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Mixed medullary-follicular carcinoma (MMFC) of thyroid is an extremely rare tumor, characterized by coexistence of morphological and immunohistochemical features of both medullary carcinoma and follicular (or papillary) carcinoma. We herein present fine needle aspiration (FNA) findings of a histology-confirmed MMFC along with a review of literature. The patient was a 64-year-old woman who had a history of Hashimoto's thyroiditis and presented with enlargement of preexisting right thyroid nodule. An US-guided FNA of the thyroid nodule was performed and conventional smears were prepared. A cytologic diagnosis of "positive for malignancy, consistent with medullary thyroid carcinoma (MTC)" was rendered based on the presence of features characteristic for MTC, and the absence of components of follicular neoplasm (adenoma and carcinoma) or papillary carcinoma. However, microscopic examination of the follow-up total thyroidectomy specimen with the aid of immunocytochemical study detected minor portion of follicular carcinoma in addition to MTC. A histologic diagnosis of MMFC was then established. While specific identification of MMFC by FNA may be difficult, it should be emphasized that adequate sampling in conjunction with the proper immunostaining panel could have highlighted the different aspects of the mixed tumor.

Low-density lipoprotein (LDL) oxidation is central to the pathogenesis of atherosclerosis. We have shown previously that the herbal mixtures Maharishi Amrit Kalash-4 (MAK-4) and Maharishi Amrit Kalash-5 (MAK-5) inhibit LDL oxidation induced by cupric ions (Cu+2) and endothelial cells in vitro and that MAK-4 reduces atherosclerosis in Watanabe heritable hyperlipidemic rabbits that were fed this herbal mixture. This study evaluates the antioxidant activity of MAK-4 and MAK-5 in vivo. Ten hyperlipidemic patients prescribed stable hypolipidemic therapy were treated with MAK-4 and MAK-5 for 18 weeks. Plasma lipoprotein, plasma lipid peroxide, and LDL oxidation studies were performed every 6 weeks. Apolipoprotein A, apolipoprotein B, and lipoprotein (a) levels were measured at baseline and 18 weeks. After 12 weeks of treatment with MAK-4 and MAK-5, a time-dependent increase in the lag phase and delay in the propagation phase of oxidation of LDL by Cu+2 and endothelial cells was seen. Lag phases at baseline and after 6, 12, and 18 weeks of MAK-4 and MAK-5 ingestion were 6.66 hours +/- 0.19 (mean +/- standard error of mean), 6.77 hours +/- 0.31, 7.22 hours +/- 0.24, and 18.00 hours +/- 0.73, respectively, for Cu(+2)-catalyzed LDL oxidation. Lag phases were 14.89 hours +/- 0.77, 13.33 hours +/- 0.50, 20.22 hours +/- 0.76, and 20.00 hours +/- 0.79, respectively, for endothelial cell-induced LDL oxidation. The levels of plasma lipid peroxide did not change significantly. No significant changes were seen in the plasma lipoproteins and the levels of apolipoprotein A, apolipoprotein B, and lipoprotein (a). The results show that MAK-4 and MAK-5 inhibit LDL oxidation in patients with hyperlipidemia. Therefore, MAK-4 and MAK-5 may be useful in the prevention and treatment of atherosclerosis.

Hypothyroidism is frequently associated with hypercholesterolemia and an increased risk for atherosclerosis, whereas hyperthyroidism is known to precipitate angina or myocardial infarction in patients with underlying coronary heart disease. We have shown previously that l-T4 functions as an antioxidant in vitro and inhibits low density lipoprotein (LDL) oxidation in a dose-dependent fashion. The present study was designed to evaluate the changes in LDL oxidation in subjects with hypothyroidism and hyperthyroidism. Fasting blood samples for LDL oxidation analyses, lipoprotein determinations, and thyroid function tests were collected at baseline and after the patients were rendered euthyroid. The lag phase (mean ± sem hours) of the Cu+2-catalyzed LDL oxidation in the hypothyroid state and the subsequent euthyroid states were 4 ± 0.0.65 and 14 ± 0.68 h, respectively (P < 0.05). The lag phase during the hyperthyroid phase was 6 ± 0.55 h, and that during the euthyroid phase was 12 ± 0.66 h (P < 0.05). The total and LDL cholesterol levels were higher in hypothyroidism than in euthyroidism and were lower in hyperthyroidism than in the euthyroid state. We conclude that LDL has more susceptibility to oxidation in both the hypothyroid and hyperthyroid states. Thus, the enhanced LDL oxidation may play a role in the cardiac disease process in both hypothyroidism and hyperthyroidism.

