Pancreatitis case study

The lesson learned from these case studies was that in vitro models can be used as screening tools when investigating direct injury to a relevant single cell type, but traditiontd two-dimensional (2D) cell culture models often bear little physical, molecular, or physiological similarity to the pancreas in vivo. This highhghts a need to continue efforts to define more complex multicell systems, such as organotypic and ex vivo models, for assessment of drug candidate-induced pancreatic toxicity. 

In a retrospective case/non-case study on 1,857,460 records, only 86,938 reports were related to the use of antidiabetic agents. Among the cases of pancreatitis, exenatide accoxmted for 709 cases. Disproportionality analysis on therapeutic classes found significant OR for exenatide (OR, 1.76 95% Cl, 1.61-1.92 P < 0.001). These data suggest that exenatide may be associated with an increased risk of pancreatitis. [42 ]... 

Hedgehog (Hh) signaling has a rich history in chemical biology with a wide variety of small-molecule probes acting on numerous signaling nodes [38]. Hh inhibition in development leads to cyclopia in vertebrates, and its dysregulation in adult humans causes basal cell carcinoma (BCG), medulloblastoma, pancreatic cancer, and others. Thus, the available tools for its perturbation can serve as a useful case study for the development and use of probe molecules in biology. 

To date, a number of simulation studies have been performed on nucleic acids and proteins using both AMBER and CHARMM. A direct comparison of crystal simulations of bovine pancreatic trypsin inliibitor show that the two force fields behave similarly, although differences in solvent-protein interactions are evident [24]. Side-by-side tests have also been performed on a DNA duplex, showing both force fields to be in reasonable agreement with experiment although significant, and different, problems were evident in both cases [25]. It should be noted that as of the writing of this chapter revised versions of both the AMBER and CHARMM nucleic acid force fields had become available. Several simulations of membranes have been performed with the CHARMM force field for both saturated [26] and unsaturated [27] lipids. The availability of both protein and nucleic acid parameters in AMBER and CHARMM allows for protein-nucleic acid complexes to be studied with both force fields (see Chapter 20), whereas protein-lipid (see Chapter 21) and DNA-lipid simulations can also be performed with CHARMM. 

Although earlier work had showed a positive association between coffee consumption and pancreatic cancer rates across countries,2 it was the much-publicized case-control study of MacMahon et al.3 in 1981 that attracted widespread attention to the question of a possible link. In that study, which was designed primarily to investigate the role of smoking and alcohol in pancreatic cancer, 369 pancreatic cancer patients prior to diagnosis and 644 hospital controls reported their typical daily coffee and tea consumption. Unexpectedly, the authors found a significantly increased risk of pancreatic cancer associated with coffee consumption (overall rela-... 

In an earlier study 5 it was found that in 33 per cent of the cases the pancreatic and bile ducts have separate openings. This and other similar variations probably occur in different percentages among populations with different racial origins. Some evidence on this point has been found in connection with the variations in the junctions of the hepatic and cystic ducts. 

The ultimate objective of an X-ray cryoenzymological study is the mapping of the structures of all kinetically significant species along the reaction pathway. In the case of ribonuclease A this has been largely achieved, as described above. Other enzymatic reactions now await application of the same techniques. Unfortunately, not all crystalline enzymes lend themselves to study by this method. In some cases it may be impossible to find a suitable cryoprotective mother liquor in others, the reaction may occur too rapidly at ordinary temperature. A reaction with Acat of 10 seconds and an activation enthalpy of —6 kcal mol will not be quenched even at — 75°C. The approach we have described in this article can be applied to only a small number of enzymes. Two likely candidates for successors to ribonuclease are the enzymes yeast triosephosphate isomerase and porcine pancreatic elastase. 

Two epidemiological studies of workers exposed to ethylene oxide revealed increased rates of leukemia. In one smdy, two cases of leukemia (0.14 expected) and three stomach cancers (0.4 expected) were observed. The other study found three cases of leukemia (0.2 expected). Because these workers had exposures to other potential carcinogens, the findings cannot be linked with certainty to ethylene oxide. The small cohort size, the small number of deaths, and uncertainties about exposure level have also been noted." A number of other studies have not found an increased rate of cancer mortality from ethylene oxide exposure. A mortality study of over 18,000 ethylene oxide workers from 14 plants producing medical supplies and foodstuffs did not find an excess of leukemia or brain, stomach, or pancreatic cancers. There was, however, an increase in non-Hodgkin lymphoma in male workers. A follow-up of 1896 ethylene oxide production workers did not find an increase in mortality from leukemia, non-Hodgkin lymphoma, or brain, pancreatic, or stomach cancers. ... 

