Is phenytoin contraindicated in patients receiving cranial irradiation ?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.     

White matter lesions,quantitative magnetic resonance imaging,and dementia

The authors performed quantitative and qualitative image analysis on a sample of the elderly population of Cache County, Utah, relating neuroimaging findings to Mini-Mental Status Examination (MMSE) scores and the presence of the apolipoprotein E epsilon4 allele. Neuroimaging measures included white, gray, and hippocampal volumes; a ventricle-to-brain ratio (VBR); and qualitative ratings of white matter lesions (WMLs) in the periventricular (PV) and centrum semiovale (CS) regions. Subjects included 85 persons with possible and probable Alzheimer disease (AD), 21 with vascular dementia (VaD), 30 with cognitive symptoms classified as mild/ambiguous (M/A), a heterogenous group of 39 non-AD or VaD subjects but diagnosed with some form of neuropsychiatric disorder ("Mixed Neuropsychiatric" group), and 20 normal control subjects aged 65 years or older. Controlling for age, sex, and length of disease, the authors found that AD and VaD subjects differed significantly from control subjects on WMLs, but only the VaD subjects significantly differed from M/A subjects. The two dementia groups also displayed, as expected, significant cerebral atrophy. The WMLs generally increased with age and severity of dementia. PV WMLs were significantly but only modestly associated with white matter volume loss and greater impairment on the MMSE. Modest correlations were also present between the quantitative measures of cerebral structure and MMSE performance. However, when degree of cerebral atrophy was controlled by using the VBR measure, WML effects on MMSE performance became nonsignificant, with the only significant relationship remaining being that between hippocampal volume and MMSE performance. There were no significant qualitative or quantitative findings related to presence of the epsilon4 allele and MMSE performance. The role of WMLs in aging and dementia is discussed.     

Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study

BACKGROUND: Previous analyses from the Cache County (UT) Study showed inverse associations between the prevalence of AD and the use of nonsteroidal anti-inflammatory drugs (NSAID), aspirin compounds, or histamine H(2) receptor antagonists (H(2)RA). The authors re-examined these associations using data on incident AD. METHODS: In 1995 to 1996, elderly (aged 65+) county residents were assessed for dementia, with current and former use of NSAID, aspirin, and H(2)RA as well as three other "control" medication classes also noted. Three years later, interval medication histories were obtained and 104 participants with incident AD were identified among 3,227 living participants. Discrete time survival analyses estimated the risk of incident AD in relation to medication use. RESULTS: AD incidence was marginally reduced in those reporting NSAID use at any time. Increased duration of use was associated with greater risk reduction, and the estimated hazard ratio was 0.45 with >/=2 years of exposure. Users of NSAID at baseline showed little reduction in AD incidence, regardless of use thereafter. By contrast, former NSAID users showed substantially reduced incidence (estimated hazard ratio = 0.42), with a trend toward greatest risk reduction among those with extended exposure. Similar patterns appeared with aspirin but not with any other medicines examined. CONCLUSIONS: Long-term NSAID use may reduce the risk of AD, provided such use occurs well before the onset of dementia. More recent exposure seems to offer little protection. Recently initiated randomized trials of NSAID for primary prevention of AD are therefore unlikely to show effects with treatment until participants have been followed for several years.     

Cytogenetic and molecular genetic analysis of tumorigenic human bronchial epithelial cells induced by radon alpha particles

To establish a cell culture model for lung carcinogenesis, independent populations of the human papillomavirus 18-immortalized human bronchial epithelial cell line BEP2D were treated with high linear energy transfer radon-simulated alpha-particles, expanded and xenotransplanted into Nu/Nu mice. Six independent cell lines were established from tumors that developed from three separate radiation treatments as follows: treatment (Tx) 1 (30 cGy--two doses), H2BT, Tx 2 (30 cGy-- single dose), R30T1L, R30T2 and R30T3L, Tx 3 (30 cGy--single dose), H1ATN and H1ATBA1. Cytogenetic analysis revealed common changes in all tumor lines: loss of the Y chromosome (ch), one of three copies of ch8, one of three copies of ch14, and one of two copies of ch4p16-pter and ch11p15-pter. Analysis of polymerase chain reaction-amplified short tandem repeats of informative loci confirmed the loss of chY in all lines and loss of heterozygosity (LOH) at eight loci spanning the length of ch8 in all lines from Tx's 1 and 2. Our data support previous studies indicating the presence of tumor suppressor genes on ch8. LOH also was confirmed on ch14 at locus D14S306 in all cell lines from Tx 2 and in one of two lines from Tx 3. This region, 14q12-q13, may contain changes in one of the five known somatostatin receptor genes (SSTR1). No LOH was detected at any of the informative loci tested for on ch4 or ch11.      

Mycobacterial infection in an inner city children's hospital

Childhood tuberculosis is perceived by many as a disease of the past. Experience in a children's hospital serving a deprived population suggested that tuberculosis and other mycobacterial infections were not declining in clinical practice. Fifty three tuberculous and 11 atypical mycobacterial infections were identified between 1978 and 1992. There was no decline in tuberculosis and nine of the 11 atypical infections occurred in the last five years. Altogether 40% of cases of tuberculosis were in non-Asian children; 32% had arrived in the UK or visited family overseas in the previous year; and 38% had a history of tuberculosis contact, usually a close adult relative. Nationally, the previous decline in tuberculosis in all ages has reversed. In the local health districts in London's east end, childhood tuberculosis has also stopped declining and seems to be increasing. It is regrettable that BCG vaccination has been abolished by some districts in the UK, against current recommendations. Childhood tuberculosis is still common in the practice described here, including among children who do not fall into conventionally recognised high risk groups. Inner city dwellers and junior doctors are both highly mobile populations, adding to the risk that paediatricians, particularly those in training, may encounter tuberculosis with little or no previous experience of the condition.     

MR imaging of blood vessels using three-dimensional reconstruction: methodology

Multisection, dual-echo magnetic resonance (MR) transaxial images of blood vessels contain both anatomic and qualitative information about flow. Even so, the images are produced as a series of two-dimensional tomographic sections from which full visualization of connected structures is difficult. A computer algorithm was developed that automatically detects flowing blood based on pixel intensity and calculated T2 and provides reconstructed views of vessels while analyzing and displaying flow characteristics. Images of abdominal vessels, aortic aneurysms, and the heart were encoded by flow and color to demonstrate depth. In addition, these data were reconstructed to derive a more accurate assessment of patency. With this technique, transaxial images can be used to analyze flow patterns, determine patent areas, and visualize all levels of vessels in a single image.     

Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study

BACKGROUND: The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. OBJECTIVES: To estimate the occurrence of AD as a function of age and number of APOE epsilon4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. DESIGN: Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. SETTING AND PARTICIPANTS: A total of 3308 elderly residents of Cache County, Utah. MAIN OUTCOME MEASURES: Cumulative incidence of AD; in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. RESULTS: Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, especially, 2 APOE, epsilon4 alleles but observed no meaningful difference in 100-year lifetime incidence related to number of epsilon4 alleles. CONCLUSIONS: The APOE epsilon4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE.Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.