Engaging multisector stakeholders to identify priorities for global health innovation, change and research: an engagement methodology and application to prosthetics service delivery in Cambodia.

PURPOSE: While innovation is known to catalyse solutions to global sustainable development challenges, lack of engagement from stakeholders during conceptualisation and development may influence the degree of success of implementation. METHODS AND MATERIALS: This paper presents a complete and novel engagement methodology, developed from value led business modelling approaches, for working with multi-sector stakeholders. The methodology can be used to determine barriers and facilitators to clinical practice innovations or translational research, within a country-specific context. The approach has then been applied in the Cambodian prosthetics and orthotics sector to provide a practice-based exemplar application of the framework. RESULTS: This approach seeks to ensure the suitability and sustainability of clinical practice and research programmes being implemented within a complex ecosystem. A theoretical basis, drawn from academic and business innovation sectors, has been consolidated and adapted for practical application to design, direct, and inform initiatives in low resource settings. CONCLUSIONS: The methods presented provide a way to both develop and articulate the mission, vision, and goals of any proposed change, and to effectively communicate these with stakeholders in a way that engages the personal and professional values that exist in their ecosystem. It provides a structured process through which meaningful conversations can happen, and a basis for relationship management with key stakeholders; intrinsic to enable a sustained legacy from research and development.

The engagement from stakeholders during conceptualisation and throughout development can determine the success, or not, of any implementation and scale of innovation.This paper presents a conceptual stakeholder-led engagement methodology, developed from value led business modelling approaches, for determining barriers and facilitators to translational global healthcare research in a country-specific context, in this case the Cambodian prosthetics and orthotics sector.Subsequent research and development work in this area needs to carefully manage and negotiate influencing factors identified through the application of the described methodology, to ensure initiatives (whether research or wider national development work) are sustainable and successful.

International Foot and Ankle Osteoarthritis Consortium review and research agenda for diagnosis, epidemiology, burden, outcome assessment and treatment.

OBJECTIVE: To summarise the available evidence relating to the diagnosis, epidemiology, burden, outcome assessment and treatment of foot and ankle osteoarthritis (OA) and to develop an agenda to guide future research. METHOD: Members of the International Foot and Ankle Osteoarthritis Consortium compiled a narrative summary of the literature which formed the basis of an interactive discussion at the Osteoarthritis Research Society International World Congress in 2021, during which a list of 24 research agenda items were generated. Following the meeting, delegates were asked to rank the research agenda items on a 0 to 100 visual analogue rating scale (0 = not at all important to 100 = extremely important). Items scoring a mean of 70 or above were selected for inclusion. RESULTS: Of the 45 delegates who attended the meeting, 31 contributed to the agenda item scoring. Nineteen research agenda items met the required threshold: three related to diagnosis, four to epidemiology, four to burden, three to outcome assessment and five to treatment. CONCLUSIONS: Key knowledge gaps related to foot and ankle OA were identified, and a comprehensive agenda to guide future research planning was developed. Implementation of this agenda will assist in improving the understanding and clinical management of this common and disabling, yet relatively overlooked condition.

Lifetime occupation is not associated with radiographic osteoarthritis of the first metatarsophalangeal joint in a cohort study of UK women.

