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Purpose: Many international guidelines recommend induction of labour beyond 41 weeks to reduce perinatal morbidity and mortality. In 2010, a new German guideline with this recommendation was published. The aim of this study was to investigate whether this recommendation influenced clinical outcome., Material and Methods: All cases with induction of labour beyond 40 weeks in 2008, 2009, 2011 and 2012 were examined. Multiple pregnancy and Caesarean section in the case history were exclusion criteria. The years before publication of the new German guideline (2008 and 2009) were compared with those afterwards (2011 and 2012) with regard to several outcome parameters like rate of labour induction, efficacy of induction of labour and foetal outcome., Results: After publication of the guideline there were more inductions of labour undertaken (300 [11.2%] vs. 472 [15.4%], p<0.0001) with less pregnancies beyond 42 weeks (9 [3%] vs. 5 [1%], p=0.0489). However, there was no difference concerning the efficacy of induction of labour, e. g., the ratio of Caesarean sections was not increased. There was no impairment of foetal outcome, in contrast, the ratio of postpartal admission to NICU was decreased (42 [14.2%] vs. 31 [6.7%], p=0.0006)., Conclusion: The new recommendation of the German guideline to induce labour beyond 41 weeks leads to more cases with induction of labour without any negative impact on its efficacy or foetal outcome., (© Georg Thieme Verlag KG Stuttgart · New York.)

Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C-->T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3-10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.

Objectives: We sought to determine the impact of implantable cardioverter-defibrillator (ICD) therapy in patients with familial arrhythmogenic right ventricular cardiomyopathy (ARVC)., Background: Arrhythmogenic right ventricular cardiomyopathy is a cause of sudden cardiac death, which may be prevented by ICD., Methods: We studied 11 families in which a 3p25 deoxyribonucleic acid (DNA) haplotype at locus ARVD5 segregated with disease and compared mortality in subjects who received an ICD with that in control subjects who were matched for age, gender, ARVC status, and family. Subjects (n = 367) at 50% a priori risk of inheriting ARVC were classified as high risk (HR) (n = 197), low risk (n = 92), or unknown (n = 78) on the basis of clinical events, DNA haplotyping, and/or pedigree position. Forty-eight HR subjects (30 males, [median age 32 years] and 18 females [median age 41 years]) were followed after ICD (secondary to ventricular tachycardia [VT] in 27%). Survival was compared with 58 HR control subjects who were alive at the same age to-the-day at which the ICD subject received the device., Results: In the HR group, 50% of males were dead by 39 years and females by 71 years: relative risk of death was 5.1 (95% confidence interval 3 to 8.5) for males. The five-year mortality rate after ICD in males was zero compared with 28% in control subjects (p = 0.009). Within five years, the ICD fired for VT in 70% and for VT >240 beats/min in 30%, with no difference in discharge rate when analyzed by ICD indication., Conclusions: The unknown mutation at the ARVD5 locus causing ARVC results in high mortality. Risk stratification using genetic haplotyping and ICD therapy produced improved survival for males.

The heparin-binding protein vascular endothelial growth factor (VEGF) is a highly specific growth factor for endothelial cells. VEGF binds to specific tyrosine kinase receptors, which mediate intracellular signaling. We investigated 2 hypotheses: (1) VEGF affects intracellular calcium [Ca2+]i regulation and [Ca2+]i-dependent messenger systems; and (2) these mechanisms are important for VEGF's proliferative effects. [Ca2+]i was measured in human umbilical vein endothelial cells using fura-2 and fluo-3. Protein kinase C (PKC) activity was measured by histone-like pseudosubstrate phosphorylation. PKC isoform distribution was observed with confocal microscopy and Western blot. Inhibition of PKC isoforms was assessed by specific antisense oligonucleotides (ODN) for the PKC isoforms. VEGF (10 ng/mL) induced a transient increase in [Ca2+]i followed by a sustained elevation. The sustained [Ca2+]i plateau was abolished by EGTA. Pertussis toxin also abolished the plateau phase, whereas the initial peak was not affected. The PKC isoforms alpha, delta, epsilon, and zeta were identified in endothelial cells. VEGF induced a translocation of PKC-alpha and PKC-zeta toward the nucleus and the perinuclear area, whereas cellular distribution of PKC-delta and PKC-epsilon was not influenced. Cell exposure to TPA led to a down-regulation of PKC-alpha and reduced the proliferative effect of VEGF. VEGF-induced endothelial cell proliferation also was reduced by the PKC inhibitors staurosporine and calphostin C. Specific down-regulation of PKC-alpha and PKC-zeta with antisense ODN reduced the proliferative effect of VEGF significantly. Our data show that VEGF induces initial and sustained Ca2+ influx. VEGF leads to the translocation of the [Ca2+]i-sensitive PKC isoform alpha and the atypical PKC isoform zeta. Antisense ODN for these PKC isoforms block VEGF-induced proliferation. These findings suggest that PKC isoforms alpha and zeta are important for VEGF's angiogenic effects.

Binding of the poorly hydrolyzable GTP analog, guanosine 5'-[gamma-thio]triphosphate (GTP[S]), to purified guanine-nucleotide-binding regulatory proteins (G proteins) has been shown to be nonreversible in the presence of millimolar concentrations of Mg2+. In porcine atrial membranes, binding of [35S]GTP[S] to G proteins was stable in the presence of 1 mM Mg2+. However, either large dilution or, even more strongly, addition of unlabelled guanine nucleotides, in the potency order, GTP[S] greater than GTP greater than or equal to guanosine 5'-[beta,gamma-imino]triphosphate greater than GDP greater than or equal to guanosine 5'-[beta-thio]diphosphate greater than GMP, markedly enhanced the observed dissociation, with 20-30% of bound [35S]GTP[S] being released by unlabelled guanine nucleotide within 20 min at 25 degrees C. Most interestingly, dissociation of [35S]GTP[S] was rapidly and markedly stimulated by agonist (carbachol) activation of cardiac muscarinic acetylcholine receptors. Carbachol-stimulated release of [35S]GTP[S] was strictly dependent on the presence of Mg2+ and an unlabelled guanine nucleotide. Although having different potency and efficiency in releasing [35S]GTP[S] from the membranes by themselves, the guanine nucleoside triphosphates and diphosphates studied, at maximally effective concentrations, promoted the carbachol-induced dissociation to the same extent, while GMP and ATP were ineffective. GTP[S]-binding-saturation experiments indicated that one agonist-activated muscarinic acetylcholine receptor can cause release of bound GTP[S] from three to four G proteins. The data presented indicate that binding of GTP[S] to G proteins in intact membranes, in contrast to purified G proteins, is reversible, and that agonist-activated receptors can even, either directly or indirectly, interact with GTP[S]-bound G proteins, resulting in release of bound guanine nucleoside triphosphate.