Inhibition of adenylyl cyclase type 5 prevents L-DOPA-induced dyskinesia in an animal model of Parkinson's disease.
The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is widely used as a therapeutic choice for the treatment of patients with Parkinson's disease. However, the long-term use of L-DOPA leads to the development of debilitating involuntary movements, called L-DOPA-induced dyskinesia (LID). The cAMP/protein kinase A (PKA) signaling in the striatum is known to play a role in LID. However, from among the nine known adenylyl cyclases (ACs) present in the striatum, the AC that mediates LID remains unknown. To address this issue, we prepared an animal model with unilateral 6-hydroxydopamine lesions in the substantia nigra in wild-type and AC5-knock-out (KO) mice, and examined behavioral responses to short-term or long-term treatment with L-DOPA. Compared with the behavioral responses of wild-type mice, LID was profoundly reduced in AC5-KO mice. The behavioral protection of long-term treatment with L-DOPA in AC5-KO mice was preceded by a decrease in the phosphorylation levels of PKA substrates ERK (extracellular signal-regulated kinase) 1/2, MSK1 (mitogen- and stress-activated protein kinase 1), and histone H3, levels of which were all increased in the lesioned striatum of wild-type mice. Consistently, FosB/ΔFosB expression, which was induced by long-term L-DOPA treatment in the lesioned striatum, was also decreased in AC5-KO mice. Moreover, suppression of AC5 in the dorsal striatum with lentivirus-shRNA-AC5 was sufficient to attenuate LID, suggesting that the AC5-regulated signaling cascade in the striatum mediates LID. These results identify the AC5/cAMP system in the dorsal striatum as a therapeutic target for the treatment of LID in patients with Parkinson's disease.


Institutional and behaviour-change interventions to support COVID-19 public health measures: a review by the Lancet Commission Task Force on public health measures to suppress the pandemic.
The Lancet COVID-19 Commission Task Force for Public Health Measures to Suppress the Pandemic was launched to identify critical points for consideration by governments on public health interventions to control coronavirus disease 2019 (COVID-19). Drawing on our review of published studies of data analytics and modelling, evidence synthesis and contextualisation, and behavioural science evidence and theory on public health interventions from a range of sources, we outline evidence for a range of institutional measures and behaviour-change measures. We cite examples of measures adopted by a range of countries, but especially jurisdictions that have, thus far, achieved low numbers of COVID-19 deaths and limited community transmission of severe acute respiratory syndrome coronavirus 2. Finally, we highlight gaps in knowledge where research should be undertaken. As countries consider long-term measures, there is an opportunity to learn, improve the response and prepare for future pandemics.


Laser therapy accelerates initial attachment and subsequent behaviour of human oral fibroblasts cultured on titanium implant material. A scanning electron microscope and histomorphometric analysis.
The aim of the study was to investigate the effect of low-level laser therapy (LLLT) on attachment and proliferation of human gingival fibroblasts (HGF) cultured on titanium implant material. HGF were exposed to gallium-aluminum-arsenide diode laser at dosages of 1.5 or 3 J/cm(2) and then cultured on commercially pure titanium discs. Cell profile areas were measured after 1, 3 and 24 h, using scanning electron microscopy and an automatic image analyzer. The results were expressed as percentage of attachment. In order to investigate the effect of LLLT on cellular growth after 8 and 10 days, HGF were cultured on titanium discs for 24 h and then exposed to laser irradiation on 3 consecutive days. Colony-forming efficiency (CFE) and clonal growth rates (CGR) were measured. Cell viability was determined by Hoechst and prodidium iodide staining. Non-lased cultures served as controls. Morphologically, the cells spread well on all titanium surfaces, indicating good attachment by both irradiated and non-irradiated cells. Fibroblasts exposed to laser irradiation had significantly higher percentages of cell attachment than the non-exposed cells (P<0.05). CFE and CGR were also enhanced for the irradiated cells (P<0.05). Cell viability was high (>90%) in the irradiated and control groups, without significant differences. It is concluded that in vitro LLLT enhances the attachment and proliferation of HGF on titanium implant material.


Sum and difference histograms for texture classification.
The sum and difference of two random variables with same variances are decorrelated and define the principal axes of their associated joint probability function. Therefore, sum and difference histograms are introduced as an alternative to the usual co-occurrence matrices used for texture analysis. Two maximum likelihood texture classifiers are presented depending on the type of object used for texture characterization (sum and difference histograms or some associated global measures). Experimental results indicate that sum and difference histograms used conjointly are nearly as powerful as cooccurrence matrices for texture discrimination. The advantage of the proposed texture analysis method over the conventional spatial gray level dependence method is the decrease in computation time and memory storage.


[Percutaneous treatment of renal transplant complications].
The use of percutaneous endourological techniques in urological complications of renal transplantation has dropped the morbidity/mortality index. These techniques, especially percutaneous nephrostomy, allow us a renal drainage route, thereby improving the recipient's clinical situation and that of the transplant as well. Also, it will allow us access to other therapeutic means such as: introducing catheters, probes for dilating stenosis, and a means of approach to percutaneous nephrolithectomy. Perirenal collections (hematoma, lymphocele, abscess) can be resolved percutaneously to a large extent, without having to resort to surgery. It was observed from the 38 percutaneous endourological procedures performed that in many cases this was the definitive treatment, and in most cases allowed us to place the patient in an acceptable surgical condition. Therefore, we may conclude by stating that percutaneous endourological techniques have proven to be effective alternatives to immediate surgical reintervention, and that they should be used when faced with any urological complication of renal transplantation.


Molecular interaction study of N1-p-fluorobenzyl-cymserine with TNF-α , p38 kinase and JNK kinase.
Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid- beta peptide (Aβ) containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Aβ and p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase- inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation,Aβ and p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-α with respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation.


Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression.
Cancers may escape elimination by the host immune system by rewiring the tumour microenvironment towards an immune suppressive state. Transforming growth factor-β (TGF-β) is a secreted multifunctional cytokine that strongly regulates the activity of immune cells while, in parallel, can promote malignant features such as cancer cell invasion and migration, angiogenesis, and the emergence of cancer-associated fibroblasts. TGF-β is abundantly expressed in cancers and, most often, its abundance associated with poor clinical outcomes. Immunotherapeutic strategies, particularly T cell checkpoint blockade therapies, so far, only produce clinical benefit in a minority of cancer patients. The inhibition of TGF-β activity is a promising approach to increase the efficacy of T cell checkpoint blockade therapies. In this review, we briefly outline the immunoregulatory functions of TGF-β in physiological and malignant contexts. We then deliberate on how the therapeutic targeting of TGF-β may lead to a broadened applicability and success of state-of-the-art immunotherapies.


MGEnrichment: A web application for microglia gene list enrichment analysis.
Gene expression analysis is becoming increasingly utilized in neuro-immunology research, and there is a growing need for non-programming scientists to be able to analyze their own genomic data. MGEnrichment is a web application developed both to disseminate to the community our curated database of microglia-relevant gene lists, and to allow non-programming scientists to easily conduct statistical enrichment analysis on their gene expression data. Users can upload their own gene IDs to assess the relevance of their expression data against gene lists from other studies. We include example datasets of differentially expressed genes (DEGs) from human postmortem brain samples from Autism Spectrum Disorder (ASD) and matched controls. We demonstrate how MGEnrichment can be used to expand the interpretations of these DEG lists in terms of regulation of microglial gene expression and provide novel insights into how ASD DEGs may be implicated specifically in microglial development, microbiome responses and relationships to other neuropsychiatric disorders. This tool will be particularly useful for those working in microglia, autism spectrum disorders, and neuro-immune activation research. MGEnrichment is available at https://ciernialab.shinyapps.io/MGEnrichmentApp/ and further online documentation and datasets can be found at https://github.com/ciernialab/MGEnrichmentApp. The app is released under the GNU GPLv3 open source license.


Cellular mechanisms of resolution of drusen after laser coagulation. An experimental study.
Naturally occurring drusen in two eyes of a rhesus monkey resolved after the application to the retina of mild laser coagulation. Clinically, resolution took place approximately nine days following treatment. The cellular mechanism for resolution was observed by light and electron microscopy over a time period of three days to six weeks after treatment. A previously unidentified phagocytic cell, probably derived from the pericyte of the choriocapillaris, was observed to remove drusenoid material after laser photocoagulation. The cell appeared to be analogous to the mesangial cell of the renal glomerulus.


Factors associated with psychiatric symptoms and psychiatric disorders in ethnic minority youth.
While ethnic diversity is increasing in many countries, ethnic minority youth is less likely to be reached, effectively treated and retained by youth mental health care compared to majority youth. Improving understanding of factors associated with mental health problems within socially disadvantaged ethnic minority youth is important to tailor current preventive and treatment interventions to the needs of these youth. The aim of this study was to explore factors at child, family, school, peer, neighbourhood and ethnic minority group level associated with mental health problems in Moroccan-Dutch youth (n = 152, mean age 13.6 ± 1.9 years). Self-reported and teacher-reported questionnaire data on psychiatric symptoms and self-report interview data on psychiatric disorders were used to divide children into three levels of mental health problems: no symptoms, only psychiatric symptoms and psychiatric disorders. Psychiatric symptoms and/or disorders were associated with more psychopathic traits, a higher number of experienced trauma and children in the family, and more conflicts with parents, affiliation with delinquent peers, perceived discrimination and cultural mistrust. Psychiatric symptoms and/or disorders were also associated with less self-esteem, parental monitoring, affiliation with religion and orientation to Dutch or Moroccan culture, and a weaker ethnic identity. For youth growing up in a disadvantaged ethnic minority position, the most important factors were found at family (parent-child relationship and parenting practices) and ethnic minority group level (marginalization, discrimination and cultural mistrust). Preventive and treatment interventions for socially disadvantaged ethnic minority youth should be aimed at dealing with social disadvantage and discrimination, improving the parent-child relationship and parenting practices, and developing a positive (cultural) identity.


