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.

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.

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.

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.

First trimester development of the human nigrostriatal dopamine system.

The aim of the present study was to characterize the morphological and neurochemical differentiation of mesencephalic dopaminergic neurons in human embryos, derived from elective first trimester abortions. Embryonic brain tissue was taken for analysis of tyrosine hydroxylase (TH) by immunohistochemistry and Western blot, and for analysis of endogenous dopamine (A) content using HPLC-ED. TH expression was first detected at 3.5 weeks of gestational age (Carnegie stage 11) by immunohistochemical staining of the primordial sympathetic trunk along both sides of the neural tube. In sagittal sections of the intact 4.5-week-old embryo, a small, distinct population of rounded, densely packed TH-immunoreactive perikarya with short primary processes was seen in the midbrain. During the latter half of the first trimester, the number of TH-stained cells as well as the length and number of axonal processes projecting toward and into the developing neostriatum increased rapidly. At the end of the first trimester, varicose fibers could be detected in the striatal anlage. In order to verify that TH was the antigen recognized by the antibodies used for immunohistochemistry on human tissue specimens, mesencephalic tissue of 5-10 weeks gestation was analyzed by Western blot technique. A single, homogeneous band with the apparent molecular weight of approximately 60 kDa was clearly detected at 5 weeks of age. The amount of TH/mg total protein increased at least 10-fold between 5-10 weeks of gestation. For comparison, the mesencephalon and the forebrain/basal ganglia were analyzed for endogenous DA content using HPLC-ED. DA was first detected at 5.5 weeks of gestational age in both mid- and forebrain, and DA levels were found to increase exponentially from 7 to 7.5 weeks of age, reaching 4-5.5 ng DA/mesencephalon and 50-75 ng DA/g caudate nucleus-putamen anlage at the end of the first trimester. Together, morphological and biochemical data presented here constitute evidence for a very early appearance, migration, and differentiation as well as functional development of human mesencephalic dopaminergic neurons and their projections into target areas during the first trimester.

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model.

The purpose of this study was to fabricate and investigate amsacrine containing polymeric rods for use in interstitial chemotherapy of malignant glioma. Ethylene vinyl acetate copolymer (EVAc) rods containing 40% amsacrine (AMSA) were fabricated successfully with an extrusion method. In vitro kinetic studies revealed a high level of reproducibility of the production process. The release of AMSA showed a biphasic pattern consistent with a matrix-type controlled-release system with an initial more rapid release rate followed by a slower and more linear release phase. Release of AMSA was observed for over 6 months and the rods continue to release in a stable fashion. In vitro studies using rat glioma (RG2) in cell culture showed that cells treated with AMSA released from the rods were killed in a dose dependent manner indicating that AMSA incorporated into the polymer remained biologically active. In vivo studies of rats with single AMSA rods implanted five days after RG2 tumour implantation revealed histological evidence of an anti-tumour effect as well as an increased survival (p < 0.0003). The mean survival of the amsacrine treated rats was 78 days with 50% still remaining alive > 5 months after implantation. All control animals developed tumours and died within 15-19 days after tumour implantation (mean = 17 days). Amsacrine implanted animals showed no significant histological or clinical evidence of toxicity. We conclude that amsacrine containing EVAc rods can be safely and efficaciously use against the RG2 experimental glioma in a rat model and warrant further investigation.

Laparoscopic creation of loop ileostomy and sigmoid colostomy.

OBJECTIVE: To evaluate the laparoscopic approach in the creation of loop ileostomies and sigmoid colostomies. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: Eighteen consecutive patients who needed faecal diversion. INTERVENTIONS: Laparoscopic loop ileostomy (n = 6) or sigmoid colostomy (n = 12). MAIN OUTCOME MEASURES: Mortality, morbidity, and duration of operation. RESULTS: There was no 30-day mortality, and no patients developed infections. The operating time (median 47 minutes, range 45-115 for ileostomies and 50, range 42-102 for colostomies) was comparable to open surgery. Two operations had to be converted to open procedures because of dense adhesions. Postoperative paralytic ileus was transient, and all patients started oral intake on the first postoperative day. CONCLUSIONS: The laparoscopic technique is easy to do, it takes no longer than open surgery, and it causes minimal trauma, allowing the patients to recover faster.

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.

Effect of high dose corticosteroids alone or combined with other drugs on survival in septic shock.

The effect of high dose corticosteroids on survival has been studied in a limited number of canine septic shock models which are reviewed in this presentation. Following injection of live bacteria neither methylprednisolone, nor gentamicin but a combination improved survival. Methylprednisolone increased survival following a slow but not a bolus infusion of endotoxin. In a recent study the effects of short term treatment with methylprednisolone, naloxone and ibuprofen were studied in endotoxin shock. All control animals died within 36 hours. Five of 9 dogs receiving the combination methylprednisolone, naloxone and ibuprofen were permanent survivors. The combined treatment with methylprednisolone and ibuprofen also increased survival. Dogs treated with methylprednisolone alone did not differ significantly from controls. It is concluded that methylprednisolone alone has no significant effect on survival in septic shock, but seems to be an important therapeutic factor to achieve increased survival.

Increased survival of endotoxin-injected dogs treated with methylprednisolone, naloxone, and ibuprofen.

The effects of methylprednisolone, naloxone, and ibuprofen--alone and in various combinations--on survival, blood pressure, hematocrit, and peripheral platelet and white blood cell counts were studied in a canine Escherichia coli endotoxin LD100 shock model. Treatment was started 10 minutes after shock induction. The dogs were kept on a respirator and given intravenous fluids for 4 hours, then disconnected from the respirator and allowed to recover. Dogs surviving 7 days were considered permanent survivors. All control animals died within 36 hours. Five of nine dogs receiving a combined treatment of methylprednisolone, naloxone, and ibuprofen were permanent survivors and showed no macroscopic abnormalities when autopsied. The combined treatment with methylprednisolone and ibuprofen also increased survival. Mortality was delayed in animals treated with methylprednisolone and naloxone. Dogs receiving ibuprofen, a cyclooxygenase inhibitor, had a rapid reversal of hypotension. Hematocrit and platelet counts were similar in all groups. The combined treatment caused an increase in the recovery rate of white blood cells.

Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor.

The arachidonic acid derivative thromboxane A2, a very potent platelet aggregator, is increased in endotoxin shock. Ibuprofen blocks the formation of thromboxane A2 and has antiplatelet and antileukocyte aggregability properties. The effects of ibuprofen on pulmonary platelet trapping, platelet and leukocyte counts, platelet aggregability, hematocrit, and blood pressure were evaluated in endotoxin-shocked dogs. The initial decrease in blood pressure and in leukocyte and platelet counts seen in endotoxin shock was not altered by ibuprofen treatment. At 2 h the ibuprofen-treated dogs had less hypotension compared to endotoxin control. Platelet counts were also higher in the ibuprofen-treated dogs at 2 h. Significant recovery of leukocytes was seen only when pretreatment was used. Pulmonary platelet trapping was significantly lower in the ibuprofen-treated dogs compared to endotoxin controls and not significantly different from the sham dogs when ibuprofen was given before endotoxin injection. This study demonstrates the efficacy of ibuprofen not only in reducing pulmonary platelet trapping but also in obviating the late hypotension in experimental endotoxin shock.