Migraine in children and adolescents: a guide to drug treatment

Migraine is a common disorder in children and adolescents, with a prevalence of 5 and 10%, respectively. Some patients may have recognisable factors that trigger or aggravate migraine attacks, such as flickering or bright lights, strong smells and noise, and where possible these should be avoided. It is also wise to maintain a lifestyle where children receive regular meals and get sufficient sleep. If used, acute pharmacological treatment should be given at the onset of an attack, followed by a rest or sleep. According to recent literature, paracetamol (acetaminophen) and ibuprofen can be recommended for the acute treatment of migraine attacks in children and adolescents, and sumatriptan nasal spray can be recommended for adolescents. The oral formulation of sumatriptan has not shown efficacy in paediatric patients, and the subcutaneous injection, although somewhat effective, is not an ideal formulation for this patient group. There are too few data on the efficacy of the other 'triptans' to recommend their use in children and adolescents. There are less data on the use of prophylactic drugs in paediatric patients. In systematic studies, only flunarizine, which is not available in many countries, and propranolol have been found to be effective. A pilot placebo-controlled study suggests that topiramate might also be effective. Several other agents are commonly used to prevent migraine attacks in children (e.g. amitriptyline, valproic acid [sodium valproate]) despite a lack of robust research into their efficacy.     

The higher toxicity of cereulide relative to valinomycin is due to its higher affinity for potassium at physiological plasma concentration

Valinomycin and cereulide are bacterial toxins with closely similar chemical structure and properties but different toxic effects. Emetic poisoning is induced by cereulide but not by valinomycin. Both are specific potassium ionophores. Such compounds may affect mitochondrial functions. Both compounds cause a potassium-dependent drop in the transmembrane inner membrane potential due to the uptake of K+ as positively charged ionophore complex. Valinomycin is more potent than cereulide at high [K+] (>80 mM), whereas cereulide in contrast to valinomycin is active already at <1 mM. With cereulide, there is a substantial lag, while valinomycin acts without lag. Both ionophores induce mitochondrial swelling in the presence of K+, in the case of cereulide with a lag. These toxins strongly inhibited respiration at the level of complex IV when used at higher concentrations than that used for detection of ionophoretic transport of K+. At high [KCl] (120 mM), valinomycin was more potent than cereulide both as ionophore and inhibitor, but at low [KCl] (2.5 mM), cereulide was much more potent. Thus, valinomycin needed 20-30 mM KCl for substantial effects, cereulide only 1-3 mM K+, which is close to its level in blood serum. This explains the higher toxicity of cereulide at low concentrations with the positively charged potassium complex being accumulated in the cell by transport through the plasma membrane driven by the membrane potential. Furthermore, with similar concentrations, the final concentration of cereulide in the cells may become higher than that of valinomycin.     

Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.     

Dominant optic atrophy: correlation between clinical and molecular genetic studies

PURPOSE: To assess the clinical picture and molecular genetics of 14 Finnish families with dominant optic atrophy (DOA). METHODS: The clinical status of family members was based on the assessment of visual acuity, colour vision, visual fields and optic nerve appearance; 31 individuals were affected, two suspect and 21 unaffected. A total of 30 coding exons and exon- intron boundaries of the OPA1 gene were sequenced in order to detect mutations. RESULTS: Half the patients were diagnosed at the age of < or = 20 years. Ten out of 20 affected individuals followed up for > or = 6 years had a progressive disease and 10 had a stable disease. According to WHO criteria, 36% of the affected patients were visually handicapped. Eight OPA1 pathogenic mutations, all but one novel, and 18 neutral polymorphisms were detected. CONCLUSION: The most sensitive indicators of DOA were optic disc pallor and dyschromatopsia. With molecular genetic analysis, asymptomatic mutation carriers and DOA cases with a mild clinical outcome were ascertained. No mutational hotspot or Finnish major mutation in the OPA1 gene could be demonstrated as most families carried a unique mutation. No obvious genotype- phenotype correlation could be detected. Detailed clinical assessment and exclusion of non-DOA families prior to mutation screening are necessary for obtaining a high mutation detection rate.     