Monoplane 3D-2D registration of cerebral angiograms based on multi-objective stratified optimization.
Registration of 3D pre-interventional to 2D intra-interventional medical images has an increasingly important role in surgical planning, navigation and treatment, because it enables the physician to co-locate depth information given by pre-interventional 3D images with the live information in intra-interventional 2D images such as x-ray. Most tasks during image-guided interventions are carried out under a monoplane x-ray, which is a highly ill-posed problem for state-of-the-art 3D to 2D registration methods. To address the problem of rigid 3D-2D monoplane registration we propose a novel multi-objective stratified parameter optimization, wherein a small set of high-magnitude intensity gradients are matched between the 3D and 2D images. The stratified parameter optimization matches rotation templates to depth templates, first sampled from projected 3D gradients and second from the 2D image gradients, so as to recover 3D rigid-body rotations and out-of-plane translation. The objective for matching was the gradient magnitude correlation coefficient, which is invariant to in-plane translation. The in-plane translations are then found by locating the maximum of the gradient phase correlation between the best matching pair of rotation and depth templates. On twenty pairs of 3D and 2D images of ten patients undergoing cerebral endovascular image-guided intervention the 3D to monoplane 2D registration experiments were setup with a rather high range of initial mean target registration error from 0 to 100 mm. The proposed method effectively reduced the registration error to below 2 mm, which was further refined by a fast iterative method and resulted in a high final registration accuracy (0.40 mm) and high success rate ([Formula: see text]96%). Taking into account a fast execution time below 10 s, the observed performance of the proposed method shows a high potential for application into clinical image-guidance systems.


4-Quinolone interactions with gyrase subunit B inhibitors.
In studies which have involved determination of fractional inhibitory concentrations, synergy has been described between the 4-quinolones, which inhibit the A subunit of DNA gyrase, and either coumermycin or novobiocin, which inhibit the B subunit of the same enzyme. In this study, fixed concentrations of ciprofloxacin or ofloxacin were combined with varying concentrations of coumermycin or novobiocin and vice versa in nutrient broth. The bactericidal activities of the different mixtures against either Staphylococcus aureus E3T or S. warneri were determined and found to be less than those of equivalent concentrations of either 4-quinolone alone. The observation that gyrase B subunit inhibitors antagonised the bactericidal activity of 4-quinolones is in accordance with the report previously made by others that ciprofloxacin combined with coumermycin was less effective than ciprofloxacin alone in treating staphylococcal endocarditis in rats. Our results indicate that both inhibitory and bactericidal activity should be taken into account when assessing possible interactions in vivo between 4-quinolones and other antimicrobial agents.


MiR- 211 represses apoptosis of nerve cells in rats with cerebral infarction through PI3K/AKT signaling pathway.
To investigate the effect of micro ribonucleic acid (miR)-211 on the apoptosis of nerve cells in rats with cerebral infarction through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. A total of 36 Sprague-Dawley (SD) rats were randomly divided into sham operation group (n=12), model group (n=12) and miR-211 mimics group (n=12). Only the common carotid artery, external carotid artery, and internal carotid artery were exposed in sham operation group, and the models of cerebral infarction were constructed via suture method in the other two groups. After modeling, the rats in sham operation group and model group were intraperitoneally injected with normal saline, while those in miR-211 mimics group were given miR-211 mimics via intraperitoneal injection. At 2 weeks after intervention, samples were collected. Neurological deficit in rats was assessed using the Zea-longa score, and Nissl staining assay was performed to observe neuronal morphology. Western blotting (WB), quantitative polymerase chain reaction (qPCR) assay and enzyme-linked immunosorbent assay (ELISA) were employed to measure the relative protein expressions of PI3K and phosphorylated AKT (p-AKT), mRNA expression of miR-211 and content of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), respectively. Additionally, the apoptosis was detected via terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay. The neuronal morphology was normal in sham operation group, while it was disordered in model group, with damaged neurons. In miR-211 mimics group, the morphology of neurons was improved. The Zea-longa score was obviously higher in model group and miR-211 mimics group than that in sham operation group (P<0.05), while it was notably lower in miR-211 mimics group than that in model group (P<0.05). Compared with those in sham operation group, the relative protein expression levels of PI3K and p-AKT remarkably declined in model group and miR-211 mimics group (P<0.05), whereas they were clearly higher in miR-211 mimics group than those in model group (P<0.05). The relative expression level of miR-211 was lower in model group and miR-211 mimics group than that in sham operation group (P<0.05), while it was markedly higher in miR-211 mimics group than that in model group (P<0.05). In comparison with sham operation group, model group and miR-211 mimics group had remarkably increased content of Bax and evidently lowered content of Bcl-2 (P<0.05), whereas compared with model group, miR-211 mimics group displayed clearly reduced Bax content and notably raised Bcl-2 content (P<0.05). The apoptosis rate was distinctly higher in model group and miR-211 mimics group than that in sham operation group (P<0.05), while it was visibly lower in miR-211 mimics group than that in model group (P<0.05). MiR-211 represses the apoptosis of nerve cells in rats with cerebral infarction by up-regulating the PI3K/AKT signaling pathway, thereby protecting nerves.


Innate and Adaptive Immunity in Giant Cell Arteritis.
Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4+ T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4+ T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8+ T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.


Pathways of infant and childhood growth that lead to type 2 diabetes.
Although a link between small body size at birth and later type 2 diabetes has been repeatedly documented, less is known about the associations between the disease and growth during infancy. The aim of this study was to explore the pathways of infant and early growth that lead to type 2 diabetes in adult life. We carried out a longitudinal study of 8760 subjects born in Helsinki from 1934 to 1944. On average, they had 8 measurements of height and weight between birth and 1 year of age and another 10 measurements between 1 and 12 years of age. We identified people with type 2 diabetes using a national register. Among babies whose birth weights were <or=3.5 kg, the rate of infant growth was unrelated to later type 2 diabetes. Among babies with birth weights >3.5 kg, slow growth in length between birth and 3 months of age predicted later disease. Rapid gain in BMI after age 2 years increased the risk of later disease in both groups of babies, but this effect was greatest among children who had slow growth in length between birth and 3 months of age. In children whose Z-scores for length decreased, an SD increase in BMI at age 12 years was associated with an odds ratio (OR) for type 2 diabetes of 1.77 (95% CI 1.50-2.09). The corresponding OR in subjects whose Z-scores for length increased was 1.42 (95% CI 1.20-1.69). Rapid gain in childhood BMI was associated with high maternal BMI and socioeconomic factors (fewer people in the home and lower social class). Babies with above-average birth weights may develop type 2 diabetes later in life if poor living conditions lead to faltering growth in length in the first few months after birth. We speculate that growth faltering at this time is associated with lifelong impairment of insulin metabolism and inability to meet the challenge of rapid childhood increase in BMI.


Valve-sparing aortic root replacement in patients with Marfan syndrome enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions.
The long-term outcomes of aortic valve-sparing (AVS) root replacement in Marfan syndrome (MFS) patients remain uncertain. The study aim was to determine the utilization and outcomes of AVS root replacement in MFS patients enrolled in the Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). At the time of this analysis, 788 patients with MFS were enrolled in the GenTAC Registry, of whom 288 had undergone aortic root replacement. Patients who had undergone AVS procedures were compared to those who had undergone aortic valve replacement (AVR). AVS root replacement was performed in 43.5% of MFS patients, and the frequency of AVS was increased over the past five years. AVS patients were younger at the time of surgery (31.0 versus 36.3 years, p = 0.006) and more likely to have had elective rather than emergency surgery compared to AVR patients, in whom aortic valve dysfunction and aortic dissection was the more likely primary indication for surgery. After a mean follow up of 6.2 +/- 3.6 years, none of the 87 AVS patients had required reoperation; in contrast, after a mean follow up of 10.5 +/- 7.6 years, 11.5% of AVR patients required aortic root reoperation. Aortic valve function has been durable, with 95.8% of AVS patients having aortic insufficiency that was graded as mild or less. AVS root replacement is performed commonly among the MFS population, and the durability of the aortic repair and aortic valve function have been excellent to date. These results justify a continued use of the procedure in an elective setting. The GenTAC Registry will be a useful resource to assess the long-term durability of AVS root replacement in the future.


Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis.
The role of liver in the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) was studied in normal subjects and patients with alcoholic liver disease by measurement of thyrotrophin (TSH) and total and free T4 and T3 in randomand serial serum samples. Also, T4 to T3 conversion rates and T3 disposal rates were compared by noncompartmental analysis. While the mean total serum T4 values were similar for the two groups, 8.6 and 8.1 mug/kl, the mean free T4 value was significantly higher in the cirrhotic patients (3.3 ng/dl) than in the normal subjects (2.1 ng/dl, P less than 0.001). The mean serum T3 value, 85 ng/dl, was significantly reduced in the hepatic patients as compared to a mean serum T3 value of 126 ng/dl in the normal subjects (P less than 0.001), while the free T3 value was 0.28 ng/dl in both groups. The reduction of the serum total and free T3 values were closely correlated with the degree of liver damage, as indicated by elevation of serum bilirubin (r equal -0.547) and reduction of serum albumin (r equal 0.471). The mean serum TSH level was 3.1 muU/ml in the normals and 7.1 muU/ml in the cirrhotic aptients ( less than 0.001). 15% of the hepatic patients had serum TSH values above 10 muU/ml, which, however, did not correlate with any of the four liver function tests studied. Serial blood sampling from two convalescing patients with alcoholic hepatitis showed a gradual normalization of serum TSH and T3 levels as the liver function improved. After oral T4 administration, 0.25 mg/day for 10 days, three of four cirrhotic patients studied failed to raise their serum T3 values. The mean T4 to T3 conversion rate of seven normal subjects was 35.7%. The mean T4 to T3 conversion rate of four cirrhotic patients studied was significantly reduced to 15.6% (P less than 0.001). The mean disposal rates of T4 and T3 of the normal subjects were 114 and 34 mug/day, respectively. The ratio of T4 disposal to T3 disposal was 3.5. In contrast, the mean T4 disposal rate, 82 mug/day, and the mean T3 disposal rate, 10 mug/day, were both reduced in the cirrhotic patients. Their ratio of T4 disposal to T3 disposal was 7.9. These findings suggest that impairment of T4 conversion in patients with advanced hepatic cirrhosis may lead to reduced T3 production and lowered serum T3 level. Therefore, the liver is one of the major sites of T4 conversion to T3.


