Genetic hypothyroid mice: normal cerebellar morphology but altered glycerol-3-phosphate dehydrogenase in Bergmann glia

The present study was undertaken to investigate the effects of thyroid deficiency on cerebellar development with mouse endocrine genetic models. Four types of mutant mice, the growth hormone- and thyroid hormone-deficient Snell dwarf mouse (dw/dw), the growth hormone-deficient little mouse (lit/lit), the primary hypothyroid mouse (hyt/hyt), and the congenital genital goiter mouse (cog/cog) were analyzed for expression of the glial enzyme marker glycerol-3-phosphate dehydrogenase (GPDH) and several other marker proteins. GPDH expression, as determined by enzyme activity and Northern blot analysis, was reduced by about 50% in the cerebellum and brainstem of the three hypothyroid mutant mice. No reduced expression was found in any region of the brain of the growth hormone-deficient lit/lit mutant. Visualization of GPDH by immunohistology showed that the immunoreactive enzyme was strikingly reduced in the Bergmann glial cells of dw/dw, hyt/hyt, and cog/cog mutant mice, particularly in the radial glial processes. To evaluate the specificity of the effect on GPDH expression, we also examined the expression of the glial cell-specific S-100 protein by immunohistology. In all mutant cerebella, both the intensity and pattern of staining of the Bergmann glial cells were indistinguishable from that of normal controls, suggesting that the Bergmann glial cells are morphologically normal in the hypothyroid mice. The morphology of the Purkinje cell neurons was similarly visualized by immunohistology using an antiserum specific for the microtubule-associated proteins. Surprisingly, the morphology of the Purkinje cell dendritic arborization also appeared unaltered in the hypothyroid mice. The results suggest that the morphological development of the mouse cerebellum is relatively unaffected by hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Individual-based model for dieldrin contamination in lake trout

An individual-based model (IBM) was applied to dieldrin contamination in the lake trout (Salvelinus namaycush) population of Lake Michigan in order to determine if a model structure originally developed for contamination by polychlorinated biphenyls (PCBs) in Lake Michigan lake trout would also apply to dieldrin contamination. Many different congeners constitute PCBs, whereas dieldrin is a single chemical compound. The model accurately accounted for the variation in dieldrin concentrations exhibited within the Lake Michigan lake trout population. The degree of variability included in dieldrin concentrations of the prey fish was similar to that used for modeling total PCBs. These results supported the argument that any heterogeneity in PCB congener distribution in Lake Michigan contributed relatively little to the observed variability in lake trout total PCB concentrations. Furthermore, these results indicate that the IBM has potential to be applicable to a variety of organochlorine contaminants. The IBM should prove useful for risk assessment of contaminants in fish.     

Are cytokines possible mediators of cancer cachexia?

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.This work was supported by a grant from the Japan-Sweden Foundation in 1991.     

In-vitro Negative Chronotropic and Inotropic Effects of a Novel Dihydropyridine Derivative,CD-832, in the Guinea-pig: Comparison with Calcium-channel Antagonists

The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca²⁺-channel antagonists. All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 > nicardipine = gallopamil > clentiazem > nifedipine = efonidipine > amlodipine = semotiadil > verapamil > diltiazem; that for the negative inotropic effect was nicardipine = gallopamil > nifedipine > verapamil > CD-832 > diltiazem > clentiazem > efonidipine = semotiadil > amlodipine. The ratio of the EC50 (the concentration of Ca²⁺ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca²⁺ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11·4, 0·29, 0·87, 35·4, 37·1, 0·65, 0·87, 0·92, 7·11 and 30·0, respectively. These findings indicate that CD-832 and the newly developed Ca²⁺ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This ‘chrono-selective’ effect of these drugs might be of benefit in the treatment of cardiovascular disorders.     

