bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression
Authors: Kondo Masaaki , Numata Kazushi , Hara Koji , Nozaki Akito , Fukuda Hiroyuki , Chuma Makoto , Maeda Shin , Tanaka Katsuaki
Published: June 2017

Background. Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. Methods. Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. Results. The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r=0.982, P<0.01, and R2=0.965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gamma-carboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. Conclusions. SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS.
The 2D Structure of the T. brucei Preedited RPS12 mRNA Is Not Affected by Macromolecular Crowding
Authors: Leeder W.-Matthias , Voskuhl Stephan , Göringer H. Ulrich
Published: June 2017

Mitochondrial transcript maturation in African trypanosomes requires RNA editing to convert sequence-deficient pre-mRNAs into translatable mRNAs. The different pre-mRNAs have been shown to adopt highly stable 2D folds; however, it is not known whether these structures resemble the in vivo folds given the extreme “crowding” conditions within the mitochondrion. Here, we analyze the effects of macromolecular crowding on the structure of the mitochondrial RPS12 pre-mRNA. We use high molecular mass polyethylene glycol as a macromolecular cosolute and monitor the structure of the RNA globally and with nucleotide resolution. We demonstrate that crowding has no impact on the 2D fold and we conclude that the MFE structure in dilute solvent conditions represents a good proxy for the folding of the pre-mRNA in its mitochondrial solvent context.
Distressing Visual Hallucinations after Treatment with Trazodone
Authors: Santos Gustavo , Moreira Ana Maria
Published: June 2017

Trazodone, a second-generation atypical antidepressant, is increasingly being used off-label, in the treatment of insomnia. Although generally well tolerated, trazodone treatment can be associated with some complications. We describe a case of a 60-year-old man who received trazodone for primary insomnia. He returned, to the emergency department, two days later with distressing visual hallucinations, which prompted inpatient treatment. Trazodone was discontinued, leading to a complete resolution of his visual hallucinations, and he was treated with mirtazapine for 6 months. There has been no relapse in a follow-up period of two years. Patients presenting with visual hallucinations without significant psychiatry history can be a challenging situation. We highlight the importance of careful anamnesis with an accurate medication history. Given the widespread use of trazodone, clinicians should be aware of this possible side effect.
Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis
Authors: Liu Cai-yun , Zhu Jie , Zheng Xiang-Yu , Ma Chi , Wang Xu
Published: June 2017

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.
Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans
Authors: Marrocco Ilaria , Altieri Fabio , Peluso Ilaria
Published: June 2017

Oxidative stress is the result of the imbalance between reactive oxygen species (ROS) formation and enzymatic and nonenzymatic antioxidants. Biomarkers of oxidative stress are relevant in the evaluation of the disease status and of the health‐enhancing effects of antioxidants. We aim to discuss the major methodological bias of methods used for the evaluation of oxidative stress in humans. There is a lack of consensus concerning the validation, standardization, and reproducibility of methods for the measurement of the following: (1) ROS in leukocytes and platelets by flow cytometry, (2) markers based on ROS‐induced modifications of lipids, DNA, and proteins, (3) enzymatic players of redox status, and (4) total antioxidant capacity of human body fluids. It has been suggested that the bias of each method could be overcome by using indexes of oxidative stress that include more than one marker. However, the choice of the markers considered in the global index should be dictated by the aim of the study and its design, as well as by the clinical relevance in the selected subjects. In conclusion, the clinical significance of biomarkers of oxidative stress in humans must come from a critical analysis of the markers that should give an overall index of redox status in particular conditions.
The Psychometric Parameters of the Farsi Form of the Arabic Scale of Death Anxiety
Authors: Dadfar Mahboubeh , Abdel-Khalek Ahmed M. , Lester David , Atef Vahid Mohammad Kazem
Published: June 2017

The aim of this study was to describe the psychometric properties of the Farsi Form of the Arabic Scale of Death Anxiety (ASDA). The original scale was first translated into Farsi by language experts using the back translation procedure and then administered to a total of 252 Iranian college students and 52 psychiatric outpatients from psychiatric and psychological clinics. The one-week test-retest reliability of the Farsi version in a sample of college students was 0.78, indicating good temporal stability and corroborating the trait-like nature of scores. Cronbach’s α was 0.90 for the college students and 0.92 for the psychiatric outpatients, indicating high internal consistency. Scale scores correlated 0.46 with Death Obsession Scale scores, 0.56 with Death Depression Scale scores, 0.41 with Death Anxiety Scale scores, and 0.40 with Wish to be Dead Scale scores, indicating good construct and criterion-related validity. A principal component analysis with a Varimax rotation yielded four factors in the sample of Iranian college students, indicating a lack of homogeneity in the content of the scale. Male students obtained a significant higher mean score than did females. It was concluded that the Farsi ASDA had good internal consistency, temporal stability, criterion-related validity, and a factor structure reflecting important features of death anxiety. In general, the Farsi ASDA could be recommended for use in research on death anxiety among Iranian college students and psychiatric outpatients.
Adoptive Cell Therapy of Induced Regulatory T Cells Expanded by Tolerogenic Dendritic Cells on Murine Autoimmune Arthritis
Authors: Yang Jie , Liu Lidong , Yang Yiming , Kong Ning , Jiang Xueyu , Sun Juan , Xie Rufeng
Published: June 2017

