Pancreatic cancer: The microenvironment needs attention too!

The abundant stromal/desmoplastic reaction, a characteristic feature of a majority of pancreatic adenocarcinomas (PDAC), has only recently been receiving some attention regarding its possible role in the pathobiology of pancreatic cancer. It is now well established that the cells predominantly responsible for producing the collagenous stroma are pancreatic stellate cells (PSCs). In addition to extracellular matrix proteins, the stroma also exhibits cellular elements including, immune cells, endothelial cells and neural cells. Evidence is accumulating to indicate the presence of significant interactions between PSCs and cancer cells as well as between PSCs and other cell types in the stroma. The majority of research reports to date, using in vitro and in vivo approaches, suggest that these interactions facilitate local growth as well as distant metastasis of pancreatic cancer, although a recent study using animals depleted of myofibroblasts has raised some questions regarding the central role of myofibroblasts in cancer progression. Nonetheless, novel therapeutic strategies have been assessed, mainly in the pre-clinical setting, in a bid to interrupt stromal-tumour interactions and inhibit disease progression. The next important challenge is for the translation of such pre-clinical strategies to the clinical situation so as to improve the outcome of patients with pancreatic cancer.

Association of classroom ventilation with reduced illness absence: a prospective study in California elementary schools.

Limited evidence associates inadequate classroom ventilation rates (VRs) with increased illness absence (IA). We investigated relationships between VRs and IA in California elementary schools over two school years in 162 3rd-5th-grade classrooms in 28 schools in three school districts: South Coast (SC), Bay Area (BA), and Central Valley (CV). We estimated relationships between daily IA and VR (estimated from two year daily real-time carbon dioxide in each classroom) in zero-inflated negative binomial models. We also compared IA benefits and energy costs of increased VRs. All school districts had median VRs below the 7.1 l/s-person California standard. For each additional 1 l/s-person of VR, IA was reduced significantly (p<0.05) in models for combined districts (-1.6%) and for SC (-1.2%), and nonsignificantly for districts providing less data: BA (-1.5%) and CV (-1.0%). Assuming associations were causal and generalizable, increasing classroom VRs from the California average (4 l/s-person) to the State standard would decrease IA by 3.4%, increase attendance-linked funding to schools by $33 million annually, and increase costs by only $4 million. Further increasing VRs would provide additional benefits. These findings, while requiring confirmation, suggest that increasing classroom VRs above the State standard would substantially decrease illness absence and produce economic benefits.

Ventilation, temperature, and HVAC characteristics in small and medium commercial buildings in California.

UNLABELLED: This field study of 37 small and medium commercial buildings throughout California obtained information on ventilation rate, temperature, and heating, ventilating, and air-conditioning (HVAC) system characteristics. The study included seven retail establishments; five restaurants; eight offices; two each of gas stations, hair salons, healthcare facilities, grocery stores, dental offices, and fitness centers; and five other buildings. Fourteen (38%) of the buildings either could not or did not provide outdoor air through the HVAC system. The air exchange rate averaged 1.6 (s.d. = 1.7) exchanges per hour and was similar between buildings with and without outdoor air supplied through the HVAC system, indicating that some buildings have significant leakage or ventilation through open windows and doors. Not all buildings had sufficient air exchange to meet ASHRAE 62.1 Standards, including buildings used for fitness centers, hair salons, offices, and retail establishments. The majority of the time, buildings were within the ASHRAE temperature comfort range. Offices were frequently overcooled in the summer. All of the buildings had filters, but over half the buildings had a filter with a minimum efficiency reporting value rating of 4 or lower, which are not very effective for removing fine particles. PRACTICAL IMPLICATIONS: Most U.S. commercial buildings (96%) are small- to medium-sized, using nearly 18% of the country's energy, and sheltering a large population daily. Little is known about the ventilation systems in these buildings. This study found a wide variety of ventilation conditions, with many buildings failing to meet relevant ventilation standards. Regulators may want to consider implementing more complete building inspections at commissioning and point of sale.

