The Patterns and Impact of Social Media Exposure of Journal Publications in Gastroenterology: Retrospective Cohort Study.
Medical journals increasingly promote published content through social media platforms such as Twitter. However, gastroenterology journals still rank below average in social media engagement. We aimed to determine the engagement patterns of publications in gastroenterology journals on Twitter and evaluate the impact of tweets on citations. This was a retrospective cohort study comparing the 3-year citations of all full-length articles published in five major gastroenterology journals from January 1, 2012, to December 31, 2012, tweeted by official journal accounts with those that were not. Multivariate analysis using linear regression was performed to control for journal impact factor, time since publication, article type, frequency of reposting by other users ("retweets"), and media addition to tweets. Secondary analyses were performed to assess the associations between article type or subtopic and the likelihood of social media promotion/engagement. A total of 1666 articles were reviewed, with 477 tweeted by the official journal account. Tweeting an article independently predicted increased citations after controlling for potential confounders (β coefficient=13.09; P=.007). There was significant association between article type and number of retweets on analysis of variance (ANOVA) (P<.001), with guidelines/technical reviews (mean difference 1.04, 95% CI 0.22-1.87; P<.001) and meta-analyses/systemic reviews (mean difference 1.03, 95% CI 0.35-1.70; P<.001) being retweeted more than basic science articles. The manuscript subtopics most frequently promoted included motility/functional bowel disease (odds ratio [OR] 3.84, 95% CI 1.93-7.64; P<.001) and education (OR 4.69, 95% CI 1.62-13.58; P=.004), while basic science papers were less likely tweeted (OR 0.154, 95% CI 0.07-0.34; P<.001). Tweeting of gastroenterology journal articles independently predicted higher 3-year citations. Wider adoption of social media to increase reach and measure uptake of published research should be considered.


Intra- and interrater agreement and reliability of the Functional Field Score.
In 2001, the American Medical Association adopted the Functional Vision Score (FVS). It is built on Functional Acuity Scores (FAS) and Functional Field Scores (FFS). The purpose of this study was to evaluate the intra- and interrater reproducibility of the FFS. The study sample was composed of 62 persons, mean age 41.8 years, from the population of patients who visited a rehabilitation centre for visually impaired adults. We analysed 30 FFSs of isopter III-4e and 58 of isopter V-4e. Two raters independently scored the plots. The smallest detectable difference (SDD) and the weighted kappa quantified agreement. The SDDs were smaller than the minimal clinically important difference (MCID) of 10 points. Thus, the MCID can be distinguished from measurement error. The intraclass correlation coefficient (ICC) quantified reliability. The intra- and inter ICCs were high (ICCs > 0.98). We concluded that both intra- and interrater reliability of the FFS were excellent.


Improved enantiospecific RP-HPLC assays for propranolol in plasma and urine with pronethalol as internal standard.
For the enantiospecific assay of propranolol in biological material, formation of diastereomeric derivatives is one possible approach. The aim of the present study was the development and optimization of three analytical methods based on different chiral reagents: phenylethylisocyanate and the acyl chloride as well as the isocyanate that are derived from the fluorescent S-flunoxaprofen. Pronethalol is used as internal standard in all three procedures and improves the coefficients of variation significantly. After extraction from human plasma or urine, propanolol is reacted with one of these compounds in anhydrous organic solvents with addition of triethylamine. The diastereomeric derivatives are then resolved on an octadecylsilane column using mixtures of water and methanol with or without addition of glacial acetic acid. Good resolutions of the diastereomeric derivatives are found under these conditions. Conjugates are cleaved prior to analysis using beta-glucuronidase-arylsulfatase and assayed as parent propranolol enantiomers. All three procedures were suitable for analysis of propranolol enantiomers in biological samples in the lower nanogram range (1-2 ng/mL). A preliminary clinical study confirmed the known enantiospecificity in the pharmacokinetics of propranolol and showed high concentrations of conjugates with R/S ratios that were similar to those of the parent enantiomers.


Apoptosis and cell death in the endocrine system.
Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with defects in Fas apoptosis. The mutation of the Fas or Fas ligand (FasL) has been observed in a minority of patients with autoimmune disease. However, dysfunction of the Fas apoptosis signaling pathway or production of soluble factors, including sFas and sFasL, may be more prevalent. Certain endocrine tissues, such as the testes, are immune privilege sites. Defects in Fas and FasL expression in immune privilege sites can trigger an inflammatory response. Other factors that trigger inflammatory diseases of the thyroid or islets may be loss of self tolerance, leading to an autoimmune response. An infectious trigger or other environmental agent can initiate organ damage, leading to release of new antigens that initiate the autoreactive process. We have developed a murine cytomegalovirus model of Sjögren's syndrome in which defects in the Fas/FasL pathway are necessary to enable chronic inflammation, even after the initial virus has been cleared. Another interaction between the endocrine system and apoptosis is by direct hormone interaction. This is exemplified by the orphan steroid receptor Nur77. Nur77 is important for T cell apoptosis after signaling through CD3. We have demonstrated that a dominant-negative Nur77 transgenic mouse exhibits a defect in thymic selection of T cells. Therefore, there are many potential mechanisms by which endocrine glands or hormones can affect the Fas apoptosis pathway, resulting in either cell death or a chronic inflammatory disease in the endocrine system, leading to hypothyroidism and diabetes. This inflammatory dysfunction can be reversed by a dominant-negative I kappa B that prevents nuclear translocation of NF-kappa B. We have developed antigen-specific, antigen-presenting cells that express high levels of FasL that can prevent tissue-specific inflammatory disease. Treatment with these cells prevents development of diabetes in NOD mice. Further understanding of the role and regulation of apoptosis in diseases of the endocrine system (e.g., diabetes, thyroiditis) should lead to better methods of treatment and prevention of these diseases.


Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study.
Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.


Endothelial function in hypertension.
Endothelial dysfunction has been documented both in the forearm and coronary beds of essential hypertensive patients. Impairment in the tonic release of nitric oxide (NO) is secondary to hypertension, while the alteration in agonist-induced endothelium-dependent vasodilation seems to be a primary defect caused both by an alteration of the L-arginine-NO pathway and the production of cyclooxygenase-dependent EDCFs, such as prostanoids or superoxide anions. These latter substances curtail endothelium-dependent vasodilation mainly by inactivating NO production. Although experimental data clearly indicate that the L-arginine-NO pathway participates in the regulation of renal hemodynamics and renal excretory function under basal and stimulated conditions, data in humans are scanty and confounded by methodological approaches. A posteriori interpretation of data obtained with intrarenal infusion of acetylcholine in kidney donors suggests that endothelium dependent vasodilation in the kidney is impaired by aging, a phenomenon well documented in the forearm and coronary circulation. Systemic infusion of L-arginine induced renal vasodilation and natriuresis in normotensive subjects, an effect which seems to be mediated mainly by intrarenal NO production. Moreover the few available data suggest that both renal vasodilation and renal production of NO in response to L-arginine are blunted in patients with essential hypertension and that superoxide anions, may be, at least partially, responsible for this alteration of the L-arginine-NO pathway. In conclusion, endothelial dysfunction has been well documented in the forearm and coronary circulation of patients with essential hypertension. Available data suggest that endothelial, dysfunction is also detectable in the kidney and that a common mechanism, probably superoxide anions, can account for this abnormality.


Grid cells form a global representation of connected environments.
The firing patterns of grid cells in medial entorhinal cortex (mEC) and associated brain areas form triangular arrays that tessellate the environment [1, 2] and maintain constant spatial offsets to each other between environments [3, 4]. These cells are thought to provide an efficient metric for navigation in large-scale space [5-8]. However, an accurate and universal metric requires grid cell firing patterns to uniformly cover the space to be navigated, in contrast to recent demonstrations that environmental features such as boundaries can distort [9-11] and fragment [12] grid patterns. To establish whether grid firing is determined by local environmental cues, or provides a coherent global representation, we recorded mEC grid cells in rats foraging in an environment containing two perceptually identical compartments connected via a corridor. During initial exposures to the multicompartment environment, grid firing patterns were dominated by local environmental cues, replicating between the two compartments. However, with prolonged experience, grid cell firing patterns formed a single, continuous representation that spanned both compartments. Thus, we provide the first evidence that in a complex environment, grid cell firing can form the coherent global pattern necessary for them to act as a metric capable of supporting large-scale spatial navigation.


Mechanism of D-cycloserine action: transport mutants for D-alanine, D-cycloserine, and glycine.
The accumulation of d-alanine and the accumulation of glycine in Escherichia coli are related and appear to be separate from the transport of l-alanine. The analysis of four d-cycloserine-resistant mutants provides additional support for this conclusion. The first-step mutant from E. coli K-12 that is resistant to d-cycloserine was characterized by the loss of the high-affinity line segment of the d-alanine-glycine transport system in the Lineweaver-Burk plot. This mutation, which is linked to the met(1) locus, also resulted in the loss of the ability to transport d-cycloserine. The second-step mutation that is located 0.5 min from the first-step mutation resulted in the loss of the low-affinity line segment for the d-alanine-glycine transport system. The transport of l-alanine was decreased only 20 to 30% in each of these mutants. A multistep mutant from E. coli W that is 80-fold resistant to d-cycloserine lost >90% of the transport activity for d-alanine and glycine, whereas 75% of the transport activity for l-alanine was retained. E. coli W could utilize either d- or l-alanine as a carbon source, whereas the multistep mutant could only utilize l-alanine. Thus, a functioning transport system for d-alanine and glycine is required for both d-cycloserine action and growth on d-alanine.


Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma.
The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Emu-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by > or =2-fold in Emu-Bcl-2 transgenic mice (P < 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Emu-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.


Asymmetric sulfur ylide reactions with boranes: scope and limitations, mechanism and understanding.
The reactions of aryl-stabilized sulfur ylides with organoboranes has been studied under a variety of conditions. At 5 or -78 degrees C, the reaction with Et3B gave a mixture of the first and second homologation products, but at -100 degrees C, only the first homologation product was obtained even with just 1.1 equiv of Et3B. Under these optimized conditions, the chiral sulfur ylides (derived from camphor sulfonic acid) with different aryl groups were reacted with Et3B to give the corresponding alcohols (95-98% yield, 96-98% ee) and amines (74-77% yield, >98% ee). The origin of the high enantioselectivity is discussed. The use of nonsymmetrical 9-BBN derivatives was also explored. It was found that whereas primary alkyl substituents gave mixtures of products derived from competing migration of the boron substituent and the boracycle, all other groups resulted in either exclusive migration of the boron substituent (Ph, hexenyl, i-Pr) or exclusive migration of the boracycle (hexynyl, cyclopropyl). The factors responsible for the outcome of the reactions involving a hindered (i-Pr) and an unhindered (propynyl) substituent were studied by DFT calculations. This revealed that, in the case of an unhindered substituent, the conformation of the ate complex is the dominant factor whereas, in the case of a hindered substituent, the barriers to interconversion between the conformers of the ate complex and subsequent migration control the outcome of the reaction.


Host Corticostriatal Fibres Establish Synaptic Connections with Grafted Striatal Neurons in the Ibotenic Acid Lesioned Striatum.
The connections between host corticostriatal afferents and neurons in intrastriatal grafts of foetal striatal tissue have been studied with electron microscopic immunocytochemistry using Phaseolus vulgaris leucoagglutinin (PHA-L) as a label of the host corticostriatal fibres. Adult rats with unilateral ibotenic acid lesions of the head of the caudate putamen received foetal cell suspension grafts from E14-15 rat embryos into the lesioned striatal area. Ten months after transplantation, multiple iontophoretic injections of PHA-L were made into the host frontal cortex. These injections labelled large numbers of corticostriatal fibres which extended across the graft - host border to form a rich axonal network mainly in the peripheral portions of the grafts. At the ultrastructural level a total of 134 PHA-L-labelled terminals were identified to form asymmetric synaptic contacts with neurons within the grafts. Of these contacts, 83% were in contact with dendritic spines, 12% with dendritic shafts, and 5% with small shafts or spines. The synaptic contacts were similar to those identified in intact regions of the host striatum that were spared by the lesion. However, the synapses in the host striatum were almost exclusively in contact with spines (98%). These results demonstrate that the corticostriatal projection, which constitutes a major source of afferent control in the normal striatum, not only extends axons into the intrastriatal striatal grafts, but also establishes synaptic connections with the implanted neuronal elements.


Evolution of intravesical immunotherapy for bladder cancer: mycobacterial cell wall preparation as a promising agent.
The intra-cavitary administration of antineoplastic agents for the treatment of non-invasive bladder cancer has met with variable results. Mytomicin-C [corrected] is effective in the prevention of tumor recurrence when administered in the immediate post-resection period, but also exhibits activity against papillary tumors. It lacks efficacy in carcinoma in-situ (CIS) of the bladder. Bacillus Calmette-Guérin (BCG) has been shown to be effective against papillary tumors, but particularly in the treatment of CIS. Unfortunately, live BCG has serious safety limitations. To review the current situation with the use of non-viable preparations of mycobacteria (M. phlei) that have been investigated for the treatment of superficial bladder cancer in limited open-label clinical trials. MCC (Urocidin) [corrected] has shown activity against a variety of tumor cells, both in vitro and in animal cancer models. Limited clinical trials have also shown it to be active against non-muscle invasive bladder tumors in patients who have previously failed one or more courses of chemotherapy and/or immunotherapy with BCG. An unique dual immunomodulatory and apoptotic mechanism of action has been proposed for MCC.


Dynamic susceptibility contrast MR imaging of plaque development in multiple sclerosis: application of an extended blood-brain barrier leakage correction.
Since the pathogenesis of multiple sclerosis (MS) lesions is not yet fully understood, we investigated the potential of dynamic susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging for a better characterization of lesion pathology. Twenty-five MS patients were examined on a 1.5 T scanner. A single dose of gadolinium (Gd)-DOTA contrast agent was injected, and echoplanar images were acquired every 0.5 seconds for 1 minute. From the signal intensity-versus-time curves, the relative cerebral blood volume (rCBV) was evaluated for regions in plaques and in gray and white matter. The rCBV calculated for acute, Gd-enhancing plaques was corrected for the effects of blood-brain barrier leakage, using a new correction algorithm. Acute plaques had significantly higher blood volumes than normal-appearing white matter (P < = 0.01). Chronic plaques that appeared hypointense on T(1)-weighted images had lower rCBV than T(1)-isointense plaques (P < = 0.03). Our results indicate that the acute phase in MS is accompanied by vasodilation. In later stages of gliosis, the perfusion decreases with increasing axonal injury. Although the DSC technique is less sensitive than conventional MR imaging, the information provided is essentially different from that obtained with any other MR method.


Modified method for automatic exposure control in pediatric brain CT-application of the standard deviation value method by use of patient's age and head size.
We examined the optimum conditions for pediatric brain CT scans. CT controls the X-ray transit dose using tube current alteration called automatic exposure control (AEC) to adjust the standard deviation (SD) value for each scanning region, and it also reduces exposure. If the SD value is inappropriate, children may be exposed to increased radiation. Therefore we acquired images of 500 children from the server, and examined the most suitable SD value for each age using the data of their SD value and age. X-ray transit control with AEC was influenced by scan position and the age of a child. We enabled accurate scanning and decreased radiation exposure by adjusting AEC to the age and the cephalic volume of each child. As a result, reduction of the X-ray exposure by up to 31.2% per slice in tube current alteration was possible using a suitable SD value for each age. On the other hand, it was possible to reduce X-ray exposure by up to 67.9% per slice with the scan technique that used age and corrected cephalic volume without adjusting AEC. Using the tube current alteration protocol for each age with the data of the SD value or cephalic volume in CT, we can more easily conduct scans of children under optimal conditions.


Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.
We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations.


Induced in-source fragmentation pattern of certain novel (1Z,2E)-N-(aryl)propanehydrazonoyl chlorides by electrospray mass spectrometry (ESI-MS/MS).
Collision induced dissociation (CID) in the triple quadrupole mass spectrometer system (QQQ) typically yields more abundant fragment ions than those produced with resonance excitation in the presence of helium gas in the ion trap mass spectrometer system (IT). Detailed product ion spectra can be obtained from one stage MS2 scan using the QQQ. In contrast, generating the same number of fragment ions in the ion trap requires multiple stages of fragmentation (MSn) using CID via in-trap resonance excitation with the associated time penalties and drop in sensitivity. The use of in-source fragmentation with electrospray ionization (ESI) followed by product ion scan (MS2) in a triple quadrupole mass spectrometer system, was demonstrated. This process enhances the qualitative power of tandem mass spectrometry to simulate the MS3 of ion trap for a comprehensive study of fragmentation mechanisms. A five pharmacologically significant (1Z, 2E)-N-arylpropanehydrazonoyl chlorides (3a-e) were chosen as model compounds for this study. In this work, detailed fragmentation pathways were elucidated by further dissociation of each fragment ion in the ion spectrum, essentially, by incorporating fragmentor voltage induced dissociation (in-source fragmentation) and isolation of fragments in a quadrupole cell Q1. Subsequently, CID occurs in cell, Q2, and fragment ions are analyzed in Q3 operated in product ion mode this process can be referred to as pseudo-MS3 scan mode. This approach allowed unambiguous assignment of all fragment ions using tandem mass spectrometer and provided adequate sensitivity and selectivity. It is beneficial for structure determination of unknown trace components. The data presented in this paper provide useful information on the effect of different substituents on the ionization/fragmentation processes and can be used in the characterization of this important class of compounds.


Simple and robust methods for support vector expansions.
Most support vector (SV) methods proposed in the recent literature can be viewed in a unified framework with great flexibility in terms of the choice of the kernel functions and their constraints. We show that all these problems can be solved within a unique approach if we are equipped with a robust method for finding a sparse solution of a linear system. Moreover, for such a purpose, we propose an iterative algorithm that can be simply implemented. Finally, we compare the classical SV approach with other, recently proposed, cross-correlation based, alternative methods. The simplicity of their implementation and the possibility of exactly calculating their computational complexity constitute important advantages in a real-time signal processing scenario.