OBJECTIVE: The study aim was to determine whether lifetime occupation was associated with the presence of radiographic osteoarthritis (ROA) of the first metatarsophalangeal joint (MTPJ) in women. METHOD: Data were collected from the prospective, population-based Chingford 1000 Women study. This cohort of women, aged 45-64 years at inception, was established in 1989 from a single general practice in Chingford, UK. Data has subsequently been collected repeatedly. Data from baseline, year six and year ten was used for the purposes of this cross-sectional study. The primary outcome was the presence of dorsal view ROA of the first MTPJ. The main exposure was lifetime occupation, categorised according to levels of occupation previously defined via international consensus: 1. Sedentary, 2. Light, 3. Light manual, 4. Heavy manual. Logistic regression analyses were conducted to quantify the relationship between lifetime occupation type and the presence of ROA of the first MTPJ, adjusting for age, body mass index and lifetime high-heeled footwear use as potential interactive variables for each decade. RESULTS: Data for 209 women were included within this study. The mean (SD) age was 57 (±5.2) years. Predominant lifetime occupation was reported as sedentary by 51.7%, as light by 0%, as light manual by 33.5% and as heavy manual by 14.8% of participants. There were no statistical associations between lifetime occupation type and the presence of ROA of the first MTPJ in either the unadjusted (OR = 0.99, CI = 0.78-1.26,P = 0.96) partially adjusted (for age and BMI; OR = 1.00, CI = 0.78-1.29, P = 0.99) or fully adjusted models (for age, BMI and lifetime high heel footwear use for each decade of working life (OR = 1.02, CI = 0.79-1.31, P = 0.91); high-heel footwear use up to 20s (OR = 0.83, CI = 0.71-1.31, P = 0.83); high-heel footwear use in 20-30s (OR = 1.00, CI = 0.75-1.3, P = 0.98); high-heel footwear use in 30-40s (OR = 1.00, CI = 0.70-1.42, P = 0.99); high-heel footwear use in 40-50s (OR = 0.90, CI = 0.58-1.40, P = 0.65); high-heel footwear use in 50s (OR = 0.63,CI = 0.36-1.09, P = 0.10). CONCLUSIONS: The findings suggest that lifetime occupation is not associated with the presence of ROA of the fist metatarsophalangeal joint. There does not appear to be any interactive effect between lifetime occupation, lifetime high-heel footwear use, age or BMI and ROA of the first MTPJ. In later life a positive trend towards increased ROA in those who reported lifetime high-heel footwear use was noted and this may be worthy of further research.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Physical activity and osteoarthritis: a consensus study to harmonise self-reporting methods of physical activity across international cohorts.

Physical activity (PA) is increasingly recognised as an important factor within studies of osteoarthritis (OA). However, subjective methods used to assess PA are highly variable and have not been developed for use within studies of OA, which creates difficulties when comparing and interpreting PA data in OA research. The aim of this study was, therefore, to gain expert agreement on the appropriate methods to harmonise PA data among existing population cohorts to enable the investigation of the association of PA and OA. The definition of PA in an OA context and methods of harmonization were established via an international expert consensus meeting and modified Delphi exercise using a geographically diverse committee selected on the basis of individual expertise in physical activity, exercise medicine, and OA. Agreement was met for all aims of study: (1) The use of Metabolic Equivalent of Task (MET) minutes per week (MET-min/week) as a method for harmonising PA variables among cohorts; (2) The determination of methods for treating missing components of MET-min/week calculation; a value will be produced from comparable activities within a representative cohort; (3) Exclusion of the domain of occupation from total MET-min/week; (4) The need for a specific measure of joint loading of an activity in addition to intensity and time, in studies of diseases, such as OA. This study has developed a systematic method to classify and harmonise PA in existing OA cohorts. It also provides minimum requirements for future studies intending to include subjective PA measures.

Do foot & ankle assessments assist the explanation of 1 year knee arthroplasty outcomes?

