Migraine incidence, comorbidity and health resource utilization in the UK.

Population-based data on migraine incidence and comorbidity are scarce. We therefore aimed to quantify incidence rates and comorbidity of diagnosed migraine and health resource utilization (HRU) in migraineurs in the UK primary care setting. We conducted a follow-up study with a nested case-control analysis on the General Practice Research Database. The study encompassed 51,688 patients with a first-time diagnosis of migraine between 1994 and 2001, and the same number of matched controls. The migraine incidence rate was 3.69 (95% confidence interval 3.66, 3.73) cases per 1000 person-years. It was around 2.5 times higher in women. Most chronic diseases were slightly more prevalent in migraineurs than in controls. Triptan users had higher health resource utilization than other migraineurs. This study shows that migraine is a common diagnosis in general practice and associated with a high prevalence of comorbidity. The increased HRU in triptan users suggests greater migraine severity.

Target-specific outgrowth from human mesencephalic tissue grafted to cortex or ventricle of immunosuppressed rats.

Human fetal mesencephalic tissue was grafted to rats with unilateral lesions of the nigrostriatal pathway. The animals were immunosuppressed with cyclosporine A. Grafts were placed either into the lateral ventricle ipsilateral to the lesion or in the cingulate cortex above corpus callosum. The grafts and newly formed fibers were visualized by immunohistochemistry with antibodies against tyrosine hydroxylase (TH) and the human Thy-1 glycoprotein. TH-positive fibers covered the total volume of striatum when the graft was placed either in the ventricle or in the cortex. When the transplant was located in the ventricle, TH-positive cells migrated from the graft into host striatum. No cell migration was seen into any other areas than striatum. Cortex and septum were sparsely reinnervated by the graft, but not to a density higher than that normally seen. Globus pallidus was totally devoid of TH-positive fibers. When the graft was placed in cingulate cortex, fiber bundles penetrated through corpus callosum into either striatum, to arborize in its dorsal parts, or followed the medial side of the lateral ventricle to ventral limbic areas, where a fiber network also was formed. Human specific Thy-1-immunohistochemistry revealed positivity only on the lesioned side. These data suggest that dopamine neurons in human mesencephalic tissue, grafted to the rat brain, can migrate specifically into host striatum. Furthermore, TH-positive fiber outgrowth occurred only into dopamine denervated areas of the host, avoiding areas that are normally not innervated by nigral neurons, but also able to reach distant target cells.

Histone deacetylase inhibitor 4-phenylbutyrate modulates glial fibrillary acidic protein and connexin 43 expression, and enhances gap-junction communication, in human glioblastoma cells.

Human glioblastoma cell cultures were established and the expression of glial fibrillary acidic protein (GFAP) and the gap-junction protein connexin 43 (Cx43) was confirmed by Western blot. Following treatment with 4-phenylbutyrate (4-PB), increased concentrations of non-phosphorylated GFAP were seen, while phosphorylated isoforms remained intact. Immunocytochemical staining of glioblastoma cells revealed an intracellular redistribution of GFAP. In addition to cytoplasmic immunostaining, GFAP immunoreactivity was also associated with the nucleus and/or the nuclear membrane. Phosphorylated and non-phosphorylated Cx43 proteins were increased 2- to 5-fold following 4-PB treatment, and were redistributed to areas of the cell surface, participating in cell-to-cell contacts. In addition, functional gap-junction coupling was amplified, as indicated by increased fluorescent dye transfer, and elevated levels of Cx43 protein were detected in parallel with enhanced gap-junction communication. Induced cell differentiation, with improved functional coupling of tumour cells, may be of importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds.

Histone deacetylase inhibitor 4-phenylbutyrate suppresses GAPDH mRNA expression in glioma cells.