Anxiety Sensitivity Differentially Predicts Factors of Interpersonal-Psychological Suicide Risk: A Consideration of Specificity.
Recent studies have identified anxiety sensitivity (AS) as a risk factor for suicidality; however, limited work has been performed to understand this risk within the context of the interpersonal-psychological theory of suicide (IPTS; Joiner, 2005). The current study examined the relationship between overall AS, each AS subfactor (cognitive, social, and physical), and the three IPTS domains (perceived burdensomeness, thwarted belongingness, and acquired capability). While each AS subfactor uniquely predicted one IPTS domain, greater overall AS only predicted greater acquired capability, suggesting that assessment of AS at the subfactor level may offer us more information about an individual's interpersonal suicide risk.


Distinguishing fibromyalgia from rheumatoid arthritis and systemic lupus in clinical questionnaires: an analysis of the revised Fibromyalgia Impact Questionnaire (FIQR) and its variant, the Symptom Impact Questionnaire (SIQR), along with pain locations.
The purpose of this study was to explore a data set of patients with fibromyalgia (FM), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who completed the Revised Fibromyalgia Impact Questionnaire (FIQR) and its variant, the Symptom Impact Questionnaire (SIQR), for discriminating features that could be used to differentiate FM from RA and SLE in clinical surveys. The frequency and means of comparing FM, RA and SLE patients on all pain sites and SIQR variables were calculated. Multiple regression analysis was then conducted to identify the significant pain sites and SIQR predictors of group membership. Thereafter stepwise multiple regression analysis was performed to identify the order of variables in predicting their maximal statistical contribution to group membership. Partial correlations assessed their unique contribution, and, last, two-group discriminant analysis provided a classification table. The data set contained information on the SIQR and also pain locations in 202 FM, 31 RA and 20 SLE patients. As the SIQR and pain locations did not differ much between the RA and SLE patients, they were grouped together (RA/SLE) to provide a more robust analysis. The combination of eight SIQR items and seven pain sites correctly classified 99% of FM and 90% of RA/SLE patients in a two-group discriminant analysis. The largest reported SIQR differences (FM minus RA/SLE) were seen for the parameters "tenderness to touch," "difficulty cleaning floors" and "discomfort on sitting for 45 minutes." Combining the SIQR and pain locations in a stepwise multiple regression analysis revealed that the seven most important predictors of group membership were mid-lower back pain (29%; 79% vs. 16%), tenderness to touch (11.5%; 6.86 vs. 3.02), neck pain (6.8%; 91% vs. 39%), hand pain (5%; 64% vs. 77%), arm pain (3%; 69% vs. 18%), outer lower back pain (1.7%; 80% vs. 22%) and sitting for 45 minutes (1.4%; 5.56 vs. 1.49). A combination of two SIQR questions ("tenderness to touch" and "difficulty sitting for 45 minutes") plus pain in the lower back, neck, hands and arms may be useful in the construction of clinical questionnaires designed for patients with musculoskeletal pain. This combination provided the correct diagnosis in 97% of patients, with only 7 of 253 patients misclassified.


Very Early Patch Stage of AIDS-related Kaposi Sarcoma: A Case Report.
Kaposi sarcoma (KS) is a vascular and lymphatic neoplasm caused by human herpesvirus 8 (HHV-8). AIDS-related KS has variable clinical courses ranging from mild disease presenting as an incidental finding to severe disease presenting as an aggressively progressing neoplasm that can lead to poor prognosis or even death. Typical clinical manifestation of KS is known as multiple cutaneous lesions on the extremities, trunk, and face with mucosal involvement. A 46-year-old male with AIDS complained of an erythematous patch on the right forearm which appeared 5 months ago. For a year, he was treated with antiretroviral drugs for AIDS. Physical examination revealed a 2.5-cm solitary erythematous patch only on the right forearm. Laboratory data revealed human immunodeficiency virus (HIV)-1 RNA of less than 40 copies/ml and a CD4 cell count of 264 cells/mm3. Histological examination revealed numerous slit-like spaces and vascular proliferation with primitive blood vessels dissecting between the collagen bundles and the dermis. Immunohistochemical staining showed positive HHV-8 nuclear staining of spindle cells. The histological features and positive HHV-8 immunohistochemical stain were consistent with the diagnosis of early patch stage of AIDS-related KS. KS can readily be misdiagnosed in early patch stage even by experienced clinicians, which leads to requirement of pathologic determination. On close inspection, it can be distinguished from other mimickers by its distinctive histologic features and immunohistochemical staining for HHV-8. Therefore, in cases of HIV-positive patients with clinically or histologically vascular-appearing mucocutaneous lesions, KS should be considered as a possible differential diagnosis.


The selection-mutation-drift theory of synonymous codon usage.
It is argued that the bias in synonymous codon usage observed in unicellular organisms is due to a balance between the forces of selection and mutation in a finite population, with greater bias in highly expressed genes reflecting stronger selection for efficiency of translation. A population genetic model is developed taking into account population size and selective differences between synonymous codons. A biochemical model is then developed to predict the magnitude of selective differences between synonymous codons in unicellular organisms in which growth rate (or possibly growth yield) can be equated with fitness. Selection can arise from differences in either the speed or the accuracy of translation. A model for the effect of speed of translation on fitness is considered in detail, a similar model for accuracy more briefly. The model is successful in predicting a difference in the degree of bias at the beginning than in the rest of the gene under some circumstances, as observed in Escherichia coli, but grossly overestimates the amount of bias expected. Possible reasons for this discrepancy are discussed.


Fluorinated diamond-like carbon as antithrombogenic coating for blood-contacting devices.
Diamond-like carbon (DLC) is being considered for widespread clinical use as a surface coating for cardiovascular devices. We synthesized fluorinated DLC (F-DLC) coatings in order to create a more hydrophobic surface with improved antithrombogenicity and flexibility when compared with conventional DLC coatings by combining the inertness of DLC films with the advantage of fluorination. The purpose of this study was to evaluate the in vitro hemocompatibility and in vivo biocompatibility of the F-DLC coating for medical devices. The in vitro whole blood model confirmed that platelet loss was lower in the F-DLC group than in the noncoated group (SUS316L), which suggests the adhesion of a smaller number of platelets to F-DLC-coated materials. Furthermore, the biomarkers of mechanically induced platelet activation (beta-thromboglobulin) and activated coagulation (thrombin-antithrombin-three complex) were markedly reduced in the F-DLC-coated group. In vivo rat implant model studies revealed no excessive local and systemic inflammatory responses in the F-DLC group. The thickness of the fibrous tissue capsule surrounding the F-DLC-coated disk was almost equal to that of the noncoated SUS316L disk, which has the favorable biocompatibility for metallic implant materials. F-DLC coating thus appears to be a promising candidate for use as a coating material in blood-contacting devices.


Chromosome abnormalities in AIDS-associated lymphadenopathy.
Cytogenetic studies were performed on direct and 24-hour culture preparations of eight lymph node biopsies from seven patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC)-associated lymphadenopathy in whom histological evidence of lymphoma was not detected. Three of these seven had chromosomal abnormalities, including chromosome instability in one and clonal chromosomal abnormalities in two; one of the latter was a t(8;14)(q24;q32). The remaining five showed normal karyotypes. Epstein-Barr virus (EBV) titers were elevated in all three patients that exhibited chromosome abnormalities, two of whom later developed malignant lymphoma. A control group of five patients with reactive lymphadenopathy not associated with AIDS failed to reveal chromosomal aberrations, but elevated EBV titers were present in two. These data are consistent with current views on the role of EBV and chromosome change in the development of lymphoma in immunodeficient states and suggest that karyotypically abnormal AIDS-related lymphadenopathy represents a prelymphomatous proliferation.


Dendritic spikes amplify the synaptic signal to enhance detection of motion in a simulation of the direction-selective ganglion cell.
The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry.


Artificial Intelligence Applied to a First Screening of Naevoid Melanoma: A New Use of Fast Random Forest Algorithm in Dermatopathology.
Malignant melanoma (MM) is the "great mime" of dermatopathology, and it can present such rare variants that even the most experienced pathologist might miss or misdiagnose them. Naevoid melanoma (NM), which accounts for about 1% of all MM cases, is a constant challenge, and when it is not diagnosed in a timely manner, it can even lead to death. In recent years, artificial intelligence has revolutionised much of what has been achieved in the biomedical field, and what once seemed distant is now almost incorporated into the diagnostic therapeutic flow chart. In this paper, we present the results of a machine learning approach that applies a fast random forest (FRF) algorithm to a cohort of naevoid melanomas in an attempt to understand if and how this approach could be incorporated into the business process modelling and notation (BPMN) approach. The FRF algorithm provides an innovative approach to formulating a clinical protocol oriented toward reducing the risk of NM misdiagnosis. The work provides the methodology to integrate FRF into a mapped clinical process.


