Dipole Localization and Test-Retest Reliability of Frequency and Duration Mismatch Negativity Generator Processes

The mismatch negativity (MMN) is an event related potential component elicited by changes in duration, frequency or intensity of the stimuli during repetitive series of equal standard stimuli. In the present study we compared duration and frequency MMN using dipole source analysis concerning both the test-retest reliability of MMN-amplitudes and the locations of the potential sources. Furthermore, the influence of attention for test-retest-reliability was studied. Therefore, two groups of healthy subjects were investigated with different attentional manipulations. Twenty-one healthy subjects had to perform a visual attention task during the recording and 21 healthy subjects had no additional task to perform. All subjects were studied twice with a time interval of 3 weeks. Test-retest reliability was sufficiently high for the frequency but slightly lower for the duration MMN. The locations of the frequency and duration MMN-dipoles were in the auditory cortex with a more anterior and caudal location for the frequency MMN-dipoles. The latter finding supports the hypothesis that the frequency and duration MMNs have separate neuronal generators.     

A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis.

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.     

Effects of 15-hydroperoxyeicosatetraenoic acid on human lymphocyte sheep erythrocyte rosette formation and response to concanavalin A associated with HLA system

The lipoxygenase product hydroperoxyeicosatetraenoic acid (HPETE) has immunosuppressive properties in vitro and in vivo. It was observed that 15-HPETE inhibit the sheep red blood cell rosette formation and the concanavalin A-induced blast transformation of human lymphocytes. This inhibition was HLA-linked. HLA-B12 subjects were less sensitive than non-B12 subjects. It is likely that HPETE acids are macrophage mediators which inhibit some lymphocyte functions.     

Prolongation of graft survival in allogeneic islet transplantation by (−) 15-deoxyspergualin in the rat

Summary The effect of 15-Deoxyspergualin, a novel drug which has been described to have anti-tumour activity, on allogeneic graft survival (Dark Agouti Lewis rats) after pancreatic islet transplantation was tested. A marked prolongation of graft survival could be shown using doses of 1.0, 2.5 and 5.0mg Deoxyspergualin/kg on day 0 until day +9 post transplantation. A maximum of 55.6 days (average) survival time was observed using 2.5mg/kg Deoxyspergualin compared to 5.2±0.6 days without immunosuppression. Using the chemiluminescence reaction of recipient monocytes after islet transplantation, a marked suppression of the monocyte system exceeding the treatment period could be observed. Since, in contrast to cyclosporin, B-cell toxicity could not be shown, the new drug seems to be a hopeful step towards successful allogeneic islet transplantation for treatment of diabetes.     

Intrathecal IgM response in disseminated cerebrospinal metastasis from malignant melanoma

Summary Neurological complications are a major cause of morbidity and mortality in patients with disseminated malignant melanoma. We have studied and correlated clinical and cerebrospinal fluid (CSF) findings in 20 patients with central nervous system metastases from malignant melanoma including 8 patients with metastatic meningeal melanomatosis (MMM) and 12 patients with solid cerebral metastases (SCM). The putative CSF tumor markers, fibronectin and ₂-microglobulin, were elevated significantly in MMM but not in SCM patients. A prominent increase in the IgM index, which reflects intrathecal B-cell stimulation, and a rise of IgG index, interleukin-6, and tumor necrosis factor- in MMM patients provide preliminary evidence for a local intrathecal immune response triggered by melanoma cell invasion of the subarachnoid space.     

Characterization of porcine coronary muscarinic receptors

Summary To determine the muscarinic receptor subtype involved in the contractile response of coronary smooth muscle, we investigated the profiles of various muscarinic receptor antagonists competing for [³H]N-methyl-scopolamine ([³H]NMS) binding to membrane preparations from porcine coronary arteries. [³H]NMS binds to a single population of muscarinic binding sites with a K_D of 135 pM and a B_max of 57 fmol/mg. The affinity profiles of AF-DX 116 [11-2((–((diethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one], atropine, 4-DAMP [4-diphenylacetoxy-N-methylpiperidine methiodide], methoctramine [N,N-bis (6-((2-methoxybenzyl) amino)hexyl)-1,8-octane-diamine tetrahydrochloride], HHSiD [hexahydrosiladi-fenidol] and pirenzepine are consistent with binding to a mixed population of muscarinic binding sites, namely of the M₂ and M₃ subtype.Binding curves for AF-DX 116 and methoctramine are shallow with Hill-coefficients significantly less than unity. Comparison of data from binding studies with results obtained in functional experiments, i.e. antagonism of methacholine induced contraction of porcine coronary artery rings, it was found that only the low-affinity pK_i values of AF-DX 116 (6.26) and methoctramine (6.51) correlated well with functional pA₂ values.It is concluded that a mixed population of the M₂ and M₃ muscarinic receptor subtypes is present in porcine coronary arteries. Functional experiments do not support the contribution of the M₂ subtype to the contractile response. Cholinergic induced contractions of porcine coronary arteries appear to be evoked via stimulation of the muscarinic M₃ receptor subtype. However, since the compounds investigated here do not markedly discriminate between cloned m₃, m₄ and m₅ receptors the involvement of muscarinic receptors different from M₁, M₂ and M₃ cannot be excluded. Send offprint requests to M. Entzeroth at the above address     

Diagnosis and treatment of risk factors in Germany and the UK

Objective

To estimate the impact of different systems of family practitioners’ payment on process of care: fee-for-service vs. capitation.

