William T. Cave

Dietary n-3 (omega-3) polyunsaturated fatty acid effects on animal tumorigenesis.

Environmental variables influence the incidence and expression of disease. Dietary fat is one environmental variable that has been associated experimentally and epidemiologically with alterations in certain types of tumorigenesis. Recently, detailed biochemical analyses have shown that not all fatty acid families possess the same tumor‐promoting potential. In general, diets containing high levels of the n‐6 polyunsaturated fatty acids have routinely enhanced tumorigenesis in lipid sensitive carcinogen‐induced and tumor transplant tumor models, whereas diets with equivalent levels of n‐3 polyunsaturated fatty acids have diminished tumorigenesis. At present, there is no definitive biochemical mechanism that fully explains these observations, but several possibilities have been proposed. One of the most attractive of these hypotheses is that each polyunsaturated fatty acid family has an individual effect on eicosanoid metabolism which determines its tumor‐promoting potential. Regardless of current uncertainties about mechanisms of action, however, results of numerous animal models affirm the importance of qualitative, as well as quantitative, dietary lipid differences on tumorigenesis. This knowledge strengthens the probability that further advances in our understanding of lipid‐tumor interrelationships will have important preventive and therapeutic medical benefits.—Cave, W. T., Jr. Dietary n‐3 (ω‐3) polyunsaturated fatty acid effects on animal tumorigenesis. FASEB J. 5: 2160–2166; 1991.

Echocardiographic characterization of the reversible cardiomyopathy of hypothyroidism

Nineteen patients with untreated hypothyroidism were evaluated by M-mode echocardiography. Asymmetric septal hypertrophy (ASH), defined as a ratio of interventricular septal thickness to left ventricular posterior wall thickness (IVS/LVPW) equal to or greater than 1.3, was identified in 17 cases. Additional abnormalities recognized by echocardiography included reduced amplitude of systolic septal excursion (SSex) [13 patients], reduced per cent of systolic septal thickening (%SST)[19 patients], reduced left ventricular outflow tract dimension (LVOT)[five patients] and systolic anterior motion of the mitral valve (SAM)[five patients]. These findings are similar to some of the echocardiographic features of idiopathic hypertrophic subaortic stenosis (IHSS). In 10 patients who returned to euthyroid state with L-thyroxine therapy, these abnormalities resolved. We conclude that long-standing hypothyroidism leads to a reversible cardiomyopathy, manifested by asymmetric septal hypertrophy with or without other echocardiographic features of a hypertrophic obstructive cardiomyopathy. This previously unrecognized features of hypothyroidism has important diagnostic and therapeutic implications.

Choriocarcinoma with hyperthyroidism: probable identity of the thyrotropin with human chorionic gonadotropin.

A 15-year-old girl developed severe hyperthyroidism secondary to metastatic choriocarcinoma. Her serum contained high levels of human chorionic gonadotropin (HCG) by radioimmunoassay and had a thyroid-stimulating activity different from that of pituitary thyrotropin (TSH) or of long-acting thyroid stimulator (LATS) in the McKenzie mouse bio-assay. Gradient ultracentrifugation localized this thyroid stimulator to a narrow zone midway between markers of transferrin and ovalbumin. On gel filtration it emerged just before albumin as a single peak coinciding with the peak for HCG. Her HCG was identical to an authentic sample of HCG in position to gel filtration columns and on gel electrophoresis. These results suggest that the thyrotropin of choriocarcinoma is HCG.

Omega-3 polyunsaturated fatty acids in rodent models of breast cancer

Quantitative increases in certain dietary fats promote mammary tumor growth, but the experimental data indicate that this tumor promoting capability is not equally expressed by all fatty acid families. There is a large body of evidence from experiments using either carcinogen-induced or transplanted animal mammary tumor models, as well as in vitro studies, which demonstrates that the omega-6 polyunsaturated fatty acids (PUFA) promote mammary tumor development more effectively than omega-3 PUFA. These data indicate that increases in the dietary levels of omega-6 PUFA enhance tumor development, while equivalent increases in dietary levels of omega-3 PUFA often delay or reduce tumor development. Several theoretical mechanisms have been proposed for these contrasting results, but as yet, no definitive explanation has been universally accepted.

