Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

Concentration of GPI-anchored proteins upon ER exit in yeast.

Previous biochemical work has revealed two parallel routes of exit from the endoplasmic reticulum (ER) in the yeast Saccharomyces cerevisiae, one seemingly specific for glycosyl-phosphatidylinositol (GPI)-anchored proteins. Using the coat protein II (COPII) mutant sec31-1, we visualized ER exit sites (ERES) and identified three distinct ERES populations in vivo. One contains glycosylated pro-alpha-factor, the second contains the GPI-anchored proteins Cwp2p, Ccw14p and Tos6p and the third is enriched with the hexose transporter, Hxt1p. Concentration of GPI-anchored proteins prior to budding requires anchor remodeling, and Hxt1p incorporation into ERES requires the COPII components Sec12p and Sec16p. Additionally, we have found that GPI-anchored protein ER exit is controlled by the p24 family member Emp24p, whereas ER export of most transmembrane proteins requires the Cornichon homologue Erv14p.

Screening colonoscopies by primary care physicians: a meta-analysis.

PURPOSE: There is currently too few endoscopists to enact a national colorectal cancer screening program with colonoscopy. Primary care physicians could play an important role in filling this shortage by offering screening colonoscopy in their practice. The purpose of this study was to examine the safety and effectiveness of colonoscopies performed by primary care physicians. METHODS: We identified relevant articles through searches of MEDLINE and EMBASE bibliographic databases to December 2007 and through manual searches of bibliographies of each citation. We found 590 articles, 12 of which met inclusion criteria. Two authors independently abstracted data on study and patient characteristics. Descriptive statistics were performed. For each outcome measure, a random effects model was used to determine estimated means and confidence intervals. RESULTS: We analyzed 12 studies of colonoscopies performed by primary care physicians, which included 18,292 patients (mean age 59 years, 50.5% women). The mean estimated adenoma and adenocarcinoma detection rates were 28.9% (95% confidence interval [CI], 20.4%-39.3%) and 1.7% (95% CI, 0.9%-3.0%), respectively. The mean estimated reach-the-cecum rate was 89.2% (95% CI, 80.1%-94.4%). The major complication rate was 0.04% (95% CI, 0.01%-0.07%); no deaths were reported. CONCLUSIONS: Colonoscopies performed by primary care physicians have quality, safety, and efficacy indicators that are comparable to those recommended by the American Society of Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Society of American Gastrointestinal Endoscopic Surgeons. Based on these results, colonoscopy screening by primary care physicians appears to be safe and effective.

How well are practice management curricula preparing family medicine residents?

BACKGROUND: While emphasis has been placed on practice management curricula in residency, studies indicate that residents are not adequately prepared. To assess the effectiveness of current practice management skills training in residency, we examined the confidence levels of family medicine residents and recent graduates in practice management skills. METHODS: A survey was sent to family medicine residency programs within South Carolina. Participants ranked their confidence level in 13 practice management skills on a 5-point Likert scale. Analysis of covariance compared confidence levels in their skills while controlling for program, gender, and age. Residency directors of these programs were also surveyed about the content of their practice management programs. RESULTS: Residents and graduates rated their confidence in all areas moderately high. Graduates rated themselves significantly more confident than residents did in seven practice management skills. CONCLUSIONS: Family medicine practice management curricula appear to be effective in establishing confidence regarding practice management skills in residents and recent graduates.

Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction.

Farnesol is a catabolite of the cholesterol biosynthetic pathway that preferentially causes apoptosis in tumorigenic cells. Phosphatidylcholine (PC), phosphatidic acid (PA), and diacylglycerol (DAG) were able to prevent induction of apoptosis by farnesol. Primary alcohol inhibition of PC catabolism by phospholipase D augmented farnesol-induced apoptosis. Exogenous PC was unable to prevent the increase in farnesol-induced apoptosis by primary alcohols, whereas DAG was protective. Farnesol-mediated apoptosis was prevented by transformation with a plasmid coding for the PA phosphatase LPP3, but not by an inactive LPP3 point mutant. Farnesol did not directly inhibit LPP3 PA phosphatase enzyme activity in an in vitro mixed micelle assay. We propose that farnesol inhibits the action of a DAG pool generated by phospholipase D signal transduction that normally activates an antiapoptotic/pro-proliferative target.

The relationship between the National Board of Medical Examiners' prototype of the Step 2 clinical skills exam and interns' performance.

