Self-portrayal concerns and their relation to safety behaviors and negative affect in social anxiety disorder.
It has been proposed that self-portrayal concerns - fundamental worries that particular negative self-attributes will become exposed during social encounters and criticized by others - underlie the experience of social anxiety (SA) and drive associated avoidance and safety behaviors (Moscovitch, 2009). The development of the Negative Self Portrayal Scale (NSPS) to assess such concerns across the dimensions of social competence, signs of anxiety, and physical appearance has helped yield promising initial findings that support the basic tenets of Moscovitch's (2009) theoretical model in samples of undergraduate students (Moscovitch & Huyder, 2011). The present study investigated the nature of self-portrayal concerns and their relation to affect and behavior in a sample of 194 community-based participants consisting of (a) 62 individuals with a principal diagnosis of generalized SAD, either with (n = 35) or without (n = 27) an additional depressive disorder diagnosis, (b) 51 individuals with another principal anxiety disorder diagnosis, either with (n = 22) or without (n = 29) an additional diagnosis of SAD, and (c) 81 healthy controls. Participants completed trait questionnaires, daily diaries of naturalistic social encounters, and a laboratory-based speech task. Results demonstrated (a) that a diagnosis of SAD confers unique risk for elevated self-portrayal concerns, (b) that such concerns predict significant variance in safety behavior use across diverse contexts, and (c) that the use of safety behaviors mediates the relation between such concerns and the experience of heightened negative affect. Implications for case conceptualization and treatment of SAD are discussed.


What is it so stressful about caring for a dying patient? A qualitative study of nurses' experiences.
The nursing shortage continues to be a problem in the United States, in part, owing to the experience of stress and burnout by practicing nurses. With an ageing population, the stress of caring for dying patients and their families is one reason for the high levels of stress and burnout. Although we know that caring for dying patients is stressful for nurses, there is little information about the specific aspects of that experience that concern them. In order to alleviate the stress and to help nurses cope more effectively with this situation, this research examined the aspects of caring for a dying patient that cause concern for nurses. This study used a grounded theory approach to examine the experiences of nurses and their particular concerns about caring for a dying patient. Nurses expressed personal concerns, concerns about the patient and their families, which include communication challenges with both patients and families.


Macroplastique for women with stress urinary incontinence secondary to intrinsic sphincter deficiency.
To evaluate the subjective and objective outcomes of MacroplastiqueR (MPQ) in women with stress urinary incontinence (SUI) secondary to intrinsic sphincter deficiency (ISD). Following Institutional Review Board (IRB) approval, charts of non-neurogenic women with SUI secondary to ISD who underwent MPQ injection and had 6 months minimum follow-up were reviewed from a prospectively maintained database. Patients were divided into 3 groups: Naive (Group I), Prior Anti-Incontinence Surgery (Group II), and combined Prior Bulking Agent and Anti-Incontinence Surgery (Group III). Data collected included SUI self-report, Urogenital Distress Inventory (UDI-6) Question 3, and VAS Quality of Life (QoL) Questionnaire scores at baseline and in follow-up. Three-dimensional ultrasound (3DUS) evaluated volume/confi guration of MPQ. Success was defi ned after the last MPQ injection as a UDI-6 Question 3 score of 0 (dry) or 1, and no reoperation for SUI. From 2011-2017, 106 of 142 women met study criteria. At a median follow-up of 20 months (mean=26 months; range: 6-71), success rate was 41% for Group I, 40% for Group II, and 65% for Group III (p = 0.22). QoL scores were signifi cantly improved over baseline in all groups. There was no signifi cant difference in clinical outcome between the asymmetrical and symmetrical group on 3DUS. The completely dry rate was highest in Group III at 29%, compared to 4% for Group I and 15% for Group II (p = 0.05). MacroplastiqueR improved subjective and objective outcome measures for SUI secondary to ISD as both a primary and secondary treatment option in women.


Large-Scale Analysis of Gene Expression and Connectivity in the Rodent Brain: Insights through Data Integration.
Recent research in C. elegans and the rodent has identified correlations between gene expression and connectivity. Here we extend this type of approach to examine complex patterns of gene expression in the rodent brain in the context of regional brain connectivity and differences in cellular populations. Using multiple large-scale data sets obtained from public sources, we identified two novel patterns of mouse brain gene expression showing a strong degree of anti-correlation, and relate this to multiple data modalities including macroscale connectivity. We found that these signatures are associated with differences in expression of neuronal and oligodendrocyte markers, suggesting they reflect regional differences in cellular populations. We also find that the expression level of these genes is correlated with connectivity degree, with regions expressing the neuron-enriched pattern having more incoming and outgoing connections with other regions. Our results exemplify what is possible when increasingly detailed large-scale cell- and gene-level data sets are integrated with connectivity data.


Retrospective observational study to investigate Sinerga, a multifactorial nutritional product, and bacterial extracts in the prevention of recurrent respiratory infections in children.
In this retrospective observational clinical study, 167 children, aged 3 to 7 years, of both sexes, with a clinical history of recurrent respiratory infections, administered with bacterial extracts of first and second generation or Sinerga a nutritional product containing palmitoylethanolamide, bovine colostrum, phenylethylamine and the new generation of probiotic kluyveromyces FM B0399, were observed. The goal of the study was to compare the supplementation with Sinerga with the supplementation with bacterial extracts, for the effect on the frequency of episodes of respiratory infection that had resulted in a prescription for antibiotics. The study focused retrospectively on the months from March 2013 to November 2012. The results showed a greater reduction in the frequency of respiratory infections with antibiotic therapy in the group of children supplemented with Sinerga than in the group treated with bacterial extracts. In particular, it was observed that 49.3% of the children supplemented with Sinerga, against 5% of those supplemented with extracts, had no infectious episodes requiring the administration of an antibiotic. 100% of subjects supplemented with Sinerga have had no more than two episodes of respiratory infection, while this condition, in the cohort treated with bacterial extracts, was observed in only 51% of cases.


Knowledge and social engagement change in intention to be screened for colorectal cancer.
Innovative technologies have been used to promote colorectal cancer (CRC) screening among the underserved. However, the impact of these innovative technologies on knowledge and social engagement likelihood as they relate to subsequent intention to be screened across different populations has not been fully explored. Using a pre-post-test design with an inflatable walk-through colon, we assessed changes in knowledge and social engagement likelihood across populations and their associations with intention to be screened in two community settings. One was a community setting in Washington State (WA); the other, a college campus in New Mexico (NM). Differential effects on knowledge and social engagement likelihood were examined across demographic groups (race/ethnicity, gender, age, education, insurance status, and geographic region). Finally, we assessed if changes in knowledge and social engagement likelihood were associated with CRC screening intention. NM males had greater gains in CRC knowledge than NM females; in WA, Hispanics, younger, less educated, and uninsured participants had greater gains in knowledge. NM females and younger WA participants were more likely to discuss CRC with their social networks than NM males and older WA participants. In WA, Hispanics and older adults reported greater intention to be screened for CRC. Change in social engagement likelihood, but not knowledge, was associated with intention to be screened. The effectiveness of health promotion technologies on knowledge and social engagement may vary across different demographic characteristics. Further, the importance of social engagement likelihood in interacting with intention to be screened was substantiated.


Interconverting receptor states at 4 degrees C for the neutrophil N-formyl peptide receptor.
With the aid of high time resolution kinetic data extracted from a flow cytometer, we determined that there are two N-formyl peptide receptor states for human neutrophils at 4 degrees C: a low affinity and a high affinity state. Competitive binding of FMLP, FNLP, and t-BOC with FNLPNTL-FL revealed different kinetic rate constants for two distinct reactions that control the lifetime of the low affinity ligand-receptor complex. For these ligands, the rate constant for dissociation of ligand from the low affinity receptor state (the first reaction) ranges in order of magnitude from 10(-2) to 1 s-1, and the conversion rate constant from the low affinity receptor state to the high affinity receptor state (the second reaction) ranges from 10(-4) to 10(-2) s-1. The antagonist t-BOC differed most significantly from the three agonists by having an association rate constant for the low affinity receptor on the order of 10(5) M-1 s-1; the value for all three agonists was on the order of 10(7) M-1 s-1. Characterization of the receptor conversion at 4 degrees C revealed that it is irreversible (or very slow) and independent of Gi protein and that neither receptor state is a form of receptor precoupled to Gi protein. The affinity conversion and the dissociation characteristics of each receptor state determine the duration of the signaling complex and may contribute to differences in ligand efficacy.


Variability in the incidence of miRNAs and genes in fragile sites and the role of repeats and CpG islands in the distribution of genetic material.
Chromosomal fragile sites are heritable specific loci especially prone to breakage. Some of them are associated with human genetic disorders and several studies have demonstrated their importance in genome instability in cancer. MicroRNAs (miRNAs) are small non-coding RNAs responsible of post-transcriptional gene regulation and their involvement in several diseases such as cancer has been widely demonstrated. The altered expression of miRNAs is sometimes due to chromosomal rearrangements and epigenetic events, thus it is essential to study miRNAs in the context of their genomic locations, in order to find significant correlations between their aberrant expression and the phenotype. Here we use statistical models to study the incidence of human miRNA genes on fragile sites and their association with cancer-specific translocation breakpoints, repetitive elements, and CpG islands. Our results show that, on average, fragile sites are denser in miRNAs and also in protein coding genes. However, the distribution of miRNAs and protein coding genes in fragile versus non-fragile sites depends on chromosome. We find also a positive correlation between fragility and repeats, and between miRNAs and CpG islands. Our results show that the relationship between site fragility and miRNA density is far more complex than previously thought. For example, we find that protein coding genes seem to be following similar patterns as miRNAs, if considered their overall distribution. However, once we allow for differences at the chromosome level in our statistical analysis, we find that distribution of miRNA and protein coding genes in fragile sites is very different from that of miRNA. This is a novel result that we believe may help discover new potential correlations between the localization of miRNAs and their crucial role in biological processes and in the development of diseases.


Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage.
Studies have linked sex-biased neurodevelopmental disorders, including autism and schizophrenia, with fetal antecedents such as prenatal stress. Further, these outcomes can persist into subsequent generations, raising the possibility that aspects of heritability in these diseases involve epigenetic mechanisms. Utilizing a mouse model in which we previously identified a period in early gestation when stress results in dysmasculinized and stress-sensitive male offspring, we have examined programming effects in second-generation offspring of prenatally stressed (F2-S) or control (F2-C) sires. Examination of gene expression patterns during the perinatal sensitive period, when organizational gonadal hormones establish the sexually dimorphic brain, confirmed dysmasculinization in F2-S males, where genes important in neurodevelopment showed a female-like pattern. Analyses of the epigenomic miRNA environment detected significant reductions in miR-322, miR-574, and miR-873 in the F2-S male brain, levels that were again more similar to those of control females. Increased expression of a common gene target for these three miRNAs, β-glycan, was confirmed in these males. These developmental effects were associated with the transmission of a stress-sensitive phenotype and shortened anogenital distance in adult F2-S males. As confirmation that the miRNA environment is responsive to organizational testosterone, neonatal males administered the aromatase inhibitor formestane exhibited dramatic changes in brain miRNA patterns, suggesting that miRNAs may serve a previously unappreciated role in organizing the sexually dimorphic brain. Overall, these data support the existence of a sensitive period of early gestation when epigenetic programming of the male germline can occur, permitting transmission of specific phenotypes into subsequent generations.


Measured changes in cataract over six months: sensitivity of the Nidek EAS-1000.
Lens opacities in 98 eyes from 63 consecutive outpatients with cataract were recorded by both retroillumination and Scheimpflug slit methods by one operator. This was repeated at 26 +/- 1 weeks. Image analysis used the EAS-1000 software. Cortical and posterior subcapsular (PSC) cataracts were measured in retroillumination images as density more than 14 cct units below background density. Linear densitometry of white scattered light along the optical axis was measured for slit images by both peak density and mean density ('area under the curve'). Retroillumination images showed no discernible change over 6 months (the regression coefficient being as for the intersession reliability). Half of the Scheimpflug slit images could not be analysed because overlying cortical changes masked the more posterior parts of the lens. The other 49 eyes showed a significant increase in nuclear white scatter after 6 months, with greater degrees of change occurring in those eyes with the greatest amount of nuclear cataract initially. This is reflected by the decreased intraclass correlation coefficient (R = 0.42). The area of lens showing greatest change was the anterior fetal nucleus. The Nidek EAS-1000 is able to detect changes over a 6-month period in nuclear density but not in cortical or PSC cataract. The rate of progression of nuclear white scatter increases as the lens opacity becomes more dense. The ability to detect change in cataract over 6 months has implications for epidemiological studies and for trials of anti-cataract drugs.


[Auto-immune disorders as a possible cause of neuropsychiatric syndromes].
Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.


Multisensory principle of heart rate regulation.
We analyzed metabolic parameters during exercise in two groups of patients with implanted dual sensor VVIR. The first group was comprised of 14 patients (mean age 37.7 years) with implanted Topaz pacemakers and the second of 9 patients with a Legend Plus pacemaker (mean age 44.7 years). A control group consisted of 54 healthy individuals (mean age 40.4 years). Testing was performed on treadmill, using a stepwise staircase loading CAEP protocol. The following directly measured and mathematically calculated parameters we used in assessing the metabolic impact of pacemaker function: minute ventilation (MV), MV/body surface, MV/body mass unit, oxygen consumption, oxygen consumption/body surface, oxygen consumption/heart rate (oxygen pulse), oxygen consumption/body mass unit, carbon dioxide production, respiratory index. For the majority of the observed parameters statistically significant difference was not found between the control group and the patients with dual sensor nor single sensor controlled rate response. However, oxygen pulse showed a statistically significant difference when comparing the group with single sensor controlled rate response with dual sensor controlled rate response as well as to the control group (p < 0.05). Also, the time of reaching the anaerobic threshold, as well as the duration of the exercise test were significantly longer in dual sensor guided rate. Since these pacemakers are particularly aimed at a population of still active patients, this finding confirms their contribution to the better quality of life and justifies their use in these patients.


A novel role for Slit2/Robo1 axis in modulating HIV-1 replication in T cells.
Slit2 is a secreted glycoprotein that has been shown to possess anti-inflammatory properties. In addition, Slit2 has been shown to modulate CXCR4-mediated functional effects in T cells. However, its role in HIV-1 pathogenesis is not known. The objective of the current study is to analyze the role of Slit2 in modulating HIV-1 replication in T cells. The effect of endogenous Slit2 expression of HIV-1 replication in T cells was studied by transient overexpression or downregulation of Slit2. The role of exogenous Slit2 was studied by analyzing the effect of soluble Slit2 protein on HIV-1 replication in T-cell lines and peripheral blood mononuclear cells (PBMCs). Studies on T-cell lines revealed a higher expression of Slit2 in Jurkat T cells compared with MT4 cells. We observed that downregulation of Slit2 in Jurkat T cells using Slit2-specific small inhibitor RNA enhanced HIV-1 replication. However, overexpression of Slit2 in MT4 cells and PBMCs reduced HIV-1 replication. As Slit2 is a secretory protein, we further analyzed the role of soluble Slit2 on HIV-1 virus replication using various cell lines and PBMCs. Our data indicated that exogenous Slit2 inhibited replication of both X4-tropic and R5-tropic HIV-1 viruses. Further studies revealed that Slit2 mediated its functional effects by binding to Robo1 receptor. Taken together, our results describe Slit2/Robo1 axis as a novel modulator of HIV-1 replication in T cells. These studies may contribute to the understanding of the immunopathogenesis of HIV-1 infection.


New clinico-epidemiologic profile of cutaneous leishmaniasis, Morocco.
During the past 20 years, cutaneous leishmaniasis has emerged as a major public health threat in Morocco. We describe distribution of Leishmania major and L. tropica in Morocco and a new focus of cutaneous leishmaniasis due to L. infantum. We recommend using molecular techniques to diagnose suspected leishmaniasis cases.


Inhibition of FSH augmented adenylate cyclase activity in porcine granulosa cells by ovarian protein.
We sought to evaluate the effects of a fraction of porcine follicular fluid, termed follicle regulatory protein (FRP), on FSH-induced adenylate cyclase activity in porcine granulosa cell membranes using Gpp(NH)p and forskolin as pharmacological probes of adenylate cyclase activity. Without FSH treatment, the addition of 100 micrograms/ml of the FRP fraction induced a significant decrease in Gpp(NH)p stimulated cyclase activity while maximal inhibition of cAMP formation was achieved with 1 mg/ml of FRP. Granulosa cells cultured with FSH reached a maximum in adenylate cyclase activity at 20 min which returned to baseline by 45 minutes. FRP induced a reduction in adenylate cyclase activity during this same interval of time. Adenylate cyclase activity of cells treated with FRP was unchanged in the presence of methyl-isobutal-xanthine. Further, when FRP was heated (56 degrees C, 45 min) or precipitated with 10% TCA, it was unable to inhibit adenylate cyclase. The 50% inhibitory dose (ID50) for FRP inhibition of adenylate cyclase activity in cells stimulated with Gpp(NH)p was 80 micrograms/ml and 500 micrograms/ml when granulosa cells were preincubated with FSH prior to Gpp(NH)p stimulation. The ID50 for the FRP inhibition of forskolin stimulated adenylate cyclase activity was 500 micrograms/ml. Gpp(NH)p stimulated adenylate cyclase activity was more sensitive than forskolin stimulated activity to inhibition by FRP. In conclusion, the data presented here demonstrate that a partially purified fraction of porcine follicular fluid inhibited FSH responsive adenylate cyclase activity in porcine granulosa cells.


Equilibrium states and ground state of two-dimensional fluid foams.
We study the equilibrium energies of two-dimensional (2D) noncoarsening fluid foams, which consist of bubbles with fixed areas. The equilibrium states correspond to local minima of the total perimeter. We present a theoretical derivation of energy minima; experiments with ferrofluid foams, which can be either highly distorted, locally relaxed, or globally annealed; and Monte Carlo simulations using the extended large-Q Potts model. For a dry foam with small size variance we develop physical insight and an electrostatic analogy, which enables us to (i) find an approximate value of the global minimum perimeter, accounting for (small) area disorder, the topological distribution, and physical boundary conditions; (ii) conjecture the corresponding pattern and topology: small bubbles sort inward and large bubbles sort outward, topological charges of the same signs "repel" while charges of the opposite signs "attract;" (iii) define local and global markers to determine directly from an image how far a foam is from its ground state; (iv) conjecture that, in a local perimeter minimum at prescribed topology, the pressure distribution and thus the edge curvature are unique. Some results also apply to 3D foams.


