Prevalence, subtypes, and correlates of DSM-IV conduct disorder in the National Comorbidity Survey Replication

Background Prior research indicates that conduct disorder (CD) is associated with a range of comorbid mental disorders. However, the actual prevalence, subtypes, and patterns of comorbidity of DSM-IV defined CD in the general U.S. population remains unknown. Method Retrospective assessment of CD and other DSM-IV disorders was conducted using fully structured diagnostic interviews among a nationally representative sample of respondents (n = 3,199) in the National Comorbidity Survey Replication. Results The estimated lifetime prevalence of CD in the U.S. is 9.5% (males = 12.0%, females = 7.1%), with a median age-of-onset of 11.6 (0.2) years. Latent class analysis identified five CD subtypes characterized by rule violations, deceit/theft, aggression, severe covert behaviors, and pervasive CD symptoms. A dose-response relationship was revealed between CD subtype severity and risk of subsequent disorders. Results also indicated that CD typically precedes mood and substance use disorders, but most often occurs after impulse control and anxiety disorders. Although both active and remitted CD is associated with increased risk of the subsequent first onset of other mental disorders, remitted CD is associated with significantly lower risk of subsequent disorders. Conclusions CD is prevalent and heterogeneous in the U.S. population, and more severe subtypes and the presence of active CD are associated with higher risk of comorbid disorders. Future prospective studies using general population samples will further inform the nature and course of this disorder.Psycholog

The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases

Since the creation of the first transgenic rabbit thirty years ago, pronuclear microinjection remained the single applied method and resulted in numerous important rabbit models of human diseases, including cardiac deficiencies, albeit with low efficiency. For additive transgenesis a novel transposon mediated method, e.g., the Sleeping Beauty transgenesis, increased the efficiency, and its application to create cardiac disease models is expected in the near future. The targeted genome engineering nuclease family, e.g., the zink finger nuclease (ZFN), the transcription activator-like effector nuclease (TALEN) and the newest, clustered regularly interspaced short palindromic repeats (CRISPR) with the CRISPR associated effector protein (CAS), revolutionized the non-mouse transgenesis. The latest gene-targeting technology, the CRISPR/CAS system, was proven to be efficient in rabbit to create multi-gene knockout models. In the future, the number of tailor-made rabbit models produced with one of the above mentioned methods is expected to exponentially increase and to provide adequate models of heart diseases

Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias

Background and Purpose Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S , loss of IKr; LQT2), KCNE1 (KCNE1‐G52R , decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart. Experimental Approach Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts. Key Results LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. Conclusion and Implications LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates

Serotonergic regulation of the buccal (feeding) rhythm of the pond snail, Lymnaea stagnalis. An immunocytochemical, biochemical and pharmacological approach

Hatching is an important phase of the development of pulmonate gastropods followed by the adult-like extracapsular foraging life. Right before hatching the juveniles start to display a rhythmic radula movement, executed by the buccal complex, consisting of the buccal musculature (mass) and a pair of the buccal ganglia. In order to have a detailed insight into this process, we investigated the serotonergic regulation of the buccal (feeding) rhythm in 100% stage embryos of the pond snail, Lymnaea stagnalis, applying quantitative immunohistochemistry combined with the pharmacological manipulation of the serotonin (5-HT) synthesis, by either stimulating (by the 5-HT precursor 5-hydroxytryptophan, 5-HTP) or inhibiting (by the 5-HT synthesis blocker para-chlorophenylalanine, pCPA) it. Corresponding to the direction of the drug effect, significant changes of the fluorescence intensity could be detected both in the cerebral ganglia and the buccal complex. HPLC-MS assay demonstrated that 5-HTP increased meanwhile pCPA decreased the 5-HT content both of the central ganglia and the buccal complex. As to the feeding activity, 5-HTP induced only a slight (20%) increase, whereas the pCPA resulted in a 20% decrease of the radula protrusion frequency. Inhibition of 5-HT re-uptake by clomipramine reduced the frequency by 75%. The results prove the role of both central and peripheral 5-HTergic processes in the regulation of feeding activity. Application of specific receptor agonists and antagonists revealed that activation of a 5-HT1-like receptor depressed the feeding activity, meanwhile activation of a 5-HT6,7-like receptor enhanced it. Saturation binding plot of [3H]-5-HT to receptor and binding experiments performed on membrane pellets prepared from the buccal mass indicated the presence of a 5-HT6-like receptor positively coupled to cAMP. The results suggest that 5-HT influences the buccal (feeding) rhythmic activity in two ways: an inhibitory action is probably exerted via 5-HT1-like receptors, while an excitatory action is realized through 5-HT6,7-like receptors

Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Association of colorectal adenoma with other malignancies in Swedish families

