Follow-up and outcomes for resection of colorectal liver metastases in Edinburgh.

AIM: The aim of this study was to assess the value of a defined follow-up protocol for patients undergoing potentially curative hepatic resection for colorectal hepatic metastases. METHODS: A standard protocol for the duration of the study consisted of clinical assessment, serum carcinoembryonic antigen (CEA) and computed tomography. Patterns of recurrence, method and timing of diagnosis and outcome were recorded. RESULTS: One hundred and ninety-one patients underwent potentially curative resection from 1989 to 2004 of whom 103 developed recurrence. The median (inter-quartile range) follow-up was 24.4 (6.5-42.3) months. The median (IQR) time to recurrence and overall survival was 25.0 (10 -not yet reached) and 45.2 (21-123) months, respectively. Seventeen patients (8.9%) underwent further surgery with curative intent. Fifty-five patients (57.9%) had recurrence diagnosed at routine follow-up with 71% (44/62) being diagnosed by CEA and CT. The CEA was elevated in 85.7% (72/84 patients) at the time of diagnosis of recurrence. CONCLUSION: Although the detection of recurrent disease is common during follow-up after hepatic resection for colorectal metastases, few patients will be suitable for further intervention with curative intent. The exact nature of the follow-up protocol remains to be determined but if it is going to be performed it should be most intensive within the first 3 years.     

Tunicamycin enhances the anticellular activity of interferon by inhibiting G1/S phase progression in 3T3 cells.

We have shown earlier that the cell growth inhibitory activity of interferon (IFN) is significantly enhanced by tunicamycin (TM) (Maheshwari et al., Science 219, 1339-1341, 1983). In this report, we investigated various regulatory points of synergistic action between TM and IFN-alpha/beta that inhibit cell growth in NIH 3T3 cells. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) viability assays showed a dose-dependent increase in percentage inhibition of the cells when treated with either TM or IFN. When doses of TM and IFN that had no significant inhibition on cell viability were used in combination, there was a pronounced suppression of DNA synthesis (tritiated thymidine incorporation). Flow cytometry studies revealed that individual treatments with either IFN or TM that did not alter the cell cycle profile, when combined, resulted in an impaired cell cycle by inhibiting G1/S progression. The blockage of G1/S transition was associated with reduction of cyclin-dependent kinase (CDK4) activity. The mRNA (analyzed by ribonuclease protection assay) and protein levels (assayed by Western blotting) of cyclins D1, D3, and CDK4 were downregulated by combined treatment with IFN and TM. An increase in the expression of p27/kipl, an inhibitor of CDK4, was observed in cells that were treated with both IFN and TM. These studies suggest that insufficient formation of the active cyclin/CDK complex could possibly be deferring the cells from normal cycling and may be responsible for the ability of TM to enhance cell growth inhibition induced by IFN.     

High and low serum potassium associated with cardiovascular events in diuretic-treated patients.

OBJECTIVE: To determine the relationship of moderately high and low concentrations of serum potassium with cardiovascular disease events among treated hypertensive patients. DESIGN: An observational cohort study with prospectively collected data. SETTING: A worksite treatment program for mild hypertension. PATIENTS: All program participants with baseline and at least one annual follow-up measure of serum potassium; 7,653 individuals with 6.7 years mean follow-up met these criteria. MAIN OUTCOME MEASURES: Outcome events were admissions to hospital because of cardiovascular disease, and deaths. The research question regarding serum potassium categories was formulated after data collection. The serum potassium concentration (mean +/- 2SD) of the study population was used to define low (3.0-3.5 mmol/l), high (5.1-5.9 mmol/l) and middle (3.6-5.0 mmol/l) categories. RESULTS: Individuals with low (n = 146) and high (n = 226) serum potassium had significantly greater risk for cardiovascular disease events than those in the middle category (n = 7,281). Multivariate adjusted hazard ratios from Cox models were 2.6 [95% confidence intervals (CI) 1.5-4.4] for the low potassium group and 1.7 (95% CI 1.0-2.7) for the high potassium group, with the middle group as reference. Among 1,679 individuals who regularly took diuretics, hazard ratios were 4.3 (95% CI 2.4-7.9) for the low potassium group and 6.7 (95% CI 2.8-15.9) for the high group. Neither low nor high potassium was significantly associated with outcome events for those not regularly using diuretics. CONCLUSIONS: These data confirm an association of mild hypokalemia with increased cardiovascular events among diuretic-treated hypertensive patients. In addition, we have found a similar increased cardiovascular risk associated with modest hyperkalemia among these patients. Whether modification of these serum potassium concentrations would alter that risk remains to be determined.     