Streptomonospora halophila sp. nov., a halophilic actinomycete isolated from a hypersaline soil.
An actinomycete strain, designated YIM 91355(T), was isolated from a soil sample collected from a hypersaline soil in Xinjiang Province, China, and its taxonomic position was investigated by using a polyphasic approach. The strain grew well on most media tested and no diffusible pigment was produced. The aerial mycelium of this organism was well developed but not fragmented and, at maturity, formed short chains of spores. Substrate mycelium was branched with non-fragmenting hyphae and single, oval to round spores were formed, borne on sporophores. Strain YIM 91355(T) contained meso-diaminopimelic acid as the diagnostic amino acid. The purified cell-wall hydrolysate contained galactose. The predominant menaquinones were MK-10(H(8)) (43.2 %), MK-10(H(6)) (17.7 %) and MK-11(H(8)) (10.4 %). Phospholipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol mannosides, phosphatidylcholine, phosphatidylinositol and an unidentified phospholipid. The major fatty acids were i-C(16 : 0), ai-C(17 : 0), 10-methyl C(17 : 0) and 10-methyl C(18 : 0). The G+C content of the genomic DNA was 72.1 mol%. Phylogenetic analysis indicated that the isolate belongs to the genus Streptomonospora of the family Nocardiopsaceae. Based on phenotypic and genotypic data, it is concluded that strain YIM 91355(T) represents a novel species of the genus Streptomonospora, for which the name Streptomonospora halophila sp. nov. (type strain YIM 91355(T) =DSM 45075(T) =KCTC 19236(T)) is proposed.


Analgesic efficacy of forced coughing versus local anesthesia during cervical punch biopsy.
To compare local anesthesia and forced coughing in terms of subjective pain perception during cervical punch biopsy. In this randomized controlled trial, 114 patients (mean age: 38.9 ± 9.0 years) scheduled for colposcopically directed cervical punch biopsy were randomly assigned to local anesthesia (n = 39), forced coughing (n = 39) and control (n = 36) groups. Pain perception was measured on a 10-cm visual analog scale (VAS) during the insertion of the speculum, injection of the local anesthetic to the cervix and the taking of the first cervical biopsy, as well as for the overall pain perceived during the entire procedure. Experimental groups were similar in age, gravidity, parity and prior curettage. The pain score obtained during the first cervical biopsy was significantly lower if local anesthesia was applied (p = 0.016). Groups were similar in other pain subscores. The duration of the entire procedure was significantly longer (p < 0.001) in the local anesthesia group, while it was not significantly different in forced coughing patients compared to controls. Local anesthesia, but not forced coughing, provides significant pain relief during cervical biopsy. Based on similarity to control data in terms of pain relief and shortening of the operation, forced coughing per se seems related neither to pain relief nor a faster cervical biopsy.


Acute respiratory, circulatory and pathological changes in the calf after intravenous injections of the galactan from Mycoplasma mycoides subsp. mycoides.
Twenty of 28 calves, 10-12 weeks of age when given intravenous injections of the galactan from Mycoplasma mycoides subsp. mycoides, showed transient apnoea, increased pulmonary arterial and decreased systemic arterial blood pressures, and increased packed-cell volume. Necropsy revealed haemorrhages associated with alveolar ducts and vessel walls, areas of pulmonary oedema, usually associated with the haemorrhages, dilated airways and, in some, capillary thrombosis. Animals that had shown changes in blood pressure and respiration in response to a dose of galactan did not react to a second dose an hour later. One goat tested died, four lambs were mildly affected and a cat and several rats and guinea-pigs did not respond. It is suggested that the galactan released biogenic amines that produced the effects listed. Immunological mechanisms were discounted on the grounds that only a small amount of antigenic material was injected at the time the reaction occurred, and neither serological nor skin tests produced any evidence of prior sensitisation to the galactan or a similar substance. A relationship between reactivity to the galactan and susceptibility to the natural disease has been suggested. This, together with the pulmonary oedema found in galactan-treated calves and in natural lesions of contagious bovine pleuropneumonia (CBPP), and the possibility that contraction of blood vessels could be an initiating cause of thrombosis indicates the role that galactan may play in the pathogenesis of CBPP.


C-C Bond Cleavage of Unactivated 2-Acylimidazoles.
2-Acylimidazoles are widely used as post-transformable carboxylic acid equivalents in chemoselective and enantioselective reactions. Their transformations, however, require pretreatment with highly reactive, toxic methylating reagents to facilitate C-C bond cleavage. Here, we demonstrate that such pretreatment can be avoided and the C-C bond cleaved under neutral conditions without the use of additional reagents or catalysts. The scope of the reaction, including the use of products reported in the literature as substrates, and some mechanistic insights are described.


Boron Triiodide-Mediated Reduction of Nitroarenes Using Borohydride Reagents.
The reduction of nitroarenes using KBH4 and I2 is described. BI3 is generated in situ and was shown to be the active reductant. Conditions were optimized for BI3 generation and then applied to a wide range of nitroarenes, including traditionally challenging substrates. The method constitutes a practical reduction option which produces low-toxicity boric acid and potassium iodide upon workup.


Investigation of the Reversible Intercalation/Deintercalation of Al into the Novel Li3VO4@C Microsphere Composite Cathode Material for Aluminum-Ion Batteries.
The Li3VO4@C microsphere composite was first reported as a novel cathode material for rechargeable aluminum-ion batteries (AIBs), which manifests the initial discharge capacity of 137 mAh g-1 and and remains at 48 mAh g-1 after 100 cycles with almost 100% Coulombic efficiency. The detailed intercalation mechanism of Al into the orthorhombic Li3VO4 is investigated by ex situ X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) of Li3VO4@C electrodes and the nuclear magnetic resonance aluminum spectroscopy (27Al NMR) of ionic liquid electrolytes in different discharge/charge states. First-principle calculations are also carried out to investigate the structural change as Al inserts into the framework of Li3VO4. It is revealed that the Al/Li3VO4@C battery goes through electrochemical dissolution and deposition of metallic aluminum in the anode, as well as the insertion and deinsertion of Al3+ cations in the cathode in the meantime. The rechargeable AIBs fabricated in this work are of low cost and high safety, which may make a step forward in the development of novel cathode materials based on the acidic ionic liquid electrolyte system.


What Constitutes Quality of Life? Perspectives of Adolescents and Young Adults With Advanced Cancer.
Adolescents and young adults (AYAs) with advanced cancer identify maintaining a good quality of life (QoL) as a central goal of end-of-life care. QoL is a dynamic and subjective overarching concept that refers to an individual's relative satisfaction with their own life. Despite its importance to AYAs with advanced cancer, a patient-centered definition of QoL is lacking in this population. This qualitative secondary analysis of semistructured interviews was conducted across 3 institutions and 1 online support community among AYA patients with advanced cancer, family caregivers, and health care providers who cared for living or recently deceased AYAs. Interviewees were asked about priorities in receipt of care. Interviews were transcribed using NVivo software for primary analysis, and previously coded excerpts were screened for references to QoL. Relevant excerpts were sorted into organizing domains. Participants included 23 AYA patients, 28 family caregivers, and 29 health care providers (including physicians, nurses, nurse practitioners, social workers, and psychologists). Four domains of QoL were identified: psychosocial and physical well-being, dignity, normalcy, and personal and family relationships. Within each domain there was agreement across AYAs, caregivers, and health care providers, with nuanced perspectives provided by AYAs of different ages. Personal and family relationships was the most frequently referenced domain of QoL among all participants. A common feature of each domain was that adaptation to current circumstances impacted perspectives on QoL. Patients valued active participation in the development of a care plan that supported these domains. AYAs with advanced cancer, their caregivers, and health care providers agree on several broad domains of QoL in this population. To provide high-quality, patient-centered care, care plans should integrate these domains to enable AYAs to maximize their QoL throughout their advanced cancer care.


Promotion of a healthy lifestyle among 5-year-old overweight children: health behavior outcomes of the 'Be active, eat right' study.
This study evaluates the effects of an intervention performed by youth health care professionals on child health behaviors. The intervention consisted of offering healthy lifestyle counseling to parents of overweight (not obese) 5-year-old children. Effects of the intervention on the child having breakfast, drinking sweet beverages, watching television and playing outside were evaluated. Data were collected with the 'Be active, eat right' study, a cluster randomized controlled trial among nine youth health care centers in the Netherlands. Parents of overweight children received lifestyle counseling according to the intervention protocol in the intervention condition (n = 349) and usual care in the control condition (n = 288). Parents completed questionnaires regarding demographic characteristics, health behaviors and the home environment at baseline and at 2-year follow-up. Cluster adjusted regression models were applied; interaction terms were explored. The population for analysis consisted of 38.1% boys; mean age 5.8 [sd 0.4] years; mean BMI SDS 1.9 [sd 0.4]. There were no significant differences in the number of minutes of outside play or television viewing a day between children in the intervention and the control condition. Also, the odds ratio for having breakfast daily or drinking two or less glasses of sweet beverages a day showed no significant differences between the two conditions. Additional analyses showed that the odds ratio for drinking less than two glasses of sweet beverages at follow-up compared with baseline was significantly higher for children in both the intervention (p < 0.001) and the control condition (p = 0.029). Comparison of the children in the two conditions showed that the intervention does not contribute to a change in health behaviors. Further studies are needed to investigate opportunities to adjust the intervention protocol, such as integration of elements in the regular well-child visit. The intervention protocol for youth health care may become part of a broader approach to tackle childhood overweight and obesity. Current Controlled Trials ISRCTN04965410.


