Familial glucocorticoid deficiency (FGD) is an autosomal recessive syndrome with hereditary adrenocortical unresponsiveness to ACTH. After the cloning of ACTH receptor or melanocortin-2 receptor (MC-2R) cDNA, several kinds of mutations in the receptor genes have been reported. However, the apparently normal ACTH receptor gene in some affected children suggests that the etiology of FGD is heterogeneous. In this short review, we describe the recent advances in the molecular biology of ACTH receptor genes, its post-receptor signal transduction in the adrenocortical cells, and the molecular genetics of the FGD and a related syndrome, Allgrove syndrome. We also discuss that this kind of work will help us to understand better about the molecular mechanism of the glucocorticoidogenesis in the human being.

Glucocorticoids↗

PubMed1997

Development of hepatic sinusoidal structure with special reference to the Ito cells.

To elucidate sinusoidal cell structure and function under normal conditions and their behavior in diseased settings, an understanding of their developmental aspects is needed. At day 10 of gestation in mice and rats or at 5 weeks of gestation in humans, the hepatic cords grow into the mesenchymal tissue of the septum transversum, and the primitive sinusoidlike structure is simultaneously observed between the liver cell cords. In the margin of the growing liver primordium, mesenchymal cells in the septum transversum are trapped in the subendothelial space. These subendothelial cells are at the early stages of organogenesis and become progenitors of the Ito cells. By days 12-14 of gestation in mice and rats or 8 weeks of gestation in humans, the basic structure of the sinusoids has developed. Embryonic hepatic sinusoids are usually lined by a continuous endothelium without basement membranes, and an incompletely fenestrated sinusoid appears at the middle gestational stage. In the late gestational stages, the Ito cells exhibit myofibroblastlike features in humans, mice, and rats. In association with this event, perisinusoidal reticular networks are gradually intensified. After birth until days 4-5 in mice and rats, the sinusoidal and perisinusoidal structures are almost completely formed, although slight morphological differences from those in adult livers still exist. What happens to sinusoidal endothelial cells and Ito cells in hepatic fibrosis-cirrhosis of the adult may be a deviated or uncontrolled occurrence of what goes on during the fetal period, i.e., a continuous nonfenestrated sinusoidal lining in the early embryonic stage and a myofibroblastlike transformation of Ito cells in late fetal life.

Animals↗

PubMed1997

C-Myc expression and its role in patients with chronic aortic regurgitation.

BACKGROUND: Proto-oncogenes have been implicated in the pathogenesis of gene-mediated myocardial remodeling. In the human heart, however, it has not been clarified whether these proto-oncogenes are related to contractile impairment and structural alteration of the myocardium. The present study is designed to investigate the relationship between the c-Myc protein expression in the myocardium and the myocardial contractile dysfunction in patients with chronic aortic regurgitation who underwent indicated for aortic valve replacement. METHODS AND RESULTS: Twelve patients (11 males and one female) with an average age of 55 years who underwent aortic valve replacement for isolated chronic aortic regurgitation were studied. The preoperative New York Heart Association class was II in four patients and III in eight. Ejection fraction, end-systolic volume index, end-systolic stress (Mirsky's form), and mass index of the left ventricle before surgery were 47+/-13%, 93+/-37 mL/m2, 223.2+/-44.4 Kdyn/cm2, and 210+/-38 g/m2, respectively. A left ventricular endomyocardial biopsy was performed to assess the myocardial cell diameter, fibrous content, and c-Myc protein expression in the myocardium. Cell diameter and fibrous content were significantly higher than those in five normal controls. C-Myc was detected in 9 of 12 present patients but in none of the normal controls. The degree of c-Myc expression had significant positive correlations with ejection fraction (r=0.93; P<.01) and end-systolic stress/end-systolic volume index (r=0.96; P<.01) and significant negative correlations with end-systolic volume index (r=-0.90; P<.01), cell diameter (r=-0.97; P<.01), and fibrous content (r=-0.92; P<.01), which suggested that the degree of c-Myc expression may have a significant negative correlation with myocardial contractility and myocardial hypertrophy. CONCLUSIONS: C-Myc expression may be related to the pathogenesis of myocardial remodeling in patients with chronic aortic regurgitation.

Adult↗

PubMed1997

CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18).

