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.

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.

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.

Analysis of the mitochondrial genome in sudden infant death syndrome.

AIM: To investigate the mitochondrial genome and its association with sudden infant death syndrome (SIDS). METHODS: Twenty SIDS infants were screened for previously reported mitochondrial DNA mutations using direct sequencing. The whole mitochondrial genome was also sequenced for six of the infants. RESULTS: Three substitutions, A11467G, A12308G and G12372A, comprising a haplogroup were present in four infants diagnosed as pure SIDS. This haplogroup was also common in a control group. CONCLUSIONS: No specific mutation or polymorphism was found in association with SIDS.

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.

Heart weight in infants--a comparison between sudden infant death syndrome and other causes of death.

UNLABELLED: Heart and body weights were compared with regard to heart pathology and cause of death in well-defined groups of infants under 1 y of age. In the period 1980 to 1998, out of 468 infants autopsied at the Department of Forensic Medicine in Stockholm, Sweden, 331 died of sudden infant death syndrome (SIDS), while 137 died of other causes. Physical violence was the known cause of death in 30 infants and cardiovascular malformations in another 19. Inflammatory alterations of the myocardium were found in 74 cases (16%): in 17 cases (3.6%) myocarditis was interpreted as the main cause of death; in 45 (10%) it was interpreted as contributing to SIDS and in 12 cases (2.5%) it was observed but judged not to be a contributory cause of death in non-SIDS victims. Two of these infants died as a result of physical violence. Body weight was the best predictor for heart weight as analysed by multiple regression, including age, sex, body weight, length, BMI and birth weight. An equation for estimating heart weight from body weight gave an accuracy within the range 0.75-1.25 in 89.2% and 85.0% of the SIDS and non-SIDS groups, respectively. CONCLUSION: Body weight is the best predictor for estimating heart weight. No evidence supported the notion that heart weight, body weight or birth weight of SIDS victims differs from non-SIDS, although heart weight in infants with cardiovascular malformations deviated from observations in the other groups.

Implantation of bioactive growth factor-secreting rods enhances fetal dopaminergic graft survival, outgrowth density, and functional recovery in a rat model of Parkinson's disease.

One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.

Sudden infant death syndrome: postmortem findings of nicotine and cotinine in pericardial fluid of infants in relation to morphological changes and position at death.

Parental smoking is considered to be an important risk factor for the sudden infant death syndrome (SIDS). We studied the concentrations of nicotine and cotinine in the pericardial fluid of SIDS and non-SIDS victims, with particular emphasis on the relationship to body position at the time of death and organ pathology. Pericardial fluid was collected during a forensic postmortem examination of 85 nonselected infants, under the age of 1 year, who died from SIDS (n = 67) and non-SIDS (n = 18) in the period from 1988 to 1994. There was no significant difference in the pericardial concentration of nicotine and cotinine between SIDS and non-SIDS victims. However, in contrast to non-SIDS victims, about 25% of the infants in the SIDS group had cotinine concentrations exceeding 30 ng/mL, indicating tobacco exposure prior to death. High concentrations of cotinine were found in infants with focal necrosis and inflammatory changes in the myocardium and the liver. Further, a relationship was found between high nicotine concentration and otitis media and also with death while cosleeping.

Adult nestin-expressing subependymal cells differentiate to astrocytes in response to brain injury.

The adult brain contains a small population of central nervous system (CNS) cells in the subependyma which, like embryonic CNS progenitor cells, express the intermediate filament nestin. In this report, the differentiation capacity in vivo of these cells was analysed following a standardized trauma. Before the trauma, the subependymal cells expressed nestin but not the astrocytic and neuronal differentiation markers glial fibrillary acidic protein (GFAP) and neurofilament respectively. In response to injury, the majority of the subependymal cells coexpressed nestin and GFAP, but never nestin and neurofilament. Furthermore, cells coexpressing nestin and GFAP were found progressively further away from the subependyma and closer to the lesion at later time points after the injury, indicating that these cells migrate towards the lesion. Nestin was in addition re-expressed in reactive astrocytes near the lesion and in non-reactive astrocytes very far from the lesion throughout the ipsilateral cortex. In conclusion, our data indicate that the nestin-positive subependymal cells are an in vivo source for the generation of new astrocytes but not neurons after injury, and that nestin re-expression in astrocytes following traumatic stimuli can be used as a sensitive marker for astroglial activation.

Unexpected death in two young infants mimics SIDS: autopsies demonstrate tumors of medulla and heart.

A total of 423 medicolegal autopsies of infants under the age of 1 year were done during a 15-year period (1980-1994) at the Department of Forensic Medicine in Stockholm. Only two instances with findings of tumors occurred. One was a unilateral oligodendroglioma involving the medullary reticular formation and inferior olivary nucleus with associated myocardial alterations; the other was a fibroma of the left heart ventricle. Both are interesting with regard to their localization--the medulla oblongata and the heart--and by causing death in a way that mimics the sudden infant death syndrome (SIDS). In the heart of the infant with oligodendroglioma, a single fascicle of hamartomatous, immature appearing heart muscle fibers was found, making the interpretation of the cause of death more intricate.

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.

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.

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.

Morphology and growth of embryonic, human dorsal root ganglion explants in long-term culture: expression of cell type-specific markers during early differentiation.

Embryonic, human spinal ganglion explants were plated at 5-12 weeks postconceptional age and cultured for 5-50 days on a semisynthetic substrate in a serum-containing culture medium without addition of antibiotics or preconditioned medium. The growth pattern in vitro was found to be age dependent. Five- to 6-week ganglia showed a characteristic semicircular growth pattern with bidirectional extension of neurites on top of a monolayer of supportive cells. Explanted 9- to 10-week ganglia showed an extensive, multidirectional neurite outgrowth with less pronounced proliferation of nonneuronal cells. Neurite extension, fasciculation, cell migration and morphology were studied immunohistochemically with antibodies to neurofilament (NF), S-100, and the Thy-1 glycoprotein. Both NF and S-100 were expressed at 5 weeks gestational age in ganglionic neurons and in proliferating Schwann cells in contact with axonal processes, respectively. NF was homogeneously distributed in both cell somata and neurites, whereas S-100 immunoreactivity showed an intense nuclear and a weaker cytoplasmic distribution in spindle-shaped, bipolar Schwann cells. This staining pattern was conserved during differentiation in long-term culture. Thy-1 was expressed on ganglionic neurites forming fascicles by the third week in culture. However, Thy-1 was never expressed until the total age of 10 weeks. In addition, Thy-1 was found on fibroblasts from the first week in culture. The distribution of Thy-1 on the cytoplasmic membrane was similar in both cell types, showing a coarsely granulated membrane staining. The temporal as well as the spatial expression of differentiation antigens in tissue sections of early embryonic spinal cord and spinal ganglia were very similar to what was observed in vitro.