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.

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.

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.

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.

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.

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

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.

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.

Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.

BACKGROUND: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. PURPOSE: The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. METHODS: To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. RESULTS: The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. CONCLUSIONS: Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.

Negative glucorticoid regulation of cyclic adenosine 3', 5'-monophosphate-stimulated corticotropin-releasing hormone-reporter expression in AtT-20 cells.

The negative glucocorticoid regulation of CRH gene expression is a critical control element in the hypothalamic-pituitary-adrenal axis. In this study, the molecular mechanisms mediating the glucocorticoid repression of cAMP-induced CRH-reporter expression in AtT-20 cells have been examined. In these cells, dexamethasone decreases forskolin-induced expression of CRH-reporter activity in a dose-dependent manner. This repression is mediated by the glucocorticoid receptor (GR) and does not require ongoing protein synthesis. Several binding sites for the GR DNA-binding domain were identified within the CRH 5'-flanking and 5'-untranslated regions utilizing in vitro DNase I protection assays. These sites were independently mutated and/or deleted. Functional studies in transfected cells suggest that none of the protected DNA sequences mediate the glucocorticoid regulation and that the regulatory element(s) mediating negative glucocorticoid regulation is contained within the CRH DNA sequences from -248 to +4 bp relative to the major transcription initiation site. To further localize the DNA sequence(s) responsive to glucocorticoids, DNA fragments containing various amounts of human CRH 5'flanking sequences were inserted 5' to the SV40 promoter. An 18-bp DNA fragment containing the CRH cAMP-responsive element is sufficient to confer both positive cAMP regulation and glucocorticoid repression of cAMP-stimulated expression to the SV40 promoter. These results suggest that glucocorticoid repression of forskolin-activated CRH-reporter expression in AtT-20 cells occurs via interference with the cAMP-mediated activation of gene expression, possibly via direct or indirect interactions between the GR and the cAMP-responsive element-binding proteins.

Rapid diagnosis and identification of cross-over sites in patients with glucocorticoid remediable aldosteronism.

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant cause of primary aldosteronism and high blood pressure resulting from a chimeric 11beta-hydroxylase/aldosterone synthase gene. Abnormal expression of aldosterone synthase causes primary aldosteronism, which can be inhibited by glucocorticoids. Diagnosis of GRA has depended on the identification of a restriction enzyme product in genomic DNA of affected individuals. Recently, a two-tube long PCR method was described that allowed diagnosis of GRA in a kindred in Australia. A similar long PCR method confirmed the diagnosis of GRA in members of five northeastern Scotland families previously identified by Southern blotting and detected affected members of five GRA families previously identified in Glasgow. A multiplex PCR protocol is described here that allows the control aldosterone synthase amplification and chimeric gene amplification to be carried out in the same tube. We describe the regions of cross-over in each of 10 kindreds identified in Scotland. To identify cross-over regions in each of the kindreds, the chimeric long PCR product was cloned and sequenced. Five cross-over sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of cross-over.

Cigarette smoking and leukocyte subpopulations in men.

Because of previously reported associations among the total leukocyte count, cigarette smoking, and risk of cardiovascular disease, we examined the relation of cigarette smoking to various leukocyte subpopulations among 3467 men aged 31 to 45 years. The median total leukocyte count was 36% higher (7840 vs. 5760 cells/mL) among current cigarette smokers than among men who had never smoked, and both stratification and regression analyses were used to examine independent associations with leukocyte subpopulations. At equivalent counts of other subpopulations, CD4+ lymphocytes and neutrophils were the cell types most strongly associated with cigarette smoking; each standard deviation change in counts of these subpopulations increased the odds of current (vs. never) smoking by approximately threefold. Furthermore, whereas 15% of the 238 men with relatively low (< 25 percentile) counts of both neutrophils and CD4+ lymphocytes were cigarette smokers, 96% of the 249 men with relatively high counts of both subpopulations were current smokers. Counts of T lymphocytes also tended to be higher among the 32 men with self-reported ischemic heart disease than among other men. These results, along with previous reports of immunologically active T lymphocytes in atherosclerotic plaques, suggest that this subpopulation may be of particular interest in studies examining the relation of leukocytes to cardiovascular disease.

Black/white differences in leukocyte subpopulations in men.

BACKGROUND: Although counts of leukocytes differ substantially between blacks and whites, and are predictive of ischaemic heart disease (IHD), racial differences in counts of leukocyte subpopulations have received less attention. METHODS: We examined black/white differences in leukocyte subpopulations among 3467 white and 493 black 31-45 year-old-men who had previously served in the US Army. Laboratory determinations were performed at a central location during 1985-1986. RESULTS: Black men had an 840 cell/microliter (or 15%) lower mean total leukocyte count than did white men, largely due to a 960 cell/microliter (or 25%) lower mean neutrophil count. Although black men also had a 20% lower mean monocyte count (= 70 cells/microliter) than did white men, their mean lymphocyte count was 10% higher (approximately = 200 cells/microliter). Counts of various leukocyte subpopulations were associated with cigarette smoking, haemoglobin levels, platelet counts, and several other characteristics, but black/white differences in counts of neutrophils, lymphocytes, monocytes and other subpopulations could not be attributed to any of the examined covariates. CONCLUSIONS: Despite the relatively low counts of leukocytes and neutrophils among black men, their lymphocyte counts are generally higher than those among white men. It is possible that black/white differences in counts of various cell types may influence race-specific rates of IHD, and future studies should attempt to assess the importance of leukocyte subpopulations in the development of clinical disease.