PURPOSE: To examine the relationship between graduates' performances on a prototype of the National Board of Medical Examiners' Step 2 CS and other undergraduate measures with their residency directors' ratings of their performances as interns. METHOD: Data were collected for the 2001 and 2002 graduates from the study institution. Checklist and interpersonal scores from the prototype Step 2 CS, along with United States Medical Licensing Examination (USMLE) Step 1 and 2 scores and undergraduate grade-point average (GPA), were correlated with residency directors' ratings (average score for six competencies, quartile ranking, and isolated interpersonal communication competency score). Stepwise linear regression was used to identify the best outcome predictors. RESULTS: Quartile ranking was more highly correlated with GPA than Step 2 CS prototype interpersonal score, USMLE Step 2 score, USMLE Step 1 score, and Step 2 CS prototype checklist score. The average score on the residency director's survey was more highly correlated with GPA than USMLE Step 2 score, USMLE Step 1 score, Step 2 CS prototype interpersonal score, and Step 2 CS prototype checklist score. The best predictors for both quartile ranking and average competency score were GPA and Step 2 CS prototype interpersonal score (R(2) = 0.26 and 0.28). CONCLUSION: Both scores from the Step 2 CS prototype significantly correlated with the interns' quartile ranking and average competency score. Only GPA and Step 2 CS prototype interpersonal score accounted for most of the variance of performance in the regression model.

Prostate cancer and sexually transmitted diseases: a meta-analysis.

BACKGROUND: Prostate cancer is the most common neoplasm of American men and the second most common cause of cancer-related deaths. Research suggests that infection and subsequent inflammation may be an important risk factor in the pathogenesis of prostate cancer. In this meta-analysis, we examine the current epidemiological evidence for the association between specific sexually transmitted diseases (STDs) and prostate cancer. METHODS: Using an English language search of Medline and CINAHL (Cumulative Index to Nursing and Allied Health) since 1966, 29 case-control studies were identified. These studies included a total of 6,022 cases of prostate cancer and 7,320 controls. Using Review Manager, combined odds ratios (ORs) were calculated for any STDs, gonorrhea, syphilis, and human papillomavirus (HPV) for prostate cancer. RESULTS: Significant elevated ORs for prostate cancer were demonstrated for any STDs (1.48, 95% confidence interval [CI] 1.26-1.73), gonorrhea (1.35, 95% CI 1.05-1.83), and human papillomavirus (1.39, 95% CI 1.12-2.06). CONCLUSIONS: This meta-analysis provides evidence of a higher rate of prostate cancer in men with a history of an exposure to gonorrhea, HPV, or any STD. Further research, especially with cohort studies, is required to confirm this potentially modifiable risk factor.

Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis.

Mastocytosis is characterized by focal heterotypic clusters of mast cells and lymphocytes in the bone marrow and by a somatically acquired activating Kit mutation, D816V. The relationship of the occurrence of this mutation to the heterotypic clusters of mast cells and lymphocytes in bone marrow is unknown. We hypothesized that these two unique features of mastocytosis were related. To explore this hypothesis, laser capture microdissected mast cells, B cells, and T cells, from both lesional and non-lesional areas of bone marrow biopsy tissues from patients with mastocytosis, were examined for the D816V mutation in their DNA, using HinfI restriction digestion of nested PCR products amplified from extracts of dissected cells. The D816V mutation was detected in mast cells, B cells, and T cells from lesional but not non-lesional areas of bone marrow tissues. B cells obtained from lesional areas of tissue were also assessed for clonality and were found to at least represent an oligoclonal population. Thus, mast cells and lymphocytes within focal aggregates in the bone marrow of those with mastocytosis are more frequently positive for the codon 816 activating mutation. Further, the B cell population is oligoclonal, suggesting that clonal proliferation is unlikely to be the basis of clustering.

Statins and cancer: a meta-analysis of case-control studies.

3-HMG-CoA reductase inhibitors (statins) block the growth of malignant cells in vitro. A meta-analysis of randomized controlled trials failed to show reduced risk of cancers in statin users. Case-control studies, however, have the advantage of examining remote exposures. This study determined the association between statins and breast cancer, colon cancer, lung cancer, prostate cancer, or any cancer in case-control studies. A comprehensive search for studies published through November 2006 was performed. Twenty case-control studies (100 129 incident cancer cases) were combined to obtain a pooled odds ratio using an inverse variance method. A funnel plot did not suggest a significant absence of unpublished data. The studies were significantly heterogeneous (P<0.01), thus a random effects model was used. The pooled OR and 95% confidence intervals for statin users and cancer were as follows: any cancer 0.71 (0.56-0.89), breast cancer 0.86 (0.60-1.23), colon cancer 0.89 (0.82-0.97), lung cancer 0.75 (0.50-1.11), and prostate cancer 0.74 (0.45-1.20). In this meta-analysis of case-control studies, we found a significant association between statin usage and any cancer, but when stratified by cancer type, only the association with colon cancer remained. On the basis of these results, randomized control trials with longer follow-up times than previously used are warranted.

Clinical use of C-reactive protein for cardiovascular disease.

Recent evidence supports an association between elevation of inflammatory markers, such as C-reactive protein, and subsequent cardiovascular disease risk. The American Heart Association released guidelines in 2003 to help clinicians know when to use such markers. Because inflammatory markers are associated with diabetes, obesity, and hypertension, knowledge of the role of such markers is extremely important for prevention and chronic disease management. Newer studies published after the guidelines, and another recent review provide further documentation of the growing role of inflammation in cardiovascular risk. Based on the available literature, this article reviews the new guidelines, more recent evidence since the guidelines, and forms recommendations for primary care clinical practice.