[Principles of revascularization in treatment of giant intracranial aneurysms].

During recent decades extra-intracranial and intra-intracranial bypasses have deserved high interest among neurosurgeon, especially in management of giant cerebral aneurysms. Development of microsurgery and neuroanesthesiological techniques, advances in neuroradiology and neurophysiology prerequisite improvement of revascularization surgery. Evolution of competitive endovascular methods pushes the surgeons to improve microneurosurgical technique of revascularization and elaboration of new approaches to management of intracranial aneurysms. In this review we discuss principles of surgery of cerebrovascular bypasses in management of giant aneurysms applied in our clinic.

Lateral supraorbital approach as an alternative to the classical pterional approach.

OBJECTIVE: The standard pterional approach has been used to approach aneurysms of the anterior circulation and the basilar tip, suprasellar tumors, cavernous lesions. The senior author (JH) established a lateral supraorbital approach as an alternative to the pterional approach after continuous trial and error. We describe the techniques of this approach based on clinical experiences. METHODS: The lateral supraorbital approach is more subfrontal and anterior than the pterional approach. This approach has been regularly used by the senior author (JH) in the last decade in more than 2000 operations for mostly aneurysms of anterior circulation, but also for tumors of the anterior fossa and parasellar area as well as the sphenoid wing area. RESULTS: This approach can be used to operate on most cases, in which the classical pterional approach would be used. There are almost no craniotomy-related complications with this approach. This approach is not suitable in certain lesions which need to be exposed from a more temporal perspective. CONCLUSION: This approach is simpler, faster, safer and less invasive than the classical pterional approach.

Subtemporal approach to basilar bifurcation aneurysms: advanced technique and clinical experience.

OBJECTIVE: The surgical treatment of basilar bifurcation aneurysms is challenging, and many of these aneurysms are currently treated by endovascular means. However, the complete closure of the aneurysm by surgical clipping still remains the best and most permanent cure for the aneurysm. The "gold standard", subtemporal approach was established and introduced by Drake and it has been adapted by the senior author Hernesniemi. We describe our present modified technique of this approach based on clinical experience. METHODS: The subtemporal approach to basilar bifurcation aneurysms has been regularly used by the senior author Hernesniemi in recent 15 years in over 200 operations in Kuopio and Helsinki, Finland. RESULTS: This approach is suitable in most basilar bifurcation aneurysms except for those high above the posterior clinoid process. To avoid temporal lobe damage, cerebrospinal fluid drainage is necessary. Benefits of subtemporal approach are short operative and retraction times, and no need for skull base resection. CONCLUSION: The subtemporal approach is simple and safe in experienced hands, and should be considered the standard method to approach most basilar bifurcation aneurysms.

AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling.

The aryl hydrocarbon receptor interacting protein (AIP) is a tumor-suppressor gene underlying the pituitary adenoma predisposition. Thus far, the exact molecular mechanisms by which inactivated AIP exerts its tumor-promoting action have been unclear. To better understand the role of AIP in pituitary tumorigenesis, we performed gene expression microarray analysis to examine changes between Aip wild-type and knockout mouse embryonic fibroblast (MEF) cell lines. Transcriptional analyses implied that Aip deficiency causes a dysfunction in cyclic adenosine monophosphate (cAMP) signaling, as well as impairments in signaling cascades associated with developmental and immune-inflammatory responses. In vitro experiments showed that AIP deficiency increases intracellular cAMP concentrations in both MEF and murine pituitary adenoma cell lines. Based on knockdown of various G protein α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-2 protein levels, irrespective of Aip mutation status. We additionally observed reduced expression of phosphorylated extracellular signal-regulated kinases 1/2 and cAMP response element-binding protein levels in mouse and human AIP-deficient somatotropinomas. This study implies for the first time that a failure to inhibit cAMP synthesis through dysfunctional Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.

Origin and distribution of neuropeptide-FF-like immunoreactivity in the spinal cord of rats.

