Copper deposition in oligodendroglial cells in an autopsied case of hepatolenticular degeneration

We present a case of hepatolenticular degeneration, so‐called Wilson’s disease (WD), in a 31‐year‐old Japanese man with broader deposition of copper in the liver, kidney and brain. The liver showed severe cirrhotic changes with macronodular pseudolobule formation, but there was little difference in immunohistochemical expression patterns of the copper transporter ATP7B between the control and present case. In the brain, there were both WD‐related lesions such as the scattering of Opalski cells and changes caused by hepatic encephalopathy including the appearance of Alzheimer type II glia. Of note, we identified copper deposits in the systemic organs, including hepatocytes, renal tubules, and in broad areas of the brain. Surprisingly, as a result of further pursuit, copper accumulation in the brain was rarely identified in neuronal cells, but in Olig2‐positive glial cells with double immunohistochemical staining. Together, this rare autopsied case suggests a novel cellular candidate affected by abnormal copper metabolism and the necessity to perform the systemic examination of copper deposition in WD.     

Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon–ribavirin‐based therapy

Aim

The optimal duration of follow‐up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long‐term follow‐up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long‐term follow‐up of patients who achieved SVR, with molecular analysis of HCV.

Methods

A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin‐based therapy and achieved SVR were enrolled. All patients were recommended for follow‐up every 6 or 12 months.

Results

The mean follow‐up period was 6.0 years (range, 1.0–13.6 years). Cumulative 5‐ and 10‐year follow‐up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5‐ and 10‐year follow‐up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non‐structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse.

Conclusions

Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin‐based therapy is durable for prolonged periods.     

Aberrant expression of an “intestinal marker” Cdx2 in pyloric gland adenoma of the gallbladder

The aim of this study was to survey Cdx2 expression in pyloric gland adenoma (PGA) of the gallbladder. We reviewed 29 PGA cases, ten (34.4%) and seven (24.1%) of which showed intestinal metaplasia (IM) and squamous morule (SM), respectively. The immunostaining for Cdx2, beta-catenin, MUC5AC, MUC2, MUC6, and M-GGMC-1 was performed and scored (0 = negative, 1+ = <10%, 2+ = 10% to <30%, 3+ = 30% to <50%, 4+ = 50% to <70%, 5+ = 70-100%). Although its scores were relatively low (1+ or 2+), Cdx2 was frequently expressed in 27 cases (93.1%). Not only goblet and/or Paneth cells were positive but also non-IM cells in PGAs, as opposed to the lack of staining in the background mucosa. Cdx2 scores were not correlated with those of IM (p = 0.485) and MUC2 (p = 0.868). Of note, Cdx2 was positive in foci of SM in all seven cases, and there was a significant difference in Cdx2 scores between PGAs with and without SM. Furthermore, the p value of scores between Cdx2 and beta-catenin was 0.051, and both mean labeling indices (LIs) were correlated (r = 0.736). With Cdx2, higher morular LIs than glandular LIs were observed (p = 0.001). Finally, we concluded that aberrant Cdx2 expression in PGAs is closely associated with nuclear beta-catenin expression and SM in contrast with IM.     

Aberrant Cdx2 expression in endometrial lesions with squamous differentiation: important role of Cdx2 in squamous morula formation

Only a few reports have described Cdx2 expression in endometrial lesions of the uterus. Our aim was to determine whether Cdx2 expression is related to squamous differentiation in endometrial lesions. Furthermore, we examined whether there is any correlation between Cdx2 and beta-catenin, a well-known marker of aberrant nuclear accumulation in endometrial squamous foci secondary to mutation. We performed immunohistochemical analysis of 225 cases (29 normal endometrium, 28 nonproliferative conditions, 21 polyps, 46 hyperplasias, and 101 endometrioid carcinomas) that included 72 cases (4 polyps, 16 hyperplasias, and 52 carcinomas) showing morular or keratinizing squamous differentiation (SD(+)). Normal endometrium and nonproliferative conditions showed no staining for Cdx2. Whereas there was a low rate of Cdx2 positivity in SD(-) polyps (5.9%) and hyperplasias (10%), all SD(+) lesions expressed Cdx2 (P < .001). Thirty-eight (73%) of the SD(+) carcinomas were positive for Cdx2, whereas only 6 SD(-) cases (14.0%) were positive (P < .001). Furthermore, the larger the number of squamous foci, the greater the number of Cdx2-positive cells that was found. The labeling indices of Cdx2 were significantly higher in morular components than in keratinizing or glandular ones (P < .001). There was a strong correlation of the labeling indices of Cdx2 and beta-catenin in squamous foci of hyperplasias and carcinomas. Using immunofluorescence, we confirmed the coexpression of the 2 markers. The Cdx2 protein is expressed frequently in endometrial lesions with squamous differentiation, especially morular-type differentiation, and correlates strongly with nuclear beta-catenin expression. These facts suggest that Cdx2 plays an important role in squamous morula formation.     

