Total mechanical energy of a ventricle model and cardiac oxygen consumption.

Mechanical energy (ENG) required by a time-varying elastance model of the ventricle was compared with oxygen consumption per beat (VO2) of the canine left ventricle contracting under a variety of loading conditions. ENG needed for this model to increase its elastance during systole is shown to be equal to the sum of the potential energy built in the elastance during systole plus the external mechanical stroke work. This ENG is equivalent to the area (PVA) bounded by the end-systolic and end-diastolic P-V curves and the systolic limb of the P-V loop trajectory in the P-V plane. There was a high correlation (r = 0.89) between VO2s documented in the literature and PVAs assessed by the author from the accompanying P-V data from both isovolumic and ejecting contractions in 11 hearts. A linear regression analysis yielded an empirical equation: VO2 (ml O2/beat) = a . PVA (mmHg . ml/beat) + b, where a = 1.37 X 10(-5) and b = 0.027, which can be used to predict VO2 from PVA. A preliminary experimental study in my laboratory confirmed the validity of this empirical equation.     

Pulmonary metastases from a low-grade endometrial stromal sarcoma confirmed by chromosome aberration and fluorescence in-situ hybridization approaches: a case of recurrence 13 years after hysterectomy

Pulmonary metastasis from low-grade endometrial stromal sarcomas (ESSs) occasionally are found after long, disease-free periods, mostly as incidental histological or radiological discoveries. We describe a case of low-grade ESS presenting as nodular pulmonary metastases finally diagnosed by estrogen-receptor staining, cytogenetic and fluorescence in situ hybridization (FISH) analyses, and perusal of the histology of hysterectomy material. An abnormal nodule in the lung field was discovered by means of chest X-ray of a 47-year-old woman. She had been disease free for 13 years after hysterectomy for an alleged leiomyoma. A computed tomographic scan revealed nodules, with fluctuation in size over the 2-year period, in both lungs. Finally the lesion in the left lung was resected, and pulmonary endometriosis was suspected because of the lack of stromal cell nuclear atypia and positive immunohistochemical reactions for estrogen and progesterone receptors. However, a characteristic karyotype was identified cytogenetically: 46, XX, t(7;17)(p15;q11), the translocation of which, specific to ESS, was confirmed by FISH analysis. A final diagnosis of pulmonary metastases from an ESS could be made by reviewing the histology of the previous uterine tumor. In this case, metastatic lesions from an ESS showed a decrease as well as an increase in size, despite the malignant potential. Immunostaining for estrogen and progesterone receptors and cytogenetic and FISH analyses, together with clinical information on the past gynecological history, are valuable diagnostic keys.     

Differential effects of phospholipase inhibitors in long-term potentiation in the rat hippocampal mossy fiber synapses and Schaffer/commissural synapses

Bath application of the inhibitors of phospholipases, nordihydroguaiaretic acid (NDGA) and p-bromophenacyl bromide (BPB), to the rat hippocampal slices suppressed long-term potentiation (LTP) in Schaffer/commissural-CA1 pyramidal synapses. On the other hand, neither of the two inhibitors suppressed LTP in mossy fiber-CA3 pyramidal cell synapses. BPB did not suppress phosphatidylinositol-specific phospholipase C (PI-PLC) activity of the slices. These results suggested that the mechanisms of LTP were quite different in the CA1 and CA3 subfields of rat hippocampus: in CA1, the involvement of an arachidonate metabolism was strongly suggested, whereas in CA3, an arachidonic acid cascade may not be necessary for LTP.     

HEPATITIS-ASSOCIATED APLASTIC ANEMIA WITH SYSTEMIC PLASMACYTOSIS

An autopsy case of hepatitis associated aplastic anemia was presented. A 58-year-old Japanese female with non-A, non-B hepatitis was admitted on August 2, 1983. Moderate grade of fever and hemorrhagic diathesis appeared on September 16, when hepatitis was evaluated as being under resolving. The peripheral blood and bone marrow findings were consistent with aplastic anemia. Since infection was suggested by increased levels of serum gamma-globulin and CRP, treatment with antibiotics as well as prednisolone and blood transfusion was initiated. Since September 21, gradual tenderness and edema on the right lower abdominal wall appeared. She died on October 3.
On postmortem examination, systemic plasmacytosis with lymphadenopathy and septic monilial infection was revealed. Numerous plasma cells were atypical, but were immunohistochemically proved to be polyclonal. The bone marrow showed a massive and diffuse plasma cell proliferation with extremely scarce myeloid cells and megakaryocytes. There was a large granulomatous lesion with monilial infection in the wall of the ileocecum. By these findings, systemic plasmacytosis was suspected to be due to chronic monilial infection.
The pathogenesis of systemic plasmacytosis in aplastic anemias and in other diseases were discussed with relation to the present case.     

