[Preconceptional use of folic acid in the region of the Kantonsspital Münsterlingen/Thurgau: has it changed over the past 10 years?]. / Die Perikonzeptionelle Folsäureprophylaxe im Einzugsgebiet des Kantonsspitals Münsterlingen(KSM)/Thurgau: Was hat sich verändert von 2000 bis 2010?

BACKGROUND: Numerous studies have shown that the preconceptional use of folic acid prevents neural tube defects. We created a study to find out whether the preconceptional use of folic acid has improved in the past 10 years, in the area of Münsterlingen, Switzerland. MATERIAL AND METHODS: We interviewed 2 groups of patients who delivered at our Institution, namely between 2000 and 2002 (period A) involving 287 women and from 2009 to 2010 (period B) involving 305 pregnant women. We asked them whether they used folic acid by means of a standardised questionnaire. RESULTS: In period B significantly more women have taken folic acid preconceptionally (period A: 27.5% vs. period B: 40.7%; p=0.001). A significant increase in folic acid intake was seen in the German speaking group from period A to B (30.3% vs. 52.7%; p=0.0005), while this was not the case in the non-German speaking group (21.4% in both periods). More multiparaé women were taking folic acid compared to nulliparae. A significant increase from period A to B was noted only in the German speaking group. Unexpectedly, in nulliparae non-German speaking women, folic acid supplementation decreased from 14% to 6.1%. DISCUSSION: We have found a significant increase in preconceptional folic acid supplementation from 2001 to 2010. The percentage of women taking folic acid is disappointingly low in all groups, particularly in nulliparae women of non-German ethnicity.

Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.

5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants.

As part of our research program toward new, potential antidepressants, a series of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activities. The design of these compounds was based on coupling of various indole derivatives, previously shown to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT(1B/1D) ligands. Binding experiments in rat frontal cortex using [(125)I]iodocyanopindolol, in calf striatum using [(3)H]5-HT, and in rat hippocampus using [(3)H]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT(1B) receptor as compared to the affinities for the 5-HT(1A) and 5-HT(1D) receptors for a number of compounds, among them 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (5), the corresponding 4-fluoro-1H-indol-3-yl analogue 21a, and the corresponding 6-fluoro-1H-indol-3-yl analogue 21b. Conformational restriction of the aniline moiety in 5 only slightly enhanced the 5-HT(1B) affinity, whereas introduction of an aniline moiety with higher conformational flexibility resulted in a less potent 5-HT(1B) receptor ligand as compared to 5. The functional 5-HT(1B/1D) antagonistic activity was investigated using the rabbit saphenous vein model as well as the [(3)H]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-evoked contractile responses with pA(2) values ranging from 7.3 to 8.7. These observations were consistent with the results of the cortical slice model, in which the ureas were found to block the sumatriptan-induced inhibition of potassium-evoked [(3)H]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increased or decreased as compared to the uncoupled indole derivatives indicating that the reuptake inhibition shown by the ureas is not only due to the indole part but also affected by the aniline moiety of the molecule. Among this series of compounds described the ureas 5, 21a, and 21b seem to be the most interesting candidates showing both 5-HT reuptake inhibition and 5-HT(1B/1D) antagonism in vitro. This dual pharmacological profile should in theory lead to a pronounced enhancement in serotonergic neurotransmission and consequently to a more efficient treatment of depression.

New selective and potent 5-HT(1B/1D) antagonists: chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides.

A series of new analogues of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (1; GR127935) as potent and selective 5-HT(1B/1D) antagonists were synthesized and evaluated pharmacologically. Their receptor binding profiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4'-aminocarbonyl and 4'-amidinyl analogues (9 and 10) of 1 had higher affinities at the rat 5-HT(1B) receptor (IC(50) = 0.93, 1. 3, and 0.5 nM, respectively) and calf 5-HT(1D) receptor (IC(50) = 37, 10, and 3 nM, respectively) than did 1 (1.6 and 52 nM for rat 5-HT(1B) and calf 5-HT(1D) receptors, respectively). In the functional in vitro testing of 5-HT(1B/1D) antagonistic properties, 2, 9, 10, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differs from 2 with a sulfonamide linker) showed more pronounced effects in the K(+)-induced 5-HT release in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 were equally potent as 1 in rabbit saphenous vein model (pA(2) > 9). A biochemical study of 2 with in vivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (a selective serotonin reuptake inhibitor, SSRI) induced 5-HT release in rat ventral hippocampus, while preventing the decrease in acetylcholine release elicited by citalopram administration. The molecular structure of 2 was determined by single-crystal X-ray analysis. The log P and log D values of these compounds were calculated. This study contributes to the SAR study of N-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT(1B/1D) antagonists.