Performance of installed cooking exhaust devices.

UNLABELLED: The performance metrics of airflow, sound, and combustion product capture efficiency (CE) were measured for a convenience sample of 15 cooking exhaust devices, as installed in residences. Results were analyzed to quantify the impact of various device- and installation-dependent parameters on CE. Measured maximum airflows were 70% or lower than values noted on product literature for 10 of the devices. Above-the-cooktop devices with flat-bottom surfaces (no capture hood)--including exhaust fan/microwave combination appliances--were found to have much lower CE at similar flow rates, compared to devices with capture hoods. For almost all exhaust devices and especially for rear-mounted downdraft exhaust and microwaves, CE was substantially higher for back compared with front burner use. Flow rate, and the extent to which the exhaust device extends over the burners that are in use, also had a large effect on CE. A flow rate of 95 liters per second (200 cubic feet per minute) was necessary, but not sufficient, to attain capture efficiency in excess of 75% for the front burners. A-weighted sound levels in kitchens exceeded 56 dB* when operating at the highest fan setting for all 14 devices evaluated for sound performance. PRACTICAL IMPLICATIONS: Natural gas cooking burners and many cooking activities emit pollutants that can reach hazardous levels in homes. Venting range hoods and other cooking exhaust fans are thought to provide adequate protection when used. This study demonstrates that airflows of installed devices are often below advertised values and that less than half of the pollutants emitted by gas cooking burners are removed during many operational conditions. For many devices, achieving capture efficiencies that approach or exceed 75% requires operation at settings that produce prohibitive noise levels. While users can improve performance by preferentially using back burners, results suggest the need for improvements in hood designs to achieve high pollutant capture efficiencies at acceptable noise levels.

[Radon progeny as an experimental tool for dosimetry of nanoaerosols].

The study of aerosol exposure, dosimetry measurements and related quantitation of health effects are important to the understanding of the consequences of air pollution, and are discussed widely in the scientific literature. During the last 10 years the need to correlate aerosol exposure and biological effects has become especially important due to rapid development of a new, revolutionary industry of nanotechnology. Quantitative assessment of aerosol particle behavior in air and in lung deposition, and dosimetry in different parts of the lung, particularly for nanoaerosols, remains poor despite several decades of study. Direct measurements on humans are still needed in order to validate the hollow cast, animal studies, and lung deposition modeling. We discuss here the use of nanoscale radon decay products as an experimental tool in the study of local deposition and lung dosimetry for nanoaerosols. The issue of the safe use of radon progeny in such measurements is discussed based on a comparison of measured exposure in 3 settings: general population, miners, and in a human experiment conducted at the Paul Scherer Institute (PSI) in Switzerland. One of the properties of radon progeny is that they consist partly of 1 nm radioactive particles called unattached activity; having extremely small size and high diffusion coefficients, these particles can be potentially useful as radioactive tracers in the study of nanometer-sized aerosols. We present a theoretical and experimental study of the correlation between the unattached activity and aerosol particle surface area, together with a method for measurement of the unattached fraction.

A fire inside: current concepts in chronic pancreatitis.

Chronic pancreatitis is a necroinflammatory process characterized pathologically by acinar atrophy and fibrosis and clinically by abdominal pain, diabetes and maldigestion. In this review we summarize some of the recent advances in the understanding of the pathogenesis of pancreatitis and how they have shaped our current understanding of chronic pancreatitis. We pay particular attention to advances in the genetic basis of idiopathic, hereditary and tropical pancreatitis as well as research into the relationship between alcohol and the pancreas. We have also reviewed current practices with respect to diagnosis and management of chronic pancreatitis.

Adverse pregnancy outcomes in women with systemic lupus erythematosus from a multiethnic US cohort: LUMINA (LVI) [corrected].