Objective.Tolerogenic dendritic cells (tDCs) can expand TGF-β-induced regulatory T cells (iTregs); however, the therapeutic utility of these expanded iTregs in autoimmune diseases remains unknown. We sought to determine the properties of iTregs expanded by mature tolerogenic dendritic cells (iTregmtDC) in vitro and explore their potential to ameliorate collagen-induced arthritis (CIA) in a mouse model.Methods. After induction by TGF-βand expansion by mature tDCs (mtDCs), the phenotype and proliferation of iTregmtDCwere assessed by flow cytometry. The ability of iTregs and iTregmtDCto inhibit CD4+T cell proliferation and suppress Th17 cell differentiation was compared. Following adoptive transfer of iTregs and iTregmtDCto mice with CIA, the clinical and histopathologic scores, serum levels of IFN-γ, TNF-α, IL-17, IL-6, IL-10, TGF-βand anti-CII antibodies, and the distribution of the CD4+Th subset were assessed.Results. Compared with iTregs, iTregmtDCexpressed higher levels of Foxp3 and suppressed CD4+T cell proliferation and Th17 cell differentiation to a greater extent. In vivo, iTregmtDCreduced the severity and progression of CIA more significantly than iTregs, which was associated with a modulated inflammatory cytokine profile, reduced anti-CII IgG levels, and polarized Treg/Th17 balance.Conclusion.This study highlights the potential therapeutic utility of iTregmtDCin autoimmune arthritis and should facilitate the future design of iTreg immunotherapeutic strategies.
High‐Intensity Exercise Reduces Cardiac Fibrosis and Hypertrophy but Does Not Restore the Nitroso‐Redox Imbalance in Diabetic Cardiomyopathy
Authors: Novoa Ulises , Arauna Diego , Moran Marisol , Nuñez Madelaine , Zagmutt Sebastián , Saldivia Sergio , Valdes Cristian , Villaseñor Jorge , Zambrano Carmen Gloria , Gonzalez Daniel R.
Published: June 2017

Diabetic cardiomyopathy refers to the manifestations in the heart as a result of altered glucose homeostasis, reflected as fibrosis, cellular hypertrophy, increased oxidative stress, and apoptosis, leading to ventricular dysfunction. Since physical exercise has been indicated as cardioprotective, we tested the hypothesis that high‐intensity exercise training could reverse the cardiac maladaptations produced by diabetes. For this, diabetes was induced in rats by a single dose of alloxan. Diabetic rats were randomly assigned to a sedentary group or submitted to a program of exercise on a treadmill for 4 weeks at 80% of maximal performance. Another group of normoglycemic rats was used as control. Diabetic rat hearts presented cardiomyocyte hypertrophy and interstitial fibrosis. Chronic exercise reduced both parameters but increased apoptosis. Diabetes increased the myocardial levels of the mRNA and proteins of NADPH oxidases NOX2 and NOX4. These altered levels were not reduced by exercise. Diabetes also increased the level of uncoupled endothelial nitric oxide synthase (eNOS) that was not reversed by exercise. Finally, diabetic rats showed a lower degree of phosphorylated phospholamban and reduced levels of SERCA2 that were not restored by high‐intensity exercise. These results suggest that high‐intensity chronic exercise was able to reverse remodeling in the diabetic heart but was unable to restore the nitroso‐redox imbalance imposed by diabetes.
Effectiveness of Physical Barriers Installation for Prevention of Incidents in Mexico City’s Subway System
Authors: Portillo-Villasana Gerardo de Jesús , Huerta-Barrientos Aida , Dillarza Andrade Yazmin
Published: June 2017

Nowadays, suicides inside the installations of subway platforms are considered a public health problem in Mexico City. One solution to prevent them is the installation of physical barriers, but their high cost is unattractive for governmental authorities. Traditional approaches of research on the effectiveness of physical barriers for preventing suicides have been limited to analyzing statistically the effects of installing platform screen doors and blue lights on subway platforms. Although considerable progress has been made in this field, many important issues remain unexplored. This study investigates the effectiveness of physical barriers installation for prevention of incidents in Mexico City subway system by means of an agent-based simulation model. Firstly, the design of physical barriers for prevention of incidents in Mexico City subway system is described. Secondly, a conceptual model of the Zócalo station subway platform is presented. Thirdly, an agent-based simulation model of Zócalo station subway platform is implemented using AnyLogic™ software considering normal operations of the subway station. This study shows that physical barriers installation on the Zócalo subway platform can effectively prevent 76% of passenger’s suicides.
The Role of Neighborhood Characteristics in Late Stage Melanoma Diagnosis among Hispanic Men in California, Texas, and Florida, 1996–2012
Authors: Harvey Valerie M. , Enos Clinton W. , Chen Jarvis T. , Galadima Hadiza , Eschbach Karl
Published: June 2017