The histone deacetylase (HDAC) inhibitor 4-phenylbutyrate (4-PB) is a non-toxic compound that can induce differentiation and promote maturation of various types of malignant cells. In the present study we show that 4-PB inhibit glioma cell proliferation, induce apoptosis and decrease mRNA expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in a concentration-dependent manner. Proliferation of established rat glioma cell lines (RG2 and C6) in culture was significantly decreased after treatment with 4-PB (2-40 mM). Low concentrations of 4-PB (2-20 mM) induced cell differentiation followed by apoptosis, whereas higher concentrations of 4-PB (40 mM) induced cell necrosis. Also, low concentrations of 4-PB significantly decreased GAPDH mRNA expression in C6 and RG2 rat glioma cells, suggesting a link between decreased cell proliferation, energy consumption, and down-regulation of GAPDH gene expression. We have found that GAPDH mRNA expression is markedly increased in human glioblastoma tissues. Therefore, the novel effect of 4-PB described here may offer means to suppress growth of glioma cells by diminishing the key reaction in glycolysis as a therapeutic approach for cancer.

Muscarinic receptors coupled to inositol phospholipid breakdown in human SH-SY5Y neuroblastoma cells: Effect of retinoic acid-induced differentiation.

In human SH-SY5Y neuroblastoma cells, carbachol stimulates inositol phospholipid breakdown with an EC(50) value of 18 ?M. The response is prevented by pirenzepine, with a Hill coefficient of 0.57 and an IC(50) value of 0.15 ?M. A Gpp[NH]p-stimulated [(3)H]phosphatidylinositol-4,5-bisphosphate hydrolysing activity was demonstrated in SH-SY5Y membrane preparations. Treatment of the cells for 3 days with retinoic acid (0.1 and 1 ?M, in 1% ethanol) caused them to differentiate. The ethanol per se increased the incorporation of tritium into the inositol phospholipids following incubation of the cells with [(3)H]myo-inositol. The inositol phospholipid response to carbachol (1000 ?M) was lower following treatment for 3 days with 1 ?M retinoic acid than with 0.1 ?M retinoic acid. The EC(50) values for carbachol, relative rates of stimulation (with respect to that produced by 1000 ?M carbachol) with arecoline, oxotremorine-M and oxotremorine, lack of synergy between carbachol and raised [K(+)] were the same in undifferentiated and retinoic acid-differentiated cells. It is concluded that (a) more than one muscarinic receptor type is coupled to the inositol phospholipid breakdown response in undifferentiated SH-SY5Y cells, and (b) retinoic acid-induced differentiation of the cells does not affect the properties of the muscarinic receptors coupled to the response, although the magnitude of the response appears to be sensitive to the retinoic acid concentration used to induce the cell differentiation.

Evidence for target-specific outgrowth from subpopulations of grafted human dopamine neurons.

Clinical and experimental grafting in Parkinson's disease has shown the need for enhanced survival of dopamine neurons to obtain improved functional recovery. In addition, it has been suggested that a limited number of surviving dopamine neurons project to the dopamine-denervated host striatum. The aim of this study was to investigate if subpopulations of ventral mesencephalic dopamine neurons project to their normal targets, i.e., dorsal vs. ventral striatum. Following implantation of human ventral mesencepahlic tissue into the lateral ventricle of dopamine-depleted rats, human-derived dopamine reinnervation was achieved both in dorsal and ventral striatum. Treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a degeneration of tyrosine hydroxylase (TH)-immunoreactive nerve fibers in dorsal striatum but not in ventral areas in some animals, while MPTP was without effect in other animals. TH-immunoreactive neurons were small and appeared shrunken in animals carrying grafts affected by the MPTP treatment. In conclusion, grafted dopamine neurons projected nerve fibers into areas that they normally innervate. Thus, when searching for factors that may enhance survival of grafted dopamine neurons it is important to study which subpopulation(s) of ventral mesencephalic dopamine neurons is affected, such that a proper reinnervation may be achieved.

Splanchnic oxygen consumption in septic and hemorrhagic shock.

