MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis.

Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-α, IFN-γ, IL-1ß, IL-6 and IL-10 by RT-PCR; prostaglandin E(2) (PGE(2)), cytoplasmic phospholipase A(2) (cPLA(2)) and myeloperoxidase by immunoassay; and COX-2 and NF- κB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A(2); reduced significantly the induced levels of TNF-α, IFN-γ, IL-1ß, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-κB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE(2) in the colon and PGE(2) metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-κB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-κB. MC-12 merits further development as an agent for the control of IBD.

Darwin's principles of divergence and natural selection: Why Fodor was almost right.

Darwin maintained that the principles of natural selection and divergence were the "keystones" of his theory. He introduced the principle of divergence to explain a fundamental feature of living nature: that organisms cluster into hierarchical groups, so as to be classifiable in the Linnaean taxonomic categories of variety, species, genus, and so on. Darwin's formulation of the principle of divergence, however, induces many perplexities. In his Autobiography, he claimed that he had neglected the problem of divergence in his Essay of 1844 and only solved it in a flash during a carriage ride in the 1850s; yet he does seem to have stated the problem in the Essay and provided the solution. This initial conundrum sets three questions I wish to pursue in this essay: (1) What is the relationship of the principle of divergence to that of natural selection? Is it independent of selection, derivative of selection, or a type of selection, perhaps comparable to sexual selection? (2) What is the advantage of divergence that the principle implies-that is, why is increased divergence beneficial in the struggle for life? And (3) What led Darwin to believe he had discovered the principle only in the 1850s? The resolution of these questions has implications for Darwin's other principle, natural selection, and permits us to readjust the common judgment made about Jerry Fodor's screed against that latter principle.

Management of abdominal and pelvic abscess in Crohn's disease.

Patients with Crohn's disease may develop an abdominal or pelvic abscess during the course of their illness. This process results from transmural inflammation and penetration of the bowel wall, which in turn leads to a contained perforation and subsequent abscess formation. Management of patients with Crohn's related intra-abdominal and pelvic abscesses is challenging and requires the expertise of multiple specialties working in concert. Treatment usually consists of percutaneous abscess drainage (PAD) under guidance of computed tomography in addition to antibiotics. PAD allows for drainage of infection and avoidance of a two-stage surgical procedure in most cases. It is unclear if PAD can be considered a definitive treatment without the need for future surgery. The use of immune suppressive agents such as anti-tumor necrosis factor-α in this setting may be hazardous and their appropriate use is controversial. This article discusses the management of spontaneous abdominal and pelvic abscesses in Crohn's disease.

Toxic megacolon associated Clostridium difficile colitis.

Toxic megacolon is a severe complication of Clostridium difficile (C. difficile) colitis. As the prevalence of C. difficile colitis increases and treatments become more refractory, clinicians will encounter more patients with C. difficile associated toxic megacolon in the future. Here, we review a case of toxic megacolon secondary to C. difficile colitis and review the current literature on diagnosis and management. We identify both clinical and radiologic criteria for diagnosis and discuss both medical and surgical options for management. Ultimately, we recommend using the Jalen criteria in conjunction with daily abdominal radiographs to help establish the diagnosis of toxic megacolon and to make appropriate treatment recommendations. Aggressive medical management using supportive measures and antibiotics should remain the mainstay of treatment. Surgical intervention should be considered if the patient does not clinically improve within 2-3 d of initial treatment.

Complications of type 1 diabetes.

The prevalence of diabetes is increasing worldwide and the concern regarding the number of new cases of diabetes relates to the development of chronic complications. It has been recognized for years that the complications are a cause of considerable morbidity and mortality worldwide and as such, negatively affect the quality of life in individuals with diabetes with an increase in disability and death. Specifically, the complications of diabetes have been classified as either microvascular (ie, retinopathy, nephropathy, and neuropathy) or macrovascular (ie, cardiovascular disease, cerebrovascular accidents, and peripheral vascular disease). For purposes of this article, the authors focus on a brief review of the major complications.

Increasing computer-aided detection specificity by projection features for CT colonography.

