Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage

We demonstrated that Flk-1⁺ cells derived frommouse embryonic stem (ES) cells can differentiate into both endothelialcells (ECs) and mural cells (MCs) to suffice as vascular progenitor cells (VPCs). In the present study, we investigated the importance ofthe stage of ES cell differentiation on effective participation inadult neovascularization. We obtained Flk-1⁺LacZ-expressing undifferentiated VPCs. Additional culture of these VPCswith vascular endothelial growth factor (VEGF) resulted in a mixture ofECs and MCs (differentiated VPCs). We injected VPCs subcutaneously intotumor-bearing mice. Five days after the injection, whereasundifferentiated VPCs were often detected as nonvascular cells,differentiated VPCs were more specifically incorporated into developingvasculature mainly as ECs. VPC-derived MCs were also detected invascular walls. Furthermore, transplantation of differentiated VPCsaugmented tumor blood flow in nude mice. These results indicate that aspecific vascular contribution in adult neovascularization can beachieved by selective transplantation of ES cell-derived VPCs inappropriate differentiation stages, which should be the basis forvascular regeneration schemes.     

Membranoproliferative glomerulonephritis and demyelinating neuropathy caused by type II mixed cryoglobulinemia associated with HCV infection

Type II cryoglobulinemia is sometimes observed in patients with HCV infection. It is also well known that some cases with membranoproliferative glomerulonephritis (MPGN) possess cryoglobulinemia, which can induce neuropathy. We treated a 73-year-old woman with hepatitis C virus (HCV) who was admitted to our department because of proteinuria. She was diagnosed as MPGN according to renal biopsy. Her ankle jerk was absent with reduced touch sensation and vibration below the knees; sural nerve biopsy revealed demyelinating neuropathy. Administration of prednisolone resulted in improved proteinuria. Cryoglobulinemia associated with HCV infection seemed to induce MPGN and demyelinating neuropathy.     

Human chorionic gonadotropin induces c-myc mRNA expression via TSH receptor in FRTL-5 rat thyroid cells.

To elucidate the gene regulation of the thyroid-cell growth-promoting activity by human chorionic gonadotropin (hCG), we investigated the effect of hCG on c-myc proto-oncogene expression in cultured rat FRTL-5 cells by the Northern blot method. hCG induced c-myc mRNA expression, which peaked at 60-120 min. A dose-dependent increase in c-myc mRNA levels was also ascertained. In the presence of crude immunoglobulin G (IgG) from 2 patients with primary hypothyroidism who had blocking type TSH-receptor antibody, c-myc mRNA expressions induced by hCG were decreased to 82% and 62%, compared with that in the presence of normal IgG. The present results suggest that the expression of c-myc mRNA is a part of the molecular mechanism through which hCG regulates the proliferation of thyroid cells, and that hCG-induced c-myc mRNA expression is presumed to be mediated in part by TSH receptors.     

A stimulatory effect of recombinant murine interleukin-7 (IL-7) on B- cell colony formation and an inhibitory effect of IL-1 alpha

Using a clonal culture system, we investigated the lymphohematopoietic effects of recombinant interleukin-7 (IL-7) obtained from conditioned media of transfected COS 1 cells. IL-7 alone acted on murine bone marrow cells and supported the formation of B-cell colonies. These colony cells were positive for B220, and some of them were also found to have either IgM or Thy-1. B220+, IgM- cells, but not B220- cells sorted from fresh bone marrow cells were able to form B cell colonies in the presence of IL-7. Thus, IL-7 supported the differentiation of B220+, IgM- cells to B220+, IgM+ cells. B220+, IgM+ cells did not proliferate in the presence of IL-7. IL-7 did not affect the myeloid colony formation supported by IL-3, IL-5, IL-6, granulocyte macrophage colony stimulating factor (GM-CSF), and G-CSF. On the other hand, lymphocyte colony formation was not affected by IL-2, IL-3, IL-4, IL-5, IL-6, GM-CSF, or G-CSF. Interestingly, IL-1 alpha inhibited IL-7- induced B cell colony formation in a dose-dependent manner, while the same concentration of IL-1 alpha enhanced the myeloid colony formation by IL-3. This reciprocal effect of IL-1 alpha may act on hematopoietic progenitor cells without accessory cells. These data show that IL-7 is a B cell growth factor and that IL-1 alpha may play an important role in differentiation of myeloid and lymphoid lineages.     

Unusual cases of acute cholecystitis and cholangitis: Tokyo Guidelines

Unusual cases of acute cholecystitis and cholangitis include (1) pediatric biliary tract infections, (2) geriatric biliary tract infections, (3) acalculous cholecystitis, (4) acute and intrahepatic cholangitis accompanying hepatolithiasis (5) acute biliary tract infection accompanying malignant pancreatic-biliary tumor, (6) postoperative biliary tract infection, (7) acute biliary tract infection accompanying congenital biliary dilatation and pancreaticobiliary maljunction, and (8) primary sclerosing cholangitis. Pediatric biliary tract infection is characterized by great differences in causes from those of adult acute biliary tract infection, and severe cases should be immediately referred to a specialist pediatric surgical unit. Because biliary tract infection in elderly patients, who often have serious systemic conditions and complications, is likely to progress to a serious form, early surgery or biliary drainage is necessary. Acalculous cholangitis, which often occurs in patients with serious concomitant conditions, such as those in intensive care units (ICUs) and those with disturbed cardiac, pulmonary, and nephric function, has a high mortality and poor prognosis. Cholangitis accompanying hepatolithiasis includes recurrent pyogenic cholangitis, an epidemic disease in Southeast Asia. Biliary tract infections, which often occur after a biliary tract operation and treatment of the biliary tract, may have a fatal outcome, and should be carefully observed. The causes of acute cholangitis associated with pancreaticobiliary maljunction differ before and after operation. Direct cholangiography is most useful in the diagnosis of primary sclerosing cholangitis. If cholangiography visualizes a typical bile duct, differentiation from acute pyogenic cholangitis is easy. This article discusses the individual characteristics, diagnostic criteria, treatment guidelines, and prognosis of these unusual types of biliary tract infection.     

