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     

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.     

Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures

Although several studies have demonstrated the efficacy of subcutaneous immunotherapy in allergic asthma, few have shown the same benefit using sublingual immunotherapy (SLIT) in asthmatic patients. This study was conducted to assess the efficacy of house dust mite (HDM) SLIT in addition to allergen avoidance and standard pharmacologic treatment. A double-blind, placebo-controlled trial was performed in 111 children (aged 5-15 yr) with HDM-induced mild-to-moderate asthma. After a 4-week baseline phase, patients were randomly assigned to receive SLIT with tablets of HDM extract (n = 55) or placebo (n = 56) for 18 months. Pharmacologic treatment was adjusted every 3 months following a step-down approach. Asthma symptom scores, reduction in use of inhaled corticosteroids and inhaled beta(2)-agonists, rhinitis symptoms, lung function tests, skin sensitivity to HDM, dust mite-specific immunoglobulin (Ig) E and IgG(4), and quality of life (QoL) were assessed during the study. After 18 months of treatment, diurnal and nocturnal asthma symptoms scores did not show significant differences between SLIT and placebo groups. Inhaled corticosteroids and inhaled beta(2)-agonists use was reduced in both groups without significant differences between groups. There were no significant differences in lung function (forced expiratory volume in 1 s and peak flow rate variations) between groups. Rhinitis symptom score decreased in both groups, with no difference between the two groups. The severity dimension of QoL was significantly improved in the SLIT group (age 6-12 yr). SLIT induced a significant reduction of skin sensitivity to HDM (p < 0.01) and a significant increase in HDM-specific IgE and IgG(4) antibodies (p < 0.001) in the SLIT group compared with the placebo group. SLIT was well tolerated with mild/moderate local adverse events. No severe systemic reactions were reported. This study indicates that, when mild-moderate asthmatic children are optimally controlled by pharmacologic treatment and HDM avoidance, SLIT does not provide additional benefit, despite a significant reduction in allergic response to HDM. Under such conditions, only a complete, but ethically unfeasible, discontinuation of inhaled corticosteroid would have demonstrated a possible benefit of SLIT.     

Complications associated with the Esophageal-Tracheal Combitube® in the pre-hospital setting

PURPOSE: The Esophageal-Tracheal Combitube (Combitube) is widely used for the management of the airway during cardiopulmonary resuscitation in the pre-hospital setting. Although serious complications have been reported with the Combitube, there is a paucity of data relative to the frequency and nature of such complications. The objective of this retrospective study was to determine the incidence and the nature of complications associated to the Combitube in the pre-hospital setting. METHODS: Since 1993, in the Quebec City Health Region, the basic life support treatment algorithm for emergency medical technicians has included the use of a Combitube as the primary airway device for management of all patients presenting with cardiac or respiratory arrest. The database of the emergency coordination services was searched for the period between 1993 and 2003 (2,981 patients). Only those patients who survived at least 12 hr were included. Medical records of these patients were reviewed to identify complications related to the use of the Combitube. RESULTS: Two-hundred-eighty (280) patients were identified. Fifty-eight (58) patients (20.7%, confidence interval (CI)95%=16.0%-25.4%) presented 69 complications: aspiration pneumonitis (n=31), pulmonary aspiration (n=16), pneumothorax (n=6), upper airway bleeding (n=4), esophageal laceration (n=3), sc emphysema (n=2), esophageal perforation and mediastinitis (n=2), tongue edema (n=2), vocal cord injury (n=1), tracheal injury (n=1), and pneumomediastinum (n=1). Thirteen of these complications (12 patients, 4.3%, CI95%=2.0%-6.3%) were judged as most likely resulting from trauma associated with insertion of the Combitube. CONCLUSION: The use of the Combitube in the pre-hospital setting is associated with a notable incidence of serious complications.     

Neuropathy associated with “benign” anti-myelin-associated glycoprotein IgM gammopathy: Clinical,immunological, neurophysiological pathological findings and response to treatment in 33 cases

We studied 33 patients presenting with a peripheral neuropathy associated with non-malignant anti-myelin-associated glycoprotein (MAG) IgM monoclonal gammopathy (MG) in an attempt to delineate their clinical, immunological, electrophysiological and pathological characteristics; we also reviewed our experience concerning long-term follow-up and therapy. Peripheral neuropathy associated with non-malignant anti-MAG IgM MG was observed mostly in males (sex ratio 7.2), and mean age at onset was 67 years (range 46–81). A predominantly sensory pattern was noted in more than 80% of cases, although some patients were affected by a predominantly motor peripheral neuropathy. Although disease progression was slow in most cases, 45% of patients suffered severe disability, and in 2 cases, the patient's death appeared to stem directly from the neuropathy. The electrophysiological findings were indicative of a demyelinating process in 90% of cases, and electron microscopic examination of nerve biopsy specimens demonstrated widening of the myelin lamellae in more than 95% of cases. Most of our patients showed a disappointing response to steroids and chemotherapy or plasma exchanges. Intravenous immune globulin, evaluated in 17 patients, had a transient, mostly subjective effect in 35% and led to a clear-cut improvement in 24% of cases. We did not observe any correlation between the severity of the clinical picture and the anti-sulphoglucuronyl paragloboside antibody titre; in individual cases, clinical improvement occurred without lowering of IgM levels. Although the severity and the rate of progression may greatly vary from patient to patient, the combination of clinical, electrophysiological and pathological features delineates a characteristic pattern in peripheral neuropathy associated with non-malignant anti-MAG IgM MG.     

Extrinsic compression of the renal artery by diaphragmatic crus

Extrinsic compression of the renal artery due to a fibromuscular band originating from the diaphragm was encountered in a 26-year-old patient who had systemic hypertension associated with stenosis and kinking of one of her renal arteries. After surgical decompression, the renal artery assumed a normal expansion with disappearance of hypertension. Six other cases of extrinsic compression of the renal artery have been found in the literature. Surgical treatment is mandatory in all cases because the mechanism that causes the lesion makes percutaneous transluminal angioplasty illusory.