Nociceptin (1-13)NH2 inhibits stimulated calcitonin-gene-related-peptide release from primary cultures of rat trigeminal ganglia neurones.

In this work we have developed and characterized primary cultures of neonatal rat trigeminal ganglia neurones; calcitonin-gene-related-peptide (CGRP) released from cells was taken as a marker of neuronal function. A significant and consistent increase in CGRP secretion was elicited by non-specific (56 mm KCl or veratridine) or specific (capsaicin) depolarizing stimuli. This paradigm was subsequently used to investigate the effects of nociceptin, an opioid-like peptide involved in central and peripheral control of nociception. We found that the nociceptin analogue nociceptin (1-13)NH2 (NOC) did not affect baseline CGRP release, but it reduced in a concentration-dependent manner CGRP release induced by all tested stimuli. NOC-induced reduction was statistically significant from 0.01 nm onward and achieved maximal effects at 10 nm. Such effects of NOC were seemingly mediated by the activation of specific ORL1 receptors, as a well-known nociceptin antagonist, N(Phe1)nociceptin (1-13)NH2, was able to completely revert NOC inhibition of capsaicin-stimulated CGRP release.

A safe immunosuppressive protocol in adult-to-adult living related liver transplantation.

BACKGROUND: In this series of 32 adult-to-adult living related liver transplantations, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen. Basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), has been extensively evaluated as induction therapy for cadaveric liver transplant recipients. PATIENTS AND METHODS: Thirty-two adult-to-adult living related liver transplantations were performed in the last 3 years. All patients received two 20 mg doses of basiliximab (days 0 and 4 posttransplantation) followed by tacrolimus (0.15 mg/kg/d; 10-15 ng/mL target trough levels) and steroids (starting with 20 mg IV switched to PO as soon as the patient was able to eat and weaned within 1-2 months). The average follow-up was 395 days after transplantation. RESULTS: Of the patients, 93.75% remained rejection-free during follow-up with an actuarial rejection-free probability of 92.59% within 3 months. Two patients (6%) had one episode of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 86.85% and 81.25%. One patient (3%) experienced one episode of sepsis. There was no evidence of cytomegalovirus infections or side effects related to the basiliximab. We found zero de novo malignancy but we observed two patients with metastatic spread of their primary malignancy during the follow-up. CONCLUSION: Basiliximab in association with tacrolimus and steroids is effective as prophylaxis of ACR among adult living related liver transplant recipients.

Dysfunction of arousal systems in sleep-related migraine without aura.

Primary headaches are closely related to sleep. Modifications in the patterns of arousal during sleep have been reported in migraine, especially in the nights preceding a headache attack. We aimed at evaluating the pattern of arousal from sleep in a group of patients affected by sleep-related migraine. We enrolled 10 consecutive patients, three males and seven females, aged between 20 and 62 years, who presented frequent attacks of migraine without aura (more than five per month), closely related to sleep (more than one-half of the attacks occurred during sleep, causing an awakening). A control group was studied, matched for age and sex. Patients and controls underwent a full-night polysomnographic study, following adaptation; arousal pattern was studied by the scoring of the high-frequency EEG arousal and by the cyclic alternating pattern (CAP). Migraineurs showed a lower CAP rate in non-rapid eye movement (NREM) sleep and, in particular, a lower number of A1 phases (low-frequency, high-amplitude EEG bursts) compared with the controls. Migraineurs also showed a lower index of high-frequency EEG arousals during rapid eye movement (REM) sleep. The reduction in the CAP rate indicates a lower level of arousal fluctuation in NREM sleep. The reduced arousal index in REM suggests a dysfunction in neural structures involved in both the control of REM sleep and the pathophysiology of migraine, such as the hypothalamus and the brainstem.

A sleep study in cluster headache.

Cluster headache (CH) is a primary headache with a close relation to sleep. CH presents a circa-annual rhythmicity; attacks occur preferably during the night, in rapid eye movement (REM) sleep, and they are associated with autonomic and neuroendocrine modifications. The posterior hypothalamus is the key structure for the biological phenomenon of CH. Our aim is to describe a 55-year-old man presenting a typical episodic CH, in whom we performed a prolonged sleep study, consisting of a 9-week actigraphic recording and repeated polysomnography, with evaluation of both sleep macrostructure and microstructure. During the acute bout of the cluster we observed an irregular sleep-wake pattern and abnormalities of REM sleep. After the cluster phase these alterations remitted. We conclude that CH was associated, in this patient, with sleep dysregulation involving the biological clock and the arousal mechanisms, particularly in REM. All these abnormalities are consistent with posterior hypothalamic dysfunction.

Multiple attack study on the available triptans in Italy versus placebo.

