Local cerebral blood flow in the brain during bicuculline-induced seizures and the modulating influence of inhibition of prostaglandin synthesis

The purpose of this study was to measure changes in local cerebral blood flow (1-CBF) during generalized seizures, and to study whether or not formation of prostaglandins or related substances contributes to the increased flow rates. Seizures were induced in ventilated rats maintained on 70% N₂O and 30% O₂ by the i. v. injection of the GABA receptor blocker bicuculline (1.2 mg-kg^-1). Formation of prostaglandins was inhibited by the administration of the fatty acid cyclo-oxygenase inhibitor indomethacin (10 mg · kg^-1)-Local CBF in 21 defined brain structures was measured autoradiographically with ^HC-iodoantipyrine as the diffusible tracer. After 20 min of continuous seizure activity 1-CBF increased 1.5-5-fold, the smallest increases (<200% of control) being observed in frontal and auditory cortex and in the caudoputamen, and the largest (>400% of control) in substantia nigra, thalamus, visual cortex, lateral geniculate and hypothalamus. In general, the largest increases in 1-CBF occurred in sensory and limbic systems (and hypothalamus) while motor systems showed a pronounced variability. In the majority of structures examined indomethacin failed to modify the CBF response during seizures. Although this result suggests that seizures, in contrast to hypercapnia, lead to an increased CBF by other mechanisms than those related to prostaglandin formation, some structures (nucleus ruber, cerebellum, and superior colliculus) showed a clearly reduced 1-CBF in indomethacin-treated animals.     

Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-α) production acting on leucocytes resembling immature dendritic cells

Patients with active SLE often have an ongoing production of IFN-α. We therefore searched for an endogenous IFN-α-inducing factor (IIF) in SLE patients and found that their sera frequently induced production of IFN-α in cultures of peripheral blood mononuclear cells (PBMC) from healthy blood donors, especially when the PBMC were costimulated with the cytokines IFN-α2b and granulocyte-macrophage colony-stimulating factor (GM-CSF). The phenotype of the IFN-α-producing cells (IPC) as determined by flow cytometry corresponded to that of the natural IPC, resembling immature dendritic cells. The IIF activity in SLE sera was sometimes as high as that of a virus and was present especially in patients with active disease and with measurable IFN-α levels in serum. The IIF had an apparent molecular weight of 300–1000 kD and appeared to consist of both immunoglobulin and DNA, possibly being immune complexes. This endogenous IFN-α inducer may be of pathogenic significance, since a reported occasional adverse effect of IFN-α therapy in patients with non-autoimmune disorders is development of anti-dsDNA antibodies and SLE.     

De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association

The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients'' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.     

Increased Plasma Free Dopamine after Treatment with Atenolol and Oxprenolol in Essential Hypertension

ABSTRACT. In 19 men aged 50 with essential hypertension, 18 weeks' treatment with atenolol (n=9) or oxprenolol (n=10) increased supine plasma free dopamine concentrations by 78% (p<0.05) and 121 % (p<0.001) respectively. Increments in plasma dopamine were observed in all patients except for one treated with atenolol. Supine peripheral venous adrenaline and noradrenaline concentrations were not influenced by β-blockade. The mechanism and significance of the present elevation of plasma free dopamine by β-blockade are unknown. However, increased plasma free dopamine may be involved in the hypotensive effect of chronic β-adrenergic blockade, both β-1 selective and non-selective, and may lend further support to decreased dopaminergic activity in essential hypertenison.     

Interferon Production in Children with Undue Susceptibility to Infections

ABSTRACT. The interferon-producing ability of peripheral blood mononuclear leukocytes obtained from children with undue susceptibility to infections was investigated. Patients were grouped according to three clinical patterns, i.e. children with mainly upper respiratory tract infec-tions, with lower respiratory tract infections and with frequent middle ear infections. There WBS no evidence of impaired mean interferon-a responses to the inducers Sendai virus and beta-hemolytic Group G streptococci in patients compared with control children, and there were no differences in this respect between the patient subgroups. A tendency to increased Concanavalin A-induced interferon-y production was seen in patients, particularly those with middle ear infections. Leukocytes from patients displayed a higher proliferative response to the T cell mitogens Concanavalin A and Lens culinaris lectin. In a minority of patients (5128) reproducibly low interferon responses to Sendai virus were found but only one of these patients showed a response below the -2 SD limit for the control group. The results therefore indicate no major defects in the interferon responses of infection-prone children, and at the most suggest that a minority of such patients may be low responders to a viral interferon inducer. Key words: Integeron, lymphocytes, infection, children.