Oxygen consumption (VO2) is dependent on oxygen delivery (DO2) in septic shock. Local hypoxia with later secondary organ failure may develop, however, despite an often hyperdynamic circulation. The splanchnic organs seem to be of vital importance in this context. In experiments performed in pigs we compared total body VO2 and DO2 with oxygen consumption and delivery in the gastrointestinal organs and the liver in two different shock states: (1) septic shock induced by peritonitis (n = 6) and (2) hemorrhagic shock (n = 6). Another group of six animals not in shock served as controls. Total, gastrointestinal, and liver DO2 decreased in a similar pattern in both septic and hemorrhagic shock. Gastrointestinal and liver VO2 increased in sepsis, whereas it was unchanged in hemorrhage. In the later phase of sepsis, liver VO2, but not gastrointestinal VO2, again decreased, because liver oxygen extraction was almost total and liver DO2 decreased further. The development of flow-dependent liver hypoxia was reflected in a decrease in liver lactate turnover (increased liver lactate release) during late sepsis. Early hypoxia in the splanchnic region is suggested as a plausible mechanism behind the development of secondary organ failure, especially in sepsis.

Pulmonary platelet trapping induced by beta-endorphin injection in the cerebrospinal fluid in dogs.

The effect of beta-endorphin injected into either the lateral ventricle or the cisterna magna on blood pressure, heart rate, peripheral platelet and leukocyte counts, hematocrit levels, catecholamines, and pulmonary platelet trapping was studied. The effect of endotoxin on the endogenous opiocortin system was also investigated. Injection of beta-endorphin caused a significant decrease in blood pressure, bradycardia, and pulmonary platelet trapping. beta-Endorphin had no effect on peripheral platelet and leukocyte counts, catecholamines, or hematocrit levels. Endotoxin shock caused a marked rise in circulating beta-endorphin and a decrease in cerebrospinal fluid beta-endorphin. Our results confirm that endotoxin shock activates the opiocortin system, and we suggest that the endorphins may participate in the evolution of the lung injury seen in septic shock.

Beta-endorphin administered into the lateral ventricle of the brain causes pulmonary platelet trapping in rabbits.

Human beta-endorphin was injected into the cerebrospinal fluid in rabbits by means of a needle inserted into the lateral ventricle of the brain. Control rabbits received an equal amount of saline. beta-Endorphin induced a significant pulmonary platelet trapping compared to control. beta-Endorphin had no effect on arterial blood pressure, heart rate, platelet aggregability ex vivo or fibrinolytic activity (fibrinolytic plates). The plasma activity of antithrombin III, kallikrein-like activity and kallikrein inhibitor determined by means of chromogenic substrates was not influenced by beta-endorphin.

Thy-1-like immunoreactivity in human brain during development.

Thy-1-like immunoreactivity was found in several areas of the immature and adult human brain, using indirect immunofluorescence techniques. In the fetal brain (31 gestational weeks) most immunoreactivity was located in the white matter with an overall granular diffuse distribution and stray fluorescent fibrous structures radiating into grey matter. At 2 months postnatally, the large axon bundles of the internal capsule traversing the caudate nucleus were strongly positive, whereas surrounding neuropil seemed to be negative. In the adult caudate nucleus no such fluorescent fibre bundles could be observed. At 8 months of age, both cerebellum and frontal cerebral cortex contained large numbers of fibrous structures in the grey matter in addition to white matter fluorescence. The molecular layer of both areas was negative. The 8-month-old cerebellum had a Thy-1 distribution similar to the adult, while in the frontal cortex cerebri the density of fluorescent structures increased gradually until adulthood. However, in the 5-year-old frontal cortex the immature granular appearance of 2-month-old cortex could still be seen, but with a greater number of radiating fluorescent bundles. In the adult brain, cerebellum contained a dense pattern of thick, fibrous fluorescent structures in white matter and the internal granular layer and in the frontal cortex thick bundles radiated into grey matter to form a plexus of coarse individual fibres in layers II and III. The hippocampal formation of the 31-week-old fetus contained a network of thin varicose fibres, ascending from the white matter. Stratum radiatum at this stage contained numerous small spots of Thy-1-like immunoreactivity, but no visible fluorescent fibres.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral and electrophysiological correlates of human mesencephalic dopaminergic xenograft function in the rat striatum.

