Distinguishing Learning Rules with Brain Machine Interfaces.
Despite extensive theoretical work on biologically plausible learning rules, clear evidence about whether and how such rules are implemented in the brain has been difficult to obtain. We consider biologically plausible supervised- and reinforcement-learning rules and ask whether changes in network activity during learning can be used to determine which learning rule is being used. Supervised learning requires a credit-assignment model estimating the mapping from neural activity to behavior, and, in a biological organism, this model will inevitably be an imperfect approximation of the ideal mapping, leading to a bias in the direction of the weight updates relative to the true gradient. Reinforcement learning, on the other hand, requires no credit-assignment model and tends to make weight updates following the true gradient direction. We derive a metric to distinguish between learning rules by observing changes in the network activity during learning, given that the mapping from brain to behavior is known by the experimenter. Because brain-machine interface (BMI) experiments allow for precise knowledge of this mapping, we model a cursor-control BMI task using recurrent neural networks, showing that learning rules can be distinguished in simulated experiments using only observations that a neuroscience experimenter would plausibly have access to.


Fibro-vascular coupling in the control of cochlear blood flow.
Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained. We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca(2+) signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+) sensor, fluo-4. Elevation of Ca(2+) in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+) signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX-1) was required for capillary dilation. The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity.


Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides.
To compare the efficacy of total skin electron beam therapy (TSEBT) with or without adjuvant topical nitrogen mustard (+/- HN2) with topical nitrogen mustard (HN2) alone as initial management of T2 and T3 mycosis fungoides (MF). A retrospective analysis of 148 patients presenting to Stanford from January, 1970 through January, 1995 within 4 months of pathologic diagnosis of MF. Fifty-five patients with T2 and 27 with T3 disease received TSEBT +/- HN2. Fifty-four patients with T2 and 12 with T3 disease received HN2 alone. Boosts with radiotherapy were usually administered to cutaneous tumors of patients with T3 disease. TSEBT +/- HN2 yielded significantly higher complete response (CR) rates than did HN2 alone in patients with T2 and T3 disease (76% vs 39%, p = 0.03 for T2, and 44% vs 8%, p < 0.05 for T3, respectively). In T2 disease, treatment with adjuvant HN2 was associated with a longer freedom from relapse following TSEBT when compared to observation following a CR to TSEBT (p = 0.068). However, no significant differences in survival were observed for different management programs for T2 or T3 disease. In T2 disease, both TSEBT and HN2 were as effective as salvage therapy as when utilized as initial therapy. However, salvage therapy in T3 disease was rarely effective. Limited tumor involvement in T3 disease did not correlate with improved survival compared to more generalized tumorous disease. MF contributed to 27% and 68% of deaths in patients with T2 and T3 disease, respectively. Because of high response rates, management of significantly symptomatic or extensive T2 MF should include TSEBT, and adjuvant HN2 should be administered after a CR to TSEBT. Patients with T2 disease who fail TSEBT or HN2 can be salvaged with the other modality. TSEBT is also an effective treatment for T3 disease. The small subset of patients with limited T3 disease may also be treated with HN2 and local radiotherapy to the tumors. Further investigations are necessary to improve the overall outcome for T3 mycosis fungoides.


Conserved phosphorylation hotspots in eukaryotic protein domain families.
Protein phosphorylation is the best characterized post-translational modification that regulates almost all cellular processes through diverse mechanisms such as changing protein conformations, interactions, and localization. While the inventory for phosphorylation sites across different species has rapidly expanded, their functional role remains poorly investigated. Here, we combine 537,321 phosphosites from 40 eukaryotic species to identify highly conserved phosphorylation hotspot regions within domain families. Mapping these regions onto structural data reveals that they are often found at interfaces, near catalytic residues and tend to harbor functionally important phosphosites. Notably, functional studies of a phospho-deficient mutant in the C-terminal hotspot region within the ribosomal S11 domain in the yeast ribosomal protein uS11 shows impaired growth and defective cytoplasmic 20S pre-rRNA processing at 16 °C and 20 °C. Altogether, our study identifies phosphorylation hotspots for 162 protein domains suggestive of an ancient role for the control of diverse eukaryotic domain families.


Near-equilibrium measurements of nonequilibrium free energy.
A central endeavor of thermodynamics is the measurement of free energy changes. Regrettably, although we can measure the free energy of a system in thermodynamic equilibrium, typically all we can say about the free energy of a nonequilibrium ensemble is that it is larger than that of the same system at equilibrium. Herein, we derive a formally exact expression for the probability distribution of a driven system, which involves path ensemble averages of the work over trajectories of the time-reversed system. From this we find a simple near-equilibrium approximation for the free energy in terms of an excess mean time-reversed work, which can be experimentally measured on real systems. With analysis and computer simulation, we demonstrate the accuracy of our approximations for several simple models.


The Anti-Inflammatory and Antioxidant Effects of Curcumin in Middle Ear Infection.
To investigate and analyze the anti-inflammatory and antioxidant efficacy of curcumin in experimentally induced middle ear infection. Twenty-four Wistar albino rats with otomicroscopic examination findings within normal limits were included in the study. Study groups were established after Streptococcus pneumoniae was inoculated into the middle ear cavity of all rats. No medication was administered to Group 1, the control group. Group 2 was administered 50 mg/kg/day amoxicillin intraperitoneally. Group 3 was administered 50 mg/kg/day amoxicillin together with 30 mg/kg/day curcumin intraperitoneally. Blood specimens and temporal bones were collected on the 10th day of medication from the 22 rats in which acute otitis media developed. Serum glutathione peroxidase and superoxide dismutase activities and malondialdehyde levels were measured. Inflammatory cell infiltration, vascular proliferation, and epithelial proliferation were assessed histopathologically in middle ear mucosa specimens, and the results were compared among the groups. Malondialdehyde levels in the group given curcumin were significantly lower than those of the control group, while serum glutathione peroxidase activity was also lower compared to that of the control group. No significant difference was observed among the groups in terms of superoxide dismutase activity. Although there were no significant findings in terms of histopathological data, epithelial proliferation in the groups receiving antibiotherapy was suppressed compared to the control group. Similarly, curcumin was observed to have a positive effect on inflammatory cell infiltration. No significant changes were observed in terms of vascular proliferation. With its wide and safe dose range, curcumin represents grounds for optimism in terms of anti-inflammatory treatment in acute otitis media.


Percutaneous electrical nerve stimulation for low back pain: a randomized crossover study.
Low back pain (LBP) contributes to considerable disability and lost wages in the United States. Commonly used opioid and nonopioid analgesic drugs produce adverse effects and are of limited long-term benefit in the management of this patient population. To compare the effectiveness of a novel nonpharmacologic pain therapy, percutaneous electrical nerve stimulation (PENS), with transcutaneous electrical nerve stimulation (TENS) and flexion-extension exercise therapies in patients with long-term LBP. A randomized, single-blinded, sham-controlled, crossover study from March 1997 to December 1997. An ambulatory pain management center at a university medical center. Twenty-nine men and 31 women with LBP secondary to degenerative disk disease. Four therapeutic modalities (sham-PENS, PENS, TENS, and exercise therapies) were each administered for a period of 30 minutes 3 times a week for 3 weeks. Pretreatment and posttreatment visual analog scale (VAS) scores for pain, physical activity, and quality of sleep; daily analgesic medication usage; a global patient assessment questionnaire; and Health Status Survey Short Form (SF-36). PENS was significantly more effective in decreasing VAS pain scores after each treatment than sham-PENS, TENS, and exercise therapies (after-treatment mean +/- SD VAS for pain, 3.4+/-1.4 cm, 5.5+/-1.9 cm, 5.6+/-1.9 cm, and 6.4+/-1.9 cm, respectively). The average +/- SD daily oral intake of nonopioid analgesics (2.6+/-1.4 pills per day) was decreased to 1.3+/-1.0 pills per day with PENS (P<.008) compared with 2.5+/-1.1, 2.2+/-1.0, and 2.6+/-1.2 pills per day with sham-PENS, TENS, and exercise, respectively. Compared with the other 3 modalities, 91 % of the patients reported that PENS was the most effective in decreasing their LBP. The PENS therapy was also significantly more effective in improving physical activity, quality of sleep, and sense of well-being (P<.05 for each). The SF-36 survey confirmed that PENS improved posttreatment function more than sham-PENS, TENS, and exercise. In this sham-controlled study, PENS was more effective than TENS or exercise therapy in providing short-term pain relief and improved physical function in patients with long-term LBP.


