Assessment of the regional economic impacts of catastrophic events: CGE analysis of resource loss and behavioral effects of an RDD attack scenario.
We investigate the regional economic consequences of a hypothetical catastrophic event-attack via radiological dispersal device (RDD)-centered on the downtown Los Angeles area. We distinguish two routes via which such an event might affect regional economic activity: (i) reduction in effective resource supply (the resource loss effect) and (ii) shifts in the perceptions of economic agents (the behavioral effect). The resource loss effect relates to the physical destructiveness of the event, while the behavioral effect relates to changes in fear and risk perception. Both affect the size of the regional economy. RDD detonation causes little capital damage and few casualties, but generates substantial short-run resource loss via business interruption. Changes in fear and risk perception increase the supply cost of resources to the affected region, while simultaneously reducing demand for goods produced in the region. We use results from a nationwide survey, tailored to our RDD scenario, to inform our model values for behavioral effects. Survey results, supplemented by findings from previous research on stigmatized asset values, suggest that in the region affected by the RDD, households may require higher wages, investors may require higher returns, and customers may require price discounts. We show that because behavioral effects may have lingering long-term deleterious impacts on both the supply-cost of resources to a region and willingness to pay for regional output, they can generate changes in regional gross domestic product (GDP) much greater than those generated by resource loss effects. Implications for policies that have the potential to mitigate these effects are discussed.


Pleistocene-recent boundary and wisconsin glacial biostratigraphy in the northern Indian ocean.
Two faunal criteria define the Pleistocene-Recent boundary in the Andaman Sea and the Bay of Bengal: there is a marked decrease in the relative abundance of the Globigerina rubescens complex and a significant increase in the radiolarian number in sediments of the Recent epoch. The stratigraphic significance of the faunal criteria is supported by a carbon-14 date (8775 years before the present) obtained from foraminiferal tests in sediment at the faunal boundary, and previous publications on the stratigraphic significance of the radiolarian number in the eastern Pacific Ocean. The Globigerina rubescens complex, with greater relative abundances indicative of glacial substages, is an accurate indicator of cold and warm climatic intervals of the Wisconsin glacial stage.


A rare case of primary nodal hemangioendothelioma.
Primary vascular tumors of the lymph nodes other than Kaposi's sarcoma are rare. The present study describes the case of a primary hemangioendothelioma in a cervical lymph node in a patient treated for a carcinoma of the large bowel. Microscopically, the structure of the lymph node was completely substituted by tumoral proliferation, with an architectural pattern consisting of anastomosing vascular channels, a number of which contained papillary projections or a tuft-like structure. This study demonstrates the potential diagnostic errors and hypothesizes the pathogenesis of this type of lesion; a vascular endothelial growth factor (VEGF)/VEGF receptor-3 (VEGFR-3) autocrine loop may be activated.


2014 Chinese guidelines for secondary prevention of ischemic stroke and transient ischemic attack.
Ischemic stroke and transient ischemic attack (TIA) are the most common cerebrovascular disorder and leading cause of death in China. The Effective secondary prevention is the vital strategy for reducing stroke recurrence. The aim of this guideline is to provide the most updated evidence-based recommendation to clinical physicians from the prior version. Control of risk factors, intervention for vascular stenosis/occlusion, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke are all recommended, and the prevention of recurrent stroke in a variety of uncommon causes and subtype provided as well. We modified the level of evidence and recommendation according to part of results from domestic RCT in order to facility the clinical practice.


Pre-symptomatic transmission of pandemic influenza H1N1 2009: investigation of a family cluster, Brazil.
We investigated the first cluster of pandemic influenza H1N1 2009 reported in Brazil in May 2009. The index case-patient had travelled from the USA and had contact with 11 relatives before she presented with symptoms. We conducted face-to-face or telephone interviews with the index case-patient and all suspect cases. We found evidence of pre-symptomatic transmission of the virus to four of her contacts. This finding has public health implications because it indicates that viral transmission in communities may not be prevented solely by isolating symptomatic case-patients.


Evidence for a role of Anopheles stephensi in the spread of drug- and diagnosis-resistant malaria in Africa.
Anopheles stephensi, an Asian malaria vector, continues to expand across Africa. The vector is now firmly established in urban settings in the Horn of Africa. Its presence in areas where malaria resurged suggested a possible role in causing malaria outbreaks. Here, using a prospective case-control design, we investigated the role of An. stephensi in transmission following a malaria outbreak in Dire Dawa, Ethiopia in April-July 2022. Screening contacts of patients with malaria and febrile controls revealed spatial clustering of Plasmodium falciparum infections around patients with malaria in strong association with the presence of An. stephensi in the household vicinity. Plasmodium sporozoites were detected in these mosquitoes. This outbreak involved clonal propagation of parasites with molecular signatures of artemisinin and diagnostic resistance. To our knowledge, this study provides the strongest evidence so far for a role of An. stephensi in driving an urban malaria outbreak in Africa, highlighting the major public health threat posed by this fast-spreading mosquito.


Sherry wines.
Sherry wines are among the most distinctive Spanish wines, mainly produced in the southern Spain (particularly in Jerez and Montilla-Moriles), using traditional practices aimed at ensuring uniform quality and characteristics over time. Several types of Sherry wines are produced depending on the winemaking conditions. Fino-type wines are characterized by a dynamic biological aging, in which a layer of yeast grows in the surface of the wine (flor velum). On the contrary, Oloroso-type sherry wines are subjected to an oxidative aging, while Amontillado-type Sherries are produced by combining both production systems. Therefore, these wines undergo different biological and chemical processes that affect distinctively their chemical composition and their aroma and sensory characteristics. Through this review, the main aspects involved in the winemaking technology of sherry wines, and the latest scientific findings related to the microbiota of the flor film and other aspects associated to the changes in their chemical and sensory composition during aging will be revised. Some new trends in sherry wine technology focused on the acceleration of the biological aging or the use of organic grapes will be also considered.


Suppressant effect of human or equine rabies immunoglobulins on the immunogenicity of post-exposure rabies vaccination under the 2-1-1 regimen: a field trial in Indonesia. MAS054 Clinical Investigator Group.
WHO's reference protocol for post-exposure rabies vaccination advises five intramuscular injections on days 0, 3, 7, 14, and 30; in addition, rabies immunoglobulins (RIG) must be given to serious cases of exposure (grade III severity). Some studies indicate that these immunoglobulins suppress the immunogenicity of rabies vaccine when administered according to an alternative protocol of four injections (2-1-1) on days 0, 7, and 21, which was therefore not recommended for grade III exposures. To test this effect, we conducted a multicentre study in Indonesia using three groups of subjects. One group received only the Vero-cell rabies vaccine (PVRV, Verorab, usual commercial lot) according to the 2-1-1 schedule. The second and third groups received the same schedule of PVRV, plus either equine rabies immunoglobulins (ERIG, 40 IU/kg body weight) or human rabies immunoglobulins (HRIG, 20 IU/kg body weight). Our results confirmed the immunoglobulin suppressant effect, which was more pronounced with human than equine immunoglobulins. In both groups receiving immunoglobulins, the seroconversion rates did not reach 100% on day 28 and the geometric mean antibody titre was lower. Thus, WHO's recommendation in 1992 of the reference protocol plus immunoglobulins for severe cases is substantiated by these results in Indonesian subjects. If the 2-1-1 regimen is chosen by the treating physician and immunoglobulins are indicated, preference should be given to purified equine RIG, which also costs less than human RIG.


Analysis of continuous first-line treatment with docetaxel and carboplatin for advanced non-small cell lung cancer.
The present study aimed to analyze the efficacy and safety of multiple cycles of docetaxel and carboplatin (CBDCA) as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients with stage III or IV NSCLC, whose treatment began between July 1999 and February 2003, were retrospectively evaluated. Relatively low doses of docetaxel and CBDCA were administered for as many cycles as possible. The primary outcome assessed was the overall survival (OS) time, and the secondary outcomes included progression-free survival (PFS) time, response rate (RR) and adverse events. The median cycle number was four (range, 2-12). The median OS time was 400 days, and for adenocarcinoma and non-adenocarcinoma, the OS time was 490 and 192 days, respectively. The median PFS time was 176 days and the RR was 66.7%. The main toxicity of the treatment was neutropenia, with grade 3 or 4 neutropenia occurring in 81.0% of patients. Continuous first-line treatment with this regimen may have encouraging effects within a certain group of advanced NSCLC patients, thereby warranting further investigations.


New tools for carbohydrate sulfation analysis: heparan sulfate 2-O-sulfotransferase (HS2ST) is a target for small-molecule protein kinase inhibitors.
Sulfation of carbohydrate residues occurs on a variety of glycans destined for secretion, and this modification is essential for efficient matrix-based signal transduction. Heparan sulfate (HS) glycosaminoglycans control physiological functions ranging from blood coagulation to cell proliferation. HS biosynthesis involves membrane-bound Golgi sulfotransferases, including HS 2-O-sulfotransferase (HS2ST), which transfers sulfate from the cofactor PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the 2-O position of α-l-iduronate in the maturing polysaccharide chain. The current lack of simple non-radioactive enzyme assays that can be used to quantify the levels of carbohydrate sulfation hampers kinetic analysis of this process and the discovery of HS2ST inhibitors. In the present paper, we describe a new procedure for thermal shift analysis of purified HS2ST. Using this approach, we quantify HS2ST-catalysed oligosaccharide sulfation using a novel synthetic fluorescent substrate and screen the Published Kinase Inhibitor Set, to evaluate compounds that inhibit catalysis. We report the susceptibility of HS2ST to a variety of cell-permeable compounds in vitro, including polyanionic polar molecules, the protein kinase inhibitor rottlerin and oxindole-based RAF kinase inhibitors. In a related study, published back-to-back with the present study, we demonstrated that tyrosyl protein sulfotranferases are also inhibited by a variety of protein kinase inhibitors. We propose that appropriately validated small-molecule compounds could become new tools for rapid inhibition of glycan (and protein) sulfation in cells, and that protein kinase inhibitors might be repurposed or redesigned for the specific inhibition of HS2ST.


