Patent foramen ovale closure. Pro and cons

Because patent foramen ovale (PFO) represents a lesion which may be repaired a number of expert clinicians believe that mechanical closure should be the primary treatment modality for patients with PFO after cryptogenic stroke; interest has grown on percutaneous devices and in the last years there has been great technological advancement of percutaneous techniques for PFO closure. However, we should not close a PFO before establishing the evidence-based indications. At the same time, efforts to develop safer and more effective closure devices are under way. These devices include those with little or no metal component and those with biodegradable discs. Ideally, we should be able to identify at-risk patients before they sustain a stroke and to prevent stroke by closing the PFO with a device that should result in complete closure, be made of material that conforms to both sides of the septum, and have no risk of erosion, infection, arrhythmia, or thrombogenicity. Randomised trials comparing medical and percutaneous closure approaches are underway, but large patient enrollment is necessary because of the low event rate in the younger patients. Meanwhile, as the complication rate from device implantation decreases and simpler devices are developed with reliability further demonstrated, the threshold for percutaneous closure is likely to decline.     

A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations

A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Abeta42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Abeta42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function.     

EEG Is an Essential Clinical Tool: Pro and Con

Summary:  The authors debate whether routine EEG is an essential clinical tool for evaluation of a first seizure. One author suggests that because of the positive predictive value of interictal spikes for seizure recurrence, the EEG is a useful tool. The other author argues that since many clinicians would not treat after a single seizure, even if the EEG were abnormal, the EEG is not essential. Both authors agree that the EEG should only be ordered with forethought to answer a specific question.     

Pro and contra: maintaining drug dependent patients on methadone

Two controversial essays published in this journal referring to methadone-maintenance of drug addicts are reviewed in respect to the medico-legal situation in Germany. Requirements for a broad scope of action for medically justified therapies are discussed. In view of politically or governmentally initiated methadone-programs, the need for medically reasonable and careful decisions on individual cases is pointed out. Instead of conflicting ideologies, empirically proved and scientifically controlled knowledge has to be worked out.     

Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency

A dimorphism in PROS1 gene (c.A2,001G, p.Pro667Pro) has been associated with significantly reduced levels of both free and total protein S in carriers of the GG genotype. It is not known how the GG genotype could influence PS levels in normals, whether it could influence the levels of protein S in carriers of mutations in PROS1 gene and whether this genotype acts as an isolated or additive risk factor for venous thrombosis. With this as background, we evaluated the association of p.Pro667Pro dimorphism with free and total protein S centrally measured in a panel of 119 normal controls, 222 individuals with low protein S and 137 individuals with normal PS levels belonging to 76 families with protein S deficiency enrolled in the ProSIT study. Transient expression of recombinant wild type protein S and p.Pro667Pro protein S was performed to evaluate the role of the A to G transition at position 2001 in vitro. The p.Pro667Pro polymorphism was also expressed together with a p.Glu67Ala variant to assess a possible influence on protein S levels in protein S deficient subjects. Free and total protein S levels were significantly lower in normal women. In normal women only was the GG genotype associated with significantly lower free protein S levels in comparison to AA and AG genotypes (P=0.032). No significant influence of GG genotype was observed in patients, either with known mutations or with low protein S levels. These data were confirmed by in vitro transient expression, showing no difference in secretion levels of the p.Pro667Pro variant (even in association with the p.Glu67Ala mutation), compared to the wild type protein S. The genotype in itself was neither a significant risk factor for venous thrombosis nor a risk modifier in patients with known mutations.