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Typical Alzheimer disease (AD) features an amnestic syndrome that reflects the progression of pathology through specific neural networks. However, a subset of patients exhibits atypical onset with prominent language, behavioral, or visuospatial deficits that are not explained by current neuropathological staging schemes. Astrogliopathy featuring tau inclusions with thorn-shaped and granular fuzzy morphologies is common in the aging brain and collectively known as aging-related tau astrogliopathy (ARTAG). Prior studies have identified tau-positive thorn-shaped astrocytes in the white matter that associate with a primary progressive aphasia phenotype in an AD cohort. However, a possible contribution of ARTAG copathology to AD clinical heterogeneity has yet to be systematically examined. To investigate whether ARTAG pathology contributes to atypical presentations, we mapped the presence and density of ARTAG subtypes throughout cortical and subcortical regions in a well-characterized cohort of AD cases enriched for atypical presentations. In our cohort, ARTAG pathology is frequent and correlates with older age and higher Braak stage. ARTAG subtypes exhibit distinct distribution patterns with subpial and subependymal deposition occurring in the amygdala, while white and grey matter astrocytic deposition are distributed throughout cortical regions. However, ARTAG pathology is equally prevalent in cases with typical and atypical clinical presentations.

Thyroid function, including growth, is TSH dependent, and most metabolic functions of TSH are thought to be mediated by cAMP. Recently, it has been suggested by several groups that growth may be an exception and that it may not be related to cAMP action. In addition, evidence has accrued indicating that the thyroid-stimulating antibody (TSAb) of Graves' disease, the metabolic actions of which are also cAMP mediated, may not be the goitrogenic agent in that syndrome. To evaluate these concepts, we used functioning rat thyroid cells (FRTL5) in monolayer culture and, as indices of growth, the incorporation of [3H]thymidine ([3H]Tdr) into DNA, the concentration of DNA measured directly, and the percentage of cells in S phase, as assessed by flow cytometry, all studied over 72 h of incubation. TSH, forskolin, and cholera toxin enhanced growth by each criterion and increased the concentration of cAMP in parallel; the effect on cAMP occurred rapidly and was maximal well in advance of influences on growth. In all instances, measures of growth promotion were minimal at 24 h and maximal at 48 h, except for [3H]Tdr incorporation, which was greater at 72 h than at 48 h. 3-Isobutyl-1-methylxanthine (IBMX) and (Bu)2 cAMP were also tested. Both enhanced all indices of growth and were as effective as TSH. Maximal responses to TSH were obtained at 100-200 microU/ml, maximal responses to both IBMX and (Bu)2cAMP occurred at 5 X 10(-4) M, and all three stimulators increased the DNA concentration and [3H]Tdr uptake and induced S phase in at least 20% of all cells in culture. The peak effect on DNA and S phase was consistently at 48 h. Epidermal growth factor (EGF) was shown to increase [3H]Tdr incorporation in a nondose-dependent fashion (10(-10) to 5 X 10(-9) M gave approximately 250% of control) over 1, 2, 3, 5, and 7 days, with no increase in DNA and a slight decrement in the concentration of cAMP. A laboratory standard TSAb-immunoglobulin G was shown to parallel TSH in both increasing cAMP (over 2 h of incubation) and growth stimulation (over 72 h). The data are entirely consistent with the view that TSH-stimulated thyroid growth is mediated by cAMP and that the established action of TSAb on adenylate cyclase is sufficient to explain goiter as well as hyperthyroidism in Graves' disease.

Lysosomal membrane permeability was assessed by measuring freely available naphthylamidase activity in intact preparations of guinea pig thyroid follicular cells following exposure of thyroid tissue to sequential stimulation by two thyroid stimulators, thyrotrophin (TSH) and thyroid stimulating immunoglobulins (TSI). These investigations showed that following labilization by TSH, the lysosomal membranes recovered and were capable of responding to a second thyroid stimulator (TSI). That such recovery represented restabilization of lysosomal membranes was confirmed by the finding that latent naphthylamidase activity was restored without a change in total activity of the enzyme.

Mast cells have an important role in allergic reactions secreting histamine and other mediators of immediate hypersensitivity. In the present study we evaluated major histocompatibility complex (MHC) class II antigen expression in mast cells and their possible role in antigen presentation. In rats, 10% of mast cells isolated from the pleural cavity expressed MHC class II antigen; after incubation with gamma interferon (INF) 80% of the cells were positive. These findings suggest that mast cells, in addition to their secretory function in allergic reactions, may also function as antigen presenting cells.

