An innovative job placement model for unemployed methadone patients: a randomized clinical trial

This article presents the outcomes of an innovative vocational rehabilitation model designed for methadone-maintained patients -- the Customized Employment Supports (CES) model. CES counselors work intensively with a small caseload of patients to overcome the vocational as well as non-vocational barriers that hinder employment, with the goal of attaining rapid job placement. A randomized clinical trial was implemented at two methadone treatment programs in New York City and was funded by the National Institute on Drug Abuse The study tested the hypothesis that patients assigned to the experimental (CES) condition would have better employment outcomes than those assigned to a control condition who received standard vocational counseling at the programs. The data were collected from May 2001 through April 2005. The efficacy sample for the analysis consisted of 168 patients who completed follow-up interviews. The sample was 58% male, 75% minority group, average age 45 years, and in methadone treatment for an average of five years. The results supported the hypothesis for two measures of employment; i.e., the CES group was significantly more likely than the control group to obtain both any paid employment and informal paid employment. However, there were no significant differences for competitive employment or total earnings. The study's limitations are noted. Implications of the findings for the improvement of vocational rehabilitation for addiction patients are discussed.     

Effect of a series of triorganotins on the immune function of human natural killer cells

Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. They are able to destroy tumor and virally infected cells. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. Organotins (OTs) have been shown to interfere with the tumor-destroying function of human NK cells. The purpose of the current study was to explore the relationship of a series of triorganotins, that differ in structure by only a single organic group, for their capacity to block NK tumor-cell destroying (lytic) function. Here we examine the series: trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT). NK cells were exposed to TMT, DMPT, MDPT or TPT for 1, 24, 48h, or 6d. A 1h exposure to TMT, at concentrations as high as 20μM, had no effect on lytic function. However, concentrations as low as 2.5μM were able to decrease NK tumor-destroying function after 6d. A 1h exposure to DMPT had no effect on lytic function, however, after 6d there was an 80-90% decrease in lytic function at 1μM. Exposure to MDPT (as low as 2.5μM) decreased NK function at 1h, after 6d there was as much as a 90% decrease at concentrations as low as 100nM MDPT. TPT decreased lytic function in a manner similar to MDPT, however, it was more effective at 1h than MDPT. The effect of the triorganotins on the ability of NK cells to bind to targets was studied, to determine if this contributed to the loss of lytic function. The relative immunotoxic potential of this series of compounds is TPT≈MDPT>DMPT>TMT.     

Matrix vesicles are enriched in metalloproteinases that degrade proteoglycans

Summary This study examined the presence of extracellular matrix processing enzymes in matrix vesicles produced by rat costochondral resting zone and growth zone chondrocytes in culture. Optimum procedures for the extraction of each enzyme activity were determined. Enzyme activity associated with chondrocyte plasma membrane microsomes was used for comparison. There was a differential distribution of the enzyme activities related to the cartilage zone from which the cells were isolated. Acid and neutral metalloproteinase (TIMP), plasminogen activator, and betaglucuronidase were highest in the growth zone chondrocyte (GC) membrane fractions when compared with matrix vesicles and plasma membranes isolated from resting zone chondrocyte (RC) cultures. There was a threefold enrichment of total and active acid metalloproteinase in GC matrix vesicles, whereas no enrichment in enzyme activity was observed in RC matrix vesicles. Total and active neutral metalloproteinase were similarly enriched twofold in GC matrix vesicles. TIMP, plasminogen activator, and betaglucuronidase activities were highest in the plasma membranes of both cell types. No collagenase, lysozyme, or hyaluronidase activity was found in any of the membrane fractions. The data indicate that matrix vesicles are selectively enriched in enzymes which degrade proteoglycans. The highest concentrations of these enzymes are found in matrix vesicles produced by growth zone chondrocytes, suggesting that this may be a mechanism by which the more differentiated cell modulates the matrix for calcification.     

Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca²⁺ channel antagonists, flunarizine and verapamil against TdP were investigated.

