A ten-year follow-up study of treatment outcome of craniopharyngiomas.

PURPOSE: Craniopharyngioma-related hypothalamic obesity is a devastating complication with limited data on whether long-term follow-up should focus on problems other than endocrine deficiencies and weight gain. The primary endpoint was the assessment of predictors of hypothalamic obesity development; the secondary endpoint was the assessment of functional outcome (endocrine deficiencies, visual acuity) at long-term follow-up. METHODS: This retrospective case-note study examined craniopharyngioma patients with at least 2 years of follow-up. Clinical, radiological and biochemical characteristics were assessed at diagnosis, postoperatively, and at last follow-up. RESULTS: Thirty-two patients met the inclusion criteria. Median follow-up period was 9.8 years (range 2.2-33 years). Longitudinal changes in body mass index (BMI) were substantial (median ΔBMI/year was +0.48 kg/m2/year, interquartile range 0.28-1.33). The prevalence of patients with hypothalamic obesity had significantly increased at last follow-up (45 vs 4%; p = 0.003). Long-term pituitary deficiencies remained high. Diabetes insipidus was common (66% vs 34%, p<0.001), with postoperative diabetes insipidus but not hypothalamic involvement, being an independent predictor for hypothalamic obesity (odds ratio 15.2, 95% confidence interval 1.3-174.8, p = 0.03). Osteodensitometry in two thirds of patients at last follow-up revealed a pathological bone density in 53% of those tested. CONCLUSIONS: Rates of hypothalamic obesity and long-term pituitary deficiencies are substantial, with postoperative diabetes insipidus being a potential marker for hypothalamic obesity development. Besides long-term monitoring of endocrine deficiencies with consideration of osteodensitometry, early weight control programmes and continuing multidisciplinary care are mandatory in craniopharyngioma patients.

Long-Term Follow-Up of Primary Medical Versus Surgical Treatment of Prolactinomas in Men: Effects on Hyperprolactinemia, Hypogonadism, and Bone Health.

OBJECTIVE: In men with prolactinomas, impaired bone density is the principle consequence of hyperprolactinemia-induced hypogonadism. Although dopamine agonists (DAs) are the first-line approach in prolactinomas, surgery can be considered in selected cases. In this study, we aimed to investigate the long-term control of hyperprolactinemia, hypogonadism, and bone health comparing primary medical and surgical therapy in men who had not had prior DA treatment. METHODS: This is a retrospective case-note study of 44 consecutive men with prolactinomas and no prior DAs managed in a single tertiary referral center. Clinical, biochemical, and radiologic response to the first-line approach were analyzed in the 2 cohorts. RESULTS: Mean age at diagnosis was 47 years (range, 22-78 years). The prevalence of hypogonadism was 86%, and 27% of patients had pathologic bone density at baseline. The primary therapeutic strategy was surgery for 34% and DAs for 66% of patients. Median long-term follow-up was 63 months (range, 17-238 months). Long-term control of hyperprolactinemia required DAs in 53% of patients with primary surgical therapy, versus 90% of patients with primary medical therapy (P = 0.02). Hypogonadism was controlled in 73% of patients. The prevalence of patients with pathologic bone density was 37% at last follow-up, with no differences between the 2 therapeutic cohorts (P = 0.48). CONCLUSIONS: Despite control of hyperprolactinemia and hypogonadism in most patients independent of the primary treatment modality, the prevalence of impaired bone health status remains high, and osteodensitometry should be recommended.

10-year follow-up study comparing primary medical vs. surgical therapy in women with prolactinomas.

While dopamine-agonists are the first-line approach in treating prolactinomas, surgery can be considered in selected cases besides non-responders or patients with dopamine-agonist intolerance. The aim of the present study was to compare the long-term outcome in women with prolactinomas treated primarily either surgically or medically who had not had prior dopamine-agonist treatment. Retrospective case-note study of all consecutive women with prolactinomas primarily managed with medical therapy or surgery in a tertiary referral centre. The clinical, biochemical, and radiological responses to first-line treatment at early and long-term follow-up were analysed. The primary therapeutic strategy was dopamine-agonists for 36 (34 %) and surgery for 71 (66 %) of the women. Baseline clinical and biochemical characteristics were not significantly different between the primary surgical and medical cohort. Median follow-up time was 90 months (range 13-408). Following primary treatment, prolactin level significantly decreased in both cohorts, on average to 13.5 µg/L (IQR 7-21; p < 0.001), and was within the normal range in 82 % of all patients. No women in the surgical cohort demonstrated permanent sequelae and morbidity was low. At final follow-up, control of hyperprolactinaemia required dopamine-agonist therapy in 64 % of women who had undergone primary medical therapy vs. 32 % of those who had primary surgical therapy (p = 0.003). Logistic regression revealed that the primary therapeutic strategy, but not adenoma size, was an independent risk factor for long-term dependence on dopamine-agonists. The present data indicate that in a dedicated tertiary referral centre, long-term control of hyperprolactinaemia in women with prolactinomas is high. In selected cases, a primary neurosurgical approach might at least be interdisciplinarily discussed with the primary goal of minimizing long-term dependence on dopamine-agonists.

