Posttraumatic syringomyelia--a serious complication in tetra- and paraplegic patients.

Post-traumatic syringomyelia (PTS) is relatively rare, but its complications can be serious. In the beginning of the operative treatment (1900-1930), scarring could be reduced to a certain degree. In modern treatment (1980 1990) a shunt implantation showed also little effect in long-term follow-up studies. Influenced by the work of B. Williams, 58 PTS patients underwent surgery to create a pseudomeningomyelocele, an artificial CSF reservoir, performed to normalize the CSF flow. In a 10-year-postoperative follow-up study (minimum observation two years), good results were obtained in more than 70%.

Reduction in late postoperative pain after iliac crest bonegraft harvesting for cervical fusion: a controlled double-blinded study of 100 patients.

BACKGROUND: A randomized prospective double-blinded study was conducted in 100 patients suffering from mono- or bisegmental cervical retrospondylosis or disc herniation. METHOD: In group I, 50 patients were treated by injection of 10 ml Ropivacaine 7,5% at the iliac crest bonegraft donor site. Local anaesthetic (LA) was injected through the wound drainage after closure of the muscle fascia, the suction drainage was opened after closure of the skin. Group II was treated with 0,9% saline. Operator and patient were blinded to the injected substance. Daily controls of pain intensity were made with the 10 cm visual analog scale from 0 (no pain) to 10 (severe pain) for 5 days. All patients were questioned regarding pain character and movement provoking pain. Additional pain medication was standardized. FINDINGS: Statistical analysis of mean pain intensity over the whole hospital stay showed a significant difference in pain intensity between the two groups (p = 0,017, Chi-Square test). The comparison between pain intensity with LA and without LA showed a gradual increase in statistical significance from day 1 to day 5 (day 1: p = 0,54, not significant; day 2: p = 0,026; day 3: p = 0,008; day 4: p = 0,004; day 5: p = 0,002). INTERPRETATION: This data shows that intra-operative blockage of peripheral nociceptive structures results in decreased pain at later time points. We conclude that wound infiltration with 7,5% Ropivacaine after bonegraft removal at the iliac crest is effective in reducing postoperative pain.

Prospective documentation and analysis of the pre- and early clinical management in severe head injury in southern Bavaria at a population based level.

Treatment of patients suffering from severe head injury is so far restricted to general procedures, whereas specific pharmacological agents of neuroprotection including hypothermia have not been found to improve the outcome in clinical trials. Albeit effective, symptomatic measures of the preclinical rescue of patients (i.e. stabilization or reestablishment of the circulatory and respiratory system) or of the early clinical care (e.g. prompt diagnosis and treatment of an intracranial space occupying mass, maintenance of a competent circulatory and respiratory system, and others) by and large constitute the current treatment based on considerable organizational and logistical efforts. These and other components of the head injury treatment are certainly worthwhile of a systematic analysis as to their efficacy or remaining deficiencies, respectively. Deficits could be associated with delays of providing preclinical rescue procedures (e.g. until intubation of the patient or administration of fluid). Delays could also be associated in the hospital with the diagnostic establishment of intracranial lesions requiring prompt neurosurgical intervention. By support of the Federal Ministry of Education and Research and under the auspices of the Forschungsverbund Neurotraumatology, University of Munich, a prospective system analysis was carried out on major aspects of the pre- and early clinical management at a population based level in patients with traumatic brain injury. Documentation of pertinent data was made from August 1998 to July 1999 covering a catchment area of Southern Bavaria (5.6 mio inhabitants). Altogether 528 cases identified to suffer from severe head injury (GCS < or = 8 or deteriorating to that level within 48 hrs) were enrolled following admission to the hospital and establishment of the diagnosis. Further, patients dying on the scene or during transport to the hospital were also documented, particularly as to the frequency of severe head injury as underlying cause of mortality. The analysis included also cases with additional peripheral trauma (polytrauma). The efficacy of the logistics and organization of the management was studied by documentation of prognosis-relevant time intervals, as for example until arrival of the rescue squad at the scene of an accident, until intubation and administration of fluid, or upon hospital admission until establishment of the CT-diagnosis and commencement of surgery or transfer to the intensive care unit, respectively. The severity of cases studied in the present analysis is evident from a mortality of far above 40% of cases admitted to the hospital, which was increased by about 20% when including prehospital mortality. The outcome data notwithstanding, the emerging results demonstrate a high efficacy of the pre- and early clinical management, as indicated by a prompt arrival of the rescue squad at the scene, a competent prehospital and early clinical management and care, indicative of a low rate of avoidable complications. It is tentatively concluded on the basis of these findings that the patient prognosis is increasingly determined by the manifestations of primary brain damage vs. the development of secondary complications.