Detection of novel coupled mutations in the katG gene (His276Met, Gln295His and Ser315Thr) in a multidrug-resistant Mycobacterium tuberculosis strain from Chennai, India, and insight into the molecular mechanism of isoniazid resistance using structural bioinformatics approaches

This study reports on the structural basis of drug resistance targeting the katG gene in a multidrug-resistant Mycobacterium tuberculosis (MDR-TB) strain with two novel mutations (His276Met and Gln295His) in addition to the most commonly reported mutation (Ser315Thr). A structural bioinformatics approach was used to predict the structure of the mutant KatG enzyme (MT). Subsequent molecular dynamics and docking studies were performed to explain the mechanism of isoniazid (INH) resistance. The results show significant conformational changes in the structure of MT leading to a change in INH binding residues at the active site, with a significant increase in the inhibition constant (Ki) of 5.67 μm in the mutant KatG-isoniazid complex (MT-INH) compared with the wild-type KatG-isoniazid complex (WT-INH). In the case of molecular dynamics studies, root mean square deviation (RMSD) analysis of the protein backbone in simulated biological conditions revealed an unstable trajectory with higher deviations in MT throughout the simulation process (1 ns). Moreover, root mean square fluctuation (RMSF) analysis revealed an overall increase in residual fluctuations in MT compared with the wild-type KatG enzyme (WT), whilst the INH binding residues of MT showed a decreased fluctuation that can be observed as peak deviations. Hence, the present study suggests that His276Met, Gln295His and Ser315Thr mutations targeting the katG gene result in decreased stability and flexibility of the protein at INH binding residues leading to impaired enzyme function.     

Medication therapy management services in West Virginia: Pharmacists' perceptions of educational and training needs

BackgroundThe Medicare Modernization Act of 2003 recognizes the challenges associated with drug therapy in elderly patients with multiple chronic diseases, and requires the development of medication therapy management services (MTMS) for such beneficiaries.ObjectiveTo assess pharmacists' perception of educational and training needs necessary to implement MTMS in community pharmacies in West Virginia, USA.MethodsSelf-administered mail surveys with an explanatory cover letter were mailed to the designated pharmacist-in-charge (PIC) of each licensed community pharmacy (506) in West Virginia. Main outcome measures included pharmacists' comfort level, perceptions of value to patients, barriers to provision of services, and pharmacists' interest in receiving education and training related to MTMS.ResultsOf the 503 surveys that were deliverable, 203 (40.4%) usable responses were received. Fifty-five (27.1%) PICs reported that MTMS are currently being provided in their pharmacy. Respondents were likely to use services that aid in the development of MTMS and disease-state management, felt relatively comfortable in providing MTMS, and had a favorable view of the value of services to patients, but reported that lack of time tended to be a barrier.ConclusionPICs in West Virginia are interested in and open to their pharmacists receiving education and training for implementation of MTMS.     

Diagnosis and treatment of tuberculous pleural effusion in 2006

Tuberculous (TB) pleural effusion occurs in approximately 5% of patients with Mycobacterium tuberculosis infection. The HIV pandemic has been associated with a doubling of the incidence of extrapulmonary TB, which has resulted in increased recognition of TB pleural effusions even in developed nations. Recent studies have provided insights into the immunopathogenesis of pleural TB, including memory T-cell homing and chemokine activation. The definitive diagnosis of TB pleural effusions depends on the demonstration of acid-fast bacilli in the sputum, pleural fluid, or pleural biopsy specimens. The diagnosis can be established in a majority of patients from the clinical features, pleural fluid examination, including cytology, biochemistry, and bacteriology, and pleural biopsy. Measurement of adenosine deaminase and interferon-gamma in the pleural fluid and polymerase chain reaction for M tuberculosis has gained wide acceptance in the diagnosis of TB pleural effusions. Although promising, these tests require further evaluation before their routine use can be recommended. The treatment of TB pleural effusions in patients with HIV/AIDS is essentially similar to that in HIV-negative patients. At present, evidence regarding the use of corticosteroids in the treatment of TB pleural effusion is not clear-cut.     

A rare association of Ebstein's anomaly of tricuspid valve with rheumatic mitral stenosis

Mitral valve abnormalities have been described in Ebstein's anomaly, but acquired rheumatic mitral valve disease is an extremely rare association. We describe a classical case of Ebstein's anomaly of tricuspid valve with severe rheumatic mitral stenosis. This patient had mild mitral regurgitation, pulmonary hypertension and atrial fibrillation.