Validation and comparison of quality-of-life measures for topical 5-fluorouracil treatment: results from a randomized controlled trial.

BACKGROUND: Topical 5-fluorouracil (5-FU) is commonly used for high-risk patients with keratinocyte carcinoma (KC). Skindex and Skin Cancer Index (SCI) are validated instruments to measure quality of life (QoL) of patients with KC and those who have had surgical treatment of KCs. AIM: To validate Skindex and SCI for topical 5-fluorouracil (5-FU) application and to compare the two QoL instruments. METHODS: We randomized 932 veterans at high risk for developing a KC to either topical 5-FU or vehicle control cream applied to the face and ears for up to 1 month. We collected their Skindex-29 and SCI scores at baseline and follow-up visits. RESULTS: Compared with controls, 5-FU reduced QoL, measured by the Skindex symptom, Skindex function and SCI social subscales (P < 0.001, P < 0.01, P = 0.02, respectively). At 1 month, significant changes in QoL in the 5-FU group were observed in the Skindex symptom (10.1, 95% CI 0.36-12.6), Skindex function (6.0, 95% CI 4.0-8.0) and SCI social (-3.5, 95% CI -6.2 to -0.8) subscales, while the other subscales of Skindex and SCI did not show significant changes. All three Skindex subscales at 1 month correlated with patient-reported symptom score and photograph-based toxicity score, whereas social subscale was the only one of the SCI subscales that correlated with patient-reported symptom and photograph-based toxicity scores. CONCLUSIONS: Our study validated Skindex symptom, Skindex function and SCI social subscales for QoL measurement during treatment with topical 5-FU. The study could not provide evidence for construct validity of the other subscales. Skindex was more responsive than SCI in the context of 5-FU treatment.

Improvement in precision of counting actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) often serve as a primary endpoint for clinical studies. However, reliability of counting these lesions is poor, even among expert dermatologists. OBJECTIVES: To investigate the reliability of counting AKs before and after a yearly consensus meeting, held annually for 4 years. METHODS: As part of the Veterans Affairs (VA) Keratinocyte Carcinoma Chemoprevention Trial, board-certified dermatologists convened annually for 4 years to individually count the number of actinic keratoses on three to five test subjects. The dermatologists then met as a group for a consensus discussion on what constituted an AK lesion on each subject. Afterwards, each dermatologist repeated the independent counting exercise on three to five new subjects. The intraclass correlation coefficient (ICC) was used to analyze the reliability of counting AKs among the dermatologists. RESULTS: Eight dermatologists participated in this exercise for 4 consecutive years. Pre-consensus discussion ICCs over 4 years were 0.18, 0.34, 0.38, 0.75, respectively, showing sustained improvement with each consensus discussion. The greatest improvement in reliability of AK counts was shown during the first year of consensus discussions, when the ICC improved from 0.18 to 0.67. There was no improvement by the fourth year of consensus discussion, with pre- and post-consensus ICCs of 0.75 and 0.75, respectively. CONCLUSIONS: Annual consensus discussions can lead to improvement in reliability of AK counts. This improvement was sustained over 4 years. By the fourth year, the discussion meeting had no effect on improvement in reliability. A consensus meeting discussion may be helpful for improving reliability in other trials.

Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression.