Re-defining Parkinson's disease.
Analyzing non-motor symptoms in Parkinson's disease (PD) leads to critically re-define and update the disorder itself. The present Editorial encompasses epidemiological and clinical studies on PD patients joined with experimental findings to provide a novel definition of PD based on clinical, neuroanatomical and neurobiological findings.In fact, the plethora of symptoms described in PD patients are due to specific anatomical alterations which cluster in specific disease phenotypes. These PDs differ for disease onset and progression, disease severity and specific cluster of non-motor disturbances. Despite the variety of PD phenotypes, it is now well established that in almost all PD subgroups (except those autosomic recessive selective disorders exemplified by Parkin disease) a core anatomical defniition exists recruiting a variety of brainstem monoamine nuclei. Such a variety of PD pathologies can be defined as monoamine brainstem disorder (MBD).


Portosystemic shunts for extrahepatic portal hypertension in children.
Twenty-three children with prehepatic portal hypertension and hemorrhage due to ruptured esophagogastric varices had portosystemic shunts. Their ages ranged from two years and seven months to 15 years. Eleven were less than eight years of age. Twenty patients had portal vein cavernomatosis and three patients had double portal veins. In 21 patients, a mesocaval type of shunt was done. A splenorenal shunt was performed in two. There was no surgical mortality. Two shunts occluded, both in rather young infants--two years and seven months and three years of age. In all the others, there was no further bleeding, and the shunts remained patent, as shown by abdominal angiograms. Neuropsychiatric disorders, probably due to hepatic encephalopathy, occurred in only one patient. On the basis of this favorable experience, we believe that an elective portosystemic shunt should, in general, be performed upon children with prehepatic portal hypertension after one major variceal hemorrhage. We favor a mesocaval type of shunt in these children because of the larger diameter of the vessels involved in the anastomosis and because it preserves the spleen, maintaining defense against subsequent infection.


Dual-band and polarization-independent infrared absorber based on two-dimensional black phosphorus metamaterials.
Two-dimensional (2D) black phosphorus (BP) with direct band gap, bridges the characteristics of graphene with a zero or near-zero band gap and transition metal dichalcogenides with a wide band gap. In the infrared (IR) regime, 2D BP materials can attenuate electromagnetic energy due to losses derived from its surface conductivity. This paper proposes an IR absorber based on 2D BP metamaterials. It consists of multi-layer BP-based nano-ribbon pairs, each formed by two orthogonally stacked nano-ribbons. The multi-layer BP metamaterials and bottom gold mirror together form a Fabry-Perot resonator that could completely inhibit light transmission to create strong absorption through the BP metamaterials. Unlike previously reported BP metamaterial absorbers, this new structure can operate at two frequency bands with absorption > 90% in each owning to the first-order and second-order Fabry-Perot resonant frequencies. It is also polarization independent due to the fourfold rotational structural symmetry. To our best knowledge, this is the first report on using BP metamaterials in an absorber that operates independent of polarization and in dual bands.


Tissue damage after acute intoxication by polychlorinated biphenyls in cockroaches.
It is common knowledge that polychlorinated biphenyls (PCBs) represent a serious threat to the health of both vertebrates and invertebrates. As far as the former are concerned, especially as regards human beings, a broad literature describes the direct and indirect effects induced by the PCBs on their systems and organs. Among invertebrates, the information available is mostly related to arthropods and is, however, very scarce. The aim of this work was to evaluate the effects of polychlorinated biphenyls (PCBs) on tissues and organs of individuals belonging to a species of Blattaria (Blattella germanica) treated with various doses of this toxic material. The pathologies found became more serious as the dosage increased and were present throughout the entire digestive system, in the fat body and in the male gonads: in these areas cell and tissue breakdown and severely damaged spermiogenesis were observed. In particular, the testes, Malpighian tubules and fat body accumulated an amorphous basophilic PAS-positive substance. Furthermore, the NOS-dependent NADPH diaphorase activity pattern in the retina and optic lobes was more evident in the treated than in the control insects.


Airway Management Protocol After Anterior Cervical Spine Surgery: Analysis of the Results of Risk Factors Associated With Airway Complication.
Retrospective comparative cohort analysis. To evaluate the effect of postoperative airway management protocol (ASAN Extubation Protocol, AEP) on incidence of airway complications for patients undergoing anterior cervical spine surgery (ACSS). Postoperative airway compromise remains crucial for patients undergoing ACSS. Despite the potential severity of these complications, the data in the published literature addressing this issue is sparse. A retrospective cohort study was performed regarding airway complications (postoperative airway edema requiring unplanned reintubation or tracheostomy) between groups of patients undergoing ACSS before and after applying our standardized protocol (AEP) for postoperative extubation. The AEP was developed based on 5 clinical risk factors reported having relation to airway complication. Postoperative patients with any oneor more risk factors were kept intubated for at least overnight and extubation was conducted according to the amount of prevertebral soft tissue swelling. A total of 538 ACSS patients were identified from 2008 to 2016. The nonprotocol group (before protocol application, 275 patients) and the Protocol group (after protocol, 263 patients) were compared; airway complication rates were significantly different between two groups (nonprotocol: 3.64% (10/275) vs. 0.76% (2/263), P = 0.024). The possible factors that may increase airway complication include operative indications (P = 0.002), trauma (P = 0.000), medical comorbidity risk (P = 0.011), combined anterior and posterior surgery (P = 0.002), and operation time longer than 5 hours (P = 0.045). In multivariate analysis, medical comorbidity risk, trauma, and airway protocol adoption were significant factors. AEP reduced the airway complication rate by odds ratio 0.125 (P = 0.013). Postoperative airway complication is not very common after ACSS. AEP contributed to reduce the incidence of airway complications. The potentially life-threatening event of loss of airway patency, even though it is a rare complication, should be cautiously analyzed with identification of risk factors before the surgery. 2.


An Overview of Adaptive Designs and Some of Their Challenges, Benefits, and Innovative Applications.
Adaptive designs are increasingly developed and used to improve all phases of clinical trials and in biomedical studies in various ways to address different statistical issues. We first present an overview of adaptive designs and note their numerous advantages over traditional clinical trials. In particular, we provide a concrete demonstration that shows how recent adaptive design strategies can further improve an adaptive trial implemented 13 years ago. Despite their usefulness, adaptive designs are still not widely implemented in clinical trials. We offer a few possible reasons and propose some ways to use them more broadly in practice, which include greater availability of software tools and interactive websites to generate optimal adaptive trials freely and effectively, including the use of metaheuristics to facilitate the search for an efficient trial design. To this end, we present several web-based tools for finding various adaptive and nonadaptive optimal designs and discuss nature-inspired metaheuristics. Metaheuristics are assumptions-free general purpose optimization algorithms widely used in computer science and engineering to tackle all kinds of challenging optimization problems, and their use in designing clinical trials is just emerging. We describe a few recent such applications and some of their capabilities for designing various complex trials. Particle swarm optimization is an exemplary nature-inspired algorithm, and similar to others, it has a simple definition but many moving parts, making it hard to study its properties analytically. We investigated one of its hitherto unstudied issues on how to bring back out-of-range candidates during the search for the optimum of the search domain and show that different strategies can impact the success and time of the search. We conclude with a few caveats on the use of metaheuristics for a successful search.


The MetaInvert soil invertebrate genome resource provides insights into below-ground biodiversity and evolution.
Soil invertebrates are among the least understood metazoans on Earth. Thus far, the lack of taxonomically broad and dense genomic resources has made it hard to thoroughly investigate their evolution and ecology. With MetaInvert we provide draft genome assemblies for 232 soil invertebrate species, representing 14 common groups and 94 families. We show that this data substantially extends the taxonomic scope of DNA- or RNA-based taxonomic identification. Moreover, we confirm that theories of genome evolution cannot be generalised across evolutionarily distinct invertebrate groups. The soil invertebrate genomes presented here will support the management of soil biodiversity through molecular monitoring of community composition and function, and the discovery of evolutionary adaptations to the challenges of soil conditions.


Germinal center B cell apoptosis requires both caspase and cathepsin activity.
Follicular dendritic cells (FDCs) select B cells during germinal center (GC) reactions. The B cells that are able to bind to the FDCs receive a signal that leads to the termination of endonuclease activity in the nuclei of those B cells. This signal must be in addition to the signals transferred through the cross-linkage of the B cell receptors and signals resulting from the interactions of the adhesion molecules lymphocyte function-associated Ag-1 and very late Ag-4 with ICAM-1 and VCAM-1, respectively. In this report, we present evidence that the FDCs silence all apoptotic processes in GC B lymphocytes and additionally switch off pre-present endonuclease activity. We also show that GC B cell apoptosis requires cathepsin activity downstream of caspase-3. This cathepsin activity is directly connected to endonuclease activity and therefore may be an interesting target for the antiapoptotic factors produced by FDCs.


Redundant visual signals boost saccade execution.
The redundant signal effect (RSE) refers to the fact that human beings react more quickly to a pair of stimuli than to only one stimulus. In previous studies of the RSE in the oculomotor system, bimodal signals have been used as the goal of the saccade. In consistency with studies using manual response times (RTs), saccadic RTs have been shown to be shorter for redundant multimodal stimuli than for single unimodal stimuli. In the present experiments, we extended these findings by demonstrating an RSE in the saccadic system elicited only by unimodal visual stimuli. In addition, we found that shorter saccadic RTs were accompanied by an increased saccadic peak velocity. The present results are of relevance for neurophysiological models of saccade execution, since the boost of saccades was elicited by two visual transients (acting as a "go" signal) that were presented not at the goal of the saccade but at various other locations.


[The kinetics of the blast transformation of lymphocytes in patients with nonrheumatic myocarditis].
Studies of lymphocyte blastogenesis with peripheral blood cultures from patients suffering from non-coronary-related diseases of the myocardium revealed considerable impairments of its kinetics in the patients with myocarditis and dystrophic injury to the cardiac muscle. The ability of the peripheral blood lymphocytes to blastogenesis correlated with the severity of the clinical symptoms of the disease. Depression of the functional activity of short-lived suppressants was observed in patients with steady residual symptoms of nonrheumatic myocarditis.


