study is a component of a major European research project, ICONZ (Integrated Control of Neglected Zoonoses). The objective of this component was to implement, and then evaluate an Integrated Control Intervention (ICI) against three dog transmitted zoonoses, namely rabies, visceral leishmaniasis, and cystic echinococcosis. This was undertaken in Sidi Kacem Province (northwestern Morocco) where 22 control and 22 treated douars (villages) were randomly allocated to two control and one evaluation interventions over a period of 13 months. Across the 44 douars, an overall total of 6922 dogs were registered, 4519 were vaccinated against rabies, and 2885 persons attended the complementary health education campaigns; whereas, within the 22 treated douars, 466 dogs received anti-sandfly collars (deltamethrin-impregnated) and 2487 were dewormed (praziquantel). Evaluation of the ICI, revealed that (i) a canine rabies vaccination coverage of 65.0% was achieved, (ii) the use of deltamethrin-impregnated collars for dogs provided highly significant protection (p = 0.01) against leishmaniasis infection of more than 44%, and up to 100% for dogs that had kept the collar until the end of the intervention, (iii) despite a non-significant difference (p>0.05), dog-deworming with praziquantel yielded a reduction in the rate of Echinococcus granulosus infection, and (iv) health education was successful in improving respondents' knowledge; However, the target communities remained unconvinced of the necessity of changing some of their risky behaviours. Lastly, the estimated total cost of the global intervention, including its research components, was US$ 143,050, of which 67% was for disease control work with clear evidence of significant economies of scale due to targeting three diseases together. It appears from this study that the integrated control approach against the three zoonoses was effective on both economic and logistical levels.


Disability from a public health perspective.
At the Nordic School of Public Health (NHV), methods to alleviate problems with disability have been seen as an important part of actions to support public health. A programme for universal design was started in 2006. Some issues of public health perspectives on disability are presented in this paper, based on discussions from a PhD course held at the NHV. During the course, the students presented papers in which they reflected on the relationship between disability and public health. These essays were collected and published in 2012 at NHV.


Management of maxillofacial injuries in Iraq.
These clinical studies reflect the experience of the author in managing 673 patients treated during the last 8 years. All patients were treated in the Maxillofacial Unit, Surgical Specialties Hospital, Medical City, Baghdad, and in the author's private clinic. Included patients were 530 males and 143 females; patients' age ranged between 1 year and 75 years (mean, 38 y). Distribution of injuries was as follows: fracture of the mandible, 287 (42.64%); middle third injuries, 39 (5.79%); orbital injuries, 236 (35.07%; including 12 cases with cranioorbital injuries); injuries in children, 27 (4.0%); fracture of the zygoma, 52 (7.73%); and fracture of the nose, 40 (5.94%).Maxillofacial injuries in this study were classified as follows: (1) craniomaxillofacial with head injuries and cerebrospinal fluid leak; (2) fracture of the middle third including Le Fort I, II, and III and midline split in the face; (3) fracture of the mandible as an isolated injury or as part of a facial skeleton injury; and (4) isolated complex injuries of the zygoma, the orbital skeleton, and the nasoethmoidal region.The technique used for treating middle third injuries was external fixation either by halo frame (with vertical rods and cheek wires) or by box frame (using 4 external pins connected by rods) or internal fixation by suspending the middle third with internal wires (0.5 mm stainless steel) from the zygomatic process of the frontal bone beneath the zygomatic arch down the lower arch bar. Fractures of the mandible were treated by gunning splint with intermaxillary fixation (IMF) or with open reduction and fixation by stainless steel wire with IMF or by IMF screw or by an arch bar and IMF. Other fractures such as fracture of the orbit were treated by bone graft, sialastic, or lyophilized dura with open reduction. Fractures of the zygoma were treated by open reduction and fixation with stainless steel wire and bone graft or by reduction without fixation. Fractures of the nose were treated by reduction with straightening of the septum with a splint (lead splint or polythene) or by external splint with plaster of Paris. With the techniques used, results from managing these cases were satisfactory.


