Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11

 Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD₅₀) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. Received: 16 June 1997 / Accepted: 23 September 1997     

Biodisponibilité de la glutamine et réponse du métabolisme protéique à l'apport de glutamine chez l'homme

Glutamine is synthetized in most tissue and accounts for two-thirds of the free amino acid pool in skeletal muscle. Glutamine is not only an interorgan nitrogen shuttle but a precursor of urinary ammonium, and a favorite fuel of the immune system and the gut (which uses ≠ 17 g of glutamine per day). Because they were designed at a time when glutamine was considered both unstable and non-essential, « tradtionalparenteral nutrition (PN) solutions are devoid of glutamine. Although « classicPN is able to maintain normal rates of glutamine turnover in healthy subjects or unstressed patients, classic PN solutions are unable to correct the precipitous depletion of glutamine pool that accompagnies catabolic illness. Glutamine becomes a « conditionally essentialamino acid in these situations. Replenishment of glutamine pool seems to stimulate protein synthesis, and improve nitrogen balance in catabolic patients. Supplementation of PN with glutamine-containing dipeptides or α-ketoglutarate (at doses of 15–50 g/d) is as effective as glutamine itself. The enteral route represents an attractive alternative for the supply of glutamine since : 1) glutamine is efficiently absorbed ; 2) nearly 50 % of enterally infused glutamine reaches systemic blood ; 3) glutamine residues present in a bound form in peptides seem to be bioavailable ; and 4) in addition to its protein anabolic effect, glutamine affects intestinal absorption and trophicity.     

Neuropsychological evaluation before and after thalamic stimulation in 9 patients with Parkinson disease]

Chronic thalamic-VIM stimulation was performed in 9 parkinsonian patients with disabling tremor and poor response to drugs. Neuropsychological assessment was performed before and after deep brain electrode implantation and stimulation. Mild cognitive disorders were observed prior to thalamic implantation. Neuropsychological testing failed to show intellectual function worsening after implantation and stimulation. We conclude that thalamic stimulation could be an appropriate treatment of untractable tremor as this could provide less neuropsychological side-effects than thalamotomy, especially in Parkinson's disease.     

Morphologic characterization of osteoblast-like cell cultures isolated from newborn rat calvaria

Summary Two methods for harvesting osteoblast-like cell populations from newborn (10 days) rat calvaria were compared. The first one consisted in culturing the periosteum-free bones and then trypsinizing the cells on the bone surface. The second one involved the migration of the osteoblasts on glass fragments before trypsinization. Since the plating efficiency, the proportion of alkaline phosphatase-positive cells, the population doubling time, and the calcium deposition were more adequate, the second method was used to further characterize the behavior of the cultures. During the first week of culture, the cells featured shapes similar to those observedin vivo on the surface of periosteum-free calvaria. They formed multilayers and, in the presence of ascorbic acid, synthetized an organic matrix containing exclusively type I collagen. Later, small amounts of type III collagen appeared. The cells were embedded in the matrix and progressively acquired the morphologic phenotype of osteocyte-like cells. The matrix mineralized in the presence of β-glycerophosphate. The technique of dropinoculation (high concentration of cells in a small volume of medium) promoted the multilayer formation and the achievement of large mineralized plates (about 1 cm²) in 3 weeks of culture.     

Concerning the differentiability of the energy function in vector quantization algorithms.

The adaptation rule of Vector Quantization algorithms, and consequently the convergence of the generated sequence, depends on the existence and properties of a function called the energy function, defined on a topological manifold. Our aim is to investigate the conditions of existence of such a function for a class of algorithms including the well-known 'K-means' and 'Self-Organizing Map' algorithms. The results presented here extend several previous studies and show that the energy function is not always a potential but at least the uniform limit of a series of potential functions which we call a pseudo-potential. It also shows that a large number of existing vector quantization algorithms developed by the Artificial Neural Networks community fall into this class. The framework we define opens the way to studying the convergence of all the corresponding adaptation rules at once, and a theorem gives promising insights in that direction.     