Patients with kidney failure are at high risk of a cardiac death and frequently develop left ventricular hypertrophy (LVH). The mechanisms involved in the cardiac structural changes that occur in kidney failure are yet to be fully delineated. Angiotensin-converting enzyme (ACE) 2 is a newly described enzyme that is expressed in the heart and plays an important role in cardiac function. This study assessed whether ACE2 plays a role in the cardiac remodelling that occurs in experimental acute kidney injury (AKI). Sprague-Dawley rats had sham (control) or subtotal nephrectomy surgery (STNx). Control rats received vehicle (n = 10), and STNx rats received the ACE inhibitor (ACEi) ramipril, 1 mg kg(-1) day(-1) (n = 15) or vehicle (n = 13) orally for 10 days after surgery. Rats with AKI had polyuria (P < 0.001), proteinuria (P < 0.001) and hypertension (P < 0.001). Cardiac structural changes were present and characterized by LVH (P < 0.001), fibrosis (P < 0.001) and increased cardiac brain natriuretic peptide (BNP) mRNA (P < 0.01). These changes occurred in association with a significant increase in cardiac ACE2 gene expression (P < 0.01) and ACE2 activity (P < 0.05). Ramipril decreased blood pressure (P < 0.001), LVH (P < 0.001), fibrosis (P < 0.01) and BNP mRNA (P < 0.01). These changes occurred in association with inhibition of cardiac ACE (P < 0.05) and a reduction in cardiac ACE2 activity (P < 0.01). These data suggest that AKI, even at 10 days, promotes cardiac injury that is characterized by hypertrophy, fibrosis and increased cardiac ACE2. Angiotensin-converting enzyme 2, by promoting the production of the antifibrotic peptide angiotensin(1-7), may have a cardioprotective role in AKI, particularly since amelioration of adverse cardiac effects with ACE inhibition was associated with normalization of cardiac ACE2 activity.

A controlled trial of a novel primary prevention program for Lyme disease and other tick-borne illnesses

To evaluate a theory-based educational program to prevent Lyme disease and other tick-borne illnesses (TBI), a randomized controlled trial of an educational program was delivered to ferry passengers traveling to an endemic area in southeastern Massachusetts. Rates of TBI and precautionary and tick check behaviors were measured over three summers in 30,164 passengers. There were lower rates of TBI among participants receiving TBI education compared with control participants receiving bicycle safety education (relative risk [RR] = 0.79) and a 60 per cent reduction in risk among those receiving TBI education who visited Nantucket Island for more than 2 weeks compared to control participants (RR = 0.41, 95 per cent confidence intervals = 0.18 to 0.95, p < .038). TBI-educated participants were also significantly more likely to take precautions (use repellent, protective clothing, limit time in tick areas) and check themselves for ticks. The study demonstrates that a theory-based Lyme disease prevention program can increase precautionary behavior and result in a significant reduction in TBI. (AU)

Developmental expression of ACE2 in the SHR kidney: a role in hypertension?

The abnormal development of the intrarenal renin-angiotensin system (RAS) is thought contribute to adult-onset hypertension in the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with complementary actions to that of ACE. Recent studies have shown that ACE2 expression is reduced in the adult SHR. However, its regulation in pre-hypertensive animals is unknown. In this study, we examine the developmental expression of ACE2 in the rodent kidney and its temporal expression, as it relates to the development of hypertension in the SHR model. Kidneys from SHR and normotensive Wistar Kyoto (WKY) rats (n=8-12/group) at birth, 6 weeks of age, and adulthood (80 days) were examined. Gene expression and activity of ACE2 were determined by real-time reverse transcription-polymerase chain reaction and quenched fluorescence assays, respectively. Renal expression was localized by in situ hybridization and immunohistochemistry. The expression and ACE2 activity are significantly increased in the SHR kidney at birth. With the onset of hypertension, the tubular expression of ACE2 falls in SHR compared to WKY and remains reduced in the adult SHR kidney. Glomerular expression is paradoxically increased in the SHR glomerulus. The overall developmental pattern of ACE2 expression in the SHR kidney is also modified, with declining expression over the course of renal development. The developmental pattern of ACE2 expression in the SHR kidney is altered before the onset of hypertension, consistent with the key role of the RAS in the pathogenesis of adult-onset hypertension. Further research is required to distinguish the contribution of these changes to the development and progression of hypertension in this model.

The foundation and launch of the Melbourne Interventional Group: a collaborative interventional cardiology project.