OBJECTIVE: To study the factors associated with an adverse pregnancy outcome in women with systemic lupus erythematosus (SLE). METHODS: SLE women from LUMINA of Hispanic, African American and Caucasian ethnicity were studied. Adverse pregnancy outcome was a miscarriage or abortion (<20 weeks), a stillbirth (> or = 20) and/or a moderate to severe preterm-baby (<34 weeks); good outcome was either a mild preterm-baby (> or = 34 weeks) or a full-term baby [C-section or vaginal delivery (38-42 weeks)]. Pregnancies occurring after SLE diagnosis (TD) were included; pregnancy outcome was the unit of analyses. The relationship between selected variables and pregnancy outcomes was examined by univariable and multivariable analyses. RESULTS: Adverse outcomes occurred in 63.7% of 102 pregnancies. In the univariable analyses, Texan Hispanic and African American ethnicities, fewer years of education, higher number of ACR criteria, renal involvement, glucocorticoid exposure and the maximum dose of glucocorticoids used prior to the pregnancy outcome were associated with an adverse pregnancy outcome. Renal involvement was independently associated with an adverse pregnancy outcome [Odds ratio (OR)=5.219 (95% Confidence Interval (CI) 1.416-19.239, p=0.0131] as were the maximum dose of glucocorticoids used prior to the pregnancy outcome (OR=1.028; CI:1.002-1.054; p=0.0315) and fewer years of education (OR=1.204; CI:1.006-1.472; p=0.0437). Ethnicity was not retained in the multivariable model. CONCLUSION: Renal involvement, the maximum dose of glucocorticoids used prior to pregnancy and fewer years of education were associated with adverse pregnancy outcomes. These data have implications for the management of women with lupus planning to become pregnant.

Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII).

The objective of this study is to examine the clinical features and outcomes of patients with systemic lupus erythematosus (SLE) whose disease began in adolescence [juvenile-onset SLE (jSLE)] compared with adult-onset patients [adult-onset SLE (aSLE)] from a large multiethnic cohort. Systemic lupus erythematosus patients of African-American, Caucasian, or Hispanic ethnicity and >or=1 year follow-up were studied in two groups: jSLE (diagnosed at

Air filter materials, outdoor ozone and building-related symptoms in the BASE study.

UNLABELLED: Used ventilation air filters have been shown to reduce indoor environmental quality and worker performance and increase symptoms, with effects stronger after reaction of filters with ozone. We analyzed data from the US EPA Building Assessment Survey and Evaluation (BASE) study to determine if ozone and specific filter media have interactive effects on building-related symptoms (BRS). We analyzed a subset of 34 buildings from the BASE study of 100 US office buildings to determine the separate and joint associations of filter medium [polyester/synthetic (PS) or fiberglass (FG)] and outdoor ozone concentration (above/below the median, 67.6 microg/m(3)) with BRS. Using logistic regression models and general estimating equations, we estimated odds ratios (ORs) and 95% confidence intervals for the association of filter medium, ozone, and filter medium x ozone with BRS. Relative to FG + low ozone, PS alone or high ozone alone, were each significantly (P < 0.05) associated only with fatigue/difficulty concentrating (ORs = 1.93 and 1.54, respectively). However, joint exposure to both PS + high ozone, relative to FG + low ozone, had significant associations with lower and upper respiratory, cough, eye, fatigue, and headache BRS (ORs ranged from 2.26 to 5.90). Joint ORs for PS + high ozone for lower and upper respiratory and headache BRS were much greater than multiplicative, with interaction P-values <0.10. Attributable risk proportion (ARP) estimates indicate that removing both risk factors might, given certain assumptions, reduce BRS by 26-62%. These findings suggest possible adverse health consequences from chemical interactions between outdoor ozone and PS filters in buildings. Results need confirmation before recommending changes in building operation. However, if additional research confirms causal relationships, ARP estimates indicate that appropriate filter selection may substantially reduce BRS in buildings, especially in high-ozone areas. PRACTICAL IMPLICATIONS: The results indicate that a better understanding of how filters interact with their environment is needed. While the mechanism is unknown and these findings need to be replicated, they indicate that the joint risk of BRS from polyester/synthetic filters and outdoor ozone above 67.6 microg/m(3) is much greater than the risk from each alone. These findings suggest potential reductions in BRS from appropriate selection of ventilation filter media or implementing strategies to reduce ozone entrained in building ventilation systems. If the relationships were found to be causal, filter replacement and ozone abatement should be undertaken.

