Hyperhomocysteinemia exacerbates the development of intimal hyperplasia in Sprague-Dawley rats: Alleviation by rosiglitazone

The amino acid intermediate homocysteine (Hcy) is formed during the metabolism of methionine to cysteine. Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for coronary atherosclerosis. The circulating levels of total Hcy (tHcy) can increase due to intake of foods rich in methionine or deficiencies of vitamins such as folate, pyridoxine and cyanocobalamin, which are required for the metabolism of Hcy. In addition, mutations in the genes coding for Hcy metabolizing enzymes can contribute to an increase in tHcy levels. Clinical and epidemiological studies have shown that an elevated level of tHcy measured in serum or plasma is a strong predictor of cardiovascular disease risk, which appears to be greatest in patients who have HHcy following a methionine load. Intimal hyperplasia (IH) (intima/media [I/M] ratio) is the universal response of a vessel to injury and may result in vasoconstriction when left unattended. The effect of dietary HHcy on balloon catheter-injured carotid artery and its modulation (if any) by the peroxisome proliferator-activated receptor agonist gamma rosiglitazone was evaluated in 12-week-old female Sprague-Dawley rats fed either a control diet or a diet containing 1% L-methionine. Once the rats were established on the diet, the group that was fed 1% L-methionine was further subdivided and either given an aqueous preparation of 3 mg/kg/day rosiglitazone or the vehicle via oral gavage for one week. This was followed by surgically injuring the left carotid artery using a Maverick Over-The-Wire catheter (2.0 mm × 20 mm, 3.2F; Boston Scientific, USA). The rats were continued on their respective diets and drug regimen for 21 days postsurgery. On day 22 of the procedure, the rats were sacrificed for collection of blood, the carotid arteries and liver for biochemical and histological evaluation. Compared with controls there was a significant increase in both tHcy levels and I/M ratio in the rats fed 1% L-methionine (5.4±0.28 μM versus 32.8±3.01 μM, P<0.002; and 0.175±0.05 versus 1.05±0.23, P<0.005, respectively). The effect of rosiglitazone in rats fed the control diet was not prominent. On the other hand, administration of rosiglitazone to the rats on the 1% L-methionine diet significantly reduced the levels of serum tHcy (16.6±2.1 μM versus 32.8±3.01 μM, P<0.001); however, the tHcy levels remained significantly elevated compared with animals on the control diet (P<0.002). The group receiving the L-methionine diet plus rosiglitazone had an inhibition in the development of IH compared with those receiving the L-methionine diet alone (I/M of 0.278±0.041 versus 1.05±0.23, P<0.01). Moreover, the development of IH in the group receiving the L-methionine diet plus rosiglitazone treatment was not significantly different from that observed in the group on the control diet without rosiglitazone (0.278±0.041 versus 0.175±0.05, respectively). These findings may have important implications in deciphering the molecular mechanisms involved in the augmentation of IH in HHcy and modulation of this process by rosiglitazone.     

Risk Factors for Highly Pathogenic Avian Influenza in Commercial Layer Chicken Farms in Bangladesh During 2011

A case–control study conducted during 2011 involved 90 randomly selected commercial layer farms infected with highly pathogenic avian influenza type A subtype H5N1 (HPAI) and 175 control farms randomly selected from within 5 km of infected farms. A questionnaire was designed to obtain information about potential risk factors for contracting HPAI and was administered to farm owners or managers. Logistic regression analyses were conducted to identify significant risk factors. A total of 20 of 43 risk factors for contracting HPAI were identified after univariable logistic regression analysis. A multivariable logistic regression model was derived by forward stepwise selection. Both unmatched and matched analyses were performed. The key risk factors identified were numbers of staff, frequency of veterinary visits, presence of village chickens roaming on the farm and staff trading birds. Aggregating these findings with those from other studies resulted in a list of 16 key risk factors identified in Bangladesh. Most of these related to biosecurity. It is considered feasible for Bangladesh to achieve a very low incidence of HPAI. Using the cumulative list of risk factors to enhance biosecurity pertaining to commercial farms would facilitate this objective.     

