Mucosal lesions of the stomach in liver cirrhosis with a special reference to phospholipid metabolism

Gastric mucosal lesions are an inevitable complication in patients with liver cirrhosis. Their etiology, however, is as yet unknown. The present study investigated phospholipid metabolism in the gastric mucosa of rats with cirrhosis induced by carbon tetrachloride. Gastric mucosal lesions were induced by taurocholic acid (TCA) which was given through a gastric tube. Levels of phospholipids, phosphatidylcholine, and disaturated-phosphatidylcholine were found to be markedly reduced at the mucosal surface in the cirrhotic rats, and they were increased in the gastric juice. Metabolism of phospholipids in the gastric mucosa was visualized by³H-choline autoradiography and the rate of phospholipid metabolism was found to be reduced. These results strongly suggest that mucosal lesions induced by bile regurgitation into the stomach are due to disturbance of phospholipid metabolism in the gastric mucosa.     

Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.     

Evaluation of cytomegalovirus-specific cytotoxic T-lymphocytes in patients with the HLA-A*02 or HLA-A*24 phenotype undergoing hematopoietic stem cell transplantation

Cytomegalovirus-specific cytotoxic T-lymphocytes (CMV-CTL) are essential for the control of CMV reactivation. To monitor the quantity and function of CMV-CTL after hematopoietic stem cell transplantation (HSCT), two CMV epitopes that bind to HLA-A*0201 NLVPMVATV (A*02NLV) and HLA-A*2402 QYDPVAALF (A*24QYD) were evaluated for their immunological potential. Samples from patients with the HLA-A*02 or HLA-A*24 serotype were analyzed by tetramer, intracellular cytokine staining and enzyme-linked immunospot (ELISPOT) assay. There were significantly more A*02NLV-specific CMV-CTL than A*24QYD (23 x 10(6) vs 0.4 x 10(6)/l). The frequency of IFN-gamma-producing cells was also higher upon stimulation with A*02NLV than with A*24QYD (2.5 vs 0.1%/CD8). Furthermore, the magnitude of CMV-CTL expansion was two- to 50-fold when cells were cultured with A*02NLV, while only an insignificant increase was observed in culture with A*24QYD. Although the number of A*24QYD-specific CMV-CTL was very low in most of the HLA-A*24 patients, the incidence of CMV reactivation did not differ between those with HLA-A*02 and HLA-A*24 serotype alone. These results suggest that an epitope other than A*24QYD plays a major role in patients with HLA-A*24. Our study also showed that A*02NLV may be a useful epitope for monitoring CMV-CTL not only in patients with HLA-A*0201 but also in those with the A*0206 genotype.     

MPO-ANCA-positive slowly progressive glomerulonephritis with focal tuft necrosis and crescents

A 37-year-old woman had been found to have proteinuria in October 1996. About 8 months later, the first renal biopsy was performed, revealing focal segmental necrotizing and crescentic glomerulonephritis. At that time, serum creatinine was 1.0 mg/dl and urinary protein 3+. In October 1999, laboratory tests revealed positivity for MPO-ANCA and a serum creatinine level of 1.42 mg/dl, anemia and proteinuria of 2+. A second renal biopsy showed almost the same histological findings. Accordingly, a diagnosis of MPO-ANCA positive glomerulonephritis was made. This patient was thought to be a rare case of MPO-ANCA-positive slowly progressive glomerulonephritis presenting focal segmental tuft necrosis and crescents.     

Successful treatment of chronic granulomatous disease with fludarabine-based reduced-intensity conditioning and unrelated bone marrow transplantation

Allogeneic hematopoietic stem-cell transplantation (HSCT) for chronic granulomatous disease (CGD) with a reduced-intensity conditioning regimen can be expected to lead to less therapy-related mortality and late-onset impairment, whereas it has also been reported to increase the risk of unsustained mixed donor chimerism and late rejection after transplantation. Herein, we report a 4-year-old boy with CGD who was successfully treated with unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (RIC). Fludarabine-based RIC, 4 Gy of total body irradiation, 120 mg/kg of cyclophosphamide, and 125 mg/m² of fludarabine, was adopted for transplantation, followed with 8.9 × 10⁸/kg mononucleated donor cells infused without T-cell depletion. Although hematopoietic engraftment was rapidly obtained by day +17, he developed unstable donor chimerism. After tacrolimus withdrawal, the patient showed grade III acute graft-versus-host disease (GVHD), and subsequently reached full donor chimerism by day +61. Twelve months post-transplant, the patient has remained well with stable and durable engraftment, 100% donor chimerism, and normal superoxide production, without the requirement of donor lymphocyte infusions (DLI).     