N-Methylated α-Amino Acids And Peptides: Synthesis And Biological Activity.
The simplest and minimal modification of a single amino acid or peptide bonds is represented by N-methylation. This can improve the pharmacokinetic properties of biologically active peptides as well as resulting in analogues that show specific biological activity such as enzyme inhibitors, receptor antagonists and agonists, building blocks in combinatorial chemistry for the screening of new potential drugs. Further, structural and conformational studies performed with N-methylated analogues of natural amino acids and peptides enabled to (i) produce stable foldamers with different topology with respect to the helix of natural and endogenous peptides, (ii) confer to modified peptides high stability against proteases and (iii) enhance lipophilicity and bioavailability for pharmacological purposes. Consequentially, it is crucial to provide optically pure N-methyl-amino acids and N-methylated peptides with a large supply. The present report will focus on the results obtained in the last decade in the field of chemical synthetic methodologies for the N-methylation of amino acids.


Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Clopidogrel is the most frequently used P2Y12 inhibitor as a component of the dual antiplatelet regimen in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prior studies have shown the variable efficacy of clopidogrel due to genotypic differences in the CYP2C19 enzyme function, which converts clopidogrel to its active metabolite. The aim of this meta-analysis is to evaluate the effectiveness of genotype testing-guided P2Y12 inhibitor prescription therapy to patients after PCI for ACS compared to non-genotype guided conventional treatment. A comprehensive literature search was performed in PubMed, Embase, and Cochrane to identify relevant trials. Summary effects were calculated using a DerSimonian and Laird random-effects model as odds ratio with 95% confidence intervals for all the clinical endpoints. Seven studies with 9617 patients were included. Genotype-guided strategy arm included prasugrel or ticagrelor prescription to patients with loss of function (LOF) of CYP219 alleles (most commonly alleles being *2 and *3) and clopidogrel prescription to those without the LOF allele. The conventional arm included patients treated with clopidogrel without genotype testing. Comparison of genotype arm with conventional arm showed decreased major adverse cardiovascular events (MACE), improved cardiovascular (CV) mortality, and reduced incidence of myocardial infarction (MI) in the genotype arm, and a similar stroke incidence in the two arms. Regarding adverse events, the incidence of stent thrombosis was lower in the genotype arm than the conventional arm. Our analysis illustrates the possible advantages of genotype-guided P2Y12 inhibitor prescription strategy compared to non-genotype-guided strategy with reductions in MACE, CV mortality, MI, and stent thrombosis. This analysis can be used as a stepping stone to conducting further trials determining the efficacy of this treatment strategy in various ACS subtypes.


Who benefits from cognitive intervention in older age? The role of executive function.
Objective: In the context of the positive impact of cognitive interventions for age-related memory concerns, clinicians are seeking information about variables that predict optimum client response. In this study of older adults, the aim was to investigate baseline predictors of gain in memory performance, i.e. prospective memory, following a memory intervention.Methods: One hundred and one healthy older adults (H0A) and 73 older people with amnestic mild cognitive impairment (aMCI) were evaluated at 6-months after participating in a 6-week memory group intervention (LaTCH). The outcome measure was a clinic-based prospective memory task. Baseline predictors included demographic variables (age, gender, education), baseline prospective memory, and cognitive resources (retrospective memory, executive function).Results: Thirty percent of the HOA and 16% of the aMCI cohorts demonstrated reliable training effects on prospective memory test performance at 6-month assessment. Through hierarchical regressions in the HOA cohort, executive function (working memory, attention set shifting) rather than retrospective memory was the best predictor of change in prospective memory. Moderated regression did not demonstrate any interactions between retrospective memory and executive function. For the memory impaired cohort (aMCI), better baseline retrospective memory predicted greater gain in prospective memory but only when executive function was also high.Conclusions: Memory groups can improve performance on clinic-based prospective memory tests in older people with concerns about memory performance, suggesting the value of further translation studies to demonstrate functional real-world gains and quality of life improvement after training. These interventions may be especially effective for those older people with better executive function (working memory, attention set shifting).


L-tryptophan in the treatment of impaired respiration in sleep.
15 subjects (mean age: 48.2 yr; 13 males, 2 females) with sleep apnea (12 obstructive, 3 central) were treated with an average dose of 2500 mg L-tryptophan (L-T) at bedtime. Comparison of pre- and post-drug polysomnograms showed significant improvement in obstructive sleep apnea but not with central sleep apnea. Most dramatic improvement is seen in subjects with obstructive sleep apnea in non-REM sleep only, but severity of apnea appears to be the most important factor determining improvement. L-T increased REM time and shortened REM latency but had no other significant effects on sleep architecture. Serotoninergic activity with a defect in feedback control of tryptophan-serotonin metabolism is postulated as a potential mechanism in the pathophysiology of obstructive sleep apnea. The enhanced usefulness of L-T in combination with protriptyline is predicted based on early preliminary work at the OSU Sleep Center. The Potential influence of dietary intake on respiratory automaticity is reviewed.


A systematic review on barriers hindering adequate cancer pain management and interventions to reduce them: a critical appraisal.
The aim of this paper is to identify the major barriers hindering adequate pain management and critically review interventions aiming to overcome them. We searched relevant literature on PubMed published between January 1986 and April 2007. The most frequently mentioned barriers for both patients and professionals were knowledge deficits, inadequate pain assessment and misconceptions regarding pain. Four interventions were identified: patient education, professional education, pain assessment and pain consultation. These interventions were never combined in multidisciplinary study protocols. Most RCTs included small groups of patients and reported no power analysis. Studies on professional education and pain assessment did not evaluate patients' outcomes. In 5 of 11 RCTs on patient education, pain intensity decreased statistically significantly. In two RCTs on pain consultation, patients' pain decreased statistically significantly, although the adequacy of pain treatment did not change. In conclusion, international guidelines on multidisciplinary interventions in pain management are partly substantiated by clinical trials.


Experimental determination of three-dimensional cervical joint mobility in the avian neck.
Birds have highly mobile necks, but neither the details of how they realize complex poses nor the evolution of this complex musculoskeletal system is well-understood. Most previous work on avian neck function has focused on dorsoventral flexion, with few studies quantifying lateroflexion or axial rotation. Such data are critical for understanding joint function, as musculoskeletal movements incorporate motion around multiple degrees of freedom simultaneously. Here we use biplanar X-rays on wild turkeys to quantify three-dimensional cervical joint range of motion in an avian neck to determine patterns of mobility along the cranial-caudal axis. Range of motion can be generalized to a three-region model: cranial joints are ventroflexed with high axial and lateral mobility, caudal joints are dorsiflexed with little axial rotation but high lateroflexion, and middle joints show varying amounts axial rotation and a low degree of lateroflexion. Nonetheless, variation within and between regions is high. To attain complex poses, substantial axial rotation can occur at joints caudal to the atlas/axis complex and zygapophyseal joints can reduce their overlap almost to osteological disarticulation. Degrees of freedom interact at cervical joints; maximum lateroflexion occurs at different dorsoventral flexion angles at different joints, and axial rotation and lateroflexion are strongly coupled. Further, patterns of joint mobility are strongly predicted by cervical morphology. Birds attain complex neck poses through a combination of mobile intervertebral joints, coupled rotations, and highly flexible zygapophyseal joints. Cranial-caudal patterns of joint mobility are tightly linked to cervical morphology, such that function can be predicted by form. The technique employed here provides a repeatable protocol for studying neck function in a broad array of taxa that will be directly comparable. It also serves as a foundation for future work on the evolution of neck mobility along the line from non-avian theropod dinosaurs to birds.


Phosphodiester Hydrogels for Cell Scaffolding and Drug Release Applications.
Given the major structural role phosphodiesters play in the organism it is surprising they have not been more widely adopted as a building block in sophisticated biomimetic hydrogels and other biomaterials. The potential benefits are substantial: phosphoester-based materials show excellent compatibility with blood, cells, and a remarkable resistance to protein adsorption that may trigger a foreign-body response. In this work, a novel class of phosphodiester-based ionic hydrogels is presented which are crosslinked via a phosphodiester moiety. The material shows good compatibility with blood, supports the growth and proliferation of tissue and presents opportunities for use as a drug release matrix as shown with fluorescent model compounds. The final gel is produced via base-induced elimination from a phosphotriester precursor, which is made by the free-radical polymerization of a phosphotriester crosslinker. This crosslinker is easily synthesized via multigram one-pot procedures out of common laboratory chemicals. Via the addition of various comonomers the properties of the final gel may be tuned leading to a wide range of novel applications for this exciting class of materials.


