Genetic susceptibility to type 2 diabetic nephropathy in human and animal models

SUMMARY:   Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents.     

Aqueous fraction of Sauropus androgynus might be responsible for bronchiolitis obliterans

Background and objective: Bronchiolitis obliterans (BO) has been reported to develop following ingestion of Sauropus androgynus (SA), a leafy shrub distributed in Southeast Asia. Little is known about direct effects of SA on airway resident cells or haematopoietic cells in vitro. Identification of the SA component responsible for the development of BO would be an important key to elucidate its mechanism. We sought to elucidate the direct effects of SA on airway resident cells or haematopoietic cells and identify the SA element responsible for the pathogenesis of BO. Methods: SA dry powder was partitioned into fractions by solvent extraction. Human and murine monocytic cells, epithelial cells and endothelial cells were cultured with SA solution or fractions eluted from SA. We also investigated the effect of SA in vivo using a murine BO syndrome (BOS) model. Results: The aqueous fraction of SA induced significant increases of inflammatory cytokine and chemokine production from monocytic lineage cells. This fraction also induced significant apoptosis of endothelial cells and enhanced intraluminal obstructive fibrosis in allogeneic trachea allograft in the murine BOS model. We found individual differences in tumour necrosis factor α (TNF‐α) production from monocytes of healthy controls stimulated by this aqueous fraction of SA, whereas it induced high‐level TNF‐α production from monocytes of patients with SA‐induced BO. Conclusions: These results suggest that an aqueous fraction of SA may be responsible for the pathogenesis of BO.     

Utility of immunohistochemical detection of prostate-specific Ets for the diagnosis of benign and malignant prostatic epithelial lesions

BACKGROUND: Human prostate-specific Ets (hPSE) belongs to the Ets family. It regulates the proliferation, differentiation, and development of prostate epithelial cells. A recent study showed that hPSE can be detected in normal glands but not in cell lines established from prostate cancer (PCA), suggesting a translational disorder of hPSE from mRNA to protein in PCA. Immunohistochemical detection of hPSE could therefore be another method of differential diagnosis of PCA from other proliferative conditions in the prostate. METHODS: An immunohistochemical detection of hPSE was carried out on the whole mounted prostatectomy specimen obtained from 19 cases with PCA. RESULTS: Basal and secretory luminar cells showed a diffuse cytoplasmic staining for hPSE in normal glands, hyperplastic glands, and prostate intraepithelial neoplasia lesions. Whereas approximately 30% of PCA lesions showed a negative staining for hPSE, the positive rate for hPSE between PCA and benign glands or prostate intraepithelial neoplasia (PIN), was statistically significant (P < 0.05). Staining intensities in normal glands, hyperplastic glands, and PIN lesions were similar, but generally stronger than those in PCA lesions. CONCLUSIONS: Negative immunoreactivity for hPSE strongly suggests malignancy in the prostate glands. Decreased immunoreactivities of glands for hPSE could suggest PCA.     

‘Atypical adenomatous hyperplasia’ in liver cirrhosis: low-grade hepatocellular carcinoma or borderline lesion?

Adenomatous hyperplasia, defined as a sizable parenchymal nodule in cirrhosis, was examined morphologically. Ninety-seven nodules of adenomatous hyperplasia were obtained from 47 cirrhotic livers and were divided into 'ordinary' (44 nodules) and 'atypical' (53 nodules) types. The former consisted of hepatocytes similar to those of the surrounding liver, and showed regularly distributed portal tracts. The latter type was composed of hepatocytes showing nuclear atypia, relative to the surrounding liver, and showed irregular or sparse portal tracts. Atypical nodules were histologically heterogeneous, possessing areas of normo-trabecular, compact, pseudoglandular and/or scirrhous patterns. Several cytological changes, such as clear cell change, small or large cell change and fatty change, were intermingled variably within a given nodule. Atypical nodules showed expansive and/or replacing growth into the surrounding liver. Atypical hepatocytes also infiltrated into the fibrous septa and portal tracts. Foci of overt hepatocellular carcinoma were found in 11 of the 53 atypical nodules. These findings suggest that ordinary adenomatous hyperplasia may be a large-sized regenerative nodule, while atypical adenomatous hyperplasia may be a hepatocellular neoplasm, a peculiar form of low-grade hepatocellular carcinoma or borderline lesion, in which overt hepatocellular carcinoma is likely to evolve through multiple steps.     