Intraosseous leiomyosarcoma arising in the epiphysis of the distal femur

Herein, we present a rare case of intraosseous leiomyosarcoma arising in the epiphysis of the distal femur and showing unusual radiographic features. A 44-year-old man presented with a pain in the left knee joint. Computed tomography revealed an intraosseous lesion with slightly increased attenuation and a thin marginal sclerotic rim in the femoral medial condyle. The signal of the lesion was hypointense on T1-weighted magnetic resonance (MR) images and hyperintense on fat-suppressed T2-weighted MR images. After gadolinium administration, the signal of the lesion was moderately and diffusely enhanced. The histological diagnosis of leiomyosarcoma was made based on a preoperative core biopsy specimen. Microscopic examination of the resected specimen revealed an ill-defined intraosseous tumor composed of proliferated atypical and mildly pleomorphic smooth muscle cells permeating among the bone trabeculae with only focal destruction of the bone trabeculae and low mitotic activity, indicating low grade leiomyosarcoma. The bone trabeculae at the periphery of the tumor were mildly thickened and anastomosed with a rim of an increased number of osteoblasts. Systemic examination showed no tumorous lesions in other anatomical sites. Leiomyosarcomas rarely present in the bone as a diffuse intertrabecular growth, even in low grade tumors.     

Evaluation of bioartificial renal tubule device prepared with human renal proximal tubular epithelial cells cultured in serum-free medium

Bioartificial renal tubule devices (BTD) use cell therapy to improve conditions commonly observed in recipients of artificial kidneys for treatment of kidney diseases. We previously reported significant improvement of the condition of acute kidney injury (AKI) animals after treatment with BTD prepared with lifespan-extended human renal proximal tubular cells (hRPTEC). However, a major obstacle to use of BTD for patients is their biological safety, because hRPTEC are cultured in medium containing fetal calf serum. To establish the biological safety of BTD, we prepared BTD with lifespan-extended hRPTEC cultured in a newly developed serum-free medium and compared these with BTD prepared with hRPTEC cultured in serum-containing conventional medium. Lifespan-extended hRPTEC cultured in serum-free medium (hRPTEC-SFM) can proliferate similar to hRPTEC cultured in serum-containing conventional medium (hRPTEC-CM). Comparison of leakage and of reabsorption of small molecules for BTD prepared with hRPTEC-SFM (BTD-SFM) with those for our previous BTD prepared with hRPTEC-CM (BTD-CM) showed transportation in these two types of BTD was almost identical. When AKI goats were treated with BTD-SFM for 26 h, increase of survival time and reduction of cytokine expression in blood cells were almost same as for AKI goats treated with BTD-CM. Quantification of the expression of some genes of hRPTEC in BTD revealed significant changes during BTD treatment for AKI goats. In conclusion, lifespan-extended hRPTEC-SFM work as well as hRPTEC-CM, and the biological safety of BTD for patients could be elevated without loss of function by preparation from hRPTEC-SFM.     

Hypertrophic obstructive cardiomyopathy with ruptured mitral chordae tendineae: a case report

A 61-year-old man was treated medically under a diagnosis of hypertrophic obstructive cardiomyopathy 7 years previously. He was transferred to our hospital because of sudden onset of dyspnea. Chest radiography showed marked pulmonary congestion. Echocardiography revealed hypertrophic obstructive cardiomyopathy, with a left ventricular pressure gradient of 120 mmHg, accompanied by severe mitral regurgitation due to ruptured chordae tendineae. Mitral valve replacement and the Morrow operation were performed. After the operation, no left ventricular outflow pressure gradient was detected by echocardiography and cardiac catheterization. The patient did well and no further cardiac symptoms were detected for 3 years.