We found significant increases in ALP and ALP isoform band 10 in the serum of patients with early insulin-dependent diabetes, rheumatoid arthritis, and in those with multiple sclerosis during periods of disease exacerbation as compared with healthy controls. The ALP isoforms were assayed by isoelectric focusing. Our data suggest that the increase in ALP and ALP-10 closely reflects the abnormal activation of T lymphocytes that is common in autoimmune diseases, and that the source of the ALP-10 is activated T lymphocytes. ALP-10 is a sensitive but nonspecific marker of an active autoimmune process and appears to have the ability to detect abnormal T-cell activation. ALP-10 may be a useful test in the screening for autoimmune disorders.

Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyroxine (T 4 ), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu 2+ -catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (μM) of each agent producing 50% inhibition in the formation of oxidized LDL ( ic 50 ) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, dl -T 4 ; 1.10, 1.40 and 1.50 for l -T 4 ; 1.13, 1.33 and 1.23 for d -T 4 ; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT 3 , T 3 , the optical antipodes of T 4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL ifprotein/6-hr incubation. The ic 50 , concentrations (μM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for d -T 4 ; 0.205 and 0.243 for l -T 4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the l -T 4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, l -T 4 . Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis.

The diagnosis of malignant mesothelioma in serosal effusions continues to be a major challenge because some of its cytomorphological features closely resemble adenocarcinomas. Immunohistochemistry is a valuable tool in the differentiation of epithelioid mesothelioma from metastatic adenocarcinomas. However, no single antibody has demonstrated absolute sensitivity or specificity. In this study, we evaluated the value of immunostaining pattern for podoplanin to differentiate mesothelioma from adenocarcinomas of various origins.Cell blocks from previously collected paraffin-embedded cell blocks of 86 effusions (18 mesothelioma, 35 reactive mesothelium, 9 breast adenocarcinoma, 14 ovarian adenocarcinoma, and 10 lung adenocarcinoma) were retrieved from the file of the Department of Pathology at University of Michigan and Lund University in Sweden and were used for the study. Slides prepared from the cell blocks were stained for podoplanin. The percentage of immunostained cells was recorded as follows: 1+ (5-25%), 2+ (26-50%), and 3+ (>50%). A stain result involving

In this study, we examined the effect of the Maharishi Ayur-Veda herbal mixtures (MAHMs) Maharishi Amrit Kalash-4 and -5 (M-4 and M-5), MA-631, and Maharishi Coffee Substitute (MCS) on low-density lipoprotein (LDL) oxidation and compared the potency of these mixtures to ascorbic acid, alpha-tocopherol, and probucol. LDL was incubated in 95% air and 5% CO2, with or without 3 microM Cu(+2), in the presence or absence of MAHMs, for 6 or 24 h. In a separate experiment, LDL was incubated as above except MAHMs were added at 0, 1.5, and 3.5 h after incubation started to assess their effect on initiation and propagation of LDL oxidation. Our results demonstrate that MAHMs caused concentration-dependent inhibition of LDL oxidation as assessed by thiobarbituric acid-reactive substances and electrophoretic mobility. The MAHM showed more antioxidant potency in preventing LDL oxidation than ascorbic acid, alpha-tocopherol, or probucol. Also, MAHMs inhibited both initiation and propagation of cupric ion-catalyzed LDL oxidation. These results suggest the importance of further research on these herbal mixtures in the investigation of atherosclerosis and free radical-induced injury.

Background: Recent guidelines for use of cardiac troponin to detect cardiac damage and for cardiovascular risk stratification have made increasingly sensitive troponin assays important. Troponin assays continue to be plagued by interferences caused by heterophilic antibodies (HAs). We evaluated the performance of a revised cardiac troponin I (cTnI) assay designed to have increased analytical sensitivity and to minimize the effect of HAs.Methods: The revised Dade Behring Dimension® cTnI assay was evaluated according to NCCLS EP5-A at five institutions. Plasma samples from 14 309 patients were assayed by the original Dimension cTnI assay. To identify samples that may have interfering HAs, samples with values >1.4 μg/L were reanalyzed on the Dade Behring Stratus® CS cTnI assay. Samples with possible interfering antibodies were also analyzed before and after selective absorbance studies on the revised Dade Behring Dimension cTnI assay.Results: The limit of quantification in the revised method was 0.1 μg/L with imprecision (CV) of 11–17% at 0.1 μg/L. Values correlated well with the Stratus CS cTnI method: revised = 1.06(original) + 0.01; r = 0.98, Sy|x = 0.25 μg/L). Falsely increased results consistent with myocardial infarction by the original Dimension cTnI assay and presumably attributable to HAs were identified in 0.17% of all patients with samples submitted for cTnI analysis. The revised Dimension cTnI assay eliminated the interference in 17 of 25 samples identified and greatly decreased the interference in the other 8.Conclusions: The revised Dimension cTnI method greatly minimizes the effect of interfering HAs. It also exhibits analytical performance characteristics consistent with recent guidelines for use of this assay to detect cardiac damage.