Selective inferior petrosal sinus sampling without venous outflow diversion in the detection of a pituitary adenoma in Cushing's syndrome.

INTRODUCTION: Conventional MRI may still be an inaccurate method for the non-invasive detection of a microadenoma in adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) with ovine corticotropin-releasing hormone (oCRH) stimulation is an invasive, but accurate, intervention in the diagnostic armamentarium surrounding CS. Until now, there is a continuous controversial debate regarding lateralization data in detecting a microadenoma. Using BIPSS, we evaluated whether a highly selective placement of microcatheters without diversion of venous outflow might improve detection of pituitary microadenoma. METHODS: We performed BIPSS in 23 patients that met clinical and biochemical criteria of CS and with equivocal MRI findings. For BIPSS, the femoral veins were catheterized bilaterally with a 6-F catheter and the inferior petrosal sinus bilaterally with a 2.7-F microcatheter. A third catheter was placed in the right femoral vein. Blood samples were collected from each catheter to determine ACTH blood concentration before and after oCRH stimulation. RESULTS: In 21 patients, a central-to-peripheral ACTH gradient was found and the affected side determined. In 18 of 20 patients where transsphenoidal partial hypophysectomy was performed based on BIPSS findings, microadenoma was histologically confirmed. BIPSS had a sensitivity of 94% and a specificity of 67% after oCRH stimulation in detecting a microadenoma. Correct localization of the adenoma was achieved in all Cushing's disease patients. CONCLUSION: BIPSS remains the gold standard in the detection of a microadenoma in CS. Our findings show that the selective placement of microcatheters without venous outflow diversion might further enhance better recognition to localize the pituitary tumor.

Manifestation of a sellar hemangioblastoma due to pituitary apoplexy: a case report.

INTRODUCTION: Hemangioblastomas are rare, benign tumors occurring in any part of the nervous system. Most are found as sporadic tumors in the cerebellum or spinal cord. However, these neoplasms are also associated with von Hippel-Lindau disease. We report a rare case of a sporadic sellar hemangioblastoma that became symptomatic due to pituitary apoplexy. CASE PRESENTATION: An 80-year-old, otherwise healthy Caucasian woman presented to our facility with severe headache attacks, hypocortisolism and blurred vision. A magnetic resonance imaging scan showed an acute hemorrhage of a known, stable and asymptomatic sellar mass lesion with chiasmatic compression accounting for our patient's acute visual impairment. The tumor was resected by a transnasal, transsphenoidal approach and histological examination revealed a capillary hemangioblastoma (World Health Organization grade I). Our patient recovered well and substitutional therapy was started for panhypopituitarism. A follow-up magnetic resonance imaging scan performed 16 months postoperatively showed good chiasmatic decompression with no tumor recurrence. CONCLUSIONS: A review of the literature confirmed supratentorial locations of hemangioblastomas to be very unusual, especially within the sellar region. However, intrasellar hemangioblastoma must be considered in the differential diagnosis of pituitary apoplexy.

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists.

Despite the fact that consensus guidelines recommend long-term dopamine agonist (DA) therapy as a first-line approach to the treatment of small prolactinoma, some patients continue to prefer a primary surgical approach. Concerns over potential adverse effects of long-term medical therapy and/or the desire to become pregnant and avoid long-term medication are often mentioned as reasons to pursue surgical removal. In this retrospective study, 34 consecutive patients (30 female, 4 male) preferably underwent primary pituitary surgery without prior DA treatment for small prolactinomas (microprolactinoma 1-10 mm, macroprolactinoma 11-20 mm) at the Department of Neurosurgery, University of Bern, Switzerland. At the time of diagnosis, 31 of 34 patients (91%) presented with symptoms. Patients with microprolactinomas had significantly lower preoperative prolactin (PRL) levels compared to patients with macroprolactinomas (median 143 µg/l vs. 340 µg/l). Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery. The postoperative PRL levels (median 3.45 µg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities. One patient suffered from hypogonadotropic hypogonadism after surgery despite postoperative normal PRL levels. Long-term remission was achieved in 22 of 24 patients (91%) with microprolactinomas, and in 8 of 10 patients (80%) with macroprolactinomas after a median follow-up period of 33.5 months. Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy.