The psychosocial context of young adult sexual behavior in Nicaragua: looking through the gender lens.
Understanding the nature and magnitude of gender differences in sexual norms among young adults in Nicaragua, and how these differences affect sexual behavior, is important for the design of reproductive health programs. A representative cross-sectional survey was conducted in six departments in the Pacific region of Nicaragua in 1998. A total of 552 never-married women and 289 never-married men aged 15-24 were interviewed about their perceptions of social pressure to engage in premarital sex; perceived social approval of and attitudes toward premarital sex and premarital pregnancy; perceived sexual activity among peers and siblings; communication with parents on sexuality issues; the psychosocial context of sexual debut; and preferred sources of information on sexuality issues. Most young men (83%) reported that they had received direct encouragement from at least one person in the last year to engage in premarital sex, and at least half perceived that their father, siblings, other relatives and friends approved of premarital intercourse. A significantly greater proportion of men than of women reported that curiosity or gaining experience motivated their sexual debut (61% vs. 21%). Men perceived themselves to have a higher risk of unplanned and unprotected sex than did women. In contrast, women held more negative attitudes toward premarital sex and were more often discouraged by parents or siblings from engaging in sex. Reproductive health programs for young Nicaraguans need to address gender-based double standards, which raise the risk of unplanned, unprotected sex and unintended pregnancy.


Exploring the nitrous acid (HONO) formation mechanism in winter Beijing: direct emissions and heterogeneous production in urban and suburban areas.
Continuous measurements of nitrous acid (HONO) were performed from December 12 to December 22, 2015 in both urban and suburban areas of Beijing to study the formation mechanism of HONO. The measurement campaign in both sites included a clean-haze-clean transformation process. HONO concentrations showed similar variations in the two sites, while they were always higher in the urban area. Moreover, correlations of HONO with NOx, NO2, NO, PM2.5 and relative humidity (RH) were studied to explore possible HONO formation pathways, and the contributions of direct emissions, heterogeneous reactions, and homogeneous reactions were also calculated. This showed that HONO in urban and suburban areas underwent totally different formation procedures, which were affected by meteorological conditions, PM2.5 concentrations, direct emissions, homogeneous reactions and heterogeneous reactions. PM2.5 concentrations and RH would influence the NO2 conversion efficiency. Heterogeneous reactions of NO2 were more efficient in suburban areas and in clean periods while direct emissions and homogeneous reactions contributed more in urban areas and in polluted periods when the concentrations of NOx and NO were at a high level.


Conformal elasticity of mechanism-based metamaterials.
Deformations of conventional solids are described via elasticity, a classical field theory whose form is constrained by translational and rotational symmetries. However, flexible metamaterials often contain an additional approximate symmetry due to the presence of a designer soft strain pathway. Here we show that low energy deformations of designer dilational metamaterials will be governed by a scalar field theory, conformal elasticity, in which the nonuniform, nonlinear deformations observed under generic loads correspond with the well-studied-conformal-maps. We validate this approach using experiments and finite element simulations and further show that such systems obey a holographic bulk-boundary principle, which enables an analytic method to predict and control nonuniform, nonlinear deformations. This work both presents a unique method of precise deformation control and demonstrates a general principle in which mechanisms can generate special classes of soft deformations.


Living conditions, lifestyle habits and health among adults before and after the COVID-19 pandemic outbreak in Sweden - results from a cross-sectional population-based study.
Studies on the public health consequences of COVID-19 pandemic showing data based on robust methods are scarce. The aim of this study was to investigate mental and physical health as well as living conditions and lifestyle habits in the general population before and after the COVID-19 outbreak in Sweden. The study is based on 2273 persons 16-84 years who responded to the national public health survey in February-May 2020 in Värmland county (overall response rate 45%). The differences between early respondents (before the outbreak, n = 1711) and late respondents (after the outbreak, n = 562) were studied using multivariate logistic regression, adjusting for background characteristics: age, gender, educational level, and country of birth. The same analyses were also completed in the corresponding survey carried out in February-June 2018. Statistically significant differences between the groups were obtained for economic difficulties and worry about losing one's job, which were more common among late respondents, and for sleeping difficulties, which were more common among early respondents after adjusting for background characteristics. There were no differences in other living conditions nor in lifestyle factors. Prevalence of good self-rated health, high blood pressure, aches in shoulders or neck, anxiety or worry and stress did not differ between the groups. In 2018, the only statistically significant difference between early and late respondents concerned economic difficulties. Very few differences in living conditions, lifestyle factors and health were observed in the study population before and after the COVID-19 outbreak. The results suggest that, in addition to a possible decrease in sleeping difficulties, the prevalence of being worried about losing one's job increased among the employed after the outbreak.


Macroprolactinemia: new insights in hyperprolactinemia.
Hypersecretion of prolactin by lactotroph cells of the anterior pituitary may lead to hyperprolactinemia in physiological, pathological and idiopathic conditions. Most patients with idiopathic hyperprolactinemia may have radiologically undetected microprolactinomas, but some may present other causes of hyperprolactinemia described as macroprolactinemia. This condition corresponds to the predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa), that have been postulated to represent prolactin monomer complexed with anti-prolactin immunoglobulins or autoantibodies. The prevalence of macroprolactinemia in hyperprolactinemic populations between 15-46% has been reported. In the pathophysiology of macroprolactinemia it seems that pituitary prolactin has antigenicity, leading to the production of anti-prolactin autoantibodies, and these antibodies reduce prolactin bioactivity and delay prolactin clearance. Antibody-bound prolactin is big enough to be confined to vascular spaces, and therefore macroprolactinemia develops due to the delayed clearance of prolactin rather than increased production. Although the clinical symptoms are less frequent in macroprolactinemic patients, they could not be differentiated from true hyperprolactinemic patients, on the basis of clinical features alone. Although gel filtration chromatography (GFC) is known to be the gold standard for detecting macroprolactin, the polyethylene glycol precipitation (PEG) method has offered a simple, cheap, and highly suitable alternative. In conclusion, macroprolactinemia can be considered a benign condition with low incidence of clinical symptoms and therefore hormonal and imaging investigations as well as medical or surgical treatment and prolonged follow-up are not necessary.


Serum adiponectin concentration: its correlation with diabetes-related traits and quantitative trait loci analysis in mouse SMXA recombinant inbred strains.
Adiponectin is thought to be an important mediator of insulin sensitivity and atherosclerosis. Using mouse 19 SMXA recombinant inbred (RI) strains, a powerful tool for analyzing multifactorial genetic traits, we found relationships between serum adiponectin levels and diabetes-related traits, body mass index, and serum lipid levels, and also determined the loci controlling serum adiponectin levels by quantitative trait loci (QTL) analysis. RI strains exhibited widely ranging serum adiponectin concentration distribution patterns and diabetes-related traits. The serum adiponectin concentration showed the strongest negative correlation with fasting serum insulin concentration, but negative correlations were also observed with serum triglycerides, cholesterol, and liver weight. In contrast, neither the body mass index nor the blood glucose concentration correlated with serum adiponectin levels. These results suggest that hypoadiponectinemia might be used as a predictor of insulin resistance. In addition, two suggestive QTLs for serum adiponectin concentration were detected on Chromosome (Chr) 7, and an A/J allele at these loci was associated with elevated serum adiponectin concentrations. Identification of genes responsible for regulating the serum adiponectin concentration might lead to the development of novel treatments for patients with diabetes concomitant with hypoadiponectinemia.


Hand Grasp Motion Intention Recognition Based on High-Density Electromyography in Chronic Stroke Patients.
Stroke is a debilitating condition that leads to a loss of motor function, inability to perform daily life activities, and ultimately worsening quality of life. Robot-based rehabilitation is a more effective method than conventional rehabilitation but needs to accurately recognize the patient's intention so that the robot can assist the patient's voluntary motion. This study focuses on recognizing hand grasp motion intention using high-density electromyography (HD-EMG) in patients with chronic stroke. The study was conducted with three chronic stroke patients and involved recording HD-EMG signals from the muscles involved in hand grasp motions. The adaptive onset detection algorithm was used to accurately identify the start of hand grasp motions accurately, and a convolutional neural network (CNN) was trained to classify the HD-EMG signals into one of four grasping motions. The average true positive and false positive rates of the grasp onset detection on three subjects were 91.6% and 9.8%, respectively, and the trained CNN classified the grasping motion with an average accuracy of 76.3%. The results showed that using HD-EMG can provide accurate hand grasp motion intention recognition in chronic stroke patients, highlighting the potential for effective robot-based rehabilitation.


nsf is essential for organization of myelinated axons in zebrafish.
Myelinated axons are essential for rapid conduction of action potentials in the vertebrate nervous system. Of particular importance are the nodes of Ranvier, sites of voltage-gated sodium channel clustering that allow action potentials to be propagated along myelinated axons by saltatory conduction. Despite their critical role in the function of myelinated axons, little is known about the mechanisms that organize the nodes of Ranvier. Starting with a forward genetic screen in zebrafish, we have identified an essential requirement for nsf (N-ethylmaleimide sensitive factor) in the organization of myelinated axons. Previous work has shown that NSF is essential for membrane fusion in eukaryotes and has a critical role in vesicle fusion at chemical synapses. Zebrafish nsf mutants are paralyzed and have impaired response to light, reflecting disrupted nsf function in synaptic transmission and neural activity. In addition, nsf mutants exhibit defects in Myelin basic protein expression and in localization of sodium channel proteins at nodes of Ranvier. Analysis of chimeric larvae indicates that nsf functions autonomously in neurons, such that sodium channel clusters are evident in wild-type neurons transplanted into the nsf mutant hosts. Through pharmacological analyses, we show that neural activity and function of chemical synapses are not required for sodium channel clustering and myelination in the larval nervous system. Zebrafish nsf mutants provide a novel vertebrate system to investigate Nsf function in vivo. Our results reveal a previously unknown role for nsf, independent of its function in synaptic vesicle fusion, in the formation of the nodes of Ranvier in the vertebrate nervous system.


