Proliferating Cell Nuclear Antigen Expression in Peribiliary Glands of Stone-Containing Intrahepatic Bile Ducts

All cases of hepatolithiasis showed features ofchronic proliferative cholangitis, and it has beenspeculated that the atypical glandular proliferationmight be a precursor to overt cholangiocarcinoma. Proliferative cell nuclear antigen (PCNA) is anuclear protein synthesized in the G₁/S phaseof the cell cycle and therefore is related to cellproliferative activity. In an attempt to assess the activity of cell proliferation ofstone-containing intrahepatic bile ducts, we conducteda study using immunohistochemical staining withmonoclonal antibody to score PCNA in intrahepatic bileducts. Thirty patients (10 men, 20 women; mean age52.4 years) having hepatolithiasis surgically resectedwere studied. Ten stone-free patients served ascontrols. All 40 specimens were immunostained for PCNA using PC 10 monoclonal antibody. PCNA of bothstone-containing and stone-free intrahepatic bile ductswere assessed by counting positive staining nuclei per500 cells and expressed as labeling index (LI), ie, percentage of positive nuclei to the totalnumber of nuclei. The PCNA LI in stone-free intrahepaticbile ducts was generally low: 10.0 ± 13.2%, 10.4± 10.7% and 7.9 ± 9.6% for extramuralglands, intramural glands, and epithelial lining,respectively. In contrast, the PCNA LI forstone-containing intrahepatic bile ducts weresignificantly higher than those of controls (P <0.001): 49.4 ± 8.3%, 40.6 ± 7.0% and 34.1± 6.8% for extramural glands, intramural glands,and epithelial lining, respectively. The extramuralglands had a significantly higher PCNA LI (P < 0.001)than the intramural glands and controls. Hyperplasia was found inall specimens, while dysplasia was found in six of 30cases with hepatolithiasis. The dysplastic cells alsohad a higher PCNA LI (P < 0.001) than thehyperplastic cells and normal epithelium. Our findingsshowed that there is marked increase of activity of cellproliferation in stone-containing intrahepatic bileducts. It is well known that genetic mutations are facilitated in proliferating cells. Therefore,our results suggest that the high epithelial turnover indysplastic cells and extramural glands had higherpotential for proliferation and neoplastictransformation in long-standing untreatedhepatolithiasis.     

Association between the characteristics of metabolic syndrome and Alzheimer’s disease

Various epidemiological studies have shown that type 2 diabetes and metabolic syndrome are highly correlated with Alzheimer’s disease (AD). Here, we sought to assess the impact of metabolic syndrome characteristics on the progression of AD. Five-week-old male, spontaneously hypertensive (n?=?32) and Wistar Kyoto (abbreviated WKY; n?=?8) rats were divided into 5 groups (each n?=?8): WKY, hypertension (HTN), streptozotocin-induced diabetes (STZ), high-fat diet (HFD), and STZ + high-fat diet-induced diabetes mellitus (DM). All animals were sacrificed and samples of the blood, liver, and brain were collected for further biological analysis. During the 15-week period of induction, the STZ and DM groups (animals injected with low-dose STZ) had significantly higher fasting glucose levels; the HFD group had elevated insulin levels, but normal blood glucose levels. The HFD and DM groups had hypercholesterolemia and higher hepatic levels of triglycerides and cholesterol. Additionally, correlations between HFD and elevated brain amyloid-beta 42 (Aβ-42), hyperglycemia and down-regulation of brain insulin receptor, and serum Aβ-42 and hepatic triglyceride concentrations (r²?=?0.41, p?<?0.05) were observed. Serum C-reactive protein and malondialdehyde did not appear to have a significant influence on the association with biomarkers of AD. Thus, our study demonstrated that rats with characteristics of metabolic syndrome had a large number of biomarkers predicting AD; however, no relationship between traditional inflammatory and oxidative markers and AD was found. Further studies are necessary to prove that these findings in rats are relevant to AD processes in humans.     

