The implementation of a hepatitis C testing service in community pharmacies: I-COPTIC consensus statement.

OBJECTIVES: This aimed to develop a blueprint for an effective community pharmacy Hepatitis C virus (HCV) testing service by producing a consensus statement. STUDY DESIGN: This was a modified Delphi process. METHODS: We recruited a heterogenous panel of experts (who had been involved in the setup or delivery of a community pharmacy HCV testing service) by purposive and chain referral methods. We had three rounds of a modified Delphi process. The first was a series of questions with free text responses and was analysed using thematic analysis, and the second and third were statements for the respondents to rate using a 7-point Likert scale. Consensus was predefined in a published protocol, and the results were reviewed by a public and patient involvement panel before the statement was finalised. RESULTS: We had 24 participants, including community and hospital-based pharmacists, local pharmaceutical committee members, charity representatives (Hepatitis C Trust), local clinical service lead, nurse specialists and doctors. The response rate of the first, second and third rounds were 100%, 96% and 88%, respectively. After the third round, we had 60 statements that reached consensus. We discussed the accepted statements with a patient and public involvement group. We used these statements to produce the I-COPTIC statement and a graphical summary. CONCLUSIONS: We developed a blueprint for the design of a gold standard community pharmacy HCV testing service. We believe this will support the successful implementation of community pharmacy testing for HCV. Community pharmacy testing is an important service to help achieve and maintain HCV elimination.

Complications and mortality associated with olecranon fractures in the elderly: a retrospective cohort comparison from a large level one trauma centre.

Background: Olecranon fractures in the elderly have an increasing incidence. This retrospective study aims to identify the complications and survivorship of these patients. Methods: All patients >70 years old treated for an olecranon fracture at our institution were identified between 2007 and 2019. Loss of reduction and/or metalwork loosening was recorded. Also noted were wound healing problems, deep/superficial infections, and any subsequent treatment including return to surgery and/or removal of metalwork. Results: From a total of 177 cases, 28 presented with concomitant fractures (16%), half of which were hip fractures. The largest treatment group underwent tension band wiring (n = 82, 46%, mean age 80.8 yrs). Twenty-one of these suffered failure of fixation (26%), all requiring return to surgery. The second largest treatment group underwent plating (n = 50 28%, mean age 80.1 yrs). Four of these suffered failure of fixation (8%), all requiring return to surgery. Forty-four patients were treated non-operatively (25%, mean age 83.8 yrs). Two patients suffered other complications (4.5%). Overall 1 year survivorship was 0.82. Discussion: Olecranon fractures in the elderly have higher than expected 1 year mortality rates. Operative management results in high complication rates, often requiring return to surgery for metalwork problems. Significant consideration of treatment options is required in this cohort.

Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: We investigated the association between self-reported skirt size (SS) and change in SS, and incidence of chronic liver disease (CLD) in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: Women recruited to UKCTOCS in England without documented CLD self-reported their current UK SS during trial participation and were asked to recall their SS when aged in 20s (via completion of a questionnaire 3-5 years after recruitment). Participants were followed up via electronic health record linkage and hazard ratios (HR) calculated for incident liver-related events (LRE). RESULTS: Three hundred twenty-two (0.3%) of 94,124 women experienced a first LRE. Compared to SS ≤ 16, rates of LRE were higher in the SS ≥ 18 groups (both when aged in 20s and at questionnaire completion). Event rates were higher if there was no change in SS or an increase in SS, compared to a decrease in SS. In the models adjusted for potential confounders, HRs for LRE were higher in the groups of women reporting SS ≥ 18 both when aged in 20s (HR = 1.39 (95% CI; 0.87-2.23)) and at questionnaire completion (HR = 1.37 (95% CI; 1.07-1.75)). Compared to a decrease in SS, HRs were higher in the no change (HR = 1.78 (95% CI; 0.95-3.34)) and increase (HR = 1.80 (95% CI; 1.01-3.21)) groups. CONCLUSION: CLD is associated with high SS and an increase in SS over time. These data suggest SS can be used in simple public health messages about communicating the risk of liver disease. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000.

Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection.

Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.

A late haemorrhagic complication in an arteriovenous malformation cured with radiosurgery. Case report.

Radiosurgery is a recognized safe form of treating and usually curing arteriovenous malformations (AVMs). Complications related to radiosurgery, especially late sequelae, are rare. Such sequelae may be secondary to incomplete treatment of the original lesion such as haemorrhage, or secondary to the radiation damage to the tissue, or both. Sometimes treatment may induce new lesions. We report a patient who had an AVM cured with radiosurgery, but developed hemisensory loss acutely and had changes on MRI in keeping with a haematoma. We discuss the possible differential diagnosis that should be considered.

Review of invasive cervical cancers and uptake of disclosure of results: an audit of procedures and response.

OBJECTIVE: To audit the process and outcome of case reviews performed for invasive cervical cancers diagnosed between 2003 and 2007, and the timely disclosure of results to the respective patients. METHODS: Invasive cervical cancer reviews were performed on all cases of cervical cancer diagnosed between 2003 and 2007. Following the review, women were classified into two categories: a group who developed invasive cancer despite adherence to the screening programme or in whom a management or diagnostic decision was determined to have been a principal factor in the development of their disease (Group A), and a second group who either had never undergone a cervical smear or had been established defaulters from the screening programme (Group B). RESULTS: Ninety-seven of the 98 cases of invasive cervical cancer diagnosed in the 4-year study period were reviewed. Sixty of the 61 women in Group A were sent an invitation to discuss the results of their case review. Thirty-six (37%) were classified as Group B, and it was deemed neither appropriate nor possible to invite the patients for a review consultation. Of the women sent an invitation, only 24 (40%) chose to attend. CONCLUSION: A policy of selective invitation for the disclosure of invasive review results is feasible. Less than one-half of patients diagnosed with cervical cancer appear to want to know how they developed cervical cancer despite previously participating in a screening programme.

Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C.

Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.

Implementing the national invasive cervical cancer audit: a local perspective.

OBJECTIVE: To monitor the effectiveness of the cervical screening programme and identify suboptimal management in order to improve patient care. DESIGN: Retrospective study. SETTING: A university hospital serving a population of 1 million people. POPULATION: All women diagnosed with a cervical cancer between 2003 and 2006. METHODS: Analysis of data from invasive cervical cancer reviews. MAIN OUTCOME MEASURE: Categorisation of cervical cancer cases according to the Invasive Cervical Cancer Audit classification. RESULTS: Eighty-seven women were diagnosed with cervical cancer during the 3-year study period. The 'lapsed attender' group accounted for the greatest number of cases (30%), followed by screen detected (26%), interval cancers (13%), never attended (12%), lost to follow-up (10%) and never invited (9%). Women who had never attended for cytology presented with higher stage disease, stage-II or above, compared with the screen-detected cases: 60% were stage II or above, compared with 13.0%, Chi-square P = 0.018. The most frequently identified screening programme problem was patient compliance, which was determined to be the principle contributing factor in 39 cases (45%) and a secondary factor in a further ten cases. CONCLUSIONS: The categorisation of cervical cancer cases has the potential of yielding invaluable information for improving programme effectiveness. Patient compliance is the greatest challenge to the screening programme, and the need for regular screening and adherence to follow-up regimens needs to be reinforced in order to maximise the efficacy of the national screening programme.

Cervical cytology/histology discrepancy: a 4-year review of patient outcome.