Coordination chemistry for antibacterial materials: a monolayer of a Cu(2+) 2,2'-bipyridine complex grafted on a glass surface.
A propyltrimethoxysilane-modified 2,2'-bipyridine ligand is synthesized and its acetonitrile solutions are used to prepare monolayers of the molecule on glass surfaces. Absorption and X-ray photoelectron spectroscopy demonstrate that the modified glass surfaces bind Cu(2+) with a 1:1 ratio with respect to the 2,2'-bipyridine moieties under the chosen preparative conditions, producing materials bearing 0.016 μg cm(-2) of copper. Although in trace amounts, the bound Cu(2+) cations exert a significant microbicidal effect against Escherichia coli and Staphylococcus aureus.


Abuse against women in rural Minnesota.
The purpose of this study was to examine the prevalence of physical, emotional, and sexual abuse in women seeking care in rural medical clinics and WIC supplemental food program sites, as well as to examine demographic and health characteristics related to abuse. This was a descriptive, cross-sectional study using a self-administered, anonymous survey. Data were collected in 8 medical clinics and 17 WIC supplemental food program sites in 9 counties of west-central Minnesota during January and February, 1997. The survey instrument asked brief screening questions on physical, emotional, and sexual abuse as well as demographic and health related questions designed to reflect the rural population and characteristics. The survey results showed that in the prior 12 months, 109 (6.6%) of the respondents reported physical abuse, 347 (21.1%) reported emotional/verbal abuse, and 35 (2.1%) reported sexual abuse. Proportional increases in risk of current abuse relative to married women were 2.1 for single, 2.5 for divorced, and 6.5 for separated women, after adjusting for other important variables. Single women with a recent status change had significantly higher risk of current abuse than women with a recent status change at all other marital status levels in adjusted analyses. Women who reported some form of abuse before age 18, and women reporting abuse as an adult prior to the last 12 months, were significantly more likely to report current abuse in all analyses. Prior abuse as an adult was the single best predictor of current abuse in a final logistic regression model.


Serum antibodies to mycobacterial antigens in active Crohn's disease.
Infection with a species of Mycobacterium has been implicated in the pathogenesis of Crohn's disease. Therefore, we attempted to determine whether a specific serum antibody response to mycobacteria occurs in patients with the disease. We tested sera of patients with active Crohn's disease and several control groups in an enzyme-linked immunosorbent assay for reactivity with two mycobacterial antigens: (a) lipoarabinomannan, a highly immunogenic somatic lipopolysaccharide present in the cell walls of all species of the Mycobacterium genus, and (b) a protoplasmic antigenic preparation from M. sp strain linda, the mycobacterium that has been specifically implicated in Crohn's disease. We found no significant elevation in immunoglobulin A, immunoglobulin G, or immunoglobulin M antibody levels to these two antigen preparations in the Crohn's disease patients. Moreover, no subset of patients (sex, age, Crohn's disease activity index, location of disease, duration of disease, operations, or response to treatment) had elevated antibody levels. As virtually all known chronic infectious diseases have an associated serologic response to the etiologic agent, our findings greatly diminish the likelihood that Crohn's disease is caused by an infection with a mycobacterium.


False recognition in younger and older adults: exploring the characteristics of illusory memories.
Roediger and McDermott (1995) demonstrated that when subjects hear a list of associates to a "theme word" that has itself not been presented, they frequently claim to recollect having heard the nonpresented theme word on the study list. In Experiment 1, we found that asking subjects to explain their remember responses, by writing down exactly what they remembered about the item's presentation at study, did not significantly diminish the rate of remember false alarms to nonpresented theme words. We also found that older adults were relatively more susceptible than younger adults to this false-recognition effect. Subjects' explanations suggested that both veridical and illusory memories were predominantly composed of associative information as opposed to sensory and contextual detail. In Experiment 2, we obtained quantitative evidence for this conclusion, using a paradigm in which subjects were asked focused questions about the contents of their recollective experience. Lastly, we found that both younger and older adults recalled more sensory and contextual detail in conjunction with studied items than with nonpresented theme words, although these differences were less pronounced in older adults.


Concordance of clinical findings and clinical judgment in the diagnosis of streptococcal pharyngitis.
It is uncertain how reliably clinicians apply clinical predictors of group A beta hemolytic streptococcal pharyngitis (GABHSP) to form a clinical impression, and how reliably this impression predicts culture results. The objective was to study clinician accuracy in diagnosing GABHSP. This was a prospective cohort study, conducted at an urgent care center of a major university. A convenience sample of 218 patients, aged 9-83 years, presenting with sore throat, was enrolled. Symptoms and signs of pharyngitis were documented on a standardized form; the likelihood of GABHSP was plotted on a visual analog scale; and throat culture was obtained. A comparison was then made between the clinical impression on presentation and the throat culture result. Throat cultures were positive for GABHSP in 41 patients (19%). The probability of GABHSP was related to node size and tenderness, tonsillar exudate and hypertrophy, and pharyngeal erythema (p<0.05); but not throat soreness, degree of fever, or cough. A strong clinical impression of GABHSP (>50% on the visual analog scale) was associated with tonsillar exudate and hypertrophy, tender nodes, and pharyngeal erythema. Together, these four predictors had a sensitivity of 71%, a specificity of 77%, and a positive predictive value of 46%. Clinicians in this study based their impression of GABHSP on the most reliable symptoms and signs. While a strong clinical suspicion of GABHSP predicted a greater probability of positive culture, the clinicians consistently overestimated the probability of GABHSP. Symptoms and signs predict GABHSP unreliably when used alone; they are helpful in modifying estimates of disease probability to facilitate optimal use of laboratory tests and antibiotics.


Advances in refractive surgery: microkeratome and femtosecond laser flap creation in relation to safety, efficacy, predictability, and biomechanical stability.
Methods of flap creation have changed over the years from the evolution of the mechanical microkeratome to the introduction of the IntraLase femtosecond laser keratome, both of which have different mechanisms of action to create corneal resections. Previous studies report the advantages and disadvantages of the mechanical microkeratome and the IntraLase femtosecond laser. The critical components in laser in-situ keratomileusis surgery remain the same, however: safety, efficiency, predictability, and biomechanical stability. Keratoectasia and flap efficiency remain a constant safety concern in laser in-situ keratomileusis surgery. Unexpectedly thick flaps as well as variable thickness continue to be a concern with safety in relation to microkeratome technology. Epithelial preservation, flap complications, and newer issues such as Transient Light Sensitivity Syndrome are safety concerns of flap creation. Improved outcomes with regards to vision, induced astigmatism, induced higher-order aberrations, and enhancement rates are seen to favor predictability of femtosecond technologies over the microkeratome. Recent biomechanical studies show improved healing with femtosecond laser flap creation compared with blade-assisted flap creation. The aim of this review is to summarize the key components for both the microkeratome and the femtosecond laser and to update on the recent advances reported on these topics.


Treatment of osteoporosis in chronic kidney disease and end-stage renal disease.
As glomerular filtration rate (GFR) declines from age-related bone loss or disease that specifically induces a decline in GFR, there are a number of metabolic bone conditions that may accompany the decline in GFR. These metabolic bone conditions span a spectrum from mild-to-severe secondary hyperparathyroidism in early stages of chronic kidney disease (CKD) to the development of additional heterogeneous forms of bone diseases each with its distinctly quantitative bone histomorphometric characteristics. Osteoporosis can also develop in patients with CKD and ESRD for many reasons beyond age-related bone loss and postmenopausal bone loss. The diagnosis of osteoporosis in patients with severe CKD or end-stage renal disease (ESRD) is not as easy to do as it is in patients with postmenopausal osteoporosis (PMO)--neither fragility fractures nor The World Health Organization bone mineral density criteria can be used to diagnose osteoporosis in this population since all forms of renal bone disease may fracture or have low "T scores". The diagnosis of osteoporosis in patients with CKD/ESRD must be done by first the exclusion of the other forms of renal osteodystrophy, by biochemical profiling or by double tetracycline-labeled bone biopsy; and the finding of low trabecular bone volume. In such patients, preliminary data would suggest that oral bisphosphonates seem to be safe and effective down to GFR levels of 15 mL/min. In patients with stage 5 CKD who are fracturing because of osteoporosis or who are on chronic glucocorticoids, reducing the oral bisphosphonate dosage to half of its usual prescribed dosing for PMO seems reasonable from known bisphosphonate pharmacokinetics, though we do need better scientific data to fully understand bisphosphonate usage in this population.