Alveolar and lung liquid clearance in anesthetized rabbits.

Alveolar and lung liquid clearance were studied over 8 h in intact anesthetized ventilated rabbits by instillation of either isosmolar Ringer lactate (2 ml/kg) or autologous plasma (2 or 3 ml/kg) into one lower lobe. The half time for lung liquid clearance of the isosmolar Ringer lactate was 3.3 h and that for plasma clearance was 6 h. In the plasma experiments, the alveolar protein concentration after 1 h was 5.2 +/- 0.8 g/dl, which was significantly greater than the initial instilled protein concentration of 4.3 +/- 0.7 g/dl (P less than 0.05). Thus alveolar protein concentration increased by 21 +/- 12% over 1 h, which matched clearance from the entire lung of 19 +/- 11% of the instilled volume. Overall the rate of alveolar and lung liquid clearance in rabbits was significantly faster than in prior studies in dogs and sheep. The fast alveolar liquid clearance rate in rabbits was not due to higher endogenous catecholamine release, because intravenous and alveolar (5 x 10(-5) M) propranolol did not slow the clearance. Also, beta-adrenergic therapy with alveolar terbutaline (10(-5) or 10(-4) M) did not increase the alveolar or lung liquid clearance rates. Phloridzin (10(-3) M) did not slow alveolar liquid clearance. However, amiloride (10(-4) M) inhibited 75% of the basal alveolar liquid clearance in rabbits, thus providing evidence that alveolar liquid clearance in rabbits depends primarily on sodium-dependent transport. This rabbit study provides further evidence for important species differences in the basal rates of alveolar liquid and solute clearance as well as the response to beta-adrenergic agonists and ion transport inhibitors.

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.

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.

Hereditary pancreatitis. Gene defects and their implications.

Hereditary pancreatitis is a rare condition characterized by acute and chronic pancreatitis transmitted in an autosomal dominant fashion. There also is an epidemiologic link to pancreatic cancer in some affected families. Failure of a secondary brake mechanism responsible for inactivation of prematurely activated cationic trypsin in acinar cells seems to be the fundamental defect in type I hereditary pancreatitis (R117H cationic trypsin), and also may explain the pathogenesis of type II hereditary pancreatitis (N211 cationic trypsin). The diagnosis is made based on clinical history and, in certain cases, by molecular diagnostic testing for these gene defects. Medical management of acute and chronic hereditary pancreatitis currently does not differ from that of nonhereditary AP. As in nonhereditary pancreatitis, the surgical approach must be tailored to the individual problem, with an understanding that disease restricted to the head of the gland is atypical and that residual acinar tissue continues to drive the disease state. Although diagnosis and management of pancreatic adenocarcinoma are similar in this cohort, the increased age-accumulated risk suggests that thoughtful screening protocols eventually may be clinically and cost-effective.

Central intravascular pressure measurements: when should we believe them?

With the widespread use of invasive hemodynamic monitoring of the pulmonary circulation to aid in diagnosis and therapy of cardiac and respiratory failure, shock, and pulmonary hypertension, diagnostic radiologists have become accustomed to interpreting chest radiographs in the context of measured intrathoracic intravascular pressures. Unfortunately, errors in measurement and interpretation of these pressures are common. Perhaps the most difficult aspect of invasive hemodynamic monitoring is the interpretation of measured pressures in the context of a variety of clinical circumstances and disease states, some of which may dramatically alter the usual relationship between the pulmonary artery wedge pressure and left ventricular preload. Without detailed information about the techniques used to obtain these measurements and the clinical status of the patient at the time that they are made, the measurements should not be used as a standard against which clinical and radiographic findings are judged.

Bowel preparation before colonoscopy. Choosing the best lavage regimen.

A review of the relevant English-language literature on bowel cleansing before colonoscopy yielded results of randomized trials comparing a variety of regimens, including polyethylene glycol (PEG)-electrolyte lavage, 3-day clear liquid diet with laxatives or prokinetics, and oral sodium phosphate, as well as these regimens combined with agents such as metoclopramide, cisapride, and senna. Balancing the importance of such factors as cleansing effectiveness, safety, ease of completion, side effects, patient tolerance, and cost, the authors recommend four methods: (1) PEG-electrolyte solution (eg, CoLyte, GoLYTELY, NuLytely) in combination with senna (eg, X-Prep), (2) PEG-electrolyte solution alone (either single dose or split dose), (3) oral sodium phosphate (Fleets Phosphosoda) given in split dose, and (4) oral magnesium citrate in combination with rectal pulsed irrigation.