Background. Hispanics diagnosed with cutaneous melanoma are more likely to present at advanced stages but the reasons for this are unknown. We identify census tracts at high risk for late stage melanoma diagnosis (LSMD) and examine the contextual predictors of LSMD in California, Texas, and Florida. Methods. We conducted a cross-sectional study using geocoded state cancer registry data. Using hierarchical multilevel logistic regression models we estimated ORs and 95% confidence intervals for the impact of socioeconomic, Hispanic ethnic concentration, index of dissimilarity, and health resource availability measures on LSMD. Results. We identified 12,493 cases. In California, late stage cases were significantly more likely to reside within census tracts composed mostly of Hispanics and immigrants. In Texas, LSMD was associated with residence in areas of socioeconomic deprivation and a higher proportion of immigrants. In Florida, living in areas of low education attainment, high levels of poverty, and a high percentage of Hispanic residents was significantly associated with LSMD. Residential segregation did not independently affect LSMD. Conclusion. The influence of contextual predictors on LSMD varied in magnitude and strength by state, highlighting both the cosegregation of social adversity and poverty and the complexity of their interactions.
A Real-Time Structure of Attitude Algorithm for High Dynamic Bodies
Authors: Li Xingcheng , Zhang Shuangbiao
Published: June 2017

To solve the real-time problem of attitude algorithm for high dynamic bodies, a real-time structure of attitude algorithm is developed by analyzing the conventional structure that has two stages, and a flow diagram of a real-time structure for a Matlab program is provided in detail. During the update of the attitude matrix, the real-time structure saves every element of attitude matrix in minor loop in real time and updates the next attitude matrix based on the previous matrix every subsample time. Thus, the real-time structure avoids lowering updating frequency, though the multisubsample algorithms are used. Simulation and analysis show that the real-time structure of attitude algorithm is better than the conventional structure due to short update time of attitude matrix and small drifting error, and it is more appropriate for high dynamic bodies.
Papillary Thyroid Carcinoma: Ectopic Malignancy versus Metastatic Disease
Authors: Agosto-Vargas Yanery’s , Gutiérrez Madeleine , Martínez José Hernán , Mangual-Garcia Michelle , Palermo Coromoto , Vélez-Maymi Sharon , Hernández-Vázquez Luis , Miranda-Rodríguez Samayra , González-Bossolo Alex , Solá-Sánchez Ernesto , Hernández-Negrón Marianne
Published: June 2017

Papillary thyroid carcinoma frequently metastasizes to regional lymph nodes. However, cervical lymph node metastasis as a sole manifestation of occult papillary thyroid carcinoma is rarely observed. Ectopic thyroid is an uncommon condition defined as the presence of thyroid tissue at a site other than pretracheal area. Approximately 1–3% of all ectopic thyroid tissue is located in the lateral neck. This entity may represent the only functional thyroid tissue in the body. Malignant transformation of ectopic thyroid is uncommon; but even rarer is the development of papillary carcinoma on it. We present a case of a 33-year-old man with an incidental lateral neck mass diagnosed after a motor vehicle accident. Total thyroidectomy and lymph node resection were completed without evidence of papillary thyroid carcinoma. Malignant transformation of heterotopic thyroid tissue was the final diagnosis. The possibility of an ectopic thyroid cancer should be considered in the differential diagnosis of a pathological mass in the neck. The uniqueness of this case strives in the rarity that the thyroid gland was free of malignancy, despite ectopic tissue being positive for thyroid carcinoma. Management strategies, including performance of total thyroidectomy, neck dissection, and treatment with radioiodine, should be based on individualized risk assessment.
Anti-Platelet Factor 4/Heparin Antibody Formation Occurs Endogenously and at Unexpected High Frequency in Polycythemia Vera
Authors: Meyer Sara C. , Steinmann Eva , Lehmann Thomas , Muesser Patricia , Passweg Jakob R. , Skoda Radek C. , Tsakiris Dimitrios A.
Published: June 2017