In humans methylene chloride exposure has been associated with a wide variety of cancers in a number of cohort and case control studies pancreatic, prostate, lung, liver, cervical, breast, and astrocytic brain tumors have been reported. Limitations in these studies include small sample size, incomplete exposure information, and concomitant exposure to other carcinogenic substances. The lARC has stated that there is not a sufficiently consistent elevation of risk across studies to make a causal interpretation credible. In a recent study of 1473 workers, followed for nearly 50 years, methylene chloride exposure level was not related to mortality due to all causes, malignant neoplasms, or lung and pancreatic cancers. ... 

Olsen GW, et al. A case-control study of pancreatic cancer and cigarettes, alcohol, coffee and diet. Am J Public Health 1989 79(8) 1016-1019. 

Subscript (ads) denotes adsorption via a thiolate linkage, while (ps) stands for a physisorbed and/or adsorbed state via different interactions. However, large dimensions of the studied molecules and their amphiphilic nature make the surface reaction mechanism more complex than in case of cystine/cysteine. Interfacial microstructure plays an important role in the determination of the surface behavior of the adsorbed molecules. From the study on the charge-transfer kinetics, the transfer coefficient a was calculated as slightly less than 0.50, while the rate constant (based on Laviron s derivations [105]) was of the order of 10 s k The same authors [106] have shown earlier that the adsorption rate constant of porcine pancreatic phospholipase A2 at mercury via one of its disulfide groups is of the order of 10 s h... 

Benson and Teta (1993) studied the mortality among 278 chlorohydrin production workers who had ever been employed at a facility in the United States between 1940 and 1967. The follow-up period was from 1940 to 1988. This was a 10-year update of an earlier study conducted by Greenberg et al. (1990). There were 147 deaths (SMR, 1.0) and 40 cancer deaths (SMR, 1.3) observed. Excesses of pancreatic cancer (SMR, 4.9 95% CI, 1.6-11.4 8 cases) and lymphatic and haematopoietic cancers (SMR, 2.9 95% CI, 1.3-5.8 ... 

Olsen et al. (1997) studied mortality among 1361 men employed at two chlorohydrin production facilities in the United States similar to that studied by Benzon and Teta (1993). There were 300 deaths (SMR, 0.9) and 75 cancer deaths (SMR, 0.9) observed. The risks of pancreatic cancer (SMR, 0.3 95% CI, 0.01-1.4 1 case) and lymphatic and haematopoietic cancers (SMR, 1.3 95% CI, 0.6-2.4 10 cases) were less than those observed by Benson and Teta and no other cancers were observ ed in excess. It was not possible to link mortality to any particular chemical exposure and levels of exposure were not reported. 

In Siemiatycki s (1991) population-based case-control study of cancer in Montreal, Canada (see monograph on dichloromethane in this volume), phenol was one of the substances evaluated 1% of the entire study population had been exposed to it at some time. Among the main occupations to which phenol exposure was attributed in this study were electric motor repairmen and foundry workers. The publication reported an association between phenol and pancreatic cancer (odds ratio, 4.8 90% CI, 1.8-12.7 n = 4) for no other site was cancer risk associated with phenol exposure. [The Working Group noted that detailed results for other sites were not provided, because they were based on small numbers, and that workers typically had multiple exposures.]... 

The incidence of acute pancreatitis as a suspected complication of finasteride treatment has been examined in a case-control study in a Danish regional population of 490 000 over 7 years. Of 302 men aged 60 and older with incident acute pancreatitis, three had been exposed to finasteride of 2994 controls 37 had been exposed to finasteride. After adjustment for alcohol-related diseases, gallstone disease, hyperlipidemia, hypercalcemia, and hyperparathyroidism, the authors found no evidence of an increased risk of acute pancreatitis in users of finasteride (48). 

Floyd A, Pedersen L, Nielsen GL, Thorlacius-Ussing O, Sorensen HT. Risk of acute pancreatitis in users of finasteride a population-based case-control study. J Clin Gastroenterol 2004 38 276-8. 

In a case-control study in 1.4 million people in Sweden, 462 who were hospitalized for pancreatitis without gallbladder disease were compared with 1781 randomly selected controls 6% of the cases and 3% of the controls had diabetes (118). Diet and insulin therapy were not associated with an increased risk, but the risk of pancreatitis with glibenclamide had a crude odds ratio of 3.2 and was higher in people aged over 70 years and in those taking beta-blockers. 

Of 62 initially autoantibody-negative patients treated with interferon alfa for chronic hepatitis C for a mean of 8 months, three developed antibodies to 21b-hydroxylase, a sensitive assay of adrenocortical autoimmunity (528). However, there were no cases of Addison s disease or subclinical adrenal insufficiency. This study suggested that the adrenal cortex is another potential target organ of autoimmune effects of interferon alfa, along with thyroid and pancreatic islet cells. 

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