Biomedical subjects

Tiit Mathiesen

Publications and source records attributed to Tiit Mathiesen.

31 records · Page 2Linked to original sources

PubMed2004

Preservation of tap vestibular evoked myogenic potentials despite resection of the inferior vestibular nerve.

Sound and skull-tap induced vestibular evoked myogenic potentials (VEMP) were studied in a 43-year-old man following inferior vestibular neurectomy. Surgery was performed because of a small acoustic neuroma. Postoperative caloric testing suggested sparing of superior vestibular nerve function on the operated side. In response to sound stimulation there were no VEMP on the operated side, irrespective of whether sounds were presented by air- or bone-conduction. This suggests sound-induced VEMP to be critically dependent on inferior vestibular nerve function and this is in agreement with present knowledge. However, VEMP were obtained in response to forehead skull taps, i.e. positive-negative VEMP not only on the healthy side but also on the operated side. This suggests remnant vestibular function on the operated side of importance for forehead skull tap VEMP, because with complete unilateral vestibular loss there are no (positive-negative) VEMP on the lesioned side. Thus, forehead skull-tap VEMP depend, at least partly, on the superior vestibular nerve function.

Acoustic Stimulation↗

PubMed2003

Neuroprotection by human neural progenitor cells after experimental contusion in rats.

Neural progenitor/stem cells (HNPC) have been suggested to contribute essential trophic factors and promote survival of degenerating neurons after traumatic brain injury. For these reasons we hypothesize that the addition of HNPC to a post-injury region could possibly protect injured neurons. Experimental brain contusions were carried out in 18 rats. Immediately post-injury, rats were injected with 0.1 ml of medium (n=8), dead cells (n=4), or live cells (n=6) in the medial border of the lesion. The rats were sacrificed 6 days post-surgery and evaluated by immunohistochemistry using a human nuclear marker (huN), hematoxylin and Fluoro-Jade (FJ). Human neural stem cells showed engraftment detectable by positive huN staining in 5/6 animals. The non-grafted animal was excluded from further analyses. Those given dead HNPC or medium showed no detectable huN immunoreactivity. A statistical comparison between the numbers of FJ positive degenerating endogenous neurons was made between rats receiving vehicle and dead cells to evaluate whether the presence of human cells would increase neuronal degeneration in comparison to vehicle alone. The rats receiving vehicle had a median of 117.5 FJ positive cells and dead progenitor cell recipients 175.0 per counted section (P<0.05, Mann-Whitney). Consequently, the animals receiving dead human cells were chosen as controls to the animals receiving live progenitor cells. The rats that received live HNPC demonstrated significantly fewer FJ positive cells per counted section than controls (58.0 vs. 175.0, P<0.01, Mann-Whitney). The post-traumatic perilesional environment allowed for the engraftment of live HNPC. The stepwise analysis indicated that host neuronal degeneration was higher in animals transplanted with non-viable human neuronal progenitor cells than in those receiving vehicle, indicating a bystander effect from introducing foreign antigen. In contrast, transplantation of viable progenitor cells attenuated neuronal degeneration, indicating that a potentially beneficial effect in progenitor cell transplantation is not limited to restoration by transplanted cells, but also improving survival of host cells.

Animals↗

PubMed2003

Increases in matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 mRNA after cerebral contusion and depolarisation.

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play major roles in physiological extracellular matrix turnover during normal development and in pathological processes. In brain, increases in MMP activity occur, for example, in multiple sclerosis, Alzheimer's disease, and after head trauma. We examined MMP-9 and TIMP-1, -2, and -3 in events after head trauma. A time-course study was carried out using two different rat injury models, cerebral contusion and depolarisation. Brains were analysed by RT-PCR and in situ hybridisation. We observed a distinct and time-dependent upregulation of MMP-9 and TIMP-1 mRNA in ipsilateral cortical areas. MMP-9 mRNA levels were upregulated 1 day after cerebral contusion with a peak at Day 4. Depolarisation per se, which also occurs after traumatic brain injury, lead to delayed increase of MMP-9 mRNA, 4 days post application. At Day 14, MMP-9 mRNA levels were indistinguishable from controls in both models. TIMP-1 mRNA increases were observed in both models 4 hr after injury, and increased further at Days 1 and 4. At Day 14, mRNA levels declined and were no higher than control levels. No alterations in mRNA levels were noted for TIMP-2 or -3. Our results support earlier reports on MMP-9 involvement in brain injury. It also shows a role for TIMP-1 in the mechanisms of trauma, where depolarisation could be the mechanism responsible for this upregulation.

