Valproate potentiates and picrotoxin antagonizes the anxiolytic action of ethanol in a nonshock conflict task

The purpose of this study was to examine the effects of the indirect GABA agonist valproate and the indirect GABA antagonist picrotoxin on the anxiolytic (anti-conflict) activity of ethanol in a behavioral conflict task that does not employ electroshock. This task (negative contrast) quantifies how animals respond to an abrupt, unexpected reduction in reward. Treatment with valproate alone did not elevated depressed behavior engendered by abrupt reduction in reward. However, when administered together with a sub-effective dose of ethanol (0.5 g/kg), valproate (50-200 mg/kg) dose-dependently potentiated the anxiolytic action of ethanol. Picrotoxin (2 mg/kg) antagonized the anxiolytic effects of a larger dose of ethanol (1.0 g/kg) given alone, as well as the ability of valproate to enhance the anxiolytic effects of smaller dose of ethanol (0.5 g/kg). As such, these data support a role for GABA in mediating the anxiolytic activity of ethanol.     

Flavin analogs with antimalarial activity as glutathione reductase inhibitors

10-(4'-Chlorophenyl)-3-methylflavin has antimalarial activity in vitro and in vivo (Cowden et al., J Med Chem 31: 799, 1988). This flavin analog and two of its derivatives were found to inhibit the antioxidant flavoenzyme glutathione reductase from human erythrocytes in its isolated form as well as in hemolysates. The mixed-type inhibition was completely reversible, the Ki-values being of the order of 1 microM. Surprisingly, the drugs were not competitive with FAD, but with GSSG, one of the enzyme's substrates. Malaria parasite glutathione reductase, extracted from Plasmodium falciparum, could also be inhibited by the compounds. Studies on the effects of the substances on P. falciparum in vitro, which were demonstrated morphologically and by growth inhibition, confirmed previous observations with 10-(4'-chlorophenyl)-3-methylflavin and showed similar parasiticidal characteristics for the two new derivatives. The activities of five other erythrocytic enzymes tested were not impaired by the drugs, nor was the nucleotide metabolism of erythrocytes and/or parasites significantly changed. Permeation into red blood cells was demonstrated for one compound by 19F-NMR-spectroscopy. Inhibition of glutathione reductase might contribute to, or account for, the antimalarial activity of this group of flavin analogs.     

The Scimitar syndrome: CT findings in partial anomalous pulmonary venous return

An anomalous pulmonary vein draining into the subdiaphragmatic inferior vena cava was initially demonstrated on computed tomographic (CT) scans. The diagnosis of scimitar syndrome was confirmed with digital subtraction angiography. In retrospect, the anomalous vein and dextroposition of the heart were shown on chest radiographs.     

Growth of Hodgkin cell lines in severely combined immunodeficient mice.

No animal model exists for the in vivo growth of Hodgkin's-lymphoma-derived cells. Neither unmanipulated Hodgkin's-disease(HD)-derived cell lines nor primary biopsy tissue could be grown in nude mice. Since the severe combined immunodeficient (SCID) mouse has been reported to be a better recipient for transplanted human lymphatic tissue than the nude mouse, we tested whether SCID mice provide suitable conditions for the in vivo growth of HD cell lines. Tumorigenicity of HD cells was tested in untreated and pre-treated SCID mice and in another combined immunodeficient mouse strain, beige/nude/X-linked immunodeficient (BNX) mouse. SCID mice supported in vivo growth of the 6 HD cell lines tested (L428, L540, L591, DEV, HD-LM2, KM-H2). Only one of the 6 lines (DEV) was tumorigenic in BNX mice. No HD cell line proliferated in T-cell-deficient nude mice. Thus, in vivo growth of HD cell lines appeared to be related to the degree of host immunodeficiency. Additional growth supportive treatments such as fibrosarcoma co-transplantation, intraperitoneal mineral oil injection or immunosuppressive pre-treatment (anti-asialo-GMI-antibody injection) permitted growth of 3 additional HD cell lines in BNX mice. The immunophenotype and karyotype of explanted graft cells were identical to the original cell lines. Our experiments describe an effective and reproducible xenograft model for growth of Hodgkin's-disease-derived cell lines. This may be of value for elucidating the growth characteristics of Hodgkin's-lymphoma-derived cells as well as for testing new therapeutic regimens.     

Assessing Alzheimer severity with a global clinical scale.

Diagnosis of dementia needs to be complemented by precise determination of disease severity across the broad spectrum of disease progression. The Mini-Mental State Exam (MMS), the Activities-of-Daily-Living assessment (ADL) and the Clinical Dementia Rating scale (CDR) were modified for direct comparability and administered to 112 outpatients and 45 nursing home residents with a range of dementia severity from mild to profound. The scales showed the highest correlations for the probable Alzheimer's disease patient group (62) (Global Assessment of Dementia; GAD vs. ADL: r = 0.91; Extended Mini-Mental Assessment; EMA vs. GAD: r = 0.91; ADL vs. EMA: r = 0.86). For these patients, scores on the individual scales tended to be similar. Disparity among the three scores for individual cases was associated with the presence of comorbidities. The high correlations and correspondence among these scales demonstrate their reliability, validity, and utility in the assessment of dementia severity. The use of an average of these measures, with their increased precision, may give a more accurate indication of dementia severity over a broader range of impairment.     

