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Biomedical subjects

M R Castro

Publications and source records attributed to M R Castro.

18 recordsLinked to original sources

On carbide dissolution in an as-cast ASTM F-75 alloy.

The solution treatment of an as-cast ASTM F-75 alloy was investigated. Microstructural evolution was followed during thermal processing, in particular with regard to the content and type of carbides formed. To evidence any probable carbide transformations occurring during the heating stage, as well as to clarify their effect on the carbide dissolution kinetics, three heating rates were studied. Image analysis and scanning electron microscopy techniques were used for microstructural characterization. For the identification of precipitates, these were electrolytically extracted from the matrix and then analyzed by X-ray diffraction. It was found that the precipitates in the as-cast alloy were constituted by both a M(23)C(6) carbide and a sigma intermetallic phase. The M(23)C(6) carbide was the only phase identified in solution-treated specimens, regardless of the heating rate employed, which indicated that this carbide dissolved directly into the matrix without being transformed first into an M(6)C carbide, as reported in the literature. It was found that the kinetics of dissolution for the M(23)C(6) carbide decreased progressively during the solution treatment, and that it was sensitive to the heating rate, decreasing whenever the latter was decreased. Because the M(23)C(6) carbide was not observed to suffer a phase transformation prior to its dissolution into the matrix, the effect of the heating rate was associated to the morphological change occurred as the specimens were heated. The occurrence of the observed phases was analyzed with the aid of phase diagrams computed for the system Co-Cr-Mo-C.

Alloys↗

Expression of the sodium iodide symporter in human kidney.

BACKGROUND: The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting that iodide transport in these tissues is conferred by the expression of functional NIS protein. METHODS: The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide accumulation studies in kidney cells. RESULTS: Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO) cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium dependent and sensitive to perchlorate. CONCLUSIONS: Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may be, at least in part, an active process driven by NIS.

Animals↗

Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.

Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A 61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2. In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract residual radionuclide activity.

Carcinoma, Papillary↗

Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake.

The ability of thyroid cancers to concentrate radioiodine (RAI) is dependent, in part, upon the expression and functional integrity of the sodium iodide symporter (NIS). However, some differentiated thyroid carcinomas (DTCs) and most undifferentiated thyroid carcinomas lack the ability to concentrate iodide and are thereby insensitive to 131I therapy. Variation of NIS protein expression may be an important factor in this behavior. We wished to determine whether NIS protein expression in primary DTC tumors correlated with the subsequent RAI uptake by metastatic lesions in the same patients. We obtained paraffin-embedded tissue specimens from 60 patients with metastatic thyroid cancer who had undergone total or near-total thyroidectomy at the Mayo Clinic for DTC and had known presence or absence of RAI uptake in their tumor deposits determined by total body scanning after thyroid hormone withdrawal. Tissue sections from the primary intrathyroidal tumors were subjected to immunostaining (IS) using a monoclonal antibody against human NIS. Slides were subsequently examined for specific IS by two independent reviewers. For each patient, whole body scan (WBS) uptake was recorded, and correlation between results of IS and WBS was analyzed. Of 43 patients with a positive WBS, 37 also had positive IS of their tumors. In six patients with negative IS, a positive WBS was documented, and in three of these cases TSH at the time of surgery was less than 0.3 mIU/liter. Of the 17 patients with negative WBS, 10 were also negative on IS. Positive IS accurately predicted a positive scan in our study in 84% of cases; the ability of the IS to detect all cases with a positive scan was 86%, and it increased to 90% when patients who were receiving thyroid hormone therapy at the time of surgery were excluded from the analysis. Overall, the results of our retrospective study suggest that NIS IS of the thyroidal primary tumor in patients with papillary and follicular thyroid cancers has substantial ability to predict the behavior of subsequent deposits of metastatic and recurrent cancer with respect to iodine trapping and concentration. Our findings require confirmation in prospective studies to more accurately determine the predictive ability of the test and its role in the postoperative management of patients with DTC. If confirmed, NIS IS of DTC primary lesions may prove useful in the management of patients with known or suspected metastatic thyroid cancer.

Antibodies, Monoclonal↗

Quantitative image analysis of laser-induced choroidal neovascularization in rat.