Immunohistochemical demonstration of epidermal growth factor and c-myc oncogene product in normal, benign and malignant thyroid tissues

The expression of epidermal growth factor (EGF) and c-myc oncogene product was studied immunohistochemically in 65 benign and malignant human thyroids. Normal thyroid tissues were usually negative with each antibody. Benign and malignant neoplastic thyroid tissues demonstrated a high percentage of stained cells. However, there was no significant difference in positivity between benign and malignant neoplastic tissues. In Graves' disease 25% of the cases were positive for EGF, and 100% for c-myc product. The effect of EGF or c-myc expression on prognosis was also examined in 42 patients with papillary thyroid carcinoma. When the cases were divided into two groups with regard to their EGF staining score (highly-expressed and poorly-expressed groups), the frequency of highly-expressed tumours was significantly higher in the recurrence-positive group compared with the recurrence-free group (86% vs 57%), but there was no significant difference between the groups in respect of c-myc expression.     

Obliterative portal venopathy: A comparative study of 184 cases of extrahepatic portal obstruction and 469 cases of idiopathic portal hypertension

Abstract A total of 184 cases of extrahepatic portal obstruction (EHPO), mostly demonstrated by intraoperative portography and studied at 17 institutes during the period 1957–1983, were compared with 469 cases of idiopathic portal hypertension (IPH) similarly studied. Of the cases of EHPO, there were 101 males and 83 females; 93 were under 20 years of age and the average age was 25.9 years (i.e. much younger than that of IPH cases). There were two age peaks, one before age 19 years and the other at age 40–49 years. One out of three adult cases had a history of abdominal surgery, but otherwise the aetiologic factor was difficult to elicit. Bleeding was the initial symptom in the majority, and splenectomy and haematological findings of hypersplenism were less pronounced compared with IPH. Liver function tests were almost always normal. The liver appeared normal macroscopically in 69% and histologically in 35%. The changes seen in the remainder were similar to those in IPH; they were less frequent in young patients than in cases above age 20 years. Compared with IPH, the wedged hepatic venous pressure in patients with EHPO was lower and the gradient from the portal venous pressure was greater. It is concluded that extrahepatic portal obstruction is less common compared with IPH in Japan, and that there are cases particularly among adults that present clinicopathological features very similar to those of IPH. It is unclear at present whether these two disorders represent two different disease entities, or whether they represent one disorder with differences in the site of involvement along the portal vein system.     

Stromal Cell‐Derived Factor 1α Induces Accumulation of Intraveneously Administered Marrow‐Derived Stromal Cells in the Partially Obstructed Rat Bladder

Objectives: We investigated the time course of the stromal cell‐derived factor 1α (SDF1α) expression and behavior of intravenously administered bone marrow‐derived stromal (BMS) cells in the urinary bladder of partial bladder outlet obstruction (PBOO) rats. Methods: Study 1: Recombinant SDF1α or saline was directly injected into the bladder wall of female rats followed by intravenous administration of BMS cells isolated from green fluorescent protein (GFP) transgenic rats. The bladder was examined with immunohistochemistry to determine whether SDF1α would enhance migration of BMS cells to the bladder. Study 2: Following surgery of PBOO or sham in female rats, bladders were removed on days 1–14, and expression of hypoxia inducible factor 1α (HIF1α) and SDF1α were examined with real‐time polymerase chain reaction (PCR) to determine if PBOO preferentially increased their expression. Study 3: Female rats underwent PBOO or sham surgery followed by intravenous administration of GFP‐positive BMS cells. Bladders were examined with immunohistochemistry on days 1–14 to determine whether BMS cells preferentially accumulated in the bladder. Results: BMS cells were accumulated in the injection site of SDF1α but not saline in the bladder. SDF1α and HIF1α increased at day 1 after PBOO compared to sham. More BMS cells accumulated in the bladder of PBOO on day 1, and some BMS cells expressed smooth muscle phenotypes by day 14. Conclusion: SDF1α induced with ischemia/hypoxia due to PBOO is implicated in the accumulation of BMS cells in the bladder and regeneration of the bladder for PBOO.     