Background.Myeloproliferative neoplasms (MPN) encounter thromboses due to multiple known risk factors. Heparin-induced thrombocytopenia (HIT) is a thrombotic syndrome mediated by anti-platelet factor 4 (PF4)/heparin antibodies with undetermined significance for thrombosis in MPN. We hypothesized that anti-PF4/heparin Ab might occur in MPN and promote thrombosis.Methods.Anti-PF4/heparin antibodies were analyzed in 127 MPN patients including 76 PV and 51 ET. Screening, validation testing, and isotype testing of anti-PF4/heparin Ab were correlated with disease characteristics.Results.Anti-PF4/heparin antibodies were detected in 21% of PV and 12% of ET versus 0.3–3% in heparin-exposed patients. Validation testing confirmed anti-PF4/heparin immunoglobulins in 15% of PV and 10% of ET. Isotype testing detected 9.2% IgG and 5.3% IgM in PV and exclusively IgM in ET. IgG-positive PV patients encountered thromboses in 57.1% suggesting anti-PF4/heparin IgG may contribute to higher risk for thrombosis in MPN. Overall, 45% of PV patients experienced thromboses with 11.8% positive for anti-PF4/heparin IgG versus 7.1% in PV without thrombosis.Conclusion.Anti-PF4/heparin antibodies occur endogenously and more frequently in MPN than upon heparin exposure. Thrombotic risk increases in anti-PF4/heparin IgG-positive PV reflecting potential implications and calling for larger, confirmatory cohorts. Anti-PF4/heparin IgG should be assessed upon thrombosis in PV to facilitate avoidance of heparin in anti-PF4/heparin IgG-positive PV.
Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer
Authors: Yang Wei-Lei , Gentry-Maharaj Aleksandra , Simmons Archana , Ryan Andy , Fourkala Evangelia Ourania , Lu Zhen , Baggerly Keith A. , Zhao Yang , Lu Karen H. , Bowtell David , Jacobs Ian , Skates Steven J. , He Wei-Wu , Menon Usha , Bast Robert C.
Published: June 2017

Purpose: The TP53 tumor-suppressor gene is mutated in >95% of high-grade serous ovarian cancers. Detecting an autologous antibody response to TP53 that might improve early detection.

Experimental Design: An immunoassay was developed to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and 944 age-matched healthy controls from the United States, Australia, and the United Kingdom. Serial preclinical samples from cases and controls were also assayed from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Results: Using a cutoff value of 78 U/mL to achieve a specificity of 97.4%, TP53 autoantibody was elevated in 30% of 50 cases from MD Anderson, 21.3% of 108 cases from the Australian Ovarian Cancer Study, and 21% of 220 cases from the UKCTOCS. Among 164 cases with rising CA125 detected with the UKCTOCS risk of ovarian cancer algorithm (ROCA), 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months before CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Similar sensitivity was obtained using assays with specific mutant and wild-type TP53.

Conclusions: TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 holds promise for earlier detection of invasive epithelial ovarian cancer. Clin Cancer Res; 23(19); 5912–22. ©2017 AACR.
Factor Analysis and Psychometric Properties of the Minnesota Nicotine Withdrawal Scale and the Minnesota Nicotine Withdrawal Scale-Revised: Italian Version
Authors: Svicher Andrea , Beghè Agnese , Mangiaracina Giacomo , Cosci Fiammetta
Published: June 2017

Background/Aims: We run Exploratory and Confirmatory Factor Analyses of the Minnesota Nicotine Withdrawal Scale (MNWS) and of the MNWS-Revised (MNWS-R). Psychometric properties were also explored. Methods: Adult Italian smokers, 366 in all, were assessed via the MNWS-R together with rating scales measuring cigarette dependence, alcohol use, anxiety sensitivity and negative affect at baseline and after 3 months. Results: The MNWS showed good psychometric properties (α = 0.85; rtt = 0.59) and a unidimensional factor structure. The 2-factor model of MNWS-R had the best fit and the factors were labelled psychological symptoms (α = 0.86; rtt = 0.59) and associated somatic features (α = 0.64; rtt = 0.45). Conclusions: MNWS showed 1 factor; MNWS-R showed 2 relatively dependent factors. The results need to be replicated in smokers in withdrawal.
Sudden Cardiac Death Substrate Imaged by Magnetic Resonance Imaging
Authors: Wu Katherine C.
Published: June 2017

Sudden cardiac death (SCD) is a devastating event afflicting 350 000 Americans annually despite the availability of life-saving preventive therapy, the implantable cardioverter defibrillator. SCD prevention strategies are hampered by over-reliance on global left ventricular ejection fraction <35% as the most important criterion to determine implantable cardioverter defibrillator candidacy. Annually in the United States alone, this results in ≈130 000 implantable cardioverter defibrillator placements at a cost of >$3 billion but only a 5% incidence per year of appropriate firings. This approach further fails to identify individuals who experience the majority, as many as 80%, of SCD events, which occur in the setting of more preserved left ventricular ejection fraction. Better risk stratification is needed to improve care and should be guided by direct pathophysiologic markers of arrhythmic substrate, such as specific left ventricular structural abnormalities. There is an increasing body of literature to support the prognostic value of cardiac magnetic resonance imaging with late gadolinium enhancement in phenotyping the left ventricular to identify those at highest risk for SCD. Cardiac magnetic resonance has unparalleled tissue characterization ability and provides exquisite detail about myocardial structure and composition, abnormalities of which form the direct, pathophysiologic substrate for SCD. Here, we review the evolution and the current state of cardiac magnetic resonance for imaging the arrhythmic substrate, both as a research tool and for clinical applications.
The Brugada Syndrome Susceptibility Gene
HEY2
Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity
Authors: Veerman Christiaan C. , Podliesna Svitlana , Tadros Rafik , Lodder Elisabeth M. , Mengarelli Isabella , de Jonge Berend , Beekman Leander , Barc Julien , Wilders Ronald , Wilde Arthur A.M. , Boukens Bastiaan J. , Coronel Ruben , Verkerk Arie O. , Remme Carol Ann , Bezzina Connie R.
Published: June 2017

Rationale:

Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near
HEY2
) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved.