Rodent models of laser-induced choroidal neovascularization (CNV) are now extensively used to identify angiogenic proteins, determine the role of specific genes with knockout mice, and evaluate the efficacy and safety of anti-angiogenic therapies. CNV is typically evaluated by fluorescein angiography or vascular endothelial cell labeling in histologic sections. The current study examined an alternative method using high molecular weight FITC-dextran (MW 2 x 10(6)) for high resolution angiography in RPE-choroid-sclera flat mounts. At 24 hr after lasering, the lesions appeared as a circular weakly fluorescent area of approximately equal diameter to the laser spot. No FITC-dextran labeled blood vessels were visible in the lesion at day 1. Three days after lasering, 47% of the lesions showed FITC-dextran labeling indicative of CNV. The incidence (71%) and extent of CNV increased by day 6, and by day 10 all lesions were vascularized, and the maximal area was attained. No significant change followed day 10, and the neovascular area remained constant through day 31. The highest rate of blood vessel growth (between 3 and 10 days after laser) correlates with the peak expression of VEGF, bFGF, and their receptors shown in previous studies. Morphologic analysis of flat mounts and histologic sections showed that the neovascular plexus in most lesions originates from deeper choroidal vessels in the center of the lesion, grows towards the neural retina, then branches circumferentially to anastamose with uninjured choriocapillaris. The microvessels in these lesions are broad and flat, similar to normal choriocapillaris. In a separate study, rats were treated daily with the angiostatic corticosteroid dexamethasone (20-500 microg kg(-1)day(-1)), and CNV was examined at day 10 in FITC-dextran labeled flat mounts and histologic sections. Dexamethasone dose-dependently inhibited CNV, and its highest dose inhibited approximately 95% of CNV labeled by FITC-dextran and resulted in lesions with no detectable Factor VIII immunostaining. High resolution angiography with FITC-dextran is reproducible and quantifiable, and it may accelerate the discovery of therapeutic agents that modulate choroidal neovascularization.

Animals↗

Thyroid nodules and cancer. When to wait and watch, when to refer.

Thyroid nodules, a common problem in clinical practice, are usually benign; only about 5% of these nodules harbor malignancy. The first step in evaluation is measurement of serum TSH levels. When the TSH value is suppressed, a hyperfunctioning nodule is likely, and scintigraphy may be helpful for confirming the diagnosis. Because thyroid cancer is extremely rare in "hot" nodules, such a finding is reassuring. Observation alone or treatment with radioiodine is a reasonable alternative to surgery in many of these patients. Fine-needle aspiration biopsy is the single most important procedure for differentiating benign from malignant thyroid nodules, and its role in evaluation and management of nodular thyroid disease cannot be overemphasized. Ultrasound, scintigraphy, and radioiodine scanning, together with measurement of various tumor markers, are useful adjuncts in the preoperative and postoperative management of patients with thyroid cancer. A carefully thought-out management plan can help reduce the risk of unnecessary surgery in these patients.

Algorithms↗

Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.

Currently, no curative therapy for metastatic prostate cancer exists. Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) would enable those cells to concentrate iodide from plasma and might offer the ability to treat prostate cancer with radioiodine. Therefore, the aim of our study was to achieve tissue-specific expression of full-length human NIS (hNIS) cDNA in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP and in subcell lines C4, C4-2, and C4-2b in vitro. For this purpose, an expression vector was generated in which full-length hNIS cDNA coupled to the prostate-specific antigen (PSA) promoter has been ligated into the pEGFP-1 vector (NIS/PSA-pEGFP-1). The PSA promoter is responsible for androgen-dependent expression of PSA in benign and malignant prostate cells and was therefore used to mediate androgen-dependent prostate-specific expression of NIS. In addition, two control vectors were designed, which consist of the pEGFP-1 vector containing the PSA promoter without NIS cDNA (PSA-pEGFP-1) and NIS cDNA without the PSA promoter (NIS-pEGFP-1). Prostate cancer cells were transiently transfected with each of the above-described expression vectors, incubated with or without androgen (mibolerone) for 48 h, and monitored for iodide uptake activity. In addition, stably transfected LNCaP cell lines were established for each vector. Prostate cells transfected with NIS/PSA-pEGFP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in a range comparable to that observed in control cell lines transfected with hNIS cDNA. Perchlorate-sensitive iodide uptake was not observed in cells transfected with NIS/PSA-pEGFP-1 and treated without androgen or in cells transfected with the control vectors. In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1. Western blotting of LNCaP and C4-2b cell membranes transfected with NIS/PSA-pEGFP-1 using a monoclonal antibody that recognizes the COOH-terminus of hNIS revealed a band with a molecular weight of 90,000 that was not detected in androgen-deprived cells or in cells transfected with the control vectors, as well as a minor band at Mr 150,000 in transiently transfected LNCaP cell membranes. In conclusion, tissue-specific androgen-dependent iodide uptake activity has been induced in prostate cancer cells by PSA promoter-directed NIS expression. This study represents an initial step toward therapy of prostate cancer with radioiodine.

