The development of bone marrow transplantation as a treatment for patients with lymphoma--twentieth Richard and Hinda Rosenthal Foundation Award Lecture

The exact immunologic mechanisms that lead to the emergence and progression of painless ("silent") thyroiditis remain unclear. We report two cases of painless postpartum thyroiditis followed by Graves' disease, where extensive immunologic evaluation supported a possible pathogenetic association. The time course of changes in thyroid function tests, 123I thyroidal uptake values, and thyrotropin receptor antibodies (TSHRAbs) were documented. The existence of stimulating TSHRAbs (TSAbs) activating the cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 4,5-bisphosphate (PIP2) signal cascades and their functional epitopes, as well as two different thyrotropin-binding inhibitory immunoglobulins (TBII) were documented in both patients at the time of diagnosis of Graves' disease. We suggest that susceptible persons may develop an immunologic response that can trigger the appearance of a mixture of species of TSHRAbs, which in turn may lead to the sequential occurrence of painless thyroiditis and Graves' disease. Additionally, the multiple phases of hyperthyroidism and hypothyroidism that can occur in these patients may reflect the existence and changing spectrum of TSHRAbs in their sera.     

Postpartum thyroiditis. A clinical, histologic, and immunopathologic study of 15 cases

Fifteen specimens from 15 patients with clinically and laboratory-proven postpartum thyroiditis were examined histologically; 8 specimens were obtained during the hypothyroid phase and the other 7 during the recovery euthyroid phase. All specimens showed focal or diffuse chronic thyroiditis. In the eight specimens taken during the hypothyroid phase and four specimens during the early recovery phase, follicular disruption and hyperplastic change of the follicle were common and characteristic histologic features. In the three specimens taken during the late recovery phase, only focal infiltration of lymphocytes was observed. This histologic change resembled that in spontaneous silent thyroiditis, as shown in the authors' previous study. The authors believe that postpartum thyroiditis and spontaneous silent thyroiditis may fit the same category clinically and histologically. In addition to performing the histologic examination, the authors examined the intrathyroidal lymphocyte subsets and HLA-DR antigen expression in the follicular cells immunohistochemically and compared them with those in chronic thyroiditis (usual type). In postpartum thyroiditis, a significant increase of helper-T-cell numbers and increased expression of HLA-DR antigen in the follicular cells were observed, suggesting an enhancement of autoimmune reactivity.     

Effects of chronic treatment of intact and hypophysectomized rats with thyroid-stimulating hormone on the metabolism of [35S]methimazole and [35S]propylthiouracil

Chronic treatment of intact rats with various doses of TSH increased the thyroidal 35S accumulation after single doses of [35S]methimazole (MMI) and [35S]propylthiouracil (PTU). However, no effect on the intrathyroidal breakdown of the drugs was observed. Thus absolute thyroidal levels of unmetabolized MMI and PTU were increased by factors of up to 2 and 3, respectively, compared to the control groups. Simultaneous decreases in the levels of thyroidal total iodine were observed. Hypophysectomized rats showed a marked inhibition of both thyroidal accumulation and oxidation of [35S]-MMI but TSH treatment of hypophysectomized rats restored the accumulation and oxidation to sham-operated and control group levels. The results show that in rats TSH has an important role in the control of thyroidal levels of antithyroid drugs currently used in the treatment of hyperthyroidism.     

Thyroiditic reactions during a course of thyroid cancer

The clinical, immunological, and immunoistochemical features of 10 thyroid cancers associated with intra and extra tumoral thyroiditis are described. These cases have been obtained from a review of 806 thyroidectomies. A proper distinction of the described pathology from the immunological and histological point of view, is emphasized, especially if compared with the prognosis of other thyroid cancers.     

Agenesis of the thyroid lobe associated with Hashimoto's thyroiditis

A thyroid hemiagenesis in association with Hashimoto's thyroiditis and mild hypofunction in a 40 years woman, is described. It is an unusual association. The clinical, hormonal, immunological, instrumental and cytological diagnosis has been established. The importance of the scintigraphic pattern and the differential diagnosis with other pathological situations, such as Plummer's disease and several destroying processes, is emphasized. It is suggested that thyroid hemiagenesis has not to be regarded as clinically insignificant, in consideration of a possible association with pathologies of the normally developed lobe (Graves' disease, myxoedema, goiter, Hashimoto's thyroiditis, and especially neoplastic degeneration) or with nonthyroid diseases (hyperparathyroidism).     