Magnetic resonance angiography of spontaneous vertebral artery dissection suspected on Doppler ultrasonography.

Spontaneous vertebral artery dissection (VAD) is a rare but well-known cause of cerebrovascular disease and is often difficult to diagnose even using conventional arteriography. While noninvasive tests such as Doppler ultrasonography and magnetic resonance imaging (MRI) have failed to provide reliable criteria for the diagnosis of VAD, the diagnostic value of magnetic resonance angiography (MRA) has not yet been undetermined. To establish the reliability of a combined noninvasive approach, 11 patients were prospectively examined for VAD by means of colour-coded duplex studies, MRI and three-dimensional time-of-flight MRA prior to conventional angiography. Among 11 patients with VAD suspected clinically as well as on Doppler ultrasonography, angiography confirmed the diagnosis in seven patients but found a vertebral artery occlusion in three and a vertebral artery stenosis in one. The combination of MRI and MRA findings led to the correct diagnosis of dissection in three patients, of vertebral artery occlusion in three patients, and of vertebral artery stenosis in one. VAD was misinterpreted as vertebral artery occlusion in four patients. Doppler ultrasonography is a valuable screening method for the detection of vertebral artery pathologies. The diagnosis of VAD can only be established if a typical intramural vessel wall haematoma is seen on T1-weighted MRI in combination with MRA findings of irregular artery stenosis or occlusion.

Noninvasive monitoring of internal carotid artery dissection.

BACKGROUND AND PURPOSE: Internal carotid artery dissection has increasingly been reported as a cause of transient ischemic attack or stroke. However, scarce data exist on the natural history of the arterial lesions and the temporal profile of recanalization. METHODS: We followed 48 patients with 50 angiographically confirmed internal carotid artery dissections by sequential duplex Doppler studies in 2- to 4-day intervals during the first weeks after the onset of symptoms and after 4 weeks in 1- to 2-month intervals for up to 2 years. We assessed sonographic features as well as the frequency and time course of resolution. RESULTS: Initial Doppler findings were abnormal in all patients, most of whom (68%) presented with a characteristic bidirectional high-resistance Doppler signal in the internal carotid artery. Gradual recanalization was found in 68% of the dissections after an average interval of 51 days. Changes of Doppler flow patterns in follow-up studies and features of intra-arterial angiography correlated with the development of internal carotid artery dissection and mirrored the recanalization process. CONCLUSIONS: Our findings suggest that Doppler sonography provides early recognition of internal carotid artery dissection and monitoring of its resolution. Thus, ultrasound studies may guide clinical decisions according to the development of the dissection.

Magnetic resonance angiography in vertebrobasilar ischemia.

BACKGROUND AND PURPOSE: Magnetic resonance angiography is a new, noninvasive technique whose diagnostic value in vertebrobasilar artery disease has not yet been determined. METHODS: Forty-one patients with acute cerebellar and/or brain-stem ischemia were examined by routine magnetic resonance imaging, extracranial and transcranial Doppler ultrasound, and selective intra-arterial arteriography. Results were correlated with magnetic resonance angiography. Magnetic resonance angiography was accomplished using a three-dimensional time-of-flight gradient-echo technique. RESULTS: Magnetic resonance angiography correctly identified all occlusions, stenoses, and an aneurysm within the distal vertebrobasilar system as revealed by conventional intra-arterial arteriography but missed the diagnosis of vertebral artery dissection in one case. This results in a sensitivity of magnetic resonance angiography of 97% and a specificity of 98.9%. However, the degree of stenoses was difficult to evaluate by magnetic resonance angiography. At least for severe obstructive lesions, this drawback can be eliminated by application of presaturation pulses, which allow the analysis of flow direction and collateral blood flow. Doppler ultrasound studies add useful hemodynamic information for less severe degrees of stenoses. CONCLUSIONS: The combined use of magnetic resonance angiography and Doppler ultrasound findings may replace the invasive intra-arterial arteriography examination in many patients with suspected macroangiopathy of the vertebrobasilar arteries.

Evidence for a separate food-entrainable circadian oscillator in the pigeon.

