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     

Spectrum of looping disturbances in stage 34 chicken hearts after retinoic acid treatment

Background: In a recently developed chick model the teratogen retinoic acid has appeared to induce a spectrum of double outlet right ventricle, which needs further detailed evaluation. It is known that retionic acid is able to induce cardiac malformations. Although the exact mechanism is not known, an interaction with neural crest cell function is thought to exist. Methods: After treatment with 1 μg all-trans retinoic acid at Hamburger and Hamilton stage 15 and reincubation until stage 34 of development 41 chicken embryos were evaluated macroscopically and microscopically, supported by graphic reconstructions. These retinoic acid treated embryos were compared with a control group (n = 8). Results: The retinoic acid treated embryos could be divided in three groups. Group 1 (23/41) had an intact septum, group 2 (11/41) had an isolated ventricular septal defect (VSD), and group 3 (7/41) had a double outlet right ventricle (DORV). Besides, in the group with an intact septum 11 hearts showed an abnormal course of the subaortic outflow tract. In the group with DORV a straddling tricuspid orifice (7/8) and a double inlet left ventricle (1/8) could be distinguished. Considering the external contour, the hearts in the DORV group all showed a dextroposed arterial pole. Malformed pharyngeal arch arteries were found in all three groups (11/41) and with a great diversity. Conclusions: The present cardiac malformations in the chicken as a result of retinoic acid treatment are part of a continuous spectrum, varying from hearts with an intact ventricular septum and a normal course of the subaortic outflow tract to a double outlet right ventricle with a straddling tricuspid orifice or even a double inlet left ventricle. A remarkable observation in this spectrum concerns the correlation of malformations of the inflow and outflow tracts, which is explained as a cardiac looping disturbance. The disturbance of the looping process seems to lead to malalignment of septal components, although, in the chick, retinoic acid does not in general interfere with the formation of these septal components themselves. © 1995 Wiley-Liss, Inc.     

Tightly clustered outbreak of group A streptococcal disease at a long-term care facility.

OBJECTIVE: To describe investigation of a tightly clustered outbreak of invasive group A streptococcal (GAS) disease associated with a high mortality rate in a long-term care facility (LTCF). DESIGN: Cross-sectional carriage survey and epidemiologic investigation of LTCF resident and employee cohorts. SETTING: A 104-bed community LTCF between March 1 and April 7, 2004. PATIENTS: A cohort of LTCF residents with assigned beds at the time of the outbreak. INTERVENTIONS: Reinforcement of standard infection control measures and receipt of chemoprophylaxis by GAS carriers. RESULTS: Four confirmed and 2 probable GAS cases occurred between March 16 and April 1, 2004. Four case patients died. The final case occurred during the investigation, before the patient was determined to be a GAS carrier. No case occurred during the 6 months after the intervention. Disease was caused by type emm3 GAS; 16.5% of residents and 2.4% of employees carried the outbreak strain. Disease was clustered in 1 quadrant of the LTCF and associated with nonintact skin. GAS disease or carriage was associated with having frequent personal visitors. CONCLUSIONS: Widespread carriage of a virulent GAS strain likely resulted from inadequate infection control measures. Enhanced infection control and targeted prophylaxis for GAS carriers appeared to end the outbreak. In addition to employees, regular visitors to LTCFs should be trained in hand hygiene and infection control because of the potential for extended relationships over time, leading to interaction with multiple residents, and disease transmission in such residential settings. Specific attention to prevention of skin breaks and proper wound care may prevent disease. The occurrence of a sixth case during the investigation suggests urgency in addressing severe, large, or tightly clustered outbreaks of GAS infection in LTCFs.     

High-resolution myocardial perfusion mapping in small animals in vivo by spin-labeling gradient-echo imaging.

An ECG and respiration-gated spin-labeling gradient-echo imaging technique is proposed for the quantitative and completely noninvasive measurement and mapping of myocardial perfusion in small animals in vivo. In contrast to snapshot FLASH imaging, the spatial resolution of the perfusion maps is not limited by the heart rate. A significant improvement in image quality is achieved by synchronizing the inversion pulse to the respiration movements of the animals, thereby allowing for spontaneous respiration. High-resolution myocardial perfusion maps (in-plane resolution=234 x 468 microm2) demonstrating the quality of the perfusion measurement were obtained at 4.7 T in a group of seven freely breathing Wistar-Kyoto rats under isoflurane anesthesia. The mean perfusion value (group average +/- SD) was 5.5 +/- 0.7 ml g(-1)min(-1). In four animals, myocardial perfusion was mapped and measured under cardiac dobutamine stress. Perfusion increased to 11.1 +/- 1.9 ml g(-1)min(-1). The proposed method is particularly useful for the study of small rodents at high fields.     

