Prenatal Exposures, Diagnostic Outcomes, and Life Experiences of Children and Youths with Fetal Alcohol Spectrum Disorder.

Children and youths diagnosed with FASD may experience a range of adverse health and social outcomes. This cross-sectional study investigated the characteristics and outcomes of children and youths diagnosed with FASD between 2015 and 2018 at the Sunny Hill Centre in British Columbia, Canada and examined the relationships between prenatal substance exposures, FASD diagnostic categories, and adverse health and social outcomes. Patient chart data were obtained for 1187 children and youths diagnosed with FASD and analyzed. The patients (mean age: 9.7 years; range: 2-19) had up to 6 physical and 11 mental health disorders. Prenatal exposure to other substances (in addition to alcohol) significantly increased the severity of FASD diagnosis (OR: 1.18): the odds of FASD with sentinel facial features (SFF) were 41% higher with prenatal cigarette/nicotine/tobacco exposure; 75% higher with exposure to cocaine/crack; and two times higher with exposure to opioids. Maternal mental health issues and poor nutrition also increase the severity of FASD diagnosis (60% and 6%, respectively). Prenatal exposure to other substances in addition to alcohol significantly predicts involvement in the child welfare system (OR: 1.52) and current substance use when adjusted for age (aOR: 1.51). Diagnosis of FASD with SFF is associated with an increased number of physical (R2 = 0.071, F (3,1183) = 30.51, p = 0.000) and mental health comorbidities (R2 = 0.023, F (3,1185) = 9.51, p = 0.000) as compared to FASD without SFF adjusted for age and the number of prenatal substances. Screening of pregnant women for alcohol and other substance use, mental health status, and nutrition is extremely important.

Maternal alcohol use, adverse neonatal outcomes and pregnancy complications in British Columbia, Canada: a population-based study.

BACKGROUND: The current study aimed to estimate the prevalence of alcohol use identified as a risk factor during pregnancies by the antenatal care providers, resulting in live births in British Columbia (BC) and to examine associations between alcohol use, adverse neonatal outcomes, and pregnancy complications. METHODS: This population-based cross-sectional study utilized linked obstetrical and neonatal records within the BC Perinatal Data Registry (BCPDR), for deliveries that were discharged between January 1, 2015 and March 31, 2018. The main outcome measures were alcohol use identified as a risk factor during pregnancy, associated maternal characteristics, pregnancy complications, and adverse neonatal outcomes. Estimates for the period and fiscal year prevalence were calculated. Chi-square tests were used to compare adverse neonatal outcomes and pregnancy complications by alcohol use during pregnancy identified as a risk factor. Logistic regression was used to examine the association between alcohol use identified as a risk factor during pregnancy and adverse neonatal outcomes and pregnancy complications, after adjusting for identified risk factors. RESULTS: A total of 144,779 linked records within the BCPDR were examined. The period prevalence of alcohol use during pregnancy identified as a risk factor was estimated to be 1.1% and yearly prevalence was 1.1, 1.1, 1.3 and 0.9% from the 2014/2015 to 2017/2018 fiscal years, respectively. Alcohol use identified as a risk factor was associated with younger maternal age, fewer antenatal visits, being primiparous, a history of mental illness, substance use and smoking. Neonates with alcohol use during pregnancy identified as a risk factor had greater odds of being diagnosed with: "low birth weight (1000-2499g)" (ICD-10: P07.1; aOR = 1.25; 95% CI: 1.01, 1.53), "other respiration distress of newborn" (ICD-10: P22.8; aOR = 2.57; 95% CI: 1.52, 4.07), "neonatal difficulty in breastfeeding" (ICD-10: P92.5; aOR = 1.97; 95% CI: 1.27, 2.92) and "feeding problems, unspecified" (ICD-10: P92.9; aOR = 2.06; 95% CI: 1.31, 3.09). CONCLUSIONS: The prevalence of alcohol use during pregnancy identified as a risk factor was comparable to previous estimates within the BCPDR. Identified prenatal alcohol exposure was associated with notable differences in maternal and neonatal characteristics and adverse neonatal outcomes. More consistent, thorough screening and prevention efforts targeting alcohol use in pregnancy are urgently needed in Canada.

Profile of Mothers of Children with Fetal Alcohol Spectrum Disorder: A Population-Based Study in Canada.