In Experiment 1, four pigeons lived in a metabolic chamber on a 12h:12h LD cycle where they maintained a reduced body weight by consuming a daily ration of food presented at the eighth hour of the photophase. Body temperature (Tb) and oxygen consumption (Vo2) increased prior to the daily feeding. The possibility that a food-entrainable oscillator timed these anticipatory responses was tested by four manipulations, conducted in successive phases, each of which involved eliminating the regularly scheduled food presentation, which is the putative entraining stimulus for such an oscillator, while the 12h:12h LD cycle remained in effect. The manipulations, and their outcomes, were: when fasting was imposed for 3 days, the anticipatory responses continued to occur; when ad lib feeding was allowed for 11 days, the anticipatory responses were mostly eliminated; when fasting was reimposed for 5 days, there was evidence that the anticipatory responses reoccurred; and, when the time of the daily feeding was phase-shifted earlier in the photophase for 8 days, anticipatory responses persisted at the original feeding time and simultaneously developed at the new feeding time. In the first phase of Experiment 2, key pecking by two pigeons produced food only during hours 9-11 of the daily photophase (12h:12h LD). In this condition, Tb increased and key pecking occurred in anticipation of the daily period of food availability. Evidence for a food-entrained oscillator was sought in a second phase when constant dim light (LL) was imposed without changing the hours of food availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for embolization from a posterior cerebral artery thrombus by transcranial Doppler monitoring.

BACKGROUND: Transcranial Doppler monitoring enables the detection of emboli passing through intracranial arteries. Comparison of the different intracranial vessels with respect to emboli detection can be of use in identifying the source of embolism. CASE DESCRIPTION: We report the case of a patient with an acute posterior cerebral artery (PCA) infarct on the right side, with evidence for high-degree ipsilateral PCA narrowing on admission. During transcranial Doppler monitoring 3 days later, we found frequent emboli-like signals in the power spectrum of the right PCA distal to the stenosis but not in any other intracranial vessels. Four days later, angiography and transcranial Doppler failed to show PCA narrowing, and transcranial Doppler monitoring of the right PCA showed no further emboli-like signals. A stenosis of the right vertebral artery was regarded as the possible source of thromboembolic narrowing of the PCA. CONCLUSIONS: We assume that in our patient a thrombotic clot in the PCA was resolved autolytically through detachment of small emboli into the distal part of the PCA. We speculate that in the early course of autolysis a larger fragment of the clot had occluded one of the distal branches, thus leading to the small PCA territory infarct.

[MR angiography of the vertebrobasilar circulatory area: the potential uses of the saturation technic to determine the direction of the flow]. / MR-Angiographie des vertebrobasilären Stromgebiets: Einsatzmöglichkeiten der Saturationstechnik zur Bestimmung der Flussrichtung.

MR angiography (MRA) combined with selective saturation techniques has proved to be a reliable method for the determination of flow direction and vascular supply at the level of the circle of Willis. We describe its application to the vertebrobasilar system (VBS) in ten volunteers and five patients with abnormal findings. In one patient with postsurgical stenosis of the brachiocephalic artery, reverse flow of the vertebral artery (VA) was demonstrated. Collateral blood flow from the anterior circulation over the posterior communicating arteries was shown in three patients with bilateral vertebral or proximal basilar artery occlusion. Due to increase of pressure during contrast injection into the contralateral VA, DSA showed reverse flow of a dissected VA in one patient. MR flow determination as well as TCD proved antegrade flow. All results correlated with both DSA and transcranial Doppler (TCD). The technique is little time consuming and is a promising add-on examination to conventional and MRA imaging of the VBS.

Stroke and dolichoectatic intracranial arteries.

During a 6-year-period, in 45 patients the diagnosis of dolichoectatic intracranial arteries was established. Dolichoectasia of the vertebrobasilar system was the most frequent finding (n = 39). Twenty-two patients presented with brain stem ischaemia, and 10 patients had ischaemic hemispheric events. Six patients had symptoms due to compression of cranial nerves. Hydrocephalus was observed once. Peak and mean flow velocities in 39 patients with dolichoectatic basilar arteries as revealed by transcranial Doppler ultrasound were significantly reduced (p less than 0.00001) when compared with an age-adjusted control group of 20 patients without evidence of vertebrobasilar dolichoectasia on angiogram. Non-invasive MR-angiography offered an excellent imaging of the vascular abnormality. The combined use of CT, TCD, MRI and MR-angiography allows reliable non-invasive diagnosis of dolichoectatic intracranial arteries. This condition seems to play an underestimated role in stroke patients, in particular with respect to the vertebrobasilar circulation.

Symptomatic and asymptomatic high-grade carotid stenoses in Doppler color-flow imaging.