OBJECTIVE: Whilst a number of risk factors for poor patient reported outcome measures (PROMs) following knee arthroplasty (KA) have been identified, unexplained variability still remains. The role of pre-operative foot and ankle status on such outcomes has not been investigated. The aim of this study was therefore to determine the association of clinical foot and ankle assessments with patient reported outcomes 1 year following KA. DESIGN: One hundred and fifteen participants from the Clinical Outcomes in Arthroplasty Study (COASt), underwent detailed foot and ankle assessments at baseline, prior to KA (2012-2014) and were followed up for self-reported outcomes 1 year after surgery. RESULTS: Thirty nine percent of subjects reported foot pain at baseline. Mean pre-operative Oxford Knee Score (OKS; 0 [worst] to 48 [best outcome]) was 21 and post-operative OKS score was 38. In fully adjusted analysis pre-operative foot pain was significantly associated with 1 year outcome (risk ratio [RR] 0.78 95% confidence interval [95% CI] 0.62, 0.98). No significant association was observed between ankle dorsiflexion or foot posture and outcome. CONCLUSIONS: Patients with pre-operative foot pain are more likely to have poorer clinically important outcomes 1 year following KA than patients without foot pain. Static ankle dorsiflexion and foot posture do not further explain post-operative KA outcomes. Consideration should also be given to address pre-operative foot pain when attempting to achieve a good clinical outcome for KA.

Multicentric squamous cell carcinoma in situ associated with papillomavirus in a ferret.

A 6-year-old castrated male ferret presented with multiple black and tan proliferative skin lesions. Histologically, the lesions were characterized by multifocal plaques of irregular epidermal hyperplasia and full-thickness dysplasia, with loss of normal epithelial stratification, loss of nuclear polarity, and rare eosinophilic intranuclear inclusion bodies in the superficial layers of the epidermis. Immunohistochemical staining with a monoclonal antibody against papillomaviruses was strongly immunoreactive. Ultrastructurally, large numbers of hexagonal viral particles approximately 50 nm were observed within the nuclei of dysplastic superficial keratinocytes. To the authors' knowledge, this is the first report of a ferret multicentric squamous cell carcinoma in situ associated with papillomavirus.

A comprehensive study of anthocyanin-containing extracts from selected blackberry cultivars: extraction methods, stability, anticancer properties and mechanisms.

The purpose of these studies was to investigate and compare the composition, stability, antioxidant and anticancer properties and mechanisms of anthocyanin-containing blackberry extracts (ACEs) from selected cultivars and using different extraction methods. ACEs were analyzed for total anthocyanin and phenolics content, polymeric color, and total antioxidant capacity (TAC). The influence of water content in the extraction system was evaluated. A 90-day stability study of the extract and a 48-h stability study of the extract in biologically relevant buffers were completed. The cytotoxic effects of ACEs on HT-29, MCF-7, and HL-60 cells were determined. H2O2 production in culture medium was measured and intracellular ROS levels were quantified. As compared to powder-derived ACEs, puree-derived ACEs contained similar amounts of anthocyanins, but greater levels of phenolics, increased TAC, significantly enhanced production of H2O2, and significantly enhanced cytotoxicity in all cell lines. Catalase could not protect cells from ACE-induced cell death. Cyanidin 3-glucoside exerted anticancer effect by acting synergistically or additively with other active components in the extracts. These data suggest that anthocyanins and non-anthocyanin phenolics in ACEs act synergistically or additively in producing anticancer effects. These studies also provide essential information for the development of fruit-derived ACEs as potential Botanical Drug Products.

Mallory-Weiss tear: predisposing factors and predictors of a complicated course.

OBJECTIVES: Little has been published regarding predictors of a complicated course after Mallory-Weiss tear (MWT). The aims of this study were to identify risk factors for a Mallory-Weiss tear and factors predictive of a complicated course. METHODS: At our university hospital, we searched a computerized endoscopy database. At our Veterans Affairs hospital we manually searched printed endoscopy reports. Proposed risk factors for MWT were: history of alcohol use, recent alcohol binge, nonbloody initial emesis, anticoagulation, other coagulopathy, nonsteroidal anti-inflammatory use, and hiatal hernia. Proposed predictors of a complicated course were: age, hematemesis, melena, hematochezia, visible vessel, adherent clot, active bleeding, multiple tears, other pathology at endoscopy, admission Hct, hypotension or orthostatic changes, and coagulopathy. A complicated course was defined on the basis of >6 U of blood transfused, rebleeding, angiography, surgery, or death. Predictors of a complicated course were evaluated using the Mann-Whitney U test or Fisher exact test. RESULTS: A total of 73 cases were reviewed. The most common risk factor was alcohol use, which was found in 44% of cases. In all, 23% of patients had no risk factors. Of the patients, 17 (23%) had a complicated course. Patients with a complicated course had a lower admission Hct (p = 0.009) and active bleeding at initial endoscopy (p = 0.013). CONCLUSION: The predictive value of active bleeding supports early endoscopy for stratification and intervention.