Objective:

We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in
Hey2
+/−
(
Hey2
heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome.

Methods and Results:

We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for
cis
-expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and
HEY2
expression (β=+0.159;
P
=0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for
HEY2
, which uncovered
KCNIP2
, encoding the β-subunit of the channel underlying the transient outward current (
I
to
), as the transcript most robustly correlating with
HEY2
expression (β=+1.47;
P
=2×10
−34
). Transcript abundance of
Hey2
and the
I
to
subunits
Kcnip2
and
Kcnd2
, assessed by quantitative reverse transcription–polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in
Hey2
+/−
mice compared with wild type. Surface ECG measurements showed less prominent J waves in
Hey2
+/−
mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V
max
in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher
I
to
and a lower sodium current (
I
Na
) density in subepicardium versus subendocardium. These transmural differences were diminished in
Hey2
+/−
mice because of changes in subepicardial cardiomyocytes.

Conclusions:

This study uncovers a role of
HEY2
in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a
HEY2
-dependent alteration of ion channel expression across the cardiac ventricular wall.
Intuitive and Reliable Estimates of the Output Gap from a Beveridge-Nelson Filter
Authors: Kamber Güneş , Morley James , Wong Benjamin
Published: June 2017

The Beveridge-Nelson decomposition based on autoregressive models produces estimates of the output gap that are strongly at odds with widely held beliefs about transitory movements in economic activity. This is due to parameter estimates implying a high signal-to-noise ratio in terms of the variance of trend shocks as a fraction of the overall forecast error variance. When we impose a lower signal-to-noise ratio, the resulting Beveridge-Nelson filter produces a more intuitive estimate of the output gap that is large in amplitude and highly persistent, and it typically increases in expansions and decreases in recessions. Notably, our approach is also reliable in the sense of being subject to smaller revisions and predicting future output growth and inflation better than other trend-cycle decompositions that impose a low signal-to-noise ratio.
A Global Perspective on Religious Participation and Suicide
Authors: Hsieh Ning
Published: June 2017

Although sociological research in the Durkheimian tradition has generally accepted that religious involvement protects against suicide, few studies have examined this theoretical proposition outside Western industrialized settings. Using multilevel models to analyze data from the World Health Organization Mortality Database and the World Values Survey (1981–2007) across 42 countries in seven geographical-cultural regions, this study explores whether religious participation is more protective against suicide in some regions than others and, if so, why. Results indicate that while religious participation is protective in Latin America, eastern Europe, northern Europe, and English-speaking countries, it may aggravate the risk of suicide in East Asia, western Europe, and southern Europe. This regional variation is the result of differences in both the degree of integration/regulation of religious communities and suicide underreporting. Overall, the findings support the network perspective of Durkheim’s classical theory and suggest that researchers should be more cautious about suicide underreporting in less industrialized settings.
Persistent Rule-Following in the Face of Reversed Reinforcement Contingencies: The Differential Impact of Direct Versus Derived Rules
Authors: Harte Colin , Barnes-Holmes Yvonne , Barnes-Holmes Dermot , McEnteggart Ciara
Published: June 2017

Rule-governed behavior and its role in generating insensitivity to direct contingencies of reinforcement have been implicated in human psychological suffering. In addition, the human capacity to engage in derived relational responding has also been used to explain specific human maladaptive behaviors, such as irrational fears. To date, however, very little research has attempted to integrate research on contingency insensitivity and derived relations. The current work sought to fill this gap. Across two experiments, participants received either a direct rule (Direct Rule Condition) or a rule that involved a novel derived relational response (Derived Rule Condition). Provision of a direct rule resulted in more persistent rule-following in the face of competing contingencies, but only when the opportunity to follow the reinforced rule beforehand was relatively protracted. Furthermore, only in the Direct Rule Condition were there significant correlations between rule-compliance and stress. A post hoc interpretation of the findings is provided.
Foreskin and the molecular politics of risk
Authors: Norton Aaron T
Published: June 2017

In this paper, I examine disputes over recent claims that male circumcision reduces HIV risk to suggest a complicated relationship between risk individualization and categorization. Whereas randomized controlled trials (RCTs) conducted in sub-Saharan Africa appear to have provided key evidence for the World Health Organization’s endorsement of male circumcision as an HIV prevention strategy, RCTs alone did not provide evidence for the underlying causal mechanism. For that, medical authorities have turned to histo-immunological studies of the foreskin’s biomolecular vulnerability to HIV, thus molecularizing risk. Some actors used these studies both as a way of shoring up results of RCTs conducted in sub-Saharan Africa and as an important rationale in arguments for making neonatal circumcision more widely available. Others, however, resisted this move to generalize the RCT results to other parts of the world, citing both contextual differences in HIV transmission patterns and conflicting scientific details regarding the biomolecular basis of the foreskin’s susceptibility. Nevertheless, by locating an abstract notion of relative risk in the body itself, I argue that histological studies of foreskin have played a key role in stabilizing male circumcision status as a new risk category, largely independent of a given individual’s risk profile.
Attributing Responsibility, Sexist Attitudes, Perceived Social Support, and Self-Esteem in Aggressors Convicted for Gender-Based Violence
Authors: Guerrero-Molina Mónica , Moreno-Manso Juan Manuel , Guerrero-Barona Eloísa , Cruz-Márquez Beatriz
Published: June 2017