Drug and cell delivery for cardiac regeneration.
The spectrum of ischaemic cardiomyopathy, encompassing acute myocardial infarction to congestive heart failure is a significant clinical issue in the modern era. This group of diseases is an enormous source of morbidity and mortality and underlies significant healthcare costs worldwide. Cardiac regenerative therapy, whereby pro-regenerative cells, drugs or growth factors are administered to damaged and ischaemic myocardium has demonstrated significant potential, especially preclinically. While some of these strategies have demonstrated a measure of success in clinical trials, tangible clinical translation has been slow. To date, the majority of clinical studies and a significant number of preclinical studies have utilised relatively simple delivery methods for regenerative therapeutics, such as simple systemic administration or local injection in saline carrier vehicles. Here, we review cardiac regenerative strategies with a particular focus on advanced delivery concepts as a potential means to enhance treatment efficacy and tolerability and ultimately, clinical translation. These include (i) delivery of therapeutic agents in biomaterial carriers, (ii) nanoparticulate encapsulation, (iii) multimodal therapeutic strategies and (iv) localised, minimally invasive delivery via percutaneous transcatheter systems.


Large field-induced-strain at high temperature in ternary ferroelectric crystals.
The new generation of ternary Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 ferroelectric single crystals have potential applications in high power devices due to their surperior operational stability relative to the binary system. In this work, a reversible, large electric field induced strain of over 0.9% at room temperature, and in particular over 0.6% above 380 K was obtained. The polarization rotation path and the phase transition sequence of different compositions in these ternary systems have been determined with increasing electric field applied along [001] direction based on x-ray diffraction data. Thereafter, composition dependence of field-temperature phase diagrams were constructed, which provide compositional and thermal prospectus for the electromechanical properties. It was found the structural origin of the large stain, especially at higher temperature is the lattice parameters modulated by dual independent variables in composition of these ternary solid solution crystals.


Price comparison of high-cost originator medicines in European countries.
In recent years, high-cost medicines have increasingly been challenging the public health budget in all countries including high-income economies. In this context, this study aims to survey, analyze and compare prices of medicines that likely contribute to high expenditure for the public payers in high-income countries. We chose the following 16 European countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Portugal, Sweden, Slovakia, Spain and United Kingdom. The ex-factory price data of 30 medicines in these countries were collected in national databases accessible through the Pharmaceutical Price Information (PPI) service of Gesundheit Österreich GmbH (Austrian Public Health Institute). The ex-factory prices (median) per unit (e.g. per tablet, vial) ranged from 10.67 cent (levodopa + decarboxylase inhibitor) to 17,000 euro (ipilimumab). A total of 53% of the medicines surveyed had a unit ex-factory price (median) above 200 Euro. For two thirds of the medicines, price differences between the highest-priced country and lowest-priced country ranged between 25 and 100%; the remaining medicines, mainly low-priced medicines, had higher price differential, up to 251%. Medicines with unit prices of a few euros or less were medicines for the treatment of diseases in the nervous system (anti-depressants, medicines to treat Parkinson and for the management of neuropathic pain), of obstructive airway diseases and cardio-vascular medicines (lipid modifying agents). High-priced medicines were particularly cancer medicines. Medicine prices of Greece, Hungary, Slovakia and UK were frequently at the lower end, German and Swedish, as well as Danish and Irish prices at the upper end. For high-priced medicines, actual paid prices are likely to be lower due to confidential discounts and similar funding arrangements between industry and public payers. Pricing authorities refer to the higher undiscounted prices when they use price data from other countries for their pricing decisions.


Subdural hematoma (SDH): assessment of macrophage reactivity within the dura mater and underlying hematoma.
Macrophages are an inherent component of the dura mater, and can be characterised in cases of subdural hematoma (SDH) by their progressive and varying accumulation within areas of damage. Gross and histological methods used to determine the age of SDH are inexact. These are in part due to the active nature of such lesions and the diverse manner in which trauma victims respond to injury. Correct diagnosis has obvious medico-legal implications. However, there is as yet no specific diagnostic method that allows the age of SDH to be reliably determined. This study investigated the progressive and orderly pattern of reactivity of resident and infiltrating dural macrophages that occurs in response to injury associated with SDH. 26 postmortem cases of traumatic SDH were examined with survival times (onset of trauma to death) ranging from a few hours and up to 31 days. Macrophage reactivity associated with the dura mater and the underlying hematoma was determined using CD68 and MHC class II immunohistochemistry and the qualitative and quantitative findings compared with the presence of iron detected using conventional Perl's Prussian blue method. The results show that CD68 and MHC class II are differentially expressed within the dura mater and hematoma in SDH, and that the expression of MHC class II is markedly upregulated in the inner aspect of the dura mater within the initial 24 hours following injury. CD68 expression can be detected quantitatively in the hematoma, 24-48 hours after SDH, and within the dura following this period. Linear regression analysis further revealed a significant and positive association between the expression of MHC class II or CD68 antigens and the progressive survival of SDH up to 31 days post-injury, which was not seen with Perl's histochemical method. The expression of MHC class II antigen was a distinguishing, and quantifiable feature particularly localized within the inner aspect of the dura from a very early stage in the progression of SDH. Widespread, diffuse and cellular MHC class II reactivity was particularly noted within the inner aspect of the dura mater in cases of SDH with survival > 10 days. Since only a proportion of this widespread immunoreactivity was accounted for by macrophages (considering CD68 immunoreactivity), a large component of this activity was more likely to be due to the reorganisation and activation of fibroblasts within inner dural layers (dural border layer), known to upregulate expression of MHC class II molecules. The expression of CD68 and MHC class II antigens provides a more informative picture of the progression of pathology associated with SDH, and may be used in conjunction with other clinicopathological factors, in further investigations that attempt to date SDH according to defined histopathological characteristics.


The phenotype of SCN8A developmental and epileptic encephalopathy.
To delineate the electroclinical features of SCN8A infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558). Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment. Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes (8/22), cortical myoclonus (8/22), and myoclonic absences (1/22). FS typically clustered and were prolonged (<20 minutes) with (1) cyanosis, hypomotor, and vegetative semiology, sometimes unnoticed, followed by (2) tonic-vibratory and (3) (hemi)-clonic manifestations ± evolution to a bilateral tonic-clonic seizure. FS had posterior-temporal/occipital onset, slowly spreading and sometimes migrating between hemispheres. Brain MRI showed progressive parenchymal atrophy and restriction of the optic radiations. SCN8A developmental and epileptic encephalopathy has strikingly consistent electroclinical features, suggesting a global progressive brain dysfunction primarily affecting the temporo-occipital regions. Both uncontrolled epilepsy and developmental compromise contribute to the profound impairment (increasing risk of death) during early childhood, but stabilization occurs in late childhood.


Effect of a Quality Improvement Program to Improve Guideline Adherence and Attainment of Clinical Standards in Dialysis Care: Report of Outcomes in Year 1.
Best practice in dialysis is synthesised in clear international guidelines. However, a large gap remains between the international guidelines and the actual delivery of care. In this paper, we report outcomes for the first year of a multifaceted dialysis improvement programme in our network. One year collaborative involving 3 haemodialysis units and a peritoneal dialysis (PD) programme involving 299 dialysis patients. Each unit addressed a different indicator (unit A - catheter-related bloodstream infection [CRBSI], unit B - pre-dialysis blood pressure [BP], unit C - dialysis dose, unit D - anaemia) with a shared aim to match the top 10% in the UK. Tailored multifaceted approaches include a modified collaborative methodology with an aim, framework, driver diagram, learning sessions, facilitated meetings, plan-do-study-act cycles and continuous measurement. Analysis of outcomes, costings, erythropoietin stimulating agent and iron use, and safety culture attributes. Unit A reduced CRBSI from 2.65 to 0.5 per 1,000 catheter days (p = 0.02). Unit B improved attainment of target BP from 37.5 to 67.2% (p = 0.003). Unit C improved attainment of target urea reduction ratio from 75.8 to 91.4% (p = 0.04). PD unit D improved attainment of target haemoglobin from 45.5 to 62.7% (p = 0.01), with no significant change in the indicators in a non-intervention unit. Safety culture attributes improved. Costs associated with admission for fluid overload and infection, erythropoietin, iron and thrombokinase use decreased 36% (£415,620-£264,143). Units that took part in this collaborative improved guideline adherence compared both to their own pre-intervention performance and a non-intervention unit. Such multifaceted interventions are a useful methodology to improve dialysis care.