OBJECTIVE: To compare the characteristics of mothers of children with Fetal Alcohol Spectrum Disorder (FASD) with mothers of typically developing control children. METHODS: The study utilized a cross-sectional, observational design, using active case ascertainment. Biological mothers were interviewed using a standardized retrospective questionnaire to collect data on demographics, living environment, pregnancy history, nutrition, alcohol and other drug use prior to and following pregnancy recognition. RESULTS: A total of 173 mothers were interviewed. Of these, 19 had a child who was diagnosed with FASD, five had a child who had received a deferred FASD diagnosis, and 37 had children who were selected into the control group as typically developing children. The remaining 112 mothers had children who did not meet diagnostic criteria for FASD. The mothers of children with FASD did not differ significantly from mothers of the control group children with respect to age, ethnicity, marital status, and employment status at the time of pregnancy. However, mothers of children with FASD had lower levels of education (p < 0.01) and were more likely to have received financial support (p < 0.05) at the time of pregnancy, to have smoked tobacco (p < 0.001), and to have used marijuana or hashish (p < 0.01) prior to pregnancy recognition, compared with mothers of control children. All mothers of children with FASD reported alcohol consumption prior to pregnancy recognition; however, only 10.5% reported alcohol consumption following pregnancy recognition. None of the mothers interviewed reported any drug use following pregnancy recognition. CONCLUSIONS: Population-based preventive interventions, including repeated screening, monitoring, and education regarding the effects of alcohol use, as well as other substances, before and during pregnancy, are needed to eliminate risk for FASD and other negative consequences on child and maternal health.

Expression of CMV protein pp65 in cutaneous malignant melanoma.

Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.

Population-based prevalence of fetal alcohol spectrum disorder in Canada.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is one of the most disabling potential outcomes of prenatal alcohol exposure. The population-based prevalence of FASD among the general population of Canada was unknown. The objective of this study was to determine the population-based prevalence of FASD among elementary school students, aged 7 to 9 years, in the Greater Toronto Area (GTA) in Ontario, Canada. METHODS: This screening study used a cross-sectional, observational design utilizing active case ascertainment, along with retrospective collection of prenatal alcohol exposure information. Data collection involved two phases. Phase I consisted of taking growth measurements, a dysmorphology examination, and obtaining a history of behavioral and/or learning problems. Phase II consisted of a neurodevelopmental assessment, maternal interview, and behavioral observations/ratings by parents/guardians. Final diagnostic screening conclusions were made by consensus by a team of experienced multidisciplinary experts during case conferences, using the 2005 Canadian guidelines for FASD diagnosis. The prevalence of FASD was estimated, taking into consideration the selection rate, which was used to account for students who dropped out or were lost to follow-up during each phase. Monte Carlo simulations were employed to derive the confidence interval (CI) for the point estimates. RESULTS: A total of 2555 students participated. A total of 21 cases of suspected FASD were identified. The prevalence of FASD was estimated to be 18.1 per 1000, or about 1.8%. Using a less conservative approach (sensitivity analysis), the prevalence of FASD was estimated to be 29.3 per 1000, or about 2.9%. Therefore, the population-based prevalence of FASD is likely to range between 2 and 3% among elementary school students in the GTA in Ontario, Canada. CONCLUSIONS: This study provides the first population-based estimate of the prevalence of FASD in Canada. The estimate is approximately double or possibly even triple previous crude estimates. FASD prevalence exceeds that of other common birth defects such as Down's syndrome, spina bifida, trisomy 18, as well as autism spectrum disorder in Canada. More effective prevention strategies targeting alcohol use during pregnancy, surveillance of FASD, and timely interventions and support to individuals with FASD and their families are urgently needed.

National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis.