Using the Swedish Family-Cancer Database covering over 11.5 million individuals, estimated relative risks (RRs) for colorectal adenoma were using Poisson's regression. The RR of colorectal adenoma was found to be increased among first-degree relatives of patients with colorectal cancer (2.72; 95% confidence interval=2.46–3.00) and among the offspring and siblings of patients with endometrial and prostate cancers. We also found an increased risk of colorectal adenoma for the offspring of individuals with stomach cancer and leukaemia, and for siblings of those with pancreatic cancer and multiple myeloma. Our results suggest that colorectal adenoma may share a genetic aetiology with cancer even at extracolorectal sites. Increases of colorectal adenoma in families affected by prostate cancer and acute leukaemia cannot be attributed to known cancer syndromes, although the play of chance cannot be excluded

Familial association of pancreatic cancer with other malignancies in Swedish families

BACKGROUND: The aim of this study was to characterise the familial association of pancreatic cancer with other malignancies. METHODS: Relative risks (RRs) of pancreatic cancer according to family history of cancer were calculated using the updated Swedish Family-Cancer Database, which includes over 11.5 million individuals. Estimates were based on Poisson regression. RRs of tumours for individuals with a parental history of pancreatic cancer were also estimated. RESULTS: The risk of pancreatic cancer was elevated in individuals with a parental history of cancers of the liver (RR 1.41; 95% CI 1.10-1.81), kidney (RR 1.37; 95% CI 1.06-1.76), lung (RR 1.50; 95% CI 1.27-1.79) and larynx (RR 1.98; 95% CI 1.19-3.28). Associations were also found between parental history of pancreatic cancer and cancers of the small intestine, colon, breast, lung, testis and cervix in offspring. There was an increased risk of pancreatic cancer associated with early-onset breast cancer in siblings. CONCLUSION: Pancreatic cancer aggregates in families with several types of cancer. Smoking may contribute to the familial aggregation of pancreatic and lung tumours, and the familial clustering of pancreatic and breast cancer could be partially explained by inherited mutations in the BRCA2 gene. British Journal of Cancer (2009) 101, 1792-1797. doi: 10.1038/sj.bjc.6605363 www.bjcancer.com Published online 13 October 2009 (C) 2009 Cancer Research U

Survival of endometrial cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage

<p>Abstract</p> <p>Background</p> <p>Population-based studies on endometrial cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for endometrial cancer patients in Germany.</p> <p>Methods</p> <p>We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. 30,906 patients diagnosed with endometrial cancer in 1997-2006 were included. Period analysis was performed to calculate 5-year relative survival (RS) in 2002-2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age-adjustment was performed using five age groups (15-44, 45-54, 55-64, 65-74, and 75+ years).</p> <p>Results</p> <p>Overall, age-adjusted 5-year relative survival in 2002-2006 was 81%. A moderate age gradient was observed, with 5-year RS decreasing from 90% in the age group 15-49 years to 75% in the age group 70+ years. Furthermore prognosis varied strongly by histologic subtypes and stage, with age-adjusted 5-year RS ranging from 43% (for sarcoma) to 94% (for squamous metaplasia), and reaching 91% for localized, 51% for regional, and 20% for distant stage. Except for age group 65-74 years, no significant improvement in survival was seen during the recent 5-year period under investigation.</p> <p>Conclusion</p> <p>In this comprehensive population-based survival analysis of patients with endometrial cancer from Germany, prognosis of endometrial cancer moderately varied by age, and strongly varied by histology and stage. While prognosis is rather good overall, further improvement in 5-year relative survival of endometrial cancer patients has been stagnating in the early 21^stcentury.</p

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives

Background Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies

Population level survival of patients with chronic myelocytic leukemia in Germany compared to the US in the early 21st century

INTRODUCTION: The advent of tyrosine kinase inhibitors has produced 5-year survival of 90 + % for chronic myelocytic leukemia (CML) patients in clinical trials. However, population level survival has been lower, especially in older patients. Here, we examine survival of patients with CML in Germany and compare it to survival of patients in the United States (US). METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients 15–69 years old diagnosed with CML were included in the analysis. Period analysis for 2002–2006 was used to provide the most up-to-date possible estimates of five-year relative survival. RESULTS: Five-year relative survival was 68.7% overall in Germany and 72.7% in the US. Survival was higher in the US for all age groups except for ages 15–39 years, but the difference was only statistically significant for ages 50–59 years (at 67.5% vs 77.7% in Germany and the US, respectively). Survival decreased with age, ranging from 83.1% and 81.9%, respectively, in Germany and the US for patients 15–39 years old to 54.2% and 54.5%, respectively, in patients 65–69 years old. Survival increased between 2002 and 2006 by 12.0% points in Germany and 17.1% points in the US. CONCLUSIONS: Five-year survival estimates were higher in the US than in Germany overall, but the difference was only significant for ages 50–59 years. Survival did not equal that seen in clinical trials for either country, but strong improvement in survival was seen between 2002 and 2006