[Conventional and semi-open kyphoplasty]. / Kyphoplastik im konventionellen und halboffenen Verfahren.

Kyphoplasty is a young method which was developed for the minimally invasive augmentation of osteoporotic vertebral fractures. In contrast to vertebroplasty, the kyphoplasty technique allows an age-dependent fracture reduction through the inflation of a special balloon in the fractured cancellous bone of the vertebral body. The cancellous bone of the fracture zone is compressed by the balloon, so that a cavity remains in the vertebral body after removing the balloon, which is filled with highly viscous augmentation material. The reduced risk of serious complications, for example epidural leakage of augmentation material, justifies progressively expanding the indications for this technique to traumatic fractures with involvement of the posterior vertebral wall and neoplastic vertebral collapse due to osteolytic metastasis. Besides the indications for the conventional percutaneous approaches, the microsurgical interlaminary approach allows the use of kyphoplasty in more complex fractures involving compression of the neural structures. Kyphoplasty induces swift pain relief and allows rapid mobilisation of patients due to the immediate stabilisation of the affected vertebral bodies. Apart from the operative intervention, the medical treatment of the primary disease and the rehabilitation of the individual patient should be optimised through an interdisciplinary approach.

Intraoperative urodynamics in spinal cord surgery: a study of feasibility.

Intraoperative monitoring (IOM) of bladder function in spinal cord surgery is a challenging task due to vegetative influences, multilevel innervation and numerous supraspinal modulating factors. Despite routine use of urodynamics in neurosurgery for implantation of bladder stimulators or denervation of nerve fibres in spastic reflex bladders, application of IOM in patients with spinal cord tumours or tethered-cord syndrome is not widespread. Combining urodynamics with sphincter electromyography (EMG) in IOM enables identification of bladder efferents responsible for contraction and continence. We monitored four patients with ependymoma of the Cauda equina, one patient with tethered-cord syndrome and two patients with cervical intramedullary tumours. In all patients undergoing operations of the Cauda equina, identification of bladder efferents responsible for detrusor contraction was possible. There was good correlation between preoperative bladder dysfunction, preoperative urodynamics and intraoperative pressure increase by bladder contraction or latency between stimulation and contraction. This method proved unsuitable for intramedullary tumours where no contraction of the bladder could be observed while stimulating the spinal cord. Intraoperative monitoring of urodynamics is an effective tool for identifying bladder efferents in the Cauda equina. Intraoperative conclusions on bladder dysfunction through registration of pressure increase and latency are possible.

[Extended kyphoplasty indications for stabilization of osteoporotic vertebral compression fractures]. / Erweitertes Anwendungsspektrum der Kyphoplastie zur Stabilisierung der osteoporotischen Wirbelfraktur.

OBJECTIVES: Percutaneous vertebroplasty with polymethylmethacrylate allows minimally invasive stabilization of osteoporotic vertebral fractures. Fracture reduction is, however, not possible and the risk of uncontrolled epidural cement leakage with burst fractures is increased. Kyphoplasty, in contrast, allows a degree of fracture reduction and provides an extended spectrum of indications through open approaches, which enable spinal decompression and augmentation of incomplete burst fractures. METHODS. In kyphoplasty a contrast-filled balloon is inflated in the vertebra until a cavern is created. A degree of reposition may be achieved depending on fracture age. Augmentation is performed with high-viscosity polymethylmethacrylate under low pressure. In cases of neural compression, interlaminary spinal decompression and kyphoplasty through the posterior wall is performed. With anterior spinal procedures, kyphoplasty can be performed without extending the approach. RESULTS: Vertebral augmentation was performed by percutaneous, interlaminary, and anterior approaches for incomplete burst fractures. Four representative cases are presented from a collective of 120 augmentations. CONCLUSIONS: Percutaneous kyphoplasty, supplemented by open approaches, enables augmentation of osteoporotic incomplete burst fractures.

Comparison of different operative modalities in post-traumatic syringomyelia: preliminary report.