BACKGROUND: Smoking during pregnancy has been linked to numerous adverse health consequences for both the developing fetus and mother. We estimated the prevalence of smoking during pregnancy by country, WHO region, and globally and the proportion of pregnant women who smoked during pregnancy, by frequency and quantity, on a global level. METHODS: For this systematic review and meta-analysis, we did a comprehensive systematic literature search for studies reporting the prevalence of smoking during pregnancy in the general population, published between Jan 1, 1985 and Feb 1, 2016, using several electronic bibliographic databases (CINAHL, Embase, ERIC, Medline, Medline in process, PsychINFO, Scopus, and Web of Science), without language or geographical restrictions. We included original research studies published in a peer-reviewed journal and assessed study quality using a tool specifically developed for use in systematic reviews addressing questions of prevalence. Studies were excluded if they did not include lifetime non-smokers in their sample or estimate, used a sample not generalisable to the general population of the respective country, or did not provide primary data. To estimate the prevalence by country, we did country-specific random-effects meta-analyses for countries with two or more available empirical studies, and we predicted the prevalence using a multilevel fractional response regression model with country-specific indicators for countries with one or no study. We estimated the proportion of female daily smokers who do not quit once pregnant by calculating the regional and global averages of the prevalence of daily smoking during pregnancy and of the prevalence of daily smoking in women. To estimate the global prevalence, by frequency and quantity, we did random-effects meta-analyses using available data from all countries and applied the respective proportions to the global prevalence estimate. We did a time-trend analysis using a univariate multilevel fractional response model. The review protocol is available on PROSPERO, registration number CRD42017075837. FINDINGS: Of 21 329 studies identified, 295 were retained for data extraction. We calculated estimates via meta-analysis for 43 countries and via statistical modelling for 131 countries. The three countries with the highest estimated prevalence of smoking during pregnancy were Ireland (38·4%, 95% CI 25·4-52·4), Uruguay (29·7%, 16·6-44·8), and Bulgaria (29·4%, 26·6-32·2). The global prevalence of smoking during pregnancy was estimated to be 1·7% (95% CI 0·0-4·5). The prevalence of smoking during pregnancy was 8·1% (95% CI 4·0-12·2) in the European Region, 5·9% (3·2-8·6) in the Region of the Americas, 1·2% (0·7-1·7) in the Southeast Asian Region, 1·2% (0·0-3·7) in the Western Pacific Region, 0·9% (0·0-1·9) in the Eastern Mediterranean Region, and 0·8% (0·0-2·2) in the African Region. Globally, 72·5% (95% CI 70·4-75·0) of pregnant women who smoked were daily smokers, and 27·5% (25·4-29·6) of them were occasional smokers; 51·8% (95% CI 50·0-53·5) women who smoked were light smokers, 34·8% (33·1-36·4) were moderate smokers, and 13·5% (12·3-14·7) were heavy smokers. Furthermore, the proportion of women who smoked daily and continued to smoke daily during pregnancy was 52·9% (95% CI 45·6-60·3), ranging from 30·6% (95% CI 25·6-36·4) in the European Region to 79·6% (44·2-100·0) in the Western Pacific Region. INTERPRETATION: Smoking during pregnancy is still a prevalent behaviour in many countries. These findings should inform smoking prevention programmes and health promotion strategies, as well as draw attention to the need for improved access to smoking cessation programmes for pregnant women. FUNDING: Centre for Addiction and Mental Health.

Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus.

A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-ß (Aß) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ), Aß, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HPτ in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HPτ, Aß, αS, and pTDP43, whereas IAPP showed no association with HPτ, Aß, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.

Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia.

Objectives: Prolonged global cerebral ischaemia leads to irreversible injury, often with lethal outcome. Brain injuries are partly caused by the uncontrolled reperfusion that occurs once the circulation is re-established. Recent animal experiments suggest that controlled reperfusion following lengthy ischaemia might prevent severe brain injury. This study aimed at further exploring cerebral alterations and outcome following prolonged global cerebral ischaemia and mechanically manipulated reperfusion. Methods: Three groups of pigs were included; one sham operated ( n = 3) and two that underwent 30-min global cerebral ischaemia. All vessels that supply the brain were isolated intrathoracically, after which they were occluded for 30 min in the ischaemic groups. In one of the ischaemic groups uncontrolled reperfusion was applied (URep, n = 6), i.e. normal circulation was restored 30 min after arrested cerebral circulation. The second ischaemic group received mechanical reperfusion (MRep, n = 6) with leucocyte-filtered blood at constant flow and pressure for 20 min using extracorporeal circulation following the 30-min ischaemia, after which normal blood flow resumed. All animals were monitored for 3 h after start of uncontrolled reperfusion. Haemodynamic parameters, arterial and sagittal sinus blood gases, cerebral oxygen extraction rates and intraparenchymal biomarkers using microdialysis were measured. Brain histology was performed post-mortem. Results: Global brain ischaemia led to the same extent of severe morphological changes at the level of light microscopy in the two ischaemic experimental groups, regardless of reperfusion protocol. Furthermore, no significant differences were found between the URep and MRep groups regarding cerebral blood gases or microdialysis biomarkers. Conclusions: Mechanical reperfusion following the current protocol does not modify brain alterations caused by 30 min of arrested cerebral circulation.