PURPOSE: A large number of false positives (FPs) generated by computer-aided detection (CAD) schemes is likely to distract radiologists' attention and decrease their interpretation efficiency. This study aims to develop projection-based features which characterize true and false positives to increase the specificity while maintaining high sensitivity in detecting colonic polyps. METHODS: In this study, two-dimensional projection images are obtained from each initial polyp candidate or volume of interest, and features are extracted from both the gray and color projection images to differentiate FPs from true positives. These projection features were tested to exclude different types of FPs, such as haustral folds, rectal tubes, and residue stool using a database of 325 patient studies (from two different institutions), which includes 556 scans at supine and/or prone positions with 347 polyps and masses sized from 5 to 60 mm. For comparison, several well-established features were used to generate a baseline reference. The experimental evaluation was conducted for large polyps (> or = 10 mm) and medium-sized polyps (5-9 mm) separately. RESULTS: For large polyps, the additional usage of the projection features reduces the FP rate from 5.31 to 1.92 per scan at the comparable by-polyp sensitivity level of 93.1%. For medium-sized polyps, the FP rate is reduced from 8.89 to 5.23 at the sensitivity level of 80.6%. The percentages of FP reduction are 63.9% and 41.2% for the large and medium-sized polyps, respectively, without sacrificing detection sensitivity. CONCLUSIONS: The results have demonstrated that the new projection features can effectively reduce the FPs and increase the detection specificity without sacrificing the sensitivity. CAD of colonic polyps is supposed to help radiologists to improve their performance in interpreting computed tomographic colonography images.

The frequency of early repeat tests after colonoscopy in elderly medicare recipients.

BACKGROUND: The frequency of early repeat and follow-up tests (RAFTs) occurring after colonoscopy has not been previously examined in the literature. RAFTs incur cost, discomfort, and inconvenience to patients who have undergone colonoscopic examination; therefore, it is important to identify factors associated with their use. METHODS: We identified elderly Medicare recipients who had colonoscopy performed in 1999 from the 5% Medicare administrative files (N = 69,282). We determined the number of early RAFTs (repeat colonoscopy, barium enema, flexible sigmoidoscopy) occurring within the year of initial colonoscopy. RESULTS: Of the study sample, 8.3% required at least one RAFT during the year. Using multivariable analysis, we found that RAFTs varied significantly with age, race, sex, income, comorbidity, provider type, and place of service. RAFTs were 22% higher in African Americans compared to whites. Gastroenterologists used 20-35% fewer RAFTs than the other provider types performing colonoscopy. CONCLUSIONS: The frequency of early RAFTs after colonoscopy occurs in 8.3% of the Medicare population. Important differences exist in the frequency of RAFTs by race and provider type.

Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects.

Despite advances in diagnosis and treatment, type 2 diabetes mellitus (T2DM), overweight/obesity, cardiovascular disease, and their sequelae are major public health burdens worldwide. The understanding of the pathophysiology of T2DM has traditionally emphasized decreased insulin secretion and increased insulin resistance, but evolving concepts now include the role of incretin hormones in disease progression. A comprehensive approach to managing patients with T2DM requires targeting both the fundamental defects of the disease and its comorbidities, including the sequelae of nonoptimal control of blood glucose, blood pressure, body weight, and lipids. Newer antidiabetes agents, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors, address fundamental defects related to glycemic control in T2DM and may have potential effects on other markers of cardiovascular risk. A redefinition of treatment success may be warranted as more data become available.

Darwin's place in the history of thought: a reevaluation.

Scholars have usually given Darwin's theory a neo-Darwinian interpretation. A more careful examination of the language of Darwin's notebooks and the language of the Origin of Species indicates that he reconstructed nature with a definite purpose: the final goal of man as a moral creature. In the aftermath of the Origin, Darwin, however, became more circumspect.

Leptin, adiposity, and testosterone in captive male macaques.

Leptin is considered to act as a signal relating somatic energetic status to the reproductive system. However, the nature of that signal and its relationship with male reproductive function across nonhuman primate species are unclear. We suggest that species-specific differences in leptin physiology may be related to the degree of environmental variation and variation in the importance of energy stores for male reproduction. In order to test the role of seasonality in species differences among nonhuman primates, we compared leptin, testosterone, and body composition in male rhesus (n = 69) and pig-tailed (n = 43) macaques. Despite having larger abdominal fat deposits, the rhesus macaques did not exhibit significantly higher leptin levels (rhesus, 2.21 +/- 0.43 ng/ml; pig-tailed, 2.12 +/- 0.39 ng/ml). Both species showed increases in leptin across adolescent, subadult, and adult age-groups (P = 0.036 for rhesus; P = 0.0003 for pig-tailed by ANCOVA). Testosterone was not significantly associated with leptin in either the rhesus (r = 0.039; P = 0.754) or pig-tailed (r = 0.2862; P = 0.066) samples. Comparison of leptin levels across the two species using univariate modeling procedures showed no significant age-group by abdominal fat interaction. These findings suggest little difference in leptin production between these two closely related species, despite the difference in breeding seasonality.