FAMILIAL OCCURRENCE OF OLIGOMEGANEPHRONIA

Oligomeganephronia (OMN) is a rare, renal hypoplasia, consisting of reduced number of hypertrophied nephrons. This disorder has been considered to be a congenital but not a genetic disease. We describe the first report, to the best of our knowledge, of familial cases of OMN; two male siblings ran rapidly downhill courses and died 11 and 8 days after births, respectively. In addition, the two patients had similar multiple anomalies; microcephaly, prominent glabella, hypertelorism, antimongoloid slant, epicanthal folds, broad nose, cleft lip and palate, downturned mouth, short philtrum, micrognathia, low set ears, hypospadias, and cryptorchism. Although the patients and the parents had normal G-banded karyotypes, 4p monosomy syndrome is suggested from clinical features. The implications of this are discussed briefly. ACTA PATHOL. JPN. 35: 449–457, 1985.     

The effect of donor-specific transfusion and cyclosporin A on small bowel transplantation in the rat

Pre-transplant blood transfusions are given as a means of desensitization to reduce the required dose of cyclosporin A (CsA). In this study, the effect of pretransplant blood transfusion on host survival and T-cell function against alloantigen were investigated. Male Lewis rats (RT1¹) were used as the recipients in all experiments, and male DA rats (RT1^a) were used as the blood and small bowel donors, and as a source of allogeneic stimulator cells. Male BUF rats (RT1^b) were used as donors of third party blood, and of allo-stimulator cells in a delayed-type hypersensitivity (DTH) response. In our experimental design, Lewis rats were divided into the following groups according to the type of administration: (1) a donor-specific blood transfusion (DST) 8 days preoperatively and a concurrent 5-day course of CsA at 10 mg/kg per day; (2) a nonspecific third party blood transfusion (NST) and CsA at 10 mg/kg per day from day 8 to day 4 preoperatively; (3) CsA alone from day 8 to day 4 preoperatively; (4) DST alone 8 days preoperatively; or (5) no treatment, being the control group. Postoperative treatment consisted of CsA at 2.5 mg/kg per day for 30 days. Rats conditioned with NST plus CsA, CsA alone, DST alone, and the untreated control rats survived for 7.2 ±1.2, 9.0 ± 2.2, 6.8 ± 0.4, and 7.4 ± 1.6 days, respectively. In contrast, the five rats conditioned with DST plus CsA survived for 100 days or more. This study demonstrates that long-term survival of a small bowel allograft can be achieved by host-conditioning with a combined treatment of DST and low-dose CsA.This paper was presented at the 10th Congress of the Asian Association of Pediatric Surgeons held in Seoul, Korea from March 26–29, 1990, and at the 90th Annual Meeting of the Japanese Surgical Society held in Sapporo, Japan in 1990.     

Rapid turnover proteins as a prognostic indicator in cancer patients

We investigated the relation between the plasma levels of various proteins, especially rapid turnover proteins (RTPs), and the prognosis in advanced cancer patients receiving total parenteral nutrition (TPN). In the patients with benign disease (n=40), RTPs increased abruptly following TPN, but in patients with malignant disease, they rose slowly. Patients with malignant disease were divided into two different groups according to the outcome; group A, surviving 3 months or more after TPN and group B, who died within 3 months after TPN initiation. Whereas the RTP levels were elevated significantly in group A, they did not show any noticeable increase in group B. There was a close correlation between the plasma protein levels at 2 weeks and the survival time after TPN initiation. Thus, using the estimated critical values of RTPs with prognostic significance, the correct prognosis rate in 37 newly treated cases was: transferrin 75.7%, prealbumin: 91.9%, retinol-binding protein: 86.5%. These results clearly indicate that the TPN-induced changes in RTPs, notably in the PA value, can be a good prognostic indicator of survival in advanced cancer patients.     

Study of subretinal intercellular space

The study of the subretinal space has been possible through a technique which allows a biochemical examination of the intercellular fluid of this space. This subretinal intercellular fluid had been collected in two fractions by saline washes of the interphotoreceptor spaces ($\text{R}\text{F}$) of the detached retina and the apical surface of the exposed retinal pigment epithelium ($\text{RPE}\text{F}$). This technique produced negligible contamination from the blood, surrounding tissues or intraocular fluids. Generally, the $\text{R}\text{F}$ contained twice the quantity of collectable proteins as the $\text{RPE}\text{F}$. Major differences between the two fractions of saline washes were in the proportional concentration of several specific proteins in these washes. Noticeable species specific differences between the electrophoretic patterns of rabbit and rat subretinal proteins were evident. This technique has been shown to be very reliable and has yielded consistant results.