Post-traumatic syringomyelia (PTS) is a relatively rare, but potentially disastrous, complication of spinal cord injury. Operative treatment by shunting procedures often shows only a short-term improvement, and the rate of recurrence of syringomyelia is high, so different treatment modalities have been used in the last years. The various results are discussed in this analysis. A prospective clinical study was conducted of 30 patients with PTS treated by shunting procedures or with pseudomeningocele over a period of 9 years, and followed with regular clinical and magnetic resonance imaging examinations. Shunting procedures like syringosubarachnoid and syringopleural or -peritoneal shunting showed good results only at the first follow-ups. In our department, we perform an artificial liquor reservoir at the level of the lesion after opening the spinal pathways and arachnoid adhesions at that level. This procedure was performed in 12 patients. Five of these had been previously operated by shunting procedures; all of them had suffered a recurrence of syringomyelia because of internal occlusion. In the group of patients treated by shunting procedures, a neurological improvement was be recorded in five, and a steady state in eight. Five patients showed a further deterioration. The performance of an artificial liquor reservoir to guarantee a free flow of cerebrospinal fluid around the lesion resulted in a neurological improvement in ten patients, with two maintaining a steady state. Our experience is that shunting procedures often show a neurological improvement only in the short term; the rate of recurrence of typical shunting complications is high. The performance of a pseudomeningocele is an encouraging new step in the treatment of PTS. Further long-term follow-up studies are necessary to assess the benefits of this new method.

[Craniocerebral trauma in sports. With recommendations for prevention]. / Das Schädel-Hirn-Trauma im Sport. Mit Empfehlungen zur Prävention.

Traumatic brain injury (TBI) is found in many sports. A mild head injury (concussion of brain) is found in more than 80%, mainly in sports with contact to others. Especially affected by death are air sports, horse riding and cycling, whereby brain damage often is the leading injury. With the example of a cycling accident the possible processing dynamics of a mild head injury with secondary brain damage through an intracranial hematoma is demonstrated in the following. For the assessment of sports ability, there is often made the division with symptoms as confusion, amnesia and unconsciousness after a mild head injury (scale 1-3). According to the gravitational scale of cerebral concussion, an adequate sports break should be kept. Postcommotional symptoms prove sports inability. A chronic brain damage is not rarely found in some combative sports. In this case the injury may result in a traumatic encephalopathia with the evaluation of dementia and in some cases also Parkinson's disease is observed. To prevent a TBI there should be worn an adequate protective headgear especially by children in training and in sports contests concerning risk sports. Further recommendations for prevention are presented and with them there will also be responded to sports ability in neurosurgical diseases.

Evidence for specific nucleocytoplasmic transport pathways used by leucine-rich nuclear export signals.

Various proteins with different biological activities have been observed to be translocated from the nucleus to the cytoplasm in an energy- and signal-dependent manner in eukaryotic cells. This nuclear export is directed by nuclear export signals (NESs), typically characterized by hydrophobic, primarily leucine, amino acid residues. Moreover, it has been shown that CRM1/exportin 1 is an export receptor for leucine-rich NESs. However, additional NES-interacting proteins have been described. In particular, eukaryotic initiation factor 5A (eIF-5A) has been shown to be a critical cellular cofactor for the nuclear export of the HIV type 1 (HIV-1) Rev trans-activator protein. In this study we compared the nuclear export activity of NESs of different origin. Microinjection of export substrates into the nucleus of somatic cells in combination with specific inhibitors indicated that specific nuclear export pathways exist for different NES-containing proteins. In particular, inhibition of eIF-5A blocked the nuclear export of NESs derived from the HIV-1 Rev and human T cell leukemia virus type I Rex trans-activators, whereas nucleocytoplasmic translocation of the protein kinase inhibitor-NES was unaffected. In contrast, however, inhibition of CRM1/exportin 1 blocked the nuclear export of all NES-containing proteins investigated. Our data confirm that CRM1/exportin 1 is a general export receptor for leucine-rich NESs and suggest that eIF-5A acts either upstream of CRM1/exportin 1 or forms a complex with the NES and CRM1/exportin 1 in the nucleocytoplasmic translocation of the HIV-1 Rev and human T cell leukemia virus type I Rex RNA export factors.

[Surgical management of tetraplegia]. / Chirurgische Versorgung bei Tetraplegie.

