Familial amyloidotic polyneuropathy (ATTR Ser50Ile): the first autopsy case report

We report an autopsy case of a pedigree of familial amyloidotic polyneuropathy (FAP) with a mutation of isoleucine-50 transthyretin (ATTR Ser50Ile). A 47-year-old man started developing severe diarrhea and weight loss at age 41 years, followed by urinary incontinence, autonomic-nervous-system abnormalities and serious heart failure; the diagnosis of FAP (ATTR Ser50Ile) was made on the basis of genetic, histochemical and immunohistochemical analysis. Six years after the initial symptoms, he died of septic shock. Autopsy revealed suppurative peritonitis, perforation of the sigmoid colon and marked systemic amyloid deposition. The total amount of amyloid deposited in the heart was greatly increased and was much lower in the thyroid gland and kidneys compared with amyloid deposits in ordinary FAP (ATTR Val30Met). Amyloid deposition in peripheral vessel walls was prominent, particularly in lymphatics and veins. His elder sister, 54 years old, started to develop orthostatic hypotension at age 49 years, followed by dysesthesia, diarrhea and severe congestive heart failure. Endomyocardial biopsy revealed severe TTR–amyloid deposition; ultrastructural examination demonstrated that amyloid fibrils were deposited disproportionately and extended radially around microvessels. These characteristic patterns of systemic amyloid deposition and distinct clinical manifestations, especially in the cardiovascular system, are considered to be a characteristic feature of ATTR Ser50Ile amyloidosis. Received: 31 August 1999 / Accepted: 19 October 1999     

Antibody masking renders HIV-1 resistant to cationic membrane filtration through alteration of its electrostatic characteristics

Previously, it was demonstrated that any human immunodeficiency virus type 1 (HIV-1) strain proliferating in peripheral blood mononuclear cells (PBMCs) in vitro, and resuspended in seronegative plasma, could be captured efficiently (mean > 95%) by a porous polypropylene (PP) membrane modified cationically. We investigated if this cationic membrane could capture HIV-1 obtained from seropositive plasma, and confirmed whether this membrane was effective for the preparation of safe plasma products against HIV-1 transmission. Thirty-six seropositive plasma samples derived from HIV-1 positive cohorts in New York and Lusaka (Republic of Zambia), including 18 cases of acquired immunodeficiency syndrome (AIDS) related complex, AIDS and five terminal cases of AIDS, were filtered through the cationic membrane to determine the reduction of RNA concentration, the gag p24 concentration, and infectious titer. Only a small reduction in RNA concentration (mean < 20%) and almost no decrease in gag concentration (mean < 2%) were obtained, despite the fact that the infectivity was eliminated entirely by the filtration. Due to the possibility that anti-HIV-1 antibodies in patients' plasma combine with HIV-1, laboratory-adapted HIV-1(HTLV-IIIB) was mixed with seropositive plasma to test the effect of antibodies on HIV-1 adsorption, and also to investigate the interfacial electrokinetic potential (zeta-potential) of both intact and plasma-treated HIV-1. The zeta-potential of HIV-1(HTLV-IIIB) in the presence of seropositive plasma was neutral as opposed to negative when stored in seronegative plasma or culture medium. Also the rate of HIV-1 capture by the membrane, as determined by the reduction in RNA concentration, sank from 95% to 20%, the same capture percentage observed when filtering plasma of patients. These findings suggested that in patients' plasma, the antibody-masked HIV-1 comprise most of the viral population, and was not trapped on the cationic membrane because of its electrostatic character. Conversely, the cationic membrane was thought to adsorb antibody-free HIV-1 exclusively. It was suggested that each viral swarm had its own zeta-potential, and this difference in electrostatic character determined the extent of the viral adsorption by the cationic membrane.     

HLA antigens in Behçet''s disease with refractory ocular attacks

HLA class I, II, and III antigens were studied in Japanese patients with Beh?et's disease with refractory ocular attacks. In addition to the increased frequency of B51, DQw3, especially TA10-negative DQw3, was increased and DQw1 was decreased significantly in this subgroup of Beh?et's disease. As for complement markers, C4A Q0 was increased. A rare variant of BF S07 was first observed in Japanese. Although the mechanism for the DQw3 association is obscure, a possible hypothesis is that an immune-response or immune-suppression gene linked to the DQ antigens modulates the disease severity and the efficacy of treatments.     

Retrospective survey of urea cycle disorders: Part 1. Clinical and laboratory observations of thirty-two Japanese male patients with ornithine transcarbamylase deficiency

In a retrospective survey done from 1978-1988 in Japan, 32 male patients with ornithine transcarbamylase (OTC) deficiency were identified. We classified a neonatal and 2 late-onset groups, depending on clinical manifestations and the age at onset; group 1 (0-28 days; N = 10), group 2 (29 days-5 years; N = 13), and group 3 (greater than 5 years; N = 9). Compared to findings in the group 2 patients, there was a higher rate of mortality and a higher incidence of mental retardation in association with a great decrease in enzyme activity in group 1. In group 3, the mortality rate and enzyme activities were similar to those in group 1. However, patients in this group were asymptomatic prior to the first episode. Enzyme activities were measured mostly in autopsy samples. The serum citrulline levels (enzyme product) were highest in this group. Thus, the mutant enzymes were apparently labile with greater activities in vivo than in vitro. Treatments, including a protein-restricted diet, arginine supplementation, and sodium benzoate administration, resulted in a favorable prognosis for survivors with partial enzyme deficiency. We wish to emphasize that the incidence of late onset of this disease is higher than heretofore considered.     