Endovascular and surgical treatment of spinal dural arteriovenous fistulas.

INTRODUCTION: The aim of this retrospective study was to evaluate the clinical outcome of patients with spinal dural arteriovenous fistulas (SDAVFs) that were treated with surgery, catheter embolization, or surgery after incomplete embolization. METHODS: The study included 21 consecutive patients with SDAVFs of the thoracic, lumbar, or sacral spine who were treated in our institution from 1994 to 2007. Thirteen patients were treated with catheter embolization alone. Four patients underwent hemilaminectomy and intradural interruption of the fistula. Four patients were treated by endovascular techniques followed by surgery. The clinical outcome was assessed using the modified Aminoff-Logue scale (ALS) for myelopathy and the modified Rankin scale (MRS) for general quality of life. Patient age ranged from 44 to 77 years (mean 64.7 years). RESULTS: Surgical as well as endovascular treatment resulted in a significant improvement in ALS (-62.5% and -31.4%, respectively, p < 0.05) and a tendency toward improved MRS (-50% and -32%, respectively) scores. Patients that underwent surgery after endovascular treatment due to incomplete occlusion of the fistula showed only a tendency for improvement in the ALS score (-16.7%), whereas the MRS score was not affected. CONCLUSION: We conclude that both endovascular and surgical treatment of SDAVFs resulted in a good and lasting clinical outcome in the majority of cases. In specific situations, when a secondary neurosurgical approach was required after endovascular treatment to achieve complete occlusion of the SDAVF, the clinical outcome was rather poor. The best first line treatment modality for each individual patient should be determined by an interdisciplinary team.

Multiple spinal extradural meningeal cysts presenting as acute paraplegia. Case report and review of the literature.

Multiple spinal extradural meningeal cysts are rare. To the authors' knowledge, there have been only four reported cases in the world literature. The authors report a case of multiple spinal extradural meningeal cysts in a 31-year-old woman presenting with acute paraplegia. Magnetic resonance imaging of the thoracolumbar spine revealed multiple extradural cystic lesions extending from T-7 to T-8 and from T-12 to L-3. Intraoperative findings demonstrated a white, fibrous, and tense cyst filled with cerebrospinal fluid-like colorless fluid. Excision of the posterior wall of the symptomatic cyst was followed by immediate neurological improvement. The examination of the pathological specimen showed a thick duralike layer of collagen and an inner membrane of arachnoid that is often not found in these lesions. The final diagnosis was based on combined imaging, intraoperative, and histopathological findings. The authors review the literature and discuss the etiological, diagnostic, and therapeutic aspects of this lesion.

Creatine treatment promotes differentiation of GABA-ergic neuronal precursors in cultured fetal rat spinal cord.

Creatine is a substrate of cytosolic and mitochondrial creatine kinases. Its supplementation augments cellular levels of creatine and phosphocreatine, the rate of ATP resynthesis, and improves the function of the creatine kinase energy shuttle. High cytoplasmatic total creatine levels have been reported to be neuroprotective by inhibiting apoptosis. In addition, creatine has direct antioxidant effects, which may be of importance in amyotrophic lateral sclerosis. In the present study, we investigated the effects of creatine [5 mM] on survival and differentiation of cultured GABA-immunoreactive (-ir) and choline acetyltransferase (ChAT)-ir rat spinal cord neurons. Furthermore, we addressed the neuroprotective potential of creatine supplementation against 3-nitropropionic acid (3-NP) induced toxicity. General cell survival and total neuronal cell density were not altered by chronic creatine treatment. We found, however, after chronic creatine and short-term creatine exposure a significantly higher density of GABA-ir neurons hinting to a differentiation-inducing mechanism of creatine. This notion is further supported by a significant higher content of GAD after creatine exposure. Creatine supplementation also exerted a partial, but significant neuroprotection for GABA-ir neurons against 3-NP induced toxicity. Interestingly, chronic creatine treatment did not alter cell density of ChAT-ir neurons but promoted their morphologic differentiation. Cell soma size and number of primary neurites per neuron were increased significantly after creatine supplementation. Taken together, creatine supplementation promoted the differentiation or the survival of GABAergic neurons and resulted in partial neuroprotection against 3-NP induced toxicity. The data suggest that creatine may play a critical role during development of spinal cord neurons.