Production of Chlamydia pneumoniae Proteins in Bacillus subtilis and Their Use in Characterizing Immune Responses in the Experimental Infection Model

Due to intracellular growth requirements, large-scale cultures of chlamydiae and purification of its proteins are difficult and laborious. To overcome these problems we produced chlamydial proteins in a heterologous host, Bacillus subtilis, a gram-positive nonpathogenic bacterium. The genes of Chlamydia pneumoniae major outer membrane protein (MOMP), the cysteine-rich outer membrane protein (Omp2), and the heat shock protein (Hsp60) were amplified by PCR, and the PCR products were cloned into expression vectors containing a promoter, a ribosome binding site, and a truncated signal sequence of the α-amylase gene from Bacillus amyloliquefaciens. C. pneumoniae genes were readily expressed in B. subtilis under the control of the α-amylase promoter. The recombinant proteins MOMP and Hsp60 were purified from the bacterial lysate with the aid of the carboxy-terminal histidine hexamer tag by affinity chromatography. The Omp2 was separated as an insoluble fraction after 8 M urea treatment. The purified proteins were successfully used as immunogens and as antigens in serological assays and in a lymphoproliferation test. The Omp2 and Hsp60 antigens were readily recognized by the antibodies appearing after pulmonary infection following intranasal inoculation of C. pneumoniae in mice. Also, splenocytes collected from mice immunized with MOMP or Hsp60 proteins proliferated in response to in vitro stimulation with the corresponding proteins.     

Effect of EEG Electrode Density on Dipole Localization Accuracy Using Two Realistically Shaped Skull Resistivity Models

The effect of number of EEG electrodes on the dipole localization was studied by comparing the results obtained using the 10-20 and 10-10 electrode systems. Two anatomically detailed models with resistivity values of 177.6 m and 67.0 m for the skull were applied. Simulated potential values generated by current dipoles were applied to different combinations of the volume conductors and electrode systems. High and low resistivity models differed slightly in favour of the lower skull resistivity model when dipole localization was based on noiseless data. The localization errors were approximately three times larger using low resistivity model for generating the potentials, but applying high resistivity model for the inverse solution. The difference between the two electrode systems was minor in favour of the 10-10 electrode system when simulated, noiseless potentials were used. In the presence of noise the dipole localization algorithm operated more accurately using the denser electrode system. In conclusion, increasing the number of recording electrodes seems to improve the localization accuracy in the presence of noise. The absolute skull resistivity value also affects the accuracy, but using an incorrect value in modelling calculations seems to be the most serious source of error.     

Prediction of permanent hearing loss in high-risk preterm infants at term age

The aim of this series was to assess hearing screenings; auditory brainstem responses (ABR), transient evoked otoacoustic emissions (TEOAE) and free field auditory responses (FF) for the prediction of permanent bilateral hearing loss in high-risk preterm infants at term post-conceptional age. A total of 51 preterm infants (gestational age <34 weeks, birth weight <1500 g) underwent examinations at term and hearing, speech and neurological development were followed up until a corrected age of 18 months. Significant hearing defects were verified by broader ABR examinations under sedation and by clinical ward observation including responsiveness to sounds and enhancement of hearing using an amplification device. Seven bilateral fails in ABR were found, together with nine bilateral fails in TEOAE and four fails in FF screening at term age. Six preterm infants were later confirmed to have a significant permanent bilateral hearing loss, four of whom had also cerebral palsy. Bilateral failure in ABR screening predicted hearing loss with a sensitivity of 100% and a specificity of 98%, TEOAE with a sensitivity of 50% and a specificity of 84% and in the FF examination at the levels of 50% and 98%, respectively. Conclusion Transient evoked otoacoustic emissions alone seem not to be so applicable to the neonatal screening of hearing in high-risk preterm infants as shown earlier in full-term infants, possibly because a hearing defect may be due to retrocochlear damage. Consequently, auditory brainstem response screening seems to be more suitable for very low birth weight preterm infants. Received: 21 September 1999 / Accepted: 5 January 2000     

Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.