Outdoor ozone and building-related symptoms in the BASE study.

UNLABELLED: Reactions between ozone and indoor contaminants may influence human health and indoor air quality. The U.S. EPA Building Assessment Survey and Evaluation (BASE) study data were analyzed for associations between ambient ozone concentrations and building-related symptom (BRS) prevalence. Multiple logistic regression (MLR) models, adjusted for personal, workplace, and environmental variables, revealed positive relationships (P < 0.05) between ambient ozone concentrations and upper respiratory (UR), dry eyes, neurological and headache BRS (odds ratios ranged from 1.03 to 1.04 per 10 mug/m(3) increase in ambient ozone concentrations). Other BRS had marginally significant relationships with ambient ozone (P < 0.10). A linear dose-response in UR symptoms was observed with increasing ambient ozone (P = 0.03); most other symptoms showed similar but not statistically significant trends. Ambient ozone correlated with indoor concentrations of some aldehydes, a pattern suggesting the occurrence of indoor ozone chemistry. Coupled with the MLR ambient ozone-BRS analysis, this correlation is consistent with the hypothesis that ozone-initiated indoor reactions play an important role in indoor air quality and building occupant health. Replication with increased statistical power and with longitudinal data is needed. If the observed associations are confirmed as causal, ventilation system ozone removal technologies could reduce UR BRS prevalence when higher ambient ozone levels are present. PRACTICAL IMPLICATIONS: This paper provides strong statistical evidence that supports (but does not prove) the hypothesis that ozone entrained into buildings from the outdoor air is involved in increasing the frequency that occupants experience and a range of upper and lower respiratory, mucosal and neurological symptoms by as much as a factor of 2 when ambient ozone levels increase from those found in low-ozone regions to those typical of high-ozone regions. Although replication is needed, the implication is that reducing the amount of ozone entrained into building ventilation systems, either by ambient pollution reduction or engineered gas-phase filtration, may substantially reduce the prevalence of these symptoms experienced by occupants.

Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected].

OBJECTIVE: To examine the factors associated with myocarditis and its impact on disease outcomes in SLE patients. METHODS: SLE patients aged > or = 16 yrs, disease duration < or = 5 yrs from LUMINA (LUpus in Minorities: NAture vs nurture), a multiethnic US cohort, were studied. Myocarditis was defined as per the category 3 of the pericarditis/myocarditis item of the SLAM-Revised (SLAM-R). Patients with concurrent pericardial involvement were excluded. Patients with myocarditis were compared with those without myocarditis or its sequelae in the preceding year. The association between myocarditis and baseline variables (T(0)) was first examined. The impact of myocarditis on disease activity over time (SLAM-R), damage accrual [SLICC Damage Index (SDI)] at last visit (T(L)) and mortality was evaluated. RESULTS: Fifty-three of the 496 patients studied had myocarditis. African American ethnicity [Odds ratio (OR) = 12.6; 95% CI 1.6, 97.8] and SLAM-R at diagnosis (OR = 1.1, 95% CI 1.0, 1.1) were significantly and independently associated with myocarditis. Myocarditis did not predict disease activity over time, but approached significance as a predictor of SDI at T(L) in multivariable analyses P = 0.051. Kaplan-Meier curves indicated that myocarditis was associated with shorter survival (log-rank = 4.87, P = 0.02), particularly in patients with > or = 5 yrs disease; however, myocarditis was not retained in the Cox proportional hazards regression model. CONCLUSIONS: Ethnicity and disease activity at diagnosis were associated with the occurrence of myocarditis in SLE. Myocarditis did not significantly impact on disease activity over time, but impacts some on damage accrual and survival, reflecting overall the more severe disease those patients experience.

Predictors of premature gonadal failure in patients with systemic lupus erythematosus. Results from LUMINA, a multiethnic US cohort (LUMINA LVIII).