Coexistent thyroiditis is associated with lower tumour stage in thyroid carcinoma

BACKGROUND: Microsatellite instability (MSI) is a new mechanism described in carcinogenesis of several tumours and seems to predispose for cancer in some chronic inflammatory diseases. As thyroiditis is thought to be both the cause and the consequence of thyroid carcinoma, it was the aim of this retrospective study to investigate the epidemiology and the influence of a coexistent thyroiditis on prognosis and clinicopathological parameters in an iodine-deficient area. METHODS: The grade of lymphocytic infiltration (LI) of 153 thyroid carcinomas was determined in paraffin-embedded tissues: G0 = no LI, G1 = peritumoral LI, G2 = peritumoral LI with follicle, G3 = diffuse LI. A non-radioactive PCR-based screening method was used for detection of MSI. RESULTS: Twenty-seven (17.7%) out of 153 carcinomas were accompanied by thyroiditis (G1, 16; G2, 5; G3, 6). Ten cases fulfilled the criteria necessary for diagnosing Hashimoto's thyroiditis. Nine out of 10 (90%) Hashimoto's cases and 16 out of 17 (94%) other thyroiditis cases were associated with a significantly (chi2 < 0.01) lower pT stage (pT1, pT2) than cases without thyroiditis. No statistical association was found by comparing multifocality or sclerosing variants with the grade of lymphocytic infiltration. MSI was detected neither in patients with severe inflammation nor in the absence of thyroiditis. CONCLUSIONS: MSI does not seem to play a role in the pathogenesis of thyroid carcinoma. Coexistent thyroiditis is associated with a lower pT stage and thus could be an indicator of a better prognosis.     

Immunopathology of Graves'-Basedow disease]

The pathogenesis Graves' disease, an autoimmune disorder, is not fully understood. Immune disturbances, genetic predisposition and environmental factors, affecting thyroid gland, appear to play the main role in contribution and development of the disease. Autoreactive T lymphocyte infiltrates in the thyroid gland and/or in the retroorbital tissues and autoantibodies to TSH receptor detected in almost all of the patients, have been considered to be responsible for hyperthyroidism, ophthalmopathy, pretibial dermopathy and goiter. In this review, we describe some recent reports on the pathophysiological and immunological aspects of the thyroidal and extrathyroidal manifestations of the Graves' disease.     

Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1(u) rats can be prevented by their reconstitution with peripheral CD4(+)CD45RC-TCR-alpha/beta+RT6(+) cells and CD4(+)CD8(-) thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1(c) rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1(u) rats, development of thyroiditis is independent of CD8(+) T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG. RT1(u) rats, development of thyroiditis was prevented by the transfer of CD4(+)CD45RC- and CD4(+)CD8(-) thymocytes from normal donors but not by CD4(+)CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-beta and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4(+)CD45RC- peripheral cells and CD4(+)CD8(-) thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-beta and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thymocytes are programmed in the periphery for their protective role. The implications of this result with respect to immunological homeostasis are discussed.     

Postpartum thyroiditis and Basedow disease

BACKGROUND: The postpartum period is characterized by a rebound in autoimmunity secondary to immune tolerance induced by pregnancy, creating favorable conditions for flare up of Graves' disease or autoimmune thyroiditis. Postpartum thyroiditis is a recognized clinical entity. CASE REPORT: Six years after onset of Graves' disease treated with antithyroid drugs, a 25-year-old woman had a high serum level of antithyroperoxidase antibodies a few months before she became pregnant. Six weeks after delivery, she developed signs of hyperthyroidism and goiter. The diagnosis of postpartum thyroiditis was retained. Her condition regressed spontaneously to euthyroidism then hypothyroidism. DISCUSSION: The therapeutic options involved underline the importance of distinguishing between Graves' disease and postpartum thyroiditis. The diagnosis of postpartum thyroiditis is based on history taking, clinical findings, and laboratory tests, especially isotope uptake.     

Carbohydrate homeostasis in chronic lymphocytic thyroiditis: increased incidence of diabetes mellitus

Twenty-one patients were seen with the diagnosis of chronic lymphocytic thyroiditis in the Endocrine Clinic during 1965-1972. Three patients developed clinical diabetes mellitus at intervals from one month to three years after the diagnosis of thyroiditis was confirmed. An additional patient, a member of the study group reported here, had asymptomatic glucose intolerance initially and developed insulin-dependent diabetes mellitus six months after the diagnosis of thyroiditis was established. Standard glucose tolerance tests were performed on 12 additional patients. One of these patients had unequivocal evidence of chemical diabetes; one other had a borderline abnormal oral glucose tolerance test. The remaining ten patients had normal glucose and insulin values during the OGTT. These studies indicate that children with chronic lymphocytic thyroiditis are at increased risk of developing diabetes mellitus when compared with the normal childhood population.     