The effect of diet on autogenous immunity to mouse mammary tumor virus in C3H/Bi mice.
Antibody levels to mouse mammary tumor virus (MuMTV) in sera of C3H/Bi, C57BL/6 and AKR mice were assayed by an enzyme-linked immunosorbent assay (ELISA). It was found that antibody levels to MuMTV were highest in sera of C3H/Bi females which have a high incidence of breast cancer and low in male C3H/Bi and female C3H/Bi foster-nursed on C57BL/6 females. Sera of C57BL/6 and AKR mice showed very low or undetectable levels of antibody to MuMTV. Reduction of caloric intake sufficient to inhibit mammary tumor formation strikingly inhibited formation of antibody against MuMTV. The lowest levels of antibody were observed in sera of mice fed 10 cal/day of a defined diet. Significantly higher levels developed in the sera of mice fed 16 cal/day of the same defined diet. The highest antibody levels against MuMTV, however, were seen in sera of mice fed lab chow ad libitum but no correlation was evident between levels of antibody and tumor size. These studies indicate that dietary caloric restriction has a profound influence on the development of both mammary adenocarcinoma and antibody responses to MuMTV.


Extending access to care across the rural US south: Preliminary results from the Alabama eHealth programme.
Using a mixed-methods formative evaluation, the purpose of this study was to provide a broad overview of the Alabama eHealth programme set-up and initial patient outcomes. The Alabama eHealth programme uses telemedicine to provide medical care to people living with HIV in rural Alabama. It was led by a community-based organisation, Medical Advocacy and Outreach (MAO), and supported by AIDS United and the Corporation for National Community Service's Social Innovation Fund with matching support from non-federal donors. We conducted and transcribed in-depth interviews with Alabama eHealth staff and then performed directed content analysis. We also tracked patients' ( n = 240) appointment attendance, CD4 counts, and viral loads. Staff described the steps taken to establish the programme, associated challenges (e.g., costly, inadequate broadband in rural areas), and technology enabling this programme (electronic medical records, telemedicine equipment). Of all enrolled patients, 76% were retained in care, 88% had antiretroviral therapy and 75% had a suppressed viral load. Among patients without missing data, 96% were retained in care, 97% used antiretroviral therapy and 93% had suppressed viral loads. There were no statistically significant demographic differences between those with and without missing data. Patients enrolled in a telemedicine programme evaluation successfully moved through the HIV continuum of care.


Survey of Canadian retail pork chops and pork livers for detection of hepatitis E virus, norovirus, and rotavirus using real time RT-PCR.
Over the past 15 years, hepatitis E virus (HEV), norovirus (NoV), and rotavirus (RV) have been hypothesized to be potentially zoonotic; swine and pork have been suggested as possible human infection sources for all 3 viruses. Our objective was to estimate HEV, NoV, and RV prevalence and load on Canadian retail pork chops and livers. Using the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) sampling platform, pork livers (n=283) and chops (n=599) were collected, processed, and assayed for the 3 viruses by four collaborating federal laboratories using validated real time reverse transcriptase polymerase chain reactions (qRT-PCR). Follow-up qRT-PCR estimating viral load in genomic copies/g was followed by nested classical RT-PCR and isolate sequencing of a partial segment of the ORF2 gene. Local alignments were performed using MUSCLE (Multiple Sequence Comparison by Log-Expectation); a phylogenetic tree was created. Twenty-five livers and 6 chops were classified 'positive' (thresholds for viral RNA detected in both replicates of the assay) or 'suspect' (thresholds detected in one of two replicates) for HEV. Follow-up qRT-PCR detected HEV on 16 livers, 0 chops, and nested classical RT-PCR, on 14 livers and 0 chops. Initial qRT-PCR classified 12 chops 'suspect' for NoV. Follow-up qRT-PCR detected viral RNA on only one sample with thresholds greater than 40 in both replicates. No amplicon was yielded, and therefore no isolate was sequenced from this sample. Partial ORF2 genes from 14 HEV isolates were sequenced, and compared via sequence identity and phylogenetic analysis with selected human case isolates listed in NCBI-GenBank. Overall, HEV prevalence on retail pork was comparable with other published reports.


A proof of concept study for the integration of robot therapy with physiotherapy in the treatment of stroke patients.
To carry out a proof of concept study for integrating robot therapy with physiotherapy in the treatment of stroke patients. A simple and 'gentle' paradigm of robot-patient interaction was designed in order to foster the re-emergence of smooth, active control patterns in coordinated shoulder/elbow reaching movements. A haptic robot was programmed according to a strategy of minimal, progressively reduced assistance, with a double representation of targets: (i) visual (circles on a screen) and (ii) haptic (robot-generated force fields). The protocol included trials with and without vision, in order to emphasize the role of proprioceptive feedback. The training paradigm included 10 sessions and more than 5000 movements. Ten chronic, hemiparetic subjects; four controls provided reference values for the performance measurements. Four performance indicators (derived from the analysis of the reaching trajectories); clinical/functional measures (Fugl-Meyer and Ashworth scales). After robot therapy reaching movements became faster and smoother. The performance in the no-vision trials was at least as good as in the vision trials. The Fugl-Meyer arm scores also increased significantly and remained approximately constant at follow-up; the Ashworth scores did not change. In spite of its simplicity, a limited number of ;gentle' robot therapy sessions appear to be beneficial, even for severely impaired patients, although no firm conclusion can be drawn at this point. However, the study provides support material for the careful design of controlled clinical trials and for a better integration with physiotherapy.


A model-based theory on the origin of downbeat nystagmus.
The pathomechanism of downbeat nystagmus (DBN), an ocular motor sign typical for vestibulo-cerebellar lesions, remains unclear. Previous hypotheses conjectured various deficits such as an imbalance of central vertical vestibular or smooth pursuit pathways to be causative for the generation of spontaneous upward drift. However, none of the previous theories explains the full range of ocular motor deficits associated with DBN, i.e., impaired vertical smooth pursuit (SP), gaze evoked nystagmus, and gravity dependence of the upward drift. We propose a new hypothesis, which explains the ocular motor signs of DBN by damage of the inhibitory vertical gaze-velocity sensitive Purkinje cells (PCs) in the cerebellar flocculus (FL). These PCs show spontaneous activity and a physiological asymmetry in that most of them exhibit downward on-directions. Accordingly, a loss of vertical floccular PCs will lead to disinhibition of their brainstem target neurons and, consequently, to spontaneous upward drift, i.e., DBN. Since the FL is involved in generation and control of SP and gaze holding, a single lesion, e.g., damage to vertical floccular PCs, may also explain the associated ocular motor deficits. To test our hypothesis, we developed a computational model of vertical eye movements based on known ocular motor anatomy and physiology, which illustrates how cortical, cerebellar, and brainstem regions interact to generate the range of vertical eye movements seen in healthy subjects. Model simulation of the effect of extensive loss of floccular PCs resulted in ocular motor features typically associated with cerebellar DBN: (1) spontaneous upward drift due to decreased spontaneous PC activity, (2) gaze evoked nystagmus corresponding to failure of the cerebellar loop supporting neural integrator function, (3) asymmetric vertical SP deficit due to low gain and asymmetric attenuation of PC firing, and (4) gravity-dependence of DBN caused by an interaction of otolith-ocular pathways with impaired neural integrator function.


Targeting olfactory bulb neurons using combined in vivo electroporation and Gal4-based enhancer trap zebrafish lines.
In vivo electroporation is a powerful method for delivering DNA expression plasmids, RNAi reagents, and morpholino anti-sense oligonucleotides to specific regions of developing embryos, including those of C. elegans, chick, Xenopus, zebrafish, and mouse. In zebrafish, in vivo electroporation has been shown to have excellent spatial and temporal resolution for the delivery of these reagents. The temporal resolution of this method is important because it allows for incorporation of these reagents at specific stages in development. Furthermore, because expression from electroporated vectors occurs within 6 hours, this method is more timely than transgenic approaches. While the spatial resolution can be extremely precise when targeting a single cell, it is often preferable to incorporate reagents into a specific cell population within a tissue or structure. When targeting multiple cells, in vivo electroporation is efficient for delivery to a specific region of the embryo; however, particularly within the developing nervous system, it is difficult to target specific cell types solely through spatially discrete electroporation. Alternatively, enhancer trap transgenic lines offer excellent cell type-specific expression of transgenes. Here we describe an approach that combines transgenic Gal4-based enhancer trap lines with spatially discrete in vivo electroporation to specifically target developing neurons of the zebrafish olfactory bulb. The Et(zic4:Gal4TA4,UAS:mCherry)(hzm5) (formerly GA80_9) enhancer trap line previously described, displays targeted transgenic expression of mCherry mediated by a zebrafish optimized Gal4 (KalTA4) transcriptional activator in multiple regions of the developing brain including hindbrain, cerebellum, forebrain, and the olfactory bulb. To target GFP expression specifically to the olfactory bulb, a plasmid with the coding sequence of GFP under control of multiple Gal4 binding sites (UAS) was electroporated into the anterior end of the forebrain at 24-28 hours post-fertilization (hpf). Although this method incorporates plasmid DNA into multiple regions of the forebrain, GFP expression is only induced in cells transgenically expressing the KalTA4 transcription factor. Thus, by using the GA080_9 transgenic line, this approach led to GFP expression exclusively in the developing olfactory bulb. GFP expressing cells targeted through this approach showed typical axonal projections, as previously described for mitral cells of the olfactory bulb. This method could also be used for targeted delivery of other reagents including short-hairpin RNA interference expression plasmids, which would provide a method for spatially and temporally discrete loss-of-function analysis.


A signature of immune function genes associated with recurrence-free survival in breast cancer patients.
The clinical significance of tumor-infiltrating immune cells has been reported in a variety of human carcinomas including breast cancer. However, molecular signature of tumor-infiltrating immune cells and their prognostic value in breast cancer patients remain elusive. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a diverse cohort of breast cancer patients with a 1-5 year tumor relapse versus those with up to 7 years relapse-free survival. The RNAs were extracted from the frozen tumor specimens at the time of diagnosis and subjected to microarray analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to immunohistochemistry staining. We determined that a network of immune function genes involved in B cell development, interferon signaling associated with allograft rejection and autoimmune reaction, antigen presentation pathway, and cross talk between adaptive and innate immune responses were exclusively upregulated in patients with relapse-free survival. Among the 299 genes, five genes which included B cell response genes were found to predict with >85% accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.