L’électroencéphalogramme n’est pas un examen légitime pour la confirmation du diagnostic de mort cérébrale

PURPOSE: In France, legislation mandates that the clinical diagnosis of brain death be confirmed by one paraclinical test before organ donation is allowed. That test may be either the electroencephalogram (EEG) or cerebral angiography. We report a case in which the clinical diagnosis of brain death was first confirmed by two EEGs performed according to the French guidelines, but ruled out by cerebral angiography. Considering that the EEG is no longer recommended to establish the diagnosis of brain death, we discuss the relevance of maintaining the EEG for brain death diagnosis in France. CLINICAL FINDINGS: A 58 yr-old man was admitted to the intensive care unit because of coma secondary to a massive subarachnoid hemorrhage with herniation below the falx shown by computed tomography. Clinical criteria of brain death were rapidly present. Two EEGs first confirmed the diagnosis but a four-vessel cerebral angiography was finally performed because the patient moved spontaneously. This cerebral angiography showed flow in the right internal carotid artery. A computed tomography performed the next day definitely confirmed the absence of brain death and organ donation did not occur. CONCLUSIONS: This case demonstrates the limitations of the EEG for this indication and suggests that angiography should be preferred. French legislation is probably maladjusted and would benefit by incorporating guidelines of other countries like Canada. International harmonization of criteria for brain death diagnosis would also be welcome.     

Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study.

We sought whether microdamage could rise in postmenopausal osteoporotic women on long-term bisphosphonates, as suggested by recent animal studies. We found few microcracks in iliac bone biopsies, despite a marked reduction in bone turnover. INTRODUCTION: Animal studies suggest that bisphosphonates (BPs) could increase microdamage frequency in a dose-dependent manner, caused by excessively suppressed bone turnover. However, there is limited data in humans receiving BP therapeutic doses for >3 yr. MATERIALS AND METHODS: We measured microcrack frequency and histomorphometry parameters on transiliac bone biopsies in 50 postmenopausal osteoporotic women (mean age = 68 yr) who had received BP therapy (3 on intravenous pamidronate, 37 on oral alendronate, and 10 on oral risedronate) for at least 3 yr (mean treatment duration = 6.5 yr). We compared these results with transiliac bone biopsies obtained from 12 cadavers. We used bulk staining with green calcein as a fluorochrome. The microcracks were quantified in three 100-microm-thick sections using optic microscopy and were confirmed by laser confocal microscopy. Microcrack frequency (number of microcracks/mm2 of bone tissue) was compared between treated women and controls using nonparametric tests. We also explored predictors of microcrack frequency, including age, duration of BP therapy, and activation frequency. RESULTS: Among treated women, cancellous bone microcrack frequency was low (mean, 0.13 microcracks/mm2) and did not differ significantly from that observed in controls (0.05 microcracks/mm2; p = 0.59). Of note, 54% of the treated women and 58% of the controls had no observable microcracks. There was no association between microcrack frequency and the duration of BP therapy (for microcracks/mm2 and duration, Spearman r = 0.04, p = 0.80) and between patients' ages and the number of microcracks (Spearman r = -0.09, p = 0.61). Although bone remodeling parameters were suppressed in treated women, we found no relationship between microcrack density and activation frequency (Spearman r = -0.003, p = 0.99). Also, microcrack frequency was not increased in women with prevalent vertebral fracture compared with those without fractures. CONCLUSIONS: Among postmenopausal osteoporotic women on long-term BPs, microcrack frequency in the iliac bone is low, despite a marked reduction of bone turnover.     

Laser treatment for further depigmentation in vitiligo

Background In patients with vitiligo, sometimes the greatest part of the skin has already lost its melanocytes. The remaining pigmented patches can be removed by using strong bleaching creams, but many adverse events have been reported with this treatment. Anew depigmentation therapy could be treatment with a Ruby laser. Methods Before treatment, the patients filled out a questionnaire about their vitiligo history. Eight patients with remaining pigmentation of the arms, hands, and face were treated once with a Ruby laser. Patients were monitored for developing repigmentation during the 9 months after treatment. Results In patients with a positive Koebner phenomenon, a permanent state of depigmentation was reached after laser therapy. None of the treated patients showed severe side-effects. Conclusions Ruby laser treatment can be an effective, fast, and safe method for removing cosmetically disturbing remnants of normal pigmentation in vitiligo patients with a positive Koebner phenomenon.     

Toxicity of the blue-green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs,as an animal model for human injury and risk assessment

Hepatotoxins from blue-green algae are increasingly recognized as a potential hazard in drinking water supplies. The clinical consequences of ingestion include acute or chronic liver injury, with the possibility of enhanced susceptibility to, and growth of, liver tumors. To establish guidelines for water safety requires the demonstration of dose-dependent effects of toxicity and experimental determination of maximum “no-adverse-effect levels.” This paper describes the use of growing pigs as a model for human injury resulting from Microcystis toxins in drinking water. Risk assessment calculations using a series of safety factors are carried out, resulting in a guideline level after incorporating an additional safety factor for tumor promotion of approximately 1.0 μg toxins/L. With the Microcystis used for this trial, that concentration corresponds to 5000 cells/mL. © 1994 by John Wiley & Sons, Inc..     

Report of an audit into third molar exodontia.

A postal audit of the main surgical variables in third molar exodontia under general anaesthesia was undertaken on consultants holding a National Health contract within the British Isles. This first paper presents the results. A response rate of 175 returned questionnaires from the 247 consultants was obtained (70.9%). Analysis revealed that the majority of consultants use antibiotics, mouthwashes, sutures, analgesics and postoperative review and the minority steroids and peroperative local anaesthetic, routinely in the majority of cases. Approximately half routinely use a chisel as opposed to a bur for bone removal. The consultants who gave all their patients steroids were significantly (p less than 0.01) more likely to possess a medical qualification than the consultants who did not.