Access to firearms and risk for suicide in middle-aged and older adults.
Elderly white men are at the highest risk for suicide. Firearms are the most common method of suicide used by both men and women in later life, and a greater proportion of older than younger suicide victims use a gun. This psychological autopsy study aimed to test hypotheses concerning the risk for suicide associated with access to and storage of firearms. Subjects included 86 suicide victims age 50 years of age and over and 86 community control subjects individually matched on age, sex, race, and county of residence. Presence of a firearm in the home was associated with increased risk for suicide, even after controlling for psychiatric illness. Elevated risk was accounted for by access to handguns rather than long guns and was more pronounced in men than women. Among subjects who kept a gun in the home, storing the weapon loaded and unlocked were independent predictors of suicide. Findings support the potential benefit for suicide prevention of restricting access to handguns. Education programs for older persons, their families, and healthcare providers concerning the risks of having a gun in the home and reinforcement of rules for safe storage may contribute to reducing the rate of suicide in older people.


Fangs in the Ghats: Preclinical Insights into the Medical Importance of Pit Vipers from the Western Ghats.
The socioeconomic impact of snakebites in India is largely attributed to a subset of snake species commonly known as the 'big four'. However, envenoming by a range of other clinically important yet neglected snakes, a.k.a. the 'neglected many', also adds to this burden. The current approach of treating bites from these snakes with the 'big four' polyvalent antivenom is ineffective. While the medical significance of various species of cobras, saw-scaled vipers, and kraits is well-established, the clinical impact of pit vipers from regions such as the Western Ghats, northeastern India, and the Andaman and Nicobar Islands remains poorly understood. Amongst the many species of snakes found in the Western Ghats, the hump-nosed (Hypnale hypnale), Malabar (Craspedocephalus malabaricus), and bamboo (Craspedocephalus gramineus) pit vipers can potentially inflict severe envenoming. To evaluate the severity of toxicity inflicted by these snakes, we characterised their venom composition, biochemical and pharmacological activities, and toxicity- and morbidity-inducing potentials, including their ability to damage kidneys. Our findings highlight the therapeutic inadequacies of the Indian and Sri Lankan polyvalent antivenoms in neutralising the local and systemic toxicity resulting from pit viper envenomings.


Group-selective reagent modification of the benzodiazepine-gamma-aminobutyric acid receptor-ionophore complex reveals that low-affinity gamma-aminobutyric acid receptors stimulate benzodiazepine binding.
The modification of membrane proteins with diethylpyrocarbonate (DEP) and diazotized sulfanilate was investigated on the binding of three benzodiazepine radioligands in three brain regions. Both of these reagents produced a dose-dependent inactivation of [3H] diazepam, [3H]flunitrazepam, and [3H]propyl beta-carboline-3-carboxylate binding to cortex, cerebellum, and hippocampus. Both DEP and diazotized sulfanilate decrease the Bmax of the benzodiazepine binding sites without altering the KD. The ability of muscimol and pentobarbital to enhance [3H]diazepam binding was not altered by DEP pretreatment in any of the three regions. Scatchard analysis indicated that, following the inactivation of 40-50% of [3H]diazepam binding by 1 mM DEP, pentobarbital and muscimol were still able to increase the affinity of [3H]diazepam binding in cortex, cerebellum, and hippocampus. In contrast, diazotized sulfanilate pretreatment abolishes the ability of muscimol and pentobarbital to enhance [3H]diazepam binding in these three regions. The effects of these reagents on [3H] gamma-aminobutyric acid (GABA) binding revealed that sulfanilate but not DEP eliminates the low-affinity GABA receptor sites in cortex and cerebellum. Thus, while both DEP and sulfanilate inactivate benzodiazepine binding sites, only sulfanilate abolishes the low-affinity GABA binding sites and the ability of the GABA agonists to enhance [3H]diazepam binding. These results suggest that the stimulation of benzodiazepine binding appears to be mediated by the low-affinity GABA receptors.


The role of surface chemistry on the toxicity of ag nanoparticles.
The role of surface chemistry on the toxicity of Ag nanoparticles is investigated using Saccharomyces cerevisiae yeast as a platform for evaluation. Combining the shape-controlled synthesis of Ag nanoparticles with a comprehensive characterization of their physicochemical properties, an understanding is formed of the correlation between the physicochemical parameters of nanoparticles and the inhibition growth of yeast cells upon the introduction of nanoparticles into the cell culture system. Capping agents, surface facets, and sample stability--the three experimental parameters that are inherent from the wet--chemical synthesis of Ag nanoparticles-have a strong impact on toxicity evaluation. Hence, it is important to characterize surface properties of Ag nanoparticles in the nature of biological media and to understand the role that surface chemistry may interplay to correlate the physicochemical properties of nanoparticles with their biological response upon exposure. This work demonstrates the great importance of surface chemistry in designing experiments for reliable toxicity evaluation and in mitigating the toxicity of Ag nanoparticles for their safe use in future commercialization.


Plating in diaphyseal fractures of the forearm.
Currently, open reduction and internal plate-screw fixation is generally accepted as the gold standard treatment of diaphyseal forearm fractures. The purpose of this retrospective study was to evaluate the clinical and radiographic outcomes of open reduction and internal fixation by using the Locking Compression Plate (LCP) implant system of radial, ulnar or combined shaft fractures of a skeletally mature patients group treated at our institution. We examined 47 patients, 44 men and 3 women, mean age 35 years (range 14-74) operated for diaphyseal fractures of the forearm. Overall 64 segments were treated: 32 ulnar and 32 radial. All patients received 3.5-mm titanium LCPs (Locking Compression Plates) with "combi-holes". Follow-ups included standard X-rays and clinical assessment according to Anderson's criteria and the DASH questionnaire. Mean follow-up was 11 months (range 6-39). The number of the patients who achieved complete consolidation was 43 with a union rate of 91.5%. They showed 37 excellent results and 6 satisfactory results according to Anderson criteria, while non-union occurred in 4 out of 64 segments (2 ulnar and 2 radial) with a non-union rate per patient of 8,5%. The mean score of the DASH scale was 13.5 (range 0-46.7). Our data show that internal plating gives good functional outcomes in the treatment of forearm diaphyseal fractures, as long as the surgical technique is perfect and carried out by expert surgeons. However, further research is desirable to better identify fracture types for which LCPs should be used.


Microdeletion syndromes, balanced translocations, and gene mapping.
High resolution prometaphase chromosome banding has allowed the detection of discrete chromosome aberrations which escaped earlier metaphase examinations. Consistent tiny deletions have been detected in some well established malformation syndromes: an interstitial deletion in 15q11/12 in the majority of patients with the Prader-Willi syndrome and in a minority of patients with the Angelman (happy puppet) syndrome; a terminal deletion of 17p13.3 in most patients examined with the Miller-Dieker syndrome; an interstitial deletion of 8q23.3/24.1 in a large majority of patients with the Giedion-Langer syndrome; an interstitial deletion of 11p13 in virtually all patients with the WAGR (Wilms' tumour-aniridia-gonadoblastoma-retardation) syndrome; and an interstitial deletion in 22q11 in about one third of patients with the DiGeorge sequence. In addition, a combination of chromosome prometaphase banding and DNA marker studies has allowed the localisation of the genes for retinoblastoma and for Wilms' tumour and the clarification of both the autosomal recessive nature of the mutation and the possible somatic mutations by which the normal allele can be lost in retina and kidney cells. After a number of X linked genes had been mapped, discrete deletions in the X chromosome were detected by prometaphase banding with specific attention paid to the sites of the gene(s) in males who had from one to up to four different X linked disorders plus mental retardation. Furthermore, the detection of balanced translocations in probands with disorders caused by autosomal dominant or X linked genes has allowed a better insight into the localisation of these genes. In some females with X linked disorders, balanced X; autosomal translocations have allowed the localisation of X linked genes at the breakpoint on the X chromosome. Balanced autosome; autosome translocations segregating with autosomal dominant conditions have provided some clues to the gene location of these conditions. In two conditions, Greig cephalopolysyndactyly and dominant aniridia, two translocation families with one common breakpoint have allowed quite a confident location of the genes at the common breakpoint at 7p13 and 11p13, respectively.


Ethanol induces endoplasmic reticulum stress in the developing brain.
Ethanol exposure during brain development causes profound damages to the central nervous system (CNS). The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins, and activation of transcription factors. Sustained ER stress ultimately leads to cell death. ER stress is implicated in various neurodegenerative processes. Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that ethanol induces ER stress in the developing brain. Seven-day-old C57BL/6 mice were acutely exposed to ethanol by subcutaneous injection and the expression of ER stress-inducible proteins (ERSIPs) and signaling pathways associated with ER stress were examined. Ethanol exposure significantly increased the expression of ERSIPs and activated signaling pathways associated with ER stress; these include ATF6, CHOP/GADD153, GRP78, and mesencephalic astrocyte-derived neurotrophic factor as well as the phosphorylation of IRE1α, eIF2α, PERK, and PKR. The ethanol-induced increase in ERSIPs occurred within 4 hours of ethanol injection, and levels of some ERSIPs remained elevated after 24 hours of ethanol exposure. Ethanol-induced increase in phosphorylated eIF2α, caspase-12, and CHOP was distributed in neurons of specific areas of the cerebral cortex, hippocampus, and thalamus. Our finding indicates that ethanol induces ER stress in immature neurons, providing novel insight into ethanol's detrimental effect on the developing CNS.