The Melbourne Interventional Group (MIG) is a voluntary collaborative venture of interventional cardiologists practicing at 12 major public and private hospitals in Victoria, designed to record data pertaining to percutaneous coronary interventions (PCI) and perform long-term follow-up. The potential advantages of collaboration involve large-scale analysis of current interventional strategies (e.g. drug-eluting stents, evaluation of new technologies and cost-effective analysis), provide a basis for multi-centred clinical trials and allow comparison of clinical outcomes with cardiac surgery. The established registry documents demographic, clinical and procedural characteristics of consecutive patients undergoing PCI and permits analysis of those characteristics at 30 days and 12 months. The registry is co-ordinated by the Centre of Clinical Research Excellence (CCRE), a research body within the Department of Epidemiology and Preventive Medicine (Monash University, Melbourne). The eventual goal of MIG is to provide a contemporary appraisal of Australian interventional cardiology practice, with opportunities to improve in-hospital and long-term outcomes of patients with coronary artery disease.

Lateralized cognitive dysfunction in patients with systemic lupus erythematosus.

This study was designed to determine whether there is a lateralized pattern of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). Fifty right-handed patients with SLE, but no history of cerebrovascular disease participated in the study. Thirty right-handed healthy subjects matched for age and education served as controls. SLE and healthy control subjects underwent a three-hour neuropsychological evaluation designed to measure attention, memory, visual spatial skills, verbal skills reasoning, psychomotor speed, and motor function. A cognitive disability index was created to identify cognitive impairment. Percentile tables based on the performance of all subjects were constructed for 20 component scores. Any subject with five or more component scores below the 25th percentile was designated impaired. Using this criterion, cognitive impairment was identified in 50% of patients with SLE and 20% of healthy controls. Patients with SLE were impaired on measures of psychomotor speed/fluency, verbal speed/fluency and verbal memory. This pattern of performance on neuropsycholgical testing was consistent with left hemisphere brain dysfunction. The observed deficits were not clearly attributable to vascular lesions and suggest immune-mediated effects on specific brain regions in a subgroup of patients with SLE.

Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2.

BACKGROUND: Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known. AIMS: This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta. METHODS: In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis. RESULTS: ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p < 0.01). ACE2 protein increased after BDL (23.5-fold; p < 0.05) as did ACE2 activity (fourfold; p < 0.05). In human cirrhotic liver, gene (>30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p < 0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels. CONCLUSIONS: ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.

Gadolinium effects on gigaseal formation and the adhesive properties of a fungal amoeboid cell, the slime mutant of Neurospora crassa.

Low gadolinium concentrations induce rapid gigaseal formation and cell adhesion to glass and plastic (polystyrene) substrates in the slime mutant of Neurospora crassa. Cellular adhesion is independent of an integrin-mediated mechanism, because pretreatment with the oligopeptide ARG-GLY-ASP-SER (RGDS) did not inhibit it, and there was no spatial correlation between integrin and adhesions. In contrast, concanavalin A and beta-galactosidase both inhibit adhesion, suggesting that adhesion is mediated by sugar moeities at the cell surface. The adhesion sites are motile in the plasma membrane, as shown by the movement of polystyrene microspheres on the cell surface. In addition to an integrin-based adhesive system, which has already been characterized in walled hyphal cells, hyphae have evolved at least two different plasma membrane-based adhesion mechanisms. The relatively non-specific sugar-mediated adhesion caused by gadolinium may be part of the mechanism of gigaseal formation in other cells. In the absence of sugar-mediated adhesion, gadolinium increases the magnitude of the gigaseal in giant unilamellar liposomes composed of phosphatidylcholine, phosphatidylethanolamine, and cholesterol, with or without the negatively charged phosphatidylserine. Thus, gigaseal formation involves at least two different mechanisms.

Identification of angiotensin converting enzyme 2 in the rodent retina.

