Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage

A sequence of 11 consecutive arginine residues (11R) is one of the best protein transduction domains for introducing proteins into cell membranes. Heme-oxygenase-1 (HO-1) is involved in heme catabolism and reduces the contractile effect of hemoglobin after subarachnoid hemorrhage (SAH). Therefore, we constructed 11R-fused HO-1 protein to achieve successful transduction of the protein into the cerebral arteries and examined the therapeutic effect of the 11R-HO-1 protein for cerebral vasospasm (CV) after SAH. We injected the 11R-HO-1 protein into the cisterna magna of male rats and, several hours after the injection, performed immunofluorescence staining and western blotting analysis of the rat basilar arteries (BAs) to determine transduction efficacy. We also assessed intraarterial HO-1 activity as cGMP (cyclic guanosine 3′, 5′-cyclic monophosphate) accumulation in SAH and determined whether protein transduction of 11R-HO-1 quantified the therapeutic effect in a rat double-hemorrhage model of SAH. The BAs expressed significantly more HO-1 in the group injected with 11R-HO-1 (3.56±0.54 (11R-HO-1) versus control (saline)), and transduction of 11R-HO-1 resulted in higher activity (>3.25-fold) in rat BAs with SAH. Moreover, the results of the rat double-hemorrhage model showed that the 11R-HO-1 protein significantly attenuated CV after SAH (317.59±23.48 μm (11R-HO-1) versus 270.08±14.66 μm (11R-fused enhanced green fluorescent protein), 252.05±13.95 μm (saline), P<0.01).     

Full-endoscopic cervical arcocristectomy for the treatment of spinal stenosis: results of a cadaver study

Purpose

Cervical spondylotic myelopathy is a multifactorial disease that is directly correlated by the degree of spinal stenosis. Surgery remains the best therapy. A posterior approach is often recommended in patients with multilevel dorsal cervical compression. Aim of the present experimental study was to evaluate the feasibility of a full-endoscopic arcocristectomy in a cadaver study.

Methods

We performed full-endoscopic arcocristectomy on ten formalin-fixed human cervical specimens. Before and after decompression we obtained high-resolution computerized tomography (CT) data to evaluate the diameter of the cervical spinal canal.

Results

Overall, surgery was possible on 55 segments in ten cadaver specimens. A mean increase of 4.1 mm (±1.2 mm) in the sagittal diameter of the cervical spinal canal could be achieved (p < 0.05, t test).

Conclusions

The full-endoscopic arcrocristectomy is feasible and achieves a sufficient decompression. This minimal invasive technique protects most of the dorsal structures and therefore probably preserves biomechanical functions, which has to be proven in future studies.     

Molekularpathologie der Lunge

Lung cancer is one of the most frequent malignancies in the western world. Its frequent association with a wide spectrum of mutations in genes encoding various signal transducers that are often linked to therapy response, emphasizes the obvious need for improved, fast and highly efficient approaches in molecular pathology. Comprehensive analyses of the mutation status of progression and therapy relevant genes can be performed by the novel sequencing forms named next generation sequencing (NGS) providing extremely high capacities for ultra-deep sequence analyses. The 454 pyrosequencing method, the sequencing by synthesis and the semiconductor sequencing platform are now available for parallel sequencing approaches of multitudinous target genes linked to multiple tumor DNA applications. The “one molecule, one clone, one read” principle by the NGS approaches supplies not only information on allele frequencies and mutation rates but also has the advantage of a very sensitive detection of low frequency variants.     

Factors predicting recurrence of chronic subdural haematoma: the influence of intraoperative irrigation and low-molecular-weight heparin thromboprophylaxis

Background  

Burr-hole drainage has become the accepted treatment of choice for chronic subdural haematoma (cSDH), although still burdened with a major recurrence rate. The current analysis was initiated to determine management-related risk factors for recurrence, i.e. postoperative low-molecular-weight heparin thromboprophylaxis, and the importance of rinsing the subdural space.     

Proof of principle: supramarginal resection of cerebral metastases in eloquent brain areas

Background

Cerebral metastases are not sharply delimitatable; therefore, microsurgical circumferential stripping of intracerebral metastases is often insufficient for preventing local tumor recurrence. Supramarginal resection significantly improves local tumor control but was suggested not to be suitable for metastases in eloquent brain areas. Therefore, we retrospectively analyzed a series of patients with cerebral metastases situated in eloquent areas for newly occurring neurologic deficits after supramarginal resection performed as awake surgery.

Methods

A retrospective analysis was performed for all patients who underwent supramarginal resection for a cerebral metastasis performed as awake surgery between June 2011 and April 2012. All metastases were localized in eloquent brain areas. Pre- and postsurgical neurologic status was documented as well as data regarding the primary cancer and histopathologic data. Postoperative MRI within 72?h was scheduled routinely to verify complete resection.