Neuropeptide FF, or F8Famide (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2; "morphine-modulating peptide"), isolated from bovine brain, is an FMRF-NH2-like peptide with morphine-modulating effects. Neuropeptide FF (NFF) is highly concentrated in spinal cords of various mammalian species. There is evidence that NFF participates in the modulation of nociceptive mechanisms. The present study was aimed at describing the distribution and origin of the neuropeptide-FF-like immunoreactivity (LI) in the rat spinal cord. For distribution studies spinal cord sections from colchicine-treated animals were processed according to the indirect immunofluorescence method. Retrograde fluorescent tracer was injected in the lumbar dorsal spinal cord to study descending NFF-LI-containing spinal pathways. NFF-immunoreactive (ir) cell bodies were detected in the substantia gelatinosa, marginal zone, laminae III, IV, and X at all levels of the spinal cord, and the dorsolateral funiculus, and dorsal gray commissure of the lumbosacral transition zone. NFF-ir fibers and terminals were identified in laminae I-IV and X, dorsolateral funiculus, intermediolateral cell column, dorsal gray commissure, sacral parasympathetic nucleus, and ventral horn. A spinal NFF-LI-containing descending pathway originating in the lamina X neurons was observed, but a supraspinal origin of descending NFF-ir fibers was not identified. According to this study the NFF-LI of the spinal cord is of intrinsic spinal origin. The anatomical distribution supports the concept that the NFF-like peptides have a role in the nociception. They may also be involved in sensory-visceral reflex arcs.

Ontogeny of the F8Famide-like (morphine-modulating) peptides in the central nervous system of rats.

FLFQPQRF-NH2 (F8Famide; FMRFamide-like peptide; morphine-modulating peptide) is a peptide isolated from bovine brain. It has some opiate analgesia modulating effects. In an adult rat central nervous system, F8Famide-like immunoreactivity is found in high concentrations in the posterior pituitary, hypothalamus, pons, medulla, and dorsal spinal cord. By using immunohistochemistry and radioimmunoassay, we studied the development of the F8Famide-immunoreactive system in the rat central nervous system during the ontogeny. F8Famide-immoreactive fibers and terminals first appeared in the median eminence on the twentieth embryonal day. Postnatally the F8Famide-immunoreactive system developed rapidly both in the brain and spinal cord, the immunoreactive structures having an adultlike distribution by the age of 1 week. A transient increase of the F8Famide-immunoreactive material was observed during the third and fourth postnatal weeks. By the age of 4 weeks, the F8Famide-containing neuronal system was adultlike both in distribution and quantity. The results suggest that the F8Famide-like peptides may act as neurotransmitters or neuromodulators from the time of their appearance in the brain and spinal cord. The early appearance and the distribution of the F8Famide-like immunoreactivity suggest that these peptides may participate, in addition to nociceptive mechanisms, in the regulation of blood pressure, feeding behaviour, and endocrine functions.

Immunohistochemical distribution and partial characterization of FLFQPQRFamidelike peptides in the central nervous system of rats.

Two peptides that are structurally related to the molluscan tetrapeptide Phe-Met-Arg-Phe-NH2 (FMRF-NH2) were recently isolated from bovine brain extract (Yang et al.: Proc. Natl. Acad. Sci. USA 82:7757-7761, '85). These peptides have an attenuating effect on morphine-induced analgesia when injected intracerebroventricularly in rats. Antisera against the two peptides--an octapeptide, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F8F-NH2), and an octadecapeptide, Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe- NH2 (A18F-NH2)--were raised in rabbits and characterized with standard radioimmunoassay and immunohistochemical blocking controls. This study was aimed at localizing neurons in the rat brain that contain immunoreactivity for these peptides. Cryostat sections of normal and colchicine-treated Sprague-Dawley rat brains were incubated with the specific antisera and the immunoreactivity was visualized by the PAP or the FITC method. Immunoreactive neurons were detected in the hypothalamus and nucleus of the solitary tract. Relatively dense networks of fibers and terminals were observed in the lateral parabrachial nucleus and in the nucleus of the solitary tract. Fibers and terminals were also seen in the lateral septum, amygdala, hypothalamus, neurohypophysis, thalamus, periaqueductal gray, and several medullary nuclei. In these areas the immunoreactivity was abolished when the antisera were incubated with the corresponding synthetic peptides F8F-NH2 and A18F-NH2. Preincubation of the antisera with neuropeptide Y (NPY) did not affect the staining. The results suggest that there are neurons in the rat brain that contain F8F-NH2- and A18F-NH2-like peptides. The neuronal system described here may have a role in the regulation of autonomic functions, such as hypothalamic control and respiratory functions. The neuronal connections of the cells containing F8F-NH2- and A18F-NH2-like peptides remain to be studied.

Central neuronal pathways containing FLFQPQRFamide-like (morphine-modulating) peptides in the rat brain.