Corticosterone methyloxidase I (CMO I) deficiency is an autosomal recessive disorder of aldosterone biosynthesis. To determine further the molecular genetic basis of CMO I deficiency, a patient of Turkish origin that suffered from CMO I deficiency was studied. Nucleotide sequencing of the PCR-amplified exons from the genomic DNA of this patient revealed a single point mutation CTG (leucine) CCG (proline) at codon 461 in exon 8 of CYP11B2, which is involved in the putative heme binding site of steroid 18-hydroxylase (P450(C18)). The expression study using a cDNA introducing the point mutation revealed that the amino acid substitution totally abolishes the P450(C18)p3 enzyme activities required for conversion of 11-deoxycorticosterone to aldosterone, even though the mutant product was detected in the mitochondrial fraction of the transfected cells. These results suggest that this point mutation causes CMO I deficiency.

Aldosterone↗

PubMed1997

Myocardial histological changes in dilated cardiomyopathy during a long-term left ventricular assist device support.

As the myocardium in patients with dilated cardiomyopathy (DCM) is deteriorating progressively, resulting in a decrease in left ventricular function, patients with end-stage DCM may require implantation of a left ventricular assist device (LVAD) unless they undergo heart transplantation. Although LVAD has been reported to provide excellent hemodynamic support, no data are currently available about the effects of long-term LVAD support on the myocardium in patients with DCM. We describe two patients with end-stage DCM who underwent LVAD implantation and were supported with LVAD for 524 and 245 days, respectively. Serial myocardial biopsies showed increases in myocardial cell diameter and intercellular fibrosis, despite excellent hemodynamic support by LVAD. These data suggest that the myocardium in patients with end-stage DCM deteriorates progressively, even if the pre-load of the left ventricle is reduced by LVAD.

Adult↗

PubMed1997

Identification of an autoantibody against alpha-enolase in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis is a chronic cholestatic liver disease in which autoreactive T cells may play an important role in the destruction of intrahepatic bile ducts. However, target antigens remain unknown. Alpha-enolase-derived peptide binds to human leukocyte antigen (HLA)-DR8, which is implicated in the development of primary biliary cirrhosis in Japanese patients. Partial homology between alpha-enolase and the inner lipoyl domain of E2 component of pyruvate dehydrogenase (PDH-E2) is also observed. METHODS: Using alpha, beta and gamma enolase isozymes obtained from humans and/or rabbits, we examined serum samples of 56 patients with primary biliary cirrhosis, 19 autoimmune hepatitis, 38 acute and chronic viral hepatitis and 36 healthy subjects by immunoblotting. RESULTS: Anti-alpha-enolase antibody was present in a significantly higher percentage of patients with primary biliary cirrhosis (16 of 56, 28.6%) and autoimmune hepatitis (6 of 19, 31.6%) than in normal subjects (p<0.005, p<0.01, respectively). Antibodies against beta and gamma-enolases were not detected in any serum sample. Although there was no significant correlation between the presence of anti-alpha-enolase antibody and clinical features of primary biliary cirrhosis, the mortality rate associated with hepatic failure in patients with positive autoantibody was significantly higher than that of antibody-negative PBC patients (6 of 16, 37.5% vs 5 of 40, 12.5%, p<0.05). CONCLUSIONS: Since alpha-enolase is expressed on the cell surface, our data suggest that the immunological reaction to alpha-enolase might be involved in biliary epithelial destruction and be relevant to the disease progression.

Acute Disease↗

PubMed1997

Immunocytochemical detection of enhanced expression of c-myc protein in the heart of cardiomyopathic hamster.

An immunocytochemical study was performed to examine the expression of cellular c-myc protein in the heart of 30-, 120- and 180-day-old cardiomyopathic Syrian UM-X7.1 hamsters. The heart of age- and sex-matched BIO-RB hamster was used as normal control. In paraffin sections, an immunostaining for c-myc was markedly increased in cytoplasm of cells from the UM-X7.1 heart as compared with that of the BIO-RB heart which showed a weak staining. However, c-myc was localized in nuclei of cells in frozen sections of the heart. Specific cell types of the heart were differentiated with anti-vimentin, and we found that the increased expression of c-myc was present in nuclei of muscle cells of the UM-X7.1 myocardium. A quantitative study of c-myc-positive nuclei of muscle and nonmuscle cells was carried out by a video micrometer. The mean number of c-myc-positive nuclei of muscle cells was significantly higher in the cardiomyopathic heart than in the control heart from hamsters of all ages studied. These results suggest that the increase of c-myc protein may relate to the pathological state or pathogenesis of the hereditary cardiomyopathy.