Distant metastases in differentiated thyroid carcinomas: a clinical and pathologic study

Of 514 patients with differentiated thyroid carcinoma treated between 1970 and 1987, 34 (6.6%) had distant metastases. Twelve patients died of their distant metastases; eight of these patients died within 5 years from the time of initial diagnosis. Death from cancer was most frequent in the seventh decade. The metastases were most often found in the lungs and bones. In the fatal group, pleural, brain, and pericardial metastases were noted. Local recurrences were found only in 24% of these 34 patients. Histologic types of primary thyroid tumors and metastatic tumors were reexamined and classified using our criteria, which were mainly based on the World Health Organization nomenclature and currently obtained pathologic observations of thyroid tumors. In 31 thyroid tumors, the surgical specimens were available for review. Twenty-four tumors were papillary and seven were follicular. Of the 24 papillary carcinomas, nine were follicular, eight were well-differentiated, and seven were trabecular. On the other hand, the seven follicular carcinomas consisted of four well-differentiated, two solid, and one oxyphilic. The majority of the thyroid tumors showed an extrathyroidal extension; however, two were intrathyroidal carcinomas and two were encapsulated carcinomas, larger than 5 cm in diameter. Distant metastases were confirmed morphologically in 18 patients (11 by surgical or biopsy material, five by autopsy, and two by cytology). The histologic types of metastatic tumors were consistent with those of primary thyroid tumors. Diagnostic 131I uptake was examined in 32 patients and absorption of diagnostic 131I in metastatic tumors was demonstrated in 21 patients. The 10-year survival rate of patients with 131I accumulating metastases (70%) was significantly better than that of patients with metastases lacking such uptake (40%). Immunoreactivity for thyroglobulin in metastatic tumors was correlated with the 131I absorption. This finding indicated that immunostaining of thyroglobulin in metastatic tumors might be useful in the prediction of the effectiveness of 131I therapy.     

Contribution of Asian mouse subspecies Mus musculus molossinus to genomic constitution of strain C57BL/6J, as defined by BAC-end sequence-SNP analysis

MSM/Ms is an inbred strain derived from the Japanese wild mouse, Mus musculus molossinus. It is believed that subspecies molossinus has contributed substantially to the genome constitution of common laboratory strains of mice, although the majority of their genome is derived from the west European M. m. domesticus. Information on the molossinus genome is thus essential not only for genetic studies involving molossinus but also for characterization of common laboratory strains. Here, we report the construction of an arrayed bacterial artificial chromosome (BAC) library from male MSM/Ms genomic DNA, covering approximately 1x genome equivalent. Both ends of 176,256 BAC clone inserts were sequenced, and 62,988 BAC-end sequence (BES) pairs were mapped onto the C57BL/6J genome (NCBI mouse Build 30), covering 2,228,164 kbp or 89% of the total genome. Taking advantage of the BES map data, we established a computer-based clone screening system. Comparison of the MSM/Ms and C57BL/6J sequences revealed 489,200 candidate single nucleotide polymorphisms (SNPs) in 51,137,941 bp sequenced. The overall nucleotide substitution rate was as high as 0.0096. The distribution of SNPs along the C57BL/6J genome was not uniform: The majority of the genome showed a high SNP rate, and only 5.2% of the genome showed an extremely low SNP rate (percentage identity = 0.9997); these sequences are likely derived from the molossinus genome.     

Immunotopographic assessment of lymphoid and plasma cell malignancies in the bone marrow

To determine the utility of tissue section immunochemistry in the evaluation of bone marrow involved by lymphoid and plasma cell malignancies, snap-frozen, undecalcified bone marrow core and aspirate samples from 23 patients with these disorders were studied with a battery of monoclonal antibodies. With techniques that preserve architecture, difficult diagnostic cases characterized by core but not aspirate involvement, or the reverse, were resolved. By means of an extensive battery of monoclonal antibodies applied to serial sections, complex tumor cell phenotypes were established in all 23 cases. In addition to the identification of straightforward monoclonal surface immunoglobulin expression in small cleaved cell lymphomas (four cases), the battery approach added immunologic certainty in malignancies with unusual or difficult phenotypes: peripheral T-cell lymphomas with idiosyncratic antigen expression, and chronic lymphocytic leukemias and small cell lymphomas with faint surface immunoglobulin expression (four cases). For the chronic lymphocytic leukemias and the small cell lymphomas, the combined IgD+, B2+, B1+, Ia+, Leu-1+ phenotype taken as a whole had greater utility than any isolated marker. The acute lymphocytic leukemias and the myelomas studied demonstrate the wide range of B-cell antigens that must be detected to account for the variety of B-cell neoplasms encountered. Additionally, the previously undescribed phenotypic subset of CALLA+ myelomas, which is of prognostic relevance, was identified. Marrow frozen section immunotyping is a major asset in the evaluation of patients with lymphoma, leukemia, and myeloma when special care is accorded to tissue handling and to treatment of endogenous peroxidase/pseudoperoxidase and interstitial immunoglobulin.