Altered regulation of tau phosphorylation in a mouse model of down syndrome aging.
Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.


Impaired pneumovax-23-induced monocyte-derived cytokine production in patients with common variable immunodeficiency.
Streptococcus pneumoniae is one of the most common infectious pathogens in common variable immunodeficiency (CVID). Both innate and adaptive immune response appears to play a role in defense against S. pneumoniae. In mice, it has been established that TLR2 and macrophages-derived cytokines (IL-6, TNF-alpha) play a crucial role in defense against S. pneumoniae. In humans, monocyte/macrophage-derived cytokines in response to S. pneumoniae have not been studied. Patients with CVID respond poorly to Pneumovax-23 (containing all capsular polysaccharides) vaccination. In this study, we show that Pneumovax-23, in a concentration and time-dependent manner, induced secretion of IL-6, IL-10, and TNF-alpha by monocytes and not by B cells or T cells from healthy controls. Furthermore, Pneumovax-23-induced secretion of IL-6 and TNF-alpha was significantly less in patients with CVID as compared with controls. In addition, Pneumovax-23-induced upregulation of TLR2 in all four subsets of monocytes; however, differences between control and CVID were not significant. Pneumovax-23-induced monocytes-derived cytokine production is impaired in CVID, which may play an important role in increased susceptibility of CVID patients to S. pneumoniae infection.


[Comparison of two lancets in the skin prick test].
The skin prick test is used to diagnose the allergic sensitization. Its results depend upon several factors, such as the lancet type. In Cuba, the most frequently used are: ALK lancet and blood lancet. To compare these two lancets regarding the size of the wheal, precision, sensitivity and specificity of the skin prick test and, finally, the preference of the patients to one of them. The study was performed in 60 allergic patients, aged 15-50 years, seen at the allergy service of Hospital Universitario Clínico Quirúrgico General Calixto García. The skin prick test was performed on the forearm of all patients included, using both lancet types. A negative control (diluent solution) was applied, together with a 54.3 mmol/L histamine solution in five replicates. The mean size of skin reaction to histamine was 6 mm, using a 1 mm single peak lancet (ALK), size was 6.5 mm when using blood lancet (significant difference p < 0.05). Precision, sensitivity and specificity of ALK lancet were 9.7, 100 and 100%, respectively. On the other hand, the respective values for blood lancet were 15.9, 96 and 87%. Of those studied, 27% presented mild pain and 3% moderate pain using the ALK lancet; while 25% showed mild pain and 10% moderate pain using the blood lancet. The ALK lancet showed more precision, sensitivity and specificity and it was preferred by the patients.


Prevalence and potential risk factors for gastrointestinal parasitic infections in children in urban Bissau, Guinea-Bissau.
Gastrointestinal (GI) parasitic infections cause significant morbidity and mortality in tropical and subtropical countries. We aimed to investigate the prevalence of GI parasitic infections in children from Bissau, Guinea-Bissau and to identify the possible risk factors for these infections. We performed an observational study on two comparable cohorts of children 2-15 y of age: one study covering health care-seeking children (n=748) and one study covering children from the background population (n=851). A total of 1274 faecal samples from the two cohorts were investigated for parasites by microscopy and the risk factors for infection were identified by logistic regression. Intestinal parasitic infections were found in 54.8% of health care-seeking children and 55.5% of children from the background population. Helminth infections were more common among health care-seeking children and were mainly due to hookworms. Pathogenic protozoa included Entamoeba histolytica/dispar and Giardia lamblia. The risk factors for infections included increasing age, household crowding and poor sanitation and water supply. We found a high prevalence of intestinal parasites among both health care-seeking children and children from the background population. Compared with previous studies, we found a decreasing prevalence of intestinal helminths. This study further identifies potential risk factors for infections, including inadequate sanitation and water supply.


Robotic catheter ventriculostomy: feasibility, efficacy, and implications.
Robotic applications hold great promise for improving clinical outcomes and reducing complications of surgery. To date, however, there have been few widespread applications of robotic technology in neurosurgery. The authors hypothesized that image-guided robotic placement of a ventriculostomy catheter is safe, highly accurate, and highly reproducible. Sixteen patients requiring catheter ventriculostomy for ventriculoperitoneal (VP) shunt or reservoir placement were included in this retrospective study. All patients underwent image-guided robotic placement of a ventricular catheter, using a preoperatively defined trajectory. All catheters were placed successfully in a single pass. There were no catheter-related hemorrhages and no injuries to adjacent neural structures. The mean distance of the catheter tip from the target was 1.5 mm. The mean operative times were 112 minutes for VP shunt placement and 42.3 minutes for reservoir placement. The mean operative times decreased over the course of the study by 49% for VP shunts and by 19% for reservoir placement. The robotic placement of a ventriculostomy catheter using a preplanned trajectory is safe, highly accurate, and highly reliable. This makes single-pass ventriculostomy possible in all patients, even in those with very small ventricles, and may permit catheter-based therapies in patients who would otherwise be deemed poor surgical candidates because of ventricle size. Robotic placement also permits careful preoperative study and optimization of the catheter trajectory, which may help minimize the risks to bridging veins and sulcal vessels.


Immunohistochemical and Molecular Investigations Show Alteration in the Inflammatory Profile of Multiple System Atrophy Brain.
Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by aggregation of α-synuclein in oligodendrocytes to form glial cytoplasmic inclusions. According to the distribution of neurodegeneration, MSA is subtyped as striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), or as combination of these 2 (mixed MSA). In the current study, we aimed to investigate regional microglial populations and gene expression in the 3 different MSA subtypes. Microscopy with microglial marker Iba-1 combined with either proinflammatory marker CD68 or anti-inflammatory marker Arginase-1 was analyzed in control, SND, and OPCA cases (n = 5) using paraffin embedded sections. Western immunoblotting and cytokine array were used to determine protein expression in MSA and control brain regions. Gene expression was investigated using the NanoString nCounter Human Inflammation panel v2 mRNA Expression Assay. Analysis of neuropathological subtypes of MSA demonstrated a significant increase in microglia in the substantia nigra of OPCA cases. There was no difference in the microglial activation state in any region. Cytokine expression in MSA was comparable with controls. Decreased expression of CX3CL1 precursor protein and significantly greater CX3CR1 protein was found in MSA. NanoString analysis revealed the >2-fold greater expression of ARG1, MASP1, NOX4, PTGDR2, and C6 in MSA.


[Current state of the problem of vertigo].
On the basis of literature and personal data the author qualifies vertigo as an important subjective symptom of a number of diseases. The author proposes and evaluates the existing classifications of vertigo and the applied terminology. The systematics of vertigo based on the clinical experience is proposed. The paper contains qualitative and quantitative characteristics of separate types of vertigo which were singled out according to the character of sensations, conditions of their appearance, time of their duration, attendant neurological and another objective symptomatics and categories of diseases. In this connection the author divides vertigo into peripheral (labyrinthiform and radicle) and central (nucleus, supra-nuclear, "higher"). Principals of treatment are described.


Cervical smears and human papillomavirus typing in sex workers.
Sex workers are at increased risk for sexually transmitted infections (STI), human papillomavirus (HPV) and hence cervical cancer. In Belgium screening for cervical cancer starts at the age of 25, and is at 3 yearly intervals. The aim of this study is to assess risks for abnormal cervical smears and HPV in sex workers and decide whether the current screening policy is sufficient for them. In an outreach programme for sex workers results of 653 smears sampled between 1992 and 2001 were analysed, and compared to a control group matched for age from the general population in 2001. Separately, 99 consecutive samples were typed for HPV and compared to an equal control group, matched for age. Smears and typing were performed according to current techniques. In the sex worker group 2.6% were diagnosed with atypical glandular cells of undetermined significance (AGUS)/atypical squamous cells of undetermined significance (ASCUS), 15.6% with low grade squamous intraepithelial lesion (LSIL), and 2.9% with high grade squamous intraepithelial lesion (HSIL), and in the control group results were 1.4%, 2.9% (p<0.001) and 0.6% (p<0.001) respectively. When considering only those under 25 years, 24.4% should have further follow up. Of the sex workers, 77.4% were positive for one or more types of HPV (55.9% for high risk HPV), in comparison with 27.6% of the control group (14.3% for high risk HPV) (p<0.001). In high risk HPV samples more LSIL and HSIL were found. Abnormal smears and high risk HPV were significantly more prevalent in sex workers than in controls. Current screening policy would miss many sex workers with an abnormal smear who should be referred for further follow up. It is proposed to screen sex workers when they enter prostitution regardless of their age.