The association between palliative care team consultation and hospital costs for patients with advanced cancer: An observational study in 12 Dutch hospitals.
Early palliative care team consultation has been shown to reduce costs of hospital care. The objective of this study was to investigate the association between palliative care team (PCT) consultation and the content and costs of hospital care in patients with advanced cancer. A prospective, observational study was conducted in 12 Dutch hospitals. Patients with advanced cancer and an estimated life expectancy of less than 1 year were included. We compared hospital care during 3 months of follow-up for patients with and without PCT involvement. Propensity score matching was used to estimate the effect of PCTs on costs of hospital care. Additionally, gamma regression models were estimated to assess predictors of hospital costs. We included 535 patients of whom 126 received PCT consultation. Patients with PCT had a worse life expectancy (life expectancy <3 months: 62% vs. 31%, p < .01) and performance status (p < .01, e.g., WHO status higher than 2:54% vs. 28%) and more often had no more options for anti-tumour therapy (57% vs. 30%, p < .01). Hospital length of stay, use of most diagnostic procedures, medication and other therapeutic interventions were similar. The total mean hospital costs were €8,393 for patients with and €8,631 for patients without PCT consultation. Analyses using propensity scores to control for observed confounding showed no significant difference in hospital costs. PCT consultation for patients with cancer in Dutch hospitals often occurs late in the patients' disease trajectories, which might explain why we found no effect of PCT consultation on costs of hospital care. Earlier consultation could be beneficial to patients and reduce costs of care.


Structural Explanations of Flavin Adenine Dinucleotide Binding in Drosophila melanogaster Cryptochrome.
Cryptochrome proteins are thought to be involved in light-sensitive magnetoreception in migratory birds triggered by flavin adenine dinucleotide (FAD) light absorption. A recent study, however, calls into question the ability of vertebrate cryptochrome proteins to bind FAD, rendering them unlikely to function as magnetoreceptive proteins. In this Letter, we investigate the structural changes occurring in Drosophila melanogaster cryptochrome, upon key amino acid mutations, which reduce FAD binding. Through computational analysis we have now suggested why some mutations do not preclude FAD binding in all vertebrate cryptochrome proteins.


Effect of folic acid supplementation on levels of circulating Monocyte Chemoattractant Protein-1 and the presence of intravascular ultrasound derived virtual histology thin-cap fibroatheromas in patients with stable angina pectoris.
Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment. In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (± B6) or placebo (± B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI). Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01). In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.


Merging metagenomics and geochemistry reveals environmental controls on biological diversity and evolution.
The metabolic strategies employed by microbes inhabiting natural systems are, in large part, dictated by the physical and geochemical properties of the environment. This study sheds light onto the complex relationship between biology and environmental geochemistry using forty-three metagenomes collected from geochemically diverse and globally distributed natural systems. It is widely hypothesized that many uncommonly measured geochemical parameters affect community dynamics and this study leverages the development and application of multidimensional biogeochemical metrics to study correlations between geochemistry and microbial ecology. Analysis techniques such as a Markov cluster-based measure of the evolutionary distance between whole communities and a principal component analysis (PCA) of the geochemical gradients between environments allows for the determination of correlations between microbial community dynamics and environmental geochemistry and provides insight into which geochemical parameters most strongly influence microbial biodiversity. By progressively building from samples taken along well defined geochemical gradients to samples widely dispersed in geochemical space this study reveals strong links between the extent of taxonomic and functional diversification of resident communities and environmental geochemistry and reveals temperature and pH as the primary factors that have shaped the evolution of these communities. Moreover, the inclusion of extensive geochemical data into analyses reveals new links between geochemical parameters (e.g. oxygen and trace element availability) and the distribution and taxonomic diversification of communities at the functional level. Further, an overall geochemical gradient (from multivariate analyses) between natural systems provides one of the most complete predictions of microbial taxonomic and functional composition. Clustering based on the frequency in which orthologous proteins occur among metagenomes facilitated accurate prediction of the ordering of community functional composition along geochemical gradients, despite a lack of geochemical input. The consistency in the results obtained from the application of Markov clustering and multivariate methods to distinct natural systems underscore their utility in predicting the functional potential of microbial communities within a natural system based on system geochemistry alone, allowing geochemical measurements to be used to predict purely biological metrics such as microbial community composition and metabolism.


Use of filter paper as a transport medium for laboratory diagnosis of cholera under field conditions.
Confirmation of a cholera epidemic is based on bacteriological identification of the agent and requires the sending of samples to a culture laboratory, often in countries with limited resources. Comparison of the use of filter paper with the use of Cary-Blair reference medium for stool transport showed that this simple transport medium is appropriate for the recovery of Vibrio cholerae.


Body mass index and chronic energy deficiency of adult males of Central Indian populations.
Data on body weight, height, and sitting height from 11,496 adult males, age 18-62 years, belonging to 38 different populations of five major social groups (scheduled tribes, scheduled castes, "other backward castes," general castes, and Muslims) of Central India were taken for our analysis to assess the nutritional status of these groups. Cormic index and body mass index (BMI) were computed, and an analysis of variance (ANOVA) was carried out among different populations as well as among social groups separately on Cormic index and BMI. Shape, size, and generalized distances among the different social groups were computed and dendrograms were drawn. The level of malnutrition is the lowest among the general castes. The opposite is the case with the scheduled castes and scheduled tribes. Comparison of the coefficient of variation shows that there is variation in weight and BMI but that there is no marked variation in the other anthropometric variables. The ANOVA on Cormic index and BMI suggests that the people within a population are more homogeneous than the people between populations. There is a positive but statistically insignificant correlation between Cormic index and BMI. The five social groups differ more in size distance than in shape distance. According to the dendrogram of generalized distance values, the Muslims and the general castes can be grouped into one cluster and the scheduled castes, scheduled tribes, and other backward castes can be grouped into another cluster.


Factors associated with physical activity referral completion and health outcomes.
Participant socio-demographic characteristics and referral reason were investigated in relation to completion and health outcomes in a Primary Care Physical Activity Referral Scheme using a prospective population-based longitudinal design. Participants (n = 1735) were recruited over a 2-year period. A three-stage binary logistic regression analysis identified the factors associated with the outcomes of completion (model 1), body mass reduction (model 2) and blood pressure reduction (model 3). Participant's age, gender, ethnicity, occupation and referral reason were the independent variables for model 1, with the variables of completion added in model 2 and completion and body mass reduction added in model 3. Logistic regression analysis revealed that increasing age is associated with the likelihood of completion (Odds Ratio, OR = 1.019; Confidence Interval, CI = 1.008-1.030; P = 0.001). Participants with a pulmonary condition are less likely to complete (OR = 0.546; CI = 0.346-0.860; P < 0.01) compared to those referred for cardiovascular conditions. For ethnicity, in comparison to the white category, patients in the mixed category are significantly more likely to achieve a reduction in body mass (OR = 3.991; CI = 1.191-13.373; P < 0.05). Those who complete are more likely to achieve a reduction in body mass (OR = 3.541; CI = 2.721-4.608; P < 0.001). When compared to the unemployed category, the skilled manual category had an increased likelihood of achieving a reduction in blood pressure (OR = 1.875; CI = 1.044-3.227; P < 0.05). Participants who completed also demonstrated an increased likelihood of a reduction in blood pressure (OR = 1.680; CI = 1.250-2.003; P < 0.001). Furthermore, those participants who achieved a reduction in body mass had an increased likelihood of achieving a reduction in blood pressure (OR = 1.292; CI = 1.008-1.641; P < 0.05). Completion is associated with health outcomes of reduced body mass and blood pressure.


Distribution of zero crossings for the profile of random rough surfaces.
The distribution of zero crossings for the profile of a statistically rough surface of a silver thin film is determined and compared with a Poisson distribution. It is shown that the density of zero crossings may be related to the autocorrelation length and might be a useful parameter for characterizing spatial information of statistically rough surfaces.


Mammography, clinical breast exam, and pap testing: correlates of combined screening.
This study examines the correlates of screening for both breast and cervical cancer combined in a single indicator. Data used were from the 1990 National Health Interview Survey of Health Promotion and Disease Prevention. We used two indices to characterize the receipt of breast and cervical cancer screening among women 50-75 years of age. The first measure compared women who had three screening exams--clinical breast examination (CBE), mammography, and Pap test--in the past two years with those who had not received all three exams. The second measure compared women who had a Pap test and at least one breast screening exam (i.e., mammogram or CBE) in the previous two years with women who were underscreened. Age, level of education, smoking status, and access to health care were associated with both outcome measures. Black women were more likely to use screening services in the office setting (i.e., CBE and Pap), without a corresponding use of mammography. Nevertheless, more black than white women received a routine Pap test in combination with a CBE, a very positive trend with respect to the successful diffusion of at least two screening procedures among older black women. The data suggest that barriers to mammography screening remain even among women who are screened by CBE and Pap. Perhaps the biggest challenge is to educate primary care physicians and their patients to view different components of preventive health--CBE, Pap smear testing, breast self-examination, and mammographic screening--as equally necessary and interrelated. Medical Subject Headings (MeSH): screening, mammography, cervical cancer, Pap, breast exam.


Nonequilibrium molecular motion in a hypersonic shock wave.
Molecular velocities have been measured inside a hypersonic, normal shock wave, where the gas experiences rapid changes in its macroscopic properties. As first hypothesized by Mott-Smith, but never directly observed, the molecular velocity distribution exhibits a qualitatively bimodal character that is derived from the distribution functions on either side of the shock. Quantitatively correct forms of the molecular velocity distribution function in highly nonequilibrium flows can be calculated, by means of the Direct Simulation Monte Carlo technique.


Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model.
B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.


Epidemiology of travelers' diarrhea and relative importance of various pathogens.
Each year 12 million persons travel from an industrialized country to a developing country in the tropics or subtropics. These travelers experience a high rate of diarrhea caused by a wide variety of enteric pathogens acquired by ingestion of contaminated food or water. One or more pathogens can be found in the stool of a majority of ill individuals. Enterotoxigenic Escherichia coli generally are the most frequently identified pathogens, having been found in a median of 42% of travelers' diarrheal episodes in studies in Latin America, 36% in Africa, and 16% in Asia. Other pathogens that cause diarrhea in a smaller fraction of ill travelers include Shigella species, Salmonella species, Campylobacter jejuni, Vibrio, Aeromonas hydrophila, Entamoeba histolytica, Giardia lamblia, rotavirus, and 27-nm viruses, including Norwalk virus. Other organisms that may cause a fraction of the episodes of travelers' diarrhea include Plesiomonas shigelloides, enteroadherent E. coli, adenovirus or other viruses, and Cryptosporidium. Mixed infections of two or more of these pathogens also occur.


Estrogen and progestin regulation of cell cycle progression.
Estrogens and progesterone, acting via their specific nuclear receptors, are essential for normal mammary gland development and differentiated function. The molecular mechanisms through which these effects are mediated are not well defined, although significant recent progress has been made in linking steroid hormone action to cell cycle progression. This review summarizes data identifying c-myc and cyclin D1 as major downstream targets of both estrogen- and progestin-stimulated cell cycle progression in human breast cancer cells. Additionally, estrogen induces the formation of high specific activity forms of the cyclin E-Cdk2 enzyme complex lacking the cyclin-dependent kinase (CDK)3 inhibitor, p21. The delayed growth inhibitory effects of progestins, which are likely to be prerequisites for manifestation of their function in differentiation, also involve decreases in cyclin D1 and E gene expression and recruitment of CDK inhibitors into cyclin D1-Cdk4 and cyclin E-Cdk2 complexes. Thus estrogens and progestins affect CDK function not only by effects on cyclin abundance but also by regulating the recruitment of CDK inhibitors and, as yet undefined, additional components which determine the activity of the CDK complexes. These effects of estrogens and progestins are likely to be major contributors to their regulation of mammary epithelial cell proliferation and differentiation.


Expression of FKBP12 in benign and malignant vascular endothelium: an immunohistochemical study on conventional sections and tissue microarrays.
FKBP12 is a cytosolic FK506 binding protein that interacts with calcineurin and thereby mediates the immunosuppressive effects of FK506. Because initial immunohistochemical staining showed abundant expression of FKBP12 in vascular endothelial cells, we evaluated whether it could serve as a marker for vascular neoplasms. We performed immunohistochemical staining of conventional sections from formalin-fixed, paraffin-embedded tissue from 59 benign and malignant vascular neoplasms using a polyclonal rabbit antiserum against FKBP12. Western blot analysis of tissue from 6 angiosarcomas showed a single band at 12 kD, consistent with the published molecular weight for the FKBP12 protein. Together, CD31, CD34, and FKBP12 identified all 59 vascular neoplasms in this study. Specificity of immunohistochemical staining was assessed on 1,321 tissues represented on 7 tissue microarrays. All proteins were occasionally expressed in non-vascular tissue. Six of 8 vascular neoplasms represented on the arrays stained for FKBP12, as did normal vessels in numerous cores. The polyclonal antiserum shows comparable sensitivity (94.9%) and specificity (96.5%) to CD34 and CD31 and may be a useful additional marker for vascular differentiation. Because we have evaluated a large number of tissues by tissue microarray, we anticipate that our estimate of the specificity of immunostaining for FKBP12 as a marker for vascular endothelium will be accurate. In addition, our findings may explain the toxic effects of FK506 on vascular endothelium of the kidney.


Hepatitis C virus RNA testing by nested PCR in blood preparations in Yugoslavia.
Patients receiving any kind of human blood preparations are in permanent danger of any infection including hepatitis C (HCV) infection. Testing for the presence of HCV in blood preparations is one of the steps towards safe medical treatment. One of the approaches for this testing is a detection of HCV nucleic acid. In this paper we describe a simple method for isolation of HCV RNA from blood preparations and control of HCV RNA presence in 19 intravenous and intramuscular products, manufactured in the National Blood Transfusion Institute in Belgrade. RT-PCR was performed according the rules saving RNA. Primers were located in 5' conserved region. Seven out of 19 batches of gamma-globulin, albumin, anti-tetanus and anti-rabies immunoglobulin preparations were found to be HCV RNA positive. For the time being, the PCR method is too expensive for routine HCV RNA testing of hundreds of blood donors per day. Serological screening test of blood donors and nested PCR testing for HCV RNA in blood preparations could be an efficient combination of tests in prevention of posttransfusion hepatitis C.


Texture analysis of aggressive and nonaggressive lung tumor CE CT images.
This paper presents the potential for fractal analysis of time sequence contrast-enhanced (CE) computed tomography (CT) images to differentiate between aggressive and nonaggressive malignant lung tumors (i.e., high and low metabolic tumors). The aim is to enhance CT tumor staging prediction accuracy through identifying malignant aggressiveness of lung tumors. As branching of blood vessels can be considered a fractal process, the research examines vascularized tumor regions that exhibit strong fractal characteristics. The analysis is performed after injecting 15 patients with a contrast agent and transforming at least 11 time sequence CE CT images from each patient to the fractal dimension and determining corresponding lacunarity. The fractal texture features were averaged over the tumor region and quantitative classification showed up to 83.3% accuracy in distinction between advanced (aggressive) and early-stage (nonaggressive) malignant tumors. Also, it showed strong correlation with corresponding lung tumor stage and standardized tumor uptake value of fluorodeoxyglucose as determined by positron emission tomography. These results indicate that fractal analysis of time sequence CE CT images of malignant lung tumors could provide additional information about likely tumor aggression that could potentially impact on clinical management decisions in choosing the appropriate treatment procedure.


Brr2p carboxy-terminal Sec63 domain modulates Prp16 splicing RNA helicase.
RNA helicases are essential for virtually all cellular processes, however, their regulation is poorly understood. The activities of eight RNA helicases are required for pre-mRNA splicing. Amongst these, Brr2p is unusual in having two helicase modules, of which only the amino-terminal helicase domain appears to be catalytically active. Using genetic and biochemical approaches, we investigated interaction of the carboxy-terminal helicase module, in particular the carboxy-terminal Sec63-2 domain, with the splicing RNA helicase Prp16p. Combining mutations in BRR2 and PRP16 suppresses or enhances physical interaction and growth defects in an allele-specific manner, signifying functional interactions. Notably, we show that Brr2p Sec63-2 domain can modulate the ATPase activity of Prp16p in vitro by interfering with its ability to bind RNA. We therefore propose that the carboxy-terminal helicase module of Brr2p acquired a regulatory function that allows Brr2p to modulate the ATPase activity of Prp16p in the spliceosome by controlling access to its RNA substrate/cofactor.


Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of involvement of oxidative stress.
Glutamate excitotoxicity is implicated in the aetiology of amyotrophic lateral sclerosis (ALS) with impairment of glutamate transport into astrocytes a possible cause of glutamate-induced injury to motor neurons. It is possible that mutations of Cu/Zn superoxide dismutase (SOD1), responsible for about 20% of familial ALS, down-regulates glutamate transporters via oxidative stress. We transfected primary mouse astrocytes to investigate the effect of the FALS-linked mutant hSOD1(G93A) and wild-type SOD1 (hSOD1wt) on the glutamate uptake system. Using western blotting, immunocytochemistry and RT-PCR it was shown that expression of either hSOD1(G93A) or hSOD1wt in astrocytes produced down-regulation of the levels of a glutamate transporter GLT-1, without alterations in its mRNA level. hSOD1(G93A) or hSOD1wt expression caused a decrease of the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1. The effects were selective to GLT-1, since another glutamate transporter GLAST protein and mRNA levels were not altered. Reflecting the decrease in GLT-1 protein, [3H]d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) or hSOD1wt. The hSOD1-induced decline in GLT-1 protein and [3H]d-aspartate uptake was not blocked by the antioxidant Trolox nor potentiated by antioxidant depletion using catalase and glutathione peroxidase inhibitors. Measurement of 2',7'-dichlorofluorescein (DCF)-induced fluorescence revealed that expression of hSOD1(G93A) or hSOD1wt in astrocytes does not lead to detectable increase of intracellular reactive oxygen species. This study suggests that levels of GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1, and is due to a property shared between the wild-type and G93A mutant form, but does not involve the production of intracellular oxidative stress.