The traumatic lesion of the cervical cord implies one of the most serious sequale after accident with severe consequences for lifetime. In patients with a relevant injury of the cervical spine in 28% neurological deficits are seen with an even higher incidence of 44% in the lower cervical spine. The risk of traumatic cervical cord injury further increases with progressing stenosis of the spinal canal and therefore a second peak of occurrence has to be observed in the elderly. In the preclinical phase even suspicion of a cervical cord lesion should lead to effective stabilization of the cervical spine and should be removed only after imaged proof of integrity. A high dosage therapy of methylprednisolon should be started as early as possible in every case of spinal cord injury. Diagnostic procedures are including x-rays of the whole spine, CT-scans for clearance of suspicious findings and pre-operative planning, image intensifiing under controlled stress for hidden instabilities and MRI for spinal cord injuries without abnormal radiological findings. Aims of operative treatment are consisting of decompression, reduction and stabilization with the aims of protection of the neurogenic structures and to secure intensive care treatment. These objectives can be met sufficiently by a single ventral approach in most instances. Dorsal approaches should be avoided whenever possible leaving the important innervation of the paracervical muscles intact. The postacute phase is marked by loss of systemic control mechanis as a consequence of the spinal shock. The consecutive deficits can be mastered only by treatment under intensive care standards. Respirator therapy is advisable especially for higher plegic lesions. Typical complications are frequent and should be watched for carefully because of the absence of pain sensation. Patients with cervical cord injuries should transferred to specialized paraplegic units for early rehabilitation as soon as possible since the rate of specific complications like decubital ulcera increases with the days of stay in non-specialized units.

Functional analysis of the human immunodeficiency virus type 1 Rev protein oligomerization interface.

The expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the action of the viral trans-regulatory protein Rev. Rev is a nuclear shuttle protein that directly binds to its cis-acting Rev response element (RRE) RNA target sequence. Subsequent oligomerization of Rev monomers on the RRE and interaction of Rev with a cellular cofactor(s) result in the cytoplasmic accumulation of RRE-containing viral mRNAs. Moreover, Rev by itself is exported from the nucleus to the cytoplasm. Although it has been demonstrated that Rev multimerization is critically required for Rev activity and hence for HIV-1 replication, the number of Rev monomers required to form a trans-activation-competent complex on the RRE is unknown. Here we report a systematic analysis of the putative multimerization domains within the Rev trans-activator protein. We identify the amino acid residues which are part of the proposed single hydrophobic surface patch in the Rev amino terminus that mediates intermolecular interactions. Furthermore, we show that the expression of a multimerization-deficient Rev mutant blocks HIV-1 replication in a trans-dominant (dominant-negative) fashion.

Interaction of the HIV-1 rev cofactor eukaryotic initiation factor 5A with ribosomal protein L5.

It has previously been shown that interaction of eukaryotic initiation factor 5A (eIF-5A) with the Rev trans-activator protein of HIV-1 mediates the transport of unspliced or incompletely spliced viral mRNAs across the nuclear envelope. Consequently, mutants of eIF-5A block Rev function and thereby replication of HIV-1 in trans, indicating that eIF-5A is a crucial protein that connects the viral Rev regulator with cellular RNA transport systems. Here we show that the ribosomal protein L5, which is the central protein component of the 5S rRNA export system, is a cellular interaction partner of eIF-5A. Functional studies demonstrate that overexpression of L5 protein significantly enhances Rev activity. Furthermore, Rev nuclear export activity is inhibited in human somatic cells by antibodies that recognize eIF-5A or L5. Our data suggest that the Rev export pathway shares components of a cellular transport system involved in the intracellular trafficking of polymerase III (5S rRNA) transcripts.

Inhibition of HIV-1 replication in lymphocytes by mutants of the Rev cofactor eIF-5A.

Eukaryotic initiation factor 5A(eIF-5A) is a cellular cofactor require d for the function of the human immunodeficiency virus type-1 (HIV-1) Rev trans-activator protein. The majority of a set of eIF-5A mutants did not support growth of yeast cells having an inactivated genomic copy of eIF-5A, indicating that the introduced mutation eliminated eIF-5A activity. Two nonfunctional mutants, eIF-5AM13 and eIF-5AM14, retained their binding capacity for the HIV-1 Rev response element:Rev complex. Both mutants were constitutively expressed in human T cells. When these T cells were infected with replication-competent HIV-1, virus replication was inhibited. The eIF-5AM13 and eIF5AM14 proteins blocked Rev trans-activation and Rev-mediated nuclear export.

