[Weaning from prolonged mechanical ventilation in neurological weaning units: an evaluation of the German Working Group for early Neurorehabilitation]. / Beatmungsentwöhnung in neurologischen Weaningzentren : Eine Bestandsaufnahme der Arbeitsgemeinschaft Neurologisch-neurochirurgische Frührehabilitation.

BACKGROUND: A significant proportion of patients with long-term mechanical ventilation (MV) and difficult or prolonged weaning suffer from primary or secondary neurological conditions and concomitant functional disorders, in addition to respiratory problems. Therefore, these patients are treated in neurological weaning departments. MATERIAL AND METHODS: Using a questionnaire members of the German Working Group for early neurorehabilitation were interviewed with respect to the structure of weaning facilities, weaning strategies, patient characteristics and treatment outcome of patients admitted for weaning in 2009. RESULTS: In the year 2009 a total of 1,486 patients were admitted to 7 participating neurological weaning units. The primary diagnosis was a neurological condition in 97.5% of the patients. In 62.9% of the patients the neurological condition was considered to be primarily responsible for the MV, 22.8% demonstrated pulmonary factors and for 3.0% a cardiac condition was determined to be decisive. In 5.0% of the patients it was not possible to ascertain a single cause or factor. Weaning was successful in 69.8% of all cases, 64.9% (965 patients) were released from the facility without MV, 274 patients (18.4%) were released with MV, 61.3% of these (168 patients) were referred to other rehabilitation facilities or into the care of the family physician and 38.7% (106 patients) were transferred to other hospitals due to special medical problems. The total mortality rate was 16.6% (247 patients deceased). CONCLUSIONS: In this first comprehensive evaluation of German neurological weaning centers for patients with long-term MV, structures and treatment outcomes were compared with recent results from the literature.

Brugada-like cardiac disease in myotonic dystrophy type 2: report of two unrelated patients.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystem disorder caused by CCTG repeat expansions within intron 1 of the ZNF9 gene on chromosome 3q. Cardiac conduction disturbances, supraventricular arrhythmias, and cardiomyopathy are described in DM2 but Brugada-like features have not yet been reported. Brugada syndrome (BS) is a genetically heterogeneous cardiac conduction disorder which is characterized by a significant ST-segment elevation upon ECG evaluations and bears an increased risk for sudden cardiac death. CASE REPORTS: We report two unrelated patients with genetically confirmed DM2 who developed clinical relevant cardiac arrhythmias with syncopal events from 35 (patient 1) and 47 years (patient 2). Brugada-like ECG findings were present in both patients. Family history was negative for BS, but the mothers of both index patients were also affected by DM2 and had different ventricular rhythm disturbances. SCN5A gene sequencing revealed an unknown genetic variant c.4140 C > A, p.N1380K, in patient 1, while no mutation was detected in patient 2. DISCUSSION: Our observations may suggest that Brugada-like cardiac arrhythmias can occur in DM2, as this seems also to be the case in DM1. The chance association of two independent inherited disorders has to be considered and cannot be excluded in one of our patients. However, on statistical grounds, this possibility cannot explain all observed cases of DM with Brugada-like cardiac disease.

[Long-term course of patients in neurological rehabilitation Phase B. Results of the 6-year follow-up in a multicenter study]. / Langzeitverlauf von Patienten der neurologischen Rehabilitation Phase B. Ergebnisse der 6-Jahres-Nachuntersuchung einer Multicenterstudie.

BACKGROUND: After conclusion of emergency care for severe neurological diseases patients in Germany are admitted at an early stage to so-called Phase B rehabilitation. No studies have been carried out on the long-term course of these patients. PATIENTS AND METHODS: In a prospective study in 2002 patients in Phase B from 9 centers were included and follow-up investigations were carried out after 5 and 6 years. Assessment instruments used were the Barthel index, the Rankin scale and the EQ-5D. Factors for the risk of a poor outcome and the chances for a good outcome were evaluated using multivariate logistic regression. RESULTS: A total of 1,280 patients were included in the study. A high age increased the risk of dying with a hazard quotient (HQ) of 1.05 (95% CI: 1.04-1.06) and high point counts in the coma remission scale (HQ 0.93; 95% CI: 0.92-0.96) and Barthel index (HQ 0.97; 95% CI: 0.97-0.98) on discharge reduced the risk of dying after 5 years. The factors swallowing impairment (OR 3.1; 95% CI: 1.7-5.5) and obligatory surveillance at the end of rehabilitation (OR 3.2; 95% CI: 1.2-8.6) increased the risk of a poor result in the Rankin scale 2-4 and the factors communication disorder (OR 5.0; 95% CI: 2.0-12.8) and PEG (percutaneous endoscopic gastrostomy) (OR 19.7; 95% CI: 2.7-144.4) on discharge increased the risk of a reduced health-related quality of life (defined as EQ-5D VAS <70) after 6 years. CONCLUSIONS: If support for bodily functions can be successfully reduced during Phase B rehabilitation, the patients will have a good outcome with respect to 5-year survival. If this is not successful the outcome is unfavorable with respect to survival and with respect to achieving self-sufficiency and health-related quality of life after 6 years.