A study on moisture isotherms of formulations: the use of polynomial equations to predict the moisture isotherms of tablet products.
The objectives of this study were to investigate the effects of manufacturing parameters on the moisture sorption isotherms of some tablet formulations and to predict the moisture isotherms of the final formulations using polynomial equations. Three tablet formulations including a placebo and 2 drug products were prepared through wet granulation, drying, compression, and coating processes. Equilibrium moisture content of excipients and granules at 25 degrees C with different relative humidities were determined using a dynamic moisture sorption microbalance, while such data for tablets were determined using desiccators. Moisture sorption isotherms were expressed in polynomial equations. Excipient isotherms were used to predict the moisture sorption isotherms of the 3 tablet products. Results showed that different physical properties of granules and tablets, such as particle size distribution, density, and porosity resulting from different granulation and compression conditions did not have significant effect on the moisture isotherms of the materials. Changing coating materials from a powder mixture to a film also did not change the moisture sorption characteristics significantly. The predicted moisture sorption isotherms of the formulations agreed well with the experimental results. These results show that moisture isotherms of solid pharmaceutical products manufactured with conventional processes may be predicted using the isotherms of excipients, and polynomial equations may be used as a tool for the prediction of moisture isotherms.


Remission of the clinical signs of atopic dermatitis in dogs after cessation of treatment with cyclosporin A or methylprednisolone.
Seventy-eight dogs with atopic dermatitis were treated for four months with either cyclosporin A or methylprednisolone. During the two months after the treatment ceased, 87 per cent of the dogs treated with methylprednisolone relapsed after a mean period of 27.9 days, whereas only 62 per cent of the dogs treated with cyclosporin A relapsed after a mean period of 40.7 days (P < .0.001). The clinical condition of the dogs was evaluated either when they relapsed, or two months after the treatment ceased if they had not relapsed. Both the skin lesions and pruritus increased significantly more markedly in the dogs treated with methylprednisolone than in those treated with cyclosporin A. At the end of the study the skin lesions were markedly less severe than before the therapy; in the dogs in both groups that did not relapse, the lesion score was improved by 77 per cent two months after the treatment had stopped, and in the dogs that did relapse the lesion scores had improved by 45 per cent and 35 per cent in the dogs treated with cyclosporin A and methylprednisolone, respectively. Pruritus remained well controlled in the dogs that did not relapse, but increased to baseline levels or close to baseline in the dogs that relapsed.


Functional similarity and molecular divergence of a novel reproductive transcriptome in two male-pregnant Syngnathus pipefish species.
Evolutionary studies have revealed that reproductive proteins in animals and plants often evolve more rapidly than the genome-wide average. The causes of this pattern, which may include relaxed purifying selection, sexual selection, sexual conflict, pathogen resistance, reinforcement, or gene duplication, remain elusive. Investigative expansions to additional taxa and reproductive tissues have the potential to shed new light on this unresolved problem. Here, we embark on such an expansion, in a comparison of the brood-pouch transcriptome between two male-pregnant species of the pipefish genus Syngnathus. Male brooding tissues in syngnathid fishes represent a novel, nonurogenital reproductive trait, heretofore mostly uncharacterized from a molecular perspective. We leveraged next-generation sequencing (Roche 454 pyrosequencing) to compare transcript abundance in the male brooding tissues of pregnant with nonpregnant samples from Gulf (S. scovelli) and dusky (S. floridae) pipefish. A core set of protein-coding genes, including multiple members of astacin metalloprotease and c-type lectin gene families, is consistent between species in both the direction and magnitude of expression bias. As predicted, coding DNA sequence analysis of these putative "male pregnancy proteins" suggests rapid evolution relative to nondifferentially expressed genes and reflects signatures of adaptation similar in magnitude to those reported from Drosophila male accessory gland proteins. Although the precise drivers of male pregnancy protein divergence remain unknown, we argue that the male pregnancy transcriptome in syngnathid fishes, a clade diverse with respect to brooding morphology and mating system, represents a unique and promising object of study for understanding the perplexing evolutionary nature of reproductive molecules.


Prosocial and Aggressive Behavior: A Longitudinal Study.
Developmental theorists have made strong claims about the fundamental prosocial or aggressive nature of the human infant. However, only rarely have prosocial behavior and aggression been studied together in the same sample. We charted the parallel development of both behaviors from infancy to childhood in a British community sample, using a two-construct, multimethod longitudinal design. Data were drawn from the Cardiff Child Development Study (CCDS), a prospective longitudinal study of a volunteer sample of parents and their firstborn children. A sample of 332 mothers was recruited from National Health Service (NHS) prenatal clinics and general practice clinics in Wales, UK, between Fall of 2005 and Summer of 2007. Potential participants represented the full range of sociodemographic classifications of neighborhoods. Participating families were divided about equally between middle- and working-class families, were somewhat more likely to have sons than daughters, and the majority (90%) were in a stable partnership. In response to standard categories recommended for use in Wales at the time, the majority (93%) of mothers reported themselves as Welsh, Scottish, English, or Irish; most others named a European or South Asian nationality. Of the 332 families agreeing to participate, 321 mothers (Mage = 28 years) and 285 partners (Mage = 31 years) were interviewed during the pregnancy and 321 of the families contributed data at least once after the child's birth. After an initial home visit at 6 months, data collection occurred in four additional waves of testing when children's mean ages were approximately 1, 1.5, 2.5, and 7 years. Data collection alternated between family homes and Cardiff University. Of those families seen after the child's birth, 89% were assessed at the final wave of testing. Data collection ended in 2015. Methods included direct observation, experimental tasks, and collection of reports from mothers, fathers, other relatives or family friends, and classroom teachers. Interactions with a familiar peer were observed at 1.5 years. Interactions with unfamiliar peers took place during experimental birthday parties at 1 and 2.5 years. At 7 years, parents were interviewed, parents and teachers completed questionnaires, and the children engaged in cognitive and social decision-making tasks. Based on reports from parents and other informants who knew the children well, individual differences in both prosocial behavior and aggression were evident in children. Both types of behavior showed stability across the second and third years. The association between prosocial behavior and aggression changed over time: at 1.5 years, they were not significantly related (the association approached zero), but they became negatively correlated by 3 years. Different patterns were seen when children played with familiar versus unfamiliar peers. At 1.5 years, when children were observed at home with a familiar peer, prosocial behavior and aggression were unrelated, thus showing a pattern of results like that seen in the analysis of informants' reports. However, a different pattern emerged during the experimental birthday parties with unfamiliar peers: prosocial behavior and aggression were positively correlated at both 1 and 2.5 years, contributing to a general sociability factor at both ages. Gender differences in prosocial behavior were evident in informants' reports and were also evident at the 1-year (though not the 2.5-year) birthday parties. In contrast, gender differences in both prosocial behavior and aggression were evident by 7 years, both in children's aggressive decision-making and in their parents' and teachers' reports of children's aggressive behavior at home and school. By age 7, children's aggressive decision-making and behavior were inversely associated with their verbal skills, working memory, and emotional understanding. Some children had developed aggressive behavioral problems and callous-unemotional traits. A few (12%) met diagnostic criteria for conduct disorder or oppositional-defiant disorders, which had been predicted by early angry aggressiveness and lack of empathy for other people. Taken together, the findings revealed a gradual disaggregation of two ways in which children interact with other people. Individual differences in both prosocial behavior and aggression revealed continuity over time, with gender differences emerging first in prosocial behavior, then in aggression. Restrictions in the participant sample and the catchment area (e.g., all were first-time parents; all were drawn from a single region in the United Kingdom) mean that it is not possible to generalize findings broadly. It will be important to expand the study of prosocial behavior and aggression in other family and environmental contexts in future work. Learning more about early appearing individual differences in children's approaches to the social world may be useful for both educational and clinical practice.


Protein profile of exosomes from trabecular meshwork cells.
To better understand the role of exosomes in the trabecular meshwork (TM), the site of intraocular pressure control, the exosome proteome from primary cultures of human TM cell monolayers was analyzed. Exosomes were purified from urine and conditioned media from primary cultures of human TM cell monolayers and subjected to a two dimensional HPLC separation and MS/MS analyses using the MudPIT strategy. Spectra were searched against a human protein database using Sequest. Protein profiles were compared to each other and the Exocarta database and the presence of specific protein markers confirmed by Western blot analyses of exosomes from aqueous humor and human TM cell strains (n=5) that were untreated, or exposed to dexamethasone and/or ionomycin. TM cell exosomes contained 108 of the 143 most represented exosome proteins in ExoCarta, including previously characterized markers such as membrane organizing and tetraspanin proteins. Several cell-specific proteins in TM exosomes were identified including myocilin, emilin-1 and neuropilin-1. All TM exosome proteins had flotation densities on sucrose gradients and release responses to ionomycin typical for exosomes. Taken together, TM exosomes have a characteristic exosome protein profile plus contain unique proteins, including the glaucoma-causing protein, myocilin; suggesting a role for exosomes in the control of intraocular pressure.