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that activates several signaling cascades. We determined the extent to which ceramide is a second messenger for TNF-α-induced signaling leading to cytoskeletal rearrangement in Rat2 fibroblasts. TNF-α, sphingomyelinase, or C2-ceramide induced tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin, and stress fiber formation. Ly 294002, a phosphatidylinositol 3-kinase (PI 3-K) inhibitor, or expression of dominant/negative Ras (N17) completely blocked C2-ceramide- and sphingomyelinase-induced tyrosine phosphorylation of FAK and paxillin and severely decreased stress fiber formation. The TNF-α effects were only partially inhibited. Dimethylsphingosine, a sphingosine kinase (SK) inhibitor, blocked stress fiber formation by TNF-α and C2-ceramide. TNF-α, sphingomyelinase, and C2-ceramide translocated Cdc42, Rac, and RhoA to membranes, and stimulated p21-activated protein kinase downstream of Ras-GTP, PI 3-K, and SK. Transfection with inactive RhoA inhibited the TNF-α- and C2-ceramide-induced stress fiber formation. Our results demonstrate that stimulation by TNF-α, which increases sphingomyelinase activity and ceramide formation, activates sphingosine kinase, Rho family GTPases, focal adhesion kinase, and paxillin. This novel pathway of ceramide signaling can account for ∼70% of TNF-α-induced stress fiber formation and cytoskeletal reorganization.

The present studies tested the hypothesis that some effects of tumor necrosis factor-alpha (TNF-alpha) are mediated by activation of sphingomyelinases and the production of ceramides. Differentiated 3T3-L1 adipocytes were incubated with short-chain ceramide analogs, (C2- and C6-ceramides: N-acetyl- and N-hexanoyl-sphingosines, respectively), and this treatment increased 2-deoxyglucose uptake in the absence of insulin progressively from 2-24 h. This effect was inhibited by blocking the activations of mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI 3-kinase), and ribosomal S6 kinase which mediated an increase in GLUT1 concentrations. Long-term increases in PI 3-kinase activity associated with insulin receptor substrate-1 (IRS-1) increased the proportion of GLUT1 and GLUT4 in plasma membranes. These events explain the increases in noninsulin-dependent glucose uptake and incorporation of this glucose into the fatty acid and glycerol moieties of triacylglycerol. The mechanisms by which TNF-alpha and ceramides increase PI 3-kinase activity were investigated further by using rat2 fibroblasts. Incubation for 20 min with TNF-alpha, bacterial sphingomyelinase, or C2-ceramides increased PI 3-kinase activity by about fivefold, and this effect depended upon a stimulation of tyrosine kinase activity and an increase in Ras-GTP. This demonstrates the existence of a novel signaling pathway for TNF-alpha that could contribute to the effects of this cytokine in stimulating basal glucose uptake. By contrast, treating the 3T3-L1 adipocytes for 2-24 h with C2-ceramide diminished insulin-stimulated glucose uptake by decreasing the insulin-induced translocation of GLUT1 and GLUT4 to plasma membranes. This inhibition was observed when there was no increase in basal glucose uptake, and it occurred downstream of PI 3-kinase. Our work provides further mechanisms whereby TNF-alpha and ceramides produce insulin resistance and decrease the effectiveness of insulin in stimulating glucose disposal from the blood. Conversely, TNF-alpha and ceramides increase the ability of adipocytes to take up glucose and store triacylglycerol in the absence of insulin.

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The autonomic nervous system plays a major role in metabolism regulation by modulating metabolic pathways directly or indirectly via control of hormone (particularly insulin) secretion in various organs and tissues. In addition, the system modulates the proliferation and differentiation of some cell types. This activity is directly controlled by certain brain areas, particularly those located in the hypothalamus. A feedback loop signals metabolic changes at the periphery to these brain areas. This review focuses on the role of the autonomic nervous system in the activity and plasticity of pancreas and adipose tissues under normal conditions or in obesity, with special attention to the importance of alterations in these functions.