Photodissociation of alkyl iodides in helium nanodroplets. I. Kinetic energy transfer.
The photodissociation of (fluorinated) alkyl iodides in helium nanodroplets at a wavelength of 266 nm has been investigated by means of ion imaging techniques. It is found that a significant fraction of the created fragments escapes from the helium droplets. The speed and kinetic energy distributions of these fragments are found to be notably modified with respect to the corresponding gas phase distributions. The fragments, furthermore, show a speed dependent angular distribution. The loss of kinetic energy as well as the reduction of the anisotropy parameter show a strong mass dependence. These observations point to a nonthermal escape process in which the kinetic energy and momentum transfer from the fragments to the solvent is governed by binary collisions with the individual helium atoms making up the droplet. Monte Carlo simulations based on hard-sphere binary collisions substantiate this interpretation of the data.


[Vertical stratification of epiphytic bryophytes found on Quercus humboldtii (Fagaceae) from boyacá, Colombia].
Oak forest represents an ecologically important plant formation in Colombia, partly due to the large amount of epiphyte flora that harbors, especially non-vascular plants which have been poorly studied in Colombia. One of the biggest oak forests in the country is the one found in the Parque Natural Municipal "Robledales de Tipacoque" (PNMRT), in Boyacá, municipality of Tipacoque. The epiphyte bryoflora was evaluated in Q. humboldtii, using canopy climbing techniques and dividing the trees (25 individuals sampled) each into five layers (base, trunk, inner canopy, middle and outer canopy). A total of 365 samples were collected: 29% liveworts and 71% mosses. Hepatics represented 10 families, 16 genera and 26 species; mosses 11 families, 26 genera and 49 species. Considering the tree layers, the most diverse one was the base with 51 species, followed by the trunk with 43; in the canopy, the inner canopy was found the most diverse with 28 species, and was followed by the middle canopy with 18, and the outer canopy with 15. A species similarity index shows that the trunk and the middle canopy were the most closely related (0.42) in terms of species composition. The results showed that non-vascular plants were mostly found in lower layers (base and trunk), where the diversity was greater, richer (species number), and this might be caused by the microclimatic conditions in these places, such as higher humidity, lower light intensity and shade. Thus, some species are considered shade epiphytes (ombrophiles) because they are unique to these areas, like Bazzania gracilis and Taxilejeunea pterigonia, among others. Likewise, Jungermannia sp. is considered a sun epiphyte (heliophilous) because it is found only in the outer canopy. We concluded that Q. humboldtii could be considered as a potential host for the conservation of non-vascular epiphytes in Colombian forests.


DNA Origami Route for Nanophotonics.
The specificity and simplicity of the Watson-Crick base pair interactions make DNA one of the most versatile construction materials for creating nanoscale structures and devices. Among several DNA-based approaches, the DNA origami technique excels in programmable self-assembly of complex, arbitrary shaped structures with dimensions of hundreds of nanometers. Importantly, DNA origami can be used as templates for assembly of functional nanoscale components into three-dimensional structures with high precision and controlled stoichiometry. This is often beyond the reach of other nanofabrication techniques. In this Perspective, we highlight the capability of the DNA origami technique for realization of novel nanophotonic systems. First, we introduce the basic principles of designing and fabrication of DNA origami structures. Subsequently, we review recent advances of the DNA origami applications in nanoplasmonics, single-molecule and super-resolution fluorescent imaging, as well as hybrid photonic systems. We conclude by outlining the future prospects of the DNA origami technique for advanced nanophotonic systems with tailored functionalities.


An 18-month follow-up on the effectiveness of a sexuality workshop: some methodological pitfalls.
Students from four health sciences programs (Medicine, Nursing, Occupational Therapy and Physiotherapy) participated in a two-day Sexuality Workshop and completed pre- and post-workshop questionnaires dealing with sexual attitudes, comfort, and knowledge. Eighteen months later, these students were asked to complete the same questionnaires. Not only had they sustained the gains made during the workshop, but they continued to show improvement in the three areas during this interval. However, of greater importance than the positive finding is the need to understand the range of methodological problems encountered in carrying out this type of follow-up educational inquiry and in seeking measures for improving the validity and generalizability of such research.