Transfer of autoimmune thyroiditis and resolution of palmoplantar pustular psoriasis following allogeneic bone marrow transplantation

We report an unusual case of a patient who was cured of one autoimmune disease (palmoplantar pustular psoriasis (PPP)) but developed another autoimmune disease (autoimmune thyroiditis) after allogeneic BMT. A 40-year-old man suffering from AML with PPP underwent allogeneic BMT from his HLA-identical sister for the treatment of AML. The patient experienced complete clearance of the cutaneous PPP despite the cessation of immunosuppressive therapy for over 2 years. However, he developed hyperthyroidism with anti-thyroglobulin antibodies 5 months after BMT, although he had showed normal thyroid functions without anti-thyroglobulin antibodies before BMT. The donor had no history of thyroid diseases and showed normal thyroid functions but was positive for anti-thyroglobulin antibodies. Thus, even when the donor is in a subclinical state, autoimmune thyroiditis may be transferred from donors to recipients by BMT.     

Metoprolol abolishes exercise-induced left ventricular dysfunction in patients with silent ischemia

Left ventricular systolic function is reduced during episodes of silent ischemia in patients with coronary artery disease (CAD). Left ventricular ejection fraction (LVEF) is increased at least 5 absolute percent during exercise in most normal subjects; however, in patients with CAD, LVEF often remains unchanged or decreases. The anti-ischemic effect of beta-adrenergic receptor blockade is well documented, including a reduction of exercise-induced electrocardiographic ST depressions; however, the effect of these drugs on left ventricular volume changes during exercise in patients with silent ischemia is unknown. The aim of this study was to evaluate the effect of a cardio-selective beta-blocking agent, metoprolol, on rest and exercise LVEF in patients with silent ischemia, using radionuclide cardiography. Fifteen patients with silent ischemia completed a double-blind, placebo-controlled crossover study at rest and during submaximal exercise. LVEF remained unchanged during exercise in the placebo phase (56% to 58%; p = NS), but even though LVEF tended to decrease 56% during rest after metoprolol versus 52% after placebo (p = NS), the LVEF increase from rest to exercise resembled a normal LVEF response, 52% to 58% (p = 0.005). Exercise-induced electrocardiographic ST depressions were also reduced during metoprolol treatment. In patients with silent ischemia, the exercise-induced change in LVEF rises significantly during metoprolol treatment. The mechanism may be a reduction in myocardial ischemia as indicated by a reduction in ischemic electrocardiographic findings.     

Hürthle cell tumor dwelling in hot thyroid nodules: preoperative detection with technetium-99m-MIBI dual-phase scintigraphy

Single injection dual-phase scintigraphy (early and late acquisitions) with 99mTc-MIBI was used to differentiate benign and malignant hot thyroid nodules. METHODS: Thirteen euthyroid and two hyperthyroid patients displaying a hot thyroid nodule on the 99mTc scan due to an autonomously functioning thyroid nodule (AFTN) underwent early (15-30 min) and late (3-4 hr) thyroid scintigraphy after the administration of 740-1000 MBq 99mTc-MIBI. Visual scoring was done to assess nodular tracer uptake and retention. In addition, the nodular-to-thyroid (N/T) uptake ratio in the early and late image and the washout rates (WO) from the nodule and thyroidal tissue were measured. All patients underwent thyroid surgery. RESULTS: Histopathology revealed a Hürthle cell tumor in three nodules, a benign adenoma with oxyphilic metaplasia in two nodules and a benign adenoma without oxyphilic cells in the remaining 10 nodules. The Hürthle cell tumor nodules displayed intense and persistent uptake of 99mTc-MIBI (N/T was 2.81 +/- 0.52 and 5.53 +/- 1.06 in early and late images, respectively; WO from the nodule was 12.33 +/- 0.47, WO from the thyroidal tissue was 22.00 +/- 3.56). The benign nodules showed intense uptake in the early image and intense uptake to absent retention in the late image (N/T was 2.94 +/- 1.31 and 1.62 +/- 0.50 in the early and late images, respectively; WO from the nodule was 20.25 +/- 2.92, WO from the thyroidal tissue was 20.33 +/- 2.92). CONCLUSION: Single injection dual-phase 99mTc-MIBI scintigraphy of the thyroid with AFTN can identify nodules as a result of the activity of a Hürthle cell tumor, since these tumors cause intense and persistent tracer uptake in contrast with a benign AFTN.     