Cognitive behavioral therapy: a meta-analysis of race and substance use outcomes.
Cognitive behavioral therapy (CBT) is an effective intervention for reducing substance use. However, because CBT trials have included predominantly White samples caution must be used when generalizing these effects to Blacks and Hispanics. This meta-analysis compared the impact of CBT in reducing substance use between studies with a predominantly non-Hispanic White sample (hereafter NHW studies) and studies with a predominantly Black and/or Hispanic sample (hereafter BH studies). From 322 manuscripts identified in the literature, 16 met criteria for inclusion. Effect sizes between CBT and comparison group at posttest had similar effects on substance abuse across NHW and BH studies. However, when comparing pre-posttest effect sizes from groups receiving CBT between NHW and BH studies, CBT's impact was significantly stronger in NHW studies. T-test comparisons indicated reduced retention/engagement in BH studies, albeit failing to reach statistical significance. Results highlight the need for further research testing CBT's impact on substance use among Blacks and Hispanics.


[Method of evaluating the functional activity of viral antigens].
A method for evaluation of the functional activity of viral antigens in their interaction with antibodies, has been developed. The proposed index of the functional activity is the quantitative characteristic of the neutralization process as a whole. The results obtained with this method correspond to those of the seroepidemiologic test: the diagnostic agents prepared from tick-borne encephalitis virus strains and clones, known as functionally active, showed greater activity in comparison with the reference strain. The proposed method can be used for the determination of the functional activity of viral antigens in different serologic tests.


Pharmacological treatment for insomnia in patients with major depressive disorder.
Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. Sleep disturbances in MDD should be recognized as at least one of the following: (1) a domain of depressive psychopathology; (2) a consequence of rhythm disruptions; (3) a manifestation of comorbidities of sleep disturbances; (4) a manifestation of the influence of sex hormones in the brain in MDD; (5) a general medical comorbidity; and (6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non-structured interviews. Other methods such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretins and the endocannabinoid system.


The temporal decay of eye gaze adaptation effects.
Recent findings demonstrate that the perception of other people's eye gaze direction can be dramatically biased by previous adaptation to that gaze direction. Here, we further investigated this aftereffect by examining its development over time, with particular attention to the potential role of the ambiguity of the test stimulus. Following adaptation to gaze to one direction, participants' ability to correctly classify gaze to the adapted direction was severely impaired, both for ambiguous and relatively unambiguous test stimuli. Of particular importance, this aftereffect decreased over time but remained measurable up to 7 minutes post adaptation, with its decline following an exponential decay function. The implications of the present findings are discussed with respect to both coding mechanisms involved in gaze perception and a potential role of adaptation effects in real life situations.


Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells.
Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood. More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation in vivo are lacking. In Drosophila pupae, Notch signals during cytokinesis to regulate the intra-lineage pIIa/pIIb decision in the sensory organ lineage. Here, we identify two pools of Notch along the pIIa-pIIb interface, apical and basal to the midbody. Analysis of the dynamics of Notch, Delta, and Neuralized distribution in living pupae suggests that ligand endocytosis and receptor activation occur basal to the midbody. Using selective photo-bleaching of GFP-tagged Notch and photo-tracking of photo-convertible Notch, we show that nuclear Notch is indeed produced by receptors located basal to the midbody. Thus, only a specific subset of receptors, located basal to the midbody, contributes to signaling in pIIa. This is the first in vivo characterization of the pool of Notch contributing to signaling. We propose a simple mechanism of cell fate decision based on intra-lineage signaling: ligands and receptors localize during cytokinesis to the new cell-cell interface, thereby ensuring signaling between sister cells, hence intra-lineage fate decision.


Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials.
Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.


Molecular identification and expression analysis of Toll-like receptor 3 in common carp Cyprinus carpio.
The Toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system that responds to specific pathogen-associated molecular patterns (PAMP) during infections. TLR3 is a putative pattern recognition receptor (PRR) for dsRNA, a common by-product of viral replication. This study reports the identification and characterization of a full-length orthologue of TLR3 (CcTLR3) in the common carp Cyprinus carpio. It is 2899 base pairs (bp) encoding 904 amino acid residues with a calculated molecular mass of 102 744 Da and an estimated isoelectric point of 6.89. The deduced amino acid sequence is characterized by a signal peptide, 14 leucine-rich repeat (LRR) motifs, a transmembrane domain and a Toll-interleukin (IL)-1 receptor (TIR) domain. Real-time polymerase chain reaction (RT-PCR) analysis indicated that CcTLR3 mRNA transcripts could be detected in a wide range of tissues. Although C. carpio is resistant to grass carp Ctenopharyngodon idella reovirus (GCRV), after injection with GCRV, CcTLR3 expression was downregulated from 24 h post-injection (P < 0.05) and returned to control levels at 72 h post-injection (P > 0.05). Antiviral effector Mx mRNA expression, however, was upregulated from 24 h post-injection (P < 0.05) and recovered to control levels at 96 h post-injection (P > 0.05). The results provide a better understanding of the anti-GCRV mechanism and antiviral immune responses in fish, and help to develop suitable strategies to reduce viral diseases in fish.


Cochlear Implantation: The Variation in Cochlear Height.
This study aimed to identify the association between different cochlear metrics, including the basal turn diameter (A-value), the basal turn width (B-value), and the height of the cochlea (H-value). We also reported an association between H-value and hearing outcomes with cochlear implants (CI). This is a retrospective study that included all patients who underwent CI procedures between 2012 and 2018 at a tertiary center and have; preoperative high-resolution computed tomography (CT), normal cochlea, postoperative follow-up duration of at least 2 years, scores of the category auditory performance II (CAP-II), and speech intelligibility rating (SIR) scales. A total of 65 ears implanted with CI in 46 patients (24 boys and 20 girls; mean age of 7 (±10) years) fulfilled the inclusion criteria. We found significant positive correlations between A vs B, A vs H, and B vs H (P-value = 0.008, 0.018, and 0.0039, respectively). We also found a significant positive relationship between A, B, and H values and cochlear duct length (CDL) (P-value < 0.0001, 0.008, and 0.018, respectively). Finally, the H-value was significantly correlated with the SIR (P-value = 0.027). However, its correlation with the CAP score was not statistically significant (P-value = 0.62). Cochlear height significantly correlated with CDL and the other cochlear parameters. The variation in cochlear height can also affect speech outcomes in patients undergoing CI. Therefore, the H-value together with the other cochlear metrics should be adequately assessed preoperatively in CI patients.


Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the Wnt signaling pathway.
Tumor angiogenesis is essential for invasive tumor growth and metastasis. Dickkopf-1 (DKK-1), an antagonist of Wnt signaling, participates in tumor development and progression. We evaluated whether DKK-1 stimulation induces angiogenesis and the endothelial-mesenchymal transition (EnMT). Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant DKK-1 (rDDK-1) or conditioned medium from a culture of DKK-1-transfected 293 cells. Following stimulation, the expression levels of angiogenesis-related factors and EnMT related markers were determined by immunoblot assays. In addition, the effects of exogenous DKK-1 on angiogenesis and EnMT were assessed by tube-formation, cell invasion, and wound-healing assays. Human hepatoma cells, such as Hep3B and Huh-7, showed high levels of DKK-1 expression, whereas 293 cells and HUVECs showed little or no DKK-1 expression. Increased endothelial cell tube formation and invasiveness were observed in HUVECs treated with concentrated conditioned medium from DKK-1-overexpressing 293 cells or rDKK-1. DKK-1-stimulated HUVECs also exhibited increased motility in wound-healing assays. Furthermore, the expression levels of angiogenesis-related factors, including vascular endothelial growth factor receptor 2 and vascular endothelial-cadherin, were increased in DKK-1-stimulated HUVECs. The expression of EnMT markers, such as vimentin and Twist, was also increased in DKK-1-stimulated HUVECs. However, no significant change in β-catenin or GSK3β expression was observed. Our in vitro data suggest that DKK-1 can enhance angiogenesis and EnMT by HUVECs independent of the Wnt signaling pathway. Modulation of DKK-1 expression may facilitate development of novel strategies to control tumor angiogenesis and metastasis.


Salmonid follicle-stimulating hormone (GtH I) mediates vitellogenic development of oocytes in the rainbow trout, Oncorhynchus mykiss.
Rainbow trout (Oncorhynchus mykiss) were subjected to unilateral ovariectomy (ULO) during early vitellogenesis to examine the endocrine responses mediating the recruitment and growth of oocytes in the secondary (vitellogenic) growth phase. ULO induced recruitment of a second population of primary oocytes into the vitellogenic growth phase that then grew at a faster rate than oocytes in the control fish. Seven days post-ULO, the concentration of plasma salmonid FSH (sFSH = GtH I) was significantly higher than in controls and was elevated for at least 54 days. Maximal concentrations of sFSH in ULO fish (Day 21 post-ULO) were twice (10 ng/ml) those in controls. The data show that sFSH plays a primary role in mediating vitellogenic development. After ULO, plasma concentrations of estradiol-17beta were significantly lower than in controls up until 21 days post-ULO. Thereafter, plasma concentrations of estradiol-17beta did not differ from those in controls. The changes in concentrations of plasma estradiol-17beta and sFSH in the ULO fish demonstrated that the secretion of sFSH is probably not controlled by negative feedback of estradiol-17beta alone; in fish, as in mammals, it is likely that intragonadal autocrine/paracrine factors, such as inhibin and activin, also participate in the regulation of sFSH secretion. Plasma concentrations of testosterone did not appear to differ between the control and ULO fish. The responses in the production of estradiol-17beta and testosterone indicate that the dynamics of sex steroid synthesis in ovarian follicles in ULO fish was different than in the ovaries of control fish.