Dietary ω-3 polyunsaturated fats and breast cancer

Abstract Although early experimental investigations concluded that quantitative increases in dietary fat promote mammary tumor growth, recent studies have indicated that not all fatty acid families equally express this tumor-promoting capability. This article provides an overview of some of the experimental evidence demonstrating that the ω-6 polyunsaturated fats have significantly different mammary tumor-promoting capabilities from those of the ω-3 polyunsaturated fats. Collectively, these data indicate that whereas increasing dietary levels of ω-6 polyunsaturated fatty acids enhances tumor development, equivalent increases in dietary levels of ω-3 polyunsaturated fatty acids delay or reduce tumor development. Some of the theoretical mechanisms proposed for these contrasting results and their supporting experimental data are discussed.

Dietary fish lipids do not diminish platelet adhesion to subendothelium

Clinical trials suggest that dietary fish lipids offer protection against pathologic thrombosis. Measurements of platelet aggregation and bleeding time indicate that these protective effects are mediated in part through alterations of platelet function. We studied the effects of supplementary fish lipids (MaxEPA) on platelet adhesion to arterial subendothelium utilizing a modified Baumgartner flow chamber. Template bleeding times were also performed, and platelet lipid composition was determined by gas chromatographic analysis. The results showed that platelet lipid composition was altered significantly during the study. However, total platelet adhesion to arterial subendothelium was not changed by ingestion of fish lipids during the study period. Bleeding times showed some prolongation in most subjects (range: ‐1.0 to +6.75 min), with a mean change of +0.75 min. We conclude that, in individuals maintained on ad libitum diets, the supplemental amount of fish oil used in this study was enough to induce a significant alteration in platelet lipid composition, but these changes were unaccompanied by any impairment in the ability of platelets to adhere to subendothelium in our model system.

Hypercalcemia in Two Patients With Sarcoidosis and Mycobacterium avium intracellulare Not Mediated by Elevated Vitamin D Metabolites

Introduction:To describe 2 unusual cases of hypercalcemia due to granulomatous diseases with normal vitamin D metabolites and no other ready explanation for the hypercalcemia. Methods:We present the clinical, laboratory and pathologic findings of 2 patients with hypercalcemia and review previous reports of hypercalcemia in granulomatous diseases without elevated vitamin D metabolites. Results:Hypercalcemia was described in various granulomatous diseases including sarcoidosis, tuberculosis, berylliosis, leprosy and, rarely, in fungal infections. Elevated serum level of vitamin D or its metabolites was linked to the pathogenesis of hypercalcemia in these disorders. The authors present the clinical, laboratory and pathologic findings in 2 patients who presented with hypercalcemia and normal vitamin D metabolites with no other ready explanation for the hypercalcemia. The first patient was diagnosed with Mycobacterium avium, whereas the second patient was found to have sarcoidosis. Conclusion:Although hypercalcemia in granulomatous diseases has been attributed to be mediated by elevated vitamin D metabolites, there have been several case reports that documented normal values of active vitamin D metabolites. This report illustrates the regulatory feedback mechanisms of vitamin D synthesis and introduces the term “inappropriately normal” vitamin D metabolites levels in light of low levels of parathyroid hormone.

A comparative study between individuals receiving thymic irradiation in infancy and their nontreated siblings: clinical and laboratory thyroid abnormalities

While impairment of thyroid function has been demonstrated for high-dose external radiation (e.g., for Hodgkins disease), the long-term functional effects of low-dose external radiation have not been fully explored. One hundred fifty-three subjects with a past history of thymic irradiation during infancy were stratified into three dose levels and compared with 51 nonirradiated subjects from a sibling cohort with respect to previously undiagnosed clinical and laboratory thyroidal abnormalities. There was no apparent association between previous thymic irradiation and mean serum levels of T4, free T4, TSH, or antithyroid antibodies, nor was the prevalence of undetected hypothyroidism or hyperthyroidism significantly altered in the irradiated group. Serum thyroglobulin levels were elevated in subjects with palpable thyroid nodules, all of which occurred in thymic-irradiated subjects. Thus persons who have received low-level external thymic irradiation in infancy should continue to have periodic thyroid examinations, but routine serial measurement of other serum thyroidal parameters does not appear to be indicated.