High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined.
Homozygous sickle cell disease in the eastern province of Saudi Arabia is clinically mild. Circulating fetal hemoglobin levels of 16.0 +/- 7.4% were found in these anemic patients, but only 1.09 +/- 0.97% in their sickle trait parents. To determine whether these sickle cell anemia patients inherit an increased capacity to synthesize fetal hemoglobin, a radioimmunoassay of fetal and adult hemoglobin was performed on erythroid progenitor (BFU-E)-derived erythroblasts from Saudi Arabian sickle cell patients and their parents. Mean fetal hemoglobin content per BFU-E-derived erythroblast from Saudi Arabian sickle cell patients was 6.2 +/- 2.4 pg/cell or 30.4 +/- 8.6% fetal hemoglobin (normal 1.1 +/- 0.7 pg/cell and 5.1 +/- 1.8%). Linear regression analysis of % HbF in peripheral blood versus % HbF per BFU-E-derived cell showed a positive correlation with an r of 0.65. The variance of the intrinsic capacity to produce HbF may account for almost 40% (r2) of the variance of circulating fetal hemoglobin but other factors, particularly selective survival of F cells, must also contribute significantly. Despite virtually normal HbF levels in sickle trait parents of these Saudi patients, mean fetal hemoglobin production per BFU-E-derived erythroblast in these individuals was elevated to 3.42 +/- 1.79 pg/cell or 16.1 +/- 6.4% fetal hemoglobin, and the magnitude of fetal hemoglobin production found in parents correlated with that of the patients. These data indicate that the high fetal hemoglobin in Saudi sickle cell disease is genetically determined but expressed only during accelerated erythropoiesis. Further evidence of such genetic determination was provided by analysis of DNA polymorphisms within the beta-globin gene cluster on chromosome 11. This revealed a distinctive 5' globin haplotype (+ + - + +) on at least one chromosome 11 in all high F SS and AS tested. The precise relationship of this haplotype to HbF production in this population remains to be defined.


Increasing health worker capacity through distance learning: a comprehensive review of programmes in Tanzania.
Tanzania, like many developing countries, faces a crisis in human resources for health. The government has looked for ways to increase the number and skills of health workers, including using distance learning in their training. In 2008, the authors reviewed and assessed the country's current distance learning programmes for health care workers, as well as those in countries with similar human resource challenges, to determine the feasibility of distance learning to meet the need of an increased and more skilled health workforce. Data were collected from 25 distance learning programmes at health training institutions, universities, and non-governmental organizations throughout the country from May to August 2008. Methods included internet research; desk review; telephone, email and mail-in surveys; on-site observations; interviews with programme managers, instructors, students, information technology specialists, preceptors, health care workers and Ministry of Health and Social Welfare representatives; and a focus group with national HIV/AIDS care and treatment organizations. Challenges include lack of guidelines for administrators, instructors and preceptors of distance learning programmes regarding roles and responsibilities; absence of competencies for clinical components of curricula; and technological constraints such as lack of access to computers and to the internet. Insufficient funding resulted in personnel shortages, lack of appropriate training for personnel, and lack of materials for students.Nonetheless, current and prospective students expressed overwhelming enthusiasm for scale-up of distance learning because of the unique financial and social benefits offered by these programs. Participants were retained as employees in their health care facilities, and remained in their communities and supported their families while advancing their careers. Space in health training institutions was freed up for new students entering in-residence pre-service training. A blended print-based distance learning model is most feasible at the national level due to current resource and infrastructure constraints. With an increase in staffing; improvement of infrastructure, coordination and curricula; and decentralization to the zonal or district level, distance learning can be an effective method to increase both the skills and the numbers of qualified health care workers capable of meeting the health care needs of the Tanzanian population.


Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.
In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.


Focus-of-attention from local color symmetries.
In this paper, a continuous valued measure for local color symmetry is introduced. The new algorithm is an extension of the successful gray value-based symmetry map proposed by Reisfeld et al. The use of color facilitates the detection of focus points (FPs) on objects that are difficult to detect using gray-value contrast only. The detection of FPs is aimed at guiding the attention of an object recognition system; therefore, FPs have to fulfill three major requirements: stability, distinctiveness, and usability. The proposed algorithm is evaluated for these criteria and compared with the gray value-based symmetry measure and two other methods from the literature. Stability is tested against noise, object rotation, and variations of lighting. As a measure for the distinctiveness of FPs, the principal components of FP-centered windows are compared with those of windows at randomly chosen points on a large database of natural images. Finally, usability is evaluated in the context of an object recognition task.