Informing a culturally appropriate approach to oral health and dental care for pre-school refugee children: a community participatory study.
Pre-school children in families of recently settled refugees often have very high rates of early childhood caries (ECC). ECC is associated with a high level of morbidity and is largely preventable, however effective culturally appropriate models of care are lacking. This study aimed to provide a deeper understanding of the refugee experience related to early oral health by exploring pre-school refugee families (i) understanding of ECC and child oral health, (ii) experiences of accessing dental services and (iii) barriers and enablers for achieving improved oral health. The knowledge gained will be critical to the development of effective early oral health programs in refugee children. Community based participatory qualitative methodology using focus groups of resettled refugee families and community refugee nurse interviews. A community reference group was established and a bi-lingual community research associate was employed. Transcripts were analysed for thematic content using NVivo software. There were 44 participants: eight focus groups (nine countries of origin) and five interviews. Emergent themes were (i) the major influence of parents' previous experience, including their beliefs about deciduous (baby) teeth, traditional feeding practices and poverty; and a consequent lack of understanding of the importance of early oral health and early dental caries, (ii) the burden of resettlement including prioritising, parenting, learning about new foods and how to assimilate into the community, and (iii) refugees' difficulties in accessing both information and dental services, and the role of schools in addressing these issues. An Opportunities for Change Model was proposed. The main implication of the study is the demonstration of how enhanced understanding of the refugee experience can inform improvement in early oral prevention and treatment. The community participatory methodology of the study provided a basis for cross-cultural understanding and has already assisted in translating the findings and raising awareness in the provision of targeted refugee oral health services.


Genomic analysis reveals key aspects of prokaryotic symbiosis in the phototrophic consortium "Chlorochromatium aggregatum".
'Chlorochromatium aggregatum' is a phototrophic consortium, a symbiosis that may represent the highest degree of mutual interdependence between two unrelated bacteria not associated with a eukaryotic host. 'Chlorochromatium aggregatum' is a motile, barrel-shaped aggregate formed from a single cell of 'Candidatus Symbiobacter mobilis", a polarly flagellated, non-pigmented, heterotrophic bacterium, which is surrounded by approximately 15 epibiont cells of Chlorobium chlorochromatii, a non-motile photolithoautotrophic green sulfur bacterium. We analyzed the complete genome sequences of both organisms to understand the basis for this symbiosis. Chl. chlorochromatii has acquired relatively few symbiosis-specific genes; most acquired genes are predicted to modify the cell wall or function in cell-cell adhesion. In striking contrast, 'Ca. S. mobilis' appears to have undergone massive gene loss, is probably no longer capable of independent growth, and thus may only reproduce when consortia divide. A detailed model for the energetic and metabolic bases of the dependency of 'Ca. S. mobilis' on Chl. chlorochromatii is described. Genomic analyses suggest that three types of interactions lead to a highly sophisticated relationship between these two organisms. Firstly, extensive metabolic exchange, involving carbon, nitrogen, and sulfur sources as well as vitamins, occurs from the epibiont to the central bacterium. Secondly, 'Ca. S. mobilis' can sense and move towards light and sulfide, resources that only directly benefit the epibiont. Thirdly, electron cycling mechanisms, particularly those mediated by quinones and potentially involving shared protonmotive force, could provide an important basis for energy exchange in this and other symbiotic relationships.


IL-27 Limits Type 2 Immunopathology Following Parainfluenza Virus Infection.
Respiratory paramyxoviruses are important causes of morbidity and mortality, particularly of infants and the elderly. In humans, a T helper (Th)2-biased immune response to these infections is associated with increased disease severity; however, little is known about the endogenous regulators of these responses that may be manipulated to ameliorate pathology. IL-27, a cytokine that regulates Th2 responses, is produced in the lungs during parainfluenza infection, but its role in disease pathogenesis is unknown. To determine whether IL-27 limits the development of pathogenic Th2 responses during paramyxovirus infection, IL-27-deficient or control mice were infected with the murine parainfluenza virus Sendai virus (SeV). Infected IL-27-deficient mice experienced increased weight loss, more severe lung lesions, and decreased survival compared to controls. IL-27 deficiency led to increased pulmonary eosinophils, alternatively activated macrophages (AAMs), and the emergence of Th2 responses. In control mice, IL-27 induced a population of IFN-γ+/IL-10+ CD4+ T cells that was replaced by IFN-γ+/IL-17+ and IFN-γ+/IL-13+ CD4+ T cells in IL-27-deficient mice. CD4+ T cell depletion in IL-27-deficient mice attenuated weight loss and decreased AAMs. Elimination of STAT6 signaling in IL-27-deficient mice reduced Th2 responses and decreased disease severity. These data indicate that endogenous IL-27 limits pathology during parainfluenza virus infection by regulating the quality of CD4+ T cell responses and therefore may have therapeutic potential in paramyxovirus infections.


Metastasis Suppressor NME1 Modulates Choice of Double-Strand Break Repair Pathways in Melanoma Cells by Enhancing Alternative NHEJ while Inhibiting NHEJ and HR.
Reduced NME1 expression in melanoma cell lines, mouse models of melanoma, and melanoma specimens in human patients is associated with increased metastatic activity. Herein, we investigate the role of NME1 in repair of double-stranded breaks (DSBs) and choice of double-strand break repair (DSBR) pathways in melanoma cells. Using chromatin immunoprecipitation, NME1 was shown to be recruited rapidly and directly to DSBs generated by the homing endonuclease I-PpoI. NME1 was recruited to DSBs within 30 min, in concert with recruitment of ataxia-telangiectasia mutated (ATM) protein, an early step in DSBR complex formation, as well as loss of histone 2B. NME1 was detected up to 5 kb from the break site after DSB induction, suggesting a role in extending chromatin reorganization away from the repair site. shRNA-mediated silencing of NME1 expression led to increases in the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways of double-strand break repair (DSBR), and reduction in the low fidelity, alternative-NHEJ (A-NHEJ) pathway. These findings suggest low expression of NME1 drives DSBR towards higher fidelity pathways, conferring enhanced genomic stability necessary for rapid and error-free proliferation in invasive and metastatic cells. The novel mechanism highlighted in the current study appears likely to impact metastatic potential and therapy-resistance in advanced melanoma and other cancers.


Somatotrophs and lactotrophs: an immunohistochemical study of Gallus domesticus pituitary gland at different stages of induced moult.
The objective of this study was to determine the distribution of somatotrophs and lactotrophs and conduct a morphometrical analysis of immunoreactive somatotrophs and lactotrophs in the pituitary glands of White Leghorn Hens (Gallus domesticus) during the period of induced moult. We divided the periods of induced moulting into three phases viz. 7, 14 and 21 days. The labeled alkaline-phsphatase method with anti-GH (growth hormone) and anti-PRL (prolactin) as a primary antibody was used to detect somatotrophs and lactotrophs, in the midsagital sections of chicken adenohypophysis. Immunohistochemistry showed that somatotrophs are not only confined to the cephalo-caudal axis but can also be found in the caudal lobe; while lactotrophs were distributed in both lobes of the anterior pituitary gland at all stages of moulting (7, 14 and 21 days). Lactotrophs were of different shapes but somatotrophs were oval to round in morphology. At the given stages of induced moulting, some hypertrophied lactotrophs were also present after 7 days of induced moult in the anterior pituitary gland. However, there were moulting-related changes: from 7 to 21 days of induced moulting the immunoreactive-PRL cell population decreased, while the mean lactotroph size was more than that of somatotrophs. Basic quantitative and morphological information relating to somatotrophs and lactotrophs during the period of induced moult in laying hens is reported here and the changes brought about by induced moulting are restricted to PRL positive cells rather than GH positive cells.


Neuroimaging in Parkinson's disease: focus on substantia nigra and nigro-striatal projection.
The diagnosis of Parkinson disease is based on clinical features; however, unmet need is an imaging signature for Parkinson disease and the early differential diagnosis with atypical parkinsonisms. A summary of the molecular imaging and MRI recent evidences for Parkinson disease diagnosis will be presented in this review. The nigro-striatal dysfunction explored by dopamine transporter imaging is not a mandatory diagnostic criterion for Parkinson disease, recent evidence supported its utility as in-vivo proof of degenerative parkinsonisms, and there might be compensatory mechanisms leading to an early overestimation. The visualization of abnormalities in substantia nigra by MRI has been recently described as sensitive and specific tool for Parkinson disease diagnosis, even in preclinical conditions, whereas it is not useful for distinguishing between Parkinson disease and atypical parkinsonisms. The relationship between the nigral anatomical changes, evaluated as structural alterations or neuromelanin signal decrease and the dopaminergic nigro-striatal function needs to be further clarified. With the hopeful advent of potential neuroprotective drugs for PD, it is crucial to have imaging measures that are able to detect at risk subjects. Moreover it is desirable to increase the knowledge about which measure better predicts the probability and the time of clinical conversion to PD.


Use of urinary biomarkers of renal ischemia in a lamb preclinical left ventricular assist device model.
Evaluation of thrombogenicity is a critical component in the preclinical testing and development of blood pumps. Left ventricular assist devices (LVADs), because of their device routing, can produce thromboembolic showers to the kidney resulting in renal cortical ischemia or infarctions. Although postmortem evaluation of renal pathology can confirm ischemic events and infarctions, there are no validated and highly sensitive real-time measures of renal ischemia in the preclinical models. In this article, we report the evaluation of urinary biomarkers of ischemic tubular damage in a lamb preclinical LVAD model. We found that urinary excretion of glutathione-S-transferase-π, heat shock protein 1B, and hepatitis A virus cellular receptor 1 homologue precursor (HAVCR1/kidney injury molecule 1) were upregulated in toxic ischemic renal injury as well as in the immediate postoperative period in an LVAD-implanted lamb. These markers were consistent with both gross and histologic pathology, and proved far more sensitive for renal injury than serum blood urea nitrogen or creatinine concentrations.