Design

Cross sectional international survey using cardiovascular prevention as an indicator of the quality of care.

Setting

Family physicians’ practices in Germany (fee-for-service) and the UK (capitation).

Subjects

778 patients attending for consultation regardless of morbidity or risk factor status.

Main outcome measures

Intervals since last consultation, since last BP-measurement, prevalence of known hypertension.

Results

There is a higher overall level of activity under FFS, but under capitation FPs seem to concentrate their efforts on the more severely ill or at risk. This would explain that under different systems of remuneraton the quality of care (outcome) is usually similar.

Conclusions

In areas of uncertainty FFS seems to stimulate activity or intervention, whereas under capitation FPs are rather reluctant to engage in procedures or interventions that are not sufficiently evaluated. Under prepaid remuneration FPs adjust in a way that the quality of care does not suffer.     

Presynaptic α2A-adrenoceptors inhibit the release of endogenous dopamine in rabbit caudate nucleus slices

₂-Adrenoceptors modulating the release of dopamine were identified and characterized in slices of the head of the rabbit caudate nucleus. Release of endogenous dopamine was measured by fast cyclic voltammetry as the increase in the extracellular concentration of dopamine elicited by electrical stimulation. The electrochemical signal was identified as dopamine by means of the oxidation potential, the voltammogram and the fact that the signal was not changed by desipramine, which inhibits the high affinity uptake of noradrenaline, but was greatly increased by nomifensine, which in addition inhibits the high affinity uptake of dopamine.Stimulation by 6 pulses/100 Hz increased the extracellular concentration of dopamine by about 85 nM. The selective ₂-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced this release with an EC₅₀ of 173 nM and by maximally 75%. The ₂-adrenoceptor agonists clonidine and oxymetazoline only tended to cause a decrease. Six drugs, including oxymetazoline, were tested as antagonists against UK 14,304. Their order of antagonist potency (pK_D values in brackets) was rauwolscine (8.0) > oxymetazoline (7.5) > 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; 7.3) > phentolamine (7.1) > corynanthine (5.1) prazosin (< 6). Given alone, the antagonists did not change the release of dopamine elicited by 6 pulses/100 Hz, and the same was true for the dopamine receptor antagonist sulpiride. When caudate slices were stimulated by 10 pulses/1 Hz, sulpiride increased the release of dopamine. Desipramine and rauwolscine, in contrast, again caused no change.It is concluded that dopaminergic axons in the rabbit caudate nucleus possess release-inhibiting ₂-adrenoceptors. The antagonist affinities indicate that they belong to the _2A subtype. In this, they agree with all presynaptic ₂-autoreceptors studied so far in rabbits as well as with the ₂-heteroreceptors modulating the release of serotonin in rabbit brain cortex, suggesting that at least the majority of presynaptic ₂-adrenoceptors in the rabbit are _2A. The agonist sensitivity of the caudate presynaptic ₂-adrenoceptors is low in comparison with cerebrocortical presynaptic ₂-autoreceptors, possibly due to absence of a receptor reserve. Correspondence to: N. Limberger at the above address     

Cardiovascular effects of agmatine,a “clonidine-displacing substance”, in conscious rabbits

Agmatine has been identified as a clonidine-displacing substance in extracts from bovine brain. We studied its effect on cardiovascular regulation and the role played in this effect by ₂-adrenoceptors.In conscious rabbits, agmatine 10 g kg^–1 injected intracisternally (i.e.) caused no change, whereas agmatine 30, 100 and 300 g kg^–1 i.e. increased renal sympathetic nerve firing, the plasma concentration of noradrenaline and adrenaline and arterial blood pressure. Heart rate tended to be decreased. Yohimbine 1.5 g kg^–1 i.e. caused no change, whereas yohimbine 5, 15 and 50 g kg^–1 increased renal sympathetic nerve activity, the plasma concentration of noradrenaline and adrenaline, blood pressure and heart rate. In rabbit brain cortex slices preincubated with [³H]-noradrenaline, agmatine 1 to 100 M did not modify the electrically evoked overflow of tritium (either 4 pulses at 100 Hz or 36 pulses at 3 Hz). The evoked overflow was reduced by 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14304) 0.03 to 30 nM (4 pulses at 100 Hz), and this inhibition was not affected by agmatine 10 and 100 M. Agmatine did not change the basal efflux of tritium.The results show that agmatine, like yohimbine, causes central sympathoexcitation when given i.e., but agmatine differs from yohimbine in that it does not increase heart rate. Agmatine acts neither as an agonist nor as an antagonist at the ₂-autoreceptors in rabbit brain cortex. ₂-Adrenoceptors, therefore, are probably not involved in its cardiovascular effects. An action at imidazoline receptors in the medulla oblongata or some other hitherto unknown mechanism may be responsible for the sympathoexcitation.