Identification of Prominin-2 as a new player of cardiomyocyte senescence in the aging heart.

The aging heart is characterized by a number of structural changes leading to ventricular stiffness, impaired resistance to stress and increased risk of developing heart failure (HF). Genetic or pharmacological removal of senescent cells has recently demonstrated the possibility to relieve some cardiac aging features such as hypertrophy and fibrosis. However, the contribution of the different cell types in cardiac aging remains fragmentary due to a lack of cell-specific markers. Cardiomyocytes undergo post-mitotic senescence in response to telomere damage, characterized by persistent DNA damage response and expression of the classical senescence markers p21 and p16, which are shared by many other cell types. In the present study, we used transcriptomic approaches to discover new markers specific for cardiomyocyte senescence. We identified Prominin2 (Prom2), encoding a transmembrane glycoprotein, as the most upregulated gene in cardiomyocytes of aged mice compared to young mice. We showed that Prom2 was upregulated by a p53-dependent pathway in stress-induced premature senescence. Prom2 expression correlated with cardiomyocyte hypertrophy in the hearts of aged mice and was increased in atrial samples of patients with HF with preserved ejection fraction. Consistently, Prom2 overexpression was sufficient to drive senescence, hypertrophy and resistance to cytotoxic stress while Prom2 shRNA silencing inhibited these features in doxorubicin-treated cardiac cells. In conclusion, we identified Prom2 as a new player of cardiac aging, linking cardiomyocyte hypertrophy to senescence. These results could provide a better understanding and targeting of cell-type specific senescence in age-associated cardiac diseases.

Assessment of IgA anti-PT and IgG anti-ACT reflex testing to improve Bordetella pertussis serodiagnosis in recently vaccinated subjects.

OBJECTIVES: Quantifying IgG antibodies to pertussis toxin (PT) is the most specific and sensitive method for the serodiagnosis of a Bordetella pertussis infection. Since PT is a component of acellular pertussis vaccines, anti-PT IgG is also induced by vaccination, precluding pertussis serodiagnosis based exclusively on anti-PT IgG in recently vaccinated subjects. Here, we aim to identify additional B. pertussis-specific serological markers that can discriminate between infection and recent vaccination. METHODS: The clinical usefulness of measuring IgA directed to the vaccine antigen PT and IgG directed to non-vaccine antigens (Fim2/3, LPS, ACT, CatACT) was evaluated in nine well characterized subject groups, aged 10-89 years (n = 390). Serum anti-PT IgG levels (>125 IU/mL) served as an indicator for a recent B. pertussis infection. Comparing symptomatic pertussis-infected subjects (n = 140) with recently vaccinated, non-infected subjects (n = 100) revealed the optimal cut-off, accuracy, sensitivity and specificity for each single parameter. RESULTS: For pertussis diagnosis in recently vaccinated subjects, the measurement of anti-PT IgA (cut-off 15 IU/mL) and anti-ACT IgG (cut-off 15 U/mL) resulted in accuracies of 95% (91.5-97.1) and 87.5% (82.7-91.1), sensitivities of 92.9% (87.4-96.0) and 83.6% (76.5-88.8) and specificities of 98% (93.0-99.4) and 93% (86.3-96.6), respectively. Comparing anti-PT IgA levels between the youngest (10-19 years, n = 38) and oldest (70-89 years, n = 17) age groups revealed an age-dependent increase in antibody levels in pertussis-infected subjects (p < 0.0001). CONCLUSIONS: Reflex testing of anti-PT IgA and anti-ACT IgG improves pertussis serodiagnosis in recently vaccinated symptomatic subjects with elevated anti-PT IgG levels. Furthermore, both markers can discriminate between vaccination and recent infection in pertussis serosurveillance studies.

Validación de la escala de afecto positivo y negativo en población chilena y su aplicación en personas migrantes residentes en Chile / Validation of the positive and negative affect scale in the Chilean population and its application in migrant people