Contribution of cardiac muscle cell disorganization to the clinical features of hypertrophic cardiomyopathy

Heart failure rarely develops in the setting of hypertrophic cardiomyopathy (HCM). Because of this, cardiac muscle cell disorganization (CD), which is a histologic characteristic of HCM, is not believed to be responsible for the development of systolic dysfunction. The aim of the present study was to clarify whether CD can cause systolic dysfunction and ventricular dilation in patients with HCM. Sixteen hearts from patients with HCM obtained at autopsy were divided into two groups: group A (n = 11), without biventricular dilation, and group B (n = 5), with dilation. Specimens consisting of transverse and longitudinal tissue sections of the ventricles were prepared, and the extent of CD and interstitial fibrosis was quantified, using light microscopy. None of the patients in group A had had chronic congestive heart failure, while all of the patients in group B had died of congestive heart failure. In group B, CD was not limited to the interventricular septum. Rather, diffuse CD was observed in both ventricular free walls. The extent of CD was significantly greater in group B than in group A, while the degree of interstitial fibrosis was similar in the two groups (13.6% in group A vs 14.6% in group B). These results suggest that CD may be responsible for systolic dysfunction and ventricular dilation. Received: July 11, 2000 / Accepted: November 25, 2000     

Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan.

Secondary hypertension (SH) including endocrine hypertension has been reported to be uncommon. We estimated the prevalence of SH among hypertensive patients. We prospectively studied 1,020 hypertensive patients. As an initial screening, we measured plasma aldosterone concentration, plasma renin activity, serum cortisol concentration and plasma catecholamine concentration and conducted abdominal ultrasonography (US). As a secondary screening, we performed furosemide plus upright test, captopril renography, dexamethasone suppression test, 24-h urine catecholamine measurement and abdominal CT. Finally, primary aldosteronism with the exception of idiopathic hyperaldosteronism, pheochromocytoma, and Cushing's syndrome were diagnosed by histopathological examination of surgical specimens. Idiopathic hyperaldosteronism was clinically diagnosed by adrenocorticotrophic hormone (ACTH)-stimulated adrenal venous sampling and renovascular hypertension by renal arteriography. There were 61 patients with primary aldosteronism, 5 with renovascular hypertension, 11 with Cushing's syndrome, 10 with preclinical Cushing's syndrome and 6 with pheochromocytoma, and the prevalence of SH was 9.1% among 1,020 hypertensive patients. In 76 (82%) of 93 patients with SH, hypertension was cured or improved after unilateral adrenalectomy, transsphenoidal pituitary adenectomy or percutaneous transluminal angioplasty. With the exception of US and CT, all initial and secondary screening tests were found to be sensitive and specific for differentiating SH from essential hypertension (EH). In conclusion, the measurement of various hormone concentrations was very sensitive for ruling out SH--a condition for which, in the present study, there were few specific signs or symptoms--while CT and US examinations were not always useful for differentiating SH from EH. The prevalence of curable SH among hypertensive subjects was higher in this study, which was conducted by our simple method of screening tests, than in previous reports. Hypertensive patients should be screened for SH and the underlying disease treated appropriately to avoid long-term use of antihypertensive drugs and risks of atherosclerotic complications.     

Identification of hepatitis C virus 1b-derived peptides recognized by both cellular and humoral immune systems in HCV1b(+) HLA-A24(+) patients.

Despite scientific advances, the therapeutic options for hepatitis C virus (HCV) are limited by poor response rates. HCV1b is particularly resistant to standard interferon therapy. The inhibition of the progression of chronic hepatitis and liver cirrhosis and the prevention of the occurrence and recurrence of hepatocellular carcinoma (HCC) are important and thus, there is a need for new therapeutic modalities for HCV1b infection. We, therefore, investigated highly immunogenic peptides and report in this study three novel candidate peptides (at positions 711-720 in envelope 2 protein, 885-893 in non-structural protein 2 and 1716-1724 in non-structural protein 4B) among 35 peptides of conserved regions of HCV1b proteins containing HLA-A24 binding motifs tested. Namely, HCV(711-720), HCV(885-893) and HCV(1716-1724) induced HLA-A24-restricted and peptide-specific cytotoxic T lymphocytes (CTLs) activity in peripheral blood mononuclear cells (PBMCs) from 7, 6 and 5 of 12 patients and also were recognized by plasma of 8, 5 and 7 of 12 HCV1b(+) patients, respectively. These results may provide new insight into the development of a peptide-based specific immunotherapy for HCV1b(+) HLA-A24(+) patients.