Alcohol and substance abuse identified during pregnancy: maternal morbidity, child morbidity and welfare interventions

Aim: To study the relations between postnatal maternal morbidity, child morbidity and welfare interventions in families with prenatal alcohol or substance abuse. Methods: A register‐based longitudinal retrospective cohort study. The exposed cohort included 638 children born to 524 women followed‐up during pregnancy for alcohol or substance abuse 1992–2001. Non‐exposed children (n = 1914) born to control women were matched for maternal age, parity, number of foetuses, month of birth and delivery hospital of the index child. Perinatal and follow‐up data of both cohorts were collected from national registers until 2007. Results: Postnatal maternal abuse‐related healthcare utilization and use of medication were associated with child out‐of‐home care. Significant differences were in particular observed in the categories of maternal mental and behavioural disorders caused by psychoactive substance use as well as injury and poisoning. Maternal inpatient care for mental and behavioural disorders peaked at the time of child out‐of‐home care. Maternal abuse‐related healthcare utilization was associated with early child healthcare utilization and use of medication for mental and behavioural disorders. These associations were largely explained by the association with child out‐of‐home care. Conclusions: Postnatal maternal abuse‐related morbidity is associated with significant early child morbidity, use of medication and timing of out‐of‐home care.     

Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas

Large congenital melanocytic nevi (CMN) are at an increased risk of developing melanoma. Several forms of secondary proliferations can arise in congenital nevi on rare occasions. Although some of these closely resemble melanoma both clinically and histologically, metastasis is rare. We used comparative genomic hybridization to analyze chromosomal aberrations in different types of proliferations arising in CMN and compared them to typical congenital nevi, clear-cut melanomas arising in congenital nevi, as well as primary cutaneous melanomas that were not associated with a CMN. Cases of CMN and CMN with secondary proliferations were assigned to six groups according to the predominant histological pattern: group I, bland congenital nevi (n = 6); group II, congenital nevi with foci of increased cellularity (n = 4); group III, CMN with a proliferation simulating superficial spreading melanoma in situ (n = 3); group IV, CMN with a proliferation simulating nodular melanoma (n = 9); group V, proliferating neurocristic hamartoma (n = 1); and group VI, melanoma arising in congenital nevus (n = 6). No aberrations were found in groups I to III, whereas seven of nine cases of group IV, and one of one case of group V, showed aberrations. In group IV six of seven cases with aberrations (86%) showed numerical aberrations of whole chromosomes exclusively. This pattern differed significantly from the findings in melanoma that arose within CMN (n = 6), group VI, or independent of CMN (n = 122) in which only 5% showed numerical changes only. The single case in group V showed aberrations similar to melanoma. The finding of frequent numerical chromosomal aberrations in atypical nodular proliferations arising in CMN identifies these as clonal neoplasms with a genomic instability consistent with a mitotic spindle checkpoint defect. This difference compared to the aberration pattern found in melanoma might explain their more benign clinical behavior and may be of diagnostic value in ambiguous cases.     

Sandwich type ELISA and a fluorescent cytometric microbead assay for quantitative determination of hepatitis B virus X antigen level in human sera

The hepatitis B virus X protein (HBxAg) is responsible for severe complications of HBV infections including primary hepatocellular carcinoma. A sandwich type ELISA and a flow cytometric microbead assay for quantitative determination of serum levels of Hbx-Ag are introduced. We have previously developed monoclonal antibody families against well-conserved epitopes on HbxAg, characterized by different immunohistochemical and immunoserological techniques. Special selection of the antibody pairs provided highly sensitive and highly specific tools for quantitative immunoassay development. The resulting assays were tested on human sera (208 samples) collected from patients suffering from different clinical forms of HBV infection. The sensitivity range of the sandwich type ELISA was between 4 and 2000 ng/ml as measured on both the recombinant antigen and the sera of chronic hepatitis patients. A further flow cytometric microbead assay was established and tested in parallel with the ELISA. The quantitative results of these two immunoserological techniques were in strong correlation and they were found to be highly specific and sensitive on clinical samples. The HBxAg ELISA technique is applicable for routine clinical laboratory measurements, and our HBxAg microbead technique is recommended for complex multiparametric measurements combined with other markers.     