Coping with mild inflammatory catamenial acne

BACKGROUND: Acne is a multifactorial disease exhibiting distinct clinical presentations. Among them, the catamenial type is a matter of concern for young women. Some oral contraceptives may help without, however, clearing the skin condition. AIM: The present open study aimed at evaluating the effect of overnight applications of a paste made of petrolatum,15% zinc oxide and 0.25% miconazole nitrate. METHOD: The split-face trial was conducted in 35 women. A non-medicated cream was used as control. Clinical evaluations and biometrological assessments on cyanoacrylate follicular biopsies were performed monthly for 3 months. Comedometry and the density in autofluorescent follicular casts were used as analytical parameters. In addition, the five most severe cases at inclusion were tested at the completion of the study for follicular bacterial viability using dual flow cytometry. RESULTS: Compared with baseline and to the control hemi-face, the medicated paste brought significant improvement of acne. The number of papules and their redness were reduced beginning with the first treatment phase. A reduction in the follicular fluorescence was yielded beginning with the second treatment phase. The ratios between injured and dead bacteria, on the one hand, and live bacteria, on the other hand were significantly increased at completion of the study. CONCLUSION: A miconazole paste applied for 1 week at the end of the ovarian cycle has a beneficial effect on catamenial acne.     

Sparing of perceptual implicit memory despite suppression of the electrophysiological word repetition effect: a study with general anesthetic isoflurane.

OBJECTIVE: Much effort has been devoted to the search for the neurophysiological correlates of implicit memory. A commonly held view is that the early portion (250-500 ms) of the event-related potential (ERP) word repetition effect reflects processes important for perceptual implicit memory whereas the latter portion reflects processes implicated in explicit memory. It is, however, difficult to disentangle with certainty the relative contributions of each form of memory on ERPs since both forms co-exist in normal subjects. To dissociate ERP effect related to implicit and explicit memory, we used isoflurane sedation in normal subjects to suppress explicit remembering while sparing implicit memory. These ERPs were compared with those of non-medicated control subjects. METHODS: Thirteen subjects performed an incidental encoding task for words presented auditorily during the inhalation of a subanesthetic dose of isoflurane. After termination of isoflurane administration, we assessed free recall and recorded ERPs during a syllable completion task (implicit memory) and during a passive listening task (ERP repetition effect). Eleven non-medicated control subjects were tested in a similar manner. RESULTS: The controls showed robust early and late ERP repetition effect. The isoflurane group had implicit memory without free recall and showed no ERP repetition effect. CONCLUSIONS: These findings failed to show an association between any part of the repetition effect and perceptual implicit memory. The results are consistent with the view that processes linked to explicit memory contribute to the ERP repetition effect since there was a marked difference in free recall between the control and isoflurane groups. SIGNIFICANCE: The present study shows that the reversible alterations of memory by general anesthetics can be used to study the neurophysiological correlates of memory processes.     

Retroperitoneal rhabdomyosarcoma revealed by acute kidney failure in children. Report of a case

Retroperitoneal sarcomas are rare tumors representing 0.1% to 0.2% of all malignant tumors. They are usually revealed by an abdominal mass (33%), possibly associated with pain (41%). Edema of the lower limbs is reported in 10% of cases. Acute renal failure with anuria by bilateral ureteral compression, associated with invasion of the inferior vena cava has not been previously reported.     

Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found. First, the extent of bioavailability was identical for the two formulations but the rate of bioavailability seemed to be different, with the p.o. solution, being more rapidly absorbed (tmax = 1.50 h). The effect of administration time was more obvious for the solution as shown by a lower quantitative absorption as well as a delay in time to reach the maximal concentration. Regardless of formulation and administration time, the t1/2 beta was about 10 hours and the mean MRT value was 11 hours.