OBJECTIVE: To investigate the diagnosis, review and management of women identified as having a cytology/histology discrepancy. METHODS: A review of all patients diagnosed with a discrepancy between referral smear and cervical histology was performed between January 2003 and December 2004. Cases were followed for a minimum of 4 years and patient management and outcome reviewed. RESULTS: A significant discrepancy was identified in 79 cases, 0.1% of all smears (n = 80,926) analysed during the study period. A discrepancy between cytology and histology, obtained from large loop excision of the transformation zone (LLETZ), was confirmed by multidisciplinary review in 42 cases (53.2%). In 37 cases (46.8%) the cytological and/or histological diagnosis was revised; the cytology was significantly more likely than the histology to be amended (chi square P = 0.005), most often because cytology had been overcalled. Of the confirmed discrepancy cases, 33 (78.6%) were due to high-grade squamous cell or glandular abnormalities on cytology with a negative, inflammatory or human papillomavirus (HPV) infection on histology (HGC/NH). HGC/NH cases were managed by cytological follow-up in 29 (87.9%), of which 72.4% of the smears were negative when performed at least 6 months post-excision. During the 4-year follow-up period six women with a confirmed HGC/NH underwent a repeat cervical excision (hysterectomy or LLETZ), and of these, HPV effect was seen in two cases but no cervical intraepithelial neoplasia was detected in any of the histological specimens. CONCLUSION: Cytology overcall was responsible for the majority of cytology/histology discrepancies. A confirmed discrepancy is not an indication for a further excisional biopsy but follow-up is essential because a small percentage of patients may have disease that has been missed.

Discharge planning from hospital to home.

BACKGROUND: Discharge planning is a routine feature of health systems in many countries. The aim is to reduce hospital length of stay and unplanned readmission to hospital, and improve the co ordination of services following discharge from hospital thereby bridging the gap between hospital and place of discharge. Sometimes discharge planning is offered as part of an integrated package of care, which may cover both the hospital and community. The focus of this review is discharge planning that occurs while a patient is in hospital; we exclude studies that evaluate discharge planning with follow up care. OBJECTIVES: To determine the effectiveness of planning the discharge of patients moving from hospital. SEARCH STRATEGY: Relevant studies were identified using Medline, Embase, SIGLE database for grey literature, Bioethics database, Health Plan, Psych. Lit, Sociofile, CINAHL, Cochrane Library, Econ Lit, Social Science Citation Index, EPOC register. The review was updated using the EPOC trials register in August 2002. STUDY DESIGN: randomised controlled trials (RCTs) that compare discharge planning (the development of an individualised discharge plan) with routine discharge care. PARTICIPANTS: all patients in hospital. INTERVENTION: the development of an individualised discharge plan. DATA COLLECTION AND ANALYSIS: Data analysis and quality assessment was undertaken independently by two reviewers using a data checklist. Studies are grouped according to patient group (elderly medical patients, surgical patients, and those with a mix of conditions), and by outcome. MAIN RESULTS: Three new studies were included in this update. In total we included eleven RCTS: 6 trials recruited patients with a medical condition (2,368 patients), and four recruited patients with a mix of medical and surgical conditions (2,983 patients), one of these four recruited medical and surgical patients as separate groups, and the final trial recruited 97 patients in a psychiatric hospital and from a general hospital. We failed to detect a difference between groups in mortality for elderly patients with a medical condition (OR 1.44 95% CI 0.82 to 2.51), hospital length of stay (weighted mean difference -0.86, 95% CI -1.9 to 0.18), readmission rates (OR 0.91 95% CI 0.67 to 1.23) and being discharged from hospital to home (OR 1.15 95% CI 0.72 to 1.82). This was also the case for trials recruiting patients recovering from surgery and those recruiting patients with a mix of medical and surgical conditions. One trial comparing a structured care pathway for patients recovering from a stroke with multidisciplinary care reported a significant rate of improvement in functional ability and quality of life for the control group (median change in Barthel score between 4 to 12 weeks of 2 points for the treatment group, versus 6 for the control group, p<0.01); (Euroqol scores at 6 months 63 for the treatment group, vs. 72 for the control group, p<0.005). Two trials reported that patients with medical conditions allocated to discharge planning reported increased satisfaction compared with those who received routine discharge. No statistically significant differences were reported for overall health care costs. REVIEWER'S CONCLUSIONS: The impact of discharge planning on readmission rates, hospital length of stay, health outcomes and cost is uncertain. This reflects a lack of power as the degree to which we could pool data was restricted by the different reported measures of outcome. It is possible that even a small reduction in length of stay, or readmission rate, could have an impact on the timeliness of subsequent admissions in a system where there is an shortage of acute hospital beds.

Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

PROPOSED SERVICE: The service proposed is the use of implantable cardioverter defibrillators (ICDs) in the management of risk factors leading to sudden cardiac death (SCD). ICDs are similar in size to a pacemaker and are intended to prevent death due to life-threatening ventricular tachyarrhythmias. EPIDEMIOLOGY AND BACKGROUND: SCD occurs in approximately 100,000 people annually in the UK and is usually due to ventricular tachyarrhythmia. Increasing numbers of people are surviving a first episode of ventricular tachyarrhythmia and are at high risk of further episodes. Standard treatments for those at high risk have been anti-arrhythmic drugs, catheter ablation or surgery and, increasingly, vasodilating beta-blockers. METHODS: Electronic databases were searched for the period 1980-99. In addition, bibliographies of related papers were assessed for relevant studies, and experts were contacted to identify additional published and unpublished references. Studies were included if they were systematic reviews, meta-analyses or randomised controlled trials (RCTs) comparing ICDs with conventional therapy in people at high risk of SCD. NUMBER AND QUALITY OF STUDIES AND DIRECTION OF EVIDENCE: Seven RCTs on effectiveness the majority of which were of good quality, eight cost-effectiveness analyses most of which were older studies and based on non-UK data, and two good-quality literature reviews one of which was a critical appraisal of the literature of effectiveness and cost-effectiveness of ICD therapy, and the other a review of the cost-effectiveness of ICD therapy. These showed changes in absolute risk of total mortality ranging from an increase of 1.7% to a reduction of 22.8% (relative risk reductions of -7% to +54%). SUMMARY OF BENEFITS: Estimated benefits from RCT data are 0.23-0.8 additional years of life with ICD therapy compared with anti-arrhythmic drug therapy. COSTS: Unit cost of ICDs (based on 1999/2000 prices), ranges from pound 12,500 to pound 22,000. Total discounted costs for 3 years range from pound 20,000 to pound 29,000. COST-EFFECTIVENESS: Cost-effectiveness estimates in the literature identified range from $11,000 to $146,000 per life-year saved. Using UK cost data from three hospitals and trial survival data from one RCT, the estimate of cost-effectiveness from this review ranges between pound 20,250 and pound 87,000 per life-year saved. COST-UTILITY: Cost per quality-adjusted life-year is estimated by the authors of this review at pound 21,300 to pound 108,800 (using survival data from one trial and quality-of-life indices derived from clinical opinion). These figures remain speculative until quality-of-life data from ongoing trials are available to inform future UK cost-effectiveness/utility analyses. IMPLICATIONS: If implemented for indications supported by evidence from RCTs, ICDs may cost the NHS in excess of pound 24 million per annum. FUTURE RESEARCH: Future research should include the use of British Pacing and Electrophysiological Group registries to assess the use of different types of ICD and current service provision.

Prenatal diagnosis of dominant dystrophic epidermolysis bullosa, by COL7A1 molecular analysis.

We report the first direct molecular prenatal diagnosis, undertaken for the autosomal dominant form of dystrophic epidermolysis bullosa (DDEB). The proband had a moderately severe form of DDEB, with episodic blistering of skin and mucosal involvement. Diagnostic histopathological examination, using electron microscopy to evaluate skin from a fresh blister, demonstrated a zone of cleavage beneath the epidermal-dermal junction, thereby assigning the EB as dystrophic. DNA analysis of COL7A1, the gene encoding type VII collagen, identified a heterozygous transversion (G to A) in the triple helix domain (G2043R). For any subsequent pregnancy, the affected mother and the unaffected father of the proband requested prenatal prediction, which was thereafter carried out in DNA extracted from a chorionic villus sample obtained at 11 weeks of gestation. Restriction enzyme analysis of COL7A1 exons 73 and 74 amplified by PCR, demonstrated the presence of the G2043R mutation, and the pregnancy was subsequently terminated. Molecular analysis of DNA extracted from fetal tissues confirmed the prenatal prediction.

