Toxic epidermal necrolysis; 15 years'' experience in a Dutch burns centre

BACKGROUND: Toxic epidermal necrolysis (TEN) is a severe and potentially fatal drug reaction characterized by an extensive skin rash with blisters and exfoliation, frequently accompanied by mucositis. The wounds caused by TEN are similar to second-degree burns and severe cases may involve large areas of skin loss. OBJECTIVES: Analysis of our results in patients with TEN and evaluation of the variety of therapeutic interventions that has been studied and suggested in TEN. PATIENTS/METHODS: Retrospective analysis of 19 consecutive patients with TEN treated in our burns centre between 1989 and 2004. RESULTS: Immediate withdrawal of any potentially fatal drug, maximum supportive care, and a restricted and tailored antibiotic, medical and surgical treatment regimen confined mortality to 21%, whereas prognosis scores like APACHE II and SCORTEN predicted mortality of 22 and 30%, respectively. A positive contribution of selective digestive decontamination is suggested but has yet to be established. CONCLUSIONS: Because of a potentially fatal outcome, fast referral of a patient suspected of TEN to a specialized centre (mostly a burns unit or specialized dermatology centre) for expert wound management and tailored comprehensive care is strongly advised and contributes to survival.     

Quantification of Basal and Stimulated ROS Levels as Predictors of Islet Potency and Function

We have developed a luminol-based assay using intact islets, which allows for quantification of reactive oxygen species (ROS). In addition, an index capable of characterizing metabolic and mitochondrial integrity prior to transplantation was created based on the capacity of islets to respond to high glucose and rotenone (mitochondrial respiratory chain complex I inhibitor) by production of ROS. To validate this assay, lipid peroxidation and antioxidative defense capacity were evaluated by detection of malondialdehyde (MDA) levels and glutathione peroxidase activity (GPx), respectively. Also, flow cytometric analyses of ROS (dihydroethidine), apoptosis (Annexin V, active caspases), necrosis (Topro3), and mitochondrial membrane potential (JC-1) were done in parallel to correlate with changes in luminol-measured ROS. ATP/ADP ratios were quantified by HPLC and the predictive value of ROS measurement on islet functional potency was correlated with capacity to reverse diabetes in a streptozotocin-induced diabetic NOD.scid mouse model as well as in human transplant recipients. Our data demonstrate that levels of ROS in islets correlate with the percentage of apoptotic cells and their functional potency in vivo. The ROS indices following glucose and rotenone exposure are indicative of metabolic potency and mitochondrial integrity and can be used as surrogate markers to evaluate the quality of islets prior to transplantation.     

Studies on the optimal conditions for inactivation of Bordetella pertussis organisms with glutaraldehyde for preparation of a safe and potent pertussis vaccine

The optimal conditions for inactivation of Bordetella pertussis organisms with glutaraldehyde for the production of a safe and potent whole cell pertussis vaccine were investigated. Two bacterial harvests from B. pertussis strain 10536 were treated with glutaraldehyde, each with 0.025, 0.05 and 0.1% concentrations of glutaraldehyde for 10, 60 and 120 min. The nine types of glutaraldehyde-inactivated pertussis vaccine (GIPV) and conventional heat-inactivated pertussis vaccine (HIPV) preparations made from two bacterial harvests were comparatively evaluated for the mouse weight gain test (MWGT), potency, and the histamine-sensitization (HS) and leucocytosis-promoting-factor (LPF) tests. The minimum period for killing the B. pertussis organisms with glutaraldehyde was>10 min for 0.025%, 10 min for 0.05% and 5 min for 0.1% concentration. The average loss in opacity varied from 5 to 10% for GIPV preparations and was 14% for HIPV preparations. The GIPV preparations except those inactivated with 0.025% glutaraldehyde for 10 min (GIPV-A) were much less toxic than the HIPV preparations in the MWGT. The GIPV-A preparations did not pass the MWGT. The GIPV preparations were also much less toxic in HS and LPF tests than the HIPV preparation. The potency of GIPV preparations inactivated with 0.05% glutaraldehyde for 10 min (GIPV-D) was similar to that of HIPV preparations. The prolonged treatments with glutaraldehyde reduced the potency. The GIPV-D preparation with good potency and less toxicity was found to be inactivated with glutaraldehyde under optimal conditions. All the preparations were innocuous in the abnormal toxicity test.     

EMPACT syndrome

Background: Seizure prophylaxis with phenytoin is a common measure in oncologic patients with brain metastases. In these patients, generalized severe adverse drug reactions such as erythema multiforme (EEM) may occur. However, in a subgroup of patients with brain radiation therapy, EEM‐like lesions develop particularly in the radiation field. Most recently, the acronym EMPACT ( E rythema M ultiforme associated with P henytoin A nd C ranial radiation T herapy) was proposed to specifically describe this syndrome. Patient/Method: Here, we report on EMPACT syndrome in a 46‐year‐old woman. Therapeutic measures included seizure prophylaxis with phenytoin and total brain radiation therapy of brain metastases from bronchial carcinoma. Three weeks after introduction of phenytoin, the patient presented with EEM‐like skin lesions restricted to the original radiation field and facial mucocutaneous involvement. After a few days, the rash spread to the upper part of the body. She was also in poor general condition. Results: The immediate cessation of phenytoin therapy, combined with administration of systemic corticosteroids and high dose immunoglobulins along with intensive local treatment and pain medications, resulted in complete resolution of the skin eruption. Patch testing to phenytoin was positive after 72 hours. Conclusion: EMPACT should be classified as an specific entity among the EEM‐like drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin. We propose including specific type IV‐sensitization to phenytoin into the definition of EMPACT.     