We examined 63 patients with 31 symptomatic and 44 asymptomatic carotid stenoses with Doppler color-flow imaging (DCFI); conventional Doppler duplex had shown a hemodynamic obstruction (greater than or equal to 80% stenosis) in all patients. Analysis of plaque surface morphology demonstrated more ulcerated plaques in symptomatic (43%) than asymptomatic (23%) stenoses. Although the frequency of homogeneous and heterogeneous plaques was not different, calcific lesions were more frequent in asymptomatic (46% versus 29%), and echolucent plaques, probably indicating mural thrombi, were more frequent in symptomatic (29% versus 11%) stenosis. Color-coded hemodynamic patterns, such as jet flow, poststenotic turbulence, or reversed flow, were not different in symptomatic and asymptomatic stenoses. Comparison of DCFI with 30 angiograms showed agreement in plaque surface analysis in 70%. DCFI measurements of area reduction in cross sections correlated with angiography in 85%, while DCFI tended to underestimate the degree of stenosis from diameter reduction in longitudinal cuts. The advanced DCFI technique identified distinct morphologic features but no hemodynamic patterns, separating symptomatic from asymptomatic high-grade carotid stenoses.

Does orthotopic liver transplantation heal Wilson's disease? Clinical follow-up of two liver-transplanted patients.

Two patients with Wilson's disease (WD) underwent orthotopic liver transplantation, one for subacute liver failure and the other for severe oesophageal haemorrhage. After transplantation both patients fully recovered within five months, and copper metabolism returned to normal. Follow-up examinations were continued for 4 and 6 years. Clinical as well as electrophysiological testing in these two patients yielded better results than in most of 12 WD-patients being conventionally treated for a similar period or even longer.

[Cerebrovascular disorders--clinical aspects and follow-up]. / Zerebrale Durchblutungsstörungen--Klinik und Verlauf.

The observation of the spontaneous course of the extracranial vascular process as a characteristic cause of cerebral ischemia has shown that vascular changes occur largely independently from the appearance of cerebral functional disturbances in the associated vascular territory. Hemodynamic factors play a minor role; while with the present standard methods available, embolic mechanisms can be insufficiently analyzed. The prospective developmental observations of morphologic and fluid-dynamic aspects and supplemental cell biology and metabolic analysis provide new criteria for an individual risk evaluation of the various mechanisms causing pathologically different cerebral function disturbances, and their analysis has crucial significance for a therapy plan.

Prognosis of asymptomatic carotid occlusion.

Ninety-four asymptomatic patients with internal carotid artery occlusion were followed for a mean of 44 months, 16% suffered strokes and 11.7% reported transient ischemic attacks (TIA). The annual stroke and TIA rates were 4.4% and 3.2%, respectively, the annual mortality was 11.3%. In 27 asymptomatic patients progression of extracranial arterial disease to occlusion was observed: 7.4% of these patients suffered from stroke and 18.5% reported TIA's during that period. Thus the annual stroke rate was lower (1.9%) but the TIA rate higher (4.7%) than post-occlusive rates. These data reflect an increase risk in patients with progressive high-degree carotid stenosis which continues after occlusion. This may favour carotid endarterectomy for selected patients in the pre-occlusive state because medical treatment has not been shown to prevent progression of stenosis to occlusion.

Compensatory mechanisms in patients with asymptomatic carotid artery occlusion.

Twelve patients with asymptomatic occlusion of one (n = 8) or both (n = 4) internal carotid arteries were examined by positron emission tomography (PET) and transcranial Doppler ultrasound. PET measurements included the determination of the regional cerebral blood flow (rCBF), oxygen extraction ratio (rOER), cerebral metabolic rate of oxygen (rCMRO2), and cerebral metabolic rate of glucose consumption (rCMRGlc). Transcranial Doppler ultrasound (TCD) was used to determine the pathways and efficacy of collateralization via the circle of Willis and included spectrum analysis of flow velocities within the middle and anterior cerebral arteries as well as vasoreactivity tests. In correspondence with ultrasound evidence of a haemodynamically effective intracranial collateral circulation no significant differences between patients and controls were observed for rOER, rCMRO2 and rCMRGlc, but rCBF was globally reduced. Furthermore, in all patients with unilateral carotid occlusion PET excluded side asymmetries of any parameter studied. In contrast, flow velocity parameters measured by TCD were significantly reduced ipsilateral and significantly increased contralateral to the carotid obstruction. Vasodilative capacities, however, remained preserved even in the territory of the occluded carotid system. These data indicate that patients with asymptomatic carotid occlusion compensate by haemodynamic and not by metabolic mechanisms in contrast to symptomatic patients.