Is random screening of value in detecting glucocorticoid-remediable aldosteronism within a hypertensive population?

INTRODUCTION: Glucocorticoid-remediable aldosteronism (GRA) is a rare inherited cause for hypertension associated with a significant morbidity and mortality at an early age. Individuals with this abnormality frequently present with severe hypertension which is resistant to standard antihypertensive therapy, a strong family history of hypertension, intracranial haemorrhage, and sporadic hypokalaemia. However many affected individuals may appear phenotypically indistinguishable from normal essential hypertensives but remain at high risk of morbidity and mortality. OBJECTIVE: To determine how effective random or targeted screening of hypertensive patients is for the detection of GRA. DESIGN: A prospective study involving the screening of 300 hypertensive patients chosen at random attending the Aberdeen Hypertension Clinic and, during the same period, the targeted screening of patients with a medical and family history suggestive of GRA. SETTING: A University hospital with a primary catchment of 500,000 inhabitants and a hypertension clinic population of over 8500 patients. RESULTS: Random screening failed to identify any GRA mutation-positive individuals. Targeted screening of selected individuals revealed two index families and four further families containing 40 mutation-positive individuals. CONCLUSION: Targeted screening of hypertensive individuals with a family history of hypertension, cerebral haemorrhage, a history of hypertension from an early age, resistant hypertension which has proven difficult to control and hypokalaemia revealed two index cases and four further individuals and 30 hypertensive and 10 normotensive members of their families with GRA.

Ventilation is greater in women than men, but the increase during acute altitude hypoxia is the same.

We wished to determine whether the previously reported lower arterial or alveolar P(CO2) in women than men, and in luteal (LUT) compared with follicular (FOL) menstrual cycle phase would persist during normal oral contraceptive use and during early altitude exposure. Ventilation and blood gases were measured at baseline (636 mmHg approximately 5400 ft, 1650 m) and during simulated altitude at 426 mmHg ( approximately 16000 ft, 4880 m), after 1 h (A1) and during the 12th h (A12), in 18 men (once) and in 19 women twice, during LUT and FOL and in 20 women twice while on placebo (PLA) or highest progestin dose (PIL) oral contraceptives. At baseline, Pa(CO2) was significantly higher in men than all women by 3.3 mmHg. When progesterone-progestin (PRO) was elevated in women, Pa(CO2) was significantly lower than in FOL and PLA, but the latter were still significantly lower than men. At altitude the P(CO2) differences between men and women and PRO levels persisted, with PA(CO2) falling by 3.6 and 7.3 mmHg at A1 and A12 in all, indicating an equivalent increase in alveolar ventilation. The mean arterial-end tidal P(CO2) difference was never >2 mmHg in the groups, indicating no VA/Q mismatch related to gender, PRO levels or altitude. All women had higher breathing frequency than men, resulting in greater deadspace ventilation. At altitude, the mean Pa(O2) was approximately 44 mmHg (Sa(O2) approximately 79%) for all, indicating equivalent oxygenation, but alveolar-arterial P(O2) differences were greater in women than men and higher when PRO was elevated. These results show that, relative to men, women have a compensated respiratory alkalosis, accentuated with elevated PRO. However, the ventilation response to acute altitude is the same in women and men.

Expression and penetrance of the hereditary pancreatitis phenotype in monozygotic twins.