Electrostatic properties of membrane lipids coupled to metarhodopsin II formation in visual transduction.
Changes in lipid composition have recently been shown to exert appreciable influences on the activities of membrane-bound proteins and peptides. We tested the hypothesis that the conformational states of rhodopsin linked to visual signal transduction are related to biophysical properties of the membrane lipid bilayer. For bovine rhodopsin, the meta I-meta II conformational transition was studied in egg phosphatidylcholine (PC) recombinants versus the native rod outer segment (ROS) membranes by means of flash photolysis. Formation of metarhodopsin II was observed by the change in absorbance at 478 nm after a single actinic flash was delivered to the sample. The meta I/meta II ratio was investigated as a function of both temperature and pH. The data clearly demonstrated thermodynamic reversibility of the transition for both the egg PC recombinants and the native ROS membranes. A significant shift of the apparent pK(a) for the acid-base equilibrium to lower values was evident in the egg PC recombinant, with little meta II produced under physiological conditions. Calculations of the membrane surface pH using a Poisson-Boltzmann model suggested the free energies of the meta I and meta II states were significantly affected by electrostatic properties of the bilayer lipids. In the ROS membranes, phosphatidylserine (PS) is needed for full formation of meta II, in combination with phosphatidylethanolamine (PE) and polyunsaturated docosahexaenoic acid (DHA; 22:6omega3) chains. We propose that the PS surface potential leads to an accumulation of hydronium ions, H(3)O(+), in the electrical double layer, which drive the reaction together with the large negative spontaneous curvature (H(0)) conferred by PE plus DHA chains. The elastic stress/strain of the bilayer arises from an interplay of the approximately zero H(0) from PS and the negative H(0) due to the PE headgroups and polyunsaturated chains. The lipid influences are further explained in terms of matching of the bilayer spontaneous curvature to the curvature at the lipid/rhodopsin interface, as formulated by the Helfrich bending energy. These new findings guide current ideas as to how bilayer properties govern the conformational energetics of integral membrane proteins. Moreover, they yield knowledge of how membrane lipid-protein interactions involving acidic phospholipids such as PS and neutral polyunsaturated DHA chains are implicated in key biological functions such as vision.


Nuclear magnetic resonance (NMR) studies of homeopathic solutions.
The efficacy of homeopathy is controversial. Nuclear magnetic resonance (NMR) has been used to study homeopathic solutions, showing provocative results. We examined the reproducibility of one of the allegedly positive studies. 1H NMR spectra were recorded for Sulphur D4, diluted and succussed up to D30 (called potentization) at two different frequencies (300 and 500 MHz). The Sulphur solution had been potentiated according to homeopathic principles with deionized water and alcohol. Water proton T1 relaxation measurements were performed also at 20 MHz for the different potentiated Sulphur solutions. Furthermore, the homeopathic remedy Betula alba 30c (birch pollen extract) and appropriate control solution (deionized water, unsuccussed solutions and placebo globules) were measured analogously, both with frequencies giving spectra and T1 relaxometry. The Sulphur remedies showed identical one dimensional proton spectra (1H NMR) at 300 and 500 MHz, regardless of dilution/succussion stage, from D4 to D30. Furthermore, Betula 30c as a potentiated solution and its controls (ethanol dilutions and Betula diluted but not succussed) showed identical spectra. Nor were there any statistically significant differences in longitudinal (T1) relaxation times between deionized water and Sulphur D10 to D30 preparations. The shorter T1 of the Sulphur D4 preparation could be ascribed to the higher microviscosity within the sample matrix caused by the high concentration of dissolved material. Also, the T1 values of the Betula alba 30c preparation (in globular form) and control placebo globules were identical. In conclusion, published results from NMR research on homeopathy indicating differences between homeopathic solutions and control samples could not be reproduced.


Prevalence of asthma-associated symptoms in Turkish children.
The aim of the first national cross-sectional survey was to determine the prevalence of asthma-like respiratory symptoms and the associated risk factors among children aged 0-17 via interview with the parents by primary care physicians. They were selected through stratified two-stage cluster probability sampling in urban and rural parts of randomly selected 27 of 81 administrative districts in Turkey. Data was collected for 46,813 children (23,512 males and 23,301 females) of whom 66 percent resided in urban areas. The prevalence of physician-diagnosed asthma was 0.7 percent. The lifetime and current (last 12 months) prevalences were 14.7 percent and 2.8 percent for asthma, and 15.1 percent and 3.4 percent for wheezing respectively. The presence of personal atopy and history of family atopy were the most significant risk factors for current prevalences of wheezing, and asthma [adjusted Odds ratios (OR) and 95% confidence intervals (CI) were 6.2 (CI=4.0-9.5) and 1.8 (CI=1.3-2.4) for wheezing, and 8.5 (CI=5.6-12.9) and 1.9 (CI=1.4-2.5) for asthma, respectively]. Though there were no significant differences among those residing in urban versus rural areas regarding the current prevalences of asthma and wheezing, those living in coastal areas had considerably higher current prevalences than those inland (OR=2.6, CI=1.9-3.5 for wheezing, and OR=2.3, CI=1.7-3.1 for asthma). Residence in northern Turkey appeared to be a significant risk factor for wheezing (OR=1.9, CI=1.4-2.5), and children resident in southern Turkey exhibited the highest risk for occurrence of asthma (OR=1.5, CI=1.1-2.0) compared with eastern Turkey. In conclusion, the respiratory symptoms associated with asthma were an important cause of morbidity in childhood in Turkey. The discrepancy between prevalence of physician-diagnosed asthma and lifetime and/or current asthma prevalence figures may reflect the reluctancy of both physicians and parents to diagnose this condition. Besides strongest associations with personal atopy and atopic heredity, there were significant differences in prevalence rates between children residing in different regions, supporting the role of environmental factors.


Tentative evidence for striatal hyperactivity in adolescent cannabis-using boys: a cross-sectional multicenter fMRI study.
Adolescents' risk-taking behavior has been linked to a maturational imbalance between reward ("go") and inhibitory-control ("stop")-related brain circuitry. This may drive adolescent drug-taking, such as cannabis use. In this study, we assessed the non-acute effects of adolescent cannabis use on reward-related brain function. We performed a two-site (United States and Netherlands; pooled data) functional magnetic resonance imaging (fMRI) study with a cross-sectional design. Twenty-one abstinent but frequent cannabis-using boys were compared with 24 non-using peers on reward-related brain function, using a monetary incentive delay task with fMRI. Focus was on anticipatory and response stages of reward and brain areas critically involved in reward processing like the striatum. Performance in users was normal. Region-of-interest analysis indicated striatal hyperactivity during anticipatory stages of reward in users. Intriguingly, this effect was most pronounced during non-rewarding events. Striatal hyperactivity in adolescent cannabis users may signify an overly sensitive motivational brain circuitry. Frequent cannabis use during adolescence may induce diminished ability to disengage the motivational circuit when no reward can be obtained. This could strengthen the search for reinforcements like drugs of abuse, even when facing the negative (non-rewarding) consequences.


Age-Related Degree and Criteria Differences in Semantic Categorization.
Individual differences in semantic categorization are commonplace. Individuals apply a word like SPORTS to different instances because they employ different conditions for category membership (vagueness in criteria) or because they differ regarding the extent to which they feel the term can be applied given fixed conditions (vagueness in degree). Three individuals may, for instance, disagree as to whether chess and hiking are SPORTS, because one believes SPORTS are competitive in nature, while the other two require SPORTS to be effortful (vagueness in criteria). On the basis of whether they consider hiking sufficiently effortful or not, the latter two individuals might still disagree as to whether to call it a SPORT (vagueness in degree). We investigated whether there are systematic age-related differences in semantic categorization by analyzing the categorization decisions of 1,868 adults for eight semantic categories with a formal model that allows the two sources of categorization differences to be disentangled. We found that young and older adults assess instances differently with respect to the categorization conditions and that older adults employ a lower threshold for category membership than young adults do. We recommend that these criteria and degree differences are taken into account in studies of age-related semantic processing.


Vitamin C, vitamin E and cancer (review).
The influences of vitamin C and vitamin E on cancer reported in the literature are reviewed. Several correlational studies and case-control studies suggest that the consumption of vitamin C-containing foods is associated with lower risk for certain cancers, particularly gastric and esophageal cancer. No definite links between dietary vitamin E and human cancer have been demonstrated. Animal and in vitro studies have shown that vitamins C and E can effectively inhibit the formation of carcinogenic nitrosamines. However, animal studies examining the effects of these two vitamins on other chemically-induced cancers are not conclusive. Vitamin C supplementation has been reported to inhibit skin, nerve, lung and kidney carcinogenesis. Vitamin E has been shown to inhibit skin, liver, oral, ear duct, and forestomach carcinogenesis; and to enhance, to have no effect on, or to inhibit mammary gland or colon carcinogenesis, depending upon the method of administration, the level of dietary selenium or fat, and the species and strain of animals used. Both vitamin C and vitamin E can inhibit mutagenesis and carcinogenesis in vitro. Each of the vitamins has been shown to inhibit tumor cell growth and carcinogen-induced DNA damage. The mechanism of action of the two vitamins against carcinogens is not clearly understood. Several suggested mechanisms of action include modification of the metabolism of polycyclic hydrocarbons, reduction of mutagenic activity and reaction with genotoxic free radicals. It is concluded that the potential usefulness of vitamin C and vitamin E in the prevention and treatment of cancer should not be ignored because under certain experimental conditions these two vitamins exert inhibitory effects on chemical carcinogenesis. More carefully standardized and controlled experiments are required to adequately evaluate this potential.