Rare case of aggressive angiomyxoma presenting as a retrovesical tumor

Aggressive angiomyxoma (AAM) is a rare mesenchymal benign tumor that preferentially involves the pelvic and perineal regions in relatively young females. We report here a rare case of AAM presenting as a retrovesical tumor in a male patient. A 59-year-old man undergoing abdominal ultrasound examination because of benign prostatic hyperplasia was found to have a retrovesical mass. Computed tomography and magnetic resonance imaging of the pelvis showed the retrovesical tumor to be 7.4 x 6.7 cm. The tumor was resected, and diagnosed histopathologically as AAM. The patient showed no recurrence 26 months after resection. Although the majority of retrovesical tumors are considered to be sarcoma or neurogenic tumor, AAM should also be recognized as a differential diagnosis.     

Adenocarcinoma of the female urethral diverticulum treated by multimodality therapy

A 75-year-old female presented with a 7-month history of intermittent macrohematuria and urinary retention. Physical examination revealed a firm, round mass on the anterior vaginal wall. The diagnosis by urethroscopy and radiological evaluation was localized urethral diverticular tumor. Pathological examination of the biopsy specimen revealed adenocarcinoma. The patient received two courses of intra-arterial and systemic chemotherapy using cisplatin, 5-fluorouracil and leucovorin, followed by radiation to the urethra. The tumor shrunk markedly after chemotherapy. The patient underwent total urethrectomy and vesicostomy. Two years after the operation, she had no evidence of recurrence. Adenocarcinoma of the female urethral diverticulum is rare and has been treated by surgery and/or radiation. The present case is the first case of it being treated by multimodality therapy including chemotherapy.     

Electrophysiological Abnormalities of the Atrial Muscle in Patients with Manifest Wolff-Parkinson-White Syndrome Associated with Paroxysmal Atrial Fibrillation

We investigated the electrophysiological properties of the atrial muscle in 33 patients with manifest Wolff-Parkinson-White syndrome. Group I consisted of 13 patients with paroxysmal atrial fibrillation and group II consisted of 20 patients without paroxysmal atrial fibrillation. The anterograde and retrograde effective refractory periods of the accessory pathway and the inducibility of atrioventricular reciprocating tachycardia were not significantly different between the two groups. Endocardial electrograms, obtained by right atrial catheter mapping, were recorded during sinus rhythm from 12 sites of the right atrium in 12 of the 13 group I patients and in all group II patients. An abnormal atrial electrogram was defined as 100 msec or longer in duration, and/or the occurrence of eight or more deflections. Ten (83%) of the 12 group I patients had abnormal atrial electrograms, while only two (10%) of the 20 group II patients had abnormal atrial electrograms, and the difference was significant (P less than 0.01). Thirty-six (26%) of the total 139 electrograms obtained from 12 group I patients and two (1%) of the total 199 electrograms obtained from 20 group II patients fulfilled the criteria for an abnormal atrial electrogram, and the difference was significant (P less than 0.01). The fragmented atrial activity zone, interatrial conduction delay zone, and repetitive atrial firing zone obtained by right atrial extrastimulation were significantly wider in group I than in group II, respectively. It was concluded that electrical abnormalities of the atrial muscle may play an important role in the occurrence of paroxysmal atrial fibrillation in patients with Wolff-Parkinson-White syndrome.