Creatine promotes the GABAergic phenotype in human fetal spinal cord cultures.

In the present study, we investigated the expression pattern of cytosolic brain specific-BB-CK and ubiquitous mitochondrial-creatine kinases (uMt-CK) in developing human spinal cord. Consequently, we studied the effects of creatine treatment on cultured fetal human spinal cord tissue. We found that both CK isoforms were expressed in fetal spinal cord at all time points investigated (5 to 11.5 weeks post conception) and correspondingly specific CK activity was detected. Chronic creatine exposure resulted in significantly higher densities of GABA-immunoreactive neurons in the cultures, while total neuronal cell density was not altered, suggesting a differentiation inducing mechanism of creatine supplementation. Taken together, our observations favour the view that the creatine phosphocreatine system plays an important role in the developing CNS.

Effect of laser soldering irradiation on covalent bonds of pure collagen.

Laser tissue welding and soldering is being increasingly used in the clinical setting for defined surgical procedures. The exact induced changes responsible for tensile strength are not yet fully investigated. To further improve the strength of the bonding, a better understanding of the laser impact at the subcellular level is necessary. The goal of this study was to analyze whether the effect of laser irradiation on covalent bonding in pure collagen using irradiances typically applied for tissue soldering. Pure rabbit and equine type I collagen were subjected to laser irradiation. In the first part of the study, rabbit and equine collagen were compared using identical laser and irradiation settings. In the second part of the study, equine collagen was irradiated at increasing laser powers. Changes in covalent bonding were studied indirectly using the sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) technique. Tensile strengths of soldered membranes were measured with a calibrated tensile force gauge. In the first experiment, no differences between the species-specific collagen bands were noted, and no changes in banding were found on SDS-PAGE after laser irradiation. In the second experiment, increasing laser irradiation power showed no effect on collagen banding in SDS-PAGE. Finally, the laser tissue soldering of pure collagen membranes showed virtually no determinable tensile strength. Laser irradiation of pure collagen at typical power settings and exposure times generally used in laser tissue soldering does not induce covalent bonding between collagen molecules. This is true for both rabbit and equine collagen proveniences. Furthermore, soldering of pure collagen membranes without additional cellular components does not achieve the typical tensile strength reported in native, cell-rich tissues. This study is a first step in a better understanding of laser impact at the molecular level and might prove useful in engineering of combined collagen-soldering matrix membranes for special laser soldering applications.

Repeated laser-assisted high-flow bypass for recurrent giant intracranial aneurysm.

The treatment of intracranial aneurysms is changing as endovascular obliteration possibilities and long-term results are being published in regard to outcome. However, not all aneurysms are amenable to direct endovascular or surgical treatment. In such situations, a high flow bypass for flow preservation can be considered as indirect treatment alternative, enabling a trapping of the aneurysm or occlusion of the feeding artery. We present the case history of a 57 year-old patient suffering of a recurrent giant intracranial carotid aneurysm. The aneurysm could be excluded using a new cerebral high-flow bypass technique for which no temporary occlusion of any intracranial vessels is required. This technique reduces the risks of perioperative neurological complications.

Leiomyomatoid angiomatous neuroendocrine tumor (LANT) of the pituitary: a distinctive biphasic neoplasm with primitive secretory phenotype and smooth muscle-rich stroma.

