Genetic mapping of genes regulating the thymus size in back-cross rats between the laboratory BUF/Mna strain and the MITE strain derived from the wild rat, Rattus norvegicus

The thymoma prone BUF/Mna (B) rat is a useful model for Studying the genes responsible for thymus enlargement during the stage of young growth. Among the strains of rats, B rats have the largest thymuses at al stages of life. A locus, Ten-1 , which contributes to thymus enlargement in back-cross (BC) rats between the B and WKY/NCrj (W) strains, was mapped on chromosome 1. To determine the precise location of the bus, (B×(B×MITE)F1) BC rats were generated by crossing the B strain with the Inbred MITE (M) strain, which was established from captured, Japanese wild rats, and were examined by linkage study using polymerase chain reaction with 67 microsatellite markers. Linkages with thymus enlargements were found In genotypes of seven markers, BSIS, LSN, MYL2, IGF2, PBPC2, D1Mgh11 , and D1Mit6 , by X^2-test and Student's t -test, which confirmed the presence of the genetic locus associated with thymus enlargement, Ten-1 , in this region. Paradoxically, a suppressive locus, Tsu-1 , to thymus enlargement was also found on chromosome 3, showing linkages of phenotype of the small thymus with genotypes of SCN2A, CAT D3Mit16 , and D3Mit13 . By analyses of mapmaker/exp and mapmaker/qtl, Ten-1 was mapped at 4.6 cM proximal from IGF2 locus on chromosome 1 and Tsu-1 at 4.0 cM proximal from CAT locus on chromosome 3, respectively.     

Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.     

Distribution of Antigens Detected with MB1, MB2 and MB3 on Non-hematopoietic Human Organs and Various Tumors

We have examined the distribution of antigens detected by MB1, MB2 and MB3 on non-hematopoietic normal human tissues and various types of benign and malignant tumors. MB1 and MB2 reacted with various organs, such as the epithelium of various glands, smooth muscle cells, vascular endothelial cells, and peripheral nerve tissue. The distributions of these two antibodies were essentially identical. Reactivity with MB3 was confined to the ductal eDithelium of salivary glands, the pancreas, and sweat glands, and the cortex of the adrenal gland. lmmunoblotting analysis demonstrated that MB1 and MB2 reacted with a few bands of an extract of myometrial cytoskeletal fraction and salivary gland cytosol fraction, whereas MB3 failed to show any bands on these materials. The reactivities of MB1 and MB2 with various neoplasms were similar to those in normal organs, with slight variations of staining pattern and preponderance in well differentiated tumors. Exceptionally, carcinoid tumor and small round cell tumors, such as small cell carcinoma or neuroblastoma, were not reactive with MB1 and MB2. MB3 reacted with several cases of well differentiated benign and malignant epithelial tumors in various organs, and exceptional cases of malignant schwannoma and glioma. These results indicate that the antigens detected by MB1 and MB2 are distributed broadly on non-hematopoietic normal organs, whereas those detected by MB3 are confined to exceptional cases of epithelial and non-epithelial tumors. Thus, although the use of MB1, MB2 and MB3 is of little value for differential diagnosis of various tumors, these three antibodies may be useful for determining of the origin of some tumor types. Acta Pathol Jpn 42: 339–346, 1992.     

New method to determine oxygen cost for contractility

We developed a new method to determine the oxygen cost for myocardial contractility and applied it to epinephrine in the excised cross-circulated dog heart. We utilized the relation between myocardial oxygen consumption (VO2) and the systolic pressure-volume area (PVA) which represents the total mechanical energy generated by contraction. We first obtained a reference VO2-PVA relation in a baseline contractile state. Then, the end-diastolic and stroke volumes were fixed constant and a global index of ventricular contractility, Emax, was enhanced by infusing epinephrine. The VO2-PVA data point was shifted linearly right-upward with the increases in Emax. From the slopes of both the reference VO2-PVA relation line and the regression line of VO2 on PVA during the gradually increased Emax, we calculated the oxygen cost for contractility, i.e., the ratio of the elevation of the VO2-PVA relation to enhanced Emax in each heart. The ratio was 0.00095 +/- 0.00013 ml O2.ml.mmHg-1.beat-1.100 g LV-2. The result indicates that the oxygen cost for contractility can be reliably and efficiently determined by this new method.     

A case of multiple myeloma producing granulocyte colony-stimulating factor

A case of multiple myeloma (IgA-Λ) with marked granulocytosis, which measured up to 9.9×104/mm³, Is described. Matured neutrophiles were predominant and blasts were not found in the peripheral blood. The serum granulocyte colony-stimulating factor (G-CSF) was notably elevated. The disease ran a chronic course and granulocytosis and elevated serum G-CSF continued. The patient developed atelectasis and bronchopneumonia, and died of respiratory failure. At autopsy, bone marrow showed marked myeloid hyperplasia in varying states of differentiation. The enlarged spleen also disclosed numerous myeloid cells of varying differentiation. Small aggregations of atypical plasma cells were present in the marrow and spleen. Immunohisto-chemically, atyplcal plasma cells were positive for anti-G-CSF antibody, which Indicated G-CSF secretion from the myeloma cells. To our knowledge, this is the first reported case of G-CSF-producing multiple myeloma.     

Late onset type I familial amyloidotic polyneuropathy: Presentation of three autopsy cases in comparison with 19 autopsy cases of the ordinary type

Clinicopathological features of three autopsy cases of extremely rare late onset type I familial amyloldotic polyneuropathy were presented and compared with 19 autopsy cases of the ordinary type. In the late onset cases, the ages at onset and at death were 27.5 and 24.5 years older, respectively, compared with the ordinary type. Also, duration of the total clinical course form onset to death was 3.7 years less than in the late onset cases. The degree of amyloid deposition was more marked in the heart of the late onset cases, causing prominent cardiac hypertrophy. It was also marked In the kidneys or thyroid of two cases, but slight to moderate in the peripheral or autonomic nervous tissues in all cases. Immunohistochemical Investigation demonstrated the presence of transthyretin (TTR) as an amyloid precursor protein and of serum amyloid P-component in amyloid deposits in various organs and tissues of the late onset type. These findings, as well as serum levels of variant TTR, were similar to those of the ordinary type. These results suggest that there are some factors other than the amyloid precursor protein that effect the degree of amyloid deposition.     

Dissociation of pressure-rate product from myocardial oxygen consumption in dog

Although the pressure-rate product (double product; DP) is generally recognized as a good index of myocardial oxygen consumption (VO2), catecholamines are reported to change the VO2-DP relationship. However, the separate influences of chronotropism and inotropism on the VO2-DP relation have not been studied. Therefore, we examined these influences in anesthetized open-chest dogs by cardiac pacing and dobutamine infusion. We observed two different VO2-DP lines under the separate chronotropic and inotropic changes. We interpreted such VO2-DP relations by the concept of the pressure-volume area (PVA). PVA is a measure of total mechanical energy for ventricular contraction and is a specific area in the ventricular pressure-volume (P-V) diagram circumscribed by the end-systolic and end-diastolic P-V relation curves and the systolic segment of the P-V trajectory. The empirical VO2-PVA relation that had been obtained in our previous studies reasonably simulated the dissociation of DP from VO2 under separate changes in chronotropism and inotropism.