Changes in gene expression with iron loading and chelation in cardiac myocytes and non-myocytic fibroblasts.

Iron overload is associated with long-term cardiac iron accumulation and tissue changes such as fibrosis. To determine short-term iron-dependent changes in expression of genes associated with iron homeostasis and fibrosis we measured mRNA on Northern blots prepared from cultured rat neonatal cardiomyocytes and non-myocytes (fibroblasts) as a function of iron loading and chelation. Transferrin receptor mRNA was reduced in myocytes exposed to various concentrations of iron for 3 days and this decline was associated with a 63% decline in iron-response element (IRE) binding of iron regulatory protein-1, indicating that myocytes utilize IRE-dependent mechanisms to modulate gene expression. In myocytes iron caused a dose-dependent decline in mRNAs coding for transforming growth factor- beta(1)(TGF- beta(1)), biglycan, and collagen type I while plasminogen activator inhibitor-1 mRNA was unaffected by iron loading and decorin mRNA doubled. Total TGF- beta bioactivity was also decreased by iron loading. Thus, the effects of iron loading on genes related to cardiac fibrosis are gene-specific. Addition of deferoxamine for 1 day did not have any significant effect on any of these genes. Parallel changes in gene expression were exhibited by non-myocytes (fibroblasts), where chelation also decreased TGF- beta(1)mRNA and activity, and mRNA for collagen type I and biglycan, and collagen synthesis. In addition to these changes in transcripts associated with matrix formation the mRNA of the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase was unaffected by iron loading but doubled in both cell types upon treatment with deferoxamine. These findings suggest that in both cardiac myocytes and non-myocyte fibroblasts gene expression is coupled to intracellular iron pools by gene-specific and IRE-dependent and idependent mechanisms. This linkage may influence matrix deposition, a significant component of cardiac injury.

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells.

The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCND1 was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.

Tumor metastasis biopsy as a surrogate marker of response to melanoma immunotherapy.

In patients undergoing immunotherapy for metastatic melanoma, the clinical response in immunotherapeutic trials may be partial or difficult to detect. Tumor metastasis biopsy allows direct characterisation of an anti-tumor immunological response. During a phase I/II trial of granulocyte macrophage colony stimulating factor (GM-CSF) transduced autologous melanoma immunotherapy, the cellular response was examined by immunohistochemical analysis in a limited number of tumor biopsies taken from patients who either responded or progressed. Clinical response was associated with tumor infiltration by CD4+ and CD8+ T-cells, macrophages and differentiated dendritic cells (DC), and expression of HLA-DR by the tumor cells. This tumor infiltration was associated with increased melanoma-specific peripheral blood precursor cytotoxic T-lymphocyte (pCTL) and the ability to obtain tumor-infiltrating lymphocytes in vitro. In contrast, progression or a lack of clinical response was associated with a lack of T-cell and DC infiltration into the tumor tissue in all such biopsies. Macrophages and eosinophils infiltrated these tumors, while T-cells and DC were present at some distance from the tumor. These preliminary data strongly suggest that the location and extent of T-cell and DC infiltration, as well as the expression of HLA-DR by tumor cells are associated with a clinical response in this form of melanoma immunotherapy.

Temperature and pH dependence of the metarhodopsin I-metarhodopsin II equilibrium and the binding of metarhodopsin II to G protein in rod disk membranes.

