Postischemic treatment of neonatal cerebral ischemia should target autophagy.

OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia.

Sorting out measures and definitions of screening participation to improve comparability : the example of colorectal cancer.

Participation is a key indicator of the potential effectiveness of any population-based intervention. Defining, measuring and reporting participation in cancer screening programmes has become more heterogeneous as the number and diversity of interventions have increased, and the purposes of this benchmarking parameter have broadened. This study, centred on colorectal cancer, addresses current issues that affect the increasingly complex task of comparing screening participation across settings. Reports from programmes with a defined target population and active invitation scheme, published between 2005 and 2012, were reviewed. Differences in defining and measuring participation were identified and quantified, and participation indicators were grouped by aims of measure and temporal dimensions. We found that consistent terminology, clear and complete reporting of participation definition and systematic documentation of coverage by invitation were lacking. Further, adherence to definitions proposed in the 2010 European Guidelines for Quality Assurance in Colorectal Cancer Screening was suboptimal. Ineligible individuals represented 1% to 15% of invitations, and variable criteria for ineligibility yielded differences in participation estimates that could obscure the interpretation of colorectal cancer screening participation internationally. Excluding ineligible individuals from the reference population enhances comparability of participation measures. Standardised measures of cumulative participation to compare screening protocols with different intervals and inclusion of time since invitation in definitions are urgently needed to improve international comparability of colorectal cancer screening participation. Recommendations to improve comparability of participation indicators in cancer screening interventions are made.

Estimating the cost-effectiveness of modern screening mammography programmes

Context: The debate about the balance of risks and benefits of mammography screening has prompted a comprehensive review by an independent panel in the UK. However, the panel's remit did not cover the important economic dimension of breast cancer screening. Methods: The life histories of two cohort studies of 50-year-old women, who would be eligible within the National Health Service (NHS) breast screening programme (NHSBSP), were simulated over 35 years, using a life table approach. One cohort participant was offered screening at age 50 and triennially thereafter until age 70, assuming 75% attendance, while the other received no screening. Based on the findings from the panel's report, the cost-effectiveness of the NHSBSP was assessed for various scenarios of screening effect on breast cancer incidence (base case scenario: screening advances diagnosis by 5 years; 10% incidence reduction after screening stops).

RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance.

Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB.

Diagnostic reliability of an immunochromatographic test for Chagas disease screening at a primary health care centre in a rural endemic area

Many patients with Chagas disease live in remote communities that lack both equipment and trained personnel to perform a diagnosis by conventional serology (CS). Thus, reliable tests suitable for use under difficult conditions are required. In this study, we evaluated the ability of personnel with and without laboratory skills to perform immunochromatographic (IC) tests to detect Chagas disease at a primary health care centre (PHCC). We examined whole blood samples from 241 patients and serum samples from 238 patients. Then, we calculated the percentage of overall agreement (POA) between the two groups of operators for the sensitivity (S), specificity (Sp) and positive (PPV) and negative (NPV) predictive values of IC tests compared to CS tests. We also evaluated the level of agreement between ELISAs and indirect haemagglutination (IHA) tests. The readings of the IC test results showed 100% agreement (POA = 1). The IC test on whole blood showed the following values: S = 87.3%; Sp = 98.8%; PPV = 96.9% and NPV = 95.9%. Additionally, the IC test on serum displayed the following results: S = 95.7%; Sp = 100%; PPV = 100% and NPV = 98.2%. Using whole blood, the agreement with ELISA was 96.3% and the agreement with IHA was 94.1%. Using serum, the agreement with ELISA was 97.8% and the agreement with IHA was 96.6%. The IC test performance with serum samples was excellent and demonstrated its usefulness in a PHCC with minimal equipment. If the IC test S value and NPV with whole blood are improved, then this test could also be used in areas lacking laboratories or specialised personnel.

Rapid detection of MRSA in screening specimens during a hospital outbreak.