Actual and predicted prevalence of alcohol consumption during pregnancy in Latin America and the Caribbean: systematic literature review and meta-analysis / Prevalência real e prevista do consumo de álcool na gravidez na América Latina e Caribe: revisão sistemática da literatura e meta-análise / Prevalencia real y prevista del consumo de alcohol durante el embarazo en América Latina y el Caribe: revisión bibliográfica sistemática y metanálisis

ABSTRACT Objective To estimate the prevalence of alcohol consumption during pregnancy among the general population of Latin America and the Caribbean, by country, in 2012. Methods Three steps were taken: a comprehensive, systematic literature search; meta-analyses, assuming a random-effects model for countries with published studies; and regression modelling (data prediction) for countries with either no published studies or too few to obtain an estimate. Results Based on 24 existing studies, the pooled prevalence of alcohol consumption during pregnancy among the general population was estimated for Brazil (15.2%; 95% confidence interval [95%CI]: 10.4%–20.8%) and Mexico (1.2%; 95%CI: 0.0%–2.7%). The prevalence of alcohol consumption during pregnancy among the general population was predicted for 31 countries and ranged from 4.8% (95%CI: 4.2%–5.4%) in Cuba to 23.3% (95%CI: 20.1%–26.5%) in Grenada. Conclusions Greater prevention efforts and measures are needed in the countries of Latin America and the Caribbean to prevent pregnant women from consuming alcohol during pregnancy and decrease the rates of Fetal Alcohol Spectrum Disorder. Additional high quality studies on the prevalence of alcohol consumption during pregnancy in Latin America and the Caribbean are also needed.

RESUMO Objetivo Estimar a prevalência do consumo de álcool na gravidez na população geral da América Latina e Caribe, por país, em 2012. Métodos Três etapas foram realizadas: (i) uma busca sistemática abrangente da literatura científica, (ii) meta-análises a partir de um modelo de efeitos aleatórios para os países com estudos publicados e (iii) modelos de regressão (predição de dados) para os países sem nenhum estudo publicado ou com um número muito pequeno de estudos para obter uma estimativa. Resultados Com base em 24 estudos identificados, estimou-se a prevalência conjunta do consumo de álcool na gravidez na população geral no Brasil (15,2%; intervalo de confiança de 95% [IC 95%] 10,4%–20,8%) e no México (1,2%; IC 95% 0,0%–2,7%). A prevalência do consumo de álcool na gravidez na população geral foi prevista em 31 países, variando de 4,8% (IC 95% 4,2%–5,4%) em Cuba a 23,3% (IC 95% 20,1%–26,5%) em Granada. Conclusões Um grande esforço de prevenção com a adoção de medidas preventivas se faz necessário nos países da América Latina e Caribe para prevenir o uso de álcool entre gestantes durante a gravidez e reduzir os índices de transtornos do espectro alcoólico fetal. Também são necessários outros estudos de alta qualidade da prevalência do consumo de álcool na gravidez na América Latina e no Caribe.

RESUMEN Objetivo Calcular la prevalencia del consumo de alcohol durante el embarazo en la población general de América Latina y el Caribe desglosada por país y para el año 2012. Métodos Se siguieron tres pasos: 1) una búsqueda bibliográfica sistemática y amplia; 2) metanálisis, en los que se supuso un modelo de efectos aleatorios respecto de los países sobre los que se disponía de estudios publicados; y 3) el modelado de regresión (predicción de datos) respecto de los países sobre los que no se disponía de ningún estudio publicado o estos eran demasiado escasos para obtener estimaciones. Resultados Sobre la base de los 24 estudios existentes, se calculó la prevalencia combinada del consumo de alcohol durante el embarazo en la población general de Brasil (15,2 %; intervalo de confianza [IC] del 95 %: 10,4-20,8 %) y México (1,2 %; IC del 95 %: 0,0-2,7 %). También se calculó la prevalencia prevista del consumo de alcohol durante el embarazo en la población general de 31 países, cálculo que arrojó datos comprendidos entre 4,8 % (IC del 95 %: 4,2-5,4 %) en Cuba y 23,3 % (IC del 95%: 20,1-26,5 %) en Granada. Conclusiones Es preciso redoblar los esfuerzos de prevención e intensificar las medidas en los países de América Latina y el Caribe para impedir que las embarazadas consuman alcohol durante el embarazo a fin de reducir las tasas de los trastornos del espectro alcohólico fetal. También se deben realizar más estudios de buena calidad sobre la prevalencia del consumo de alcohol durante el embarazo en América Latina y el Caribe.