ALTERED MERISTEM PROGRAM1 suppresses ectopic stem cell niche formation in the shoot apical meristem in a largely cytokinin-independent manner.
Plants are able to reiteratively form new organs in an environmentally adaptive manner during postembryonic development. Organ formation in plants is dependent on stem cell niches (SCNs), which are located in the so-called meristems. Meristems show a functional zonation along the apical-basal axis and the radial axis. Shoot apical meristems of higher plants are dome-like structures, which contain a central SCN that consists of an apical stem cell pool and an underlying organizing center. Organ primordia are formed in the circular peripheral zone (PZ) from stem cell descendants in which differentiation programs are activated. One mechanism to keep this radial symmetry integrated is that the existing SCN actively suppresses stem cell identity in the PZ. However, how this lateral inhibition system works at the molecular level is far from understood. Here, we show that a defect in the putative carboxypeptidase ALTERED MERISTEM PROGRAM1 (AMP1) causes the formation of extra SCNs in the presence of an intact primary shoot apical meristem, which at least partially contributes to the enhanced shoot meristem size and leaf initiation rate found in the mutant. This defect appears to be neither a specific consequence of the altered cytokinin levels in amp1 nor directly mediated by the WUSCHEL/CLAVATA feedback loop. De novo formation of supernumerary stem cell pools was further enhanced in plants mutated in both AMP1 and its paralog LIKE AMP1, indicating that they exhibit partially overlapping roles to suppress SCN respecification in the PZ.


Voltage- and temperature-dependent rare-earth dopant contribution to the interfacial magnetic anisotropy.
The control of magnetic materials and devices by voltages without electric currents holds the promise of power-saving nano-scale devices. Here we study the temperature-dependent voltage control of the magnetic anisotropy caused by rare-earth (RE) local moments at an interface between a magnetic metal and a non-magnetic insulator, such as Co|(RE)|MgO. Based on a Stevens operator representation of crystal and applied field effects, we find large dominantly quadrupolar intrinsic and field-induced interface anisotropies at room temperature. We suggest improved functionalities of transition metal tunnel junctions by dusting their interfaces with rare earths.


Epstein-Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase.
Epstein-Barr virus (EBV) infects both B lymphocytes and oropharyngeal epithelium, and it has been argued that the true reservoir of virus persistence in vivo is the self-renewing basal epithelial compartment. The identification of oral hairy leukoplakia (HL) of AIDS patients as a clinically apparent focus of EBV replication in lingual epithelium therefore provides a means of studying the EBV-epithelial cell interaction in situ. Replicative EBV DNA and productive cycle antigens are restricted to the upper, more differentiated epithelial layers in HL, and here we have applied highly sensitive in situ hybridization and immunohistological methods to examine the lower basal/suprabasal layers for evidence of latent EBV infection. We could not detect EBV DNA in these layers using an in situ DNA hybridization protocol which, on reference B cell lines, detected 1 viral genome/cell. Likewise, using sensitive in situ RNA hybridization for both the small non-polyadenylated EBER RNAs (abundant transcripts seen in all known forms of EBV latency) and the latent membrane protein (LMP) mRNA (the most abundant viral mRNA in B lymphoblastoid cell lines), the basal/suprabasal cells in HL were consistently negative; immunohistological staining with specific monoclonal antibodies also gave no evidence of latently infected LMP-positive cells. When the biopsy extracts were analysed by immunoblotting with selected human antisera, in addition to abundant productive cycle antigens, a band of constant size (66K) was observed which also reacted with immunopurified antibodies monospecific for one of the latency-associated nuclear antigens, EBNA 1; the cellular origin of this EBNA 1 could not be ascertained, but it is possible that in HL the protein is expressed during the productive cycle. The absence of demonstrable EBV latency in the basal/suprabasal cells of HL suggests that this is purely a virus replicative lesion which is sustained by continual re-infection of the maturing epithelium, not by the maturation of latently infected cells from the basal compartment.


Innovative Medical Technology and the Treatment Decision-Making Process in Multiple Sclerosis: A Focus Group Study to Examine Patient Perspectives.
Disease-modifying therapies are given to people with multiple sclerosis (MS) to reduce disease progression and relapse frequency. Current modes of administration include oral, injectable and infusion therapy and the treatment decision-making process is complex. A novel mode of treatment administration, an implantable device, is currently under development, yet patient attitudes about the device are unknown. The aim of this study was 1) to understand the treatment decision-making process from the patient perspective and 2) to explore the possible acceptance of an implant to treat MS. Focus groups with people with MS were conducted in the Netherlands. Three topics were addressed: the treatment decision-making process, the current treatment landscape, and attitudes about the implantable device. All focus groups were recorded and transcribed and data were analyzed by raw data coding and creating themes. An online survey was conducted in the Netherlands to quantify interest in an implant. Two focus group sessions were held (n=16 participants) and n=93 persons filled out the survey. The main theme that emerged was the constant uncertainty persons with MS face throughout their disease course and during treatment decisions (when to start, stop, continue or switch treatment). Patients were generally positive towards the implant but felt that efficacy and safety should be guaranteed. People with MS want some form of control over their disease and treatment course. New medical technologies, such as an implant, may enhance the treatment landscape and with caution we postulate that it may be accepted by patients as a new mode of administration, though further research is needed. For medical technologies to be successful, patients should be engaged early on in the design process.


Molecular and structural basis of polo-like kinase 1 substrate recognition: Implications in centrosomal localization.
Polo-like kinase (Plk1) is crucial for cell cycle progression through mitosis. Here we present the molecular and structural mechanisms that regulate the substrate recognition of Plk1 and influence its centrosomal localization and activity. Our work shows that Plk1 localization is controlled not only by the polo box domain (PBD); remarkably, the kinase domain is also involved in Plk1 targeting mechanism to the centrosome. The crystal structures of the PBD in complex with Cdc25C and Cdc25C-P target peptides reveal that Trp-414 is fundamental in their recognition regardless of its phosphorylation status. Binding measurements demonstrate that W414F mutation abolishes molecular recognition and diminishes centrosomal localization. Therefore, Plk1 centrosomal localization is not controlled by His-538 and Lys-540, the residues involved in phosphorylated target binding. The different conformations of the loop, which connects the polo boxes in the apo and the PBD-Cdc25C and PBD-Cdc25C-P complex structures, together with changes in the proline adjacent to the phosphothreonine in the target peptide, suggest a regulatory mechanism to detect binding of unphosphorylated or phosphorylated target substrates. Altogether, these data propose a model for the interaction between Plk1 and Cdc25C.


Oxazinoindolines as fluorescent H+ turn-on chromoionophores for optical and electrochemical ion sensors.
We propose here a new class of fluorescent H(+) turn-on oxazinoindoline (Ox) dyes as chromoionophores suitable for the development of polymeric ion-selective membranes. Through rational design, oxazinoindolines with varying basicities and tunable absorption bands that extend to the near-infrared region were prepared. The basicities of the compounds were evaluated by potentiometry and fluorescence spectroscopy. By comparing the potentiometric lower detection limit with chromoionophore I (pKa = 14.80 ± 0.03 in PVC-NPOE), pKa values were determined for Ox Y, Ox R, and Ox B to be 9.80 ± 0.03, 12.85 ± 0.03, and 12.95 ± 0.03, respectively. Unlike conventional pH indicators that involve only a protonated and deprotonated form, a third species, arising from the thermal isomerization of the Ox compounds in polar solvents, may influence the overall protonation equilibrium. Interestingly, this results in an apparent pKa increase in the fluorescence mode when more polar PVC-NPOE membranes were utilized. The isomerization is suppressed in nonpolar PVC-DOS membranes. Na(+)-selective optical sensors were successfully prepared using the Ox dyes as an early application of the compounds in ion-selective optical sensors. The compounds were also successfully evaluated in a dynamic electrochemistry (chronopotentiometry) sensing mode for the detection of total alkalinity.


Antibodies to transcobalamin II block in vitro proliferation of leukemic cells.
The plasma protein transcobalamin II (TCII) binds and delivers cobalamin (Cbl; vitamin B12) to all cells, which internalize the TCII/Cbl complex by receptor-mediated endocytosis. Congenital deficiency of TCII results in intracellular Cbl deficiency, one effect of which is to disrupt DNA synthesis, leading to megaloblastic anemia. We report here an in vitro culture system in which cell growth is dependent on delivery of Cbl to cells by TCII. Recombinant human holo-TCII was shown to support in dose-dependent manner the growth of the human erythroleukemic cell line K562 and the murine lymphoma cell line BW5147. Free Cbl also supported cell growth; however, at 100- to 1,000-fold higher concentrations than those effective in the presence of apo-TCII. To determine if cellular depletion of Cbl could be achieved by interfering with interactions between TCII/Cbl and its cell-surface receptor, several monoclonal antibodies raised against human TCII were studied. Three antibodies, found to compete for the same binding site on TCII, proved to be effective inhibitors of TCII/Cbl-dependent cell growth. Our results suggest that monoclonal anti-TCII antibodies that block the function of this protein may prove useful in antitumor therapies.


Tobiano spotting pattern in horses: linkage of To with AlA and linkage disequilibrium.
In a study of 2,786 tobiano and non-tobiano horses involved in paint horse breeding programs throughout the United States, the inheritance of the tobiano color pattern gene was tracked in pedigrees using the tightly linked polymorphic albumin gene. The dominant tobiano allele (T(o)), which produces the tobiano spotting pattern in horses, was in coupling with both AIA and AIB alleles at the albumin locus. The frequency of the T(o):AIA linkage phase among all the homozygous tobiano horses in this study including offspring and parents (N = 127), was 0.08. The T(o):AIB linkage phase was the most frequent (0.92). Linkage disequilibrium exists between the tobiano and albumin loci. The linkage disequilibrium parameter (D) was calculated as D = 0.056 at 79% of maximum linkage disequilibrium.