Time- and momentum-resolved image-potential states of 2H-MoS2 surface.
Rydberg-like image potential states (IPSs) form special series surface states on metal and semiconducting surfaces. Here, using time-resolved and momentum-resolved multi-photon photoemission (mPPE), we measured the energy positions, band dispersion, and carrier lifetimes of IPSs at the 2H-MoS2 surface. The energy minima of the IPSs (n = 1 and 2) were located at 0.77 and 0.21 eV below the vacuum level. In addition, the effective masses of these two IPSs are close to the rest mass of the free electron, clearly showing nearly-free-electron character. These properties suggest a good screening effect in the MoS2 parallel to the surface. The multi-photon resonances between the valence band and IPS (n = 1) are observed, showing a k‖-momentum-dependent behavior. Our time-resolved mPPE measurements show that the lifetime of photoexcited electrons in the IPS (n = 1) is about 33 fs.


Lead, zinc, copper, and cadmium in fish and sediments from the Big River and Flat River Creek of Missouri's Old Lead Belt.
The Old Lead Belt of Missouri was a major lead-producing region for over a century. Several large tailings piles and other industrial wastes remain behind, though mining operations in the region ceased in 1972. Samples of stream sediments and fish were collected from established sites on the Big River and Flat River Creek over a 3-year period from 1998 to 2000 to evaluate ongoing remediation efforts and determine the current impact of residual mining wastes. Benthic sediments and fish taken in the vicinity of inactive industrial sites were found to contain elevated concentrations of Pb, Zn, Cu, and Cd. Concentrations of Pb and Zn in fillets of suckers and sunfish, as well as in whole bodies of sunfish, correlate well with metal concentrations observed in surficial sediments. The results of analyses provide valuable quantitative information regarding specific sources, current levels of contamination, potential risk to public health, and will allow more accurate assessment of continuing remediation efforts.


The birth and life of lipid droplets: learning from the hepatitis C virus.
LDs (lipid droplets) are probably the least well-characterized cellular organelles. Having long been considered simple lipid storage depots, they are now considered to be dynamic organelles involved in many biological processes. However, most of the mechanisms driving LDs biogenesis, growth and intracellular movement remain largely unknown. As for other cellular mechanisms deciphered through the study of viral models, HCV (hepatitis C virus) is an original and relevant model for investigations of the birth and life of these organelles. Recent studies in this model have raised the hypothesis that the HCV core protein induces the redistribution of LDs through the regression and regeneration of these organelles in specific intracellular domains.


[Nutritional status of the HIV patient. Description and clinical course of a group of patients over a year].
To know the nutritional and immunological status of a sample of patients infected by HIV and their evolution over a one-year period. Relationship between nutritional status, immunological status and clinical evolution. Longitudinal descriptive study of 30 HIV-infected patients. Anthropometric evaluation (weight, height, skin folds, arm circumference) and immunological assessment (CD4 and CD4/CD8). means, absolute and relative frequencies, Student's T test. 30 patients, 73.3% males and 27.7% female. Mean age 34.7 years. Initial nutritional assessment: 30% of patients had normal weight, 36.7% presented mild undernourishment, 16.7% moderate undernourishment, 6.7% were overweight and 10% were obese. The evolution of CD4 and CD4/CD8 levels was not significantly influenced by nutritional status. The patients in the study presented a deterioration of their nutritional status, as assessed by triceps skin fold. The nutritional status of the HIV-infected patients in our study is not dependent on their immunological status. The diagnosis and treatment of their de-nourishment on diagnosis of HIV infection will contribute to the prevention of complications, thus reducing the human and health-care costs. An increase in food intake, on its own, does not improve the condition of the patients, indicating the need to provide them with the necessary dietary supplements from the early stages of illness.


A kinetic model for Ca2+ efflux mediated by the Ca2+ + Mg2+-activated ATPase of sarcoplasmic reticulum.
We present a model for Ca2+ efflux from vesicles of sarcoplasmic reticulum (SR). It is proposed that efflux is mediated by the Ca2+ + Mg2+-activated ATPase that is responsible for Ca2+ uptake in this system. In the normal ATPase cycle of the ATPase, phosphorylation of the ATPase is followed by a conformational change in which the Ca2+-binding sites change from being outward-facing and of high affinity to being inward-facing and of low affinity. To mediate Ca2+ efflux, it is proposed that the ATPase can adopt a conformation in which the Ca2+-binding sites are of low affinity but still outward-facing. It is shown that experimental data on the rates of Ca2+ efflux can be simulated in terms of this model, with Ca2+-binding-site affinities previously proposed to explain ATPase activity [Gould, East, Froud, McWhirter, Stefanova & Lee (1986) Biochem. J. 237, 217-227]. Effects of Mg2+ and adenine nucleotides on efflux rates are explained. It is suggested that Ca2+ efflux from SR mediated by the ATPase could be important in excitation-contraction coupling in skeletal muscle.


Prevention of fungal infections in hematology patients.
Endogenous infections such as candidiasis can be minimized by oral fluconazole prophylaxis, although oral or intravenous amphotericin, or itraconazole, are suitable for certain patients. Exogenous fungal infections most commonly are transmitted by the airborne route, but the benefits of high-efficiency particulate air-filtered room air probably are diminishing as broad-spectrum prophylaxis against Aspergillus species and other fungi improves. However, high-risk environmental sources such as construction work always must be avoided near neutropenic patients. Reactivation of quiescent pulmonary Aspergillus infection can be prevented by surgical resection during remission, or by systemic amphotericin prophylaxis during subsequent neutropenic episodes.


Association of HLA-E polymorphism with severe bacterial infection and early transplant-related mortality in matched unrelated bone marrow transplantation.
Despite prophylactic measures, susceptibility to severe infections in patients who had undergone bone marrow transplantation (BMT) is quite variable. To evaluate the potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections, we analyzed 77 unrelated-donor (UD) BMT pairs identically matched for classical HLA class I and class II alleles. Multivariate analysis taking into account the patient-, donor- and transplant-related factors showed that bacterial infections and transplant-related mortality (TRM) at day 180 were high when the donor genotype was HLA-E*0101/E*0101 (hazard ratio [HR]=2.20; P=0.03 and HR=2.12, P=0.048, respectively), suggesting that homozygous state for HLA-E*0101 allele is a risk factor for early severe bacterial infections and TRM in UD-BMT.


Neointima formation impairs endothelial muscarinic receptors while enhancing prostacyclin-mediated responses in the rabbit carotid artery.
The purpose of this study was to determine whether the generation of a neointima, an early step in the development of atherosclerosis, affects endothelium-dependent or -independent vasodilation. The neointima was induced, within 7 days, by positioning a nonocclusive silicone collar around one carotid artery in rabbits. After 1, 2, 7, or 14 days segments were cut from the collar-surrounded region of this artery as well as from the sham-operated contralateral artery and were used for isometric tension recording or for bioassay of nitric oxide (NO). The acetylcholine-induced release of NO was significantly reduced at 7 days. The tension recordings suggested that this already occurred at the earliest stages of neointima formation. Neither the capacity of the endothelial cells to form NO in response to the calcium ionophore A23187 nor the capacity of the underlying smooth muscle cells to relax in response to sources of exogenous NO (3-morpholinosydnonimine and nitroglycerin) was affected by the neointima. Therefore, the impaired endothelium-dependent relaxations to acetylcholine are presumably due to a defect at the level of the endothelial muscarinic receptors. The presence of a fully developed neointima did not alter the responsiveness to isoproterenol and forskolin but enhanced prostacyclin-mediated responses (assessed by iloprost and 13-hydroxyoctadecadienoic acid). These results illustrate selective alterations of endothelial and smooth muscle cell function in intima generation before fatty streak formation.


Conformal ultrasound imaging system for anatomical breast inspection.
Ultrasound tomography has considerable potential as a means of breast cancer detection because it reduces the operator-dependency observed in echography. A half-ring transducer array was designed based on breast anatomy, to obtain reflectivity images of the ductolobular structures using tomographic reconstruction procedures. The 3-MHz transducer array comprises 1024 elements set in a 190-degree circular arc with a radius of 100 mm. The front-end electronics incorporate 32 independent parallel transmit/receive channels and a 32-to-1024 multiplexer unit. The transmit and receive circuitries have a variable sampling frequency of up to 80 MHz and 12-bit precision. Arbitrary waveforms are synthesized to improve the signal-to-noise ratio and to increase the spatial resolution when working with low-contrast objects. The setup was calibrated with academic objects and a needle hydrophone to develop the data correction tools and specify the properties of the system. The backscattering field was recorded using a restricted aperture, and tomographic acquisitions were performed with a pair of 0.08-mm-diameter steel wires, a low-contrast 2-D breast phantom, and a breast-shaped phantom containing inclusions. Data were processed with dedicated correction tools and a pulse compression technique. Objects were reconstructed using the elliptical back-projection algorithm.


