Evidence for the genetic control of estradiol-regulated responses. Implications for variation in normal and pathological hormone-dependent phenotypes

The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.     

Movement-related potential measures of different modes of movement selection in Parkinson's disease

Movement-related potentials were recorded preceding self-paced voluntary movements in patients with Parkinson's disease and in healthy subjects of the same age group. We compared the Readiness Potential preceding joystick movements in a fixed direction and preceding joystick movements in freely selected directions. In normal subjects the Readiness Potential amplitude was higher preceding freely selected movements than preceding movements in a fixed direction. The Readiness Potential in Parkinson patients failed to be modified by the different modes of movement selection. The modulation of the Readiness Potential by different ways of preparing for movement might be due to the supplementary motor area (SMA) being more strongly engaged by tasks requiring internal control of movements than by tasks that are externally structured. The results suggest that this task-dependent variation of SMA activity is reduced in Parkinson's disease. A failing capacity to adapt SMA activity to different task demands has previously been suggested by evidence from positron emission tomography studies using similar tasks.     

Addition of the MSA1 signal and anchor sequences to the malaria merozoite surface antigen 1 C-terminal region enhances immunogenicity when expressed by recombinant vaccinia virus

Genes encoding four different C-terminal fragments of a Plasmodium falciparum merozoite surface antigen were generated: MSA1C-(Si,A), containing signal and anchor regions of MSA1; MSA1C-(Si,nA), containing the signal but not the anchor; MSA1C-(nSi,A), containing the anchor but not the signal, and MSA1C-(nSi,nA) containing neither the signal nor the anchor region. Each gene was inserted into the thymidine kinase region of vaccinia virus, under the control of a synthetic strong early/ late promoter. When the plasmodial genes were expressed in cells infected by the recombinant vaccinia virus, the two proteins containing the signal region were transported to the surface of infected cells. Infection of mice and rabbits with the latter recombinant viruses stimulated C-terminal-specific antibody levels that were 10-80-fold higher than those induced by the two recombinant viruses without the signal region. The combination of the signal and anchor regions with the C-terminal MSA1 protein also generated the most effective neutralization in a P. falciparum invasion assay.     

Genotoxicity and cytotoxicity in male B6C3F1 mice following exposure to mixtures of 1,3-butadiene and styrene

1,3-Butadiene and styrene are oxidized, in part, by cytochrome P450 2E1 and have been shown to metabolically interact in rodents exposed by inhalation to mixtures of both compounds. Because the reactive metabolites of butadiene and styrene are thought to be responsible for the toxicity of each compound, metabolic interactions may alter the response in animals exposed to mixtures of butadiene and styrene compared with the response in animals exposed to butadiene alone or styrene alone. The purpose of this study was to quantitate alterations in genotoxicity and cytotoxicity in male B6C3F1 mice exposed to mixtures of butadiene and styrene. Male B6C3F1 mice were exposed to 6.25, 62.5, 200, or 625 ppm butadiene alone, 50 ppm styrene alone, or mixtures of 6.25, 62.5, 200, or 625 ppm butadiene and 50 ppm styrene. Genotoxicity was assessed by quantitating the frequency of micronucleated polychromatic erythrocytes in bone marrow. Cytotoxicity was assessed by counting total spleen and thymus cells and by quantitating the frequency of polychromatic erythrocytes in the peripheral blood. Butadiene and mixtures of butadiene and styrene were genotoxic in mice, as shown by a significant increase in the frequency of micronucleated polychromatic erythrocytes. The increased frequency following exposure to mixtures of butadiene and styrene was not significantly different compared with the frequency following exposure to butadiene alone. Styrene and mixtures of butadiene and styrene were cytotoxic in mice, as shown by significantly decreased number of spleen cells. Exposure to mixtures of butadiene and styrene with butadiene concentrations of 62.5 or 625 ppm significantly reduced the number of thymus cells. Exposure to 200 ppm or 625 ppm butadiene alone, or to mixtures of 200 ppm or 625 ppm butadiene and 50 ppm styrene, significantly reduced the frequency of polychromatic erythrocytes in the peripheral blood. The results of the study demonstrate that exposure to mixture of butadiene and styrene does not reduce the respective genotoxicity of butadiene or cytotoxicity of styrene.     

Results of bone scintigraphy in horses used for show jumping, hunting, or eventing: 141 cases (1988-1994)

OBJECTIVE: To determine anatomic patterns and clinical importance of increased radiopharmaceutical uptake in bones of horses used for show jumping, hunting, and eventing. DESIGN: Retrospective study. ANIMALS: 141 horses evaluated because of lameness. PROCEDURE: Medical records were reviewed, and information on results of physical examination, radiography, and scintigraphy were obtained. Scintigrams were evaluated to identify areas of increased radio-pharmaceutical uptake. RESULTS: 834 areas of increased radiopharmaceutical uptake were identified. Scintigraphy of the vertebral column was performed in 78 horses, and 50 had areas of increased radiopharmaceutical uptake involving the spinous processes. Scintigraphy of the proximal phalanx of the forelimb was performed in 88 horses. Similarly, scintigraphy of the proximal phalanx of the hind limb was performed in 99 horses, and scintigrams of 374 proximal phalanges were available for review. One hundred fifty-five scintigrams had areas of increased radiopharmaceutical uptake. Scintigraphy of the tarsal joint was performed in 99 horses, and scintigrams of 198 joints were available for review. Eighty-five had areas of increased radiopharmaceutical uptake. Overall, 214 of 834 areas of increased radiopharmaceutical uptake were definitively associated with lameness. CLINICAL IMPLICATIONS: Results of this study suggest that jumping creates unique stresses on the bones of horses. The distinctive patterns of increased radiopharmaceutical uptake identified in this study suggest that horses used for jumping may have a predilection to develop orthopedic disease at specific sites distinct from those in racehorses.     

Patient satisfaction and symptom relief after anal dilatation

Anal dilatation is used as a simple method of treatment and has been used for both anal fissure and haemorrhoids. This study examined longer-term results among a cohort of 162 patients, 132 of whom responded to a detailed questionnaire, an 82% response (66 patients were male; age range 17-75 years, median 42 years). Follow-up ranged from 16 months to 36 months (median 27 months) after anal dilatation (68 patients for fissure, 32 for haemorrhoids, and 32 for both). In the early months after dilatation, 83% had symptomatic improvement and 76% remained improved. Five (7%) patients with fissure and 11 with haemorrhoids (17%) required further hospital treatment, while 10% and 17%, respectively, had received further treatment from their general practitioners (GPs). Seventy-one percent said they would have a further anal dilation if symptoms recurred. There was no difference in results obtained by surgeons of different seniority. Complications--bleeding (29%) and difficulty controlling flatus (15%) or faeces (8%)--resolved in all cases. The results of anal dilatation for fissure are generally satisfactory in the longer term, with a trend toward better symptom relief in patients with fissure compared with those with haemorrhoids. We do not recommend anal dilatation as the sole treatment of patients with haemorrhoids, but it may be a useful adjunct to other treatments such as banding or sclerotherapy. Morbidity was generally acceptable and the majority of our patients would be prepared to have this procedure again if their symptoms were to return.