On-line miniaturized asymmetrical flow field-flow fractionation-electrospray ionization-tandem mass spectrometry with selected reaction monitoring for quantitative analysis of phospholipids in plasma lipoproteins.
A direct analytical method for high speed quantitative analysis of lipids in human blood plasma using on-line chip-type asymmetrical flow field-flow fractionation-electrospray ionization-tandem mass spectrometry (cAF4-ESI-MS/MS) with selected reaction monitoring (SRM) is described in this study. Utilizing a miniaturized cAF4 channel, high speed size separation of high density lipoproteins (HDL) and low density lipoproteins (LDL) from plasma samples can be accomplished at a microflow rate along with simultaneous desalting of lipoproteins, both of which are conducive to direct ESI of lipids in lipoproteins. This study demonstrates that the SRM method to monitor phospholipids during cAF4-ESI-MS/MS can be successfully applied to the quantitation of lipid molecules in plasma lipoproteins without the need of a separate lipid extraction process. For quantitation of lipids in HDL and LDL during cAF4-ESI-MS/MS runs, a protein standard (carbonic anhydrase, 29 kDa) was added to each plasma sample as an internal standard such that a peak intensity of y67(+5) ions, which are high abundant SRM product ions of CA, could be utilized to calculate the relative intensity of each lipid molecule. The developed method was applied to plasma samples from 10 patients with coronary artery disease (CAD) and 10 healthy control samples, and quantitative analysis of 39 lipid molecules including phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, phosphatidylglycerols, and phosphatidylinositols, resulted in the selection of 13 PL species showing more than 2.5 fold difference in relative abundance (p<0.01) between the groups. The present study demonstrates a high speed analytical method for determining plasma lipid content and distribution without an organic solvent extraction of lipids from plasma.


Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity.
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors. Thus, while protecting against autoimmunity, Aire also limits the generation of melanoma-reactive T cells. Here, we show that Aire deficiency in mice expands the pool of CD4+ T cells capable of melanoma cell eradication and has additive effects with anti-CTLA-4 antibody in slowing melanoma tumor growth and increasing survival. Moreover, pharmacologic blockade of central T cell tolerance and peripheral checkpoint blockade in combination enhanced antimelanoma immunity in a synergistic manner. In melanoma patients treated with anti-CTLA-4 antibody, clinical response to therapy was associated with a human Aire polymorphism. Together, these findings suggest that Aire-mediated central tolerance constrains the efficacy of peripheral checkpoint inhibition and point to simultaneous blockade of Aire and checkpoint inhibitors as a novel strategy to enhance antimelanoma immunity.


Are We on the Same Page? Shared Mental Models to Support Clinical Teamwork Among Health Professions Learners: A Scoping Review.
To conduct a scoping review to explore the construct of shared mental models (SMMs) in the context of clinical teamwork among health professions learners. The authors searched the PubMed, ERIC, CINAHL, Scopus, Web of Science, PsychINFO, and EMBASE databases for English-language articles published between 2000 and 2016. Eligible articles mentioned SMMs in relation to clinical teamwork and included health professions learners. Two reviewers screened studies for eligibility and extracted data to determine the depth and breadth of the literature on SMMs. The authors examined definitions of the SMM construct in the context of clinical teams, educational interventions using SMMs, and the measurement of SMMs. Of the 1,273 articles retrieved, 23 met the inclusion criteria. SMMs were defined in less than two-fifths of the articles (9/23). All articles applied the construct to improvements in hospital-based patient safety, often in high-intensity settings (14/23). Most articles included graduate-level physicians (21/23) within clinical teams (18/23). Interventions designed to foster SMMs (6/23) included teamwork curricula/training and teamwork supportive tools. Measurements of SMMs (7/23) included a qualitative task analysis, quantitative analyses of speech, a concept mapping, and Likert-type surveys. In health professions education, the SMM construct lacks clear definition. Few studies described educational interventions aimed at SMM development, and few attempted to measure the construct. The authors propose an operational definition of SMMs in health care and illustrate how interventions intended to foster SMMs, such as team trainings or planning exercises and communication tools, could be developed, implemented, and assessed.


A single-center, randomized double-blind placebo-controlled study evaluating the effects of poly-gamma-glutamate on human NK cell activity after an 8-week oral administration in healthy volunteers.
A randomized double-blind placebo-controlled immunity study involving 99 healthy volunteers was performed to investigate the effect of poly- γ -glutamate ( γ -PGA) on human natural killer (NK) cell activity in peripheral blood. The volunteers were randomly assigned to one of three groups and orally treated with solutions (25 mL) containing 0 mg (placebo), 250 mg (low dosage), or 500 mg (high dosage) of γ -PGA. Each volunteer took one dose every 12 hours for 8 weeks. Blood samples were drawn before the initial treatment and at the 4th and the 8th weeks of treatment. NK cell activity was assessed by measuring its degranulation, cytokine production, and cytotoxicity against the K562 cell line. Our results revealed that the cytotoxic activities of NK cells from the high-dosage γ -PGA group were significantly higher (P < 0.05 for all comparisons) compared to the low dosage and placebo groups at weeks 4 and 8 after the initial treatment. This increase in the NK cell activity among peripheral blood mononuclear cells (PBMCs) of healthy individuals was also confirmed in vitro (as assessed by the degranulation and cytokine production). These results suggest that the oral administration of γ -PGA induces a cell-mediated immunity by increasing the NK cell activity in humans.


[Gastric pacing to treat morbid obesity: two years experience in four patients].
Gastric pacing to treat morbid obesity has been found to be safe and the implant technique simple to perform. Appetite is reduced and satiety is increased after the implant. There are two components in the Implantable Gastric Stimulation (IGS): (a) an electrical stimulator connected to a (b) bipolar lead that is positioned in the muscle wall of the stomach. We describe the optimal procedure to safely place the components. We present our results after preliminary experiences. From August 2005 to January 2006, 4 patients (F) mean age 44 (33-63) underwent to IGS implant. The mean BMI was 41.8 (378-47), mean weight 117.2 Kg (107-133) . The IGS was activated 30 days after implant. Fasting and postprandial plasma ghrelin concentrations after a test meal were measured before and 1, 2, 3 and 6 months after implanting operation. All procedures were successfully completed laparoscopically. There were no major operative complications. Postoperative course was uneventful in all cases. One patient was lost to follow up after six months. Postoperative lead dislodgement and cutaneous decubitus occurred in another patient, making necessary the removing of the device. For the other two patient only in one there was a significant weight loss (49 Kg), in the second weight was unchanged. Plasma ghrelin concentrations were no correlated among patients, and results were not in line with what waited by the producer. Morbid obese patients can undergo IGS implantation by laparoscopy with minimal perioperative complications. Attention to technical details is essential. In accordance with the producer (Medtronic) our data demonstrate that gastric pacing is a safe procedure for selected patients supported by adequate psychological treatment, but outcome about weight loss should be evaluated among bigger trial, as our experience didn't give satisfactory results, and therefore discouraged us to carry on with the study.


[Occult anterior sacral meningocele].
The anterior sacral meningocele is a rare form of spinal dysraphism located in the presacral extraperitoneal space. It is generally asymptomatic and appears as a small pelvic mass. We present a case of a 10 year-old male that develops a bacteria meningitis because of a pararectal abscess that is connected with an anterior sacral meningocele. We successfully treated it using a posterior approach. The aim of the surgery is to repair the dural defect and to obliterate the communication between the thecal sac and the herniation defect. The posterior approach is the simplest and most effective surgical technique because the lower risk of neurological injury than the anterior approach.


Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent hypoxia breathing program in patients at risk for or with mild COPD.
The aim of this study was to provide information on heart rate and blood pressure responses during a 3-week intermittent hypoxia breathing program in COPD patients. Sixteen participants with COPD symptoms were randomly assigned to a hypoxia or control group and completed a 3-week intermittent hypoxia breathing program (five sessions per week, each consisting of three to five breathing cycles, each cycle lasting 3-5 minutes with 3-minute breaks between cycles). During the breathing cycles, the hypoxia group received hypoxic air (inspired fraction of oxygen 15%-12%), whereas the control group received normal air (sham hypoxia). During the breaks, all participants breathed normoxic room air. Arterial oxygen saturation, systolic and diastolic blood pressure, and heart rate were measured during the normoxic and hypoxic/sham hypoxic periods. For each breathing cycle, changes from normoxia to hypoxia/sham hypoxia were calculated, and changes were averaged for each of the 15 sessions and for each week. Changes in arterial oxygen saturation were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences in weeks 1, 2, and 3. During the course of the intermittent hypoxia application, no between-group differences were detected for blood pressure or rate pressure product values. Changes in heart rate were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures), with post hoc differences only in week 3. Averages over all 15 sessions were significantly higher in the hypoxia group for heart rate and rate pressure product, and tended to be increased for systolic blood pressure. The applied intermittent hypoxia breathing program resulted in specific and moderate heart rate and blood pressure responses, and did not provoke a progressive increase in blood pressure during the hypoxic cycles in the course of the application.


The Emerging Role of Dual GLP-1 and GIP Receptor Agonists in Glycemic Management and Cardiovascular Risk Reduction.
The incretin pathway is a self-regulating feedback system connecting the gut with the brain, pancreas, and liver. Its predominant action is on the postprandial glucose levels, with extraglycemic effects on fat metabolism and endovascular function. Of the two main incretin hormones released with food ingestion, the actions of glucagon-like peptide-1 (GLP-1) have been exploited for therapeutic benefit. However, little attention has been paid to glucose-dependent insulinotropic polypeptide (GIP) until the recent experimental introduction of dual agonists, or "twincretins". Interestingly, simultaneous activation of both receptors is not only replicative of normal physiology, it seems to be an innovative way to enhance their mutual salubrious actions. In patients with type 2 diabetes, dual agonists can have powerful benefits for glucose control and weight reduction. Additionally, there is mounting evidence of their favorable cardiovascular impact, making them potentially appealing pharmacologic agents of choice in the future. Although we seem to be poised on the horizons of exciting new breakthroughs, much knowledge has yet to be gained before these novel agents are ready for prime time.