This work analyzes how the assumption of responsibility by aggressors convicted for gender-based violence is related to sexist attitudes, self-esteem and perceived functional social support. Similarly, the predictive capacity of these variables is studied with respect to the aggressors’ minimization of the harm done and a lack of attributing responsibility to themselves. The participants in the research were males condemned to prison sentences for crimes related with gender-based violence in Spain. The instruments applied were the Attribution of Responsibility and Minimization of Harm Scale, the Ambivalent Sexism Inventory (ASI), the Rosenberg Self-Esteem Scale (RSE), the Functional Social Support Questionnaire (FSSQ), and the Social Desirability Scale (SDS). The study concludes that sexist attitudes are related with a greater lack of attribution of responsibility, as well as with a greater tendency to minimize the harm done by the aggression. In addition, the aggressors with low self-esteem use self-defense as a strategy to justify the violence. Similarly, the presence of an adequate social support network for the aggressor increases the attribution of responsibility on the part of those convicted for gender-based violence.
Shifts in the realized retirement age: Europe in times of pension reform and economic crisis
Authors: Komp Kathrin
Published: June 2017

Many recent policy reforms aimed to delay retirement. Such a delay seems important because population ageing makes it a necessity for financially sound pension schemes and a sufficiently large workforce. However, pension reforms do not only affect when people retire, they likewise affect what influences the realized retirement age. Moreover, the 2008 economic crisis restructured labour markets, thereby affecting retirement. This article investigates recent shifts in the realized retirement age and influences on it. It does this through multilevel analyses of international data from the Survey of Health, Ageing and Retirement in Europe. It compares individuals who retired in 2005/2006 to those who retired in 2012/2013, thereby identifying changes over time. Findings show that the realized retirement age increased. Simultaneously, inequalities in the realized retirement age decreased within and between countries. Thus, while the economic crisis reshaped social inequalities, pension reforms constrained the options for retirement. Consequently, policymakers need not worry about the economic crisis defeating the goals pursued with pension reforms. However, policymakers and researchers do need to consider new inequalities in life courses and the meaning of retirement. Also, researchers need to consider how social change may have altered social mechanisms when conducting literature reviews on retirement.
Intrathecal Grafting of Unencapsulated Adrenal Medullary Tissue can Bring CD4 T Lymphocytes into CSF: A Potentially Deleterious Event for the Graft
Authors: Tkaczuk J. , Bes J. C. , Duplan H. , Sallerin B. , Tafani M. , Charlet J. P. , Abbal M. , Lazorthes Y. , Ohayon E.
Published: June 2017

Adrenal medullary tissue including chromaffin cells was grafted intrathecally in cancer patients to relieve intractable pain. The central nervous system (CNS) is considered an immune privileged site. Therefore, non-HLA-matched and unencapsulated tissue was grafted in 15 patients and 1 sham control in a series of at least 20 grafts. We observed an increase in CSF lymphocyte counts in 15/20 allografts (75%). In contrast to peripheral blood, CD4 T cells predominated in the CSF, but failed to exhibit an activated phenotype (CD25+ CD45RO+ HLA-DR+). The positive effect of graft on pain, the high met-enkephalin levels, the absence of any increase in CSF cytokine levels particularly for IFN-γ or IL-2 (but not IL-10 and IL-6), indirectly indicated that the graft was tolerated despite the presence of CSF lymphocytes. The single treatment failure and three of four cases of partial efficacy occurred in grafts where CSF lymphocytes were present. Moreover, when assayed (n = 7), the CD4+ CSF lymphocytes still retained the capacity to exhibit ex vivo a normal or enhanced frequency of T CD4 cells producing IFN-γ and IL-2. Taken together, our observations indicate that impairment of the local immunosuppressive balance can lead to activation of those CSF CD4 T cells and drive a rejection process. This study suggests further work on the purification and/or the immunoisolation of tissues grafted in the CNS will be necessary, particularly when the possibility of long-term and repeated grafting is considered.
Simultaneous Pancreas–Kidney (SPK) Transplantation from Controlled Non-Heart-Beating Donors (NHBDs)
Authors: D'alessandro Anthony M. , Odorico Jon S. , Knechtle Stuart J. , Becker Yolanda T. , Hoffmann Robert M. , Kalayoglu Munci , Sollinger Hans W.
Published: June 2017