The burden of disease attributable to cannabis use in Canada in 2012.

BACKGROUND AND AIMS: Cannabis use is associated with several adverse health effects. However, little is known about the cannabis-attributable burden of disease. This study quantified the age-, sex- and adverse health effect-specific cannabis-attributable (1) mortality, (2) years of life lost due to premature mortality (YLLs), (3) years of life lost due to disability (YLDs) and (4) disability-adjusted life years (DALYs) in Canada in 2012. DESIGN: Epidemiological modeling. SETTING: Canada. PARTICIPANTS: Canadians aged ≥ 15 years in 2012. MEASUREMENTS: Using comparative risk assessment methodology, cannabis-attributable fractions were computed using Canadian exposure data and risk relations from large studies or meta-analyses. Outcome data were obtained from Canadian databases and the World Health Organization. The 95% confidence intervals (CIs) were computed using Monte Carlo methodology. FINDINGS: Cannabis use was estimated to have caused 287 deaths (95% CI = 108, 609), 10,533 YLLs (95% CI = 4760, 20,833), 55,813 YLDs (95% CI = 38,175, 74,094) and 66,346 DALYs (95% CI = 47,785, 87,207), based on causal impacts on cannabis use disorders, schizophrenia, lung cancer and road traffic injuries. Cannabis-attributable burden of disease was highest among young people, and males accounted for twice the burden than females. Cannabis use disorders were the most important single cause of the cannabis-attributable burden of disease. CONCLUSIONS: The cannabis-attributable burden of disease in Canada in 2012 included 55,813 years of life lost due to disability, caused mainly by cannabis use disorders. Although the cannabis-attributable burden of disease was substantial, it was much lower compared with other commonly used legal and illegal substances. Moreover, the evidence base for cannabis-attributable harms was smaller.

Alcohol use, smoking and their co-occurrence during pregnancy among Canadian women, 2003 to 2011/12.

INTRODUCTION: The co-occurrence of alcohol use and smoking during pregnancy has been shown to have a negative synergistic effect on fetal and perinatal risks. The objectives were to: 1) obtain an estimate of the prevalence of smoking during pregnancy in Canada by province and territory from 2003 to 2011/12; 2) determine if the prevalence of smoking during pregnancy has increased or decreased over time; 3) investigate whether smoking status is differentially associated with alcohol use during pregnancy; and 4) examine the risk factors predictive of alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy. METHODS: Secondary data analysis was conducted using five cycles of the Canadian Community Health Survey (CCHS; 2003, 2005, 2007/08, 2009/10 and 2011/12). The prevalence of smoking during pregnancy, and 95% confidence interval (CI) was calculated by province and territory and by year. The likelihood ratio test was used to determine if the prevalence of smoking during pregnancy has increased or decreased over time. The relationship between smoking status and alcohol use during pregnancy was explored using a quasi-Poisson regression model. A multinomial logistic regression model was utilized to determine which factors were predictive of alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy. RESULTS: In Canada, between 2003 and 2011/12, the weighted pooled prevalence of smoking during pregnancy was 14.3% (95% CI: 13.6%-15.0%). Women who smoked daily during pregnancy, occasionally during pregnancy, or had a lifetime history of smoking (but did not smoke while pregnant) were 2.54 (95% CI: 2.11-3.06, P < 0.0001), 2.71 (95% CI: 2.25-3.27, P < 0.0001), and 2.09 (95% CI: 1.85-2.37, P < 0.0001), respectively, times more likely to have consumed alcohol during pregnancy, compared to pregnant women who were lifetime non-smokers when controlling for age, household income, ethnicity and CCHS cycle. Risk factors that predicted alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy differed. CONCLUSION: It is apparent that smoking in any capacity, whether during pregnancy or not, increases the likelihood that a woman consumed alcohol while pregnant. Ascertaining smoking status among pregnant women and women of childbearing age could be a useful screening method for identifying those at-risk of consuming alcohol during pregnancy, and vice versa.

Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade.

Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

Subtyping of gliomas of various WHO grades by the application of immunohistochemistry.

AIMS: In 2010, four subtypes (classical, proneural, mesenchymal, and neural) of glioblastoma multiforme (GBM) were defined by molecular genetic analyses. The objective of this study was to assess whether gliomas, independently of the type and grade, could be subdivided into protein-based subtypes. METHODS AND RESULTS: A tissue microarray (TMA) approach was applied to incorporate tissue samples of low-grade and high-grade gliomas into five TMAs. High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor α, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC). Glioma could be subdivided into four subtypes by IHC. The majority of the low-grade gliomas were of the proneural subtype, i.e. high p53 expression (63% of grade II). The classical subtype, with high EGFR and low p53 expression, was most common in GBMs (39%), followed by the proneural (29%) and mesenchymal (with high CD44 and MERTK expression) (29%) subtypes, a frequency that is in line with previously published data based on molecular genetics. CONCLUSIONS: Assessment of the expression of the five proteins EGFR, CD44, MERTK, p53 and OLIG2 is sufficient for subtyping gliomas, and can be recommended for implementation in clinical practice for both low-grade and high-grade gliomas.

A study of embryonic stem cell-related proteins in human astrocytomas: identification of Nanog as a predictor of survival.

Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high-grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c-Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c-Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p = 0.0039), high-grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

Program-specific cost-effectiveness analysis: breast cancer screening policies for a safety-net program.

BACKGROUND: Every Woman Counts (EWC), a California breast cancer screening program, faced challenging budget cutbacks and policy choices. METHODS: A microsimulation model evaluated costs, outcomes, and cost-effectiveness of EWC program mammography policy options on coverage for digital mammography (which has a higher cost than film mammography but recent legislation allowed reimbursement at the lower film rate); screening eligibility age; and screening frequency. Model inputs were based on analyses of program claims data linked to California Cancer Registry data, Surveillance, Epidemiology, and End Results data, and the Medi-Cal literature. Outcomes included number of procedures, cancers, cancer deaths, costs, and incremental cost per life-year. RESULTS: Projected model outcomes matched program data closely. With restrictions on the number of clients screened, strategies starting screening at age 40 years were dominated (not cost-effective). This finding was highly robust in sensitivity analyses. Compared with no screening, biennial film mammography for women aged 50 to 64 years was projected to reduce 15-year breast cancer mortality by nearly 7.8% at $18,999 per additional life-year, annual film mammography was $106,428 per additional life-year, and digital mammography $180,333 per additional life-year. This more effective, more expensive strategy was projected to reduce breast cancer mortality by 8.6%. Under equal mammography reimbursement, biennial digital mammography beginning at age 50 years was projected to decrease 15-year breast cancer mortality by 8.6% at an incremental cost per additional life-year of $17,050. CONCLUSIONS: For the EWC program, biennial screening mammography starting at age 50 years was the most cost-effective strategy. The impact of digital mammography on life expectancy was small. Program-specific cost-effectiveness analysis can be completed in a policy-relevant time frame to assist policymakers faced with difficult program choices.

Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival.

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

Health care burden and cost associated with fetal alcohol syndrome: based on official Canadian data.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a group of disorders caused by prenatal alcohol exposure. From this group, Fetal Alcohol Syndrome (FAS) is the only disorder coded in the International Classification of Diseases, version 10 (ICD-10). This coding was used to gain an understanding on the health care utilization and the mortality rate for individuals diagnosed with FAS, as well as to estimate the associated health care costs in Canada for the most recent available fiscal year (2008-2009). METHODS: Health care utilization data associated with a diagnosis of FAS were directly obtained from the Canadian Institute for Health Information (CIHI). Mortality data associated with a diagnosis of FAS were obtained from Statistics Canada. RESULTS: The total direct health care cost of acute care, psychiatric care, day surgery, and emergency department services associated with FAS in Canada in 2008-2009, based on the official CIHI data, was about $6.7 million. The vast majority of the most responsible diagnoses, which account for the majority of a patient's length of stay in hospital, fall within the ICD-10 category Mental and Behavioural Disorders (F00-F99). It was evident that the burden and cost of acute care hospitalizations due to FAS is increasing -1.6 times greater in 2008-2009, compared to 2002-2003. The mortality data due to FAS, obtained from Statistics Canada (2000-2008), may be underreported, and are likely invalid. DISCUSSION: The official data on the utilization of health care services by individuals diagnosed with FAS are likely to be underreported and therefore, the reported cost figures are most likely underestimated. The quantification of the health care costs associated with FAS is crucial for policy developers and decision makers alike, of the impact of prenatal alcohol exposure, with the ultimate goal of initiating preventive interventions to address FASD.