Point-of-Care Ultrasound to Diagnose Postpericardiotomy Syndrome in a Child.
We report a case of a patient presenting with abdominal pain after cardiac surgery who was noted on point-of-care ultrasound (POCUS) to have pericardial and pleural effusion, in addition to ascites. The most notable findings were pleural and pericardial effusions, which combined with symptomatology met criteria for postpericardiotomy syndrome. Point-of-care ultrasound expedited the diagnosis of a pericardial effusion with impending tamponade and transfer for pericardiocentesis and placement of pericardial drain.


Classification of autism spectrum disorder based on sample entropy of spontaneous functional near infra-red spectroscopy signal.
To assess the possibility of distinguishing autism spectrum disorder (ASD) based on the characteristic of spontaneous hemodynamic fluctuations and to explore the location of abnormality in the brain. Using the sample entropy (SampEn) of functional near-infrared spectroscopy (fNIRS) from bilateral inferior frontal gyrus (IFG) and temporal cortex (TC) on 25 children with ASD and 22 typical development (TD) children, the pattern of mind-wandering was assessed. With the SampEn as feature variables, a machine learning classifier was applied to mark ASD and locate the abnormal area in the brain. The SampEn was generally lower for ASD than TD, indicating the fNIRS series from ASD was unstable, had low fluctuation, and high self-similarity. The classification between ASD and TD could reach 97.6% in accuracy. The SampEn of fNIRS could accurately distinguish ASD. The abnormality in terms of the SampEn occurs more frequently in IFG than TC, and more frequently in the left than in the right hemisphere. The results of this study may help to understand the cortical mechanism of ASD and provide a fNIRS-based diagnosis for ASD.


CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope.
Löfgren's syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3-restricted manner. Using ELISPOT analysis, a greater number of IFN-γ- and IL-2-secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS.


Human respiratory syncytial virus viroporin SH: a viral recognition pathway used by the host to signal inflammasome activation.
Respiratory syncytial virus (RSV) remains the leading cause of serious viral bronchiolitis and pneumonia in infants and young children throughout the world. The burden of disease is significant, with 70% of all infants being infected with RSV within the first year of their life. 40% of those children discharged from hospital have recurrent, repeated respiratory symptoms and wheezing for at least 10 years. The infection is also an important illness in the elderly and immunocompromised individuals. Ongoing symptoms relate to continued lung inflammation. One cytokine that is associated with RSV infection is IL-1β, but the mechanism of activation remain unclear. In the current study, we set out to decipher the molecular mechanisms of RSV-induced inflammasome activation. Using deletion mutants of the virus and measuring IL-1β secretion, as well as caspase 1 expression via western blotting, we demonstrate that the NLRP3 inflammasome is activated through the small hydrophobic (SH) RSV viroporin which induces membrane permeability to ions or small molecules. Confocal microscopy revealed that during virus infection, SH seems to accumulate within lipid rafts in the Golgi compartments. Upon RSV infection, SH gets localised in the cell membranes and intracellular organelle membranes, and then induces permeability by disrupting membrane architecture, thus leading us to believe that formation of viral ion channels in lipid bilayers of cells is a viral recognition pathway used by the host to signal inflammasome activation.


High-level quadriplegia: an occupational therapy challenge.
Rehabilitation of the C1 to C4 quadriplegic person is a relatively recent phenomenon. Few rehabilitation facilities accept the challenge these patients present. This paper describes a comprehensive occupational therapy program for the C1 to C4 quadriplegic person. It presents the objectives and mechanisms for treating these individuals (e.g., range of motion, strengthening existing musculature, functional activities training, pressure sore prevention, and equipment prescription) and introduces new approaches to increasing function through current therapeutic and engineering technological advances. The quality of life of these patients may well be determined by their exposure to functional activities in occupational therapy.


Responses of the Peyer's Patches in Germ-Free Mice to Antigenic Stimulation.
Lymph nodes, spleens, and Peyer's patches of germ-free mice are relatively inactive. The tissues are small and contain rare, small, indistinct, germinal zones. When exposed to antigenic stimuli (Salmonella paratyphi A and lymphocytic choriomeningitis virus), the tissues become larger and germinal zones appear coincident with antibodies in the blood. The Peyer's patches were activated if antigen was absorbed from the intestinal lumen into the circulation but not if the antigen was administered parenterally. There was no demonstrable immunological response by the germ-free mouse to Streptococcus faecalis.


Isolation of brucella abortus from two dogs in contact with bovine brucellosis.
On a farm where several cattle were serologically positive for bovine brucellosis, three dogs were found to have titres greater than 400 i.u. to Brucella abortus. The titres persisted until the dogs were killed over two months later. Two male dogs were necropsied. B. abortus was isolated from the spleen of both dogs. While farm dogs are not thought to be a major reservoir of bovine brucellosis they may be considered as possible carriers in imfected herds and should be considered during the investigation and eradication of bovine brucellosis.


[Dehydration due to gastro-enteritis in children].
Gastroenteritis is the commonest cause of dehydration in children. Infants and young children dehydrate more easily than adults if fluid intake is insufficient or fluid loss too high because of the combination of a large extracellular volume, a large insensible loss and a mediocre concentrating capacity of the kidney. Fluid loss due to gastroenteritis is often accompanied by electrolyte and acid-base disturbances. Oral rehydration with oral rehydration salts (ORS) is nearly always possible. Re-evaluation after 6 hours is advised especially in young children. Early (< 6-24 hours) resumption of feeding is important. If rehydration with frequent small amounts of ORS at home fails, continuous nasogastric tube feeding in the hospital is a good alternative. In dehydration exceeding 10% of body weight intravenous rehydration is necessary.


A general radiologist looks at congestive heart failure.
Congestive heart failure may be difficult to detect. Determination of cardiac size is untrustworthy. Changes in the hili (vessels, bronchi) are reliable. Pulmonary edema may be atypical. Vascular redistribution must be interpreted accurately. Congestive changes with chronic obstructive lung disease may be difficult or impossible to detect. Pleural fluid may present atypically. Changes in pleural surfaces other than in bases produce "new" signs.


Small RNA pyrosequencing in the protozoan parasite Entamoeba histolytica reveals strain-specific small RNAs that target virulence genes.
Small RNA mediated gene silencing is a well-conserved regulatory pathway. In the parasite Entamoeba histolytica an endogenous RNAi pathway exists, however, the depth and diversity of the small RNA population remains unknown. To characterize the small RNA population that associates with E. histolytica Argonaute-2 (EhAGO2-2), we immunoprecipitated small RNAs that associate with it and performed one full pyrosequencing run. Data analysis revealed new features of the 27nt small RNAs including the 5'-G predominance, distinct small RNA distribution patterns on protein coding genes, small RNAs mapping to both introns and exon-exon junctions, and small RNA targeted genes that are clustered particularly in sections of genome duplication. Characterization of genomic loci to which both sense and antisense small RNAs mapped showed that both sets of small RNAs have 5'-polyphosphate termini; strand-specific RT-PCR detected transcripts in both directions at these loci suggesting that both transcripts may serve as template for small RNA generation. In order to determine whether small RNA abundance patterns account for strain-specific gene expression profiles of E. histolytica virulent and non-virulent strains, we sequenced small RNAs from a non-virulent strain and found that small RNAs mapped to genes in a manner consistent with their regulation of strain-specific virulence genes. We provided a full spectrum analysis for E. histolytica AGO2-2 associated 27nt small RNAs. Additionally, comparative analysis of small RNA populations from virulent and non-virulent amebic strains indicates that small RNA populations may regulate virulence genes.


Predicting the presence of depressive symptoms in the HIV-HCV co-infected population in Canada using supervised machine learning.
Depression is common in the human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infected population. Demographic, behavioural, and clinical data collected in research settings may be of help in identifying those at risk for clinical depression. We aimed to predict the presence of depressive symptoms indicative of a risk of depression and identify important classification predictors using supervised machine learning. We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). The Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) was administered in the FS sub-study; participants were classified as being at risk for clinical depression if scores ≥ 10. We developed two random forest algorithms using the training data (80%) and tenfold cross validation to predict the CES-D-10 classes-1. Full algorithm with all candidate predictors (137 predictors) and 2. Reduced algorithm using a subset of predictors based on expert opinion (46 predictors). We evaluated the algorithm performances in the testing data using area under the receiver operating characteristic curves (AUC) and generated predictor importance plots. We included 1,934 FS sub-study visits from 717 participants who were predominantly male (73%), white (76%), unemployed (73%), and high school educated (52%). At the first visit, median age was 49 years (IQR:43-54) and 53% reported presence of depressive symptoms with CES-D-10 scores ≥ 10. The full algorithm had an AUC of 0.82 (95% CI:0.78-0.86) and the reduced algorithm of 0.76 (95% CI:0.71-0.81). Employment, HIV clinical stage, revenue source, body mass index, and education were the five most important predictors. We developed a prediction algorithm that could be instrumental in identifying individuals at risk for depression in the HIV-HCV co-infected population in research settings. Development of such machine learning algorithms using research data with rich predictor information can be useful for retrospective analyses of unanswered questions regarding impact of depressive symptoms on clinical and patient-centred outcomes among vulnerable populations.


Human beta-globin gene sequences injected into mouse eggs, retained in adults, and transmitted to progeny.
Foreign gene sequences were retained in two adult mice (out of 62 analyzed) from fertilized eggs injected with a recombinant plasmid containing the human beta-globin genomic region and the herpes simplex viral thymidine kinase gene. The intact human and viral genes were found in DNA of one of the animals and, in the other, at least part of the human globin gene was present. The latter individual transmitted these sequences to its progeny in a Mendelian ration. Thus, human DNA may be incorporated into the germ line of mice for in vivo studies of regulation of gene expression in development, genetic diseases, and malignancy.


Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra.
Brain-derived neurotrophic factor (BDNF) has potent effects on survival and morphology of dopaminergic neurons and thus its loss could contribute to death of these cells in Parkinson's disease (PD). In situ hybridization revealed that BDNF mRNA is strongly expressed by dopaminergic neurons in control substantia nigra pars compacta (SNpc). In clinically and neuropathologically typical PD, SNpc BDNF mRNA expression is reduced by 70% (P = 0.001). This reduction is due, in part, to loss of dopaminergic neurons which express BDNF. However, surviving dopaminergic neurons in the PD SNpc also expressed less BDNF mRNA (20%, P = 0.02) than their normal counterparts. Moreover, while 15% of control neurons had BDNF mRNA expression >1 SD below the control mean, twice as many (28%) of the surviving PD SNpc dopaminergic neurons had BDNF mRNA expression below this value. This 13% difference in proportions (95% CI 8-17%, P < or = 0.000001) indicates the presence of a subset of neurons in PD with particularly low BDNF mRNA expression. Moreover, both control and PD neurons displayed a direct relationship between the density of BDNF mRNA expression per square micrometer of cell surface and neuronal size (r(2) = 0.93, P </= 0.00001) which was lost only in PD neurons expressing the lowest levels of BDNF mRNA. If BDNF is an autocrine/paracrine factor for SNpc dopaminergic neurons, loss of BDNF-expressing neurons may compromise the well-being of their surviving neighbors. Moreover, neurons expressing particularly low levels of BDNF mRNA may be those at greatest risk of injury in PD and possibly the trigger for the degeneration itself.


Erythropoietin: physiology and molecular mechanisms.
Erythropoietin, the primary regulator of erythropoiesis, is produced by the kidney and levels vary inversely with oxygen availability. Hypoxia-inducible factor-1 (HIF-1), a major transcriptional regulator of several hypoxia-sensitive genes, including erythropoietin, is functionally deactivated by oxygen in a reaction catalyzed by prolyl hydroxylase. Erythropoietin acts by binding to a specific trans-membrane dimeric receptor which has been found in erythroid and non-erythroid cell types. The interaction between erythropoietin and its receptor ultimately leads to conformational change and phosphorylation of the receptor and expression of genes coding for proteins that are anti-apoptotic. Development of erythropoietin stimulating agents is an area of active research. To date, research has focused on activating the erythropoietin receptor, prevention of HIF-1 inactivation, and gene therapy. Even with biologically effective therapies, defining appropriate hemoglobin targets remains challenging. For example, despite decades of clinical trials, target hemoglobin levels in chronic kidney disease remain uncertain, as hemoglobin targets above 13 g/dl have been associated with both benefit (quality of life) and harm (cardiovascular events).


Shifting Strategies in the Treatment of Pediatric Craniopharyngioma.
Craniopharyngiomas represent one of the most challenging diseases to treat. Despite their benign histology, and after many decades of surgical experience and technological advancements, there is still no clear consensus regarding the most effective management for this tumor. Due to their location and aggressive local characteristics, purely surgical approaches all too often result in unacceptable morbidity. Partial resection combined with radiation therapy results in similar control rates when compared to aggressive surgery, while also minimalizing the neuro-endocrinological morbidity. In this manuscript, we describe the historical progression of the shifting strategies in the management of pediatric craniopharyngioma. Time has also altered our expectations for outcomes, evolving from purely morbidity and mortality to simple Glasgow Outcomes Scales, now to formal neuro-psychometric and quality of life data.


Chromosome evolution in African cichlid fish: contributions from the physical mapping of repeated DNAs.
Cichlid fishes have been the subject of increasing scientific interest because of their rapid adaptive radiation that has led to extensive ecological diversity and because of their enormous importance to tropical and subtropical aquaculture. To further understanding of chromosome evolution among cichlid species, we have comparatively mapped the SATA satellite DNA, the transposable element ROn-1, and repeated sequences in the bacterial artificial chromosome clone BAC-C4E09 on the chromosomes of a range of African species of Cichlidae, using fluorescence in situ hybridization. The SATA satellite DNA was mapped in almost all the centromeres of all tilapiine and haplochromine species studied. The maintenance and centromeric distribution of the SATA satellite DNA in African cichlids suggest that this sequence plays an important role in the organization and function of the centromere in these species. Furthermore, analysis of SATA element distribution clarifies that chromosome fusions occurred independently in Oreochromis and Tilapia genera, and led to the reduced chromosome number detected in O. karongae and T. mariae. The comparative chromosome mapping of the ROn-1 SINE-like element and BAC-C4E09 shows that the repeated sequences have been maintained among tilapiine, haplochromine and hemichromine fishes and has demonstrated the homology of the largest chromosomes among these groups. Furthermore, the mapping of ROn-1 suggested that different chromosomal rearrangements could have occurred in the origin of the largest chromosome pairs of tilapiines and non-tilapiines.


Temporal expectation in focal hand dystonia.
Patients with writer's cramp present sensory and representational abnormalities relevant to motor control, such as impairment in the temporal discrimination between tactile stimuli and in pure motor imagery tasks, like the mental rotation of corporeal and inanimate objects. However, only limited information is available on the ability of patients with dystonia to process the time-dependent features (e.g. speed) of movement in real time. The processing of time-dependent features of movement has a crucial role in predicting whether the outcome of a complex motor sequence, such as handwriting or playing a musical passage, will be consistent with its ultimate goal, or results instead in an execution error. In this study, we sought to evaluate the implicit ability to perceive the temporal outcome of different movements in a group of patients with writer's cramp. Fourteen patients affected by writer's cramp in the right hand and 17 age- and gender-matched healthy subjects were recruited for the study. Subjects were asked to perform a temporal expectation task by predicting the end of visually perceived human body motion (handwriting, i.e. the action performed by the human body segment specifically affected by writer's cramp) or inanimate object motion (a moving circle reaching a spatial target). Videos representing movements were shown in full before experimental trials; the actual tasks consisted of watching the same videos, but interrupted after a variable interval ('pre-dark') from its onset by a dark interval of variable duration. During the 'dark' interval, subjects were asked to indicate when the movement represented in the video reached its end by clicking on the space bar of the keyboard. We also included a visual working memory task. Performance on the timing task was analysed measuring the absolute value of timing error, the coefficient of variability and the percentage of anticipation responses. Patients with writer's cramp exhibited greater absolute timing error compared with control subjects in the human body motion task (whereas no difference was observed in the inanimate object motion task). No effect of group was documented on the visual working memory tasks. Absolute timing error on the human body motion task did not significantly correlate with symptom severity, disease duration or writing speed. Our findings suggest an alteration of the writing movement representation at a central level and are consistent with the view that dystonia is not a purely motor disorder, but it also involves non-motor (sensory, cognitive) aspects related to movement processing and planning.


Blood loss with mifepristone--misoprostol abortion: measures from a trial in China, Cuba and India.
We compared bleeding patterns following early mifepristone-misoprostol abortion with those following early surgical abortions ( < or = 56 days gestation LMP). We analyzed women's reports of their bleeding and clinical measures of blood loss, and modeled the relationships between different bleeding measures and indicators of success and satisfaction. Using data from a multicenter trial held in China, Cuba and India, we fit bivariate and multivariate models to analyze bleeding patterns, controlling for a range of demographic, experiential and medical factors (n = 1373). Medical abortion patients perceived their bleeding to be heavier than did the surgical patients; however, there were few statistically significant differences in clinical measures of blood loss between the two groups, and blood loss rarely represented a medical problem. Nationality, far more than actual levels of bleeding, influenced women's impressions about blood loss. Although medical abortion patients saw their bleeding as heavier than did the surgical patients, their perceptions of heavier bleeding did not prevent them from having higher satisfaction levels. One exception was that if bleeding exceeded prior expectations, women with the medical method were more likely to be dissatisfied. Pain and cramps, which often accompanied bleeding, were an independently significant factor in predicting satisfaction with the method. In order for women to know what to expect with medical abortion, they must be informed beforehand about the level of bleeding that generally accompanies the procedure vs. excessive bleeding that would signal a clinical problem.


Light and scanning electron microscopy of the same human metaphase chromosomes.
A technique has been developed to examine the same G-banded human metaphase chromosomes, first in the light microscope and then in the scanning electron microscope (SEM). A structural involvement in chromosome banding was confirmed by a positional correlation between the G-positive bands observed in the light microscope and the circumferential grooves between the quaternary coils of the metaphase chromosomes, observed in the SEM. In further support of this the regions between the grooves showed a positional relationship with the G-negative or reverse (R) bands. The examination of slightly extended metaphase chromosomes in the light microscope demonstrated that the G-banding pattern corresponded to that described by the Paris nomenclature for metaphase chromosomes. The arrangement of the circumferential grooves of the same chromosomes, observed in the SEM, was shown to relate to that described by the Paris nomenclature for prometaphase chromosomes. Therefore, using the SEM it is possible to demonstrate the details of prometaphase banding in metaphase chromosomes.


Glomus jugulare tumours--combined treatment: part I.
Total en bloc removal is the ideal surgical treatment for glomus jugulare tumours. Efforts to accomplish this have been made periodically since shortly after this tumour was first identified in the early 1940s. A method of removal using a combined approach through the neck and temporal bone is described here. This method is preceded by pre-operative irradiation therapy and on occasion by embolization. The early results obtained using this method in 19 patients are reported.


