The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.     

Total anatomic correction of interrupted aortic arch complex. Experience in 4 infants

In two cases of interrupted aortic arch (IAA) of type A, one associated with a ventricular septal defect (VSD) and one with an aortopulmonary window, and two of type B, both associated with a VSD, total anatomic repair was performed at respective ages of 6 months and 24, 8 and 3 days. All four operations were performed through a median sternotomy, using profound hypothermia and circulatory arrest. The repair included resection of the patent ductus arteriosus, direct end-to-side anastomosis of the descending to the ascending aorta and closure of the VSD or, in one case, of the aortopulmonary window. The two oldest infants (with type A IAA) survived. Reexamination two years postoperatively demonstrated good width of the aortic anastomosis with no gradient. In the child who had had an aortopulmonary window there was a proximal tight stenosis of the right pulmonary artery, which was corrected at reoperation. Total anatomic correction of IAA through an anterior approach is technically feasible and the aortic anastomosis seems to grow satisfactorily. The management of very sick neonates with IAA remains a great challenge.     

Adjuvant TACE inhibitor treatment improves the outcome of TLR2<Superscript>-/-</Superscript>mice with experimental pneumococcal meningitis

Background  

Streptococcus (S.) pneumoniae meningitis has a high lethality despite antibiotic treatment. Inflammation is a major pathogenetic factor, which is unresponsive to antibiotics. Therefore adjunctive therapies with antiinflammatory compounds have been developed. TNF484 is a TNF-alpha converting enzyme (TACE) inhibitor and has been found efficacious in experimental meningitis. Toll-like receptor 2 (TLR2) contributes to host response in pneumococcal meningitis by enhancing bacterial clearing and downmodulating inflammation. In this study, TNF484 was applied in mice, which lacked TLR2 and exhibited a strong meningeal inflammation.     

CT scans and lipohaemarthrosis in hip fractures

Computed tomography was performed on 40 patients with recent hip trauma. Radiographs of 25 showed a fracture of the femoral neck with slight displacement; 24 of these had intra-articular fluid and 20 had a lipohaemarthrosis on the CT scan. In 15 patients, radiographs at the time of admission were normal but suspicion of fracture remained. A fracture was later verified in five patients, four of whom had lipohaemarthrosis on admission. In the remaining 10 patients no fracture could be detected; only one patient had a hip joint effusion but no free fat. Thus all 24 patients with lipohaemarthrosis had an intracapsular fracture of the hip. We suggest CT for patients with hip trauma and negative radiographs. The presence of a lipohaemarthrosis of the hip strongly suggests an intra-articular fracture of either the femoral neck or the acetabulum.     

The effect of major railway accidents on the psychological health of train drivers—I. Acute psychological responses to accident

The acute psychological reactions of 101 train drivers to on-the-track accidents were studied by means of clinical interviews and questionnaires (Impact of Event Scale, GHQ-20 and a questionnaire addressing stress symptoms, pre-accident expectancies and worries). More than half of the train drivers reported moderate to high intrusive distress (mean 11.3) within hours to days after the accident but only 1/3 reported symptoms of acute psychophysiological arousal. Intrusive symptoms related to visual impressions were most frequently reported. Avoidance was less prevalent (mean 8.8).

Clinical interviews, relationship between pre-accident worries and severity of the acute responses and positive correlation between GHQ-scores relating to the fortnight preceding the accident and IES-intrusion scores, suggest that premorbid variables may influence the stress response. Involvement in more than two previous accidents invoked a feeling of vulnerability and produced stronger acute responses. Post-accident experiences involving various personal contacts did not correlate with the stress responses in this study and only a few drivers experienced such events in a negative way. Denial of the possibility of being involved in accidents was not associated with increased risk of strong acute responses, indicating that denial does not predict poor outcome in healthy persons exposed to situations where possibility of avoiding the event is outside the control of the person.     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.     

Pharmacokinetics of ketanserin in patients with essential hypertension

Summary The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%.During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy.The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy.Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.     

Conventional radiography in transient synovitis of the hip in children

Conventional radiography was performed at diagnosis and at follow-up 5 to 9 months later in 70 children with transient synovitis of the hip. Twenty-four of the patients also had CT examination at diagnosis. The cartilaginous and osseous reaction in the conventional antero-posterior radiographs was studied as was the relation between the radiographic and CT findings concerning fat planes, joint effusion, and position of the hip joint. At diagnosis there was significant increase in the medial joint space and at follow-up examination there was significant increase in medial and cranial joint space, metaphyseal width and acetabular roof width. There was a correlation of a bulging lateral 'capsular fat plane' to the position of abduction in the affected hip which explains the asymmetry in the lateral fat plane observed in these patients.     

Neuropeptide Y and calcitonin gene-related peptide: effects on glucagon and insulin secretion in the mouse

Neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) are both intrapancreatic neuropeptides that are known to inhibit stimulated insulin secretion. In the present study, we examined their influences on basal and stimulated glucagon and insulin secretion in the mouse. Either NPY or CGRP was injected intravenously at two dose levels (0.85 or 4.25 nmol/kg). When injected alone, neither of them did affect basal plasma glucagon levels but CGRP reduced basal plasma insulin levels. Glucagon secretion stimulated by the cholinergic agonist carbachol was modestly inhibited by NPY at 4.25 nmol/kg (P less than 0.01) but not affected by CGRP. In contrast, glucagon secretion stimulated by the beta 2-adrenoceptor agonist terbutaline was markedly inhibited by NPY already at the lower dose level (P less than 0.01) and potentiated by CGRP (P less than 0.01). Insulin secretion stimulated by carbachol was inhibited by CGRP (P less than 0.01) but not affected by NPY, whereas terbutaline-induced insulin secretion was inhibited by both NPY (P less than 0.05) and CGRP (P less than 0.01). We conclude that the two intrapancreatic neuropeptides NPY and CGRP have opposite actions on stimulated glucagon secretion in the mouse: NPY in an inhibitory and CGRP in a potentiatory direction. Both peptides, however, inhibit insulin secretion stimulated by terbutaline.     

Differential expression of acidic and basic FGF in the rat substantia nigra during development.

Both acidic (aFGF) and basic (bFGF) fibroblast growth factors have been shown to be present in the adult rat ventral mesencephalon and to exert effects on cultured mesencephalic cells. In the present study we have examined the expression of aFGF and bFGF in the rat ventral mesencephalon at various stages of development. bFGF was present at all ages examined [embryonic day 16 (E16) to postnatal day 90 (P90)]. In contrast, aFGF was not detectable at embryonic and early postnatal ages, but was observed at later (P20, P60, P90) postnatal stages. These data suggest that aFGF and bFGF may have functions in mesencephalic dopamine neurones in different stages of development.