The aim of the study is to evaluate the efficacy and tolerability of the five triptans that are commercially available in Italy (zolmitriptan 2.5 mg, rizatriptan 10 mg, sumatriptan 100 mg, almotriptan 12.5 mg and eletriptan 40 mg). The study was conducted in single-blind versus placebo and its duration was 18 months. At the Headache Centre of the 'Agostino Gemelli' Hospital in Rome we selected 42 patients, suffering from headache with and without aura (International Headache Society Committee on Headache Classification, 1988 Cephalalgia 8:1-96), whose headache frequency ranged between 1- and 4-monthly crises. For a total of 25 crises, for every five consecutive crises, a different triptan was taken. The end-points of the study were as follows: response at 2 h, 'pain free' at 2 h and 'sustained pain free' (at 24 h). The intra-patient consistency and the tolerability were also evaluated. Thirty patients completed the study and the statistical analysis was only applied to these patients. No substantial difference in terms of the efficacy of the triptans was noted; all triptans were well tolerated. These results suggest the possibility of testing different triptans in the same patient in order to identify the ideal drug for every patient.

Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study.

The objectives of this paper are to evaluate the efficacy and tolerability of topiramate, given at the dose of 100 mg/day, in the prophylactic treatment of migraine. The hypothesis that migraine is the result of a condition of neuronal hyperexcitability and the quest for drugs that are able to limit the number of crises justifies the attempt to utilise the new antiepileptic drugs in the prophylaxis of this pathology, which is so important due to its high prevalence and due to the high disability it causes. The study was randomised double-blind versus placebo, lasting 16 weeks, and was preceded by a run-in period of 4 weeks. One hundred and fifteen patients were randomly allocated to treatment with topiramate (TPM) or placebo: 35 patients completed the study in the TPM group and 37 patients in the placebo group. At the end of the double-blind phase of study, in the TPM group, we recorded a significant reduction in the frequency of migraine crises (from 5.26 at baseline to 2.60 in the last 4 weeks), a significant reduction in the quantity of symptomatic drugs taken as compared to the placebo control group (from 6.17+/-1.80 SD to 2.57+/-0.80) and a significant downward trend in the number of days of disability over the 16-week period of therapy. In the TPM group, side effects were transient and well tolerated. TPM has thus proven its efficacy and tolerability in the prophylaxis of migraine.

Internal auditory canal metastasis.

This report deals with 3 cases of internal auditory canal metastasis, an extremely rare lesion, few cases having been reported in the international literature. Since pre-operative diagnosis is fundamental in the planning of a correct therapeutic strategy, it is important that the neurotologist be aware of the possibility of their occurrence in this particular area. Metastasis can occur unilaterally as well as bilaterally; the latter being the case in 1 of the patients described herein. Correct pre-operative diagnosis is particularly difficult in patients in whom the primary tumour has not been detected at the time of identification of the lesion in the internal auditory canal. The only characteristic, specific of metastasis, is the presence of multifocal cerebral lesions. However, these were detected in only 1 of the present cases. On the contrary, in cases of a single metastasis, both magnetic resonance imaging and computed tomography usually fail to show any distinctive feature when compared to the most common tumours of the internal auditory canal (vestibular schwannomas and meningiomas). Bilateral metastases can also be misdiagnosed as neurofibromatosis type 2. Clinical data that should alert the clinician are: rapidly progressive sensorineural hearing loss, followed by onset of progressive facial nerve weakness. Radiotherapy and/or chemotherapy are the two main treatment modalities, while surgical removal is reserved for selected cases of a single metastasis. Albeit, due to the paucity of specific radiological and clinical characteristics, surgical removal is often necessary to reach the correct diagnosis, as occurred in 2 of the present patients.

Antiepileptic drugs in migraine prophylaxis: state of the art.

Antiepileptic drugs have proven their efficacy in the prophylactic treatment of migraine. Our study comprises a clinical trial that examines the efficacy of gabapentin and topiramate and a description of the pharmacologic characteristics and the efficacy of tiagabine, lamotrigine, levetiracetam and zonisamide. Antiepileptic drugs have multiple modes of action which can explain their efficacy in reducing neuronal excitability which is proven in epilepsy and postulated in migraine. The relationship between epilepsy and migraine has, in fact, been much debated but never convincingly proven. Antiepileptic drugs could be useful in migraine prophylaxis as some of these have determined a reduction in the monthly frequency and intensity of crises in subjects suffering from migraine with and without aura. These are the aims that have been proposed by the U.S. Headache Consortium Evidence-Based Guidelines. Further double-blind placebo-controlled studies are necessary in order to assess their safety and efficacy.

Reduced habituation to experimental pain in migraine patients: a CO(2) laser evoked potential study.