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

Signaling by either the TCR or glucocorticoid receptor (GR) induces apoptosis in thymocytes. Interestingly, it has been shown previously that hybridoma T cells escape apoptosis induced by either TCR or GR when both of these receptors signal simultaneously. Whether such mutual antagonism is present in primary thymocytes was the subject of the present study. Both glucocorticoids (GC) and anti-TCR/CD28 (or anti-CD3/CD28) mAb induced apoptosis in total thymocytes. When these signals were present at the same time, GC-induced apoptosis was partially inhibited by TCR/CD3 signaling. Costimulation by anti-CD28 enhanced the inhibitory effects of anti-CD3 on GC-induced apoptosis about 30-fold. However, subset analysis revealed that most cells rescued from GC-induced apoptosis were mature CD4+ and CD8+ thymocytes, and these cells were resistant to TCR/CD3-induced apoptosis in the absence of GC. Similar results were obtained with mature splenic CD4+ and CD8+ T cells. TCR/CD3 signaling alone, while inducing apoptosis in CD4+(CD8+)TCRlow thymocytes, rescued a small subset of CD4+(CD8+)TCRlow thymocytes from GC-induced apoptosis. Thus, TCR signaling increasingly reverses GC-induced apoptosis as thymocyte development progresses. As GC are infinitely present in vivo, these findings support a model wherein TCR signaling may be required to prevent GC-induced apoptosis both under basal and immune challenging conditions.     

Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. Here, we demonstrate elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS.     

The novel αB‐crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next‐generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB‐crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB‐crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.     

Diagnosis of atrial fibrillation in heart failure patients with implantable cardioverter defibrillator or cardiac resynchronisation therapy

IntroductionImplantable cardioverter defibrillators register various types of arrhythmias. Thus they can be exploited to better identify patients with atrial fibrillation episodes and increase the proportion of patients who may benefit from implementation of pharmacological prophylaxis of thromboembolic events, most of which are asymptomatic. The aim of the study was to assess of the frequency, symptoms and predisposing factors for the occurrence of atrial fibrillation episodes in patients with an implanted implantable cardioverter defibrillator (ICD) and cardiac resynchronisation therapy with defibrillator (CRT-D) based on the analysis of intracardiac electrocardiograms (EGM/IEGM) records.Material and methodsThe study included 174 consecutive outpatients with heart failure, sinus rhythm and an implanted cardioverter defibrillator and cardiac resynchronisation therapy with defibrillator. Follow-up visits with analysis of IEGM records occurred every 3 months. During a mean follow-up of 20 months, 901 visits were carried out. One hundred forty-seven patients had at least 1 year of follow-up.ResultsAtrial fibrillation episodes in the study group occurred in 54 (31.0%) patients and 71.4% were asymptomatic. Predisposing factors were: history of paroxysmal atrial fibrillation (37.0% vs. 13.3%, p < 0.001), atrioventricular conduction abnormalities (42.6% vs. 20.0%, p = 0.002), intraventricular conduction abnormalities (59.3% vs. 40.8%, p = 0.02) and more severe mitral regurgitation (7.4% vs. 0.8%, p = 0.04). Chronic renal disease was a risk factor for death in the study group. No stroke occurred during the study.ConclusionsEpisodes of paroxysmal atrial fibrillation in patients with systolic heart failure and implanted cardioverter-defibrillator systems are quite common. The majority of the episodes recorded in the study were asymptomatic.     

Quality of life in heart failure patients undergoing hybrid comprehensive telerehabilitation versus usual care – results of the Telerehabilitation in Heart Failure Patients (TELEREH-HF) Randomized Clinical Trial

IntroductionHybrid comprehensive telerehabilitation (HCTR) consisting of telecare (with psychological telesupport), telerehabilitation and remote monitoring of implantable devices might be an innovative option improving heart failure (HF) patients’ quality of life (QoL) and emotional health. The aim of the study was to investigate the influence of HCTR on various facets of QoL in HF patients in comparison with usual care (UC) alone.Material and methodsThe present analysis formed part of a multicenter, randomized trial that enrolled 850 HF patients (NYHA I–III, LVEF ≤ 40%). Patients were randomized 1 : 1 to HCTR plus UC or UC only. Patients underwent either an HCTR program or UC with observation. The psychological intervention in the HCTR group included supportive psychological counseling via mobile phone. The Medical Outcome Survey Short Form 36 Questionnaire was used to assess QoL. Measurements were made before and after a 9-week intervention (HCTR group)/observation (UC group).ResultsAfter the intervention, the HCTR group showed significant improvement in overall QoL, physical domain (PD) of QoL, and 4 areas of QoL (physical functioning (PhF), role functioning related to physical state (RF), general health (GH), vitality (VI)). A significant positive change in QoL in the UC group was observed only in VI and social functioning. There were also significant differences in QoL after 9-week intervention/observation between the two groups. The results showed greater improvement in HCTR for overall QoL (p = 0.009), PD of QoL (p = 0.0003) and three specific areas of QoL: PhF (p = 0.001), RF (p = 0.003), bodily pain (BP) (p = 0.015).ConclusionsIn comparison to UC, HCTR resulted in improvement in overall QoL, PD of QoL and 3 specific areas of QoL: PhF, RF and BP.