From January 1993 through June 1999, 18 simultaneous pancreas–kidney transplants (SPKs) were performed from controlled non-heart-beating donors (NHBDs) and 339 SPKs were performed from heart-beating donors (HBDs). No difference in donor characteristics was noted except for warm ischemic time, which was 14.8 min (range 4–46 min) for NHBDs. Following transplantation, no difference in pancreatic function was noted; however, a higher rate of enteric conversions was seen in pancreas transplants from NHBDs (32% vs. 13%; p < 0.01). Hemodialysis for acute tubular necrosis (ATN) was higher in kidney transplants from NHBDs (22.2% vs. 4.1%; p = 0.009) as was discharge serum creatinine (1.7 mg/dl vs. 1.5 mg/dl; p < 0.05). Also, the number of patients remaining rejection free was lower for NHBDs and approached significance (33.3% vs. 50.1%; p = 0.07). However, no difference in patient survival (100% vs. 95.4%) or pancreatic (87.4% vs. 86.5%) and renal (86.3% vs. 86.3%) allograft survival was noted during the study period. Our results indicate that SPK transplantation from controlled NHBDs is a viable method for increasing the number of pancreas and kidney transplants available for transplantation.
Successful Suppression of the Early Rejection of Pig Islets in Monkeys
Authors: Rijkelijkhuizen Josephine K. R. A. , Bouwman Eelco , Van Der Burg Michel P. M. , Ringers Jan , Ossevoort Miriam A. , Kuhn Eva M. , Frost Pat , Jonker Margreet
Published: June 2017

Primary nonfunction (PNF) is seen very frequently after xenogeneic transplantation of islets of Langerhans. In a pig-to-rat model we recently observed that no PNF occurs when the islets are kept in culture at 37°C for 1–2 weeks prior to transplantation. In order to investigate the rejection mechanisms in a preclinical model, we transplanted cultured porcine islets under the capsule of both kidneys in four cynomolgous monkeys. Islets were isolated from adult sows by means of digestion with Liberase in University of Wisconsin solution (UWS). The digest was purified by a density gradient of OptiPrep in UWS. Highly purified (>95%) islets were cultured 1–2 weeks in RPMI. All monkeys showed significant titers of preformed anti-pig antibodies. The immunosuppression of the monkeys consisted of cyclophosphamide (Cy) (2 days), cyclosporin A (CsA), and prednisolone. Anticipating a fast rejection we carried out nephrectomies at different time points within 2 weeks after transplantation. Following unilateral nephrectomy, well-preserved islets with no signs of rejection were observed between 3 and 7 days posttransplant. Later, between days 11 and 15 posttransplant, histology in the first three animals demonstrated no islets. In the fourth monkey histology on day 11 showed islets with excellent morphology and some small focal infiltrates. The highest CsA blood levels (around 1000 ng/ml) were found in animals with the best graft survival. We conclude that cultured porcine islets can be grafted without hyperacute rejection in monkeys with preformed anti-pig antibodies. In the presence of high levels of CsA only marginal signs of a cellular immune response were observed 11 days after transplantation.
Clinical Significance of the Cellular Pharmacodynamics of Tacrolimus in Living-Donor Liver Transplantation
Authors: Mijiti Abuduxukuer , Matsuno Naoto , Takeuchi Hironori , Unezaki Sakae , Nagao Takeshi , Hirano Toshihiko
Published: June 2017

Successful immunosuppressive therapy is critical for liver transplantation; however, a considerable number of patients experience fatal rejection or alternatively exhibit serious infection resulting from excessive immunosuppression. The in vitro tacrolimus response of peripheral blood mononuclear cells (PBMCs) before transplantation was compared to the clinical outcome up to 4 weeks after operation in 28 living-donor liver transplant recipients treated with tacrolimus. The tacrolimus IC50 values against concanavalin A-induced PBMC blastogenesis in vitro were calculated. These recipients were classified into two groups with the mean tacrolimus IC50 (0.18 ng/ml) as the cutoff point, after which the clinical outcome between the patient groups was compared. The allograft rejection incidence in the low-sensitivity group (IC50 < 0.18 ng/ml; n = 16) was 6/12 (50.0%), which was significantly higher than the incidence of 2/16 (12.5%) in the high-sensitivity group (IC50 > 0.18 ng/ml; n = 12) ( p = 0.0297). In contrast, the infection incidence in the high-sensitivity group was 6/16 (37.5%), which was significantly higher than that of the low-sensitivity group (1/12; 8.3%) ( p = 0.0401). These data suggest that patients exhibiting a low PBMC sensitivity to tacrolimus have a risk of rejection, whereas highly sensitive patients have a risk of infection in living-donor liver transplantations under tacrolimus therapy.
Hepatocyte Immobilization on Phema Microcarriers and its Biologically Modified Forms
Authors: Dixit Vivek , Piskin Erhan , Arthur Marika , Denizli Adil , Tuncel Suleyman A. , Denkbas Emir , Gitnick Gary
Published: June 2017