Adenocarcinoma↗

Changes in bone density after exposure to oral anticoagulants: a meta-analysis.

Oral anticoagulants are putative risk factors for osteoporosis, but observational cross-sectional studies describing their effects on bone mineral density have reported conflicting results, prospective studies are not available, and randomized trials are not feasible. To determine the association between exposure to oral anticoagulants and changes in bone density, we systematically reviewed nine original cross-sectional studies on the effect of long-term exposure to any oral anticoagulant on bone density in adults. The effect size was assessed by standardized mean difference (SMD, exposed minus unexposed) and pooled by skeletal site; results are reported in standard deviation units. Bone density was significantly decreased among exposed subjects in the ultradistal radius (SMD, -0.39; 95% CI, -0.67 to -0.10) but not in the distal radius (SMD, -0.47; 95% CI, -0.97 to 0.04), lumbar spine (SMD, -0.27; 95% CI, -0.59 to 0.05), femoral neck (SMD, 0.03; 95% CI, -0.22 to 0.29) or femoral trochanter (SMD, -0.18; 95% CI, -0.48 to 0.11). The evidence should be considered with caution, but it is consistent with a negative association of oral anticoagulants with bone density in the ultradistal radius, although not in the spine or hip. This suggests that long-term oral anticoagulation might be associated with no more than a modest increase in osteoporotic fracture risk, but this should be verified in future longitudinal studies.

Administration, Oral↗

Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells.

The thyroid sodium-iodide symporter (NIS) is responsible for iodide concentrating ability within thyroid follicular cells. We sought to develop monoclonal antibodies against human NIS (hNIS) for use as reagents in structure-function studies of the protein, as well as potential tools in the assessment of NIS expression in benign and malignant thyroid tissues. Synthetic peptides corresponding to the second ExMD and to the carboxy-terminal ExMD of hNIS were produced and utilized as antigens to develop monoclonal antibodies, which were tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with a pcDNA3 plasmid containing the gene for the full-length hNIS, or a control vector. Western blotting showed a major band with molecular weight (MW) of approximately 97 kDa and several minor bands with MW of approximately 160 kDa, 68 kDa, 30 kDa, and 15 kDa, all specific for hNIS-transfected cells. Immunohistochemistry was performed in various types of thyroid tissues and nonthyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, intermediate staining in papillary and follicular thyroid cancer, and no staining in Hürthle cell cancer or in nonthyroidal tissue. The staining was specific for the follicular epithelium in each of the tissues and was most intense in the basolateral portion of the cell membrane. Overall, our observations indicate that the monoclonal antibodies are specific for hNIS and will be invaluable reagents for investigating the role of NIS in thyroid disease.

Amino Acid Sequence↗

Monoclonal antibodies against the human sodium iodide symporter: utility for immunocytochemistry of thyroid cancer.

The recent cloning of the thyroidal protein that is responsible for iodide transport, the sodium iodide symporter (hNIS), has made possible studies designed to characterize its structure, function and expression in thyroidal tissues. Using a mannose binding protein (MBP)-hNIS fusion protein as antigen, we have developed mouse monoclonal antibodies against hNIS to utilize as tools in such studies. Twenty-four clones were initially recovered which recognized the MBP-hNIS fusion protein, but only two of them were specific for hNIS while the others recognized MBP alone. Both antibodies were found to be immunoglobulin G (IgG) 1kappa (kappa). The specificity of antibodies was tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with the pcDNA3 plasmid containing the full-length hNIS cDNA, or cells transfected with the pcDNA3 vector. A major band with a molecular weight (MW) of approximately 97 kDa, and several minor bands with MW of approximately 160 kDa, approximately 68 kDa, approximately 30 kDa and approximately 15 kDa, were detected specifically in the hNIS-transfected cells. After enzymatic deglycosylation, the major band was present at 68 kDa, as expected based upon the amino acid sequence of hNIS. Immunohistochemistry was performed with several different types of thyroid tissue and non-thyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, with intermediate staining in papillary and follicular thyroid cancers and an absence of staining in Hürthle cell cancer. The staining was specific for the follicular epithelium and was concentrated in the basolateral portion of the cell membrane. These monoclonal hNIS antibodies should prove useful in the characterization of NIS expression in benign and malignant thyroid tissue and in studies characterizing its structure and function.

Animals↗

Clomiphene-induced severe hypertriglyceridemia and pancreatitis.