Synchronization and spatiotemporal patterns in coupled phase oscillators on a weighted planar network.
To reveal the relation between network structures found in two-dimensional biological systems, such as protoplasmic tube networks in the plasmodium of true slime mold, and spatiotemporal oscillation patterns emerged on the networks, we constructed coupled phase oscillators on weighted planar networks and investigated their dynamics. Results showed that the distribution of edge weights in the networks strongly affects (i) the propensity for global synchronization and (ii) emerging ratios of oscillation patterns, such as traveling and concentric waves, even if the total weight is fixed. In-phase locking, traveling wave, and concentric wave patterns were, respectively, observed most frequently in uniformly weighted, center weighted treelike, and periphery weighted ring-shaped networks. Controlling the global spatiotemporal patterns with the weight distribution given by the local weighting (coupling) rules might be useful in biological network systems including the plasmodial networks and neural networks in the brain.


Efficient X-ray scintillating lead(ii)-based MOFs derived from rigid luminescent naphthalene motifs.
Solid-state X-ray scintillators are widely applied in medical imaging and space exploration. However, it is still a great challenge to probe into the intrinsic nature of scintillating behaviour due to the ambiguous structure-function relationship. Herein, four structure-defined X-ray scintillating Pb(ii)-based metal-organic frameworks (SMOFs) were successfully obtained under solvothermal conditions, [Pb(1,4-ndc)(DMF)]n (SMOF-1), [Pb(1,4-ndc)(DMA)]n (SMOF-2), [Pb2(2,6-ndc)2(H2O)]n·nDMF (SMOF-3) and [Pb4(2,6-ndc)3Cl2]n (SMOF-4), where 1,4-H2ndc = 1,4-naphthalene dicarboxylate, 2,6-H2ndc = 2,6-naphthalene dicarboxylate, DMF = N,N-dimethylformamide, and DMA = N,N-dimethylacetamide. SMOFs 1-4 show scintillating signals under X-rays triggered by a highly purified tungsten target. Compared with SMOFs 1-3, SMOF-4 exhibits excellent scintillating performance owing to its solvent-free and denser structure, which favours more efficient conversion ability of X-rays to visible light. X-ray stimulated luminescence (XSL) spectra present multiple emission peaks, which is further confirmed by wavelength-dependent luminescence spectra under UV-Vis light, and density of state and DFT calculations. The synergistic effects of heavy metal Pb(ii) centres as effective X-ray absorbers and organic ligands as luminescent motifs endow these Pb(ii)-based MOFs with application prospects in X-ray detection.


Metabolic networks and their evolution.
Since the last decade of the twentieth century, systems biology has gained the ability to study the structure and function of genome-scale metabolic networks. These are systems of hundreds to thousands of chemical reactions that sustain life. Most of these reactions are catalyzed by enzymes which are encoded by genes. A metabolic network extracts chemical elements and energy from the environment, and converts them into forms that the organism can use. The function of a whole metabolic network constrains evolutionary changes in its parts. I will discuss here three classes of such changes, and how they are constrained by the function of the whole. These are the accumulation of amino acid changes in enzyme-coding genes, duplication of enzyme-coding genes, and changes in the regulation of enzymes. Conversely, evolutionary change in network parts can alter the function of the whole network. I will discuss here two such changes, namely the elimination of reactions from a metabolic network through loss of function mutations in enzyme-coding genes, and the addition of metabolic reactions, for example through mechanisms such as horizontal gene transfer. Reaction addition also provides a window into the evolution of metabolic innovations, the ability of a metabolism to sustain life on new sources of energy and of chemical elements.


[Pharmacokinetic and clinical effectiveness of rectally administered theophylline].
The bronchodilatory effect of Neo-Biphyllin Mikroklysma (400 mg Theophylline [T], 600 mg Diprophylline [D], 600 mg Proxyphylline [P], corresponding to 5.2 mg/kg bodyweight of T, and 7.8 mg/kg of D and P, respectively) was studied on 5 consecutive days with one daily rectal application in a double-blind crossover design in 8 patients with chronic obstructive lung disease. Serum levels following rectal application are lower than after oral administration. On the 5th day they are only slightly higher than on the 1st day. The mean serum levels (microgram/ml) achieved after 2 h are 6.1 for T, 1.0 for D and 7.7 for P, after 8 h 3.5 for T, 0.9 for D and 4.8 for P. The pulmonary function parameters (FEV1, VC, RV, TLC and Raw) show an improvement, however, in comparison with placebo the results are statistically not significant. A correlation between the serum levels and the functional improvement cannot be established, even after taking into consideration the equipotency on a weight-for-weight basis according to the in vitro effect of the three compounds on the isolated guinea pig trachea [Boardman, 1980]. No side effects or local intolerance were reported. The use of the combination enema is particularly suitable for children or self-application by adults. Yet according to our findings larger doses or more frequent applications are required.


First report of Colletotrichum cliviicola causing anthracnose disease of cowpea (Vigna unguiculata L. Walp) in Nigeria.
Cowpea (Vigna unguiculata L. Walp) is a staple crop for millions of people in sub-Saharan Africa. However, its production is challenged by various abiotic and biotic constraints, including fungal diseases. In February 2020, around 10% of cowpea plants in IITA-Ibadan research plots (N7°29'49'' E3°53'49'') had symptoms of cowpea anthracnose disease (CAD). Symptoms included reddish brown spots, necrotic lesions, and vein streaks (Fig. 1). Diseased leaves were collected and taken to the laboratory, cut into small discs (3 mm in diameter) at advancing edges of lesions, and surface disinfected. Dry leaf discs were plated on PDA and incubated at 28°C for 5 days and sub-cultured in PDA for another 7 days. Isolates yielded phenotypes similar to Colletotrichum spp. (Fig. 2). DNA templates of four isolates (CC17 NG, CC19 NG, CC21 NG, and CC24 NG) were amplified using primers of the actin (ACT; ACT512F and ACT783R) (Carbone and Kohn, 1999) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; GDF and GFR) (Templeton et al., 1992) genes and sequenced. The sequences were deposited in GenBank (accession numbers OP716557 to OP716560 for ACT and OP716561 to OP716564 for GADPH). BLASTn results on NCBI showed 98-100% identity of the four isolates with C. cliviicola. A bi-locus phylogenetic tree revealed that the isolates belong to the species C. cliviicola (Fig. 3) when compared with existing sequences in the GenBank (Table 1). To fulfill Koch's postulates, pathogenicity of each of the four C. cliviicola isolates was confirmed on 2-week-old cowpea plants cv. Ife Brown in screenhouse assays. Inocula were prepared from 7-d-old cultures washed with sterile water containing 0.1% TWEEN®20. Fungal suspensions were adjusted to 106 conidia/ml. Inoculations were carried out using the brush method. Leaves inoculated with sterile water containing 0.1% TWEEN®20 served as negative controls. Plants were kept in the screenhouse at room temperature for 21 days. All four C. cliviicola isolates produced CAD symptoms on inoculated leaves, while control leaves remained asymptomatic (Fig. 4). Each inoculated isolate was successfully re-isolated from symptomatic tissues and their identity confirmed. The fungus C. cliviicola is distributed in tropical and subtropical regions and has a wide host range, including several legumes (Damm et al. 2018). To our knowledge, this is the first report of C. cliviicola causing CAD in Nigeria and the world. There is the need to conduct a comprehensive distribution survey and develop appropriate control strategies in Nigeria. In addition, breeding for resistance to CAD in Nigeria should gear the efforts to all causal agents of the disease that occur across the country because historically CAD has been attributed to C. lindemuthianum and C. destructivum.


Cannabis use disorder and the lungs.
Cannabis is one of the world's most widely used recreational drugs and the second most commonly smoked substance. Research on cannabis and the lungs has been limited by its illegal status, the variability in strength and size of cannabis cigarettes (joints), and the fact that most cannabis users also smoke tobacco, making the effects difficult to separate. Despite these difficulties, the available evidence indicates that smoking cannabis causes bronchitis and is associated with changes in lung function. The pattern of effects is surprisingly different from that of tobacco. Whereas smoking cannabis appears to increase the risk of severe bronchitis at quite low exposure, there is no convincing evidence that this leads to chronic obstructive pulmonary disease. Instead, cannabis use is associated with increased central airway resistance, lung hyperinflation and higher vital capacity with little evidence of airflow obstruction or impairment of gas transfer. There are numerous reports of severe bullous lung disease and pneumothorax among heavy cannabis users, but convincing epidemiological data of an increased risk of emphysema or alveolar destruction are lacking. An association between cannabis and lung cancer remains unproven, with studies providing conflicting findings.


Immune status in very preterm neonates.
Preterm neonates are at increased risk of sepsis compared with those born at term. We investigated immune status at birth and early neonatal life in very preterm neonates and its association with short-term outcomes. Prospective observational study conducted at a university hospital recruiting 113 preterm neonates (23-32 weeks) and 78 controls. Monocyte major histocompatibility complex (MHC) class II expression, serum, and ex vivo lipopolysaccharide stimulated levels of six cytokines (tumor necrosis factor α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and IL-12p70) were measured in umbilical cord blood and over the first 7 days. The presence of neonatal sepsis and histologic chorioamnionitis was recorded. Prematurity (preterm labor and preterm premature rupture of membranes cohorts), neonatal sepsis, and histologic chorioamnionitis were associated with significant reduction in monocyte MHC class II expression. Neonates who had evidence of subsequent protracted sepsis had low levels of MHC class II expression at birth. Serial monocyte MHC class II expression revealed a fall by day 2, in all preterm neonates, with the degree being influenced by both prematurity and sepsis, and incomplete recovery by day 7, suggesting immunoparalysis in preterm premature rupture of membranes and preterm labor cohorts. Whole blood lipopolysaccharide stimulation assay showed significantly lower tumor necrosis factor α, values in preterm neonates who subsequently developed sepsis indicating a degree of immunoparalysis. Our data support the concept that fetal exposure to inflammation before preterm delivery leads to subsequent endotoxin hyporesponsiveness (immunoparalysis), which increases the risk of subsequent sepsis and associated organ dysfunction.