Objectives: To compare the results of rapid PCR screening for MRSA using the GeneXpert system with those of cultures in an outbreak setting. Methods: GeneXpert was used for screening MRSA in nose, throat, groin, and other clinical samples during a 6-month period. Samples were performed using a double-swab transystem. When >1 sample was found positive in a screening set, all second swabs of the set were analysed by culture. Results: From June to October 2009, 7568 rapid tests were performed, among which 432 (5.7%) were positive (nose: 149/2090, 7.1%; throat: 98/2078, 4.7%; groin: 152/2080, 7.3%; urine: 14/1090, 1.3%; wounds: 18/150, 12%; and others:1/27, 3.7%), and 84 (1.1%) were invalid. A total of 1517 samples were analyzed by both rapid PCR and culture. Rapid tests had a sensitivity of 0.896 compared to cultures, a specificity of 0.769, a PPV of 0.763, and a NPV of 0.899. The rapid test was found to be less sensitive in throat samples (0.81) than in nose or inguinal samples (0.93 for both). In 32/192 (16%) patients a positive rapid PCR result was not confirmed by culture, despite several subsequent screening samples in some patients. Cycle threshold (Ct) for SCCmec of these PCR positive reactions were all >30. Conclusions: GeneXpert MRSA was found to be suitable for the rapid detection in nose, inguinal, and throat samples, however with a lower sensitivity in the later. Negative cultures in 16% of our PCR-positive patients raised the question of false positivity or higher sensitivity of GeneXpert. Further work is needed to investigate these cases.

Neonatal adaptation of energy and protein metabolism

During the last decade, the development of "bedside" investigative methods, including indirect calorimetry, nutritional balance and stable isotope techniques, have given a new insight into energy and protein metabolism in the neonates. Neonates and premature infants especially, create an unusual opportunity to study the metabolic adaptation to extrauterine life because their physical environment can be controlled, their energy intake and energy expenditure can be measured and the link between their protein metabolism and the energetics of their postnatal growth can be assessed with accuracy. Thus, relatively abstract physiological concepts such as the postnatal timecourse of heat production, energy cost of growth, energy cost of physical activity, thermogenic effect of feeding, efficiency of protein gain, metabolic cost of protein gain and protein turnover have been quantified. These results show that energy expenditure and heat production rates increase postnatally from average values of 40 kcal/kgxday during the first week to 60 kcal/kgxday in the third week. This increase parellels nutritional intakes as well as the rate of weight gain. The thermogenic effect of feeding and the physical activity are relatively low and account only for an average of 5% each of the total heat production. The cost of protein turnover is the highest energy demanding process. The fact that nitrogen balance becomes positive within 72 hours after birth places the newborn in a transitional situation of dissociated balance between energy and protein metabolism: dry body mass and fat decrease while there is a gain in protein and increase in supine length. This particular situation ends during the second postnatal week and soon thereafter the rate of weight gain matches the statural growth. The goals of the following review are to summarize recent data on the physiological aspects of energy and protein metabolism directly related to the extrauterine adaptation, to describe experimental approaches which recently were adapted to the newborns in order to get "bedside results" and to discuss how far these results can help everyday's neonatal practice.

Influence on screening performance of second reading strategies in two lowvolume programs

BACKGROUND: The European Guidelines specify a minimum of 5,000 screening cases to be read yearly by radiologists carrying out second reading in non-centralized programs. This professional requirement is difficult to reach and/or to implement in regional programs covering a sparse population with a high number of participating radiology units, so that alternative blind double reading strategies must be devised. OBJECTIVE: To evaluate the effect on breast cancer screening performances of two second reading strategies used in non-centralized, low-volume programs. METHODS: Reading performances in two Swiss regional breast cancer screening programs (cantons of Wallis and Vaud), covering female populations, aged 50-69, of about 31'000 and 72'000 inhabitants were computed and compared. Both programs had similar screening regimens and organizations, but differed with respect to second reading. One setting applied a selective strategy whereby only experienced radiologists performed second reading; the other elicited not to restrict second readers on the basis of their individual screening activity. Analysis included some 140,000 mammograms performed between 1999 and 2005. RESULTS: Overall, screening performances improved with increasing total volume of reading, albeit not in a linear fashion. Regardless of setting, radiologists attained a higher level of screening accuracy when performing second rather than first readings, and incident rather than prevalent screening cases. The effect of a selective, small group of second readers appeared to impact favorably on the false-positive rate and other indicators of screening quality. As the learning curve depends on the number of mammograms read, these distinct strategies may bear different outcome in the long run. Implications and practical issues for low-volume programs are discussed.

Maladies vasculaires: quels dépistages au cabinet du praticien [Vascular diseases: what screening could be done in the office?]