Clomiphene has been available for clinical use since 1960 and has been successfully used to aid fertility in women with certain anovulatory disorders. It is a synthetic estrogen analog, of the triphenylethylene derivative group, and its biochemical structure is similar to that of tamoxifen. Estrogen and tamoxifen lower total and low-density lipoprotein cholesterol and increase triglyceride and high-density lipoprotein cholesterol levels. In patients with baseline hypertriglyceridemia, these agents can induce severe hypertriglyceridemia and pancreatitis. The actions of clomiphene on lipid metabolism have not been studied, and to our knowledge, no cases of severe hypertriglyceridemia related to the use of clomiphene have been described. We report the case of a woman who developed 2 episodes of clomiphene-induced hypertriglyceridemia and pancreatitis while receiving this drug for treatment of infertility. Given the striking structural similarity between clomiphene and tamoxifen, it is likely that clomiphene is capable of inducing severe hypertriglyceridemia in patients with certain underlying lipid disorders by a mechanism similar to that of tamoxifen.

Adult↗

Correlation of VEGF expression by leukocytes with the growth and regression of blood vessels in the rat cornea.

PURPOSE: To determine the temporal and spatial relationships between neovascularization and basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) mRNA and protein expression in the rat cornea after cautery with silver nitrate. METHODS: In female Sprague-Dawley rats, a silver nitrate applicator was placed on the central cornea to elicit circumferential angiogenesis, and blood vessel growth was quantified by digital image analysis of corneal flat-mounts. Total RNA or protein was extracted from whole corneas until 1 week after cautery, and bFGF and VEGF mRNA and protein levels were determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). To localize VEGF mRNA and protein, paraformaldehyde-fixed and paraffin-embedded histologic cross sections of corneas were examined by in situ hybridization and immunohistochemistry. Macrophages were identified by ED2 immunohistochemistry. To examine the regulation of VEGF, rats were treated with dexamethasone (0.5 mg/kg per day) and hyperoxia (70% O2). RESULTS: The neovascular response progresses in three phases: (1) a nonproliferative phase preceding vessel growth (< or = 48 hours after cautery); (2) a proliferative phase with maximal growth rate between 3 and 4 days; and (3) a regressive phase (day 7) with a decrease in vessel density accompanying the completion of vessel elongation. In corneas after cautery, bFGF mRNA expression was unchanged, and bFGF protein concentration decreaseed by 97% after 24 hours and returned to control levels by day 7. In contrast, VEGF164 and VEGF188 mRNA splice variants and protein peaked 48 hours after cautery, remained elevated 4 days after cautery, and decreased to near baseline by day 7. The peak concentration of VEGF in the cornea at 48 hours was calculated to be 720 pM, which is sufficient to evoke a functional response. In situ hybridization and immunohistochemistry showed VEGF expressed initially in neutrophils (24 - 48 hours) and subsequently in macrophages (4 days) adjacent to the cautery site. Treatment with either dexamethasone or systemic hyperoxia inhibited both neovascularization and the increase in VEGF expression. Dexamethasone inhibited 27% of cautery-induced VEGF upregulation at 24 hours and 23% at 48 hours, hyperoxia inhibited 32% at 24 hours and 43% at 48 hours, and combined treatment with both dexamethasone and hyperoxia had an additive effect (56% inhibition at 24 hours). CONCLUSIONS: VEGF production by leukocytes correlates temporally and spatially with cautery-induced angiogenesis in the rat cornea. Both inflammatory products and hypoxia appear to sufficiently increase VEGF expression near the cautery lesion to increase vascular permeability of limbal vessels and induce endothelial cell migration and proliferation.

Animals↗

Nautical accidents. Unique injuries.

Not much has been written about nautical injuries, although the increasingly popular recreational boating activities and other water sports are becoming a significant source of injury and death. The authors review common and not-so-common nautical injuries and possible preventive measures.

Accidents↗

Kinetics of IgM and IgG responses in neonatally thymectomized Swiss mice under persistent immunization with sheep red blood cells.

The kinetics of IgM and IgG responses (direct and indirect PCF) in the Swiss mice, neonatally thymectomized, injected three times a week with 5 X 10(8) sheep erythrocytes at the age of two months, were exactly the same as the controls from the same litters. The thymectomized animals showed a statistically significant decrease in both responses (18.6 and 30.2%, respectively). The kinetics of the switch from IgM to IgG and of the latter response inhibition, is the same in both the control and the thymectomized animals.

Animals↗

Long-term use of oral anticoagulants and the risk of fracture.