Physical activity completed when young has residual bone benefits at 94 years of age: a within-subject controlled case study.
Physical activity is recommended for skeletal health because bones adapt to mechanical loading. The young skeleton shows greatest plasticity to physical activity-related mechanical loads, but bones are most at risk of failure later in life. The discrepancy raises the question of whether the skeletal benefits of physical activity completed when young persist with aging. Here we present a unique case wherein the cortical bone benefit of physical activity completed over five decades earlier could be established within an individual aged in their tenth decade of life. Specifically, we compared bone properties at the midshaft humerus between the throwing and nonthrowing arms of a 94-year-old former Major League Baseball player who ceased throwing 55 years earlier. By performing analyses within-subject, the long-term skeletal benefit of physical activity completed when young could be assessed independent of inherited and systemic traits. Also, as the subject threw left-handed during his throwing career, but was right-hand dominant in all other activities throughout life, any lasting skeletal benefits in favor of the throwing arm could not be attributable to simple arm dominance. Analyses indicated that any cortical bone mass, area and thickness benefits of throwing-related physical activity completed when young were lost with aging, possibly due to accelerated intracortical remodeling. In contrast, the subject's throwing (nondominant) arm had greater total cross-sectional area and estimated strength (polar moment of inertia) than in his dominant arm, despite muscle indices favoring the latter. These data indicate that physical activity completed when young can have lasting benefits on bone size and strength, independent of the maintenance of bone mass benefits.


Genital mycoplasma infections among women in an urban community of northern Nigeria: do we need to search for them?
To determine the incidence of genital Mycoplasma infection among females in Jos. High vaginal swab (HVS) and or Endocervical swab (ECS) samples were obtained from 476 females undergoing vaginal examinations along with other females who volunteered to enroll in the study Samples were processed using standard laboratory procedures for the isolation of Mycoplasma species while information such as age, marital status, occupation and other clinical data were obtained using a questionnaire. The results obtained were analysed using SPSS 11.0 statistical methods and P values = or < 0.05 were considered significant. The overall incidence of genital Mycoplasma infection was found to be 29.6% (n=141); M. hominis, 12.1% (n=57); U. urealyticum 9.4% (n=45); mixed infection, 6.7% (n=32), and other Mycoplasmas, 1.4% (n= 7). Majority of the isolates were from those aged 20-35 years old (most sexually active group); 83% (n=52) of those who presented with vaginal discharge were infected with Mycoplasma spp. (P< 0.05); also, the incidence of infection among the separated/divorce/widowed group was significantly higher than the married group (P<0.05). Mycoplasmas are common genital organisms, hence should be sought out for from ECS probably on routine basis for suspected genital tract infections.


Acute aortic syndromes and aortic emergencies.
Acute aortic syndrome (AAS) and emergencies are relatively uncommon but are considered as life threatening, potentially fatal conditions. Different forms of aortic emergencies/AAS are often clinically indiscernible. Prompt and accurate diagnosis of these entities significantly influences prognosis and guides therapy. We aim to elucidate the pertinent role that radiology plays in the management of acute aortic diseases, with contrast-enhanced computed tomography angiography (CTA) being the most rapid and robust imaging technique.


Plasma insulin levels and incidence of hypertension in African Americans and whites.
Hyperinsulinemia may play an important role in the pathogenesis of hypertension in whites but the role of hyperinsulinemia in hypertension in African Americans is controversial. We studied the relationship between insulin levels and subsequent incidence of hypertension in 140 African Americans and 237 whites who were initially screened for possible participation in the Trials of Hypertension Prevention, phase 1. Plasma insulin and serum glucose were measured at baseline and at a follow-up examination 7 years later. Blood pressure was measured by trained observers using a random-zero sphygmomanometer. Incident hypertension was defined as an average systolic pressure of 160 mm Hg or higher and/or diastolic pressure of 95 mm Hg or higher at a single visit and/or use of antihypertensive medication during follow-up. Over the 7 years of follow-up, the incidence of hypertension was 25.7% in the African Americans and 25.3% in the whites. Baseline plasma insulin and insulin-to-glucose ratio were associated with an increased risk of hypertension in both the African Americans and the whites. After adjustment for age, sex, race, body mass, heart rate, and alcohol consumption at baseline as well as intervention assignment in the Trials of Hypertension Prevention, phase 1, a 1-SD (21 pmol/mmol) difference in baseline insulin-to-glucose ratio was associated with a 2.77 (95% confidence interval, 1.48-5.19) odds ratio of hypertension in the African Americans and a 1.69 (95% confidence interval, 1.08-2.64) odds ratio in the whites. These results suggest that higher plasma insulin levels are associated with an increased risk of hypertension in both African Americans and whites.


Sleep Related Rhythmic Movement Disorder in older children and adults and their association with comorbid conditions - experience from two centres and literature review.
Sleep related rhythmic movement disorders (SRRMD) are highly prevalent among infants and children and tend to disappear into adolescence and adulthood. However, few reports have identified patients who had rhythmic movements at wake-sleep transition persisting into adulthood. This is a case series of SRRMD diagnosed on video-polysomnography from retrospective chart review of patients, who were 6 years or older, seen in Sleep Neurology clinics in two centres by the senior author, over a 10 years period. In addition, an updated review of all papers published on the topic, since year 2000 is being reported. A total of nine patients (2 females) with SRRMD were included in this series with age ranging between 9 and 62 years. Five patients had comorbid primary sleep disorders and four others had associated neurodevelopmental disorders. Association with other primary sleep disorders like sleep apnea and restless legs syndrome and relief with treatment of the latter, has been highlighted.


Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: correlation with disease severity.
Cystic fibrosis transmembrane conductance (CFTR) alterations are involved in the overproduction of prostaglandins (PG) in CF in vitro. We assessed the relationship between PGE-M and PGD-M urinary metabolites of PGE2 and PGD2 and CF severity. Twenty-four controls and 35 CF patients were recruited. PGE-M and PGD-M levels were measured by liquid chromatography/mass spectrometry and results were expressed as median and 25th-75th interquartile of ng/mg creatinine (Cr). PGE-M (15.63; 9.07-43.35ng/mg Cr) and PGD-M (2.16; 1.43-3.53ng/mg Cr) concentrations were higher in CF than in controls: PGE-M, (6.63; 4.35-8.60ng/mg Cr); PGD-M (1.23; 0.96-1.54ng/mg Cr). There was no correlation between metabolite levels and spirometric values. Patients with pancreatic insufficiency (n=29) had higher PGE-M levels (19.09; 9.36-52.69ng/mg Cr) than those with conserved function (n=6) (9.61; 5.78-14.34ng/mg Cr). PGE-M levels were associated with genotype severity: mild (7.14; 5.76-8.76, n=8), moderate (16.67; 13.67-28.62ng/mg Cr, n=5) and severe (22.82; 10.67-84.13ng/mg Cr). Our study confirms the key role of CFTR in the regulation of the cyclooxygenase pathway of arachidonic acid metabolism found in in vitro studies.


The costs of implementing the 1999 Canadian Asthma Consensus Guidelines recommendation of asthma education and spirometry for the family physician.
National and international asthma guidelines recommend that patients with asthma be provided with asthma education and spirometry as a component of enhanced asthma care. The cost of implementing these interventions in family physician practices is not known. The objective of the present study was to determine the cost of providing recommended asthma care to adult patients in the family practice setting. The present study was conducted using three scenarios of care in family practice. Small, medium and large asthmatic patient populations were used. The incremental costs of implementing enhanced asthma care based on the Canadian Asthma Consensus Guidelines, including the provision of spirometry and asthma education in both group and individual sessions, and the resources required for these interventions were calculated for each scenario. For a physician with 50 asthmatic patients, the cost of providing enhanced asthma care with spirometry and group education sessions was approximately 78 dollars per patient in the first year of implementation. For individual sessions, the cost increased to 100 dollars per patient for the first year. If the physician had 100 asthmatic patients, the per patient cost would decrease; however, the overall cost of the program would be 7,000 dollars. The costs of providing enhanced asthma care are significant. In most cases, physicians are inadequately reimbursed (or not reimbursed) for these interventions. In light of the evidence of the effectiveness of these interventions, health insurance plans should consider adding these services to fee schedules.


Role of cytokine receptor-like factor 1 in hepatic stellate cells and fibrosis.
To elucidate the role of cytokine receptor-like factor 1 (CRLF1) in hepatic stellate cells and liver fibrosis. Rat hepatic stellate cells (HSCs) were isolated by Nykodenz gradient centrifugation and activated by culturing in vitro. Differentially expressed genes in quiescent and culture activated HSCs were identified using microarrays. Injections of carbon tetrachloride (CCl(4)) for 4 wk were employed to induce liver fibrosis. The degree of fibrosis was assessed by Sirius red staining. Adenovirus expressing CRLF1 was injected through tail vein into mice to achieve overexpression of CRLF1 in the liver. The same adenovirus was used to overexpress CRLF1 in quiescent HSCs cultured in vitro. Expression of CRLF1, CLCF1 and ciliary neurotrophic factor receptor (CNTFR) in hepatic stellate cells and fibrotic livers was analyzed by semi-quantitative reverse transcription-polymerase chain reaction and Western blotting. Expression of profibrotic cytokines and collagens was analyzed by the same method. CRLF1 is a secreted cytokine with unknown function. Human mutations suggested a role in development of autonomous nervous system and a role of CRLF1 in immune response was implied by its similarity to interleukin (IL)-6. Here we show that expression of CRLF1 was undetectable in quiescent HSCs and was highly upregulated in activated HSCs. Likewise, expression of CRLF1 was very low in normal livers, but was highly upregulated in fibrotic livers, where its expression correlated with the degree of fibrosis. A cofactor of CLRF1, cardiotrophin-like cytokine factor 1 (CLCF1), and the receptor which binds CRLF1/CLCF1 dimer, the CNTFR, were expressed to similar levels in quiescent and activated HSCs and in normal and fibrotic livers, indicating a constitutive expression. Overexpression of CLRF1 alone in the normal liver did not stimulate expression of profibrotic cytokines, suggesting that the factor itself is not pro-inflammatory. Ectopic expression in quiescent HSCs, however, retarded their activation into myofibroblasts and specifically decreased expression of type III collagen. Inhibition of type III collagen expression by CRLF1 was also seen in the whole liver. Our results suggest that CLRF1 is the only component of the CRLF1/CLCF1/CNTFR signaling system that is inducible by a profibrotic stimulus and that activation of this system by CLRF1 may regulate expression of type III collagen in fibrosis. By regulating activation of HSCs and expression of type III collagen, CRLF1 may have an ability to change the composition of extracellular matrix in fibrosis.