We analyzed 40 cases of falsification, fabrication, or plagiarism (FFP), comparing them to other types of wrongdoing in research (n = 40) and medicine (n = 40). Fifty-one variables were coded from an average of 29 news or investigative reports per case. Financial incentives, oversight failures, and seniority correlate significantly with more serious instances of FFP. However, most environmental variables were nearly absent from cases of FFP and none were more strongly present in cases of FFP than in other types of wrongdoing. Qualitative data suggest FFP involves thinking errors, poor coping with research pressures, and inadequate oversight. We offer recommendations for education, institutional investigations, policy, and further research.
Prior studies with carbonic anhydrase (CA) inhibitors implicated mitochondrial CA in ureagenesis and gluconeogenesis. Subsequent studies identified two mitochondrial CAs. To distinguish the contribution of each enzyme, we studied the effects of targeted disruption of the murine CA genes, called Car5A and Car5B. The Car5A mutation had several deleterious consequences. Car5A null mice were smaller than wild-type littermates and bred poorly. However, on sodium-potassium citrate-supplemented water, they produced offspring in expected numbers. Their blood ammonia concentrations were markedly elevated, but their fasting blood sugars were normal. By contrast, Car5B null mice showed normal growth and normal blood ammonia levels. They too had normal fasting blood sugars. Car5A/B double-knockout (DKO) mice showed additional abnormalities. Impaired growth was more severe than for Car5A null mice. Hyperammonemia was even greater as well. Although fertile, DKO animals were produced in less-thanpredicted numbers even when supplemented with sodium-potassium citrate in their drinking water. Survival after weaning was also reduced, especially for males. In addition, fasting blood glucose levels for DKO mice were significantly lower than for controls (153 ± 33 vs. 230 ± 24 mg/dL). The enhanced hyperammonemia and lower fasting blood sugar, which are both seen in the DKO mice, indicate that both Car5A and Car5B contribute to both ammonia detoxification (ureagenesis) and regulation of fasting blood sugar (gluconeogenesis). Car5A, which is expressed mainly in liver, clearly has the predominant role in ammonia detoxification. The contribution of Car5B to ureagenesis and gluconeogenesis was evident only on a Car5A null background.
Mutations in the human carbonic anhydrase IV (hCAIV) have been associated with retinal degeneration in an autosomal-dominant form of retinitis pigmentosa (RP17). Prior in vitro cell culture studies confirmed that all of the RP17-associated hCAIV mutations cause protein misfolding, leading to endoplasmic reticulum (ER) stress–induced apoptosis in cells expressing the mutant proteins. To evaluate the physiological impacts of these folding mutants in other carbonic anhydrase IV–producing tissues, we generated two transgenic mouse lines expressing R219S or R14W hCAIV under control of the endogenous hCAIV promoter. Expression of either of these mutant proteins in kidneys caused progressive renal injury in male transgenic mice as evidenced by an age-dependent increase in the tubule cell apoptosis starting at approximately 20 weeks of age and vacuolization throughout the renal cortex in older mice. Up-regulation of the ER chaperone, BiP, was observed in the cells of the renal cortex of the male transgenic mice, suggesting ER stress as a causal factor for the renal injury. The renal injury inflicted by expression of the folding mutants was markedly enhanced by haploinsufficiency of the ER cochaperone p58 IPK . The transgenic mice expressing the hCAIV folding mutants on a p58 IPK heterozygous background showed extensive renal tubular apoptosis by approximately 10 weeks of age in both male and female mice. These data indicate that expression of the RP17-associated folding mutants of hCAIV can adversely affect tissues beyond the retina and their in vivo proteotoxicity is sensitive to modulation of the protein folding environment of the ER.
In this paper we describe our approach to understanding wrongdoing in medical research and practice, which involves the statistical analysis of coded data from a large set of published cases. We focus on understanding the environmental factors that predict the kind and the severity of wrongdoing in medicine. Through review of empirical and theoretical literature, consultation with experts, the application of criminological theory, and ongoing analysis of our first 60 cases, we hypothesize that 10 contextual features of the medical environment (including financial rewards, oversight failures, and patients belonging to vulnerable groups) may contribute to professional wrongdoing. We define each variable, examine data supporting our hypothesis, and present a brief case synopsis from our study that illustrates the potential influence of the variable. Finally, we discuss limitations of the resulting framework and directions for future research.
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