We describe a hitherto undocumented variant of dimorphic pituitary neoplasm composed of an admixture of neurosecretory cells and profuse leiomyomatous stroma around intratumoral vessels. Radiologically perceived as a macroadenoma of 3.8 cm in diameter, this pituitary mass developed in an otherwise healthy 43-year-old female. At the term of a yearlong history of amenorrhea and progressive bitemporal visual loss, subtotal resection was performed via transsphenoidal microsurgery. Discounting mild hyperprolactinemia, there was no evidence of excess hormone production. Histologically, solid sheets, nests and cords of epithelial-looking, yet cytokeratin-negative cells were seen growing in a richly vascularized stroma of spindle cells. While strong immunoreactivity for NCAM, Synaptophysin and Chromogranin-A was detected in the former, the latter showed both morphological and immunophenotypic hallmarks of smooth muscle, being positive for vimentin, muscle actin and smooth muscle actin. Architectural patterns varied from monomorphous stroma-dominant zones through biphasic neuroendocrine-leiomyomatous areas, to pseudopapillary fronds along vascular cores. Only endothelia were labeled with CD34. Staining for S100 protein and GFAP, characteristics of sustentacular cells, as well as bcl-2 and c-kit was absent. Except for alpha-subunit, anterior pituitary hormones tested negative in tumor cells, as did a panel of peripheral endocrine markers, including serotonin, somatostatin, calcitonin, parathormone and vasoactive intestinal polypeptide. Mitotic activity was absent and the MIB-1 labeling index low (1-2%). While assignment of this lesion to any established neoplastic entity is not forthcoming, we propose it is being considered as a low-grade neuroendocrine tumor possibly related to null cell adenoma.

Clinicopathologic correlations of silent corticotroph adenomas of the pituitary: report of four cases and literature review.

Silent corticotroph adenomas (SCA) are rare pituitary tumors with histologic hallmarks of corticotroph differentiation, including ACTH immunoreactivity, but lacking clinical evidence of Cushing's syndrome. We report on four female patients, aged 19-66 years, each presenting with a nonfunctional macroadenoma. Leading symptoms were headache in two cases and visual field deficits in one. One patient was incidentally diagnosed while undergoing cranial MRI for an unrelated condition. Three patients had marked obesity; none of them presented constitutional signs of Cushing's syndrome. Serum cortisol levels were moderately elevated in the two patients systematically tested in this respect. Marginal to moderate hyperprolactinemia was present in two cases. Two patients also were shown to be deficient in either gonadotroph or thyrotroph axis, while a third had a combined insufficiency of both gonadotroph and thyrotroph axis. MRI scans revealed intratumoral hemorrhage and/or cystic change in three cases, as well as tumor-related occlusive hydrocephalus in one. The latter patient was biopsied only, while the remaining underwent gross total resection. Histologically, all four lesions were diagnosed as SCA subtype I displaying intense immunoreactivity for ACTH. In three tumors, scattered cells coexpressed PRL as well. In addition, Crooke's hyaline change was noted in a significant number of tumor cells and in residual non-neoplastic corticotrophs in one case each. With MIB-1 labeling indices of 1-3%, none of the tumors qualified as atypical adenoma. We conclude that SCAs are more likely to be discovered as expansile tumors, whose advanced local space-occupying character at surgery rather than an inherently aggressive growth potential may negatively influence the clinical outcome. Subtle morphologic evidence of corticotroph suppression in residual pituitary adjacent to tumor lends further support to literature data indicating minimal or intermittent functional activity in this tumor type.

GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon.

Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), known as the GDNF family ligands (GFLs), influence the development, survival and differentiation of cultured dopaminergic neurons from ventral mesencephalon (VM). Detailed knowledge about the effects of GFLs on other neuronal populations in the VM is essential for their potential application as therapeutic molecules for Parkinson's disease. Hence, in a comparative study, we investigated the effects of GFLs on cell densities and morphological differentiation of gamma-aminobutyric acid-immunoreactive (GABA-ir) and serotonin-ir (5-HT-ir) neurons in primary cultures of E14 rat VM. We observed that all GFLs [10 ng/ml] significantly increased GABA-ir cell densities (1.6-fold) as well as neurite length/neuron. However, only GDNF significantly increased the number of primary neurites/neuron, and none of the GFLs affected soma size of GABA-ir neurons. In contrast, only NRTN treatment significantly increased 5-HT-ir cells densities at 10 ng/ml (1.3-fold), while an augmentation was seen for GDNF and PSPN at 100 ng/ml (2.4-fold and 1.7-fold, respectively). ARTN had no effect on 5-HT-ir cell densities. Morphological analysis of 5-HT-ir neurons revealed a significant increase of soma size, number of primary neurites/neuron and neurite length/neuron after GDNF exposure, while PSPN only affected soma size, and NRTN and ARTN failed to exert any effect. In conclusion, we identified GFLs as effective neurotrophic factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development.

Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures.

