Epileptic seizures,arthrogryposis, and migrational brain disorders: a syndrome?

Introduction – Arthrogryposis multiplex congenita (AMC) may be associated with multiple developmental defects. In some severely affected newborns with AMC, autopsy studies have suggested a common mechanism of malmigration at the spinal and cerebral levels. To our knowledge, a constellation of arthrogryposis, epileptic seizures, and brain migrational anomalies in adult patients has not previously been described in a clinical material. Material and methods – Six consecutive adult patients with arthrogryposis multiplex congenita and epileptic seizures form the basis of the present study. Five patients had joint contractures and reduced muscle volume restricted to the lower extremities, whereas one patient had predominantly upper extremity affection. They were studied with magnetic resonance imaging (MRI), EEG, EMG, a neuropsychological test battery, and chromosome analysis. Results – Four of them had clear evidence of migrational brain disorders, demonstrated by MRI, in three of them roughly corresponding to the focal epileptiform EEG activity. Five of the patients had partial seizures, whereas one only had generalized tonic-clonic seizures. The MRI findings included polymicrogyria, pachygyria, and fused schizencephaly. Four had neurogenic EMG changes, one had myopathic EMG features, and one had an unremarkable EMG pattern in affected muscles. All patients witL demonstrable migrational disorders showed abnormal neuropsychological features. Three patients were mentally retarded. A chromosome abnormality in the form of a ring chromosome 18 was present in one patient. Conclusion – We suggest that AMC, epileptic seizures, and migrational brain disorders may form the integral parts of a hitherto undescribed syndrome in adults. A wide-spread defect in neuronal migration along the entire neural axis may be the underlying mechanism of the cerebral and the peripheral symptoms.     

Comparison of the potential therapeutic effects of interleukin 2 or interleukin 4 secretion by a single tumour.

Engineering of a variety of rodent tumour cells to secrete either interleukin 2 (IL-2), or interleukin 4 (IL-4), has been demonstrated to reduce their tumorigenicity. However the mechanisms of action of secreted IL-2 and IL-4 have not been compared in a single rodent tumour. Here we demonstrate that the weakly immunogenic murine fibrosarcoma FS29 had reduced growth rate and in some cases was rejected by syngeneic animals, when modified to secrete either IL-2 or IL-4, but not IL-5. Immunohistochemical analysis of tumour nodules undergoing regression showed stimulation of a largely lymphocytic infiltrate by IL-2 and a macrophage and granulocyte infiltrate, with a small number of lymphocytes by IL-4. Indeed, secretion of low levels of IL-2 and IL-4 in combination resulted in optimal rejection, suggesting that the two cytokines might mobilise different and complementary effector cell mechanisms. Both IL-2 and IL-4-secreting cells failed to induce the rejection of admixed, unmodified FS29 cells. The loss of cytokine secreting cells from such admixtures occurred more rapidly for IL-2-secreting cells. Injection of IL-4-secreting, but not IL-2-secreting FS29 cells could protect mice from a delayed challenge with unmodified FS29 cells. These data suggest that IL-4 secretion stimulates the better long-term host anti-tumour response.     

The retention of [99mTc]-d,l-HM-PAO in the human brain after intracarotid bolus injection: a kinetic analysis

[99mTc]-d,l-HM-PAO (HM-PAO) was injected rapidly into the internal carotid artery and its retention in the brain was recorded by external scintillation cameras in eight human subjects. A model is described based on three compartments: the lipophilic tracer in the blood pool of the brain, the lipophilic tracer inside the brain, and the hydrophilic form retained in the brain. The retention curve initially drops abruptly, corresponding to the nonextracted fraction of the injectate leaving the brain; it then falls exponentially towards the asymptotic level of the fractional steady-state retention R. Cerebral blood flow (F) was measured using the xenon-133 intracarotid injection method. The first-pass extraction E of HM-PAO was calculated from F using an empiric regression equation. The residue curves for the whole brain after intracarotid HM-PAO injection were analyzed to yield a retention fraction (R') and the brain clearance backflux constant of lipophilic HM-PAO (k). From the kinetic model and the measured values of R', k, and F, the following parameter values could be calculated: the average retained fraction of all tracer supplied to the brain, R = 0.38 +/- 0.05 (mean +/- SD), the conversion rate constant (lipophilic to hydrophilic tracer) in the brain k3 = 0.80 +/- 0.12 min-1, the efflux rate constant (brain to blood) k2 = 0.69 +/- 0.11 min-1, the conversion/clearance ratio alpha = k3/k2 = 1.18 +/- 0.25, the influx (blood clearance) constant K1 = 0.45 +/- 0.11 ml/g/min, and the brain/blood partition ratio lambda = K1/k2 = 0.67 +/- 0.23 ml/g. Using the kinetic model and assuming constancy of alpha, an algorithm was developed that corrects for the blood flow dependent backflux of HM-PAO and results in a more linear relation between regional cerebral blood flow (rCBF) and HM-PAO distribution.     