A re-conceptualisation of acute spinal care.
The emergency care of patients who may have spinal injuries has become highly ritualised. There is little scientific support for many of the recommended interventions and there is evidence that at least some methods now used in the field and emergency department are harmful. Since prospective clinical trials are not likely to resolve these issues I propose a reconceptualisation of spinal trauma to allow a more rational approach to treatment. To do this I analyse the basic physics, biomechanics and physiology involved. I then develop a list of recommended treatment variations that are more in keeping with the actual causes of post impact neurological deterioration than are current methods. Discarding the fundamentally flawed emphasis on decreasing post injury motion and concentrating on efforts to minimise energy deposition to the injured site, while minimising treatment delays, can simplify and streamline care without subjecting patients to procedures that are not useful and potentially harmful. Specific treatments that are irrational and which can be safely discarded include the use of backboards for transportation, cervical collar use except in specific injury types, immobilisation of ambulatory patients on backboards, prolonged attempts to stabilise the spine during extrication, mechanical immobilisation of uncooperative or seizing patients and forceful in line stabilisation during airway management.


Prevalence, patterns and predictors of nursing care left undone in European hospitals: results from the multicountry cross-sectional RN4CAST study.
Little is known of the extent to which nursing-care tasks are left undone as an international phenomenon. The aim of this study is to describe the prevalence and patterns of nursing care left undone across European hospitals and explore its associations with nurse-related organisational factors. Data were collected from 33 659 nurses in 488 hospitals across 12 European countries for a large multicountry cross-sectional study. Across European hospitals, the most frequent nursing care activities left undone included 'Comfort/talk with patients' (53%), 'Developing or updating nursing care plans/care pathways' (42%) and 'Educating patients and families' (41%). In hospitals with more favourable work environments (B=-2.19; p<0.0001), lower patient to nurse ratios (B=0.09; p<0.0001), and lower proportions of nurses carrying out non-nursing tasks frequently (B=2.18; p<0.0001), fewer nurses reported leaving nursing care undone. Nursing care left undone was prevalent across all European countries and was associated with nurse-related organisational factors. We discovered similar patterns of nursing care left undone across a cross-section of European hospitals, suggesting that nurses develop informal task hierarchies to facilitate important patient-care decisions. Further research on the impact of nursing care left undone for patient outcomes and nurse well-being is required.


Treatment of SARS-CoV-2: How far have we reached?
The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.


Effect of curcumin on selenite-induced cataractogenesis in Wistar rat pups.
The present study was aimed at investigating the possible antioxidant potential of curcumin at a dose of 75 mg/kg body weight on selenite-induced cataract in experimental rat pups. Group I: Control rat pups receiving physiological saline; Group II: Selenite-induced group (15 microM/kg body wt); Group III: Selenite-induced group co-treated with curcumin (single dose of curcumin orally 75 mg/kg body wt); Group IV: Selenite-induced animals post-treated (after 24 hrs) with curcumin at a dose mentioned for group III; Group V: Rat pups were pretreated with curcumin (dose as mentioned in Group III), 24 hrs before the administration of selenite. Encapsulated lenses liver, kidney, and serum were analyzed for antioxidant enzymes and malondialdehyde, a marker of lipid peroxidation. Intraperitoneal injection of sodium selenite (15 microM/kg body wt) to 8-10-day-old rat pups led to severe oxidative stress in eye lens as evidenced by enhanced LPO levels that led to cataract formation. Sodium selenite also led to decrease in activities of SOD, GST, GPx, CAT with simultaneous decrease in the levels of GSH, vitamin C, and vitamin E. Treatment with curcumin (75 mg/kg body wt) led to a significant decrease in the levels of LPO, enzymic antioxidants, and nonenzymic antioxidants, which were similar to that of control. Curcumin suppressed selenite-induced oxidative stress and cataract formation in rat pups. The presence of oxidative stress in selenite cataract development and its prevention by curcumin support the possibility that the natural consumption of curcumin in food can help prevent the onset of senile cataract.


Predictors of seizure freedom after surgery for malformations of cortical development.
Malformations of cortical development (MCDs) are a major cause of medically refractory epilepsy. Our aim was to examine a surgical series of patients with cortical malformations to determine the prognostic factors associated with long-term seizure control. We conducted a retrospective review of 143 patients with MCD who underwent resective surgery for medically refractory epilepsy. Demographic, imaging, histopathologic, and surgical variables were analyzed for potential association with seizure freedom. Preoperative magnetic resonance imaging (MRI) was evaluated in a blind fashion and classified according to a new imaging/embryologic MCD classification system. Gray-white blurring on MRI, smaller lesions, complete resection of structural lesions, complete resection of abnormal electrocorticographic areas, and locally confined electrocorticographic abnormalities are favorable prognosticators of seizure freedom on univariate analysis. Imaging features consistent with abnormal proliferation (Barkovich class I) were associated with better outcome compared to those related to abnormal neuronal migration (class II) or abnormal cortical organization (class III). Multivariate logistic regression revealed complete resection of tissue manifesting electrocorticographic and/or MRI anatomic abnormalities as the main independent predictor of seizure freedom. Other histopathologic or demographic factors were not associated with seizure control. Long-term follow-up of patients demonstrated sustained overall rates of seizure control (72% at 2 years, 65% at 5 years, and 67% at 10 years). Surgery for MCDs can result in high rates of seizure freedom. Complete resection of electrocorticographic and anatomic abnormalities appears to be most predictive of long-term seizure control.


A variant of the IGF-I gene is associated with blood pressure but not with left heart dimensions at the age of 2 years: the Generation R Study.
A common variant of the IGF-I gene has been shown to be associated with cardiovascular disease in adulthood. The objective of this study was to examine whether this variant of the IGF-I gene is associated with blood pressure and left heart dimensions in early childhood. This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life onwards. IGF-I promoter region was genotyped in DNA obtained from cord blood. Blood pressure (systolic and diastolic) and echocardiography (left ventricular mass, left atrial diameter and aortic root diameter) measurements were performed at the age of 2 years. Analyses were performed in 538 subjects. Eight alleles of the IGF-I promoter region were identified. In total, 43% of the subjects were homozygous for the 192 bp allele (wild type), 46% were heterozygous and 11% were non-carriers. Significantly lower systolic and diastolic blood pressures were found in non-carrier subjects (difference compared with homozygous subjects: -4.4 (95% confidence interval (CI) -7.8 to -1.1) mmHg and -3.5 (95% CI: -6.9 to -0.1) mm respectively). No significant differences were found for left heart dimensions at the age of 2 years. No association was found when we used a previously proposed alternative classification of the IGF-I gene. The variant type of the IGF-I promoter region is associated with lower blood pressure but not with left heart dimensions at the age of 2 years. Follow-up studies are needed to examine whether these differences persist in later life.


Analyses of black and white differentials in the age trajectory of mortality in two closed cohort studies.
We examine the relationship of age to mortality in blacks and whites in two cohort studies, the 20-year follow-up of the Evans County, Georgia. Study population and the 25-year follow-up of the Charleston Heart Study population. We conducted analyses with two parametric forms of hazard models (Gompertz and Weibull) for total mortality experience and considered the fit of the two hazard models in each study both separately and with the data pooled. We evaluated the robustness of conclusions about differences in the age pattern of mortality for blacks and whites by comparing results from the two hazard models. Where the tests were non-nested, we used an information-based statistic (AIC) to compare the fit of the models to the data. Results were robust to the selection of the hazard function, that is both models provided evidence that mortality rates at younger ages were lower for white than black females but that mortality rates increased more rapidly with age for white females. The absolute differences and the differences in the rates of increase were in the same direction, but smaller, for males. Though both models represented the general features of mortality patterns, the information statistic suggested better performance of the Gompertz function. The Gompertz function was also less sensitive to the initial age of determination of mortality exposure.


Extraction, purification and antioxidant activities of the polysaccharides from maca (Lepidium meyenii).
Water-soluble polysaccharides were separated from maca (Lepidium meyenii) aqueous extract (MAE). The crude polysaccharides were deproteinized by Sevag method. During the preparation process of maca polysaccharides, amylase and glucoamylase effectively removed starch in maca polysaccharides. Four Lepidium meyenii polysaccharides (LMPs) were obtained by changing the concentration of ethanol in the process of polysaccharide precipitation. All of the LMPs were composed of rhamnose, arabinose, glucose and galactose. Antioxidant activity tests revealed that LMP-60 showed good capability of scavenging hydroxyl free radical and superoxide radical at 2.0mg/mL, the scavenging rate was 52.9% and 85.8%, respectively. Therefore, the results showed that maca polysaccharides had a high antioxidant activity and could be explored as the source of bioactive compounds.


Differential and limited expression of mutant alleles in multiple myeloma.
Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications.


Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial.
Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up). When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. ClinicalTrials.gov Identifier: NCT01042379.


Semiconductor nanomembranes: a platform for new properties via strain engineering.
New phenomena arise in single-crystal semiconductors when these are fabricated in very thin sheets, with thickness at the nanometer scale. We review recent research on Si and Ge nanomembranes, including the use of elastic strain sharing, layer release, and transfer, that demonstrate new science and enable the fabrication of materials with unique properties. Strain engineering produces new strained forms of Si or Ge not possible in nature, new layered structures, defect-free SiGe sheets, and new electronic band structure and photonic properties. Through-membrane elastic interactions cause the double-sided ordering of epitaxially grown nanostressors on Si nanomembranes, resulting in a spatially and periodically varying strain field in the thin crystalline semiconductor sheet. The inherent influence of strain on the band structure creates band gap modulation, thereby creating effectively a single-element electronic superlattice. Conversely, large-enough externally applied strain can make Ge a direct-band gap semiconductor, giving promise for Group IV element light sources.


Management of diabetes mellitus in older people with comorbidities.
Diabetes mellitus is a chronic disease of aging that affects more than 20% of people over 65. In older patients with diabetes, comorbidities are highly prevalent and their presence may alter the relative importance, effectiveness, and safety of treatments for diabetes. Randomized controlled trials have shown that intensive glucose control produces microvascular and cardiovascular benefits but typically after extended treatment periods (five to nine years) and with exposure to short term risks such as mortality (in one trial) and hypoglycemia. Decision analysis, health economics, and observational studies have helped to illustrate the importance of acknowledging life expectancy, hypoglycemia, and treatment burden when setting goals in diabetes. Guidelines recommend that physicians individualize the intensity of glucose control and treatments on the basis of the prognosis (for example, three tiers based on comorbidities and functional impairments) and preferences of individual patients. Very few studies have attempted to formally implement and study these concepts in clinical practice. To better meet the treatment needs of older patients with diabetes and comorbidities, more research is needed to determine the risks and benefits of intensifying, maintaining, or de-intensifying treatments in this population. This research effort should extend to the development and study of decision support tools as well as targeted care management.


Most clinical laboratory testing in Kampala occurs in high-volume, high-quality laboratories or low-volume, low-quality laboratories. A tale of two cities.
To describe key characteristics (laboratory quality, test volumes, and complexity) of clinical laboratories in Kampala, Uganda (population ~1.7 million). Cross-sectional survey using a standard questionnaire to document laboratory type and quality, as well as test menus and volumes. Quality was based on the World Health Organization-Africa Region checklist. Of the 954 laboratories identified (a density of one laboratory per 1,781 persons), 779 (82%) performed only simple kit tests or light microscope examinations. The 95% (907/954) of laboratories for whom volumes were obtained performed an average aggregate of 13,189 tests daily, for a test utilization rate of around 2 tests per individual per year. Laboratories could be segregated into eight groups based on quality, test volume, and complexity. However, 90% of the testing was performed by just two groups: (1) low-volume (≤100 tests daily), low-quality laboratories performing simple tests or (2) high-volume (>100 tests daily), high-quality laboratories. Each of these two groups did 45% of the daily testing volume (90% combined). Clinical laboratory density in Kampala (1/1,781 persons) is high, approaching that in the United States (1/1,347 persons). Low-volume/low-quality and high-volume/high-quality laboratories do 90% of the daily aggregate testing. Quality improvement (QI) schemes for Africa must be appropriate to low-volume laboratories as well as to the large laboratories that have been the focus of previous QI efforts.


Evaluation of immunohistochemical markers to detect the genotoxic mode of action of fine and ultrafine dusts in rat lungs.
Data on local genotoxicity after particle exposure are crucial to resolve mechanistic aspects such as the impact of chronic inflammation, types of DNA damage, and their role in lung carcinogenesis. We established immunohistochemical methods to quantify the DNA damage markers poly(ADP-ribose) (PAR), phosphorylated H2AX (γ-H2AX), 8-hydroxyguanosine (8-OH-dG), and 8-oxoguanine DNA glycosylase (OGG1) in paraffin-embedded tissue from particle-exposed rats. The study was based on lungs from a subchronic study that was part of an already published carcinogenicity study where rats had been intratracheally instilled with saline, quartz DQ12, amorphous silica (Aerosil(®) 150), or carbon black (Printex(®) 90) at monthly intervals for 3 months. Lung sections were stained immunohistochemically and markers were quantified in alveolar lining cells. Local genotoxicity was then correlated with already defined endpoints, i.e. mean inflammation score, bronchoalveolar lavage parameters, and carcinogenicity. Genotoxicity was most pronounced in quartz DQ12-treated rats, where all genotoxicity markers gave statistically significant positive results, indicating considerable genotoxic stress such as occurrence of DNA double-strand breaks (DSB), and oxidative damage with subsequent repair activity. Genotoxicity was less pronounced for Printex(®) 90, but significant increases in γ-H2AX- and 8-OH-dG-positive nuclei and OGG1-positive cytoplasm were nevertheless detected. In contrast, Aerosil(®) 150 significantly enhanced only 8-OH-dG-positive nuclei and oxidative damage-related repair activity (OGG1) in cytoplasm. In the present study, γ-H2AX was the most sensitive genotoxicity marker, differentiating best between the three types of particles. The mean number of 8-OH-dG-positive nuclei, however, correlated best with the mean inflammation score at the same time point. This methodological approach enables integration of local genotoxicity testing in subchronic inhalation studies and makes immunohistochemical detection, in particular of γ-H2AX and 8-hydroxyguanine, a very promising approach for local genotoxicity testing in lungs, with prognostic value for the long-term outcome of particle exposure.


Assessment of floating plastic debris in surface water along the Seine River.
This study is intended to examine the quality and quantity of floating plastic debris in the River Seine through use of an extensive regional network of floating debris-retention booms; it is one of the first attempts to provide reliable information on such debris at a large regional scale. Plastic debris represented between 0.8% and 5.1% of total debris collected by weight. A significant proportion consisted of food wrappers/containers and plastic cutlery, probably originating from voluntary or involuntary dumping, urban discharges and surface runoff. Most plastic items are made of polypropylene, polyethylene and, to a lesser extent, polyethylene terephthalate. By extrapolation, some 27 tons of floating plastic debris are intercepted annually by this network; corresponding to 2.3 g per Parisian inhabitant per year. Such data could serve to provide a first evaluation of floating plastic inputs conveyed by rivers.


Identifying Adolescent Suicide Risk via Depression Screening in Pediatric Primary Care: An Electronic Health Record Review.
The authors evaluated suicide risk rates detected via a depression screener administered within a large pediatric primary care system and examined 1-year follow-up care after adolescents' endorsement of suicide risk. Retrospective electronic health record data were extracted to examine both suicide risk rates from items endorsed on the Patient Health Questionnaire-Modified for Teens (PHQ-9-M) and primary care providers' (PCPs') follow-up suicide risk assessments on the day of depression screening among adolescents ages 12-18 years during the period of September 1, 2014, to August 31, 2016. Manual chart review was conducted, and charts were coded for several follow-up care actions (e.g., referral to behavioral health providers and provision of crisis line information) in the year after suicidality endorsement. In a sample of 12,690 adolescents, 5.1% endorsed thoughts of death or self-harm, 3.6% reported a lifetime suicide attempt, and 2.4% endorsed serious suicidal ideation within the past month. Manual chart review of a stratified random subsample of 150 of the 643 adolescents who endorsed a lifetime suicide attempt, serious ideation in the past month, or both illustrated the types of follow-up care they received. The PCPs adhered to the system's suicide assessment questions with high fidelity. Follow-up care from PCPs and other providers during the year after suicide risk endorsement was more variable. Findings demonstrate the feasibility of incorporating suicide assessment procedures into depression screening in pediatric primary care and highlight avenues for maximizing preventive care for adolescents at increased risk for suicide.


Dysfunctional meaning of posttraumatic intrusions in chronic PTSD.
The paper suggests that the negative idiosyncratic meaning of posttraumatic intrusions (e.g., 'I am going crazy') and cognitive strategies intended to control the intrusions play a major role in maintaining posttraumatic stress disorder. Two studies of 159 and 138 motor vehicle accidents survivors showed that the dysfunctional meaning of intrusions explained a proportion of the variance of the intrusion-related distress, strategies used to end the intrusions, and PTSD severity that was not explained by intrusion frequency, accident severity, or by general catastrophic thoughts when anxious. Rumination, thought suppression, and distraction when having intrusions showed substantial correlations with PTSD severity, as did avoidance of reminders of the accident. The results have implications for the treatment of chronic PTSD.