BACKGROUND: Vitamin K participates in bone metabolism and, since oral anticoagulants antagonize vitamin K, their use may increase the risk of osteoporosis. OBJECTIVE: To evaluate fracture risk at all skeletal sites following exposure to oral anticoagulants. METHODS: In a population-based retrospective cohort study, 572 Olmsted County, Minnesota, women 35 years or older at their first lifetime venous thromboembolism event between 1966 and 1990 were followed up for fractures. Risk was assessed by comparing new fractures with the number expected from sex- and age-specific fracture incidence rates for the general population (standardized incidence ratio [SIR]). RESULTS: Altogether, 480 fractures occurred during 6314 person-years of follow-up. Increasing exposure to oral anticoagulation was associated with an increased SIR for vertebral fractures: at less than 3 months of exposure, 2.4 (95% confidence interval [CI], 1.6-3.4); 3 to less than 12 months, 3.6 (95% CI, 2.5-4.9); and 12 months or more, 5.3 (95% CI, 3.4-8.0); and for rib fractures: at less than 3 months, 1.6 (95% CI, 0.9-2.7); 3 to less than 12 months, 1.6 (95% CI, 0.9-2.6); and 12 months or more, 3.4 (95% CI, 1.8-5.7). The data revealed no increased risk for other types of fractures. Oral anticoagulation for 12 months or more was an independent predictor of vertebral fractures (P = .009) and rib fractures (P = .02), but not other fractures. CONCLUSIONS: Long-term exposure to oral anticoagulation is associated with an increased risk of vertebral and rib fractures. The mechanism by which this occurs is still unclear and needs further investigation.

Administration, Oral↗

Anal paracoccidioidomycosis: an unusual presentation of disseminated disease.

We report a patient with an unusual anal ulceration. The biopsy of an anal lesion and subsequent studies revealed a disseminated form of paracoccidioidomycosis, observed in the lungs, small and large bowel. The anorectal disease frequently represents a secondary site of disease, and the patient must be better evaluated.

Anus Diseases↗

An unusual case of inappropriate secretion of thyrotropin: neoplastic or nonneoplastic?

OBJECTIVE: To report an unusual case that illustrates the difficulties in distinguishing neoplastic (nIST) from nonneoplastic inappropriate secretion of thyrotropin (nnIST). METHODS: We describe clinical, biochemical, genetic analysis, and magnetic resonance imaging (MRI) results in a patient with hyperthyroidism due to IST, and we review the related literature. RESULTS: The patient demonstrated overt clinical and biochemical hyperthyroidism with inappropriately increased thyrotropin levels, which failed to respond to thyrotropin-releasing hormone (TRH) stimulation. Sex hormone-binding globulin (SHBG) levels were in the hyperthyroid range. Alpha subunit levels were normal, as was the alpha subunit/thyrotropin molar ratio. MRI of the pituitary was negative for tumor during a 2-year period, and octreotide scan was also negative for sellar uptake. Basal oxygen consumption was abnormally increased. Genetic analysis failed to reveal mutations of the thyroid receptor b gene. The patient responded well to radioiodine ablation of his thyroid. CONCLUSION: This patient had clinical symptoms of hyperthyroidism associated with some features characteristic of nIST (increased level of SHBG, lack of thyrotropin response to TRH stimulation, absence of thyroid receptor b mutations) and others typical of nnIST (normal alpha subunit and its molar ratio to thyrotropin, absence of tumor on sellar imaging). Close follow-up with periodic MRI of the sella is important because of the possible existence of a small pituitary tumor, which may become apparent at a later date. Therapy to control symptoms is important. Hormone replacement, if needed, should be adjusted to maintain clinical euthyroidism, guided by free thyroxine levels.

Adenoma↗

Tolerance induction by continuous stimulation with dextran B512.

The thymus-independent antigen Dextran B512 was used to induce tolerance with immunogenic doses. We show the difficulty to obtain a steady state by administering weekly antigen doses. Three weekly doses were required to achieve tolerance or "homeostatic equilibrium". Three groups of mice (C57BL6 X CBA) F1 were stimulated with: a) 0.5 microgram Dextran one weekly dose for ten weeks. b) 2 micrograms Dex. one weekly dose, for twenty-two weeks, and c) 10 micrograms Dex. three times a week, administered continuously for eleven weeks. The number of anti-Dex. antibody secreting cells was determined by Cunningham and Szenberg PFC technique. Weekly continuous doses of 0.5 and 2 micrograms of antigen showed frequent fluctuations in IgM and unresponsiveness was not achieved. Nonetheless, a three times weekly dose of 10 micrograms Dex. showed IgM response with oscillations and little anti-Dex. IgG response was obtained. After eleven weeks of continuous stimulation the steady state was succeeded. This antigen triggered high levels of IgM bearing B cells in mice, and more difficult tolerance induction was known in this isotype, but also the stimulation model was an important fact in achievement of steady state.

Animals↗