OBJECTIVE: To examine the predictors of time to premature gonadal failure (PGF) in patients with systemic lupus erythematosus from LUMINA, a multiethnic US cohort. METHODS: PGF was defined according to the SLICC Damage Index (SDI). Factors associated with time to PGF occurrence were examined by univariable and multivariable Cox proportional hazards regression analyses: three models according to cyclophosphamide use, at T0 (model 1), over time (model 2) and the total number of intravenous pulses (model 3). RESULTS: Thirty-seven of 316 women (11.7%) developed PGF (19 Texan-Hispanics, 14 African-Americans, four Caucasians and no Puerto Rican-Hispanics). By multivariable analyses, older age at T0 (hazards ratio (HR) = 1.10-1.14; 95% CI 1.02-1.05 to 1.19-1.23) and disease activity (Systemic Lupus Activity Measure-Revised) in all models (HR = 1.22-1.24; 95% CI 1.10-1.12 to 1.35-1.37), Texan-Hispanic ethnicity in models 2 and 3 (HR = 4.06-5.07; 95% CI 1.03-1.25 to 15.94-20.47) and cyclophosphamide use in models 1 and 3 (1-6 pulses) (HR = 4.01-4.65; 95% CI 1.55-1.68 to 9.56-13.94) were predictors of a shorter time to PGF. CONCLUSIONS: Disease activity and Texan-Hispanic ethnicity emerged as predictors of a shorter time to PGF while the associations with cyclophosphamide use and older age were confirmed. Furthermore, cyclophosphamide induction therapy emerged as an important determinant of PGF.

Seizures in patients with systemic lupus erythematosus: data from LUMINA, a multiethnic cohort (LUMINA LIV).

OBJECTIVE: To examine the predictors of time-to-seizure occurrence and their impact on damage accrual and mortality in LUMINA, a multiethnic (Hispanic, African American and Caucasian) cohort of patients with systemic lupus erythematosus. METHODS: Seizures were defined as per the American College of Rheumatology (ARC) nomenclature and case definitions for neuropsychiatric lupus syndromes. Factors associated with time-to-seizure occurrence occurring at or after diagnosis (TD) of systemic lupus erythematosus were examined by univariable and multivariable Cox proportional hazard regression analyses. The impact of seizures on damage accrual and mortality was also examined by multivariable analyses after adjusting for variables known to affect these outcomes. RESULTS: A total of 600 patients were included in these analyses. Of them, 40 (6.7%) developed seizures at or after TD; by multivariable analyses, disease activity and younger age were independent predictors of a shorter time-to-seizure occurrence (HR = 1.10 and 1.04; 95% CI 1.04 to 1.15 and 1.00 to 1.08, p = 0.0004 and 0.0304, respectively) whereas mucocutaneous involvement (HR = 0.34, 95% CI 0.16 to 0.41, p = 0.0039) and hydroxychloroquine use (HR = 0.35, 95% CI 0.15 to 0.80, p = 0.0131) were independent predictors of a longer time-to-seizure occurrence. Seizures were an independent contributor to damage accrual but not to mortality. CONCLUSIONS: Seizures tend to occur early in the course of systemic lupus erythematosus, and contribute to damage accrual. Younger age and disease activity are independent predictors of a shorter time-to-seizure occurrence; antimalarials appear to have a protective role in seizure occurrence.

The role of inflammatory and parenchymal cells in acute pancreatitis.

The infiltration of inflammatory cells into the pancreas is an early and central event in acute pancreatitis that promotes local injury and systemic complications of the disease. Recent research has yielded the important finding that resident cells of the pancreas (particularly acinar and pancreatic stellate cells) play a dynamic role in leukocyte attraction via secretion of chemokines and cytokines and expression of adhesion molecules. Significant progress has been made in recent years in our understanding of the role of leukocyte movement (adhesion to the blood vessel wall, transmigration through the blood vessel wall and infiltration into the parenchyma) in the pathophysiology of acute pancreatitis. This review discusses recent studies and describes the current state of knowledge in the field. It is clear that detailed elucidation of the numerous processes in the inflammatory cascade is an essential step towards the development of improved therapeutic strategies in acute pancreatitis. Studies to date suggest that combination therapy targeting different steps of the inflammatory cascade may be the treatment of choice for this disease.