Leptin: sympathetic and cardiovascular effects.

Shortly after leptin was first discovered, it was hailed as the key to understanding obesity. However, it didn't take long for investigators to realize that the hormone was more than a feedback signal to inhibit further food intake. Since those early days, leptin has been well characterized in rodents. It exerts an influence in many physiologic processes, including food intake, thermoregulation, fertility, thyroid function, adrenal function, sympathetic nerve activation, renal function, blood vessel tone, and blood pressure. No longer a satiety hormone, it is being looked at from many different perspectives. One such perspective is its influence on the cardiovascular system. This review highlights some of the work in this area.

Dehydroepiandrosterone-sulfate as a biomarker of senescence in male non-human primates.

Numerous studies have suggested important and varying roles for dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) in primate physiological functions. Despite these numerous claims, specific actions and significance of DHEA and DHEA-S are still equivocal. A decline of these hormones in adult humans may have functional significance, yet there is no clear relationship between functional impairments of aging and the decline in DHEA or DHEA-S levels. This current study attempts to address the natural history of adrenal hormones by presenting non-human primate evidence of the endocrinology of aging; the age-related patterns of adrenal hormone decline in three species of the subfamily Cercopithecinae, Macaca mulatta, Macaca nemestrina, and Papio cynocephalus are compared. It is concluded that DHEA-S and cortisol represent lineage specific markers of senescence among primates and that parallel age-related patterns of DHEA-S and cortisol likely reflect lineage specific effects, or rather, phylogenetic similarities of endocrine senescence. The use of relative adrenal hormone levels to approximate species' life expectancies is discussed.

Postprandial hyperglycemia.

Much attention has been paid to fasting glucose levels in both the diagnosis and management of diabetes mellitus. This test is well ingrained in clinical practice and well accepted by our patients. However, does a fasting glucose level give the clinician a complete picture? Is postprandial hyperglycemia associated with adverse events? This article will explore postprandial glucose levels and compare them to fasting glucose levels. The importance of postprandial and post-challenge (2 hours after a standard oral glucose tolerance test) glucose levels will be discussed. Drugs which address postprandial hyperglycemia will be reviewed briefly.

Racial differences in use of colonoscopy, sigmoidoscopy, and barium enema in Medicare beneficiaries.

Colorectal cancer is often diagnosed at a later stage in blacks. We wanted to know if racial differences existed in the use of tests for detection of colorectal cancer. A 5% random sample was obtained of all Medicare beneficiaries with Part B coverage, aged 65 years and older and classified as white or black race. The numbers of colonoscopies, flexible sigmoidoscopies, and barium enemas were determined from the Physician/Supplier file. Blacks were 18% less likely to receive colonoscopy and 39% less likely to receive flexible sigmoidoscopy after controlling for age, sex, income, and access to care in a multivariable logistic regression model. Barium enema was not significantly different between the races. Black men had 25% lower use of colonoscopy and 50% decreased use of flexible sigmoidoscopy. Blacks receive less colonoscopy and flexible sigmoidoscopy than whites. Black men are particularly vulnerable to the under-use of these tests.

Timing of prophylactic surgery in prevention of diverticulitis recurrence: a cost-effectiveness analysis.

Although surgery is recommended after two or more attacks of uncomplicated diverticulitis, the optimal timing for surgery in terms of cost-effectiveness is unknown. A Markov model was used to compare the costs and outcomes of performing surgery after one, two, or three uncomplicated attacks in 60-year-old hypothetical cohorts. Transition state probabilities were assigned values using published data and expert opinion. Costs were estimated from Medicare reimbursement rates. Surgery after the third attack is cost saving, yielding more years of life and quality adjusted life years at a lower cost than the other two strategies. The results were not sensitive to many of the variables tested in the model or to changes made in the discount rate (0-5%). In conclusion, performing prophylactic resection after the third attack of diverticulitis is cost saving in comparison to resection performed after the first or second attacks and remains cost-effective during sensitivity analysis.