Human spumaretrovirus antibody reactivity in multiple sclerosis

The role of human spumaretrovirus (HSRV) infections in the pathogenesis of multiple sclerosis (MS) was investigated with recombinant HSRV env-specific enzyme-linked immunosorbent assay. The presence of HSRV antibodies was determined in pairs of serum and cerebrospinal fluid (CSF) samples from 60 MS patients. In 7 of these patients serial serum and CSF samples were obtained in relation to the clinical activity of the disease during a period of 2 years. No increased antibody reactivity was demonstrable in the MS population compared with 14 aseptic meningitis patients, 50 blood donors and 16 healthy controls. Slightly elevated levels of antibodies were demonstrable in serum and/or CSF in 4 MS patients but also in 1 patient with aseptic meningitis, 1 blood donor and 1 child. No marked serum or CSF HSRV antibody fluctuation was observed in the MS patients followed longitudinally. Thus, this study does not support the involvement of HSRV in the pathogenesis of MS.     

Cancer incidence among creosote-exposed workers.

Cancer incidence was studied among 922 creosote-exposed impregnators at 13 plants in Sweden and Norway. The subjects had been impregnating wood (eg, railroad cross-ties and telegraph poles), but no data on individual exposures were available. The study population was restricted to men employed during the period 1950-1975, and their cancer morbidity was checked through the cancer registries. The total cancer incidence was somewhat lower than expected, 129 cases versus 137 expected [standardized incidence ratio (SIR) 0.94]. Increased risks in both countries combined were observed for lip cancer (SIR 2.50, 95% confidence interval (95% CI) 0.81-5.83), skin cancer (SIR 2.37, 95% CI 1.08-4.50), and malignant lymphoma (SIR 1.9, 95% CI 0.83-3.78). Exposure to sunlight may have contributed to the risk of lip and skin cancer. The small number of cancer cases does not permit valid conclusions. The findings indicate that impregnating wood with creosote in earlier decades increased the risk of skin cancer.     

HLA-A24 and survivin: possibilities in therapeutic vaccination against cancer

Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8(+) cytotoxic T-cells. The identification of an HLA-A24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer.     

Postural responses to lateral perturbation in healthy subjects and ankle sprain patients.

The purpose of this study was to investigate postural responses of healthy subjects and patients with recent ankle sprains following a perturbation that created sway in the frontal plane. EMG data were taken from the posterior tibialis (PT) (not monitored in patients), peroneal longus (PL), and tibialis anterior muscles (TA). Subjects stood on a platform that provided a rotational perturbation (approximately 70 degrees.s-1) in the frontal plane. This perturbation had the effect of everting and loading one limb while inverting and unloading the contralateral limb. An initial response in the PT of the loaded limb and the PL of the unloaded limb was noted at approximately 50 ms following the perturbation. This was followed by a bilateral response in the TA at 60 ms. The amplitude of the TA muscle was significantly greater in the loaded limb. For ankle sprain patients a bilateral TA response and a PL response in the unloaded limb was noted at approximately 65 ms. TA response amplitude ratios between the loaded and unloaded limbs were similar to that of the healthy subjects. These data suggest that ankle sprain patients use a modified postural response following lateral perturbation as a compensation for the injury.     

A -243A-->G polymorphism upstream of the gene encoding GAD65 associates with lower levels of body mass index and glycaemia in a population-based sample of 5857 middle-aged White subjects.

AIMS: The glutamate decarboxylase gene (GAD2) encodes GAD65, an enzyme catalysing the production of the gamma-aminobutyric acid (GABA) which interacts with neuropeptide Y to stimulate food intake. It has been suggested that in pancreatic islets, GABA serves as a functional regulator of pancreatic hormone release. Conflicting results have been reported concerning the potential impact of GAD2 variation on estimates of energy metabolism. The aim of this study was to elucidate potential associations between the GAD2-243A-->G polymorphism and levels of body mass index (BMI) and estimates of glycaemia. METHODS: Using high-throughput chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the GAD2-243A-->G (rs2236418) polymorphism was genotyped in a population-based sample (Inter99) of 5857 middle-aged, unrelated Danish White subjects. RESULTS: The G-allele was associated with modestly lower BMI (P = 0.01). In a case-control study of obesity, the G-allele frequency in 2582 participants with BMI < 25 kg/m2 was 19.5% (18.4-20.6) compared with 17.1% (15.5-18.8) in 968 participants having BMI > or = 30 kg/m2 (P = 0.03), odds ratio 0.9 (0.7-1.0). Of the 5857 subjects, GG carriers had lower fasting plasma glucose levels (mmol/l) [AA (n = 3859) 5.6 +/- 0.8; AG (n = 1792) 5.5 +/- 0.8; GG (n = 206) 5.5 +/- 0.8, P = 0.008] and lower 30-min oral glucose tolerance test (OGTT)-related plasma glucose levels (AA 8.7 +/- 1.9; AG 8.6 +/- 1.9; GG 8.6 +/- 2.0, P = 0.04), adjusted for sex, age and BMI. Analysing subjects who were both normoglycaemic and glucose tolerant (n = 4431) GG carriers still had lower fasting plasma glucose concentrations: AA (n = 2895) 5.3 +/- 0.4; AG (n = 1383) 5.3 +/- 0.4; GG (n = 153) 5.2 +/- 0.4 (P = 9.10(-5)). CONCLUSION: The present study suggests that the GAD2-243A-->G polymorphism in a population of middle-aged White people associates with a modest reduction in BMI and fasting and OGTT-related plasma glucose levels.