A comparison of the effects of parental risk markers on pre- and perinatal variables in multiple patient cohorts with fetal alcohol syndrome, autism, Tourette syndrome, and sudden infant death syndrome: an enviromic analysis

The prevalence and magnitude of effect of individual risk markers for specific developmental disorders vary widely across diagnostic category. The four study cohorts for this project were patients from four diagnostic registries in North Dakota for fetal alcohol syndrome (FAS), autism, sudden infant death syndrome (SIDS), and Tourette syndrome. These four cohorts were used to estimate prevalence and magnitude of effect of parental risk markers in patients with developmental disabilities. Cases with North Dakota birth certificates were matched with controls. Using birth certificate data, we then examined five parental risk markers for each cohort and estimated direct and indirect effects for each risk marker by cohort. The authors found two significant paternal risk markers (age in SIDS and education in FAS). Significant maternal markers were age in SIDS, education in FAS, autism, and SIDS. Marital status was a significant risk marker in FAS. Effect sizes were estimated using paired t tests, odds ratios, and population attributable risk (PAR) for both direct and indirect effects for each marker. We estimated both direct and indirect effects to allow for direct comparisons of the differential effect estimates of each of these markers. The direct effect of parental markers differs across diagnostic cohorts of patients. Use of cohorts from similar denominator populations obtained from prevalence studies is a useful methodological tool for estimating the prevalence and magnitude of effect of risk markers.     

Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids

PURPOSE: To report two cases of progressive outer retinal necrosis occurring in immunocompetent individuals after treatment with corticosteroids for presumed optic neuropathy. DESIGN: Observational case report. SETTING: University-based tertiary eye hospital. METHODS: Retrospective review of existing clinical records. RESULTS: Two patients were treated empirically with systemic corticosteroids for suspected inflammatory papillopathy. Subsequently, both were diagnosed with necrotizing herpetic retinitis with features of progressive outer retinal necrosis. Anterior chamber paracentesis confirmed varicella-zoster infection. Both patients were human immunodeficiency virus negative; one patient with rheumatoid arthritis was taking etanercept. Both became completely blind in one eye despite intensive treatment with antiviral medication intravenously and intravitreally. CONCLUSIONS: Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. Initial treatment of acute, unexplained vision loss with systemic corticosteroids may lead to catastrophic visual loss in patients with evolving necrotizing herpetic retinopathy.     

Involvement of glutamate in ischemic neurodegeneration in isolated retina

Retinal ischemia, a major cause of visual loss, is believed to result from overexcitation of glutamate receptors. However, under euglycemic and normoxic conditions, exogenously applied glutamate is not neurotoxic in the retina. Under such conditions, exogenous glutamate typically causes glia swelling and requires very high concentrations to produce neurotoxicity. To determine whether ischemic conditions enhance the neurotoxicity of endogenous and exogenous glutamate, we examined the effects of simulated ischemia (deprivation of both glucose and oxygen) on retinal morphology and lactate dehydrogenase (LDH) release. In an ex vivo rat retinal preparation, glutamate was administered during simulated ischemia in the presence of riluzole, an inhibitor of glutamate release. Deprivation of both glucose and oxygen for 60 min at 30 degrees C produced severe acute neurodegeneration. This neurodegeneration, characterized by bull's eye formation in the inner nuclear layer and spongy appearance in the inner plexiform layer, was prevented by the combination of MK-801 and DNQX, antagonists of N-methyl-D-aspartate (NMDA) and non-NMDA receptors, indicating that the damage results from activation of both glutamate receptors. We also found that administration of glutamate pyruvate transaminase (alanine aminotransaminase) with pyruvate diminished the neurodegeneration during simulated ischemia. Furthermore, riluzole, an inhibitor of glutamate release, attenuated the neurodegeneration, suggesting the importance of endogenous glutamate in ischemic damage. In the presence of riluzole and simulated ischemia, exogenously applied glutamate failed to cause Müller cell swelling but was extremely neurotoxic. These results suggest that simulated ischemia enhances glutamate-mediated neurotoxicity in part by depressing glutamate uptake. When glutamate transport is impaired, sub-millimolar glutamate concentrations become profoundly neurotoxic.     

Transmission electron microscopy of intracellular particles of polyethylene from joint replacement prostheses: size distribution and cellular response

The objectives of this transmission electron microscopy study of peri-implant tissues retrieved at revision arthroplasty were to (1) determine the size distribution of intracellular polyethylene particles, and (2) assess the cellular response to phagocytosed polyethylene particles as revealed by the condition of the cellular organelles. The frequency distributions of intracellular polyethylene particle sizes for 15 cases of total hip replacement showed that more than 75% of the particles had lengths of less than 0.5 microm. More than 90% of the particles were less than 1.0 microm in size. In comparison, the frequency distribution for the particles in cellscomprising tissue retrieved from three total knee replacement prostheses showed that only 43% of the particles were less than 0.5 microm in length and 72% were less than 1 microm in size. There was no statistically significant difference in the mean particle length between the specimens from the hip and knee patients. The majority of the cells containing polyethylene were without signs of degeneration. The cytoplasmic and nuclear membranes were intact. Several electron lucent voids which once contained polyethylene particles were seen surrounded by several healthy appearing mitochondria, which displayed sharp membranes and intact cristae. There were no signs of a cytotoxic response to polyethylene at the ultrastructural level.     