Animals↗

PubMed2003

Potential complications following radiotherapy for meningiomas.

BACKGROUND: The rationale for radiotherapy of meningiomas is based on retrospective studies utilizing life-table statistics and historical controls. Most of these report minimal morbidity and high efficacy, while one study of radiation therapy for benign diseases reported a high complication rate during long-term follow-up. These reports were at variance with our personal experience in three patients. This study was therefore undertaken to corroborate the previous reports by retrospectively investigating possible adverse effects and efficacy. METHODS: The charts at Karolinska hospital were searched to identify all patients with meningiomas who were treated with conventional fractionated radiotherapy between 1975 and 1995. Surgical radicality was assessed according to Simpson. The patients were followed until recurrence, death, or a minimum of 5 years. RESULTS: Forty-five out of 1,820 patients were treated with fractionated radiotherapy. Fifty-six percent of these patients experienced serious complications from fractionated radiation treatment. The complications encompassed neuropsychological and neurologic motor and sensory deficits and were severe enough to cause hospitalization or a major change in lifestyle. Seventy-five percent of all subtotally resected and radiated meningiomas recurred during follow-up. CONCLUSION: Our historical data from a heterogenous group of consecutive patients undergoing fractionated radiation therapy in meningioma management showed an unexpectedly high rate of complications and failed to corroborate previous historical reports of low morbidity and tumor control. Dose planning and radiation treatment has improved. Our data indicate a need for prospective investigations.

Dose Fractionation, Radiation↗

PubMed2003

Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models.

OBJECTIVE: To investigate which of three subarachnoid hemorrhage (SAH) models is the most suitable for studies of pathological and pathophysiological processes after SAH. METHODS: SAH was induced in rats via intracranial endovascular perforation (perforation model), blood injection into the cisterna magna (300 microl), or blood injection into the prechiasmatic cistern (200 microl). The subarachnoid blood volume was quantitatively measured. Cerebral blood flow (CBF) (as assessed with laser Doppler flowmetry), intracranial pressure, and mean arterial blood pressure were recorded for 90 minutes after SAH. Mortality was recorded, and neuronal death was assessed in animals that survived 7 days after SAH. RESULTS: The subarachnoid blood volume was close to the injected amount after prechiasmatic SAH. In the other models, the volume varied between 40 and 480 microl. The mortality rates were 44% in the perforation SAH group, 25% in the prechiasmatic SAH group, and 0% in the cisterna magna SAH group; the corresponding values for neuronal death were 11, 44, and 28%. Cerebral perfusion pressure approached baseline values within 5 minutes after SAH in all three models. CBF decreased to approximately 35% of baseline values immediately after SAH in all groups; it gradually increased to normal values 15 minutes after SAH in the cisterna magna SAH group and to 60 and 89% of baseline values 90 minutes post-SAH in the perforation and prechiasmatic SAH groups. CBF was significantly correlated with the subarachnoid blood volume. CONCLUSION: The prechiasmatic SAH model seems to be the most suitable for study of the sequelae after SAH; it produces a significant decrease in CBF, an acceptable mortality rate, and substantial pathological lesions, with high reproducibility. The CBF reduction is predominantly dependent on the amount of subarachnoid blood.

Animals↗

PubMed2003

Deep and brainstem cavernomas: a consecutive 8-year series.

OBJECT: The goal of this study was to provide epidemiological and clinical data on the management of cavernomas of the basal ganglia and brainstem from a long-term series at one institution. METHODS: All 68 patients who were referred to the authors' department between 1992 and 2000 for deep cavernomas were evaluated by clinic examinations, review of neuroimaging examinations, and review of charts and operative notes. Twenty-nine patients underwent microsurgical procedures, which carried a 69% risk of transitory neurological deterioration. Radical excision was achieved in 25 of these patients, as determined by a review of neuroimages; the remaining four patients all experienced new hemorrhages that led to increased morbidity or even to mortality. Surgical results were better if surgery was performed early, within 1 month posthemorrhage, than if operations were postponed. In selected patients, deep lesions not reaching a pial surface could be safely removed from the thalamus, basal ganglia, or medulla oblongata. Of five patients who underwent gamma knife surgery, two experienced hemorrhages, one at 2 and the other at 5 years following treatment. Patients who did not undergo surgery had a yearly incidence of hemorrhage that was 2% in cases of incidental cavernomas and 7% in symptomatic ones. CONCLUSIONS: Over the long term, outcomes were worse following conservative treatment or shunt insertion surgery than after microsurgery of symptomatic cavernomas. Incidental cavernomas carried a low risk of neurological deterioration. Surgery should follow generally accepted indications, but only with the confidence that total removal can be safely achieved. Surgery that is performed within 10 to 30 days following ictus may be preferable to delayed surgery.