The rare occurrence of hyperthyroidism with an autonomously functioning nodule which following 131I therapy presented as toxic diffuse goitre (Graves' disease) is described in a 60 year old male. This progression was characterised by the presence of varying concentrations of IgG thyroid stimulators, thyroid stimulating immunoglobulins and thyroid growth stimulating immunoglobulins, as measured by cytochemical bioassay. It is postulated that the presence of the nodule and its associated hypersecretion of thyroid hormones may have protected the gland from the effects of IgG stimulators by bringing about inhibitory short-loop feedback on normal thyroid cells. It is further suggested that following therapeutic ablation of the nodule, normal thyroid cells became sensitive to the thyroid stimulators with the evolution of typical features of toxic diffuse goitre.

The effects of the factors time, sodium fluoride concentration, ethanol concentration, temperature of storage and type of container on the ethanol losses from stored human blood have been investigated by means of a 2 5 factorial experiment. The important factors were found to be temperature, fluoride concentration and time of storage. A detailed study of the important factors enabled three distinct mechanisms of ethanol loss to be identified. These were a highly temperature-dependent ethanol oxidation reaction which was independent of the ethanol concentration over a wide range; destruction of ethanol by the action of micro-organisms in the absence of a preservative, which could be inhibited by 0.5% (w/v) sodium fluoride, and diffusion which was found to occur from 5.6% of the polypropylene containers used in Britain for the purposes of the Road Traffic Act 1972.

We studied the expression of major histocompatibility complex (MHC) class-II antigen in mast cells of rat thyroid glands. In the normal rat thyroid, mast cells express MHC class-II antigen. In BioBreeding Wistar (BB/W) rats, the strain of animals prone to develop spontaneous autoimmune thyroiditis, the number of MHC class-II-positive mast cells was significantly higher than in normal rats (p

Thyroid-stimulating immunoglobulins (TSI) were measured, using a highly sensitive cytochemical bioassay, in plasma from 26 euthyroid women with idiopathic diffuse or multinodular goiter selected on the basis of their serum TSH responses to TRH stimulation. Thirteen were chosen because they were previously identified to have impairment in TRH responsiveness and were compared with 13 consecutive patients who had normal responses to TRH. TSI were present in a significantly greater number of those who had subnormal TRH responses (11:13) compared to those who had normal responses (3:13) P less than 0.005. Although serum T4, T3, and basal TSH values were all within the normal range, mean serum T4 and T3 values were significantly higher and basal TSH significantly lower in the 14 patients who had TSI than in the 12 in whom TSI was absent. The coexistence of impaired TRH responsiveness and TSI was associated with a family history of thyroid disease. The data suggest that TSI in patients with euthyroid goiter cause a modest increase in thyroid secretion sufficient to blunt the TSH response to TRH but not to cause clinical hyperthyroidism.

SUMMARY The thyroid stimulators TSH and thyroid stimulating immunoglobulins (TSI) have previously been distinguished in a cytochemical section bioassay (CBA) by the different times at which they caused maximum increase of lysosomal membrane permeability within guinea-pig thyroid follicular cells. The present study demonstrates that the times at which maximum stimulation occurs in the assay depends not only on the type (TSH or TSI) but also on the concentration of the stimulator. At higher concentrations of stumulator earlier times of maximum stimulation were observed for both TSH and TSI. When both stimulators were simultaneously present in plasma at higher concentrations a single peak of stimulatory activity occurred. Neutralization studies using specific antisera revealed that the single peak represented a merging of TSH and TSI peaks. These findings explain the lack of parallelism to the standard curve seen at higher concentrations of TSH or TSI in the CBA. They emphasize the necessity of measuring plasma samples at a variety of dilutions in order to achieve parallelism and to avoid intra-assay interference between TSH and TSI. When these conditions are observed CBA can be used to detect TSH and TSI with extreme sensitivity even when both are simultaneously present in plasma.

Thyroid-stimulating antibodies (TSAb) were detectable using a highly sensitive cytochemical section bioassay in plasma from all 56 hyperthyroid patients studied, including those who had either diffuse hyperplasia or nodular goiters. The maximum dilution at which TSAb was detectable ranged from 10(-2) - 10(-6). Six of these patients had scintigraphic evidence of single functioning nodules, and, surprisingly, TSAb was present in all. Of 27 patients who had nontoxic goiter, 14 (52%) had positive titers for TSAb ranging from 10(-2) - 10(-4). The mean serum T3 value in nontoxic goitrous patients who had TSAb was significantly higher than that in subjects in whom TSAb was absent; in contrast, mean serum T4 values were not significantly different in those two groups. It is concluded that idiopathic nontoxic goiter, toxic nodular goiter with functioning nodules (Plummer's disease), and toxic diffuse goiter (Graves' disease) share, in part, a common pathogenesis.