Polyhydroxyethylmethacrylate (PHEMA) based microcarriers with different bulk structures were prepared by a phase inversion polymerization technique. PHEMA surfaces were further modified chemically by glow-discharge treatment, and biologically by covalent attachment of fibrinogen and collagen. Hepatocytes were isolated from young male Wistar rats using an in situ portal vein collagenase perfusion technique. Freshly isolated hepatocytes were seeded at 6 × 105 cells/mL and microcarrier concentration was 10 g/L. Stationary microcarrier cultures were carried out in standard (nontissue culture) polystyrene petri dishes in a humidified 5% CO2 incubator at 37 ± 0.5°C. Cell attachment was followed by light microscopy by taking samples from the culture medium every 30 min. Urea and protein syntheses by microcarrier-attached hepatocytes were determined by standard techniques. Nonswellable (highly cross-linked) hydrophilic PHEMA microcarriers did not support cell attachment and viability. However, swellable (low cross-linked) PHEMA microcarriers (pretreated in FBS) allowed high attachment and cell spreading. PHEMA microcarriers treated in dimethylaminoethylmethacrylate (DMAEMA) glow-discharge plasma also improved the cell attachment characteristics of the PHEMA microcarriers. The highest attachment efficiencies (immobilization yields) were observed with the biologically modified PHEMA microcarriers, especially modified with fibronectin. Metabolic activity, as estimated by urea and protein syntheses, was also higher in these microcarriers.
Transplantation and Adoptive Cellular Therapy of Cancer: The Role of T-Cell Growth Factors
Authors: Lotze Michael T.
Published: June 2017

The ability to transfer cultured lymphocytes required the availability and the understanding of the use of the T-cell growth factors IL-2, IL-4, IL-7, and IL-12. Application of these cytokines in vitro and in vivo has allowed the modern development of adoptive transfer of tumor reactive lymphocytes to the modern immunotherapy of patients with cancer. In a randomized prospective study of IL-2 administration compared with IL-2 and lymphokine-activated killer (LAK) cells, no increase in response rate was observed. In a total of 90 patients randomized to receive LAK and IL-2 and 91 patients randomized to receive IL-2 alone, there were a total of 24 responses in patients receiving cells and IL-2 and 16 responses in those receiving IL-2 alone (no significant difference). There was some suggestion that complete responses were observed more often in melanoma patients treated with LAK and IL-2. The most interesting aspect of this study is the prolonged duration of responses, lasting for many months or years. Unfortunately, given the large numbers of variables that were examined, it became very difficult to demonstrate a clear-cut association between clinical outcome (response) and any variable that was routinely measured. Significant antitumor responses have been observed greater than expected with IL-2 alone, with the administration of tumor-infiltrating lymphocytes to patients with melanoma. We currently use hollow fiber devices (Cellco, Germantown, MD) to expand cells up through the many doublings required to generate approximately 1-2 × 1011 cells over a period of 6 wk in culture. In a recent review of the results in patients with melanoma treated on such regimens in combination with high-dose IL-2, an approximately 20-50% response rate has been observed. The factors associated with response are still unclear. Although we initially felt that it was associated with specific lysis, subsequent studies from our group suggest that the relevant factor is specific cytokine (INF-γ, GM-CSF, TNF) production upon tumor stimulation. Additional studies will need to be done to clarify these issues.
Results of a Triple Blind Clinical Study of Myoblast Transplantations without Immunosuppressive Treatment in Young Boys with Duchenne Muscular Dystrophy
Authors: Tremblay Jacques P. , Malouin F. , Roy R. , Huard J. , Bouchard J.P. , Satoh A. , Richards C.L.
Published: June 2017

The effects of myoblast transplantations without an immunosuppressive treatment on muscle strength, and the formation of dystrophin-positive fibers was studied in five young boys with Duchenne muscular dystrophy (DMD) using a triple blind design. Injections of myoblasts were made into one biceps brachii (BB), and the opposite BB, used as a control, was sham-injected; the experimenters and the patient were blind to the myoblast-injected side. At the same time, myoblasts were also injected in the left tibialis anterior (TA) of these patients. The strength developed during maximal static contractions of the elbow flexor and extensor muscles was measured with a Kin-Com dynamometer. No increase in static elbow flexion torque was measured at any time from 2 mo up to 18 mo after the transplantation. One month after the transplantation, the percentage of dystrophin-positive fibers in the myoblast-injected TA ranged from 0 to 36%, while it ranged from 0 to 4% on the control side. The expression of dystrophin in these fibers, however, was generally low, and most likely less than 10% of the normal level. In the biceps brachii of both sides 6 mo after the transplantation, less than 1.5% of dystrophin-positive fibers were detected. The injections also triggered a humoral immune response of the host. Antibodies were capable of fixing the complement, and of lysing the newly formed myotubes. One of the antigens recognized by this immune response is possibly dystrophin. These results strongly suggest that myoblast transplantations, as well as gene therapy for DMD, cannot be done without immunosuppression.