The screening of vascular pathologies in physician offices starts with precise medical history and clinical exam. Tools like the Edinburgh Claudication Questionnaire for the peripheral artery disease or the Wells score for the probability of a thromboembolic event are useful. The measure of the ankle brachial index, the D-dimers or any other biological screening are complementary. In the presence of pathological features, it is recommended to organise a specialised consultation in order to precise diagnosis, treatment and follow-up. The screening of a vascular disease is interesting not only for the management of local symptoms, but also for the associated systemic pathologies to provide a preventive medicine of good quality.

Tropical diseases screening in immigrant patients with HIV infection in a European country.

Prospective observational study of all HIV infected immigrants visited at the Infectious Diseases Department of the Hospital Universitari Vall d’Hebron from June 2010 to May 2011. Screening of most prevalent tropical diseases was performed according to geographical origin. 190 patients were included. Overall, 36.8% (70/190) patients had at least one positive result for any parasitic disease, including Chagas disease, schistosomiasis, strongyloidiasis, leishmaniasis, intestinal parasitosis and malaria. We propose a screening and management strategy of latent parasitic infections in immigrant HIV infected patients.

Should screening for Chlamydia trachomatis and Neisseria gonorrhoeae in HIV-men who have sex with men be recommended?

INTRODUCTION Sexually transmitted infections (STI) like Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) have been associated with increased risk of HIV acquisition (1). It has been also described as a high prevalence of asymptomatic CT and NG infections in men who have sex with men (MSM) (2). The aim of this study was to know the prevalence of CT and/or NG infections in asymptomatic HIV-MSM and the related factors. MATERIALS AND METHODS Prospective study of a cohort of asymptomatic HIV-MSM with follow-up in Malaga (southern Spain) during October 2012-May 2014. Patients with an opportunistic event or who received active antibiotic therapy for CT and/or NG in the previous month were excluded. All of them completed a questionnaire about sexual behaviour, barrier methods and recreational drugs use. Demographical, epidemiological, clinical, analytical and therapeutic data were also collected. Pharyngeal and rectal swabs, and urine samples were collected to be tested for CT and NG by nucleic acid amplification test (c4800 CT/NG. Roche Diagnostics, Mannheim, Germany) (3). STATISTICS ANALYSIS SPSS 17.0. RESULTS 255 patients were asked to participate and 248 of them accepted. Median age was 37.7 (30.6-46.3) years, median time since HIV diagnosis was 47.7 (10.5-104.1) months, and median CD4 cells count was 607 (440-824) cell/µL. There were 195 (78.6%) patients on antiretroviral therapy; 81.5% of them had undetectable viral load. 80.5% of the patients had a past history of STI. Infection by CT and/or NG was diagnosed in 24 (9.7%) patients. Overall four urine samples, two pharyngeal, and 15 rectal ones were positive for CT, and five pharyngeal and five rectal swabs were positive for NG. Two patients were co-infected by CT and NG: one with CT in urine and both in rectum, another with CT in urine and rectum and NG in pharynx. One patient presented CT in pharynx and rectum, and two patients NG in pharynx and rectum. Positive CT and/or NG tests were only related with detectable HIV viral load (OR 3.08, 95% CI 1.2-7.4; p=0.01). It was not related with sexual behaviour, nor with alcohol or recreational drugs use. CONCLUSIONS STI screening had a great acceptance in this population. There was a high prevalence of asymptomatic CT and/or NG infections. Rectum sample was the most effective one. Viral suppression could protect from these STI. Screening should be recommended in HIV-MSM.

Prevalence of overweight and obesity in children and adolescents in Seychelles : results of the School Screening Program in 2013

Results related to overweight and obesity in 2013: Participation to the school screening program was satisfactory in 2013, but a bit less than in previous years (4220 children seen out of a total of approximately 6000 eligible ones). Less than maximal participation to the screening program can relate to different factors, e.g.; a trend for obese children to decline participation; lack of time of school nurses to complete the screening program due to competing duties at health centre level. Good organization by the school nurses and adequate facilities for screening are also important factors for a good conduct of the screening program.

The association between alcohol screening scores and health status in male veterans.