Intracellular neuronal calcium sensor (NCS) protein VILIP-1 modulates cGMP signalling pathways in transfected neural cells and cerebellar granule neurones.

The family of intracellular neuronal calcium-sensors (NCS) belongs to the superfamily of EF-hand proteins. Family members have been shown by in vitro assays to regulate signal cascades in retinal photoreceptor cells. To study the functions of NCS proteins not expressed in photoreceptor cells we examined Visinin-like protein-1 (VILIP-1) effects on signalling pathways in living neural cells. Visinin-like protein-1 expression increased cGMP levels in transfected C6 and PC12 cells. Interestingly, in transfected PC12 cells stimulation was dependent on the subcellular localization of VILIP-1. In cells transfected with membrane-associated wild-type VILIP-1 particulate guanylyl cyclase (GC) was stimulated more strongly than soluble GC. In contrast, deletion of the N-terminal myristoylation site resulted in cytosolic localization of VILIP-1 and enhanced stimulation of soluble GC. To study the molecular mechanisms underlying GC stimulation VILIP-1 was examined to see if it can physically interact with GCs. A direct physical interaction of VILIP-1 with the recombinant catalytic domain of particulate GCs-A, B and with native GCs enriched from rat brain was observed in GST pull-down as well as in surface plasmon resonance interaction studies. Furthermore, following trituration of recombinant VILIP-1 protein into cerebellar granule cells the protein influenced only signalling by GC-B. Together with the observed colocalization of GC-B, but not GC-A, with VILIP-1 in cerebellar granule cells, these results suggest that VILIP-1 may be a physiological regulator of GC-B.

Invertebrate synapsins: a single gene codes for several isoforms in Drosophila.

Vertebrate synapsins constitute a family of synaptic proteins that participate in the regulation of neurotransmitter release. Information on the presence of synapsin homologs in invertebrates has been inconclusive. We have now cloned a Drosophila gene coding for at least two inferred proteins that both contain a region with 50% amino acid identity to the highly conserved vesicle- and actin-binding "C" domain of vertebrate synapsins. Within the C domain coding sequence, the positions of two introns have been conserved exactly from fly to human. The positions of three additional introns within this domain are similar. The Drosophila synapsin gene (Syn) is widely expressed in the nervous system of the fly. The gene products are detected in all or nearly all conventional synaptic terminals. A single amber (UAG) stop codon terminates the open reading frame (ORF1) of the most abundant transcript of the Syn gene 140 amino acid codons downstream of the homology domain. Unexpectedly, the stop codon is followed by another 443 in-frame amino acid codons (ORF2). Using different antibodies directed against ORF1 or ORF2, we demonstrate that in the adult fly small and large synapsin isoforms are generated. The small isoforms are only recognized by antibodies against ORF1; the large isoforms bind both kinds of antibodies. We suggest that the large synapsin isoform in Drosophila may be generated by UAG read-through. Implications of such an unconventional mechanism for the generation of protein diversity from a single gene are discussed.

Overexpression of bcl-2 results in reduction of cytochrome c content and inhibition of complex I activity.

Bcl-2 has been shown to exert its antiapoptotic activity predominantly at the level of mitochondria by preventing cytochrome c release. Whether Bcl-2 is involved in the regulation of mitochondrial function prior to an apoptotic stimulus remains elusive. Using functional and spectrophotometric measurements in an inducible PC12-Tet-on-bcl-2 cell line we demonstrate that induction of Bcl-2 overexpression rapidly reduced cytochrome b and c levels as well as complex I activity. To confirm that these changes were specific for Bcl-2 we generated a bcl-2 antisense construct under the control of the tetracycline responsive promotor. Transient transfection with this antisense plasmid prevented both the decrease of cytochrome b and c levels and the loss of complex I activity. The decrease of cytochrome b levels was paralleled by a decrease of cytochrome b mRNA levels while Northern blot analysis of cytochrome c mRNA expression did not reveal any overt changes in Bcl-2 cells. We propose that the antiapoptotic properties of Bcl-2 are related to the reduction of mitochondrial complex I activity and lowered mitochondrial cytochrome b and c levels.