Results

A total of 19 patients underwent awake surgery for a cerebral metastasis in eloquent brain areas. Surgery was well tolerated in all patients. Neurologic symptoms improved in five patients after surgery. In three patients, neurologic deficits existing before surgery worsened. The postoperative median National Institute of Health Stroke Scale (NIHSS) score did not differ from the preoperative value.

Conclusions

Awake surgery is a feasible tool for metastases in eloquent areas, minimizing postoperative neurologic deficits and morbidity. Therefore, eloquently situated metastases may also be eligible for supramarginal resection. Further studies are needed in order to analyze the benefit of this method in achieving better tumor control.     

Screening of nine vasoactive medicinal plants for their possible calcium antagonistic activity. Strategy of selection and isolation for the active principles of Olea europaea and Peucedanum ostruthium

Fourteen different extracts of nine vasoactive medicinal plants used in European and African phytotherapy and traditional medicine were pharmacologically tested for their possible calcium antagonistic mode of action. The criteria for the selection of plants were: use in traditional medicine in the treatment of cardiovascular diseases, ‘nonspecific’ spasmolytic activity (mode of action not known), natural compounds with structural similarities to already known ‘calcium-antagonists’ or calcium-antagonists that have been found in species of the same tribe. All plant extracts were investigated against contractions of aortic strips induced by K⁺-depolarization. Extracts derived from Ammi visnaga, Guajacum officinale, Olea europaea, Peucedanum ostruthium and Ruta graveolens showed a clear activity, while Cryptolepis sanguinolenta, Leonurus cardiaca, Passiflora incarnata and Solidago gigantea showed no effect in this test. A comparison between K⁺- and norepinephrine-induced contractions evaluated the selectivity of the inhibition, which is demonstrated by the isolation and identification strategy for the Ca⁺⁺-antagonistic principles of Olea europaea leaves and Peucedanum ostruthium rhizomes.     

Extramedullary Expansion of Hematopoietic Progenitor Cells in Interleukin (IL)-6–sIL-6R Double Transgenic Mice

Soluble cytokine receptors modulate the activity of their cognate ligands. Interleukin (IL)-6 in association with the soluble IL-6 receptor (sIL-6R) can activate cells expressing the gp130 signal transducer lacking the specific IL-6R. To investigate the function of the IL-6–sIL-6R complex in vivo and to discriminate the function of the IL-6–sIL-6R complex from the function of IL-6 alone, we have established a transgenic mouse model. Double-transgenic mice coexpressing IL-6 and sIL-6R were generated and compared with IL-6 and sIL-6R single-transgenic mice. The main phenotype found in IL-6–sIL-6R mice was a dramatic increase of extramedullary hematopoietic progenitor cells in liver and spleen but not in the bone marrow. In IL-6 single-transgenic mice and sIL-6R single-transgenic mice no such effects were observed. The high numbers of hematopoietic progenitor cells were reflected by a strong increase of peripheral blood cell numbers. Therefore, activators of the gp130 signal transducer like the IL-6–IL-6R complex may represent most powerful stimulators for extramedullary hematopoietic progenitor cells. gp130 activators may become important for the expansion of hematopoietic progenitor cells in vivo and in vitro.     

Role of ventriculoperitoneal shunt valve design in the treatment of pediatric hydrocephalus—a single center study of valve performance in the clinical setting

Purpose

Previous studies have established risk factors for ventriculoperitoneal shunt failure in children. However, the role of valve type as a determinant of complications and outcome remains unclear. The aim of this study was to compare the fixed-pressure paediGAV and the programmable Codman Hakim valves in the clinical setting.

Methods

We conducted a retrospective review of patients younger than 16 years who underwent primary implantation of a ventriculoperitoneal shunt with either valve type at our institution between January 2005 and December 2010. Shunt survival analyses were performed to identify variables associated with risk of shunt failure.

Results

Of the 44 patients in the paediGAV cohort, 50 % reached the endpoint of shunt failure with a mean time to shunt failure of 7 months. The Codman Hakim cohort comprised 29 patients, of which 55 % experienced shunt failure with a mean time to shunt failure of 8 months. Stratified analyses identified young age at implantation and posthemorrhagic hydrocephalus as risk factors for shunt failure. Shunt survival analysis revealed no significant difference with regard to valve type.

Conclusions

This study confirmed important risk factors for shunt failure in children. Despite certain limitations and biases, similar findings for both valves examined in the clinical setting were obtained. Thus, valve type does not seem to influence risk of shunt failure. Prospective, randomized, and controlled trials are required to validate these results.