Repeated rating improves value of diagnostic dopaminergic challenge tests in Parkinson's disease

Summary. Clinicians use acute challenges with levodopa (LD) and/or apomorphine (A) for diagnostic dopaminergic response tests in Parkinson's disease (PD) patients. We consecutively compared the value of both drugs with performance of repeated ratings and adverse effect recording. Oral administration of 200 mg LD was superior to subcutaneous injection of 4 mg A in terms of tolerability and onset of temporary UPDRS motor score decline ([previously untreated PD patients] LD: 4.02 [mean] ± 2.45 [SD] {significant decrease: p = 1.42E-07} vs. A: 1.58 ± 3.38 {not significant decrease: p = 0.14}, p = 0.0009; [treated PD patients] LD: 7.71 ± 4.35 {significant decrease: p = 2.48E-06} vs. A: 5.19 ± 4.32 {significant decrease: p = 7.83E-05}, p = 0.07). We suggest diagnostic acute challenge test performance with LD as first- and A as second choice due to better tolerability and valuation in combination with repeated scoring procedures to improve sensitivity and specifity. Received December 12, 2002; accepted January 20, 2003 Published online April 7, 2003 Authors' address: Prof. Dr. Th. Müller, Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany, e-mail: thomas.mueller@ruhr-uni-bochum.de     

Use of antibacterial agents in renal failure

This article reviews the pharmacokinetics of antibacterial agents in patients with normal and decreased renal function. The concepts of volume and distribution, rate of elimination, loading and maintenance doses, and therapeutic drug monitoring are delineated. Special reference is made to the intermittent dosing of cefazolin with hemodialysis. Newer, as well as traditional methods of extracorporeal circulation and the resultant changes in antibacterial agent pharmacodynamics are discussed.     

Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumour cell proliferation

Overexpression of the HER2 (neu/c-erbB-2) oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. Expression and secretion of aberrant HER2 splice variants has been reported in various cell lines and tissues and can interfere with the oncogenic HER2 activity. Here we demonstrate, using two different approaches, that expression of a truncated 100 kDa HER2 variant which encodes the extracellular domain of HER2 (HER-ECD) inhibits growth factor-mediated tumour cell proliferation. A HER2-ECD cDNA encoding the truncated variant was overexpressed in MCF7 breast cancer cells. HER2-ECD overexpression decreased spontaneous proliferation of MCF7 cells as well as heregulin-mediated soft agar colony formation. Concomitantly, heregulin-induced phosphorylation of HER4 as well as downstream activation of p44/p42 MAP-kinases was decreased. To confirm these data, ribozymes were targeted to the 3'-untranslated region of the 2.3 kb HER2-ECD mRNA which is spontaneously expressed in MKN7 gastric cancer cells. HER2-ECD-targeted ribozymes downregulated HER2-ECD expression and enhanced EGF-mediated soft agar colony formation of MKN7 cells. In parallel, EGF-induced activation of p44/p42 MAP-kinases and activation of c-Fos expression were increased in ribozyme-transfected MKN7 cells. Finally, in RT-PCR we found a trend towards a progressive loss of 2.3 kb HER2-ECD mRNA expression in more advanced gastric tumours. These data show that the HER2-ECD variant inhibits growth factor-mediated tumour cell proliferation suggesting an important role during the progression of human cancer.     

An epidemic of occupational contact dermatitis from an immersion oil for microscopy in laboratory personnel

Since November 1997, 14 successive cases of occupational contact dermatitis were observed in 13 laboratory technicians and 1 physician, working in a genetics laboratory in Leuven (Belgium) in 3 laboratories of bacteriology in Strasbourg, Montbeliard and Angers, and in the laboratory of hematology in Bordeaux (France). The dermatitis, located on the hands, forearms and face, relapsed after each exposure to an immersion oil for microscopy. Patch tests performed in 10 patients were positive to epoxy resin (ER) in the European standard series (10/10 patients) and to newly formulated Leica immersion oil (7/7), 1 patient testing negatively with the former oil. A breakdown performed in 2 patients with the oil's ingredients confirmed sensitization to liquid modified ER components, contained at >80% concentration in the oil. The presence of DGEBA was demonstrated by HPLC analysis at a +/-30% rate. Although the safety data sheet indicated a revision of the formula, nobody was alerted to the risk of sensitization and the need for skin protection. ERs, as a source of occupational allergy, can provoke epidemics of contact dermatitis in industry. This report of epidemic contact dermatitis from ERs, used for their optical properties in an immersion oil for microscopy, emphasizes the need for perpetual vigilance in occupational medicine and the usefulness of multicentre contacts in dermato-allergology.