Human cytomegalovirus infection of human embryonic stem cell-derived primitive neural stem cells is restricted at several steps but leads to the persistence of viral DNA.
Congenital human cytomegalovirus (HCMV) infection is a major cause of central nervous system structural anomalies and sensory impairments. It is likely that the stage of fetal development, as well as the state of differentiation of susceptible cells at the time of infection, affects the severity of the disease. We used human embryonic stem (ES) cell-derived primitive prerosette neural stem cells (pNSCs) and neural progenitor cells (NPCs) maintained in chemically defined conditions to study HCMV replication in cells at the early stages of neural development. In contrast to what was observed previously using fetus-derived NPCs, infection of ES cell-derived pNSCs with HCMV was nonprogressive. At a low multiplicity of infection, we observed only a small percentage of cells expressing immediate-early genes (IE) and early genes. IE expression was found to be restricted to cells negative for the anterior marker FORSE-1, and treatment of pNSCs with retinoic acid restored IE expression. Differentiation of pNSCs into NPCs restored IE expression but not the transactivation of early genes. Virions produced in NPCs and pNSCs were exclusively cell associated and were mostly non-neural tropic. Finally, we found that viral genomes could persist in pNSC cultures for up to a month after infection despite the absence of detectable IE expression by immunofluorescence, and infectious virus could be produced upon differentiation of pNSCs to neurons. In conclusion, our results highlight the complex array of hurdles that HCMV must overcome in order to infect primitive neural stem cells and suggest that these cells might act as a reservoir for the virus. Human cytomegalovirus (HCMV) is a betaherpesvirus that is highly prevalent in the population. HCMV infection is usually asymptomatic but can lead to severe consequences in immunosuppressed individuals. HCMV is also the most important infectious cause of congenital developmental birth defects. Manifestations of fetal HCMV disease range from deafness and learning disabilities to more severe symptoms such as microcephaly. In this study, we have used embryonic stem cells to generate primitive neural stem cells and have used these to model HCMV infection of the fetal central nervous system (CNS) in vitro. Our results reveal that these cells, which are similar to those present in the developing neural tube, do not support viral replication but instead likely constitute a viral reservoir. Future work will define the effect of viral persistence on cellular functions as well as the exogenous signals leading to the reactivation of viral replication in the CNS.


Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.
Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by immunohistochemistry (IHC). Samples from 17 patients (37.0%) in the Nivolumab Cohort were positive for B7-H4 expression. At univariate analyses, only B7-H4 expression was associated with significantly decreased progression-free survival (PFS; 1.7 vs. 2.0 months; p = 0.026) and with a disadvantage in terms of overall survival (OS) close to statistical significance (4.4 vs. 9.8 months; p = 0.064). At multivariate analyses, B7-H4 expression was significantly associated with decreased PFS (hazard ratio (HR) = 2.28; p = 0.021) and OS (HR = 2.38; p = 0.022). Subsequently, B7-H4 expression was compared with clinical outcomes of 27 NSCLC patients receiving platinum-based chemotherapy (Chemotherapy Cohort), but no significant association was observed. Our results suggest a negative predictive role of B7-H4 in a population of NSCLC treated with immune checkpoint inhibitors, which deserves further research.


[The immune system indices of patients with acute recurrent bronchitis].
A study of the immune system in 30 patients with acute recurrent bronchitis revealed disorders of the cellular and humoral immunity manifested in a reduction of the number of T-lymphocytes and theophylline-resistant T-cells. There was also a reduction of A and G immunoglobulins in the blood serum. These disorders remained also after normalization of the clinical picture of the disease evidencing the necessity to include immunostimulating agents in the complex treatment of patients with acute recurrent bronchitis.


How do target predictability and precueing affect the production of express saccades in monkeys?
The extent to which target predictability and precueing affect express saccade generation was determined in Rhesus monkeys. Target predictability, as manipulated by the probability with which targets appeared at various locations, had a strong influence on express saccade generation. Pre-cueing the location of the appearance of an impending single target with an identical stimulus was effective in increasing express saccade generation when there was a gap of 50-150 ms between fixation spot termination and target onset. However, precueing was not effective when the gap time was set to 0 ms in the single target task, when several simultaneous targets appeared requiring a visual discrimination to be made using an oddity task, or when the precue was not identical to the target. These findings indicate that express saccades are facilitated by a restricted set of conditions that increase the predictability of target location and identity.


Histopathological observations in COVID-19: a systematic review.
Coronavirus disease-2019 (COVID-19) has caused a great global threat to public health. The World Health Organization (WHO) has declared COVID-19 disease as a pandemic, affecting the human respiratory and other body systems, which urgently demands for better understanding of COVID-19 histopathogenesis. Data on pathological changes in different organs are still scarce, thus we aim to review and summarise the latest histopathological changes in different organs observed after autopsy of COVID-19 cases. Over the period of 3 months, authors performed vast review of the articles. The search engines included were PubMed, Medline (EBSCO & Ovid), Google Scholar, Science Direct, Scopus and Bio-Medical. Search terms used were 'Histopathology in COVID-19', 'COVID-19', 'Pathological changes in different organs in COVID-19' or 'SARS-CoV-2'. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines were used for review writing. We identified various articles related to the histopathology of various organs in COVID-19 positive patients. Overall, 45 articles were identified as full articles to be included in our study. Histopathological findings observed are summarised according to the systems involved. Although COVID-19 mainly affects respiratory and immune systems, but other systems like cardiovascular, urinary, gastrointestinal tract, reproductive system, nervous system and integumentary system are not spared, especially in elderly cases and those with comorbidity. This review would help clinicians and researchers to understand the tissue pathology, which can help in better planning of the management and avoiding future risks.


Intestinal structural changes in African green monkeys after long term psyllium or cellulose feeding.
Intestinal structure of male adult African Green monkeys (Cercopithecus aethiops ssp vervets) was studied after 3 1/2 yr of consuming diets containing 10% psyllium husk or cellulose. Scanning electron microscopy (SEM) identified mild damage (cellular swelling and disarray, and microvillar denudation and disarray) at villous tips throughout the small intestine in the psyllium-fed monkeys. The cellulose group had similar duodenal damage. Differences were not found in colons by SEM. By light microscopy, jejunum had shorter villi with psyllium feeding, based upon villous height (P less than 0.05), and length around a sectioned villus (P less than 0.1), but not based upon the number of enterocytes per villus. Jejunal and ileal circular and longitudinal muscle layer thicknesses were increased in psyllium-fed monkeys. Colonic mucosal height was significantly (P less than 0.05) reduced and muscle layer thickness was mildly reduced in the psyllium-fed monkeys. Group differences were not found in intestinal weight or length or in the weight of small intestinal mucosal scrapings. Psyllium husk may cause epithelial cell loss and muscle layer hypertrophy in the jejunum and ileum and thinning of the colonic wall after prolonged feeding.


Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model.
Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0-7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.


Trajectory of social inequalities in the treatment of dental caries among preschool children in Japan.
The longitudinal trend of dental health inequalities among preschool children has not been described. In this study, we aimed to measure the trajectory of both relative and absolute inequalities in caries treatment among preschool children in Japan. We used data from the Longitudinal Survey of Babies in the 21st Century (LSB21), which is an ongoing national representative longitudinal study. The target population was families residing in Japan with newborn baby/babies born between 10 January and 17 January or 10 July and 17 July 2001. Data regarding caries treatment history and socioeconomic status (SES) were collected using a self-reported questionnaire. SES was assessed on the basis of the parents' educational attainment. In total, 35 260 children were followed from 2.5 to 5.5 years through annual surveys. To evaluate absolute and relative inequalities, we calculated the slope index of inequality (SII) and relative index of inequality (RII), respectively. The rate of caries treatment at the age of 2.5 years was <10% for all SES groups; this increased to more than 30% at 5.5 years of age. Children with lower SES received more frequent caries treatment, and both absolute and relative social inequalities were statistically significant. SII showed a significant increase throughout the follow-up period, with values of 4.13% (95% confidence interval [CI], 3.16; 5.09) and 15.50% (95% CI, 13.68; 17.32) at 2.5 and 5.5 years of age, respectively. In contrast, RII decreased with an increase in the treatment rate for all groups, with values of 1.83 (95% CI, 1.59; 2.11) and 1.53 (95% CI, 1.46; 1.61) at 2.5 and 5.5 years of age, respectively. Our results suggest that the rate of caries treatment is higher for preschool children with lower SES in Japan, with significant widening of absolute inequalities along with the growth of the children.


Burden of illness and treatment patterns among patients with peripheral T-cell lymphoma in the US healthcare setting.
Limited real-world information exists on the characteristics or treatment patterns of patients with peripheral T-cell lymphoma (PTCL). We reported demographics, treatments and direct healthcare resource utilization (HRU) in a large cohort of US patients newly diagnosed with PTCL. Patients aged ≥18 years with a PTCL diagnosis between January 2011 and December 2016 were identified from the Inovalon MORE2 Registry. Continuous medical/pharmacy enrollment 6-months prior to and ≥1-month after the first PTCL diagnosis was required. The main focus of this study was on newly diagnosed patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus other chemotherapy. A total 2971 patients with PTCL and chemotherapy information were included in the study; 1706 (57%) received CHOP and 1265 (43%) other chemotherapy. A majority of patients (51.7%) were female; mean (standard deviation) age at index was 61.0 (±16.0), Charlson score was 4.1 (±2.9), and follow-up time was 24.6 (±16.7) months. During the variable follow-up period, HRU was similar for the CHOP and other chemotherapy cohorts; 58.1% and 59.3% had ≥1 all-cause hospitalizations, respectively. The proportion of patients with ≥1 PTCL-related hospitalizations was higher in the CHOP than in the other chemotherapy cohort (40.3% vs. 9.7%, respectively) and mean length of stay was longer (4.6 vs. 3.7 days per patient per month, respectively). This retrospective analysis of patients with PTCL revealed high levels of comorbidity and HRU; novel interventions that improve patient outcomes and reduce the HRU burden of PTCL are needed.