EXPERIMENTAL APPROACH

Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca²⁺ sparks in RyR2^R4496+/+ mouse myocytes; and (iii) peak and late I_Na in SCN5A-HEK 293 cells.

KEY RESULTS

Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I_Na. Ca²⁺ sparks were reduced with verapamil.

CONCLUSIONS AND IMPLICATIONS

Robust anti-arrhythmic efficacy was seen with both Ca²⁺ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.     

Estrogen added intermittently,but not continuously,stimulates differentiation and bone formation in SaOS-2 cells

Although it is well established that estrogen inhibits bone resorption, its effects on bone formation remain controversial. We studied the effects of intermittent and continuous treatment with estrogen on bone formation in vitro using long term cultures of SaOS-2 cells under conditions that permit mineralization. SaOS-2 cells cultured in dexamethasone, ascorbic acid and beta-glycerophosphate for up to 17 d formed mineralized bone nodules as visualized by von Kossa staining. Electron microscopic analysis of ultrathin sections of representative mineralized nodules showed the presence of mineral deposits, collagen fibrils and osteocytes. Both the mineralized nodule numbers and areas increased exponentially with time of culture after addition of beta-glycerophophate at day 8. Intermittent addition of 17beta-estradiol (E(2)) for 6 h or 24 h of every 48 h starting at day 3 or day 8 to the end of culture period resulted in a specific time- and dose-dependent stimulation of mineralized bone nodule number and area, and alkaline phosphatase activity which were accompanied with increase in cell numbers. On the other hand, continuous treatment with E(2) added every 48 h had no effect. The estrogen receptor alpha (ERalpha) mRNA expression was stimulated after 6 or 24-h (intermittent), but not after 48-h (continuous) treatment with E(2). The stimulatory effect of E(2), when added intermittently, but not continuously, on differentiation and bone formation in human osteoblasts in culture may be relevant to previous reports of stimulatory effects of E(2) on bone formation in vivo.     

Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer

BACKGROUND: Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS: Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients. CONCLUSIONS: For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.     

Differences in prognostic factors and survival among white and Asian men with prostate cancer, California, 1995-2004

BACKGROUND: There are very limited data concerning survival from prostate cancer among Asian subgroups living in the U.S., a large proportion of whom reside in California. There do not appear to be any published data on prostate cancer survival for the more recently immigrated Asian subgroups (Korean, South Asian [SA], and Vietnamese). METHODS: A study of prognostic factors and survival from prostate cancer was conducted in non-Hispanic whites and 6 Asian subgroups (Chinese, Filipino, Japanese, Korean, SA, and Vietnamese), using data from all men in California diagnosed with incident prostate cancer during 1995-2004 and followed through 2004 (n = 116,916). Survival was analyzed using Cox proportional hazards models. RESULTS: Whites and Asians demonstrated significant racial differences in all prognostic factors: age, summary stage, primary treatment, histologic grade, socioeconomic status, and year of diagnosis. Every Asian subgroup had a risk factor profile that put them at a survival disadvantage compared with whites. Overall, the 10-year risk of death from prostate cancer was 11.9%. However, in unadjusted analyses Japanese men had significantly better survival than whites; Chinese, Filipino, Korean, and Vietnamese men had statistically equal survival; and SA men had significantly lower survival. On multivariate analyses adjusting for all prognostic factors, all subgroups except SA and Vietnamese men had significantly better survival than whites; the latter 2 groups had statistically equal survival. CONCLUSIONS: Traditional prognostic factors for survival from prostate cancer do not explain why most Asian men have better survival compared with whites, but they do explain the poorer survival of SA men compared with whites.     