Using lot quality assurance sampling to improve immunization coverage in Bangladesh.

OBJECTIVE: To determine areas of low vaccination coverage in five cities in Bangladesh (Chittagong, Dhaka, Khulna, Rajshahi, and Syedpur). METHODS: Six studies using lot quality assurance sampling were conducted between 1995 and 1997 by Basic Support for Institutionalizing Child Survival and the Bangladesh National Expanded Programme on Immunization. FINDINGS: BCG vaccination coverage was acceptable in all lots studied; however, the proportion of lots rejected because coverage of measles vaccination was low ranged from 0% of lots in Syedpur to 12% in Chittagong and 20% in Dhaka's zones 7 and 8. The proportion of lots rejected because an inadequate number of children in the sample had been fully vaccinated varied from 11% in Syedpur to 30% in Dhaka. Additionally, analysis of aggregated, weighted immunization coverage showed that there was a high BCG vaccination coverage (the first administered vaccine) and a low measles vaccination coverage (the last administered vaccine) indicating a high drop-out rate, ranging from 14% in Syedpur to 36% in Dhaka's zone 8. CONCLUSION: In Bangladesh, where resources are limited, results from surveys using lot quality assurance sampling enabled managers of the National Expanded Programme on Immunization to identify areas with poor vaccination coverage. Those areas were targeted to receive focused interventions to improve coverage. Since this sampling method requires only a small sample size and was easy for staff to use, it is feasible for routine monitoring of vaccination coverage.     

High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients.

PURPOSE: Prostate cancer is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. Owing to the limitations of current clinical, serologic, and pathologic parameters in predicting disease progression, we sought to investigate the prognostic value of promoter methylation of a small panel of genes by quantitative methylation-specific PCR (QMSP) in prostate biopsies. EXPERIMENTAL DESIGN: Promoter methylation levels of APC, CCND2, GSTP1, RARB2, and RASSF1A were determined by QMSP in a prospective series of 83 prostate cancer patients submitted to sextant biopsy. Clinicopathologic data [age, serum prostate-specific antigen (PSA), stage, and Gleason score] and time to progression and/or death from prostate cancer were correlated with methylation findings. Log-rank test and Cox regression model were used to identify which epigenetic markers were independent predictors of prognosis. RESULTS: At a median follow-up time of 45 months, 15 (18%) patients died from prostate cancer, and 37 (45%) patients had recurrent disease. In univariate analysis, stage and hypermethylation of APC were significantly associated with worse disease-specific survival, whereas stage, Gleason score, high diagnostic serum PSA levels, and hypermethylation of APC, GSTP1, and RASSF1A were significantly associated with poor disease-free survival. However, in the final multivariate analysis, only clinical stage and high methylation of APC were significantly and independently associated with unfavorable prognosis, i.e., decreased disease-free and disease-specific survival. CONCLUSIONS: High-level APC promoter methylation is an independent predictor of poor prognosis in prostate biopsy samples and might provide relevant prognostic information for patient management.     

Immunohistochemical p53 expression patterns in sarcomatoid carcinomas of the upper respiratory tract