PURPOSE: An active renin-angiotensin system has been found in the retina of rats and humans. Angiotensin-converting enzyme 2 (ACE2) is a recently discovered enzymatic homologue of Angiotensin-converting enzyme (ACE) that may be an important new component of the renin-angiotensin system (RAS). This study assesses the involvement of ACE2 in the normal and diabetic rodent retina and its modulation by ACE inhibition. METHODS: Sprague-Dawley rats were randomised into three groups, control, diabetes, and diabetes plus ramipril, with diabetes induced with the cell toxin streptozocin and the study run for 24 weeks. ACE2 and ACE gene levels were measured using quantitative real-time polymerase chain reaction (QRT-PCR), ACE2 protein expression was confirmed by Western blotting, and ACE and ACE2 catalytic activity were measured using specific activity assays in the rat retina. Localisation of ACE2 mRNA and protein were determined by in situ hybridisation and immunohistochemistry, respectively. RESULTS: ACE mRNA levels were decreased to approximately 50% in the diabetic retina, but ACE2 mRNA levels were not significantly changed. ACE but not ACE2 gene expression was influenced by ramipril treatment. Following immunostaining, both ACE2 and ACE protein were localised predominantly to the inner nuclear layer (INL) but also to photoreceptors. In the diabetic retina, ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased. CONCLUSIONS: This study has identified ACE2 gene and catalytically active protein in the rodent retina. In diabetes, the major changes were a decrease in ACE but an increase in ACE2 enzymatic activity. The ACE inhibitor ramipril did not reduce ACE2 enzymatic activity.

Human esophageal cancer is distinguished from adjacent esophageal tissue by tissue cysteine concentrations.

Recent studies have suggested that cysteine, in addition to glutathione, may play a role in the genesis, pathobiology, and treatment response of rodent and human cancers. We examined the relative concentrations of cysteine and glutathione in human esophageal cancer and adjacent, minimally involved esophageal tissue. Small biopsies from tumors and adjacent esophageal tissues were placed into cold acid to allow extraction of low-molecular-mass compounds and simultaneous precipitation of macromolecules. Supernatants were analyzed by high-performance liquid chromatography with electrochemical detection for thiol content. While there was no statistically significant difference between the glutathione content of tumor versus adjacent tissue (2.2 mM vs 2.1 mM, respectively), tumor tissue had significantly higher levels of cysteine than adjacent tissue (0.21 mM vs 0.13 mM, respectively). In conclusion, cysteine content distinguishes tumor from adjacent more normal tissue.

Targeting of Asian Americans and Pacific Islanders by the tobacco industry: results from the Minnesota Tobacco Document Depository.

OBJECTIVE: The study objective was to review internal tobacco industry documents written between 1985 and 1995 regarding the Asian American and Pacific Islander (AAPI) population in the USA. These documents detail opportunities and barriers to promotion of tobacco products, as viewed by the tobacco industry and its market research firms. DATA SOURCES: /methods: Researchers reviewed tobacco industry documents from the document depository in Minneapolis, Minnesota and the tobacco industry's website, The Tobacco Archive, in a systematic fashion. A combined technique was employed using title keywords, dates, and names to search the 4(b) index. FINDINGS: A review of internal tobacco company documents reveal that during the late 1980s, the industry and its market research firms recognised the importance of the AAPI community as a potential business market. Documents describe the population growth in this community, the high prevalence of smoking in countries of origin, high purchasing power of AAPI immigrants, cultural predisposition to smoking, opportunities afforded by the high proportion of retail businesses under AAPI ownership, barriers to developing the AAPI market, comprehensive campaigns, and political and lobbying efforts. Comprehensive campaigns were designed to integrate promotion efforts in AAPI consumer, retail, and business communities. CONCLUSIONS: The documents show that the tobacco industry developed specific promotion strategies to target the AAPI population. Tobacco control initiatives in the AAPI group have been slower to develop than in other targeted ethnic groups, and may benefit by increased awareness of industry methods to promote tobacco use.