Systemic lupus erythematosus in a multiethnic US Cohort LUMINA XLVIII: factors predictive of pulmonary damage.

The objective of this study was to determine the factors predictive of time to the occurrence of pulmonary damage in systemic lupus erythematosus (SLE). Six-hundred and twenty-six SLE patients from a multiethnic (Hispanics, African Americans and Caucasians) longitudinal study of outcome were studied. Pulmonary damage was defined as per the Systemic Lupus International Collaborating Clinics Damage Index. Socioeconomic-demographic, clinical, genetic, serological features, pharmacologic treatments, behavioural, psychological and disease activity [as per the Systemic Lupus Activity Measure-Revised (SLAM-R)] were examined. Factors associated with time to the occurrence of pulmonary damage were examined by Cox proportional hazards regressions. A Kaplan-Meier survival curve was also examined. Forty-six (7.3%) patients had pulmonary damage after a mean (SD) total disease duration of 5.3 (3.6) years. Among those patients, 25 had pulmonary fibrosis, 12 pulmonary hypertension, eight pleural fibrosis, four pulmonary infarction and four shrinking lung syndrome. Seven patients had more than one type of lung damage. Cumulative rates of pulmonary damage at five and 10 years were 7.6% and 11.6%, respectively. In the multivariable analyses, age (HR = 1.033, 95% CI 1.006-1.060; P = 0.0170), pneumonitis (HR = 2.307, 95% CI 1.123-4.739; P = 0.0229) and anti-RNP antibodies (HR = 2.344, 95% CI 1.190-4.618; P = 0.0138) were associated with a shorter time to the occurrence of pulmonary damage while photosensitivity (HR = 0.388, 95% CI 0.184-0.818; P = 0.0128) and oral ulcers (HR = 0.466, 95% CI 0.230-0.942; P = 0.0335) with a longer time. Pulmonary damage is relatively common in SLE. Age, pneumonitis and anti-RNP antibodies were associated with a shorter time to the development of permanent lung disease.

Systemic lupus erythematosus in a multiethnic US cohort LUMINA LI: anaemia as a predictor of disease activity and damage accrual.

OBJECTIVE: To examine if anaemia (and its severity) is associated with disease activity and damage accrual in systemic lupus erythematosus (SLE). METHODS: Four thousand four-hundred study visits in 613 SLE patients enrolled in LUMINA were studied. Anaemia was expressed in four categories of haematocrit (Hct) as defined by the Systemic Lupus Activity Measure-Revised (SLAM-R): no anaemia (Hct >35%), mild (Hct = 30-35%), moderate (Hct = 25-29%) and severe (Hct <25%). Anti-dsDNA antibodies were measured at baseline. Disease activity was assessed with the SLAM-R and damage with the Systemic Lupus International Collaborating Clinics Damage Index (SDI). The relationship between anaemia and anti-dsDNA antibodies with the SLAM and SDI scores was examined by univariate (one-way ANOVA) and multivariate (generalized linear models and generalized estimating equation regression) analyses. RESULTS: All categories of anaemia and anti-ds DNA were significantly associated with the SLAM-R at baseline and over time. However, only moderate and severe anaemia were associated with the SDI at baseline and over time, while the presence of anti-ds DNA was only associated with the SDI over time but not at baseline. Several clinical domains of the SLAM-R and SDI were associated with anaemia at baseline and over time. CONCLUSIONS: Mild, moderate and marked anaemia are strongly associated with disease activity in SLE. Moderate and marked anaemia are associated with damage accrual. These associations are observed both early and during the course of SLE. Different levels of anaemia could be used to monitor disease activity and predict organ/system damage in SLE.