Octapeptide FLFQPQRFamide (FMRFamide-like peptide; morphine-modulating peptide), isolated from bovine brain, has some opiate analgesia modulating effects. Octapeptide FLFQPQRFamide-like immunoreactivity is found in high concentrations in the posterior pituitary, hypothalamus, pons-medulla, and dorsal spinal cord. Octapeptide FLFQPQRFamide-immunoreactive neurons of the brain are localized in the medial hypothalamus and in the nucleus of the solitary tract. High densities of octapeptide FLFQPQRFamide-immunoreactive nerve terminals are found in the median eminence, lateral parabrachial nucleus, and nucleus of the solitary tract. By using the retrograde tract tracing method combined with immunohistochemistry, we studied the central pathways interconnecting the octapeptide FLFQPQRFamide-immunoreactive structures. The octapeptide FLFQPQRFamide-immunoreactive neurons of the hypothalamus sent projections bilaterally to the nucleus of the solitary tract. The octapeptide FLFQPQRFamide-immunoreactive neurons of the nucleus of the solitary tract projected to the contralateral side of the same nucleus, to the lateral parabrachial nuclei bilaterally, and to the ipsilateral periambigual region. The results give neuroanatomical evidence of interacerebral pathways containing recently identified FLFQPQRFamide-like peptides, which may belong to a larger family of peptides. These neuroanatomical findings support the previous pharmacological studies, suggesting that the mammalian FMRFamide-like peptides may, in addition to modulatory effects on nociceptive mechanisms, participate in the regulation of blood pressure, feeding behaviour and endocrine functions.

Helodermin- and helospectin-like immunoreactivities in the rat brain: an immunochemical and immunohistochemical study.

Helodermin is an amidated peptide of 35 amino acid residues isolated from the lizard Heloderma suspectum. Homologous peptides, helospectins I and II, peptides of 38 and 37 amino acid residues, respectively, have been isolated from the lizard Heloderma horridum. This group of peptides stimulates the adenylate cyclase activity. Helodermin- and helospectin-like immunoreactivities were studied in the rat brain by using immunohistochemistry and radioimmunoassay in combination with high-performance liquid chromatography. The highest concentrations of helodermin-like immunoreactivity were found in the cerebellum and hypothalamus. The chromatographic analysis of rat brain extract revealed one main immunoreactive peak with elution properties similar to those of authentic lizard helodermin. Helodermin-immunoreactive neurons were located in the supraoptic nucleus, suprachiasmatic nucleus, periventricular nucleus, arcuate nucleus and central gray. Fibers and terminals of varying densities were observed in the bed nucleus of the stria terminalis, medial part of the central nucleus of amygdala, external layer of the median eminence, thalamus and central gray. The highest concentrations of helospectin-like immunoreactivity were found in the cerebral cortex, hypothalamus and medulla. The chromatographic analysis of brain extract revealed one major peak with elution properties similar to those of authentic helospectin I. Helospectin-immunoreactive neurons were located in the suprachiasmatic nucleus, central gray, cerebral cortex, dorsomedial hypothalamic nucleus and supramammillary nucleus. Helospectin-immunoreactive fibers and terminals were found in the bed nucleus of the stria terminalis, medial part of the central nucleus of amygdala, median eminence, lateral parabrachial nucleus, central gray, cerebral cortex, thalamus and nucleus of the solitary tract. The present study has revealed novel neuronal systems in the rat brain by using antisera against the lizard peptides helodermin and helospectin. The patterns of immunostaining suggest a role for the helodermin- and helospectin-like peptides in the hypothalamo-hypophyseal control of endocrine functions.

The distribution of pituitary adenylate cyclase-activating polypeptide-like immunoreactivity is distinct from helodermin- and helospectin-like immunoreactivities in the rat brain.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an amidated 38-residue polypeptide isolated from the ovine hypothalamus. Helodermin, a 35-amino acid peptide, and helospectins, peptides of 38 and 37 amino acid residues, have been isolated from lizard venom. PACAP, helodermin and helospectins share structural features and have a similar profile of pharmacological effects: they stimulate adenylate cyclase. We studied the distribution and characteristics of PACAP-like immunoreactivity in the rat brain with immunochemical and immunohistochemical methods and compared its distribution with that of helodermin- and helospectin-like immunoreactivities. With radioimmunoassay, the highest concentrations of PACAP-like immunoreactivity were found in the hypothalamus and cerebellum. PACAP-immunoreactive cell bodies were located immunohistochemically in the supraoptic nucleus, paraventricular and periventricular hypothalamic nuclei, and in the central grey. PACAP-immunoreactive fibres and terminals were detected in the medial part of the central nucleus of amygdala, in the median eminence and neurohypophysis, and in the central grey. No PACAP-immunoreactive structures were observed in areas such as the cerebral cortex, hippocampus, or cerebellum. The distribution of PACAP-like immunoreactivity differed considerably from the distribution of helodermin- and helospectin-like immunoreactivities. The results of this study suggest that PACAP is a neuropeptide with a role in the regulation of endocrine function in the hypothalamo-hypophyseal axis.