Blue light modulation of ion transport in the slime mutant of Neurospora crassa.

Blue light is the primary entrainment signal for a number of developmental and morphological processes in the lower eucaryote Neurospora crassa. Blue light regulates photoactivation of carotenoid synthesis, conidiation, phototropism of perithecia and circadian rhythms. Changes in the electrical properties of the plasma membrane are one of the fastest responses to blue light irradiation. To enable patch-clamp studies on light-induced ion channel activity, the wall-less slime mutant was used. Patch-clamp experiments were complemented by non-invasive ion-selective measurements of light-induced ion fluxes of slime cells using the vibrating probe technique. Blue light usually caused a decrease in conductance within 2-5 minutes at both negative and positive voltages, and a negative shift in the reversal potential in whole-cell patch-clamp measurements. Both K+ and Cl- channels contribute to the inward and outward currents, based on the effects of TEA (10 mM) and DIDS (500 microM). However, the negative shift in the reversal potential indicates that under blue light the Cl- conductance becomes dominant in the electrical properties of the slime cells due to a decrease of K+ conductance. The ion-selective probe revealed that blue light induced the following changes in the net ion fluxes within 5 minutes: 1) decrease in H+ influx; 2) increase in K+ efflux; and 3) increase in Cl- influx. Ca2+ flux was unchanged. Therefore, blue light regulates an ensemble of transport processes: H+, Cl-, and K+ transport.

Association between hospital and surgeon procedure volume and outcomes of total hip replacement in the United States medicare population.

BACKGROUND: The mortality and complication rates of many surgical procedures are inversely related to hospital procedure volume. The objective of this study was to determine whether the volumes of primary and revision total hip replacements performed at hospitals and by surgeons are associated with rates of mortality and complications. METHODS: We analyzed claims data of Medicare recipients who underwent elective primary total hip replacement (58,521 procedures) or revision total hip replacement (12,956 procedures) between July 1995 and June 1996. We assessed the relationship between surgeon and hospital procedure volume and mortality, dislocation, deep infection, and pulmonary embolus in the first ninety days postoperatively. Analyses were adjusted for age, gender, arthritis diagnosis, comorbid conditions, and income. Analyses of hospital volume were adjusted for surgeon volume, and analyses of surgeon volume were adjusted for hospital volume. RESULTS: Twelve percent of all primary total hip replacements and 49% of all revisions were performed in centers in which ten or fewer of these procedures were carried out in the Medicare population annually. In addition, 52% of the primary total hip replacements and 77% of the revisions were performed by surgeons who carried out ten or fewer of these procedures annually. Patients treated with primary total hip replacement in hospitals in which more than 100 of the procedures were performed per year had a lower risk of death than those treated with primary replacement in hospitals in which ten or fewer procedures were performed per year (mortality rate, 0.7% compared with 1.3%; adjusted odds ratio, 0.58; 95% confidence interval, 0.38, 0.89). Patients treated with primary total hip replacement by surgeons who performed more than fifty of those procedures in Medicare beneficiaries per year had a lower risk of dislocation than those who were treated by surgeons who performed five or fewer of the procedures per year (dislocation rate, 1.5% compared with 4.2%; adjusted odds ratio, 0.49; 95% confidence interval, 0.34, 0.69). Patients who had revision total hip replacement done by surgeons who performed more than ten such procedures per year had a lower rate of mortality than patients who were treated by surgeons who performed three or fewer of the procedures per year (mortality rate, 1.5% compared with 3.1%; adjusted odds ratio, 0.65; 95% confidence interval, 0.44, 0.96). CONCLUSIONS: Patients treated at hospitals and by surgeons with higher annual caseloads of primary and revision total hip replacement had lower rates of mortality and of selected complications. These analyses of Medicare claims are limited by a lack of key clinical information such as operative details and preoperative functional status.