Increase in the chronically monitored cerebrospinal fluid pressure after experimental brain injury in rats

An enzyme-linked immunosorbent assay to detect thyroglobulin autoantibodies (TGAB) in canine serum was developed and validated. The test result for each sample was derived from the optical density readings (OD) and expressed as an Ab-score(%) calculated from three in-house calibrators. The assay specifically detected TGAB as judged from lack of response in the assay after samples had been incubated with specific antigen. Intra- and interassay coefficients of variation ranged from 2.0-4.9% and 4.6-9.9%, respectively. The detection limit, an Ab-score of 5.6%, was close to the median Ab-score of 10% observed in healthy dogs (n = 132). The median Ab-score of dogs with primary hypothyroidism and lymphocytic thyroiditis (n = 11), skin diseases (n = 35), and non-thyroidal diseases (n = 63) was 340%, 12%, and 8%, respectively. The prevalence of TGAB in hypothyroid dogs with lymphocytic thyroiditis (sensitivity) was 91% (95% confidence limits: 59%-99%). In dogs with dermatological diseases without lymphocytic thyroiditis the prevalence of TGAB was 3% corresponding to a specificity of 97% (95% confidence limit: 85%-100%). In dogs with non-thyroidal diseases and healthy dogs the prevalence of TGAB was 5% and 6%, respectively. The diagnostic accuracy of serum TGAB was evaluated by subjecting the data from 11 dogs with lymphocytic thyroiditis and 35 control dogs without lymphocytic thyroiditis to receiver-operating characteristic curve analysis. The area under the receiver-operating characteristic curve (W = 0.966; 95% confidence limit 87%-100%) was significantly higher than that of a worthless test (0.5) (P < 0.0001), thereby indicating that serum TGAB measurements distinguished between dogs with and without lymphocytic thyroiditis.     

Simultaneously found transient hypothyroidism due to Hashimoto's thyroiditis, autoimmune hepatitis and isolated ACTH deficiency after cessation of glucocorticoid administration

We present a 42-year-old woman with concomitant transient hypothyroidism due to Hashimoto's thyroiditis, autoimmune hepatitis and isolated ACTH deficiency. Two months after ceasing prednisolone (5 mg/day) for uveitis, she was discovered incidentally to have liver dysfunction with hypergammaglobulinemia, later diagnosed as autoimmune hepatitis by histological examination of the biopsied liver. In addition, primary hypothyroidism due to Hashimoto's thyroiditis and secondary hypocortisolism due to isolated ACTH deficiency were revealed by endocrinological examination. Although not treated, her liver dysfunction and hypothyroid state recovered simultaneously, and the isolated ACTH deficiency was restored six months later. We concluded, after a needle-biopsy of the thyroid, that the transient hypothyroidism was due to Hashimoto's thyroiditis and the reversible ACTH deficiency was probably due to autoimmune hypophysitis. This case shows that cessation of steroid treatment may transiently exacerbate the polyglandular autoimmune syndrome.     

Silent glutamatergic synapses and nociception in mammalian spinal cord

Neurons in the superficial dorsal horn of the spinal cord are important for conveying sensory information from the periphery to the central nervous system. Some synapses between primary afferent fibres and spinal dorsal horn neurons may be inefficient or silent. Ineffective sensory transmission could result from a small postsynaptic current that fails to depolarize the cell to threshold for an action potential or from a cell with a normal postsynaptic current but an increased threshold for action potentials. Here we show that some cells in the superficial dorsal horn of the lumbar spinal cord have silent synapses: they do not respond unless the holding potential is moved from -70 mV to +40 mV. Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter of the raphe-spinal projecting pathway, transforms silent glutamatergic synapses into functional ones. Therefore, transformation of silent glutamatergic synapses may serve as a cellular mechanism for central plasticity in the spinal cord.     