Nitric oxide (NO) mediates a variety of physiological functions in the central nervous system and acts as an important developmental regulator. Striatal interneurons expressing neuronal nitric oxide synthase (nNOS) have been described to be relatively spared from the progressive cell loss in Huntington's disease (HD). We have recently shown that creatine, which supports the phosphagen energy system, induces the differentiation of GABAergic cells in cultured striatal tissue. Moreover, neurotrophin-4/5 (NT-4/5) has been found to promote the survival and differentiation of cultured striatal neurons. In the present study, we assessed the effects of creatine and NT-4/5 on nNOS-immunoreactive (-ir) neurons of E14 rat ganglionic eminences grown for 1 week in culture. Chronic administration of creatine [5mM], NT-4/5 [10ng/ml], or a combination of both factors significantly increased numbers of nNOS-ir neurons. NT-4/5 exposure also robustly increased levels of nNOS protein. Interestingly, only NT-4/5 and combined treatment significantly increased general viability but no effects were seen for creatine supplementation alone. In addition, NT-4/5 and combined treatment resulted in a significant larger soma size and number of primary neurites of nNOS-ir neurons while creatine administration alone exerted no effects. Double-immunolabeling studies revealed that all nNOS-ir cells co-localized with GABA. In summary, our findings suggest that creatine and NT-4/5 affect differentiation and/or survival of striatal nNOS-ir GABAergic interneurons. These findings provide novel insights into the biology of developing striatal neurons and highlight the potential of both creatine and NT-4/5 as therapeutics for HD.

The GDNF family members neurturin, artemin and persephin promote the morphological differentiation of cultured ventral mesencephalic dopaminergic neurons.

Neurturin (NRTN), artemin (ARTN), persephin (PSPN) and glial cell line-derived neurotrophic factor (GDNF) form a group of neurotrophic factors, also known as the GDNF family ligands (GFLs). They signal through a receptor complex composed of a high-affinity ligand binding subunit, postulated ligand specific, and a common membrane-bound tyrosine kinase RET. Recently, also NCAM has been identified as an alternative signaling receptor. GFLs have been reported to promote survival of cultured dopaminergic neurons. In addition, GDNF treatments have been shown to increase morphological differentiation of tyrosine hydroxylase immunoreactive (TH-ir) neurons. The present comparative study investigated the dose-dependent effects of GFLs on survival and morphological differentiation of TH-ir neurons in primary cultures of E14 rat ventral mesencephalon. Both NRTN and ARTN chronically administered for 5 days significantly increased survival and morphological differentiation of TH-ir cells at all doses investigated [0.1-100 ng/ml], whereas PSPN was found to be slightly less potent with effects on TH-ir cell numbers and morphology at 1.6-100 ng/ml and 6.3-100 ng/ml, respectively. In conclusion, our findings identify NRTN, ARTN and PSPN as potent neurotrophic factors that may play an important role in the structural development and plasticity of ventral mesencephalic dopaminergic neurons.

Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system.

Cell replacement therapy using mesencephalic precursor cells is an experimental approach for the treatment of Parkinson's disease (PD). A significant problem associated with this procedure is the poor survival of grafted neurons. Impaired energy metabolism is considered to contribute to neuronal cell death after transplantation. Creatine is a substrate for mitochondrial and cytosolic creatine kinases (CK) and buffers cellular ATP resources. Furthermore, elevated cellular creatine levels facilitate metabolic channeling and show antiapoptotic properties. Exogenous creatine supplementation therefore might offer a tool for improvement of dopaminergic neuron survival. The present study aimed at investigating the effects of creatine on cell survival of rat embryonic day 14 (E14) ventral mesencephalic neurons grown as organotypic free-floating roller tube (FFRT) cultures. We found that the brain-specific isoform of CK (BB-CK) and the ubiquitous mitochondrial isoform (uMt-CK) are expressed at high levels in FFRT cultures and colocalize with tyrosine hydroxylase immunoreactive (TH-ir) cells. Exposure of these cultures to creatine induced an increase in the content of the BB-CK isotype. Creatine (5 mM) administration starting at day in vitro (DIV) 7 resulted in a significant increase (+35%) in TH-ir cell density at DIV21. In addition, we observed that creatine treatment provided neuroprotection against 1-methyl-4-phenyl pyridinium ion (MPP+)-induced TH-ir cell loss in the FFRT culture system, resulting in a significantly higher density (+19%) of TH-ir neurons in creatine-treated cultures compared to corresponding controls. The decrease of TH-ir neurons in the MPP+-treated group corresponded with an increase in immunoreactivity for active caspase-3, an effect that was not seen in the group receiving creatine supplementation. In conclusion, our data imply that creatine administration is beneficial for the survival of TH-ir neurons encountering harmful conditions.