INTRODUCCIÓN: Aunque la escala de afecto positivo y negativo propuesta por Mroczek y Kolarz no ha sido tan ampliamente utilizada como otros instrumentos, las adecuadas propiedades psicométricas publicadas hasta ahora, sumado a la rapidez de su aplicación; la sitúan como un instrumento adecuado para medir el componente hedónico del bienestar subjetivo. En este sentido, la validación de la escala en Chile permitirá a los investigadores tener a disposición un instrumento breve y fiable con el cual medir el bienestar subjetivo. OBJETIVO: El objetivo inicial de este estudio fue validar en Chile la escala de afecto positivo y negativo propuesta por Mroczek y Kolarz. MÉTODOS: Se reclutó a una muestra no probabilística de 155 chilenos junto con una muestra de 308 inmigrantes adultos residentes en Chile de nacionalidades colombiana, peruana y venezolana. La muestra de chilenos se utilizó para la validación de la escala. Se evaluó la validez de constructo (α de Cronbach y análisis factorial exploratorio), y luego la validez concurrente a través de correlaciones bivariadas con la medida de "sentimiento de felicidad" de Wold (1995) y de "satisfacción con la vida" de Keyes, Shmotkin & Ryff (2002). Finalmente, se valoraron las diferencias en la expresión de afecto de los chilenos en comparación con la de los migrantes. RESULTADOS: El índice de fiabilidad fue de α = 0,92 para la subescala de afecto positivo y de α = 0,75 para la subescala de afecto negativo. El análisis factorial exploratorio reprodujo de manera idéntica las cargas factoriales propuestas en el instrumento original con saturaciones de los ítems > 0,35 por factor. Los migrantes colombianos y venezolanos muestran mayor expresión de afecto positivo que los chilenos, mientras que esta diferencia no se observa al comparar chilenos con peruanos. CONCLUSIÓN: La escala de afecto positivo y negativo presenta propiedades psicométricas adecuadas para medir la expresión de afecto (bienestar hedónico) en la población chilena.

INTRODUCTION: Although the positive and negative affect scale proposed by Mroczek and Kolarz has not been widely used as other instruments, the adequate psychometric properties reported and the simplicity of the application, place it as an adequate instrument to measure the hedonic component of subjective well-being. Thus, the scale validation in Chile will allow researchers to have available a short and reliable instrument in order to measure subjective well-being. OBJECTIVE: The initial objective of this study was to validate in Chile the "Positive and negative affect scale" proposed by Mroczek and Kolarz. METHODS: A non-probabilistic sample of 155 Chileans and a sample of 308 adult immigrants residing in Chile of Colombian, Peruvian and Venezuelan nationality were recruited. The sample of Chileans was used to validate the scale. The construct validity (Cronbach's α and exploratory factor analysis) and the concurrent validity through bivariate correlations with other measures were estimated. Finally, the differences in the affect expression of Chileans in comparison with migrants' people were evaluated. RESULTS: The reliability index was α = 0.92 for the positive affect sub-scale and α = 0.75 for the negative affect sub-scale. The exploratory factor analysis reproduced in the same way the factorial loadings proposed in the original instrument with saturations > 0.35 per item. Colombian and Venezuelan migrants show greater expression of positive affect than Chileans, while this difference is not observed when comparing Chileans with Peruvians. CONCLUSION: The positive and negative affect scale has adequate psychometric properties to measure the expression of affect (hedonic well-being) in the Chilean population.

Pertussis diagnosis in Belgium: results of the National Reference Centre for Bordetella anno 2015.

In 2015, the Belgian National Reference Centre for Bordetella analyzed 4110 respiratory samples by qPCR and 4877 serum samples by serology. Whereas about 50% of respiratory samples were from infants and children below the age of five, serum samples were distributed among all age categories. A total of 394 (9·6%) cases was diagnosed as positive for Bordetella pertussis by qPCR and 844 (17·3%) cases were diagnosed as acute infection by serology (anti-pertussis toxin (PT) IgG > 125 IU/ml). Another 1042 (21·4%) sera had anti-PT IgG between 55 and 125 IU/ml reflecting a vaccination or pertussis infection during the last 1-2 years. Seventy per cent of the pertussis cases diagnosed by qPRC were in infants and children younger than 14 years old, whereas the highest number of sera with anti-PT levels >125 IU/ml was in the age group of 10-14 years old. Based on the limited data of the last vaccination (reported for only 15% of the samples), recent booster vaccination in the teenager group may have contributed only minimally to these elevated anti-PT levels. The highest number of sera with anti-PT titers between 55 and 125 IU/ml was found in the age category 50-59 years old. It is clear that pertussis continues to be a problem in Belgium and that other vaccination strategies (maternal vaccination, cocoon vaccination) and ultimately better vaccines will be needed to control this highly infectious respiratory disease.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Quantification of IgM and IgA anti-pneumococcal capsular polysaccharides by a new ELISA assay: a valuable diagnostic and prognostic tool for common variable immunodeficiency.

PURPOSE: Existing ways of assessing CVID patients at risk of pulmonary infections are not universally accepted. The need to identify additional prognostic factors allowed us to evaluate the anti-polysaccharide IgA and IgM responses in 125 CVID patients immunized with the 23-valent pneumococcal polysaccharide (PS) vaccine (Pneumovax(®)). METHODS: We used a new anti-PS23 IgM and IgA ELISA assay, which evaluates a global response to all 23 polysaccharides contained in Pneumovax(®). RESULTS: Anti-PS23 IgM and/or IgA antibodies were detectable in a minority of CVID patients. Antibody responses were correlated to B cell subpopulations and serum immunoglobulin concentrations. The non responders had a higher incidence of pneumonia and bronchiectasis and responders had the lowest incidence of respiratory complications. CONCLUSIONS: This new ELISA assay allows for studying vaccine response in patients on Ig replacement therapy. This test also is an additional method of evaluation of specific antibody responses representing a valuable contribution to identify prognostic marker in CVID patients.