OBJECTIVES: Alcohol use is associated with self-reported health status. However, little is known about the concurrent association between alcohol screening scores and patient perception of health. We evaluated this association in a sample of primarily older male veterans.METHODS: This secondary, cross-sectional analysis included male general medicine outpatients from 7 VA medical centers who returned mailed questionnaires. Screening scores from the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire were divided into 6 categories (0, 1­3, 4­5, 6­7, 8­9, and 10­12). Outcomes included scores on the 8 subscales and 2 component scores of the 36-item Short Form Health Survey (SF-36). Unadjusted and adjusted linear regression models were fit to characterize the association between AUDIT-C categories and SF-36 scores. Models were adjusted for demographic characteristics, smoking, and site?both alone and in combination with 14 self-reported comorbid conditions.RESULTS: Male respondents (n = 24,531; mean age = 63.6 years) represented 69% of those surveyed with the SF-36. After adjustment, a quadratic (inverted U-shaped) relationship was demonstrated between AUDIT-C categories and all SF-36 scores such that patients with AUDIT-C scores 4­5 or 6­7 reported the highest health status, and patients with AUDIT-C scores 0, 8­9, and =10 reported the lowest health status.CONCLUSIONS: Across all measures of health status, patients with the most severe alcohol misuse had significantly poorer health status than those who screened positive for alcohol misuse at mild or moderate levels of severity. The relatively good health status reported by patients with mild-moderate alcohol misuse might interfere with clinicians' acceptance and adoption of guidelines recommending that they counsel these patients about their drinking.

The role of polymerase chain reaction of high-risk human papilloma virus in the screening of high-grade squamous intraepithelial lesions in the anal mucosa of human immunodeficiency virus-positive males having sex with males.

OBJECTIVES To evaluate the advantages of cytology and PCR of high-risk human papilloma virus (PCR HR-HPV) infection in biopsy-derived diagnosis of high-grade squamous intraepithelial lesions (HSIL = AIN2/AIN3) in HIV-positive men having sex with men (MSM). METHODS This is a single-centered study conducted between May 2010 and May 2014 in patients (n = 201, mean age 37 years) recruited from our outpatient clinic. Samples of anal canal mucosa were taken into liquid medium for PCR HPV analysis and for cytology. Anoscopy was performed for histology evaluation. RESULTS Anoscopy showed 33.8% were normal, 47.8% low-grade squamous intraepithelial lesions (LSIL), and 18.4% HSIL; 80.2% had HR-HPV. PCR of HR-HPV had greater sensitivity than did cytology (88.8% vs. 75.7%) in HSIL screening, with similar positive (PPV) and negative predictive value (NPV) of 20.3 vs. 22.9 and 89.7 vs. 88.1, respectively. Combining both tests increased the sensitivity and NPV of HSIL diagnosis to 100%. Correlation of cytology vs. histology was, generally, very low and PCR of HR-HPV vs. histology was non-existent (<0.2) or low (<0.4). Area under the receiver operating characteristics (AUROC) curve analysis of cytology and PCR HR-HPV for the diagnosis of HSIL was poor (<0.6). Multivariate regression analysis showed protective factors against HSIL were: viral suppression (OR: 0.312; 95%CI: 0.099-0.984), and/or syphilis infection (OR: 0.193; 95%CI: 0.045-0.827). HSIL risk was associated with HPV-68 genotype (OR: 20.1; 95%CI: 2.04-197.82). CONCLUSIONS When cytology and PCR HR-HPV findings are normal, the diagnosis of pre-malignant HSIL can be reliably ruled-out in HIV-positive patients. HPV suppression with treatment protects against the appearance of HSIL.

Dépistage du cancer du sein par l'examen physique: qui en bénéficie? [Physical examination in screening for breast cancer: who benefits?].

A survey was undertaken among a representative sample of the female population, aged 20 to 74, of the Canton of Vaud, Switzerland (total population 550,000) to assess the knowledge, attitudes and practices of women in respect to breast cancer and its prevention. The present study focuses on access by women to medical preventive measures (breast examination by physician and information on breast self-examination). The data are analyzed in relation to the individual risk factors affecting women, in particular age. While with age the risk of breast cancer grows in a linear fashion, the proportion of women having their breast examined by a physician declines. Women over 50 who had no children before the age of 30 constitute an especially high risk category, with the lowest access to information and prevention. This is explained in large part by the fact that they consult gynecologists less often. In this regard it should be noted that a visit to a gynecologist's office is associated much more often with breast examination than a visit to a family physician. It is important to take such findings into account in providing more appropriate and complete care for those groups. This involves sensitization of the physician and improved information for the women themselves.