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Oxidized low-density lipoprotein (ox-LDL) plays an important role in atherogenesis. Atheroma formation is reduced significantly in Watanabe heritable hyperlipidemic (WHHL) rabbits by antioxidants such as probucol and vitamin E. The herbal mixture Maharishi Amrit Kalash-4 (MAK-4) inhibits Cu+2 -induced LDL oxidation, and enzymatic- and nonenzymatic-induced microsomal lipid peroxidation. We tested the effect of MAK-4 on the development of atheroma in WHHL rabbits. Eleven rabbits were divided into two groups: controls (n = 5) and a group fed 6% (w/w) MAK-4 (n = 6). Blood was drawn for biochemical analysis every two months and at necropsy, six months after the special diet was started. The aortas were preserved in formalin. The percentage area of aortic arch covered with visible plaque in the MAK-4 group (22.5 +/- 4.2%, mean +/- SE) was significantly reduced (p0.01) compared to the control group (47.6 +/- 6.8%, mean +/- SE). The MAK-4 group showed a significant decrease (p0.05) in lipid peroxide, and a significant increase (p0.05) in glutathione peroxidase and resistance of LDL to endothelial cell-induced and cupric ion-catalyzed oxidation (4.5 h and 5 h lag phase, respectively, for the MAK-4 group; 0 h lag phase for both for the controls). These findings suggest MAK-4 reduces atheroma formation through its antioxidant activity.

Oxidized lipoproteins have been implicated as important factors in the pathogenicity of atherosclerosis. Thus, antioxidants play a significant role in inhibiting a critical step in atheroma progression. Previously, we demonstrated that thyronine analogs inhibit Cu 2+ -induced low density lipoprotein (LDL) oxidation. In the present study, we examined the effect of thyronine analogs on endothelial cell (EC)-induced LDL oxidation. LDL was incubated with or without EC in the presence or absence of various concentrations of thyronine, vitamin C, or probucol at 37 ° in a humidified atmosphere (95% air, 5% CO 2 ). Thyronine analogs, probucol, and vitamin C inhibited EC-induced LDL oxidation in a concentration-dependent manner. The concentration of each agent (μM) producing 50% inhibition ( ic 50 ) of EC-induced LDL oxidation for thiobarbituric acid reactive substances (TBARS) and electrophoretic mobility, respectively, was as follows: 0.294 and 0.417 for levothyroxine ( l -T 4 ); 0.200 and 0.299 for l -triiodothyronine ( l -T 3 ); 0.125 and 0.264 for dextro-thyroxine ( d -T 4 ); 0.203 and 0.304 for reversed triiodothyronine (rT 3 ); 1.02 and 1.44 for probucol; and 13.6 and 14.9 for vitamin C. Thyroid binding globulin (TBG) inhibited EC-induced LDL oxidation; further, thyronines bound to TBG exhibited more antioxidant activity than unbound thyronines. Pretreatment of EC with any of the thyronines decreased the ability of EC to oxidize LDL. Also, our results showed that a synergistic interaction exists between vitamin C and T 4 in the inhibition of EC-induced LDL oxidation. The T 4 and TBG concentrations that inhibited LDL oxidation were in the physiological range. We conclude that T 4 , like the pharmacological agent probucol, reduces oxidative modification of LDL and thus may act as a natural inhibitor of atherogenesis.

Brain cellular functions are affected by free radicals. Arachidonic acid and its 12-lipoxygenase metabolites have been proposed as important in enhancing long-term potentiation associated with learning. It has been reported that Student Rasayana (SR), an herbal mixture, improves brain functions. In this study we evaluated the antioxidant capacity of SR and its effect on lipoxygenase activity. Both alcoholic and aqueous extracts of SR inhibited enzymatic- and nonenzymatic-induced microsomal lipid peroxidation in a concentration-dependent manner. The agent concentrations (micrograms/mL) that produced 50% inhibition (IC50) of enzymatic- and nonenzymatic-induced microsomal lipid peroxidation, respectively, were 99.1 +/- 3.9 and 1992.0 +/- 122.7 for the aqueous extract, and 17.7 +/- 0.9 and 646.7 +/- 79.7 for the alcoholic extract. The aqueous extract inhibited soyabean lipoxygenase (SLP)-induced LDL oxidation in a concentration-dependent manner (IC50: 515.5 +/- 11.5), whereas the alcoholic extract enhanced SLP-induced LDL oxidation. Simultaneous addition of aqueous and alcoholic extracts inhibited SLP-induced LDL oxidation. The alcoholic extract (but not the aqueous extract) enhanced the ability of SLP to induce oxidation of linoleic acid. Rats fed 2% (w:w) SR showed inhibition of toluene-induced brain microsomal lipid peroxidation. These results suggest SR improves brain functions through scavenging free radicals as well as increasing the second messenger for long-term potentiation.