Antiestrogen action in breast cancer cells: Modulation of proliferation and protein synthesis,and interaction with estrogen receptors and additional antiestrogen binding sites

Summary Antiestrogens have proven to be effective in controlling the growth of hormone-responsive breast cancers. At the concentrations of antiestrogens achieved in the blood of breast cancer patients taking antiestrogens (up to 2 × 10^–6 M), antiestrogens selectively inhibit the proliferation of estrogen receptor-containing breast cancer cells, and this inhibition is reversible by estradiol. Antiestrogens also inhibit estrogen-stimulation of several specific protein synthetic activities in breast cancer cells, including increases in plasminogen activator activity, progesterone receptor levels and production of several secreted glycoproteins and intracellular proteins.Antiestrogens bind with high affinity to the estrogen receptor and to additional microsomal binding sites to which estrogens do not bind. These latter sites, called antiestrogen binding sites (AEBS), are present in equal concentrations in estrogen receptor-positive and -negative breast cancer cells and are present in a wide variety of tissues, with highest concentrations being found in the liver. The antiestrogenic and growth suppressive potencies of a variety of antiestrogens correlate best with their affinity for estrogen receptor and not with affinity for AEBS.Antiestrogens undergo bioactivation and metabolismin vivo and hydroxylated forms of the antiestrogen have markedly enhanced affinities for the estrogen receptor. Detailed studies with high affinity radiolabelled antiestrogens indicate that antiestrogens induce important conformational changes in receptor that are reflected in the enhanced maintenance of a 5 S form of the estrogen receptor complex; reduced interaction with DNA; and altered activation and dissociation kinetics of the antiestrogen-estrogen receptor complex. These conformational changes effected by antiestrogens likely result in different interactions with chromatin, causing altered cell proliferation and protein synthesis.Analyses of the rates of synthesis and turnover of the estrogen receptor through pulse-chase experiments utilizing the covalently attaching antiestrogen, tamoxifen aziridine, and studies employing dense amino acid labeling of estrogen receptor reveal that the antiestrogen-occupied receptor is degraded at a rate (t 1/2 = 4 h) similar to that of the control unoccupied receptor. Hence, antiestrogens do not prevent estrogen receptor synthesis and they do not either accelerate or block estrogen receptor degradation.Our findings raise serious doubts about the role of the AEBS in mediating directly the growth suppressive actions of antiestrogens, and suggest that interaction with the estrogen receptor is most likely the mechanism underlying the growth-inhibitory effects of antiestrogens. At present, the role of the AEBS in the actions of antiestrogens or in possible antiestrogen metabolism remains unclear.     

Non-O1 Vibrio cholerae Bacteremia in Patients with Cirrhosis: 5-yr Experience from a Single Medical Center

Objectives: To assess the clinical features and susceptibility of cirrhotic patients to non-01 Vibrio cholerae bacteremia and to provide our therapeutic experiences in this rare and highly lethal infection. Methods: Twenty-eight blood culture isolates of non-01 V. cholerae were identified by our clinical microbiology laboratory between July 1989 and June 1994. Patients with underlying cirrhosis and the aforementioned bacteremia were retrospectively reviewed. Results: Twenty-one cirrhotic patients (16 male, five female; mean age, 50.9 yr; range 28–67 yr) were identified and classified as Child B (6 cases) and Child C (15 cases). Bacteremic episodes occurred most often from March to September. Seafood ingestion (seven cases) and seawater exposure (two cases) were risk factors, but nosocomial infections were also noted in six cases. Presenting symptoms and signs included ascites (95.2%), fever (81%), abdominal pain (52.4%), diarrhea (33.3%), and cellulitis with bullae Formation (19%). Concurrent spontaneous bacterial peritonitis was determined in 10 cases, seven with positive ascites cultures. Antibiotic therapy (either cephalothin with gentamicin or ceftriaxone alone) cured most of the bacteremic episodes. The overall case-fatality rate was 23.8%, hut 75% of the deaths were observed in patients with skin manifestation. Conclusions: Patients with decompensated cirrhosis are susceptible to non-01 V. cholerae bacteremia and should not ingest raw sea food or expose skin wounds to salt water. A high index of suspicion and early administration of antibiotics may lower the mortality rate.