[Anemia and nutritional status of infants from two to five months of age treated in facilities of the Ministry of Health of Peru, 2012].
Determine the characteristics of the levels of anemia in infants from two to five months of age treated in facilities of the Ministry of Health of Peru during 2012. This cross-sectional study uses the nutritional status information system of the National Center for Food and Nutrition, National Institute of Health of Peru in 2012. Records of 7,513 infants from two to five months of age treated in small outpatient clinics, centers and hospitals of the Ministry of Health of Peru's 25 regions were analyzed. Descriptive statistics and logistic regression techniques were used for data analysis. 10.2% (95% CI 9.5-10.9) of the infants had anemia, with frequency differences by month of age (p<0.001), altitude, (p<0.001) regions (p<0.001) and type of facility (p<0.001). In the multivariate analysis, factors associated with anemia were: age of 4 months (OR 1.2; 95% CI 1.0-1.5), age of 5 months (OR 1.4; 95% CI 1.2-1.6), obesity (OR 0.7; 95% CI 0.5-1.0) and chronic malnutrition (OR 1.3; 95% CI 1.0-1.6). The presence of anemia and chronic malnutrition before 6 months of age was evidenced, as well as that the probability of anemia increases with age and is associated with some components of nutritional status.


Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase I randomised controlled trial.
There is an urgent need for an effective tuberculosis (TB) vaccine. Heterologous prime-boost regimens induce potent cellular immunity. MVA85A is a candidate TB vaccine. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal vaccination routes would boost cellular immunity to the Mycobacterium tuberculosis antigen 85A (Ag85A). Between December 2013 and January 2016, 36 bacille Calmette-Guérin-vaccinated, healthy UK adults were randomised equally between 3 groups to receive 2 MVA85A vaccinations 1 month apart using either heterologous (Group 1, aerosol-intradermal; Group 2, intradermal-aerosol) or homologous (Group 3, intradermal-intradermal) immunisation. Bronchoscopy and bronchoalveolar lavage (BAL) were performed 7 days post-vaccination. Adverse events (AEs) and peripheral blood were collected for 6 months post-vaccination. The laboratory and bronchoscopy teams were blinded to treatment allocation. One participant was withdrawn and was replaced. Participants were aged 21-42 years, and 28/37 were female. In a per protocol analysis, aerosol delivery of MVA85A as a priming immunisation was well tolerated and highly immunogenic. Most AEs were mild local injection site reactions following intradermal vaccination. Transient systemic AEs occurred following vaccination by both routes and were most frequently mild. All respiratory AEs following primary aerosol MVA85A (Group 1) were mild. Boosting an intradermal MVA85A prime with an aerosolised MVA85A boost 1 month later (Group 2) resulted in transient moderate/severe respiratory and systemic AEs. There were no serious adverse events and no bronchoscopy-related complications. Only the intradermal-aerosol vaccination regimen (Group 2) resulted in modest, significant boosting of the cell-mediated immune response to Ag85A (p = 0.027; 95% CI: 28 to 630 spot forming cells per 1 × 106 peripheral blood mononuclear cells). All 3 regimens induced systemic cellular immune responses to the modified vaccinia virus Ankara (MVA) vector. Serum antibodies to Ag85A and MVA were only induced after intradermal vaccination. Aerosolised MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination. Boosting with aerosol-inhaled MVA85A enhanced the intradermal primed responses in Group 2. The magnitude of BAL MVA-specific CD4+ T cell responses was lower than the Ag85A-specific responses. A limitation of the study is that while the intradermal-aerosol regimen induced the most potent cellular Ag85A immune responses, we did not boost the last 3 participants in this group because of the AE profile. Timing of bronchoscopies aimed to capture peak mucosal response; however, peak responses may have occurred outside of this time frame. To our knowledge, this is the first human randomised clinical trial to explore heterologous prime-boost regimes using aerosol and systemic routes of administration of a virally vectored vaccine. In this trial, the aerosol prime-intradermal boost regime was well tolerated, but intradermal prime-aerosol boost resulted in transient but significant respiratory AEs. Aerosol vaccination induced potent cellular Ag85A-specific mucosal and systemic immune responses. Whilst the implications of inducing potent mucosal and systemic immunity for protection are unclear, these findings are of relevance for the development of aerosolised vaccines for TB and other respiratory and mucosal pathogens. ClinicalTrials.gov NCT01954563.


A cohort study evaluating the association between concurrent mental disorders, mortality, morbidity, and continuous treatment retention for patients in opioid agonist treatment (OAT) across Ontario, Canada, using administrative health data.
Due to the high prevalence of mental disorders among people with opioid use disorder, the objective of this study was to determine the association between concurrent mental disorders, mortality, morbidity, and continuous treatment retention for patients in opioid agonist treatment in Ontario, Canada. We conducted a retrospective cohort study of patients enrolled in opioid agonist treatment between January 1, 2011, and December 31, 2015. Patients were stratified into two groups: those diagnosed with concurrent mental disorders and opioid use disorder and those with opioid use disorder only, using data from the Ontario Health Insurance Plan Database, Ontario Drug Benefit Plan Database. The primary outcome studied was all-cause mortality using data from the Registered Persons Database. Emergency department visits from the National Ambulatory Care Database, hospitalizations Discharge Abstract Database, and continuous retention in treatment, defined as 1 year of uninterrupted opioid agonist treatment using data from the Ontario Drug Benefit Plan Database were measured as secondary outcomes. Encrypted patient identifiers were used to link information across databases. We identified 55,924 individuals enrolled in opioid agonist treatment, and 87% had a concurrent mental disorder diagnosis during this period. We observed that having a mental disorder was associated with an increased likelihood of all-cause mortality (odds ratio (OR) 1.4; 95% confidence interval (CI) 1.2-1.5). For patients diagnosed with mental disorders, the estimated rate of ED visits per year was 2.25 times higher and estimated rate of hospitalization per year was 1.67 times higher than for patients with no mental disorders. However, there was no association between having a diagnosis of a mental disorder and 1-year treatment retention in OAT-adjusted hazard ratio (HR) = 1.0; 95% CI 0.9 to 1.1. Our findings highlight the consequences of the high prevalence of mental disorders for individuals with opioid use disorder in Ontario, Canada.


The flavonoid chrysin attenuates colorectal pathological remodeling reducing the number and severity of pre-neoplastic lesions in rats exposed to the carcinogen 1,2-dimethylhydrazine.
Phenolic compounds are naturally occurring, bioactive substances with marked antioxidant and anti-inflammatory potential. The flavonoid chrysin, found in high levels in honey bee propolis, inhibits the activity of enzymes involved in carcinogenesis. We have investigated the effect of chrysin on pre-neoplastic colorectal lesions (ACF, aberrant crypt foci) in a rat model of chemical carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Female Wistar rats weighing 137.2 ± 24.3 g received weekly one subcutaneous injection of DMH (20 mg/kg) for 10 weeks. The animals were divided into five groups each with seven animals: Group 1, 0.9% saline; Group 2, DMH+0.9% saline; Group 3, DMH+chrysin (10 mg/kg); Group 4, DMH+chrysin (100 mg/kg); Group 5, DMH+chrysin (200 mg/kg). Groups 2 and 3 showed a significant increase in ACF number, nucleolus organizer regions per enterocyte nucleus and nitrite/nitrate serum levels compared with Group 1. Groups 4 and 5 presented a significant reduction in all these parameters compared with Group 2. The levels of antioxidant minerals (copper, magnesium, selenium, zinc) and the number of enteroendocrine and mucin-producing cells were significantly reduced in Groups 2 and 3 but were similar in Groups 4 and 5 compared with Group 1. Chrysin, at 100 mg/kg and 200 mg/kg, was effective in attenuating pathological colorectal remodeling, reducing the number of pre-neoplastic lesions in rats exposed to DMH. Some of these effects might be attributable to the recovery of antioxidant mineral levels, a reduction in systemic nitrosative stress and an inhibition of the cellular proliferation induced by this flavonoid.


Posterior circulation cerebrovascular syndromes: diagnosis and management.
One in five strokes affects the posterior circulation. Diagnosing posterior circulation stroke can be challenging, as the vascular anatomy can be variable, and because presenting symptoms are often non-specific and fluctuating. Nevertheless, making the correct diagnosis is important, as these strokes have a high chance of recurrence, can be life threatening, and can lead to equally life-threatening complications. Investigation and management largely follow those for stroke in general, although some specific differences exist. These include the preferred use of MRI for diagnosing posterior fossa lesions, the management of basilar artery thrombosis, which may have a longer time window for recanalisation therapy, and the use of endovascular therapies for secondary prevention, which, so far, have not shown any benefit in the treatment of vertebral or basilar artery stenosis. In this review, we summarise the anatomy, aetiology and presentation of posterior circulation stroke, and discuss current approaches to management.


How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology.
Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson's disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand their role in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of α-syn antibodies using well-defined and well-characterized preparations of various α-syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 α-syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of α-syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar α-syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic tools or therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.