Tracheal perforation by an oesophageal stent.

In a 63 year-old female patient with oesophageal carcinoma a tracheal perforation by an oesophageal stent was diagnosed. A first attempt of tracheal stenting was not successful due to spontaneous dislocation of the stent. Therefore, a shorter stent was chosen and correctly placed in a second session. This case report on an oesophagotracheal fistula provides a summary of this complication in advanced oesophageal cancer.

[Tobacco use characteristics among apprentices in Vocational Centers]. / Caractéristiques du tabagisme chez les adolescents en Centre de formation des apprentis.

BACKGROUND: Most smokers start smoking during adolescence and become dependent before 20 years old. In France, vocational trainees are a population not much explored. The objective of our study is to present tobacco use characteristics among apprentices in Vocational Centers (VC). METHODS: This cross-sectional exhaustive study covered 1814 students (among whose 943 smokers) entering in a 1st year of the eight participating Vocational Centers in the Lorraine region (Eastern France, 2.3 million inhabitants, 16,500 vocational trainees), during the school years 2007-2008 and 2008-2009. Data collection concerned the sociocultural environment, tobacco use habits, degree of dependency to tobacco and co-addictions. RESULTS: Among the study population, 52.0% declared they were smokers among whom 89.4% daily smokers, and 5.7% were ex-smokers. The average age of tobacco use initiation was 12.1 years (standard deviation [SD]=2.1) and the average age at inception of regular cigarette smoking was 13.8 years (SD=1.6). Current consumption of the smokers was 12.8 cigarettes per day (SD=7.8). The average score of smoking addiction was 6.1 (SD=2.8), according to the Hooked On Nicotine checklist test (score from 0 to 10=strongly dependent). Finally, 37.1% of students (58.9% among smokers) smoked or have smoked cannabis. CONCLUSION: The high prevalence of smoking in Vocational Centers, the early start of tobacco use and the high tobacco consumption among apprentices show that they are overexposed compared to the general population of adolescents. In addition, these young people are already dependant to tobacco use. This underlines the need of specific measures dedicated to this population that amounts to 361,500 individuals in France.

Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans.

Influence of inherited and acquired thrombophilic defects on the clinical manifestations of mixed cryoglobulinaemia.

OBJECTIVE: To investigate the contribution of inherited and acquired thrombophilic defects to the clinical manifestations of mixed cryoglobulinaemia vasculitis. METHODS: The following thrombophilic defects were investigated in 64 consecutive patients with HCV-associated mixed cryoglobulinaemia: aPLs, lupus anti-coagulant, homocysteinaemia, protein C and protein S concentrations, activated protein C resistance, plasminogen activator inhibitor-1 4G4G and 5G5G genotypes, and the presence of mutations of factor V (Leiden and H1299R), of prothrombin (G20210A) and of methyl tetrahydrofolate reductase (C677T and A1298C). Additional variables were demographic data, duration of the disease, cryocrit level and vascular risk factors (diabetes, hypertension, hypercholesterolaemia and smoking habit). The following clinical manifestations of mixed cryoglobulinaemia were analysed as dependent covariates: severity of purpura, presence of necrotic skin ulcers, presence of peripheral neuropathy and presence of kidney disease. RESULTS: Logistic regression analysis identified hyperhomocysteinaemia as a risk factor for severe purpura (P < 0.0001) and for the presence of skin ulcers (P < 0.0001), whereas none of the other thrombophilic defects influenced the clinical presentation of mixed cryoglobulinaemia. Purpura improved in two patients after lowering homocysteine with vitamin supplementation. CONCLUSIONS: Hyperhomocysteinaemia may be a risk factor for severe cutaneous manifestations in mixed cryoglobulinaemia.

Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts.