Pancreatic MAP kinase pathways and acetaldehyde.

Alcohol abuse is a major cause of pancreatitis, a condition that can manifest as both acute necroinflammation and chronic damage (acinar atrophy and fibrosis). It is generally accepted that alcohol-induced pancreatic injury is a consequence of the metabolism of alcohol by the pancreas (via the oxidative and non-oxidative pathways) producing the toxic metabolites acetaldehyde and fatty acid ethyl esters (FAEEs) respectively. Ethanol oxidation within the pancreas also leads to oxidant stress within the gland. Acetaldehyde, oxidant stress and FAEEs cause numerous molecular changes in pancreatic acinar cells which predispose the gland to autodigestion and necroinflammation. An important recent development relates to the identification of pancreatic stellate cells (PSCs) as the key mediators of alcohol-induced pancreatic fibrosis, when activated by ethanol, acetaldehyde or oxidant stress. Recent studies implicate the mitogen activated protein kinase (MAPK) pathway, a major signalling pathway in mammalian cells, as a critical regulator of the effects of ethanol and acetaldehyde on acinar cells as well as PSCs. Particularly important are the modulatory effects of ethanol and its metabolites on downstream transcription factors NF-kappaB and AP-1 (which regulate inflammatory responses via cytokine production) in acinar cells. In PSCs, additional signalling molecules identified as important to the process of ethanol and acetaldehyde-induced PSC activation include protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and peroxisome proliferator-activated receptor gamma (PPARgamma). Interestingly, cross-talk has been demonstrated between PI3K and MAPK in acetaldehyde-treated PSCs. The above advances in the identification of relevant signalling molecules may enable therapeutic targeting of these pathways so as to prevent/reduce alcohol-induced acute as well as chronic injury of the pancreas.

Predictors of post-partum damage accrual in systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (XXXVIII).

OBJECTIVE: To determine the impact of pregnancy on systemic lupus erythematosus (SLE) outcome. METHODS: SLE patients, age >or=16 yrs, disease duration

Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis.

BACKGROUND AND AIMS: Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol induced pancreatic fibrosis. PSC activation is invariably associated with loss of cytoplasmic vitamin A (retinol) stores. Furthermore, retinol and ethanol are known to be metabolised by similar pathways. Our group and others have demonstrated that ethanol induced PSC activation is mediated by the mitogen activated protein kinase (MAPK) pathway but the specific role of retinol and its metabolites all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-RA) in PSC quiescence/activation, or its influence on ethanol induced PSC activation is not known. Therefore, the aims of this study were to (i) examine the effects of retinol, ATRA, and 9-RA on PSC activation; (ii) determine whether retinol, ATRA, and 9-RA influence MAPK signalling in PSCs; and (iii) assess the effect of retinol supplementation on PSCs activated by ethanol. METHODS: Cultured rat PSCs were incubated with retinol, ATRA, or 9-RA for varying time periods and assessed for: (i) proliferation; (ii) expression of alpha smooth muscle actin (alpha-SMA), collagen I, fibronectin, and laminin; and (iii) activation of MAPKs (extracellular regulated kinases 1 and 2, p38 kinase, and c-Jun N terminal kinase). The effect of retinol on PSCs treated with ethanol was also examined by incubating cells with ethanol in the presence or absence of retinol for five days, followed by assessment of alpha-SMA, collagen I, fibronectin, and laminin expression. RESULTS: Retinol, ATRA, and 9-RA significantly inhibited: (i) cell proliferation, (ii) expression of alpha-SMA, collagen I, fibronectin, and laminin, and (iii) activation of all three classes of MAPKs. Furthermore, retinol prevented ethanol induced PSC activation, as indicated by inhibition of the ethanol induced increase in alpha-SMA, collagen I, fibronectin, and laminin expression. CONCLUSIONS: Retinol and its metabolites ATRA and 9-RA induce quiescence in culture activated PSCs associated with a significant decrease in the activation of all three classes of MAPKs in PSCs. Ethanol induced PSC activation is prevented by retinol supplementation.