Animals↗

PubMed1997

Endosonography-guided endoscopic resection of duodenal carcinoid tumor.

Endoscopic resection techniques using snare polypectomy with or without submucosal saline injection have also been applied to resect smaller duodenal carcinoid tumors. We report on two patients where endoluminal ultrasound using a small diameter probe was used to visualize the adherence of the carcinoids to the underlying wall layers and the separating effect of subtumoril saline injection. One patient, in whom a clear separation between the tumor and the underlying tissue after saline injection was visualized, underwent successful endoscopic resection. In the other patient no clear separation could be achieved after saline injection and the patient underwent surgical removal of his tumor; both tumors were 1 cm or less in their maximal diameter.

Aged↗

PubMed1997

Autonomic differences between athletes and nonathletes: spectral analysis approach.

The purpose of this study was to assess the adaptive effects of endurance training on autonomic function in athletes with spectral analysis of cardiovascular variability signals. Continuous ECG, arterial blood pressure (ABP), and respiratory signals were recorded from 15 athletes (VO2max > 55 mL.min-1.kg-1) and 15 nonathletes (VO2max < 45 mL.min-1.kg-1) during 10 min at sitting position. Autonomic function was assessed by low frequency power (LF power: 0.06-0.14 Hz) and high frequency power (HF power: the region of the respiratory frequency based on respiratory spectrum) obtained from the autospectra of RR interval, systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) variability signals. The spontaneous baroreflex sensitivity was evaluated by the moduli, BRSLF and BRSHF, of the transfer function between RR interval and SAP variability in LF and HF bands. The resting HR in athletes was significantly lower than that in nonathletes. The HF power, an index of parasympathetic activity, in RR interval spectra were significantly higher in athletes than in nonathletes. Meanwhile, the LF power (an indicator of sympathetic activities contributing to RR interval and of ABP variabilities) showed no significant difference between both groups, although that of athletes was slightly less than that of nonathletes. Also, BRSLF and BRSHF were not significantly different between athletes and nonathletes. These results indicate that endurance training results in the enhanced vagal activities in athletes, which may contribute in part to the resting bradycardia.

Adult↗

PubMed1997

A novel splicing junction mutation in the gene for the steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a relatively common genetic disorder of adrenal and gonadal steroidogenesis and is the most severe form of CAH. As typical affected individuals cannot produce any steroid hormones or can only produce low levels of steroid hormones in the adrenals and gonads, including glucocorticoids, mineralcorticoids, and sex steroids, a genetic defect in the cholesterol side-chain cleavage enzyme, cytochrome P450scc (CYPXIA1), has been postulated to be the cause of their insufficient production to date. Recently, Lin and co-workers proved a link between mutations of the steroidogenic acute regulatory protein (StAR) gene and the lipoid CAH phenotype. Therefore, we investigated both the cytochrome P450scc and StAR genes in a Korean family with a fairly mild form of lipoid CAH to identify the mutation(s) causing this disease. The result was that no mutations could be found in the two genes, except for a thymine (T) insertion into intron 2 of the StAR gene, 3 bp from the splice donor site of exon 2. PCR-amplified StAR genes from a normal subject and the patient were cloned into an expression vector and then introduced into COS-7 cells. Northern blot and reverse transcriptase-PCR analyses indicated that the StAR messenger ribonucleic acid derived from the vector with the normal StAR gene spliced exons 2 and 3 correctly, whereas most, but not all, StAR messenger ribonucleic acid derived from the vector with the T-inserted StAR gene could not remove intron 2. We concluded from these results that the T insertion into the StAR gene accounts for the lipoid CAH phenotype in this patient.

Adrenal Hyperplasia, Congenital↗

PubMed1997

[Non-Hodgkin's lymphoma associated with polymyositis].

A 67-year-old man was admitted to with severe nasal congestion. One year previously, he had been suffered from polymyositis (PM) and had been treated with prednisolone. Physical examination and computed tomography revealed a mass in the upper pharynx. Biopsy revealed non-Hodgkin's lymphoma (diffuse medium, B-cell type). Bone marrow aspiration also revealed the infiltration by lymphoma cells. The patient achieved a complete remission after combination chemotherapy (cyclophosphamide, adriamycin, vincristine, prednisolone). However, one month later, he suffered from central nervous system involvement of lymphoma cells, and he died of an aspiration pneumonia. Polymyositis/dermatomyositis associated with non-Hodgkin's lymphoma is extremely rare.

Aged↗