Potency variation of small-molecule chymase inhibitors across species

Chymases (EC 3.4.21.39) are mast cell serine proteinases that are variably expressed in different species and, in most cases, display either chymotryptic or elastolytic substrate specificity. Given that chymase inhibitors have emerged as potential therapeutic agents for treating various inflammatory, allergic, and cardiovascular disorders, it is important to understand interspecies differences of the enzymes as well as the behavior of inhibitors with them. We have expressed chymases from humans, macaques, dogs, sheep (MCP2 and MCP3), guinea pigs, and hamsters (HAM1 and HAM2) in baculovirus-infected insect cells. The enzymes were purified and characterized with kinetic constants by using chromogenic substrates. We evaluated in vitro the potency of five nonpeptide inhibitors, originally targeted against human chymase. The inhibitors exhibited remarkable cross-species variation of sensitivity, with the greatest potency observed against human and macaque chymases, with K_i values ranging from ∼0.4 to 72 nM. Compounds were 10-300-fold less potent, and in some instances ineffective, against chymases from the other species. The X-ray structure of one of the potent phosphinate inhibitors, JNJ-18054478, complexed with human chymase was solved at 1.8 Å resolution to further understand the binding mode. Subtle variations in the residues in the active site that are already known to influence chymase substrate specificity can also strongly affect the compound potency. The results are discussed in the context of selecting a suitable animal model to study compounds ultimately targeted for human chymase.     

Epidemiological considerations following long-term surveillance of invasive group A streptococcal disease in The Netherlands, 1992–2003

A nationwide laboratory-based surveillance system for invasive group A streptococcal (GAS) infections was conducted in The Netherlands from March 1992 until December 2003. Until 1996, all isolates submitted were evaluated clinically and demographically. During this period there was a transition from passive to active surveillance for some of the participating laboratories, corresponding to a national coverage of 50%. During active surveillance, participating laboratories submitted twice as many isolates from invasive GAS disease, whereas the relative submission of isolates representing very severe manifestations (toxic shock-like syndrome, fatality) did not increase. From 1997 onwards, invasiveness was defined solely on the basis of source of isolation (without clinical evaluation). During the period of microbiological and clinical evaluation, microbiological evaluation alone was found to be specific (> 99%), but had limited sensitivity (66%). Estimation of the true rate of invasive GAS disease should be based on an active surveillance system with inclusion of both microbiological and clinical data.     

Atypical Allergic Colitis in Preterm Infants

ABSTRACT. Two atypical cases of colitis due to cow's milk protein intolerance (CMPI) are reported, affecting preterm infants. One developed a toxic dilatation of the colon and responded well to a casein hydrolysate based feed. The second presented insidiously and failed to tolerate a casein hydrolysate, but responded well to a chicken-based modular feed.     

氧化胆固醇对动脉毒性作用的研究

将Wistar大鼠随机分成氧化胆固醇组(Och)、纯胆固醇组(Pch)和对照组,分别用氧化胆固醇混合物(250mg/kg bw/d)、纯胆固醇(250mg/kg bw/d)以及悬浮固醇用的明胶液体给大鼠灌胃,连续二天。于第二次灌胃后18小时,从大鼠尾静脉注射伊文思兰溶液,并于注射后2小时处死;取出主动脉用荧光显微分光光度术测定主动脉内膜的通透性。此外,另一部分动物在第二次灌胃后24小时处死,取出主动脉作扫描电镜的内膜观察。结果表明,Och大鼠主动脉内膜的通透性显著高于Pch组与对照组大鼠(P<0.01),而Pch组大鼠主动脉内膜的通透性和对照组无显著差异(P>0.05)。     

"Chronic painter''s syndrome". A reanalysis of psychological test data in a group of diagnosed cases, based on comparisons with matched controls

Twenty solvent-exposed workers, most of them painters, had been diagnosed as cases of toxic encephalopathy in 1978/79. Two years later they were re-examined with an extensive battery of neuropsychological tests. Their performance was unchanged on retesting. We have now compared their test results with those of non-exposed control subjects. Previous impressions of significant intellectual impairment in the solvent-exposed patients could not be confirmed when the influence of age, education, and intelligence was taken into consideration. The present group with presumed toxic encephalopathy is assumed to be representative of other patients who were similarly diagnosed in our department. The presently reanalyzed cases had been diagnosed as brain damaged and reported as such in the literature. Thus, they may have contributed to the formation of the concept of the "chronic painters' syndrome" with dementia.