Inflatable bouncer-related fractures in children.
Inflatable bouncers or moonbouncers are very popular in private and public settings and are usually perceived as very safe attractions, but are associated with frequent fractures in children. To date, there are no publications in the medical literature about these types of injuries. The purpose of this study was to show skeletal injuries related to inflatable bouncer use, describe their characteristics, and determine possible risk factors and preventive measures. Demographic data and injury characteristics were analyzed for all patients who were treated for inflatable bouncer-associated injuries in the pediatric fracture clinic of a level I trauma center from October 2002 to March 2007. Forty-nine patients were treated for inflatable bouncer-related fractures. Children ranged in age from 1.5 to 15 years old (mean age, 7.8 years) with a male-female ratio of approximately 3:1. The most commonly injured region was the upper extremity (65.5%, n = 32). The most commonly injured area was the elbow (31%, n = 15), and the most common single diagnosis was supracondylar humerus fracture (22%, n = 11). Diaphyseal long bone fractures were found in 18% (n = 9) of the patients and nondiaphyseal in 71% (n = 35). One patient (2%) had an open fracture. Mechanisms of injury included collision of 1 person with another (67%), falling out of a bouncer onto a hard object outside the device (19%), and twisting motion to the leg (14%). There was no adult supervision in many of the incidents (43%), and the presence of different-aged children inside the jumper took place in 52% cases. Inflatable bouncers can cause serious orthopaedic injuries. Children playing in the bouncer should be placed in small groups according to their size and should be closely supervised at all times. Case series. Level IV evidence.


Can an Alternative Outflow Strategy be Utilized for High-Risk Bridged Patients with Previous Cardiac Surgery?
The HeartWare ventricular assist device (HVAD) is an implantable continuous-flow centrifugal pump that has allowed the development of sternal-sparing techniques, with the use of alternative outflow strategies. We compared early outcomes for patients bridged with the conventional versus alternative outflow graft strategy. From January 2013 to October 2014, 89 patients with HVAD implantation were identified. Survival was analyzed with Kaplan-Meier methods, and a log-rank test was used to compare outcomes between groups. Thirty patients (34%) had ≥1 previous sternotomy before HVAD implantation. Eight patients (27%) were approached using an alternative outflow graft technique with outflow graft connection to the descending aorta (n = 4, 50%) or left subclavian artery (n = 4, 50%), whereas 22 (73%) were implanted via a conventional sternotomy approach with the outflow graft to the ascending aorta. Preoperative characteristics (age, Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and Lietz-Miller score) were comparable between groups (all p > 0.05). Median follow-up was 4.7 (2.8-9.3) months of support. Outcomes were comparable between conventional and alternative outflow groups; survival at 6 months was 74% for the conventional group and 83% in the alternative outflow group. An alternative outflow graft strategy can be utilized to support bridged patients with a history of prior sternotomy.


Characterization of congenital anomalies in individuals with choanal atresia.
To review a tertiary care pediatric hospital's experience with choanal atresia and stenosis (CA/S) related to associated congenital anomalies (birth defects, including minor abnormalities) and genetic disorders. Retrospective case series. Tertiary care pediatric hospital. Individuals with CA/S. Identification of congenital anomalies, neurologic abnormalities, and developmental disabilities in individuals with CA/S. One hundred twenty-nine individuals with CA/S were evaluated between July 1, 1997, and July 1, 2007. Choanal atresia and stenosis was an isolated finding in 34 patients (26.4%) and was associated with other anomalies in 95 patients (73.6%). Specific conditions were diagnosed in 66 patients (51.2%); CHARGE (coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies) syndrome was the most common diagnosis (33 patients [25.6%]). Numerous conditions were seen, including chromosomal abnormalities, single-gene defects, deformations, and those caused by teratogens. Choanal atresia and stenosis was unilateral in 62 patients (48.1%) and was bilateral in 60 patients (46.5%). Unilateral cases were more likely to be isolated (30 patients [53.2%]). Bilateral cases were more likely to be associated with specific disorders or multiple congenital anomalies (60 patients [98.4%]). There was no difference in laterality among unilateral cases. Choanal atresia and stenosis is associated with a wide range of disorders. Congenital anomalies, neurologic abnormalities, and developmental disabilities are commonly identified in affected individuals. Bilateral CA/S is more commonly seen in patients in whom specific diagnoses or other congenital anomalies are identified. Unilateral CA/S occurs more frequently in isolated cases. A comprehensive evaluation is recommended in individuals with CA/S to evaluate for other congenital anomalies, neurologic abnormalities, developmental delays, and evidence of a specific underlying disorder.


Adenylate cyclase toxin from Bordetella pertussis enhances cisplatin-induced apoptosis to lung cancer cells in vitro.
The present study examined the possibility to enhance lung cancer cell cytotoxicity and apoptosis of the anticancer drug cisplatin by exposure with adenylate cyclase (AC) toxin from Bordetella pertussis. A malignant mesothelioma cell line (P31) and a small-cell lung cancer cell line (U1690) were exposed to increasing concentrations of cisplatin and AC toxin, alone or in combination. Cytotoxicity was determined by a fluorescein-based assay and apoptosis by flow cytometry quantification of annexin V binding. Caspase-3, -8, and -9 activities were measured by enzyme activity assays. The cytotoxicity of AC toxin was time and dose dependent with an LD50 value at 72 h of 3 and 7 mg/L for P31 cells and U1690 cells, respectively. Cisplatin showed a similar time- and dose-dependent cytotoxicity, which was increased in the presence of a low toxic concentration (1 mg/L) of AC toxin. Furthermore, cisplatin caused a dose-dependent increase of annexin V binding cells of both cell lines after 24-h incubation, which was also enhanced in combination with AC toxin. AC toxin (1 mg/L) increased cisplatin-induced caspase-3, -8, and -9 activities in U1690 cells. Only minor increases of caspase-8 and -9 were noted for P31 cells. The present results, together with the knowledge that bacterial toxins decrease side effects of traditional cancer treatment, suggest a possibility to use them to enhance the therapeutic effect of cancer chemotherapy with reduced clinical adverse effects.


Surface plasmon optical study of the interfacial phase transition of elastinlike polypeptide grafted on gold.
The conformational changes in elastinlike polypeptides (ELPs) grafted to a solid/solution interface via different architectures were studied using surface plasmon resonance spectroscopy and surface plasmon field-enhanced fluorescence spectroscopy (SPFS). SPFS provides a simple and convenient optical method to study the influence of the grafting method and the graft density on the conformational changes in ELPs at the solid-solution interface as a function of environmental variables. A typical response of the ELP, consistent with its stimuli responsiveness, was a gradual collapse upon increasing the ionic strength; this effect was inversely correlated with the surface graft density of the ELP.


The effect of substituting alternative grains in the diet on the nutritional profile of the gluten-free diet.
The only treatment for coeliac disease is lifelong adherence to a gluten-free diet. Several studies have reported nutritional deficiencies in individuals on a gluten-free diet. The present study aimed to determine whether the nutritional profile of gluten-free diet could be improved through the use of alternative grains. A retrospective review of diet history records by a celiac specialist dietitian were used to establish a 'standard' gluten-free dietary pattern. An 'alternative' gluten-free dietary pattern was developed that substituted naturally gluten-free grains or gluten-free products made from 'alternative' flours (oats, high fibre gluten-free bread and quinoa) in the standard pattern. A paired t-test was performed to identify statistical significance between the 'alternative' and standard gluten-free dietary pattern. Analysis of standard pattern indicated that 38% of meals and snacks contained no grain or starch choice. Of those meals that contained a grain or starch component, rice was the grain chosen 44% of the time. The inclusion of alternative grains or grain products provided a higher nutrient profile compared to the standard gluten-free dietary pattern (P = 0.002). Several nutrients; protein (20.6 g versus 11 g), iron (18.4 mg versus 1.4 mg), calcium (182 mg versus 0 mg) and fibre (12.7 g versus 5 g) were significantly increased by changing the grain or starch component in the dietary pattern. The B vitamin content (riboflavin, niacin and folate) was improved, although this was not statistically significant (P = 0.125). The inclusion of alternative grain-based products increased the nutrient profile of the gluten-free dietary pattern significantly.


Contribution of ultrasonography to endometrial cancer screening in patients with hereditary nonpolyposis colorectal cancer/Lynch syndrome.
Screening for endometrial cancer is recommended in women at risk for hereditary nonpolyposis colorectal cancer/Lynch syndrome. No screening tool has been validated. The objective of this study was to assess the performance of ultrasonography used to screen for atypical hyperplasia and cancer in women at risk for hereditary nonpolyposis colorectal cancer/Lynch syndrome. Endometrial biopsy was the reference standard. Of 85 women with mismatch repair gene mutations or Amsterdam II criteria who were studied prospectively at our institution, 58 had 96 paired ultrasound-biopsy evaluations and were included in the study. Transvaginal or transabdominal ultrasonographic finding was considered normal if no polyps or intrauterine abnormalities were seen and if the maximum endometrial thickness was less than 4 mm in postmenopausal women not receiving hormonal replacement therapy or less than 6 mm in other women. Endometrial biopsy results were categorized as not interpretable, normal, or showing atypical hyperplasia or cancer. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio of ultrasonography were computed. The 58 patients had a mean age of 42.5 years and a median follow-up duration of 51.4 months (range, 17-106 months; 246 patient exposure years). Cancer was diagnosed in 2 patients. Ultrasonography had 100% sensitivity and 100% negative predictive value, 2.2 positive likelihood ratio, and 0 negative likelihood ratio. No interval cancers occurred. Ultrasonography had high sensitivity and an excellent negative likelihood ratio in this study. Further studies are needed, and ultrasonography should be compared with clinical follow-up, diagnostic hysteroscopy, or endometrial biopsy alone.