While human fetal xenografts placed into immunocompromised animal hosts have been shown to survive and grow, their ability to function and influence the host tissue has not been fully examined. Therefore, we implanted grafts of human fetal mesencephalic tissue intracranially into rats with unilateral 6-hydroxydopamine lesions of their nigrostriatal dopaminergic innervation and tested the rats behaviorally for reductions in apomorphine-induced rotations. The purpose of this study was to test the ability of these grafts to provide a functional reinnervation by comparing the behavioral changes with the morphology and presence of electrophysiologically active dopaminergic neurons within the graft and with firing rates of host striatal neurons. Adult Sprague-Dawley rats that had been unilaterally lesioned and that showed a stable two peak pattern of apomorphine-induced rotations received grafts of human fetal mesencephalic tissue placed directly into the lesioned striatum. These rats were then further tested each month for five months for reductions in their turning behavior. At 5 to 6 months postgrafting, electrophysiological recordings were made of cells within the graft and within the host striatum. The rats were then examined immunohistochemically to evaluate graft survival and extent of reinnervation of the host tissue. The rats receiving mesencephalic dopaminergic grafts demonstrated a 79% reduction in their apomorphine-induced rotations. Electrophysiological recordings revealed spontaneously active dopaminergic neurons within the graft as well as host striatal cell firing rates consistent with those of dopamine-innervated cells. Furthermore, immunohistochemical studies confirmed graft survival and revealed marked fiber outgrowth from the graft into and throughout the striatum. Taken together these findings provide evidence that grafts of human fetal mesencephalic tissue are able to produce behavioral improvements in lesioned animals which are associated with the presence of dopaminergic neurons within the graft and are consistent with normal host striatal cell activity levels.

Effect of cyproheptadine on endotoxin-induced pulmonary platelet trapping.

The adult respiratory distress syndrome (ARDS) seen in endotoxin shock is accompanied by the release of beta-endorphin. The hypotension that is seen in endotoxin shock can also be produced by injection of beta-endorphin and is effectively blocked by the use of antiserotonin drugs. Serotonin injection in dogs causes lung changes similar to those seen in endotoxin shock. Pulmonary platelet trapping (PPT) is one of the factors in the evolution of ARDS. The effects of cyproheptadine, an antiserotonin drug, were evaluated on PPT in dogs injected with endotoxin. Dogs treated with cyproheptadine both prior to and after induction of endotoxin shock were compared with the standard endotoxin shock model. Blood pressure, platelet aggregability, and wet/dry lung weight ratio were studied in all groups. Posttreatment with cyproheptadine obviated PPT indicating the applicability of cyproheptadine in the treatment of ARDS. Pretreated dogs had PPT not significantly different from endotoxin controls, suggesting that blocking of serotonin before shock activates other vasoactive substances, which may include prostaglandins or prostaglandin derivates.

Improved migraine management in primary care: results of a patient treatment experience study using zolmitriptan orally disintegrating tablet.

The 'Zomig Appropriate for Primary care' programme was developed to address the needs of primary care physicians (PCPs) to improve migraine management. As part of the programme, an international, open-label, 6-month clinical study was performed. The study included new and tangible outcome variables relevant to PCPs and recruited patients presenting in primary care with an established migraine diagnosis. Patients treated up to three migraine attacks per month with zolmitriptan orally disintegrating tablet (ODT) 2.5 mg. All other migraine attacks occurring during the study period were treated with the patient's usual migraine medication (including other triptans). Questionnaires were used to record patient treatment experiences at the study end. The primary end-point was the proportion of patients wanting to continue using zolmitriptan ODT. Some 595 patients treated 7171 migraine attacks with zolmitriptan ODT. Of the 504 patients who completed the 6-month questionnaire, 380 (75.4%) wished to continue using zolmitriptan ODT. The results of the study indicate that patient-orientated end-points are more motivational and meaningful to physicians than traditional end-points used in controlled clinical trials, allowing them to make informed decisions regarding migraine management.

Identification of a neodeterminant in complexes of human brain Thy-1.