A Highly Selective Chemosensor for Cyanide Derived from a Formyl-Functionalized Phosphorescent Iridium(III) Complex.
A new phosphorescent iridium(III) complex, bis[2',6'-difluorophenyl-4-formylpyridinato-N,C4']iridium(III) (picolinate) (IrC), was synthesized, fully characterized by various spectroscopic techniques, and utilized for the detection of CN(-) on the basis of the widely known hypothesis of the formation of cyanohydrins. The solid-state structure of the developed IrC was authenticated by single-crystal X-ray diffraction. Notably, the iridium(III) complex exhibits intense red phosphorescence in the solid state at 298 K (ΦPL = 0.16) and faint emission in acetonitrile solution (ΦPL = 0.02). The cyanide anion binding properties with IrC in pure and aqueous acetonitrile solutions were systematically investigated using two different channels: i.e., by means of UV-vis absorption and photoluminescence. The addition of 2.0 equiv of cyanide to a solution of the iridium(III) complex in acetonitrile (c = 20 μM) visibly changes the color from orange to yellow. On the other hand, the PL intensity of IrC at 480 nm was dramatically enhanced ∼5.36 × 10(2)-fold within 100 s along with a strong signature of a blue shift of the emission by ∼155 nm with a detection limit of 2.16 × 10(-8) M. The cyanohydrin formation mechanism is further supported by results of a (1)H NMR titration of IrC with CN(-). As an integral part of this work, phosphorescent test strips have been constructed by impregnating Whatman filter paper with IrC for the trace detection of CN(-) in the contact mode, exhibiting a detection limit at the nanogram level (∼265 ng/mL). Finally, density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were performed to understand the electronic structure and the corresponding transitions involved in the designed phosphorescent iridium(III) complex probe and its cyanide adduct.


Anti-ulcerogenic mechanism of magnesium in indomethacin induced gastric ulcer in rats.
The gastric mucosa is continuously exposed to various agents like food condiments, spices, alcohol, acids and drugs, some of which are implicated in the pathogenesis of gastric ulcer. Magnesium compounds commonly used as laxatives and antacids have been reported to prevent ulcer formation but the mechanisms underlying this potential is unknown. This study therefore seeks to evaluate the gastro-protective mechanism of magnesium in the stomach through its effect on the parietal and mucus cells. Thirty-six male albino rats divided into 6 groups of 6 rats each were used. Group 1 was control, Group 2 was ulcer induced and untreated, Group 3 was treated with 500mg/kg b.w magnesium alone, Group 4 was pre-treated with 500mg/kg b.w magnesium before inducing ulcer, Group 5 was pre-treated with 500mg/kg b.w magnesium and 20mg/kg omeprazole 4 hours before inducing ulcer, Group 6 was treated with 20mg/kg omeprazole 4 hours before inducing ulcer. Animals were sacrificed 6 hours after ulcer induction and their stomachs were removed for ulcer scoring and histological analysis. A significant reduction was observed in the ulcer scoring of magnesium pre-treated ulcerated rats (9.4±0.8) compared with ulcerated untreated (20.8±0.9) groups. Parietal cell count of magnesium pre treated ulcerated group significantly decreased (169.7±18.9) compared with ulcerated untreated group (310.5±34.7). Mucous cell count of magnesium pre-treated ulcerated group (264.6±8.3) significantly increased compared with ulcerated untreated group (170.0±17.7). This study shows that magnesium possesses anti-ulcerogenic properties due to its ability to reduce the number of parietal cell and increase mucous cell counts.


Variability in abciximab (ReoPro) prescribing: evidence based or budget driven?
Abciximab improves outcomes in patients undergoing percutaneous transluminal coronary intervention (PTCA). Clinicians, however, have expressed concerns that they do not have enough budget to administer abciximab to all eligible patients. We studied the patterns of prescribing of abciximab and identified factors that correlate with the level of usage. In each of all 13 Dutch PTCA centres one opinion-leading cardiologist was approached to provide data on the abciximab prescribing in their centre and to co-operate in an interview on this topic. We performed linear regression analysis in which the level of abciximab prescribing was the dependent variable. Potential determinants investigated were the number of PTCAs performed, the criteria for abciximab prescribing, funding and possible financial restrictions, participation in clinical trials in the past, percentage stenting, and desired level of abciximab prescribing. All 13 PTCA centres in the Netherlands participated in our study. The level of abciximab prescribing varied from 2 to 36% of all PTCAs. The criteria for patient selection significantly differed between centres. Together budget, investigatorship, size, and type of the institution were highly predictive for the level of abciximab prescribing (R2 = 0.93, p < 0.001). The more patients doctors had included in clinical trials in the past, the higher was the likelihood that they had prescribed abciximab. Shortly after its introduction, patterns of abciximab prescribing varied widely between PTCA centres. There was no agreement on which patients to select for this preventive treatment. Budget and involvement in clinical trials in the past were important predictors of the level of prescribing in each centre.


[The influence of the morphometric parameters of the intercondylar notch on rupture of the anterior cruciate ligament].
Morpohometric parameters of the intercondylar notch of femur present one of the substantial risk factors for rupture of the anterior cruciate ligament (ACL). In morphometric studies of the knee the most often referred indexes are notch width index and notch shape index. The aim of this study was to identificate the morphometric parameters of the intercondylar notch as risk factors for ACL rupture. This study included 99 patients divided into two groups: the study group (n=57) composed of patients with chronic instability of the knee because of previos rupture of the ACL, and the control group (n=42) composed of patients with lesion of the knee, but without rupture of the ACL. Measuring the width and height of intercondylar notch and epicondylar width was observed on a horizontal MR section. According to these values notch width and notch shape indexes were calculated. The study group had statistically significantly higher (p < 0.05) intercondylar notch and lesser notch shape index than the control group (p < 0.05). The difference was highly statistically significant (p < 0.01) only in males, but not in females (p > 0.05). Absolute dimensions of the morphometric parameters of the distal part of the femur had highly statatistically significant larger values (p < 0.01) in males than females, exept in case of the intercondilar height in the control group (p > 0.05). Enhanced height of the intercondylar notch as well as lesser value of the notch shape index are associated with rupture of the ACL in males but not in females.


Resveratrol inhibits dimethylnitrosamine-induced hepatic fibrosis in rats.
Resveratrol, a phytoalexin found in grapes and red wines, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of resveratrol on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Oral administration of resveratrol (20 mg/kg daily for 4 weeks) remarkably prevented the DMN-induced loss in body and liver weight, and inhibited the elevation of serum alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin levels. Resveratrol also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde due to its antioxidant effect. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the resveratrol treated rats, the result of which was consistent with the reduction in type I collagen mRNA expression and the histological analysis of liver tissue stained with Sirius red. The reduction in hepatic stellate cell activation, as assessed by alpha-smooth muscle actin staining, and the reduction in transforming growth factor-beta1 mRNA expression were associated with resveratrol treatment. In conclusion, resveratrol exhibited in vivo hepatoprotective and antifibrogenic effects against DMN-induced liver injury, suggesting that resveratrol may be useful in the prevention of the development of hepatic fibrosis.


Patient reported barriers to enrolling in a patient portal.
Previous studies of patient portals have found low rates of enrollment and significant disparities in enrollment by race and ethnicity. As the reasons for these findings are unclear, we sought to identify patient reported barriers to enrollment in a patient portal. We conducted a telephone survey of patients in one urban general internal medicine clinic. Patients were eligible if they did not enroll within 30 days of receiving an electronic order inviting participation. Our primary outcomes were: (a) reasons for not enrolling in the patient portal; (b) reasons for not attempting enrollment; and (c) perceived benefits of the portal. Participants' (N=159) mean age was 51 years, 48% were black, 72% female, and 70% had a college degree or greater. 63% of respondents not enrolling reported never attempting enrollment despite remembering receiving an order. Most of these 63% did not attempt enrollment because of lack of information or motivation. Smaller proportions reported not attempting enrollment because of negative attitudes toward the portal (30%) or computer related obstacles (8%). Overall, respondents favorably viewed most patient portal features, however black respondents were less likely than white respondents to consider features assisting self-management such as getting test results (69% vs 86%; p<0.05) as important. Adjusting for age, gender, education, and chronic disease did not substantially change results. Strategies to increase enrollment in patient portals need to ensure patients understand patient portal features and receive follow-up reminders. Interventions to reduce racial disparities in enrollment must address attitudinal barriers and not focus solely on improving access.


A tropical geometric approach to exceptional points.
Non-Hermitian systems have been widely explored in platforms ranging from photonics to electric circuits. A defining feature of non-Hermitian systems is exceptional points (EPs), where both eigenvalues and eigenvectors coalesce. Tropical geometry is an emerging field of mathematics at the interface between algebraic geometry and polyhedral geometry, with diverse applications to science. Here, we introduce and develop a unified tropical geometric framework to characterize different facets of non-Hermitian systems. We illustrate the versatility of our approach using several examples and demonstrate that it can be used to select from a spectrum of higher-order EPs in gain and loss models, predict the skin effect in the non-Hermitian Su-Schrieffer-Heeger model, and extract universal properties in the presence of disorder in the Hatano-Nelson model. Our work puts forth a framework for studying non-Hermitian physics and unveils a connection of tropical geometry to this field.