Endovascular treatment of posterior circulation cerebral aneurysms by using Guglielmi detachable coils: a 10-year single-center experience with special regard to technical development.

BACKGROUND AND PURPOSE: The purpose of this study was to analyze the immediate and long-term angiographic and clinical results of endovascular treatment of posterior circulation aneurysms with special regard to technical development. MATERIALS: Between 1993 and 2003, 46 patients with 47 aneurysms of the posterior circulation were referred to our institution for endovascular treatment. Mean angiographic follow-up was 1.7 years. Clinical follow-up was determined at hospital discharge and by using a questionnaire for long-term follow-up (mean, 3.3 years). To analyze technical development, patients treated before (group 1) and after (group 2) implementation of 3D Guglielmi detachable coils (3D GDCs) in 1999 were compared. Multivariate analysis was performed to determine factors predictive of clinical and technical outcome. RESULTS: Overall, at initial treatment complete occlusion was achieved in 27 (57.4%) aneurysms, a neck remnant was present in 16 (34.0%) aneurysms, incomplete occlusion was achieved in 3 (6.4%) aneurysms, and in 1 (2.1%) case occlusion was not attempted. Procedure-related permanent morbidity was 4.3%, and the mortality rate was 0%. There was no rebleeding of treated aneurysms. Complete occlusion at initial treatment (P = .003) and recanalization rate (P = .008) correlated with aneurysm sac size. A statistically significant relationship between Hunt and Hess/World Federation of Neurologic Surgeons clinical grading scale score and clinical outcome (Glasgow Outcome Score) was found (P < .05). Subgroup analysis revealed that a higher initial obliteration rate of larger aneurysms was achieved in group 2 (3D GDC, 22 patients, 22 aneurysms) than in group 1 (23 patients, 24 aneurysms; P = .03). At angiographic follow-up, overall recanalization was 47.1% in group 2 and 47.6% in group 1. Aneurysm neck size was not found to be correlated with occlusion and recanalization rate. CONCLUSION: In our series, GDC technology was an effective and safe technique for the treatment of posterior circulation aneurysms. Aneurysm sac size was predictive for occlusion rate and the Hunt and Hess/World Federation of Neurologic Surgeons grade for clinical outcome. The introduction of 3D GDCs into our practice significantly improved the initial occlusion rate but did not affect the incidence of recanalization.

Effect of GDNF on differentiation of cultured ventral mesencephalic dopaminergic and non-dopaminergic calretinin-expressing neurons.

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for ventral mesencephalic (VM) dopaminergic neurons. Subpopulations of dopaminergic and non-dopaminergic VM neurons express the calcium-binding proteins calbindin (CB) and calretinin (CR). Characterization of the actions of GDNF on distinct subpopulations of VM cells is of great importance for its potential use as a therapeutic molecule and for understanding its role in neuronal development. The present study investigated the effects of GDNF on the survival and morphological differentiation of dopaminergic and non-dopaminergic neurons in primary cultures of embryonic day (E) 18 rat VM. As expected from our results obtained using E14 VM cells, GDNF significantly increased the morphological complexity of E18 CB-immunoreractive (CB-ir), tyrosine hydroxylase (TH)-ir, and CR-ir neurons and also the densities of CB-ir and TH-ir neurons. Interestingly, densities of E18 CR-ir neurons, contrarily to our previous observations on E14 CR-ir neurons, were significantly higher after GDNF treatment (by 1.5-fold). Colocalization analyses demonstrated that GDNF increased the densitiy of dopaminergic neurons expressing CR (TH+/CR+/CB-), while no significant effects were observed for TH-/CR+/CB- cell densities. In contrast, we found that GDNF significantly increased the total fiber length (2-fold), number of primary neurites (1.4-fold), number of branching points (2.5-fold), and the size of neurite field per neuron (1.8-fold) of the non-dopaminergic CR-expressing neurons (TH-/CR+/CB-). These cells were identified as GABA-expressing neurons. In conclusion, our findings recognize GDNF as a potent differentiation factor for the development of VM dopaminergic and non-dopaminergic CR-expressing neurons.