Human Thy-1 glycoprotein was purified from brain cortex membranes. Antibodies were produced in rabbits by immunization with purified Thy-1 and with brain homogenate. Both preparations of antibodies reacted with monomers of 125I-labeled Thy-1. In addition, the antibodies against the purified antigen also recognized a determinant which was absent, or present in very low amounts, in homogenates of human brain. Analysis by gel filtration in Nonidet-P40 or deoxycholate revealed the presence of complexes of purified Thy-1 that were specifically precipitated by antibodies against this determinant. It was also shown that anti-monomer antibodies were unable to react with the complex form of Thy-1. These complexes seemed to be composed of a varying number of Thy-1 molecules. By treatment with sodium dodecyl sulfate, the multimers were completely dissociated into monomers. The tendency to complex formation seems to be unique for human Thy-1, since Thy-1 analogues of other species do not show this property when isolated.

Characterization of a hydrophilic form of Thy-1 purified from human cerebrospinal fluid.

Thy-1 is a developmentally regulated cell surface glycoprotein in nervous tissue. An inositol-containing glycolipid structure is covalently attached to its carboxyl terminus, which anchors the protein to the cell membrane. In the present paper we report the characterization of a water-soluble form of Thy-1, purified from human cerebrospinal fluid (CSF). In contrast to the membrane-bound form of Thy-1 (M-Thy-1) isolated from human brain cerebral cortex, CSF-Thy-1 behaved like a completely hydrophilic glycoprotein, as analyzed by charge-shift electrophoresis in the presence of detergents and by liposome incorporation experiments. CSF-Thy-1 displayed a slightly higher apparent molecular weight in sodium dodecyl sulfate-polyacrylamide gel electrophoresis than M-Thy-1. Digestions with endoglycosidases demonstrated that this difference in size was correlated to different processing of the three N-linked oligosaccharides, and the mobilities of the deglycosylated molecules were indistinguishable in sodium dodecyl sulfate gels. A Pronase-resistant carboxyl-terminal fragment was isolated from the CSF-Thy-1 after trypsin digestion and compared with the corresponding structure of M-Thy-1, obtained by treatment either with bacterial phosphatidylinositol-specific phospholipase C or with human serum (as a source of phosphatidylinositol-specific phospholipase D). The major fragment from CSF-Thy-1 behaved identically, with respect to size and charge, to the carboxyl-terminal fragment from M-Thy-1 solubilized by phospholipase D. These findings suggest an in vivo release of phosphatidylinositol-anchored Thy-1 glycoprotein from brain cells by the action of an endogenous phospholipase D.

Radiology in laparoscopic cholecystectomy. A retrospective study.

Laparoscopic cholecystectomy (LC) is attempted in all our patients scheduled for cholecystectomy. The related standard radiologic procedures are preoperative ultrasonography (US) and preoperative cholangiography (PCA). In a retrospective study of 214 patients scheduled for LC over a 2-year period we have reviewed the radiologic and clinical records. Preoperative US revealed stones in the common bile duct (CBD) in 8 patients, all treated with endoscopic papillotomy before or after operation. PCA was successful in 176 patients (82%) and gave crucial information in 22 patients including 8 with stones in the CBD not preoperatively diagnosed, 6 with anomalous anatomy, and 8 with malpositioned surgical clip on the cystic duct. In 26 patients LC was converted into open surgery, but in only one case due to CBD stone revealed at PCA. Seventeen patients had minor postoperative complications, all managed conservatively. We consider preoperative US and PCA appropriate radiologic investigations in conjunction with LC.

Timing of antibiotic treatment in non-perforated gangrenous appendicitis.

OBJECTIVE: To assess whether antibiotic treatment with cefuroxime and tinidazole started during the operation was as effective as treatment started before operation in patients with gangrenous non-perforated appendicitis. DESIGN: Prospective randomised study. SETTING: University hospital, Sweden. SUBJECTS: 114 patients with gangrenous, non-perforated appendicitis who had had antibiotics started before operation and 120 whose treatment was started during operation out of a total of 575 who presented with a presumptive diagnosis of appendicitis. MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: There were no deaths, and the rates of infective complications were 1/114 (0.9%) and 3/120 (3%), respectively. The median hospital stay was four days in both groups. CONCLUSION: Antibiotic treatment started during the operation is not significantly worse at preventing infective complications in non-perforated, gangrenous appendicitis than treatment started before the operation.