Is transesophageal echocardiogram mandatory in patients undergoing ablation of atrial fibrillation with uninterrupted novel oral anticoagulants? Results from a prospective multicenter registry.
Transesophageal echocardiography (TEE) is recommended in patients undergoing atrial fibrillation (AF) ablation, but use of this strategy is variable. To evaluate whether TEE is necessary before AF ablation in patients treated with novel oral anticoagulants (NOACs). We performed a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation on uninterrupted NOACs (apixaban and rivaroxaban). All patients were on NOACs for at least 4 weeks before ablation. Heparin bolus was administered to all patients before transseptal catheterization to maintain a target activated clotting time above 300 seconds. A subset of 86 patients underwent brain diffuse magnetic resonance imaging (dMRI) to detect silent cerebral ischemia (SCI). A total of 970 patients (514 [53%] apixaban patients and 456 [47%] rivaroxaban patients) were enrolled for this study. The mean age was 69.5 ± 9.0 years, with 824 patients (85%) having nonparoxysmal AF, and 636 patients (65.6%) were male. The average CHA2DS2-VASc score was 3.01 ± 1.3 and CHADS2 score was ≥2 in 609 patients (62.8%). Intracardiac echocardiogram ruled out left atrial appendage thrombus in all patients whose left atrial appendage was visualized (692, 71%), and detected "smoke" in 407 patients (42%). SCI at postprocedure dMRI was detected in 2.3% (2/86). One thromboembolic event (transient ischemic attack) (0.10%) with positive dMRI occurred in a patient on uninterrupted rivaroxaban with longstanding persistent AF. Our study illustrates that performing AF ablation while on uninterrupted apixaban and rivaroxaban without TEE is feasible and safe. This finding has important clinical and economic relevance.


When should orthostatic blood pressure changes be evaluated in elderly: 1st, 3rd or 5th minute?
Detection of orthostatic hypotension (OH) is very important in geriatric practice, since OH is associated with mortality, ischemic stroke, falls, cognitive failure and depression. It was aimed to determine the most appropriate time for measuring blood pressure in transition from supine to upright position in order to diagnose OH in elderly. Comprehensive geriatric assessment (CGA) including Head up Tilt Table (HUT) test was performed in 407 geriatric patients. Orthostatic changes were assessed separately for the 1st, 3rd and 5th minutes (HUT1, HUT3 and HUT5, respectively) taking the data in supine position as the basis. The mean age, recurrent falls, presence of dementia and Parkinson's disease, number of drugs, alpha-blocker and anti-dementia drug use, and fasting blood glucose levels were significantly higher in the patients with versus without OH; whereas, albumin and 25-hydroxy vitamin D levels were significantly lower (p<0.05). However, different from HUT3 and HUT5, Charlson Comorbidity Index and the prevalence of diabetes mellitus were higher, the use of antidiabetics, antipsychotics, benzodiazepine, opioid and levodopa were more common (p<0.05). Statistical significance of the number of drugs and fasting blood glucose level was prominent in HUT1 as compared to HUT3 (p<0.01, p<0.05). Comparison of the patients that had OH only in HUT1, HUT3or HUT5 revealed no difference in terms of CGA parameters. These results suggests that orthostatic blood pressure changes determined at the 1st minute might be more important for geriatric practice. Moreover, 1st minute measurement might be more convenient in the elderly as it requires shorter time in practice.


[Specificity of suprathreshold test methods in automated perimetry].
The specificity of suprathreshold automated perimetry of the central visual field was investigated comparatively with the Fieldmaster Model 225 computer perimeter, utilizing five different test strategies. The clinical study comprised 30 eyes of 30 healthy subjects. The test strategies were: (1) threshold-related supraluminosity of 5 dB with constant supraluminosity between 0 degrees and 30 degrees eccentricity; (2) threshold-related supraluminosity of 5 dB, increasing the luminosity according to the sensitivity gradient of the retina at 15 degrees eccentricity; (3) threshold-related supraluminosity of 5 dB and stepwise increase of luminosity every 5 degrees of eccentricity; (4) threshold-related supraluminosity of 3 dB and stepwise increase of luminosity every 5 degrees of eccentricity; (5) central stimuli luminosity of 200 asb and stepwise increase of luminosity every 5 degrees of eccentricity. The highest specificity of the visual field examination was obtained with test strategy 3, followed by 5, 4 and 2. The lowest specificity was obtained with test strategy 1.


Disulfide core cross-linked PEGylated polypeptide nanogel prepared by a one-step ring opening copolymerization of N-carboxyanhydrides for drug delivery.
A novel disulfide core cross-linked PEGylated polypeptide nanogel has been synthesized by a one-step ring opening copolymerization of γ-benzyl L-glutamate N-carboxyanhydride and L-cystine N-carboxyanhydride using an amino group-terminated poly(ethylene glycol) methyl ether as initiator. Characterization of products confirms the formation of a core cross-linked PEGylated nanogel with disulfide linkages with a size of about 250 nm, and these studies also confirm that this nanogel can easily be broken by glutathione. Cell viability experiments show the good biocompatibility of the as-prepared polymer. Studies relating to loading and controlled release of indomethacin under reduction-sensitive conditions reveal that the nanogel is a good candidate for drug delivery systems.


Multiple marker screening for Down syndrome--whom should we screen?
The multiple marker test highlights the complexities of an expanding number of genetic tests that family physicians can offer to their patients. Many concerns surround the use of the multiple marker test, including a poor understanding of the test by physicians and patients, limited sensitivity, increased anxiety among women, and the risks of amniocentesis in patients who have false-positive results. An online search of the medical literature was used to select English-language articles addressing the burden of suffering from Down syndrome, and efficacy, cost-effectiveness, and psychological effects of screening. Down syndrome occurs in 0.99 per 1000 births, and the risk increases with age. Between 10% and 20% of infants die in the first year, predominantly from heart defects. Special education, the move away from institutionalization, and more employment opportunities have improved the outlook for these persons. The multiple marker test has an overall detection rate for Down syndrome of 56% with a 7% false-positive rate. A laboratory cutoff ratio of 1:190 is the most efficient for optimizing the detection rate and minimizing the false-positive rate. Limited screening to women older than 30 years appears most cost-effective, reducing losses of normal fetuses secondary to amniocentesis and the number of pregnant patients requiring pretest counseling. The family physician needs to inform the patient of the nature, purpose, and risks of screening including the psychological effects. Pretest counseling should be nondirective.


Cystatin C level as a predictor of death and cardiovascular events after liver transplantation.
The diagnosis of renal failure is important in cirrhosis. Cystatin C (Cys) has been suggested not only to be a sensitive marker of renal function, but also a stronger predictor of the risk of death and cardiovascular events in heart failure. Our aims were to investigate plasma Cys concentrations for the detection of moderately impaired renal function and its association with mortality and cardiovascular events among cirrhotic patients after liver transplantation (OLT). Clinical and biochemical data, including Cys levels, were analyzed in 99 cirrhotic candidates for OLT. We recorded cardiovascular events. Receiver-operator characteristics curves showed a similar efficiency to detect a creatinine clearance <60 mL/min per 1.73m(2) (Cys = 0.753; creatinine [Cr] = 0.799; glomerular filtration rate [GFR, Cockcroft-Gault formula] = 0.842; urea = 0.823; P = .001). However, at cutoff concentrations of 1.3 mg/dL, Cr showed great specificity (96%) but poor sensitivity (13%), while the sensitivity of Cys was superior (83%) with moderate specificity (55%) at a cutoff of 1400 ng/mL. Over a median follow-up of 2.7 years, 14 patients developed a cardiovascular event, including, 11 who displayed Cys levels >1400 ng/mL before OLT, showing a significant difference (P < .05) compared to patients who showed no cardiovascular event. Kaplan-Meier analysis Cys discriminated significantly better than the Model for End-Stage Liver Disease score between survivors and nonsurvivors (P < .05). Cys determinations could be a valuable tool for early diagnosis of renal dysfunction among cirrhotic patients. Furthermore, it may predict the risk of death and cardiovascular events after OLT.


Anti-CD44-Conjugated Olive Oil Liquid Nanocapsules for Targeting Pancreatic Cancer Stem Cells.
The latest trends in cancer research and nanomedicine focus on using nanocarriers to target cancer stem cells (CSCs). Specifically, lipid liquid nanocapsules are usually developed as nanocarriers for lipophilic drug delivery. Here, we developed olive oil liquid NCs (O2LNCs) functionalized by covalent coupling of an anti-CD44-fluorescein isothiocyanate antibody (αCD44). First, O2LNCs are formed by a core of olive oil surrounded by a shell containing phospholipids, a nonionic surfactant, and deoxycholic acid molecules. Then, O2LNCs were coated with an αCD44 antibody (αCD44-O2LNC). The optimization of an αCD44 coating procedure, a complete physicochemical characterization, as well as clear evidence of their efficacy in vitro and in vivo were demonstrated. Our results indicate the high targeted uptake of these αCD44-O2LNCs, and the increased antitumor efficacy (up to four times) of paclitaxel-loaded-αCD44-O2LNC compared to free paclitaxel in pancreatic CSCs (PCSCs). Also, αCD44-O2LNCs were able to selectively target PCSCs in an orthotopic xenotransplant in vivo model.


Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays.
Intact parathyroid hormone (I-PTH) assays react with non-(1-84)PTH, large carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. They account for up to 50% of I-PTH in renal failure and may be implicated in PTH resistance. We wanted to know if they were secreted by the parathyroid glands and generated by peripheral metabolism of PTH(1-84). Anesthetized normal and nephrectomized (NPX) rats were injected i.v. with 1.5 microg human (h) PTH(1-84). Blood was obtained from 8 rats at 2, 4, 6, 8, 12, 24, 48 and 96 min. I-PTH (Allegro I-PTH) was measured in all samples. Pools of serum were fractionated by HPLC at each time point and the fractions assayed to quantitate hPTH(1-84) and non-(1-84)PTH. Secretion studies were performed with dispersed cells from 5 parathyroid adenomas. The serum of 10 patients with primary hyperparathyroidism and cell supernatants were fractionated by HPLC and were analyzed as described. hPTH(1-84) disappeared from serum biexponentially. The half-life of the first exponential was similar in normal (2.08 min) and NPX (1.94 min) rats, while that of the second was longer in NPX rats (32.4 vs 20.9 min). The residual quantity of hPTH(1-84) under the curve was greater in NPX (6964+/-2392 pmol) than in normal rats (3229+/-561 pmol; P<0.001). Non-(1-84)PTH concentration was maximal at 8 min in both groups and was higher in NPX (92.8+/-13.8 pmol/l) than in normal rats (38.8+/-7.2 pmol/l; P<0.01). The area under the curve of non-(1-84)PTH was also greater in NPX (1904+/-405 pmol) than in normal rats (664+/-168 pmol; P<0.001). All parathyroid adenomas secreted non-(1-84)PTH. It represented 21.1+/-3.9% of secreted and 32.5+/-1.3% of circulating I-PTH in primary hyperparathyroidism. Non-(1-84)PTH, like other C-PTH fragments, originates from both the peripheral metabolism of hPTH(1-84) and from parathyroid gland secretion. Renal failure influences its concentration by increasing the amount of substrate available and by reducing non-(1-84)PTH clearance. Its higher proportion in serum relative to cell supernatants in primary hyperparathyroidism reflects the added role of peripheral metabolism and the longer half-life of fragments.


Age-related changes in the prevalence of precipitating antibodies to BK virus in infants and children.
Nearly 1000 sera from children were tested by immunoelectro-osmophoresis against BK virus, and age-specific prevalence rates were estimated from birth until the age of 12 years. Declining rates during the first 12 months showed the waning of passive immunity, which at birth reflects the mother's immune status. The changes of prevalence suggested that the peak incidence of primary infections occurred at about 2 years, with an estimated peak annual rate of 24.6%.


Novel adjuvant strategies for experimental malaria and AIDS vaccines.
Adjuvant research has improved the ability of biotechnology to generate novel vaccines. Numerous strategies for enhancing the immunogenicity of synthetic peptides and proteins have been identified. This overview focuses on adjuvant development and vaccine delivery systems that provide new tools for amplifying the effectiveness of ongoing malaria and AIDS vaccine development programs. In addition, some of the complex challenges and issues that have become associated with the delivery of modern vaccines in man are outlined. As adjuvant research continues to open new opportunities in vaccine development, there is renewed expectation that further generations of safe and potent vaccines will be possible against a broad spectrum of infectious agents and cancer.


Electrophysiological evaluation of human induced pluripotent stem cell-derived cardiomyocytes obtained by different methods.
The human induced pluripotent stem cells (hiPSCs) derived cardiomyocytes (CMs) (hiPSC-CMs) retain the same genetic information as the donor, and they have been shown to faithfully recapitulate the disease phenotypes of various genetic cardiac diseases. The hiPSC-CMs can be utilized in multiple types of studies and in most cases, the functionality of hiPSC-CMs is of interest. For the functional analyses, the hiPSC-CMs need to be manipulated after differentiation, e.g. enriched or dissociated into single-cell stage. For the functional assessments to be reliable and reproducible, the cell culture environment should support the cells in an optimal manner. The aim of the present study was to evaluate the effect of various differentiation methods, as well as coating materials used for the dissociated cells on the functionality of the differentiated hiPSC-CMs. The different protocols not only had different differentiation efficiencies, but they also yielded functionally different hiPSC-CMs. Additionally, the coating material had a major effect on the functionality of the hiPSC-CMs. The results of the present study emphasize that the cardiac differentiation method and the coating material have a major effect on hiPS-CMs' characteristics. Thus, when different hiPSC lines and results obtained in different labs are compared, extra care should be taken to check the conditions when results are compared.


Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.
Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses. We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050. Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis. The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed. Bill & Melinda Gates Foundation.


Tumor-targeted Salmonella as a novel anticancer vector.
There has been little investigation of bacteria as gene delivery vectors. Here, we demonstrate that genetically engineered Salmonella have many of the desirable properties of a delivery vector, including targeting of multiple tumors from a distant inoculation site, selective replication within tumors, tumor retardation, and the ability to express effector genes, such as the herpes simplex virus thymidine kinase (HSV TK). When wild-type Salmonella were introduced into melanoma-bearing mice, the bacteria were found within the tumor at levels exceeding 10(9) per g, although as pathogens, they caused the death of the mice. However, when attenuated, hyperinvasive auxotrophic mutants were used, the tumor-targeting and amplification phenomena were retained, whereas their pathogenicity was limited. With such attenuated strains, the tumor:liver ratios ranged between 250:1 and 9000:1. When these auxotrophs were inoculated i.p. into C57B6 mice bearing B16F10 melanomas, they suppressed tumor growth and prolonged average survival to as much as twice that of untreated mice. A plasmid containing the HSV TK gene with a beta-lactamase secretion signal was constructed that, when expressed, resulted in translocation to the periplasm and phosphorylation of the prodrug ganciclovir. Melanoma-bearing animals inoculated with HSV TK-expressing Salmonella showed ganciclovir-mediated, dose-dependent suppression of tumor growth and prolonged survival in addition to that seen with bacteria alone. The results demonstrate that attenuated Salmonella would be useful both for inherent antitumor activity and delivery of therapeutic proteins to cancer cells in vivo.


[Ectopic mammary gland on the back].
A supernumerary, fully developed mammary gland between both shoulder blades above the vertebral column was discovered in a 32-year-old woman when it caused symptoms. It was removed by operation. Histological examination revealed fibrous mastopathy. The only abnormal radiological feature was a spina bifida of T6 at the site of the ectopic breast.


The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury.
The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) permeability alterations and brain edema formation in a rodent traumatic brain injury (TBI) model. The brains of adult male Sprague-Dawley rats (400-425 g) were injured using the Marmarou closed-head force impact model. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (2ME2, an inhibitor of HIF-1α), was administered intravenously 30 minutes after injury. The rats were killed 24 hours after injury and their brains were examined for protein expression, BBB permeability, and brain edema. Expression of HIF-1α, AQP-4, and MMP-9 as well as expression of the vascular basal lamina protein (laminin) and tight junction proteins (zona occludens-1 and occludin) was determined by Western blotting. Blood-brain barrier disruption was assessed by FITC-dextran extravasation, and brain edema was measured by the brain water content. Significant (p < 0.05) edema and BBB extravasations were observed following TBI induction. Compared with sham-operated controls, the injured animals were found to have significantly (p < 0.05) enhanced expression of HIF-1α, AQP-4, and MMP-9, in addition to reduced amounts (p < 0.05) of laminin and tight junction proteins. Edema was significantly (p < 0.01) decreased after inhibition of AQP-4, MMP-9, or HIF-1α. While BBB permeability was significantly (p < 0.01) ameliorated after inhibition of either HIF-1α or MMP-9, it was not affected following inhibition of AQP-4. Inhibition of MMP reversed the loss of laminin (p < 0.01). Finally, while inhibition of HIF-1α significantly (p < 0.05) suppressed the expression of AQP-4 and MMP-9, such inhibition significantly (p < 0.05) increased the expression of laminin and tight junction proteins. The data support the notion that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular pathway cascade involving AQP-4 and MMP-9. Pharmacological blockade of this pathway in patients with TBI may provide a novel therapeutic strategy.


A coupled discrete/continuum model for describing cancer-therapeutic transport in the lung.
We propose a computational simulation framework for describing cancer-therapeutic transport in the lung. A discrete vascular graph model (VGM) is coupled to a double-continuum model (DCM) to determine the amount of administered therapeutic agent that will reach the cancer cells. An alveolar cell carcinoma is considered. The processes in the bigger blood vessels (arteries, arterioles, venules and veins) are described by the VGM. The processes in the alveolar capillaries and the surrounding tissue are represented by a continuum approach for porous media. The system of equations of the coupled discrete/continuum model contains terms that account for degradation processes of the therapeutic agent, the reduction of the number of drug molecules by the lymphatic system and the interaction of the drug with the tissue cells. The functionality of the coupled discrete/continuum model is demonstrated in example simulations using simplified pulmonary vascular networks, which are designed to show-off the capabilities of the model rather than being physiologically accurate.