Citations

Abstract Background: Low-density lipoprotein cholesterol (LDL-C) has been the cornerstone measurement for assessing cardiovascular risk for nearly 20 years. Content: Recent data demonstrate that apolipoprotein B (apo B) is a better measure of circulating LDL particle number (LDL-P) concentration and is a more reliable indicator of risk than LDL-C, and there is growing support for the idea that addition of apo B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease (CVD) would enhance patient management. In this report, we review the studies of apo B and LDL-P reported to date, discuss potential advantages of their measurement over that of LDL-C, and present information related to standardization. Conclusions: In line with recently adopted Canadian guidelines, the addition of apo B represents a logical next step to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) and other guidelines in the US. Considering that it has taken years to educate physicians and patients regarding the use of LDL-C, changing perceptions and practices will not be easy. Thus, it appears prudent to consider using apo B along with LDL-C to assess LDL-related risk for an interim period until the superiority of apo B is generally recognized.

Abstract Background: Improvements in cardiac troponin (cTn) assays have increased the rapidity with which clinicians can identify patients with changing cTn concentrations (rise or fall) indicative of acute myocardial injury. The aim of the present study was to characterize a new, high-sensitivity cTnI (hs-cTnI) assay and examine whether increased sensitivity can result in still earlier detection of evolving injury. Methods: We determined the limit of detection, precision profiles, and preliminary estimates of the 99th percentile for the Beckman Coulter hs-cTnI assay in 125 healthy individuals (age <55 years, 54% male). We compared AccuTnI® and hs-cTnI to assess whether change criteria for early concentration changes (i.e., ≥3SD for low concentrations and 20% difference for concentrations >0.10 μg/L) were exceeded in the first 2 specimens (median time between specimens, 1 h; 25th–75th percentile, 1–3 h) from subjects with symptoms suggestive of cardiac ischemia (n = 290). Results: The limit of detection for the hs-cTnI assay was 2.06 ng/L, and the 20% CV and 10% CV concentrations were 2.95 and 8.66 ng/L, respectively. The preliminary 99th percentile estimates in lithium heparin, serum, and EDTA plasma were 9.20, 8.00, and 8.60 ng/L, respectively. In 108 patients with myocardial injury based on the peak AccuTnI concentration, applying the change criteria on the 2 earliest specimens identified 81% (95% CI 73%–88%) of patients using the hs-cTnI assay compared to 62% (53%–71%) using the AccuTnI assay (P < 0.001). Conclusions: Although more extensive validation studies are required, this Beckman Coulter hs-cTnI assay appears to detect patients with evolving myocardial injury earlier.

Abstract The economics of medicine have drastically changed during the past quarter century. Institutions may be faced with difficult decisions concerning graduate medical education (GME), particularly as it relates to the growth of existing programs and the creation of new programs. The authors describe a tool that they developed that can consistently measure the value of individual training programs while aligning with an institution's strategic priorities. This tool, the assessment metric scorecard, permits the annual prioritization of GME programs by the leadership of Mayo Clinic, Jacksonville, Florida. The scorecard also provides valuable data regarding the strengths and weaknesses of individual programs. The metric seeks to evaluate GME programs on the basis of four broad areas: Research, Teaching, Patient Service, and a General category. The assessment metric scorecard has been used since 2004; this article reports on its use for the academic years 2004–2005 and 2005–2006. The scorecard has proved to be a helpful tool for the yearly evaluation and prioritization of GME programs at the authors' institution. The overall mean score of the GME programs increased, which suggests a positive trend. This scorecard is flexible; modifications of the relative weights of the metrics can be made to align it with the strategic priorities of other institutions. The resources necessary to implement the scorecard are minimal.

Following infection, naïve CD8 + T cells bearing pathogen-specific T cell receptors (TCRs) differentiate into a mixed population of short-lived effector and long-lived memory T cells to mediate an adaptive immune response. How the TCR regulates memory T cell development has remained elusive. Using a mutant TCR transgenic model, we found that point mutations in the TCR β transmembrane domain (βTMD) impair the development and function of CD8 + memory T cells without affecting primary effector T cell responses. Mutant T cells are deficient in polarizing the TCR and in organizing the nuclear factor κB signal at the immunological synapse. Thus, effector and memory states of CD8 + T cells are separable fates, determined by differential TCR signaling.

Background. Laparoscopic ventral hernia repair (LVHR) can be challenging in patients with large abdominal wall defects and loss of domain (LOD). When hernia contents are reduced, the pneumoperitoneum preferentially fills the sac, leaving no space for mesh manipulation. This study presents a modification for LVHR in LOD patients, as well as outcomes for a series of patients. Methods. Between September 2002 and August 2004, 10 patients with large ventral hernias and LOD underwent attempts at LVHR. The technique is modified by placing additional trocars to allow for fixation from above the mesh. Patient data were harvested from a prospective database and analyzed. Results. All hernias were recurrent in nature. Mean defect size was 626 cm 2 , requiring 1 to 4 pieces of sutured Gore Dualmesh for a tension-free repair. Three patients' procedures were aborted after adhesiolysis, with concerns about missed enterotomies. All 3 underwent delayed mesh placement within the same hospitalization. Only 2 were successful. The third patient had significant bowel edema precluding mesh placement. Two patients were converted to open repairs (Rives—Stoppa and component separation). There were no mortalities, but there were 2 major complications: inferior vena cava thrombosis and transient abdominal compartment syndrome. In follow-up (7.7 months) there were 2 recurrences secondary to excision of infected mesh. Conclusion. It is possible to obtain a successful LVHR in patients with large defects and LOD. The technique is complex and is modified to allow for mesh fixation from above the mesh. Frequent change in patient positioning allows for visualization below the fascial defect.

MVB (multivesicular body) formation occurs when the limiting membrane of an endosome invaginates into the intraluminal space and buds into the lumen, bringing with it a subset of transmembrane cargoes. Exvagination of the endosomal membrane from the cytosol is topologically similar to the budding of retroviral particles and cytokinesis, wherein membranes bud away from the cytoplasm, and the machinery responsible for MVB sorting has been implicated in these phenomena. The AAA (ATPase associated with various cellular activities) Vps4 (vacuolar protein sorting 4) performs a critical function in the MVB sorting pathway. Vps4 appears to dissociate the ESCRTs (endosomal sorting complexes required for transport) from endosomal membranes during the course of MVB sorting, but it is unclear how Vps4 ATPase activity is synchronized with ESCRT release. We have investigated the mechanisms by which ESCRT components stimulate the ATPase activity of Vps4. These studies support a model wherein Vps4 activity is subject to spatial and temporal regulation via distinct mechanisms during MVB sorting.

ABSTRACT The role of combination antibiotic therapy with a beta-lactam and a fluoroquinolone for bacteremia caused by gram-negative bacilli, to our knowledge, has not been previously described. Much of the previous study of combination therapy has included beta-lactams and aminoglycosides. We conducted a large retrospective cohort study to evaluate 28-day all-cause mortality in patients with monomicrobial bacteremia due to aerobic gram-negative bacilli who received either a combination of beta-lactams and fluoroquinolones or beta-lactam monotherapy. We enrolled adult patients admitted to Mayo Clinic hospitals from 1 January 2001 to 31 October 2006 in the study. After stratification of patients by Pitt bacteremia scores, we used Cox regression models to estimate the hazard ratios (HR) for 28-day all-cause mortality after adjusting for the propensity to receive combination therapy. We identified 398 and 304 unique patients with bacteremia caused by gram-negative bacilli who received single and combination antibiotic therapy, respectively. In less severely ill patients with Pitt bacteremia scores of <4, combination therapy was associated with lower 28-day mortality than single therapy (4.2% [9 of 214] versus 8.8% [28 of 319]; adjusted HR, 0.44; 95% confidence interval [CI], 0.20 to 0.98; P = 0.044). In critically ill patients with Pitt bacteremia scores of ≥4, there was no difference in 28-day mortality between combination and single therapy (25.6% [23 of 90] versus 27.8% [22 of 79]; adjusted HR, 0.87; 95% CI, 0.47 to 1.62; P = 0.660). These findings were consistent for 14-day all-cause mortality. In this large cohort, we found for the first time that combination therapy with beta-lactams and fluoroquinolones was associated with a reduction in 28-day all-cause mortality among less severely ill patients with bacteremia caused by gram-negative bacilli.

Recent evidence suggests that the microbial community in the human intestine may play an important role in the pathogenesis of obesity. We examined 184,094 sequences of microbial 16S rRNA genes from PCR amplicons by using the 454 pyrosequencing technology to compare the microbial community structures of 9 individuals, 3 in each of the categories of normal weight, morbidly obese, and post-gastric-bypass surgery. Phylogenetic analysis demonstrated that although the Bacteria in the human intestinal community were highly diverse, they fell mainly into 6 bacterial divisions that had distinct differences in the 3 study groups. Specifically, Firmicutes were dominant in normal-weight and obese individuals but significantly decreased in post-gastric-bypass individuals, who had a proportional increase of Gammaproteobacteria . Numbers of the H 2 -producing Prevotellaceae were highly enriched in the obese individuals. Unlike the highly diverse Bacteria , the Archaea comprised mainly members of the order Methanobacteriales , which are H 2 -oxidizing methanogens. Using real-time PCR, we detected significantly higher numbers of H 2 -utilizing methanogenic Archaea in obese individuals than in normal-weight or post-gastric-bypass individuals. The coexistence of H 2 -producing bacteria with relatively high numbers of H 2 -utilizing methanogenic Archaea in the gastrointestinal tract of obese individuals leads to the hypothesis that interspecies H 2 transfer between bacterial and archaeal species is an important mechanism for increasing energy uptake by the human large intestine in obese persons. The large bacterial population shift seen in the post-gastric-bypass individuals may reflect the double impact of the gut alteration caused by the surgical procedure and the consequent changes in food ingestion and digestion.