Molecular characterization of a cDNA encoding functional human deoxyhypusine synthase and chromosomal mapping of the corresponding gene locus.

Deoxyhypusine synthase is essentially required for the post-translational formation of hypusine, a modification of a specific lysine residue in eukaryotic initiation factor 5A, which appears to be pivotal for cell proliferation. From a human peripheral blood mononuclear cells cDNA library we isolated two independent sequences encoding biologically active deoxyhypusine synthase. DNA sequence analysis revealed a 369 amino acid protein with a molecular mass of 41.055 kDa. This recombinant deoxyhypusine synthase showed significant catalytic activity in synthesis of deoxyhypusine after in vitro transcription and translation as well as upon expression in Escherichia coli. Using a panel of somatic rodent-human cell hybrids we localized the deoxyhypusine synthase gene to human chromosome 19.

[Neurologic rehabilitation in Bavaria. Study of the development of admission capacity of rehabilitation clinics 1992 to 1994]. / Neurologische Rehabilitation in Bayern. Untersuchung zur Entwicklung der Aufnahmekapazitäten der Rehabilitationskliniken 1992 bis 1994.

In order to get information about capacities of neurorehabilitation for patients with acquired brain injuries or stroke in Bavaria, a survey concerning the time interval between registration and admission of the patient (waiting period) was carried out. Structured interviews by telephone were performed and all departments of neurorehabilitation and neurosurgery in Bavaria were included. The waiting period was calculated for the last 3 years and for each phase of rehabilitation using rehabilitation phase model A-D, which was proposed by the Deutscher Verband Rentenversicherungsträger (Association of German social pension Insurancies). As a result, a significant shortening of the waiting period over the last 3 years for almost all phases of rehabilitation has been demonstrated. We therefore conclude that an over capacity may develop in Bavarian neurorehabilitation, at least in certain regions. Quantity seems to be obtained. Next goal required is control of quality.

Scanning mutagenesis of the arginine-rich region of the human immunodeficiency virus type 1 Rev trans activator.

The structural proteins of human immunodeficiency virus type 1, for example, Gag and Env, are encoded by unspliced and incompletely spliced viral transcripts. The expression of these mRNAs in the cytoplasm, along with their commensurate translation, is absolutely dependent on the virally encoded Rev trans activator. Previous studies have demonstrated that Rev binds directly to its substrate mRNAs via an arginine-rich element that also serves as its nuclear localization sequence. In an attempt to define the specific amino acid residues that are important for in vivo activity, we have constructed a series of missense mutations that scan across this region. Our data demonstrate that all eight arginine residues within this element can, individually, be substituted for either leucine or lysine with no apparent loss of function. Importantly, these findings suggest that no single amino acid within the arginine-rich domain of Rev is, by itself, essential for activity and that considerable functional redundancy is therefore likely to exist within this region. Interestingly, one mutant in which a tryptophan had been substituted for a serine failed to accumulate exclusively in the nucleus but still bound RNA in a manner that was indistinguishable from that of the wild-type protein. This observation indicates that features of the arginine-rich region that are additional to those required for RNA binding are important for Rev's correct accumulation in the nucleus.

Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.

(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug.

Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation.

Expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the presence of the viral trans-activator protein Rev. Rev is localized in the nucleus and binds specifically to the Rev response element (RRE) sequence in viral RNA. Furthermore, the interaction of the Rev activation domain with a cellular cofactor is essential for Rev function in vivo. Using cross-linking experiments and Biospecific Interaction Analysis (BIA) we identify eukaryotic initiation factor 5A (eIF-5A) as a cellular factor binding specifically to the HIV-1 Rev activation domain. Indirect immunofluorescence studies demonstrate that a significant fraction of eIF-5A localizes to the nucleus. We also provide evidence that Rev transactivation is functionally mediated by eIF-5A in Xenopus oocytes. Furthermore, we are able to block Rev function in mammalian cells by antisense inhibition of eIF-5A gene expression. Thus, regulation of HIV-1 gene expression by Rev involves the targeting of RRE-containing RNA to components of the cellular translation initiation complex.