Ultrastructural localization of neuropeptide FF, a new neuropeptide in the brain and pituitary of rats.

The octapeptide FLFQPQRF-NH2 or neuropeptide FF ('F8Famide'; FMRFamide-like peptide'; 'morphine-modulating peptide') has been isolated from the bovine brain. In this study, the ultrastructural localization of neuropeptide FF-like immunoreactivity was examined with pre-embedding immuno-electron microscopy in the nucleus of the solitary tract and in the posterior lobe of the pituitary gland of an adult rat. Neuropeptide FF-like immunoreactivity was detected only in neuronal structures of the medial and commissural nuclei of the solitary tract and in the neurohypophysis. In the medulla, the peroxidase-antiperoxidase reaction product was localized in large (100 nm) dense-cored vesicles and in the cytoplasm of the neuronal perikarya, dendrites and axon terminals. In the labeled terminals, small (50 nm) clear vesicles rimmed with the peroxidase-antiperoxidase reaction product were seen. Synaptic contacts of labeled perikarya and dendrites with unlabeled axon terminals were observed. Labeled axon terminals formed contacts with unlabeled dendrites and perikarya. In the posterior lobe of the pituitary gland, neuropeptide FF-like immunoreactivity was localized in nerve terminals frequently associated with blood vessels. The results suggest that neuropeptide FF-like peptides are localized exclusively in neuronal structures and that they are synthesized in cell somata and released from axon terminals. In the brain, neuropeptide FF-like peptides may act as neuromodulators involved in the regulation of autonomic functions. The localization of neuropeptide FF-like immunoreactivity in the neurohypophysis suggests endocrine regulatory functions of these peptides.

Neuropeptide FF is colocalized with catecholamine-synthesizing enzymes in neurons of the nucleus of the solitary tract.

Neuropeptide FF (NFF) is an amidated octapeptide of bovine origin. It has some antiopioid-like effects and it elevates blood pressure when injected intravenously in rats. NFF-immunoreactive nerve cells and terminals are localized in large numbers in the dorsomedial caudal brainstem which is a region involved in central regulation of blood pressure. We compared the localization of NFF-immunoreactive neurons with medullary catecholamine-synthesizing neurons by using immunohistochemical double-labeling and light microscopic mirror methods. NFF and tyrosine hydroxylase coexisted in a minor portion of the NFF neurons in the nucleus of the solitary tract and occasional cell bodies were stained with both NFF and PNMT (phenylethanolamine N-methyltransferase) antisera. The results have anatomical correlation with previous pharmacological reports, suggesting that NFF is present in neuronal systems involved in cardiovascular reflex arcs.

Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study.

OBJECTIVE: To find out the effect of carmustine (bischloroethyl-nitrosourea) combined with a biodegradable polymer in the treatment of malignant (Grades III and IV) gliomas, applied locally, at the time of the primary operation. METHODS: Prospective, randomized double-blind study of an active treatment group versus a placebo group. Conducted at the Departments of Neurosurgery of the University Hospitals of Helsinki, Tampere, and Turku in Finland and Trondheim in Norway. The study consisted of 32 patients (16 in each treatment group) enrolled between March 23, 1992, and March 19, 1993. The study was planned to include 100 patients but had to be terminated prematurely, because the drug that was being used had become unobtainable. The main outcome measures included the survival times of patients after the operations and the application of an active drug or placebo. RESULTS: The median time from surgery to death was 58.1 weeks for the active treatment group versus 39.9 weeks for the placebo group (P = 0.012). For 27 patients with Grade IV tumors, the corresponding times were 39.9 weeks for the placebo group and 53.3 weeks for the active treatment group (P = 0.008). At the end of the study, six patients were still alive, five of whom belonged to the active treatment group. CONCLUSION: Carmustine applied locally in a biodegradable polymer at the time of primary operation, seems to have a favorable effect on the life span of patients with high-grade gliomas.

Light and electron microscopic immunocytochemistry of proenkephalin-derived peptides in septal neurons.