Sarcomatoid carcinoma of the upper respiratory tract is a phenotypically complex neoplasm that has triggered much thoughtful discussion regarding histogenic origin and morphologic classification. In particular, its putative epithelial lineage and distinction from a pseudosarcomatous reaction are sometimes questioned. Little is known about the genetic alterations underlying sarcomatoid carcinoma. Although about 45% of conventional squamous cell carcinomas of the upper respiratory tract harbor p53 mutations, the p53 status of sarcomatoid carcinomas is not well established. p53 immunohistochemical analysis using the monoclonal antibody D07 was performed on 23 sarcomatoid carcinomas of the upper respiratory tract. Twenty tumors were biphasic, having dual epithelial and spindled components. In four of these biphasic tumors, the epithelial and spindled components were separately analyzed for p53 gene mutations by sequence analysis. p53 immunohistochemistry was also performed on 19 cases of postradiation stromal atypia. Strong and diffuse p53 staining was detected in 18 (78%) of the 23 sarcomatoid carcinomas. When the spindled component was compared with its corresponding epithelial component, identical patterns of p53 protein expression were noted in 19 (95%) of the 20 biphasic tumors. Weak p53 staining was observed in one (5%) of the 19 cases of postradiation stromal atypia. In the four biphasic tumors evaluated by DNA sequence analysis, p53 status was always the same in the paired epithelial and spindle cell components. These findings help further dispel the notion that sarcomatoid carcinoma represents a reactive spindle cell proliferation (pseudosarcoma) or a collision between a carcinoma and a sarcoma (collision tumor). Instead, the epithelial and spindled components share a common pathway of tumorigenesis despite their conspicuous divergence at the phenotypic level.     

Dysfunction of the p53 tumor suppressor pathway in head and neck cancer

It is important to examine the abnormality of the entire p53 tumor suppressor pathway in head and neck cancer. We examined the mRNA expressions of p53 regulatory factors, p33ING1 and p14ARF, and a p53-target gene, p21WAF1 in head and neck cancer. Nine of 14 benign pleomorphic adenomas (PAs) and 7 of 8 malignant salivary gland tumors (MSGTs) expressed p33ING1 mRNA. Thirteen of 14 PAs expressed p14ARF mRNA, however, only 1 of 8 MSGTs expressed p14ARF mRNA. Eight of 14 PAs and 7 of 8 MSGTs expressed p21WAF1 mRNA. In salivary gland tumors, there was clear correlation between the expression of p33ING1 and p21WAF1 (p<0.0001, r2=0.53). However, there was no correlation between the expression of p14ARF and p21WAF1 (p=0.6543, r2=0.009). Twenty-six of 28 oral squamous cell carcinomas (SCCs) expressed p33ING1 mRNA. Nineteen of 28 oral SCCs expressed p14ARF mRNA. All of the oral SCCs expressed p21WAF1 mRNA. In oral SCCs, the expressions of both p33ING1 (p=0.009, r2=0.181) and p14ARF (p=0.0009, r2=0.271) correlated with the expression of p21WAF1. Interestingly, 24 of 26 oral SCCs (92%) showed either abnormality of p53 itself or loss of expression of p53 regulatory factors, p33ING or p14ARF. These results suggest that head and neck cancer often involve the dysfunction of p53 tumor suppressor pathway.     

Socioeconomic inequality of cancer mortality in the United States: a spatial data mining approach

Background  

The objective of this study was to demonstrate the use of an association rule mining approach to discover associations between selected socioeconomic variables and the four most leading causes of cancer mortality in the United States. An association rule mining algorithm was applied to extract associations between the 1988–1992 cancer mortality rates for colorectal, lung, breast, and prostate cancers defined at the Health Service Area level and selected socioeconomic variables from the 1990 United States census. Geographic information system technology was used to integrate these data which were defined at different spatial resolutions, and to visualize and analyze the results from the association rule mining process.     

Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non- competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.      

Prevalence and impact of chronic childhood conditions in Auckland, New Zealand

Objective : To establish the prevalence of specific chronic conditions of childhood in the Auckland area and to quantify resource use by these children.
Methodology : Estimates were made from available registry data and published data sources of the population of children with selected chronic conditions resident in the Auckland Area Health Board area. Resource use data were extracted for admissions to Auckland public hospitals and from providers of community based technology services.
Results : The largest community prevalence groups are those with asthma, intellectual handicap, congenital heart disease and epilepsy. Children aged 0-14 with chronic conditions accounted for at least 14340 hospital days stay in Auckland in 1992 at an estimated minimum cost of $7.9 million. Over 200 children are dependent on technological aids at home.
Conclusions : There are sparse data on the numbers and needs of children with chronic conditions in the population. A non-categorical approach which crosses disease entities may be the best method of meeting common needs.