Silent synapses in the developing rat visual cortex: evidence for postsynaptic expression of synaptic plasticity

In the developing visual cortex activity-dependent refinement of synaptic connectivity is thought to involve synaptic plasticity processes analogous to long-term potentiation (LTP). The recently described conversion of so-called silent synapses to functional ones might underlie some forms of LTP. Using whole-cell recording and minimal stimulation procedures in immature pyramidal neurons, we demonstrate here the existence of functionally silent synapses, i.e., glutamatergic synapses that show only NMDA receptor-mediated transmission, in the neonatal rat visual cortex. The incidence of silent synapses strongly decreased during early postnatal development. After pairing presynaptic stimulation with postsynaptic depolarization, silent synapses were converted to functional ones in an LTP-like manner, as indicated by the long-lasting induction of AMPA receptor-mediated synaptic transmission. This conversion was dependent on the activation of NMDA receptors during the pairing protocol. The selective activation of NMDA receptors at silent synapses could be explained presynaptically by assuming a lower glutamate concentration compared with functional ones. However, we found no differences in glutamate concentration-dependent properties of NMDA receptor-mediated PSCs, suggesting that synaptic glutamate concentration is similar in silent and functional synapses. Our results thus support a postsynaptic mechanism underlying silent synapses, i.e., that they do not contain functional AMPA receptors. Synaptic plasticity at silent synapses might be expressed postsynaptically by modification of nonfunctional AMPA receptors or rapid membrane insertion of AMPA receptors. This conversion of silent synapses to functional ones might play a major role in activity-dependent synaptic refinement during development of the visual cortex.     

The importance of ambulatory ECG monitoring for determining the prognosis of patients with stable stenocardia]

149 patients with coronary artery disease and stable angina pectoris underwent coronary angiography and had coronary artery stenosis over 50 per cent. All the patients were also subjected to 24-h Holter monitoring at primary examination and 12-18 months after it. Typical ischemic ST changes were defined by transient horizontal or descending ST depressions > 1.0 mV (measured 80 ms after the J point) lasting at least for a minute. 75 (50.3 per cent) patients had episodes of silent myocardial ischemia. The course of the disease was assessed in follow-up period of 12-18 months. Four variants of the course were determined: cardiac events (16 patients), the disease progression (33 patients), a stable course (75 patients), clinical remission (25 patients). A significant correlation between the occurrence, the slope and duration of silent ischemia, the data of selective coronary angiography and clinical course of ischemic heart disease was established. Cardiac events occurred in 87.5% of the patients with silent myocardial ischemia who had total ischemic burden 30 minutes or more and/or ST-segments decrease 3.0 mm and more during heart rate less than 100 beat-min. The stable course was registered in patients with silent ischemia or without it with similar frequency. Clinical remission of angina pectoris in the patients with silent ischemia was observed rarely. The results of this study demonstrate that silent ischemia is an important prognostic factor.     

The nerves of two''s, three''s and four''s: a simple method for learning the neuroanatomy of the forearm

Mukali (Aningeria robusta) is an exotic wood from the Sapotaceae family. We describe the case of a 31-year-old woman who developed bronchial asthma and contact urticaria after occupational exposure to mukali. A positive immediate response was observed in the skin prick test, bronchial challenge and the rubbing test performed with a mukali wood extract. We suggest that an IgE-mediated immunological mechanism could explain these findings. Our case report identifies another wood dust capable of inducing occupational asthma.     

Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves' disease and Hashimoto's thyroiditis

Vascular endothelial growth factor (VEGF) is one of the angiogenic factors. We examined both thyroid volume and intrathyroidal vascular area by color flow Doppler ultrasonography in patients with Graves' disease (GD), Hashimoto's thyroiditis (HT), and subacute thyroiditis. The serum concentrations of thyroid hormones, TSH, TSH receptor antibodies, and VEGF were also examined. There was a significant increase in serum VEGF levels in patients with untreated GD and goitrous HT compared with those in healthy subjects. The serum VEGF levels in untreated patients with subacute thyroiditis were significantly higher than those in patients with untreated GD or HT. There was a significant correlation between serum VEGF levels and the ratio of intrathyroidal vascular area and thyroid area in untreated patients with GD who had a goiter larger than or equal to 40 cm3. There was also a significant correlation between serum VEGF and TSH levels in patients with HT who were hypothyroid and had a goiter. Serum VEGF levels decreased significantly in these patients after treatment; this was accompanied by a significant decrease in intrathyroidal vascular area and thyroid volume. Our study demonstrates that VEGF appears to play an important role in intrathyroidal angiogenesis in patients with GD and goitrous HT.