The equilibria between metarhodopsins I and II (MI and MII) and the binding of MII to retinal G protein (G) were investigated, using the dual wavelength absorbance response of rod disk membrane (RDM) suspensions to a series of small bleaches, together with a nonlinear least-squares fitting procedure that decouples the two reactions. This method has been subjected to a variety of theoretical and experimental tests that establish its validity. The two equilibrium constants, the amount of active G protein (that can bind to and stabilize MII) and the fraction bleached by the flash, have been determined without a priori assumptions about these values, at temperatures between 0 and 15 degrees C and pHs from 6.2 to 8.2. Binding of G to MII in normal RDM exhibits 1:1 stoichiometry (not cooperative), relatively weak, 2-4 x 10(4) M-1 affinity on the membrane, with a pH dependence maximal at pH 7.6, and a low thermal coefficient. The reported amount of active G remained constant even when its binding constant was reduced more than 10-fold at low pH. The method can readily be applied to the binding of MII to other proteins or polypeptides that stabilize its conformation as MII. It appears capable of determining many of the essential physical constants of G protein coupled receptor interaction with immediate signaling partners and the effect of perturbation of environmental parameters on these constants.

Characterization of Fe2+ and Fe3+ transport by iron-loaded cardiac myocytes.

Plasma iron overload causes cardiac iron accumulation leading to toxicity and organ failure. In order to understand the basis of iron acquisition, we examined mechanisms of Fe3+ and Fe2+ uptake in control and iron-loaded cardiomyocyte cultures. Iron loading increased rates of Fe3+ and Fe2+ uptake, primarily by increasing Vmax. Inhibition of Fe3+ transport by impermeable Fe2+ chelators and the presence of a cell surface ferricyanide reductase activity are consistent with a role for redox cycling in Fe3+ uptake. However, flavoproteins and copper-dependent oxidases known to be required for redox-active iron transport in yeast do not appear to be involved in iron uptake by cardiac myocytes, nor do the abundant cardiac L-type Ca2+ channels. The data suggest that both redox states of iron contribute to cardiac iron accumulation in iron overload.

Beyond alcohol: beverage consumption and cardiovascular mortality.

This paper reviews epidemiological investigations which have identified an inverse relationship between alcohol consumption and death from coronary heart disease: evidence from studies of mixed populations as well as of single-sex populations have, on the whole, demonstrated that this relationship is independent of sex or age. This 'cardioprotective effect' of alcohol can be explained, at least in part, by ethanol-related increases in high density lipoprotein cholesterol and reduced platelet coagulability. With certain beverages, especially red wine, phenolic compounds may provide additional protection by altering eicosanoid metabolism in favour of increased prostacyclin and decreased thromboxane synthesis, as well as antioxidant functions which prevent the peroxidation of low-density lipoprotein. Trans-resveratrol, a tri-hydroxy stilbene present in the skins of specific grape cultivars, is a constituent of certain red wines which may play a crucial role in modulating lipoprotein metabolism, eicosanoid synthesis, oxidation and coagulation. Preliminary studies using the human hepatoma cell line HepG2 are described, demonstrating that this compound has no effect upon cell viability or overall protein synthesis in these cells, and at high concentrations DNA synthesis as measured by radioactive thymidine incorporation is enhanced. Reduced intracellular concentration and secretion of apolipoprotein B have been shown to occur in response to resveratrol although a clear dose-dependency has not yet been demonstrated. The mechanisms underlying these changes as well as the effects upon the synthesis and secretion of other apolipoproteins are under active investigation in our laboratory.

Metastases: mechanisms, pathways, and cascades.

Metastases are the major cause of treatment failure in cancer patients. Sixty percent of patients with newly diagnosed solid tumors (excluding skin cancers other than melanoma) have clinically evident or microscopic metastases when the primary tumor is diagnosed [1]. Dissemination of malignant cells throughout the body and their survival to form secondary growths constitute a complicated process dependent on both host and tumor properties. This review outlines the mechanisms involved in the metastatic process, the pathways of tumor spread throughout the body, and the common routes used by various tumors.