Transfer of DDT used in malaria control to infants via breast milk.

The transfer of p,p'-DDT (1,1,1-tricholoro-2,2-bis(4-chlorophenyl)ethane) and its metabolites to infants via breast-feeding was studied in an area of KwaZulu, South Africa, where DDT is used to interrupt malaria transmission. Samples of whole blood were collected from 23 infants, together with samples of breast milk from their respective mothers. The mean sigma DDT (total DDT) in the whole blood was 127.03 micrograms.l-1 and that in the breast milk, 15.06 mg.kg-1 (milk fat). The % DDT (% DDT of sigma DDT) was significantly higher in the infant blood than in the breast milk (P less than 0.05). A multiplicative regression analysis indicated that sigma DDT increased significantly (P less than 0.01) in infant whole blood with infant age. Multiple regression showed that 70.0% of the variation in sigma DDT was due to the variation in parity of the mother, age of the infant, and the sigma DDT in breast milk. These variables accounted also for 76.3% of the variation in p,p'-DDE but only for 38.2% of that in p,p'-DDT. Organochlorines were therefore largely transferred to the infant from the mother, with DDT in the environment playing a secondary role.     

Early Postnatal Changes in the Somatodendritic Morphology of Ankle Flexor Motoneurons in the Rat

The development of locomotor function in the rat spans the first 3 postnatal weeks. We have studied morphological features of the soma and dendrites of motoneurons innervating the physiological flexor muscles of the ankle, tibialis anterior and extensor digitorum longus, by intracellular injection in vitro between the first and ninth postnatal days. We obtained serial optical sections of 96 adequately filled motoneurons in whole-mounted hemisected spinal cords by confocal microscopy, projected them onto a single plane and analysed them morphometrically. On the day after birth, the somatodendritic surfaces of most such motoneurons were covered in growth-associated spiny, thorny or hair-like appendages. These had disappeared from the soma by the fourth postnatal day and from most proximal dendrites by day 7, but were still common distally on day 9. During this period there was little or no net growth of either the soma (which was still much smaller than in the adult) or the dendritic tree. A dorsal dendritic bias was present and 'sprays' of long, loosely bundled dorsal dendrites were often seen. The mean number of primary dendrites remained constant at about eight, and their combined diameter was already significantly correlated with mean soma diameter, as in the adult cat. Thus, the critical neonatal period during which these ankle flexor motoneurons are known to change their electrophysiological properties and to be particularly sensitive to interference with neuromuscular interaction is characterized by major changes in the neuronal surface, presumably linked to synaptogenesis.     

Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings.

Thirty patients admitted after suffering closed head injuries, with Glasgow Coma Scale scores ranging from 3 to 15, were evaluated with transcranial Doppler ultrasound monitoring. Blood flow velocity was determined in the middle cerebral artery (MCA) and the intracranial portion of the internal carotid artery (ICA) in all patients. Because proximal flow in the extracranial ICA declines in velocity when arterial narrowing becomes hemodynamically significant, the extracranial ICA velocity was concurrently monitored in 19 patients. To assess cerebral perfusion, cerebral blood flow (CBF) measurements obtained with the intravenous 133Xe technique were completed in 16 patients. Vasospasm, designated as MCA velocity exceeding 120 cm/sec, was found in eight patients (26.7%). Severe vasospasm, defined as MCA velocity greater than 200 cm/sec, occurred in three patients, and was confirmed by angiography in all three. Subarachnoid hemorrhage (SAH) was documented by computerized tomography in five (62.5%) of the eight patients with vasospasm. All cases of severe vasospasm were associated with subarachnoid blood. The time course of vasospasm in patients with traumatic SAH was similar to that found in patients with aneurysmal SAH; in contrast, arterial spasm not associated with SAH demonstrated an uncharacteristically short duration (mean 1.25 days), suggesting that this may be a different type of spasm. A significant correlation (p less than 0.05) was identified between the lowest CBF and highest MCA velocity in patients during the period of vasospasm, indicating that arterial narrowing can lead to impaired CBF. Ischemic brain damage was found in one patient who had evidence of cerebral infarction in the territories supplied by the arteries affected by spasm. These findings demonstrate that delayed cerebral arterial spasm is a frequent complication of closed head injury and that the severity of spasm is, in some cases, comparable to that seen in aneurysmal SAH. This experience suggests that vasospasm is an important secondary posttraumatic insult that is potentially treatable.     

Pharmacokinetic aspects of a combination of metoclopramide and paracetamol. Results of a human kinetic study and consequences for migraine patients]

An open trial was carried out in eight healthy male and female volunteers to examine the bioavailability as well as the main kinetic parameters of Migr?nerton (metoclopramide and paracetamol; CAS 364-64-5 and CAS 103-90-2, resp). in comparison with reliable literature data. The results reported here clearly show that the absorption of both active ingredients from the fixed combination is complete and that therapeutically relevant plasma concentrations are achieved within 30 min. Bioavailability as well as tmax, t1/2, and time-lag are comparable with data resulting from reliable and internationally acknowledged kinetic studies. The fixed combination was shown to be kinetically compatible with regard to all parameters determined for metoclopramide and paracetamol.