Adult↗

PubMed2003

High-resolution profiling of an 11 Mb segment of human chromosome 22 in sporadic schwannoma using array-CGH.

Previous low-resolution schwannoma studies have reported diverse frequencies (30-80%) of 22q deletions, involving the neurofibromatosis-2 tumor suppressor (NF2) gene. We constructed an array spanning 11 million base pairs of 22q encompassing the NF2 gene, with 100% coverage and an average resolution of 58 kb. Moreover, the 220 kb genomic sequence encompassing the NF2 gene was covered by 13 cosmids to further enhance the resolution of analysis. The rationale of this array-CGH study was to map and size 22q deletions around the NF2 gene in sporadic schwannoma using a reliable method with maximal resolution. We studied tumor and constitutional DNA from 47 patients and detected heterozygous deletions in 21 (45%) tumors, which could be classified into three profiles. The predominant profile (12/21) was a continuous deletion of the 11 Mb segment, consistent with monosomy 22. The second profile, comprising five schwannomas, was also in agreement with a continuous 11 Mb heterozygous deletion. However, these displayed a distinctly different level of deletion when compared to the first profile, suggesting a considerable amount of normal tissue in the tumor samples. This is the first report demonstrating the sensitivity of array-CGH to discriminate such samples. The third profile was composed of four cases displaying interstitial deletions of various sizes. Two of these did not encompass the NF2 locus, which further emphasize the importance of other loci in schwannoma development. This is the first high-resolution study performed on a large series of tumors, using an array continuously covering 1/3 of a human chromosome. Our findings warrant further studies of an extended tumor series on a full 22q genomic array, to better define additional, putative 22q-located loci important for schwannoma development. Our array also provides a new diagnostic tool for analysis of NF2 gene deletions in patients affected with neurofibromatosis-2.

Adult↗

PubMed2002

A new experimental model in rats for study of the pathophysiology of subarachnoid hemorrhage.

A new experimental model of subarachnoid hemorrhage (SAH) in rats is described. A needle was stereotaxically placed in the prechiasmatic cistern and 300, 250 or 200 microl of blood was injected manually, keeping the intracranial pressure (ICP) at the mean arterial blood pressure (MABP) level. An acceptable mortality was observed only after injection of 200 microl of blood. In this group, MABP and ICP increased immediately after SAH, but soon approached baseline levels. The subarachnoid blood was mainly distributed in the basal cisternal system and its estimated volume was about 95% of the amount injected. This new model resembles clinical SAH, is very reproducible, easy to use and seems to be a suitable model for studies of the pathophysiology of SAH.

Animals↗

PubMed2002

Characterization of Bax and Bcl-2 in apoptosis after experimental traumatic brain injury in the rat.

This study was undertaken to fulfill the need for additional data on the dynamics of Bax and Bcl-2 expression in conjunction to the cell death that ensues following experimental brain contusion. Adult Sprague-Dawley rats were subjected to a unilateral experimental controlled cortical contusion and killed at 1, 2, 4, 6 and 10 days post injury (dpi). Cell death was examined by the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method together with immunohistochemistry for cellular markers. Expression of Bax and Bcl-2 were analyzed by immunohistochemistry and in situ hybridization. The number of TUNEL-positive cells was highest at 1 dpi and decreased with time. At all time points, 10-16% of the TUNEL-positive cells showed an apoptotic nuclear morphology. The apoptotic features were restricted to neurons and some inflammatory cells. Immunohistochemistry for Bax revealed a translocation of Bax from a diffuse to a granular distribution in neurons. An up-regulation of Bax mRNA at 6 dpi was discernible. This increase was associated with a statistically significant increase in number of cells with up-regulated and translocated Bax protein. Moreover, a statistically significant increase of Bcl-2 mRNA was detected at 10 dpi. The potential window for anti-apoptotic treatment to salvage neurons is wide. The susceptibility of neurons to necrosis and apoptosis through different pathways during a prolonged post-traumatic period indicate that different pharmacological strategies may be required at different time points after trauma.

Animals↗

PubMed2002

Expression of IGF-II, IGFBP-2, -5, and -6 in meningiomas with different brain invasiveness.

