Chronic wasting disease (CWD) of elk (Cervus elaphus nelsoni) and mule deer (Odocoileus hemionus) is one of three naturally occurring forms of prion disease, the others being Creutzfeldt-Jakob disease in humans and scrapie in sheep. In the last few decades, CWD has spread among captive and free-ranging cervids in 13 US states, two Canadian provinces and recently in Korea. The origin of the CWD agent(s) in cervids is not known. This study describes the development of a transgenic mouse line (TgElk) homozygous for a transgene array encoding the elk prion protein (PrP C ) and its use in propagating and simulating CWD in mice. Intracerebral injection of one mule deer and three elk CWD isolates into TgElk mice led to disease with incubation periods of 127 and 95 days, respectively. Upon secondary passage, the incubation time was reduced to 108 and 90 days, respectively. Upon passage into TgElk mice, CWD prions (PrP Sc ) maintained the characteristic Western blot profiles seen in CWD-affected mule deer and elk and produced histopathological modifications consistent with those observed in the natural disease. The short incubation time observed on passage from cervid to mouse with both mule deer and elk CWD brain homogenates and the demonstrated capacity of the animals to propagate (mouse to mouse) CWD agents make the TgElk line a valuable model to study CWD agents in cervid populations. In addition, these results with this new transgenic line suggest the intriguing hypothesis that there could be more than one strain of CWD agent in cervids.

The characteristic clinical heterogeneity of sickle cell anemia (HbSS) may be, in part, a result of its interactions with alpha-thalassemia. Although alpha-thalassemia clearly affects some hematologic features of HbSS, its role in modulating the vasoocclusive severity of disease is not clear. To further explore this relationship, we examined the incidence of painful episodes, acute chest syndrome, aseptic bone necrosis, and leg ulcers in 3 patient groups with sickle cell disease: (1) 2,147 patients over age 2 yr, stratified according to mean corpuscular volume (MCV); (2) 183 patients selected on the basis of microcytosis and elevated HbA2, on whom globin biosynthesis studies were done; and (3) 125 patients who had alpha-globin genotype assigned by restriction endonuclease gene mapping. When patients were stratified by MCV, there was a reciprocal relationship between HbA2 levels and MCV, reflecting the presence of patients with beta o and alpha- thalassemia in the low MCV groups. The erythrocyte indices and HbA2 levels in patients classified as HbSS-alpha-thalassemia, by either globin synthesis studies or gene mapping, were very similar to those previously reported by others. Neither microcytosis, beta o, or alpha- thalassemia appeared to provide any clear protection from the vasoocclusive complication evaluated, and the prevalence of aseptic necrosis was increased in patients with microcytosis over age 20 yr and in groups with alpha-thalassemia. The effects of a reduced MCV and mean corpuscular hemoglobin concentration (MCHC), of possible benefit by themselves, when accompanied by a reduction in hemolysis and rise in hemoglobin concentration, as in HbSS-alpha-thalassemia, may cause sufficient rise in blood viscosity in critical vascular beds to impair blood flow and negate any amelioration of vasoocclusive complications in HbSS.

In humans the a-globin genes are duplicated and closely linked. Whereas The number and arrangement of the human a-globin genes has been established by utilizing the techniques of molecular hybridization and restriction endonuclease analysis. In most populations the a loci are duplicated and closely linked on chromosome 16 (1-4), each diploid cell containing four a-globin genes. Deletion of variable numbers of a genes occurs in subjects from several racial groups (2, 5-7) and is associated with a decrease or absence of a-globin synthesis characteristic of the different a-thalassemia syndromes (8). In Chinese and Thai populations, the reduction in a-chain synthesis is generally proportional to the number of genes deleted; individuals with a-thalassemia 2 ("silent carrier"), a-thalassemia 1 (a-thalassemia trait), Hb (15); (ii) interaction with a-thalassemia determinants cis or trans to the variant locus (16); and (iii) heterogeneity in the number of a-globin genes that does not produce an imbalance in globin chain synthesis-i.e., variable gene dosage (9,17,18). Subjects synthesizing 31% or 55% Hb J Mexico appear to fit the first model because these individuals possess four a genes (15) Hb G Philadelphia (a68 Asn-Lys) is the most common a-chain variant and occurs in approximately 1 in 5000 American Blacks (21). Most studies indicate that Hb G heterozygotes synthesize either 33% or 50% of the abnormal chain (17,22), although there is a single report of individuals who synthesize approximately 20% Hb G (18). Genetic studies suggest that in most subjects the aG locus is the only functional a locus on the affected chromosome (16,22,23). Whether inheritance of the aG-bearing chromosome confers a-thalassemia has been the subject of debate. Rieder et al. (23) tTo whom reprint requests should be addressed.

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