The habituation to sensory stimuli of different modalities is reduced in migraine patients. However, the habituation to pain has never been evaluated. Our aim was to assess the nociceptive pathway function and the habituation to experimental pain in patients with migraine. Scalp potentials were evoked by CO(2) laser stimulation (laser evoked potentials, LEPs) of the hand and facial skin in 24 patients with migraine without aura (MO), 19 patients with chronic tension-type headache (CTTH), and 28 control subjects (CS). The habituation was studied by measuring the changes of LEP amplitudes across three consecutive repetitions of 30 trials each (the repetitions lasted 5 min and were separated by 5-min intervals). The slope of the regression line between LEP amplitude and number of repetitions was taken as an index of habituation. The LEPs consisted of middle-latency, low-amplitude responses (N1, contralateral temporal region, and P1, frontal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). The latency and amplitude of these responses were similar in both patients and controls. While CS and CTTH patients showed a significant habituation of the N2/P2 response, in MO patients this LEP component did not develop any habituation at all after face stimulation and showed a significantly lower habituation than in CS after hand stimulation. The habituation index of the vertex N2/P2 complex exceeded the normal limits in 13 out of the 24 MO patients and in none of the 19 CTTH patients (P<0.0001; Fisher's exact test). Moreover, while the N1-P1 amplitude showed a significant habituation in CS after hand stimulation, it did not change across repetitions in MO patients. In conclusion, no functional impairment of the nociceptive pathways, including the trigeminal pathways, was found in either MO or CTTH patients. But patients with migraine had a reduced habituation, which probably reflects an abnormal excitability of the cortical areas involved in pain processing.

Occupational head injury and subsequent glioma.

We report the case of a policeman who suffered a severe head injury to the right temporoparietal lobe while driving a police car. Four years later, the patient developed a neoplasm at the precise site of the meningocerebral scar. Histological examination confirmed a glioblastoma multiforme adjacent to the dural scar. Radiological documentation of the absence of tumor at the time of injury, exact localization of the neoplasm in the injured cerebral area, and latency of the cancer supported the hypothesis of a causal relationship with brain trauma. Physicians faced with brain neoplasms in adults should carefully investigate the patient's personal history of head trauma. When a relationship with occupational head injury is probable, reporting of suspect occupational illness is compelling.

Peripheral neuropathy with hypomyelinating features in adult-onset Krabbe's disease.

We describe three brothers suffering from Krabbe's disease with onset in the fifth decade. The proband showed a complete deficiency of leukocyte enzyme galactocerebrosidase and was found to be heterozygous for two previously described mutations: G > A809 and 502T/del consisting of a 30 kb deletion. In all three brothers the neurological examination showed features of asymmetrical peripheral neuropathy associated with pyramidal signs and the electrophysiological examination showed a generalized slowing of nerve conduction velocities. Two patients died at 59 and 61 years of age due to respiratory failure. Both the proband and his brother underwent a sural nerve biopsy. In the former the most striking finding was the presence of uniformly thin myelin sheaths without evidence of demyelination; a complete absence of fibers was found in the latter. Our findings confirm that peripheral neuropathy may be the presenting feature of late-onset Krabbe's disease. Hypomyelination rather than demyelination may represent the distinguishing pathological finding of this condition.

Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study.

OBJECTIVE: Gabapentin is an antiepileptic drug of new generation that increases brain GABA levels. We report the results of a three-month randomised double-blind placebo-controlled study on the effects of gabapentin in the prophylaxis of patients with migraine meeting the IHS criteria. PATIENTS AND METHODS: We treated 63 patients suffering from migraine with or without aura. Patients treated their attack at home using symptomatic drugs and clinical assessment was recorded on a diary. After a washout of 8 week from any other prophylactic treatment, all patients were treated with 1200 mg/day of gabapentin; this is our therapeutic plan: 400 mg/day from 1st to 3rd day, 800 mg/day from 4th to 6th day and 1200 mg/day from 7th day. RESULTS: No patients withdrew, gabapentin was well tolerated; adverse events (somnolence, dizziness, tremor, fatigue and ataxia) generally were transient and mild to moderate in severity and in 13 patients (27%) only occurred. At the end of treatment, in such case, we reported a significative reduction of frequency and intensity of migraine in 30 patients treated with gabapentin. DISCUSSION: Our observations indicate that gabapentin is well tolerated by patients and that reduces headache frequency and use of symptomatic drugs in both groups. Gabapentin shows to have an effective therapeutic action in the prophylactic treatment of migraine.

Production and secretion of thioredoxin from transformed human trophoblast cells.