Meningiomas show clinical characteristics that vary from very benign to clearly malignant with rapid invasive growth and metastases. This study was undertaken to analyze the expression of members in the insulin-like growth factor (IGF) system in meningiomas showing different degrees of brain invasion. Tissue samples from 16 meningiomas were analyzed for members in the IGF family by mRNA in situ hybridization. The meningiomas comprised three groups: I. Benign meningiomas that did not interfere with the arachnoid plane and showed no edema. II. Benign meningiomas that did not respect the arachnoid plane and tumors that caused edema. III. Aggressive and malignant meningiomas that caused edema and showed brain invasion. IGF-II mRNA was identified in all tumors analyzed, and with a clear increase in expression observed in group III tumors. IGFBP-2 mRNA was detected in equal levels in all tumors. IGFBP-5 mRNA levels were highest in the benign group without edema (I) of meningiomas whereas IGFBP-6 mRNA levels were highest in the group with brain invasion (III). Brain invasiveness in degrees from respect of the arachnoid membrane progressing to frank brain invasion correlated with increases in IGF-II and IGFBP-6 expression. High levels of IGFBP-6 may not inhibit IGF-II actions, which is known to be growth promoting in tumors. Instead, IGFBP-6 appears to have an importance for the characteristics of edema and brain invasion in meningiomas.

Aged↗

PubMed2002

Nitric oxide synthase expression after human brain contusion.

OBJECTIVE: Nitric oxide is a universal mediator of biological effects in the brain, and it has been implicated in the pathophysiological processes of traumatic brain injury. Experimental studies have indicated posttraumatic up-regulation of the three different isoforms of nitric oxide synthase (NOS) (i.e., inducible NOS [iNOS], endothelial NOS, and neuronal NOS) after brain trauma. This study was undertaken to investigate the cellular sources and tissue compartments of nitric oxide produced by human patients undergoing surgical treatment for contusional brain injuries. METHODS: Contused brain tissue specimens from eight consecutive patients who underwent surgical treatment for brain contusions 3 hours to 5 days after trauma were evaluated in immunohistochemical analyses. Double-staining assays were used to define which cells produced the different isoforms. RESULTS: Increases in iNOS-positive cells were detectable within 6 hours after trauma, with a peak at 8 to 23 hours. Expression of iNOS after trauma was detected in neurons, macrophages, neutrophils, astrocytes, and oligodendrocytes. The cellular sources of iNOS differed at different times after trauma. No detectable difference in the expression of the neuronal or endothelial isoforms was observed for trauma patients, compared with control subjects. CONCLUSION: iNOS expression was up-regulated in a time-dependent manner in human brain tissue obtained from patients undergoing surgical treatment for contusional trauma. Our human data largely parallel experimental findings in rats, indicating that such trauma models are relevant for experimental studies and treatment trials.

Adolescent↗

PubMed2002

Hyperbaric oxygen treatment of postoperative neurosurgical infections.

OBJECTIVE: To evaluate the clinical usefulness of hyperbaric oxygen (HBO) therapy for neurosurgical infections after craniotomy or laminectomy. METHODS: The study involved review of medical records, office visits, and telephone contacts for 39 consecutive patients who were referred in 1996 to 2000. Infection control and healing without removal of bone flaps or foreign material, with a minimum of 6 months of follow-up monitoring, were considered to represent success. RESULTS: Successful results were achieved for 27 of 36 patients, with a mean follow-up period of 27 months (range, 6-58 mo). One patient discontinued HBO therapy because of claustrophobia, and two could not be evaluated because of death resulting from tumor recurrence. In Group 1 (uncomplicated cranial wound infections), 12 of 15 patients achieved healing with retention of bone flaps. In Group 2 (complicated cranial wound infections, with risk factors such as malignancy, radiation injury, repeated surgery, or implants), all except one infection resolved; three of four bone flaps and three of six acrylic cranioplasties could be retained. In Group 3 (spinal wound infections), all infections resolved, five of seven without removal of fixation systems. There were no major side effects of HBO treatment. CONCLUSION: HBO treatment is an alternative to standard surgical removal of infected bone flaps and is particularly useful in complex situations. It can improve outcomes, reduce the need for reoperations, and allow infection control without mandatory removal of foreign material. HBO therapy is a safe, powerful treatment for postoperative cranial and spinal wound infections, it seems cost-effective, and it should be included in the neurosurgical armamentarium.

Adolescent↗

PubMed2000

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy.

Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity ('allodynia') was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly upregulated in all nerve injured rats in comparison to sham-operated controls. Interestingly, ED-1-, TNF-alpha- and IL-6-positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non-allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-alpha. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-inflammatory interleukins after nerve damage could influence the development of neuropathic pain.

Animals↗