Ceruloplasmin levels in antineutrophil cytoplasmic antibody-positive patients

Anti-myeloperoxidase (MPO) antibodies are associated with the development of anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis. The imbalance between the protease-antiprotease activity in the neutrophils has been implicated in the pathogenesis of ANCA-related vasculitis. Ceruloplasmin is an acute-phase protein that has antiproteinase and antioxidant properties and inhibits MPO activity. We attempted to study the association between serum ceruloplasmin and ANCA in childhood vasculitis. Forty-five ANCA-related diseases were included in the study. The age range was 4-16 years. Patients were divided into two groups based on indirect immunofluorescence and/or ELISA specificity (MPO). Twenty-six patients had p-ANCA- and 19 patients had c-ANCA-positive disease. Nine patients with Henoch-Sch?nlein purpura were studied as an ANCA-negative control group. Serum ceruloplasmin levels in p-ANCA-, c-ANCA-positive patients, and controls were 125.85+/-93.48 mg/dl, 59.79+/-17.60 mg/dl, and 64.34+/-18.77 mg/dl, respectively, and were significantly higher in patients with p-ANCA ( P<0.05). Ceruloplasmin levels were significantly decreased in remission ( P<0.05). Median MPO level in p-ANCA-positive patients was 15.2 (5-250) and was negative in all c-ANCA-positive patients. There was a significant positive correlation between MPO and ceruloplasmin levels ( r=0.70, P<0.05). Of 26 patients (53.8%) in the p-ANCA-positive group, 14 had renal involvement. The patients with renal disease had significantly higher ceruloplasmin levels than others (151.17+/-92.14 and 134.64+/-95.16 mg/dl respectively, P<0.05). In conclusion, the increase in ceruloplasmin levels during the acute phase suggests that this might be an activation criterion or a response to neutrophil-mediated tissue injury. Increased ceruloplasmin levels together with p-ANCA positivity may be predictive for renal involvement and a serious clinical course. The correlation between ceruloplasmin and MPO levels supports their association. Further studies are necessary to elucidate whether genetic and/or functional alterations in ceruloplasmin are effective in the pathogenesis of vasculitis.     

National Patterns of Depression Treatment in Primary Care

BACKGROUND: While past studies suggest that primary care physicians underdiagnose and undertreat depression, little is known about recent national patterns of depression treatment. METHOD: Using the 1995 and 1996 National Ambulatory Medical Care Surveys, we analyzed 1322 primary care office visits by patients reported to have depression. Rates of psychotherapy/mental health counseling, antidepressant use, and benzodiazepine use were assessed. Independent predictors of depression therapy were examined using multiple logistic regression. Where instructive, we compared the practices of primary care physicians with those of psychiatrists (2418 depression visits). RESULTS: Primary care physicians reported depression in 7.8% of their office visits. For these depression visits, antidepressants (42%) were the most common form of treatment, followed by psychotherapy/mental health counseling (28%) and benzodiazepines (21%). Among specific antidepressants, selective serotonin reuptake inhibitors were most often prescribed by primary care physicians (26% of depression visits). Rates of antidepressant and benzodiazepine use varied significantly by primary care specialty. In addition, geographic region and health insurance status influenced the likelihood of receiving benzodiazepines. In their depression visits, psychiatrists reported psychotherapy/mental health counseling (88%) most frequently, followed by antidepressants (64%) and benzodiazepines (25%). CONCLUSION: The predominant use of selective serotonin reuptake inhibitors suggests that primary care physicians have begun to adopt new therapeutic strategies for depression. The modest rate of antidepressant therapy for a clinical population specifically identified by primary care physicians as having depression may indicate undertreatment of depression in primary care settings. Furthermore, high rates of benzodiazepine use are inconsistent with treatment guidelines, and variations in treatment patterns suggest that nonclinical factors influence depression management.     

Effects of topical application of mitomycin-C and 5-fluorouracil on myringotomy in rats.

OBJECTIVE: The effects of topical application of Mitomycin-C (MMC) and 5-fluorouracil (5-FU) for maintaining myringotomy patency were investigated in this experimental study. STUDY DESIGN: We performed simple myringotomy with a knife on 140 tympanic membranes of 70 rats. Rats were divided in two study groups and a control group. Each study group had 60 tympanic membranes, and the control group had 20. We applied Mitomycin-C (0.4 mg/ml) in Group A, 5-fluorouracil (50 mg/ml) in Group B topically, and sterile saline in the control group for 10 minutes. Examination was made with otoendoscope on days 1, 3, 5, 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70, and patency rates were recorded. RESULTS: MMC and 5-FU Groups remained open for a mean of 46.17 days and 14.62 days, respectively. The control ears healed within 10.4 days. Fibrosis of the MMC-treated group was the same as that of 5-FU-treated groups. Fibrosis of both study groups was significantly lower than that of the control group. CONCLUSIONS: MMC is more effective than 5-FU, which is more effective than the simple myringotomy procedure in extending the patency of myringotomies in rat tympanic membranes (p < 0.05). Both medications are useful as an adjunct in preventing myringotomy closure.     

Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor cell lines

Mutations of proto-oncogene c-kit in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. However, no study has been published concerning the effects of imatinib on GIST cells with various types of KIT mutation. To investigate the effects of imatinib on various c-kit mutations found in GISTs, cell proliferation and apoptosis assays were performed in two GIST cell lines with different KIT mutations. One of the cell lines, GIST-T1, revealed a heterozygous deletion of exon 11 in the c-kit, while the other cell line, GIST882, possessed a homozygous missense mutation of exon 13 in the c-kit gene. Imatinib inhibited proliferation and induced apoptosis in both cell lines. Imatinib potently suppressed proliferation of the GIST882 cell line at the concentration of 1.0 microM, whereas it inhibited the GIST-T1 at 0.1 microM. In two types of activating mutant KIT, imatinib could inhibit the constitutive activation of both types of KIT mutant, although the antiproliferative effect on GIST882 was weaker than on GIST-T1. Western blot analysis revealed that apoptosis related proteins were activated or suppressed by imatinib in both cell lines in the respective manner. Our results suggest that the apoptotic signal trans-duction caused by imatinib in GISTs is susceptible to various types of KIT mutation.     

Cancer scene investigation: how a cold virus became a tumor killer

Oncolytic therapy is a novel anticancer treatment with attenuated lytic viruses such as adenovirus (Ad). These viruses kill the host cells through their lytic replication cycle and are thus distinct from classical gene therapy viruses, which serve as gene delivery agents and do not replicate. Oncolytic Ads are genetically engineered so as to replicate only in cancer cells. Their replication cycle leads to viral multiplication, the killing of the host cells and spreading of the infection throughout the tumor. Following success in preclinical studies, their anti-tumor potential is now being evaluated in the clinic. Three oncolytic Ads (dl1520, Ad5-CD/TKrep, and CV706) have completed Phase I and II clinical trials in cancer patients where their administration via multiple routes and in combination with chemo- or radiotherapies, has demonstrated overall safety. These viruses are being re-engineered to arm them with additional therapeutic genes, bolstering their oncolytic activity with a bystander effect. For example, Ad5-CD/TKrep delivers a therapeutic prodrug-activating (suicide) gene. These data indicate that oncolytic Ads are a promising novel cancer treatment approach that can be combined with other modalities, such as gene therapy and classical chemo- and radiotherapies. Further improvements to enhance their specificity, targeting and oncolytic activity are needed however, as these first-generation viruses showed modest anti-tumor activity. To improve their efficacy in the clinic, it will be important to devise and incorporate novel monitoring techniques in the clinical trials, such as analysis of viral replication in biopsies and through the use of creative noninvasive imaging technologies.     

Effect of cyclosporine A on total homocysteine level in a rabbit model

BACKGROUND: Moderate hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Cyclosporine (CsA) has been suggested to interfere with folate-assisted remethylation of homocysteine, thus causing hyperhomocysteinemia. But, this issue is controversial. In this experimental study, we attempted to determine the association between CsA administration and total homocysteine levels. Working with rabbits that have normal creatinine levels, we obviated the misleading effects of renal functional variations, which are the most important confounding factors affecting total homocysteine level. METHODS: Male New Zealand rabbits fed a standard quantity of diet received 10 days of subcutaneous injections of 10 mg/kg per day CsA. After these loading doses, CsA (20 mg/kg) was administered subcutaneously three times a week for 20 days. After first 30 days, the rabbits were followed for another 30 days without CsA therapy. Plasma creatinine, BUN, and total homocysteine levels were measured on days 0, 10, 30, and 60. RESULTS: There were no significant changes in BUN results on days 0, 10, 30, and 60 (P > .05). There was a slight, but significant, increase in mean creatinine levels during CsA administration (P < .01). However, the mean creatinine levels remained in the normal ranges during the 60 days of study. No significant changes were observed in total homocysteine levels (P > .05) compared to baseline, 10-, 30-, and 60-day values. CONCLUSION: Our experimental research minimized confounding factors. It showed that CsA does not increase total homocysteine levels, confirming clinical studies that reported no association between CsA and total homocysteine.     

Trefoil factor expression in biliary epithelium of graft-versus-host disease of the liver after allogeneic hematopoietic cell transplantation

BACKGROUND: The aims of this study were to determine the presence of trefoil factor family-3 (TFF3) expression in biliary epithelial cells (BECs) of chronic graft-versus-host disease (cGVHD) of the liver after allogeneic hematopoietic cell transplantation, to compare such expression in chronic liver diseases (CLD) with/without predominantly biliary disease, and to assess the effect of bile duct injury on the degree of TFF3 expression in BECs of cGVHD. METHODS: A total of 82 paraffin-embedded liver biopsy samples were reviewed. These samples were basically divided into two distinct groups according to the presence of ductal injury: group 1 with CLD and predominantly biliary disease (n=26: 17 cGVHD and 9 primary biliary cirrhosis [PBC]) and group 2 with CLD and predominantly parenchymal liver disease (n=56: 20 steatohepatitis and 36 chronic viral hepatitis). Group 2 was used as the controls. Immunohistochemistry was performed using a polyclonal anti-TFF3 antibody. Real-time quantitative PCR was used for the detection of TFF3 mRNA expression. RESULTS: Positive TFF3 immunohistochemical staining and the presence of TFF3 messenger RNA gene expression was demonstrably higher in group 1 than that in group 2 (P<0.0001 and P<0.05, respectively). No significant difference in terms of positive TFF3 stained BECs between GVHD and PBC samples was observed (P>0.05). The extent of TFF3 expression in GVHD samples with severe ductal injury were significantly more common than that of GVHD samples with mild/moderate ductal injury (P<0.0001). CONCLUSIONS: The expression of TFF3 in cGVHD of the liver is increased in response to bile duct damage and repair. Such expression seems to be related the severity of ductal injury.