Cancer survival in Costa Rica, 1995-2000

The Costa Rica national tumour registry was founded in 1976 and nationwide data collection commenced in 1980. Cancer registration is predominantly done by passive methods. The registry contributed data on survival for invasive cancers of breast and cervix and in situ cancer of the cervix registered during 1995-2000. Followup has been carried out predominantly by passive methods, with median follow-up ranging from 31-47 months. The proportion of cases with histological confirmation of cancer diagnosis was 92% for invasive cancers and almost 100% for in-situ cancer of the cervix; death certificates only (DCOs) comprised 3%, and 78-86% of total cases registered were included for survival analysis. The one-, three- and five-year relative survival were 93%, 77% and 68%, respectively for breast cancer; the corresponding figures for invasive cervix cancer were 83%, 61% and 54%, respectively. The five-year relative survival for in-situ cervix cancer was 99%. A decreasing survival with increasing age group at diagnosis was noted for in-situ cancer of the cervix, while it fluctuated for invasive breast and cervix cancers. A decreasing survival with increasing clinical extent of disease was noted for invasive breast and cervix cancers.     

Quality of cancer care among foreign‐born and US‐born patients with lung or colorectal cancer

BACKGROUND:

Disparities in care have been documented for foreign‐born cancer patients in the United States. However, few data are available regarding patients with lung and colorectal cancer. In the current study, the authors assessed whether patient‐reported quality and receipt of recommended care differed between US‐born and foreign‐born cancer patients.

METHODS:

The authors collected surveys and medical records for a population‐based cohort including white, Hispanic, and Asian adults (2205 US‐born and 890 foreign‐born individuals) with lung or colorectal cancer diagnosed in California from 2003 through 2005. Logistic regression was used to assess the association between nativity and patient‐reported quality of care and receipt of recommended treatments (adjuvant chemotherapy for stage III colon cancer, adjuvant chemotherapy and radiotherapy for stage II/III rectal cancer, and curative surgery for stage I/II nonsmall cell lung cancer). The authors also assessed whether language explained any differences in care by nativity.

RESULTS:

Overall, 46% of patients reported excellent care, but foreign‐born patients were less likely than US‐born patients to report excellent quality of care (adjusted odds ratio [AOR], 0.80; 95% confidence interval [95% CI], 0.65‐1.00), a difference partly explained by the language of the survey, an indicator of English proficiency. Rates of recommended therapies ranged from 64% to 85%; foreign‐born patients were less likely to receive chemotherapy and radiotherapy for stage II/III rectal cancer (AOR, 0.35; 95% CI, 0.12‐0.99). Rates of other treatments did not differ significantly by nativity.

CONCLUSIONS:

Foreign‐born cancer patients reported lower quality of care and were less likely to receive some cancer therapies than patients born in the Unites States. Better coordination of care and communication regarding cancer treatments and expanded use of interpreters may lessen these disparities. Cancer 2010. © 2010 American Cancer Society.     

MLPA mutation detection in Argentine HNPCC and FAP families

Colorectal cancer (CC) is the secondary cause of death in the Western countries of which approximately 15% are considered to be hereditary. The hereditary forms are Familial Adenomatous Polyposis (FAP) and Hereditary Non Polyposis Colorectal Cancer (HNPCC) which is the commonest form. The detection of mutations in the MMR and apc related genes, allows the development of health prevention strategies. Different molecular diagnostic strategies are available for the detection of mutations in these genes, i.e. DGGE, SSCP and direct sequencing. However, deletions and duplications of one or more consecutive exons, which account for around 50% of the total alterations in MMR genes, cannot be detected by PCR based methodologies due to the non quantitative nature of these techniques. The aim of our work has been the standardization of a methodology, called Multiplex Ligation-Dependent Probe Amplification, which allows the detection of genomic deletions and duplications as primary analysis in HNPCC and FAP patients in Argentina. In this case, we inform that the application of MLPA allowed the detection of a missence mutation, without the need for direct sequencing of the complete genes involved. A PCR/RFLP strategy was afterwards designed to detect the C<T change on codon 718 of mlh1 gene in members of the family. For a developing country like Argentina, which has limited resources for genetic diagnosis, this MLPA application has avoided an unaffordable cost as the complete sequencing of all the involved genes. The application of MLPA in our country contributes to improvement in the diagnosis of hereditary CC and allows the development of preventive health interventions.