Specific antibodies against different opioid peptides derived from proenkephalin were used in light and electron microscopic studies to locate septal enkephalin-containing cells. Immunoreactive neurons were demonstrated only after pretreatment of the animals with colchicine. They were found in all three subdivisions of the lateral septal nucleus and in the ventral limb of the nucleus of the diagonal band. The medial septal nucleus and the dorsal limb of the nucleus of the diagonal band were devoid of immunoreactive cells. Electron microscopy showed intracellular enkephalin-like immunoreactivity with all antisera used in this study. The reaction was found in the cytoplasm, sometimes associated with the rough endoplasmic reticulum. Numerous enkephalin-immunoreactive nerve terminals and fibres were detected in the lateral septal nucleus, but axon terminals making contacts with enkephalin-immunoreactive neurons did not contain enkephalin-like immunoreactivity. The results suggest that some septal neurons synthesise proenkephalin. These cells may be either local interneurons or output cells to areas which receive innervation from the septal complex.

Kainic acid-induced changes in histamine-immunoreactive nerve fibers in the rat brain.

Histamine is found in neurons and their long projections in the mammalian brain. The mammalian histaminergic system consists of nerve cell bodies in the tuberomammillary nucleus, and extensive, crossing projections to various brain areas. In addition to the tuberomammillary histaminergic system, histamine is found in rhombencephalic neurons during fetal development of rat. To investigate if histamine has a function in growth and regeneration of the nervous system, small injections of kainic acid were made into different parts of the rat brain. Histamine-immunoreactive nerve fibers were seen in and around the lesions 2 to 15 weeks after the injection. The density of these fibers was higher than that of the control side. The results suggest that histamine is either accumulated in pre-existing fibers or that sprouting of histamine-containing nerves is induced by the lesions. The newly established in situ hybridization method for the enzyme histidine decarboxylase may reveal possible dynamic changes in enzyme regulation associated with the lesions.

Neuroanatomy of morphine-modulating peptides.

Antisera against two mammalian peptides related to the molluscan cardioexcitatory peptide Phe-Met-Arg-Phe-NH2 were used to locate immunoreactive neurons in the rat brain, nerve fibres and terminals in the spinal cord, sympathetic ganglion cells and adrenal chromaffin cells. Immunoreactivity for the newly characterised octa- and octadecapeptide was detected in nerve cell bodies in the hypothalamic area, including parts of the dorsomedial, periventricular and paraventricular nuclei, and in the nucleus tractus solitarii. Nerve terminals in the superficial laminae of the spinal cord were also immunoreactive for these peptides, while the sensory ganglia were nonreactive. Some principal ganglion cells in the superior cervical ganglia exhibited bright immunofluorescence for the peptides, and a few adrenal medullary cells were immunoreactive. The presence of these peptides in the substantia gelatinosa of the spinal cord suggests that they may be involved in sensory neurotransmission, especially in the mechanisms mediating pain. In the hypothalamo-hypophysial system these peptides may be involved in the regulation of hormonal systems. They may also act as co-transmitters in the sympathetic nervous system.

The antiopioid peptide, neuropeptide FF, enhances the effects of acute morphine on the cerebral monoamines in rats.

The effects of neuropeptide FF (NPFF) on the changes induced by acute morphine in cerebral monoamines were studied in male Wistar rats. We measured the concentrations of noradrenaline (NA), 5-hydroxytryptamine (5-HT), dopamine and their main metabolites in the limbic area (LIM), hypothalamus (HYP) and lower brain stem (LBS). NPFF 10 micrograms x 3 at 20 min intervals, i.c.v., bilaterally) did not alter the concentrations of monoamines or their metabolites. Morphine (10 mg kg-1, s.c., 1 h) did not alter NA or 5-HT or their metabolites in any brain area studied, but elevated 3,4-dihydroxyphenylacetic acid (DOPAC) and/or homovanillic acid (HVA) in LIM and HYP. Combination of morphine and NPFF decreased NA in LIM, elevated 3-methoxy-4-hydroxyphenylethylene glycol in HYP and LBS as well as 5-hydroxyindoleacetic acid in LIM and HYP. These responses are typical to morphine at doses larger than 10 mg kg-1, and suggest a synergistic effect of the two compounds. Further, the morphine-induced elevations of DOPAC and HVA were potentiated by NPFF in LIM and HYP. In conclusion, our results suggest that NPFF does not attenuate but rather enhances the changes induced by acute morphine in the cerebral monoamines.