The basal levels of mRNAs encoding two metalloproteinases, collagenase and stromelysin, were increased as a function of in vitro serial subcultivation (cellular aging) of human fibroblasts. Procollagenase and prostromelysin synthesis and secretion were also greater in the old cultures (late passage). In contrast, the steady-state expression of mRNA for an inhibitor of metalloproteinases, tissue inhibitor of metalloproteinase-1 (TIMP-1), in late-passage cultures was lower than that in young cell cultures (early passage). Each mRNA was analyzed using total RNA preparations isolated from normal fibroblast cultures at different phases of the in vitro life span and from cultures derived from donors with the premature senescence syndromes characterized as Werner syndrome, progeria (Hutchinson-Gilford) syndrome, or Cockayne syndrome. In normal cell cultures expression of metalloproteinase mRNAs was increased after the culture had completed greater than 90% of the in vitro life span, and the reduction in TIMP-1 mRNA expression occurred after the culture had completed greater than 74% of the in vitro lifespan. In Werner syndrome cultures expression of metalloproteinase and TIMP-1 mRNAs was similar to the level of expression observed in late-passage cell cultures. Levels of metalloproteinase and TIMP-1 mRNA expression in progeria and Cockayne syndromes were similar to those of early-passage cell cultures. To determine if young and old cells were each responsive to mediators of metalloproteinase synthesis, cultures were treated with phorbol ester or cytokines. 12-O-tetradecanoylphorbol-13-acetate treatment increased the steady-state levels of all three mRNAs in young, old, and Werner syndrome cultures and increased procollagenase levels in all cultures. Early- and late-passage cell cultures also responded to cytokines. Interleukin-1 alpha treatment increased collagenase and stromelysin mRNA levels while transforming growth factor-beta reduced the steady-state levels of both transcripts. Neither cytokine affected the steady-state level of TIMP-1 mRNA. The results indicate that in vitro cellular aging is associated with changes in expression of mRNAs encoding proteins that mediate inflammatory responses and connective tissue remodeling.

[Topical application of a 0.1% ciclopiroxolamine solution for the treatment of pityriasis versicolor]. / Topische Anwendung einer 0.1%igen ciclopiroxolamin-Lösung zur Behandlung der Pityriasis versicolor.

90 patients suffering from pityriasis versicolor used a 0.1% solution of ciclopiroxolamine for a topical four week treatment. 74% of the patients were cured clinically and mycologically after a four week-therapy. Following additional 4 weeks the responder rate rose to 86%.

[The value of the social service unit in ambulatory gerontopsychiatric management]. / Der Stellenwert der Sozialstation in der ambulanten gerontopsychiatrischen Versorgung.

Care of aged mentally diseased patients is one of the subjects whose reform had been underlined as particularly urgent in the 1975 report on the state of psychiatry in the Federal Republic of Germany. Whereas in psychiatric hospitals there is now evidence of a growing trend to reduced hospital stay and to readmission after a period of release, no change seems to be in sight in respect of caring for the aged on an outpatient basis. The financial losses suffered by public health care organisations for aged mental outpatients have resulted in housing an increasing number of mentally ill persons of old age in homes for the aged, instead of caring for them as psychiatric outpatients. Since more and more aged persons will be represented among the population in future, it is more than ever before imperative to arrive at suggestions for a feasible solution. The article reviews the present situations (including acceptance of existing institutions by the aged) and explains the importance of public social care units in outpatient care of elderly people. The assessment was made by means of an official questionnaire operation in the Land of Baden-Württemberg. Efforts are suggested in respect of revised basis rules of organisation and staff to improve public outpatient gerontopsychiatric care.

[Need for social psychiatric services--a management model in scientific evaluation]. / Zur Notwendigkeit Sozialpsychiatrischer Dienste--Ein Versorgungsmodell in der wissenschaftlichen Erprobung.

Social-psychiatric services have for a long time been a focus in the controversial discussion about the further development of outpatient mental health care. Presented is the Baden-Württemberg Social Psychiatric Services model, which is oriented towards outpatient social welfare provision of persons with chronic mental illness, complementing the medical-psychiatric treatment provided by office-practice psychiatrists. Evaluation of the Social Psychiatric Service for its first year of full operation, 1984, has shown that this type of service delivery organization is capable, above all, of reaching persons with "recently" chronic mental illness, who are serviced in the framework of community mental health care systems mainly on an outpatient basis. Provision of care, i.e. of social welfare and counselling measures, may in this group constitute an efficient contribution towards their social rehabilitation. Effective functioning of this organizational model presupposes sufficiently well-established cooperation with other facilities and services involved in service provision, which, as the Baden-Württemberg trial has shown, can in actual fact be ensured.

Potency of biosynthetic human insulin determined in vitro.

Biosynthetic human insulin (BHI) obtained from separately synthesized A- and B-chains by recombinant DNA technology with Escherichia coli fermentation was compared with human and pork insulin of high purity in vitro. Applying four biologic tests (glucose oxidation and glucose incorporation into the lipids by rat epididymal fat pads, inhibition of lipolysis, and ATP depletion of isolated fat cells) and three receptor assays (binding competition with human fat cells, IM-9 lymphocytes, and rat liver cell plasma membranes), we could not discern significant differences of the half-maximum response by these seven methods. The only variance occurred with the ATP-depletion assay. This method disclosed 10% greater maximum reversion of isoproterenol-induced ATP depletion by BHI when compared with pork insulin.