Impaired T cell proliferation by ex vivo BET-inhibition impedes adoptive immunotherapy in a murine melanoma model.
Activation of naïve CD8+ T cells stimulates proliferation and differentiation into cytotoxic T-lymphocytes (CTLs). Adoptive T Cell Therapy (ACT) involves multiple rounds of ex vivo activation to generate enough CTLs for reinfusion into patients, but this drives differentiation into terminal effector T cells. Less differentiated CTL populations, such as stem cell memory T cells, are more ideal candidates for ACT because of increased self-renewal and persistent properties. Ex vivo targeting of T cell differentiation with epigenetic modifiers is a potential strategy to improve cytotoxic T-lymphocyte (CTL) generation for ACT. We established a pipeline to assess the effects of epigenetic modifiers on CD8+ T cell proliferation, differentiation, and efficacy in a preclinical melanoma model. Single treatment with epigenetic modifiers inhibited T cell proliferation in vitro, producing CD44hiCD62Lhi effector-like T cells rather than a stem cell memory T cell phenotype. Most epigenetic modifying agents had no significant effect on ACT efficacy with the notable exception of the bromodomain and extraterminal (BET)-inhibitor JQ1 which was associated with a decrease in efficacy compared to unmodified T cells. These findings reveal the complexity of epigenetic targeting of T cell differentiation, highlighting the need to precisely define the epigenetic targeting strategies to improve CTL generation for ACT.


Study protocol for a randomised trial of nicotine-free cigarettes as an adjunct to usual NRT-based cessation practice, in people who wish to stop smoking.
Current smoking cessation treatments focus on addressing the pharmacological dependence of smokers on nicotine. However, new strategies are needed that address both nicotine dependence and the psychological dependence on cigarettes as the source of nicotine. Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates. This paper describes the protocol for a large randomised-controlled trial to test the effect of using nicotine-free cigarettes together with NRT on long-term quit rates. This single-blind, randomised trial aims to recruit 1,410 participants through the national telephone-based Quitline service in New Zealand. Participants in the treatment arm will be asked to stop smoking nicotine-containing cigarettes on their chosen Quit day and smoke ad libitum nicotine-free (Quest 3) cigarettes for six weeks. At the same time people in this group will be asked to start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Participants in the control arm will be asked to stop smoking completely on their chosen Quit day and start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Data collection will occur at baseline, three and six weeks, and three and six months after Quit day. The primary outcome is the proportion of participants who self-report seven-day point prevalence abstinence at six months since Quit date. Smoking prevalence in New Zealand has changed little in recent years (particularly in Māori, the indigenous people of New Zealand) and additional options for smokers who want to quit are needed. Although a variety of methods are available to help, many are expensive, have side effects, and despite their use most quit attempts still fail. This trial will test the balance of benefits and risks of a new strategy for people to overcome nicotine dependence. Since smoking is the leading cause of lost healthy life years in New Zealand, if proven effective this strategy is likely to have substantial public health benefits.


NF-kappaB or AP-1-dependent reporter gene expression is not altered in human U937 cells exposed to power-line frequency magnetic fields.
A number of studies have reported that human leukemia cells respond to exposure to power-line frequency electromagnetic fields (EMFs), providing evidence for an EMF-induced signaling pathway involving activation of protein tyrosine kinases (PTKs), phospholipase-Cy and protein kinase C (PKC). Because activation of PKC is also important in the signaling pathways that regulate the transcription factors NF-kappaB and AP-1, we evaluated the effect of exposure to a 60 Hz EMF on NF-kappaB or AP-1-dependent reporter gene expression in cells of the human promonocytic U937 leukemia cell line. Reporter genes were electroporated into U937 cells and activation of the NF-kappaB or AP-1 signaling pathway was evaluated by measuring chloramphenicol acetyltransferase (CAT) protein by CAT ELISA. In contrast to the effects of well-understood chemical or biological agents, the exposure to magnetic-field intensities of 0.08, 0.1, 1.0 or 1.3 mT had no effect on the NF-kappaB or AP-1 signaling pathways.


Union Type and Depressive Symptoms Among Mexican Adults.
Diversity in union type is increasing around the world as cohabitation and higher order unions become more prevalent in developing and developed countries. This necessitates a more nuanced understanding of how different union types relate to individual well-being across social settings. In this study, the authors analyze nationally-representative data from Mexico in cross-sectional and change models to evaluate differences in depressive symptoms across union type (marital vs. cohabiting and first vs. higher order unions) among Mexican men and women. The findings suggest that cohabiting unions do not provide the same mental health benefits as marital unions (especially for men). Repartnering is also associated with higher depressive symptoms (especially for women), which indicates possible lasting mental health disadvantages of divorce/separation or entrance into lower quality second unions. These results suggest that the changing family context in Mexico, which includes increasing cohabitation and union instability, may have important consequences for individuals' psychological well-being.


Protective Regulatory T Cell Immune Response Induced by Intranasal Immunization With the Live-Attenuated Pneumococcal Vaccine SPY1 via the Transforming Growth Factor-β1-Smad2/3 Pathway.
Vaccine effectiveness is mainly determined by the mechanism mediating protection, emphasizing the importance of unraveling the protective mechanism for novel pneumococcal vaccine development. We previously demonstrated that the regulatory T cell (Treg) immune response has a protective effect against pneumococcal infection elicited by the live-attenuated pneumococcal vaccine SPY1. However, the mechanism underlying this protective effect remains unclear. In this study, a short synthetic peptide (P17) was used to downregulate Tregs during immunization and subsequent challenges in a mouse model. In immunized mice, increase in immune cytokines (IL-12p70, IL-4, IL-5, and IL-17A) induced by SPY1 were further upregulated by P17 treatment, whereas the decrease in the infection-associated inflammatory cytokine TNF-α by SPY1 was reversed. P17 also inhibited the increase in the immunosuppressive cytokine IL-10 and inflammatory mediator IL-6 in immunized mice. More severe pulmonary injuries and more dramatic inflammatory responses with worse survival in P17-treated immunized mice indicated the indispensable role of the Treg immune response in protection against pneumococcal infection by maintaining a balance among acquired immune responses stimulated by SPY1. Further studies revealed that the significant elevation of active transforming growth factor β (TGF-β)1 by SPY1 vaccination activated FOXP3, leading to increased frequencies of CD4+CD25+Foxp3+ T cells. Moreover, SPY1 vaccination elevated the levels of Smad2/3 and phosphor-Smad2/3 and downregulated the negative regulatory factor Smad7 in a time-dependent manner during pneumococcal infection, and these changes were reversed by P17 treatment. These results illustrate that SPY1-stimulated TGF-β1 induced the generation of SPY1-specific Tregs via the Smad2/3 signaling pathway. In addition, SPY1-specific Tregs may participate in protection via the enhanced expression of PD-1 and CTLA-4. The data presented here extend our understanding of how the SPY1-induced acquired Treg immune response contributes to protection elicited by live-attenuated vaccines and may be helpful for the evaluation of live vaccines and other mucosal vaccine candidates.


Non-invasive imaging of sympathetic innervation of the pancreas in individuals with type 2 diabetes.
Compromised pancreatic sympathetic innervation has been suggested as a factor involved in both immune-mediated beta cell destruction and endocrine dysregulation of pancreatic islets. To further explore these intriguing findings, new techniques for in vivo assessment of pancreatic innervation are required. This is a retrospective study that aimed to investigate whether the noradrenaline (norepinephrine) analogue 11C-hydroxy ephedrine (11C-HED) could be used for quantitative positron emission tomography (PET) imaging of the sympathetic innervation of the human pancreas. In 25 individuals with type 2 diabetes and 64 individuals without diabetes, all of whom had previously undergone 11C-HED-PET/CT because of pheochromocytoma or paraganglioma (or suspicion thereof), the 11C-HED standardised uptake value (SUVmean), 11C-HED specific binding index (SBI), pancreatic functional volume (FV, in ml), functional neuronal volume (FNV, calculated as SUVmean × FV), specific binding index with functional volume (SBI FV, calculated as SBI × FV) and attenuation on CT (HU) were investigated in the entire pancreas, and additionally in six separate anatomical pancreatic regions. Generally, 11C-HED uptake in the pancreas was high, with marked individual variation, suggesting variability in sympathetic innervation. Moreover, pancreatic CT attenuation (HU) (p<0.001), 11C-HED SBI (p=0.0049) and SBI FV (p=0.0142) were lower in individuals with type 2 diabetes than in individuals without diabetes, whereas 11C-HED SUVmean (p=0.15), FV (p=0.73) and FNV (p=0.30) were similar. We demonstrate the feasibility of using 11C-HED-PET for non-invasive assessment of pancreatic sympathetic innervation in humans. These findings warrant further prospective evaluation, especially in individuals with theoretical defects in pancreatic sympathetic innervation, such as those with type 1 diabetes.