Thioredoxin is a redox active protein which has been implicated in reproductive processes. In this study we investigated the intracellular production and extracellular secretion of placental thioredoxin by human cytotrophoblast cell lines which were used as in-vitro model systems. Results clearly demonstrated that thioredoxin is not only synthesized by these cells but is also secreted and that while the intracellular thioredoxin is present only as a 12 kDa form, it would appear that the extracellular thioredoxin is present in two forms, a predominant 12 kDa form accompanied by a lower amount of a 10 kDa form. The observed localization and possible secretion of thioredoxin at the feto-maternal interface suggest important roles for this protein during pregnancy. Intracellular thioredoxin may be involved in the prevention of cellular damage due to oxidative stress whereas extracellular thioredoxin may act to integrate the actions of the cytokine network operating at the feto-maternal interface thereby assisting with implantation and the successful establishment of pregnancy.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

We report the clinical, pathological, and genetic findings of a case of MELAS syndrome. This was a man who died for metabolic failure at the age of 27 years. His familiar history was positive for hypoacusia and stroke. He was of short stature and presented mild mental retardation. Since the age of 21 he suffered from recurrent brain-ischemic lesions mainly in the occipital lobes, documented by repeated CT scans. The laboratory data and muscle biopsy disclosed lactic acidosis with ragged red fibres. Neurophysiological data and peripheral nerve biopsy showed an axonal neuropathy. A point mutation in the tRNALeu(UUR) gene of mitochondrial DNA was detected in 5 post-mortem tissues and in muscle biopsy. No defects of mitochondrial respiratory chain were detected. The histological and ultrastructural studies of the brain showed multiple and heterogeneous ischemic lesions with no obvious alterations of cerebral blood vessels. These lesions do not correspond to the vascular territories of main cerebral arteries. Our observations support the hypothesis that local metabolic alterations would play a crucial role in the pathogenesis of cerebral ischemic lesions in MELAS. The correlation between genetic, biochemical, and pathological data are discussed.

A re-examination of the association of 'early pregnancy factor' activity with fractions of heterogeneous molecular weight distribution in pregnancy sera.

The association of 'early pregnancy factor' ('EPF') activity in early pregnancy sera with multiple fractions of heterogeneous molecular mass was re-examined to test whether previously perplexing observations could be explained by a new multi-factorial model of the serum components required for this activity expression. Gel permeation fractionation of human pregnancy sera revealed 'EPF' activity associated with fractions containing components ranging in MW from < or = 1 kDa to > or = 500 kDa. A significant activity peak was observed eluting on the total volume (Vt) of the column, indicating the presence of active molecules of very low molecular mass. Multiple activity peaks were also observed in the macromolecular fractionation region ranging in apparent molecular weight from 12 kDa, through 25, 70 and 250 to > or = 500 kDa. Analysis of these fractions revealed that they all contained thioredoxin and active moieties of low molecular mass, with the latter probably directly associated with the former. Adsorption with specific anti-thioredoxin antibodies removed from these fractions the capacity to display 'EPF' activity. Further analyses revealed that in these fractions thioredoxin played a permissive role allowing the low molecular mass active moieties to express activity in the bioassay in the presence of otherwise counteracting substances. The results of these studies are consistent with the proposal that 'EPF' activity expression in pregnancy sera is due to the presence of a multi-factorial system in which thioredoxin plays an essential permissive role in concert with active moieties of low molecular mass.

Post-traumatic malignant glioma. Report of a case.

Only a few cases reported in the literature fulfil the currently established criteria for accepting the traumatic origin of some intracranial tumors. A case of post-traumatic glioma is presented. Several years after sustaining a commotive left parietal trauma, our patient developed symptoms of intracranial tumor. Neuroimaging (CT and MRI) showed a large neoplasia in the left temporo-parietal-occipital region, and stereotactic biopsy revealed a mixed glioma in continuity with the scar resulting from the trauma.

Multiple sclerosis associated with peripheral demyelinating neuropathy.

We report clinical, electrophysiological, magnetic resonance imaging, and nerve biopsy findings of 2 patients with definite multiple sclerosis and peripheral demyelinating disease. Although it is not easy to assess the real incidence of peripheral neuropathy in patients with multiple sclerosis, this association seems to be rare. The combination of central and peripheral demyelination may be a fortuitous coincidence, but it appears improbable. Alternatively, these patients may represent a specific subpopulation and common immunopathogenetic mechanisms (such as immunological factors, endothelial alterations, and abnormal expression of adhesion molecules) may underly both central and peripheral myelin involvement. The study of these cases might clarify specific mechanisms of pathogenetic significance in demyelinating diseases.

Guinea pig serum L-asparaginase: purification, and immunological relationship to liver L-asparaginase and serum L-asparaginases in other mammals.

L-asparaginase, an enzyme used in the treatment of acute lymphocytic leukemia, is found in the serum of only a few mammalian groups, including the guinea pig and its close relatives in the superfamily Cavioidea. This report describes the purification and characterization of L-asparaginase from guinea pig serum. Antiserum against the purified enzyme cross-reacted with sera from other Cavioidean species but not with mouse serum. Relatively weak cross-reaction with unpurified L-asparaginase in guinea pig liver indicates a significant degree of evolutionary divergence.