BACKGROUND: Hereditary pancreatitis (HP) is a rare autosomal dominant disorder with variable expression and an overall lifetime penetrance of 80%. We hypothesised that (1) monozygotic twins within similar environments would develop the typical signs of HP at a similar age, and (2) if penetrance were due to modifier genes or environment, all twin pairs would be concordant for expression of HP. AIM: Identify monozygotic twins with HP and determine the penetrance, concordance, and age of onset of symptoms. METHODS: Twins from HP kindreds were identified from the Midwest Multicenter Pancreatic Study group database, referrals, and literature searches. Each twin set was assessed for phenotypic expression, concordance, and difference in age of phenotypic onset of pancreatitis. The difference in onset of symptoms for symptomatic affected non-twin sibling pairs as well as non-twin pairs that were mutation, sex, and age matched were calculated as two comparison groups. RESULTS: Seven of 11 monozygotic pairs identified were suitable for evaluation and four were concordant for pancreatitis. Forty eight affected sibling pairs and 33 pairs of mutation, sex, and age matched (cationic trypsinogen R122H (30 pairs) and N29I (three pairs)) subjects were identified for comparison groups. The median (quartiles Q1, Q3) difference in the age of phenotypic onset in the concordant twins was 1 (0, 2.4) years, 2 (1, 6) for the affected siblings, and 7 (2, 15) years in the comparison control group. Three of the seven sets of twins (43%) were discordant for phenotypic expression of pancreatitis. The overall penetrance in the seven pairs of monozygotic twins was 78.6%. CONCLUSIONS: Genetic and/or environmental factors contribute to expression and age of onset of HP. Nuclear genes or general environmental factors alone cannot explain the 80% penetrance. Determining the mechanism of non-penetrance may help in developing a strategy to prevent the phenotypic expression of pancreatitis in individuals with an underlying genetic predisposition.

Left medial temporal cytosolic choline in early onset depression.

OBJECTIVE: Previous studies have linked the choline (Cho) resonance seen in proton magnetic resonance spectroscopy (1H-MRS) to major depressive disorder (MDD). We endeavoured to clarify the possible involvement of cytosolic choline in the amygdala (anterior medial temporal region) of juvenile subjects with MDD. METHOD: A total of 11 age- and sex-matched MDD and control pairs aged 14 to 18 years participated in long-echo proton magnetic resonance spectroscopic imaging (1H-MRSI) of the amygdala. Compounds available include N-acetyl-aspartate (NAA), creatine-phosphocreatine (Cr) and choline-containing compounds. RESULTS: Subjects with depression demonstrated lower left amygdala Cho-Cr ratios, compared with control subjects (paired t = 2.624, df 10, P = 0.025). Left amygdala NAA-Cr and right amygdala Cho-Cr and NAA-Cr did not differ significantly between subjects with depression and control subjects. In subjects with depression, simple regression revealed a negative trend between left amygdala Cho-Cr and Beck Depression Inventory (BDI) score (F = 3.509, P = 0.098). Right amygdala NAA-Cr and Cho-Cr did not differ significantly. CONCLUSION: Cytosolic choline appears to be involved in the pathophysiology of early-onset MDD, likely secondary to corticosteroid-neuroendocrine-driven changes.

Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines.

Interleukin (IL) -6 and IL-8 are cytokines that have been shown to play a role in several pancreatic diseases, including acute pancreatitis, chronic pancreatitis, and pancreatic adenocarcinoma. Previously, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) and gram-negative bacterial lipopolysaccharide stimulate production of IL-6 and IL-8 and activation of the transcription factor NF-kappaB in the well-differentiated pancreatic ductal adenocarcinoma cell lines CAPAN-1 and CAPAN-2. In these studies we have examined the effect of chain-breaking and glutathione-enhancing antioxidants on NF-kappaB activation and production of IL-6 and IL-8 in these cell lines. Generally, suppression of NF-kappaB activation correlated well with inhibition of IL-6 and IL-8 secretion. In the CAPAN-2 cell line, antioxidants inhibited both NF-kappaB activation and IL-6 and IL-8 secretion. In the CAPAN-1 cell line, antioxidants generally failed to suppress both NF-kappaB activation and IL-6 and IL-8 secretion. The single exception was the chain-breaking antioxidant butylated hydroxyanisole (BHA), which markedly inhibited IL-6 and IL-8 secretion, but had no effect on NF-kappaB activation. These findings may have implications for the treatment of acute and chronic pancreatitis and pancreatic cancer.

Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study.

BACKGROUND: Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available. AIM: To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene. METHODS: Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree. RESULTS: A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred. CONCLUSIONS: The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.

Alcohol feeding and lipopolysaccharide injection modulate apoptotic effectors in the rat pancreas in vivo.

The purpose of this study was to determine if alcohol consumption and endotoxin injection change the rate of apoptosis in the pancreas. Rats were fed a Lieber-DeCarli diet for 14 weeks. At 14 weeks, the animals were injected with lipopolysaccharide (LPS) or saline and killed. The pancreata were resected and snap frozen. Apoptosis was detected by TUNEL assay. Caspase-3 activity, Bcl-2 (protein), and Fas ligand (mRNA) were assayed in pancreas extracts and alpha-amylase in plasma. Alcohol feeding significantly decreased alpha-amylase and caspase-3 activity, and significantly increased Bcl-2. LPS injection increased caspase-3 activity and decreased Bcl-2. Fas ligand mRNA was increased only in alcohol-fed, LPS-injected rats. TUNEL labeling was significantly increased only in alcohol-fed, LPS-injected rats. These data show that (a) long-term alcohol feeding suppresses apoptosis in the pancreas; (b) LPS increases the rate of apoptosis in the pancreas; (c) caspase-3 activity and Bcl-2 expression change in opposite directions; (d) TUNEL positivity and Fas ligand expression are increased, and Bcl-2 is decreased in ethanol-fed + LPS-injected rats. These results suggest that prolonged alcohol consumption may sensitize acinar cells to endotoxin-induced injury and raise the possibility that a similar mechanism may cause pancreatitis in human alcoholics.

Preventive strategies and therapeutic options for hereditary pancreatitis.

Much has been learned about hereditary pancreatitis. Much still remains to be explained, including the characteristic 20% nonpenetrance, variable expressivity, and factors affecting risk for pancreatic cancer. There is much work to be done.

Cytokine production by CAPAN-1 and CAPAN-2 cell lines.

Recently, there has been a great deal of interest in the role of cytokines in acute pancreatitis. Serum levels of IL-1, IL-6, and TNF-alpha have been demonstrated to be elevated in acute pancreatitis. We hypothesized that cytokines may be produced primarily by pancreatic parenchymal cells. Reasoning that ductal epithelium is the cell type most likely to be exposed to noxious stimuli in common causes of pancreatitis, such as ERCP and passage of a gallstone, we examined the response of well differentiated pancreatic ductal adenocarcinoma cell lines to stimuli known to stimulate cytokine production in other cells. CAPAN-1 and CAPAN-2 cells were incubated with endotoxin or TNF-alpha. The supernatant was assayed for production of IL-1, IL-6, and IL-8 by ELISA. The cells were assayed for activation of the transcription factor NF-kappaB by electrophoretic mobility shift assay. There was no detectable production of IL-1 by either cell line. CAPAN-1 cells had concentration-dependent production of IL-6 and IL-8 in response to both endotoxin and TNF-alpha. CAPAN-2 cells had concentration-dependent production of IL-6 and IL-8 in response to TNF-alpha. They had low level expression of IL-8 that was unaffected by any concentration of LPS, and no detectable production of IL-6 in response to LPS. These findings suggest that pancreatic duct cells may take an active part in the pathogenesis of acute pancreatitis through the production of cytokines.