Eosinophilic granuloma showing rapid regression. Report of a mandibular case with application of a modified PNA staining method for demonstration of Langerhans-type histiocytes.

A mandibular eosinophilic granuloma in a 16-year-old male is reported. This case showed rapid regression, which was clearly demonstrated by histopathological examinations of both preoperative biopsy and surgical materials. Transformation from an eosinophilic granuloma to a xanthomatous granuloma with multinucleated giant cells was observed after only 26 days. Special staining of paraffin sections with peanut agglutinin (PNA) and use of electron microscopy showed that the main component of the lesion in the biopsy material was Langerhans-type histiocytes. These cells had disappeared from the lesion by the time of the operation. At the same time, the number of infiltrating eosinophils was also markedly reduced. It seems appropriate to consider that the rapid regression of this disease was correlated with the rapid reduction in the number of Langerhans-type histiocytes appearing in the granulomatous foci, as well as the number of infiltrating eosinophils.     

Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats

p21(Cip1/WAF1), known as a cell-cycle inhibitory protein, facilitates neurite outgrowth from neurons when present in the cytoplasm. The molecular mechanism of this action is that p21(Cip1/WAF1) forms a complex with Rho-kinase and inhibits its activity. As myelin-derived inhibitors of axonal outgrowth act on neurons by activating Rho, that is responsible for the lack of spontaneous regeneration of the injured central nervous system (CNS), Rho-kinase may be a good molecular target against injuries in the CNS. In this study, we delivered TAT-fusion protein of cytoplasmic p21(Cip1/WAF1) locally after dorsal hemisection of the thoracic spinal cord in rats. The treatment significantly stimulated axonal regeneration and recovery of hindlimb function, and inhibited the cavity formation in the spinal cord after the injury. Cytoplasmic p21(Cip1/WAF1) may provide a potential therapeutic agent that produces functional regeneration following CNS injuries.     

A new method for preventing pulse pileup in scintillation detectors

A new method for preventing pulse pileup in scintillation detectors is proposed. In the new method (G-INT), the energy of an event is calculated from the 'gated integral' of the pulse signal and the period of integration. The period of integration is not fixed but is shortened by the arrival of the succeeding pulse so as to avoid post-pulse pileup. The effect of pre-pulse pileup is corrected by subtracting the remnant energy of the preceding pulses, which is calculated from the gated integral of the preceding pulse. To avoid error due to short pulse intervals, pre- and post-pulse deadtimes are imposed. The method is similar to Wong's method (W-SUM) that depicts the energy by the 'weighted sum' of the current signal and the integrated signal. The performance of G-INT has been studied by Monte Carlo simulation in comparison with W-SUM, the variable sampling-time technique and simple delay-line clipping. It is shown that G-INT provides the smallest degradation in pulse height resolution for a given count rate capability. The difference between G-INT and W-SUM is explained by the difference in the amount of statistical noise involved in the gated integral and in the weighted sum.     

Fine structure of hepatic sinusoids and their development in human embryos and fetuses

The fine structure of the hepatic sinusoids of 81 human embryos and fetuses and their development from 5 to 12 weeks gestation were studied. At 5 weeks gestation, sinusoid-like structures and Kupffer-like cells were observed between liver cell cords. Between 6 and 8 weeks gestation the sinusoids were completely developed. Definite Kupffer cells appear at this developmental stage, when the bone marrow has not yet formed. Floating macrophages form cell aggregates in the sinusoids which contact endothelial cells and settle as Kupffer cells. Erythroblastophagia is observed in Kupffer cells and macrophages. The endothelial linings are closed, with the attenuated cell processes and intercellular junctions between the adjoining endothelial cells. No transition was observed between Kupffer cells and endothelial cells. The findings suggest that Kupffer cells in the human embryo are extrahepatic in origin and that they reach the sinusoids via the circulatory system. Ito cells, which store fat, originate from mesenchymal cells in the septum transversum.     

Carcinosarcoma Of The Esophagus With Osseous And Cartilagenous Production A Combined Study Of Keratin Immunohistochemistry And Electron Microscopy

A case of polypoid carcinosarcoma of the esophagus is presented. Histologically the bulk of the tumor consisted of a sarcomatous tissue having large foci of osseous and cartilagenous differentiation and infiltrating deeply the wall, whereas a superficially, invasive squamous cell carcinoma associated with insitu carcinoma was located at the base and luminal surface of the polypoid tumor. Intermingling of the carcinomatous and sarcomatous elements was found only in areas where they appeared to be collided. Ultrastructurally the sarcomatous portion contained cells with fibroblastic features but with no typical epithelial characteristics. Immunoperoxidase staining of the paraffinembedded histologic sections for keratin proteins revealed, however, some positive spindle cells indicative of epithelial nature in the sarcomatous area, but the great majority of the sarcoma cells were devoid of keratin. These combined findings strongly suggest that the sarcomatous component in our case of true carcinosarcoma is derived from mesenchymal transformation (metaplasia) of the squamous carcinoma cells. The findings were discussed in light of the previous pertinent literature. ACTA PATHOL, JPN. 34: 669–678, 1984.