CDKN2A promoter methylation is related to the tumor location and histological subtype and associated with Helicobacter pylori flaA(+) strains in gastric adenocarcinomas

Alves MKS, Lima VP, Ferrasi AC, Rodrigues MA, de Moura Campos Pardini MI, Rabenhorst SHB. CDKN2A promoter methylation is related to the tumor location and histological subtype and associated with Helicobacter pylori flaA(+) strains in gastric adenocarcinomas. APMIS 2010; 118: 297–307. Promoter hypermethylation of CDKN2A (p16^INK4A protein) is the main mechanism of gene inactivation. However, its association with Helicobacter pylori infection is a controversial issue. Therefore, we examined a series of gastric adenocarcinomas to assess the association between p16^INK4A inactivation and H. pylori genotype (vacA, cagA, cagE, virB11 and flaA) according to the location and histological subtype of the tumors. p16^INK4A expression and CDKN2A promoter methylation were found in 77 gastric adenocarcinoma samples by immunohistochemistry and methylation‐specific PCR, respectively. Helicobacter pylori infection and genotype were determined by PCR. A strong negative correlation between immunostaining and CDKN2A promoter region methylation was found. In diffuse subtype tumors, the inactivation of p16^INK4A by promoter methylation was unique in noncardia tumors (p = 0.022). In addition, H. pylori‐bearing flaA was associated with non‐methylation tumors (p = 0.008) and H. pylori strain bearing cagA or vacAs1m1 genes but without flaA was associated with methylated tumors (p = 0.022 and 0.003, respectively). Inactivation of p16^INK4A in intestinal and diffuse subtypes showed distinct carcinogenic pathways, depending on the tumor location. Moreover, the process of methylation of the CDKN2A promoter seems to depend on the H. pylori genotype. The present data suggest that there is a differential influence and relevance of H. pylori genotype in gastric cancer development.     

Quality assessment of the detailed anomaly ultrasound scan

Objectives: The objective of this study is to assess the quality of the views in the detailed anomaly ultrasound scan and examine the parameters that influence it.

Methods: Prospective study on singleton pregnancies examined at 20–24 weeks. Detailed views of all fetal organs were classified by the examiner as optimal/suboptimal. The duration of the examination was observed. Maternal characteristics, Fat Index (FI) (distance between the skin and the surface of the uterus), and fetal position were recorded.

Results: The study population consisted of 940 singleton pregnancies. Optimal visualization of all fetal structures was achieved in 66% of cases. Significant predictors were BMI, FI, and fetal position. None of the women with BMI?≥?44 and none of the women with FI?≥?60?mm had optimal visualization of all fetal structures. Median duration of the examination was 23?min. In 75% of cases, it was completed in the first attempt. Maternal weight, FI, and fetal position were the significant independent predictors of total examination time.

Conclusions: Optimal visualization of the fetal anatomy is restricted by maternal parameters and fetal position. The main limitation is accumulation of abdominal fat, usually but not always related to maternal obesity. The FI may be recorded as a measure of technical difficulty. The anomaly scan should be allocated at least 30?min scanning time.     

Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n?=?346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c??= .616 for HCT-CI and c??=?.647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.     

Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls

Background:  There is increasing recognition of major depressive disorder (MDD) in adolescence. In adult MDD, abnormalities of fronto-striatal and fronto-cingulate circuitries mediating cognitive control functions have been implicated in the pathogenesis and been related to problems with controlling negative thoughts. No neuroimaging studies of cognitive control functions, however, exist in paediatric depression. This study investigated whether medication-naïve adolescents with MDD show abnormal brain activation of fronto-striatal and fronto-cingulate networks when performing tasks of attentional and cognitive control.
Methods:  Event-related functional magnetic resonance imaging was used to compare brain activation between 21 medication-naïve adolescents with a first-episode of MDD aged 14–17 years and 21 healthy adolescents, matched for handedness, age, sex, demographics and IQ. Activation paradigms were tasks of selective attention (Simon task), attentional switching (Switch task), and motor response inhibition and error detection (Stop task).
Results:  In all three tasks, adolescents with depression compared to healthy controls demonstrated reduced activation in task-relevant right dorsolateral (DLPFC), inferior prefrontal cortex (IFC) and anterior cingulate gyrus (ACG). Additional areas of relatively reduced activation were in the parietal lobes during the Stop and Switch tasks, putamen, insula and temporal lobes during the Switch task and precuneus during the Simon task.
Conclusions:  This study shows first evidence that medication-naïve adolescents with MDD are characterised by abnormal function in ACG and right lateral prefrontal cortex during tasks of attention and performance monitoring, suggesting an early pathogenesis of these functional abnormalities attributed to MDD.     

First-generation endometrial ablation: roller-ball vs loop vs laser

Hysteroscopic guided or first generation endometrial ablation methods include transcervical endometrial resection, and rollerball and laser ablation. These techniques have been shown to be effective and safe alternatives to hysterectomy for dysfunctional uterine bleeding resulting in reduction in menstrual blood loss and dysmenorrhoea, correction of anaemia and improvement in quality of life. Compared with hysterectomy, treatment is associated with lower morbidity, shorter hospitalisation and faster recovery, and reduced treatment costs. As a result, the 1st generation ablation techniques are recognized as the "gold standard" ablation methods. There are many similarities between the three techniques with respect to surgical principles and effectiveness. Certainly, menstrual improvement and patient satisfaction are similar with all three methods. In contrast, the complication profile of the three techniques is different, but surgical experience is arguably a much more important arbiter of patient safety than the technique itself.     

Respiratory viruses in childhood asthma

PURPOSE OF REVIEW: Several epidemiological studies have confirmed the association between viral respiratory infections and wheezing episodes or exacerbations of asthma in childhood. In contrast, whether particular viral infections can be protective or able to initiate asthma is still debated; recent studies reported herein have added to our understanding in several different domains, including natural history, virology and mechanisms. RECENT FINDINGS: Animal studies support the possibility that severe infections with respiratory syncytial virus early in life may be able to diverge the immune response towards an allergic phenotype; however, in human studies, predisposition seems dominating. Human rhinoviruses are increasingly being shown to be equally important as respiratory syncytial virus even in infancy. Newly discovered respiratory viruses have also been associated with asthma exacerbations. The interferon pathway is currently scrutinized with respect to virus-induced inflammation; furthermore, indications that viral infections may be associated with remodeling phenotypes have been recently published. SUMMARY: Notwithstanding the progress in epidemiology and pathogenesis of virus-induced asthma, more effort is needed in assessing possible strategies for treatment. Current treatments seem to be relatively ineffective, but new pathways give a hopeful message for future therapies.     

Influenza burden,prevention, and treatment in asthma‐A scoping review by the EAACI Influenza in asthma task force

To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma‐related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma.     

CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes

Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT.Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival.Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n?=?3; 300 mg, n?=?4) and 23 for 14 days per cycle (150 mg, n?=?4; 200 mg, n?=?19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively.CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.)     

Low-level deficits in beat perception: Neither necessary nor sufficient for explaining developmental dyslexia in a consistent orthography

This article reports two different studies examining the theoretical account of low-level deficits in beat perception as an alternative explanation of developmental dyslexia in Greek, an orthographically consistent language. Study I examined the relationship of amplitude rise time and frequency discrimination with measures of phonological processing, working memory, and reading fluency in a large unselected sample of Grade 4 children. Study II examined the presence of beat perception deficits in groups of Grade 2, 4, and 6 children with dyslexia and their chronological age controls. The results provided no evidence to support meaningful associations between beat perception tasks and reading or the theoretical account of beat perception deficits as a sufficient explanation or contributing factor to dyslexia. Implications on the importance of auditory processing in reading in orthographically consistent languages are discussed.