Transforming growth factor J3 type II receptor (TGFpRII) mutation in gastric lymphoma without mutator phenotype

A new mutation in the serine-threonine klnase domain of the transforming growth factor β type II receptor (TGFpRII) was found in a case of diffuse, B cell non-Hodgkin's lymphoma of the stomach. A mfssense mutation (ACA to GCA, Thr to Ala) was detected In exon 5, and a wild type allele was also present. This Is the first naturally occurring mutation in the klnase domain of this gene identified in human primary lymphoma. The replication error at three loci was negative, and the poly A tract of exon 3, which is frequently a target of mismatch repair genes, was intact. Malignant lymphoma of B cell origin in the stomach Is an addition to an expanding catalogue of tumors with TGFβRII alterations, and the biological sequelae of the change in the functional domain and the clinical characteristics of the patient in this study are intriguing.     

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

Primrose syndrome is a congenital malformation syndrome characterized by intellectual disability, developmental delay, progressive muscle wasting, and ear lobe calcification. Mutations in the ZBTB20 gene have been established as being accountable for this syndrome. In this study, a novel de novo ZBTB20 mutation, NM_001164342.2:c.1945C>T (p.Leu649Phe), has been identified through whole exome sequencing (WES) in a female patient presenting a typical Primrose phenotype. Because the present patient exhibited recurrent otitis media, detailed immunological examinations were performed in this study and subnormal immunoglobulin levels were firstly identified in a Primrose patient. Anatomical anomaly of the inner ear has never been reported in this patient and WES data did not include any relevant variants causally linked with the immunologic defect. Thus, there is a possibility of a relation between an unclassified immunodeficiency with selective IgG2 deficiency and Primrose syndrome and this may be the reason of recurrent otitis media frequently observed in Primrose patients. Because subnormal levels of IgG2 in this patient might be caused by an unrelated and still uncharacterized genetic cause, further studies are required to prove the causal link between aberrant ZBTB20 function and immunodeficiency.     

IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of IL-12 p40 overexpression in intestinal epithelia on enterocolitis mediated by Th1 cells in IL-10-deficient (IL-10(-/-)) mice on a C57BL/6J background. IL-10 deficient (IL-10(-/-))/T3b-IL-12 p40+ (IL-12 p40+) mice and IL-10(-/-)/T3b-IL-12 p40- (IL-12 p40-) mice were generated by crossing T3b-IL-12 p40 transgenic mice and IL-10(-/-) mice. At 8 weeks of age, IL-12 p40+ mice did not show any clinical manifestations of colitis. The colon length of IL-12 p40- mice became shorter than that of IL-12 p40+ mice. The histological score of IL-12 p40+ mice was lower. Interferon-gamma (IFN-gamma) production was suppressed in both the mesenteric lymph node cell culture and colon tissue culture of IL-12 p40+ mice. There was no significant difference in IL-4 production and tumor necrosis factor-alpha (TNF-alpha) production between the two groups. These results show that overexpression of IL-12 p40 in intestinal epithelia prevents enterocolitis in IL-10(-/-) mice by suppressing IFN-gamma production, and suggest a potential clinical application of IL-12 p40 for Crohn's disease. Furthermore, these results also suggest that local gene transduction in the intestinal epithelium may be a potent therapeutic approach for Crohn's disease.     

Clostridium sordellii phospholipase C: gene cloning and comparison of enzymatic and biological activities with those of Clostridium perfringens and Clostridium bifermentans phospholipase C

The gene encoding Clostridium sordellii phospholipase C (Csp) was cloned and expressed as a histidine-tagged (His-tag) protein, and the protein was purified to compare its enzymatic and biological activities with those of Clostridium perfringens phospholipase C (Cpa) and Clostridium bifermentans phospholipase C (Cbp). Csp was found to consist of 371 amino acid residues in the mature form and to be more homologous to Cbp than to Cpa. The egg yolk phospholipid hydrolysis activity of the His-tag Csp was about one-third of that of His-tag Cpa, but the hemolytic activity was less than 1% of that of His-tag Cpa. His-tag Csp was nontoxic to mice. Immunization of mice with His-tag Cbp or His-tag Csp did not provide effective protection against the lethal activity of His-tag Cpa. These results indicate that Csp possesses similar molecular properties to Cbp and suggest that comparative analysis of toxic and nontoxic clostridial phospholipases is helpful for characterization of the toxic properties of clostridial phospholipases.     

Hyperglycemia potentiates H(2)O(2) production in adipocytes and enhances insulin signal transduction: potential role for oxidative inhibition of thiol-sensitive protein-tyrosine phosphatases

Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H(2)O(2)) that facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs) that are negative regulators of insulin action. As hyperglycemia is associated with increased cellular reactive oxygen species, we postulated that high glucose conditions might potentiate the H(2)O(2) generated by insulin and modulate insulin-stimulated protein phosphorylation. Basal H(2)O(2) generation was increased threefold in differentiated 3T3-L1 adipocytes by growth in 25 mM glucose versus 5 mM glucose. High glucose increased the sensitivity of the insulin-stimulated H(2)O(2) signal to lower concentrations of insulin. Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. In primary rat adipocytes, high glucose increased insulin-stimulated H(2)O(2) production and potentiated the oxidative inhibition of total PTP and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). These studies indicate that high glucose can enhance insulin stimulated H(2)O(2) generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC.