Diagnosis of antiphospholipid syndrome

Antiphospholipid syndrome is a multisystem autoimmune disease, characterized by recurrent vascular thrombosis and/or pregnancy losses in the presence of persistently positive antiphospholipid antibodies. In clinical practice, testing for anticardiolipin antibodies and lupus anticoagulant is mandatory for the laboratory diagnosis of antiphospholipid syndrome. Identification of patients with antiphospholipid syndrome is important, as prophylactic anticoagulant therapy may prevent thrombosis from recurring, and treatment during pregnancy can improve fetal and maternal outcome.     

LDL concentration is correlated with the removal from the plasma of a chylomicron-like emulsion in subjects with coronary artery disease

In animal model studies, the uptake of chylomicron remnants after entering in the space of Disse occurs mainly by low-density lipoprotein (LDL) receptor and LDL receptor-related protein (LRP). In subjects, the relative importance of each one of these receptors for the clearance of chylomicron remnants is not fully understood. In our study, LDL cholesterol and apolipoprotein (apo) B were correlated to the plasma kinetics of a chylomicron-like emulsion in 77 subjects (11 women, mean age 58 +/- 12 years) with coronary artery disease (CAD). Their total cholesterol was 227 +/- 25 mg/dl, triglyceride 159 +/- 25 mg/dl, LDL cholesterol 148 +/- 27 mg/dl, HDL cholesterol 40 +/- 9 mg/dl, apo A1 1.80 +/- 0.53 g/l and apo B 1.65 +/- 0.48 g/l. The emulsion was double-labeled with 3H-triolein and 14C-cholesteryl oleate and injected intravenously after 12-h fasting. The decay curves of the radioisotopes were determined from blood samples collected at predetermined intervals during 60 min. A negative correlation between FCR of the emulsion cholesterol esters and LDL cholesterol and apo B plasma concentrations was found (r=-0.4, P=0.005 and r=-0.3, P=0.01, respectively) whereas FCR of the emulsion triglycerides did not correlate with any of the plasma lipids or apolipoprotein parameters. Concluding, in patients with CAD, LDL catabolic pathway significantly influences the removal from plasma of chylomicron remnants.     

Validation of computed tomography image integration into the EnSite NavX mapping system to perform catheter ablation of atrial fibrillation

Introduction: The complex anatomy of the left atrium (LA) makes location of ablation catheters difficult using fluoroscopy alone, and therefore 3D mapping systems are now routinely used. We describe the integration of a CT image into the EnSite NavX System with Fusion and its validation in patients undergoing atrial fibrillation (AF) or left atrial tachycardia (AT) catheter ablation. Methods and Results: Twenty‐three patients (61 ± 9.2 years, 16 male) with paroxysmal (14) and persistent (8) AF and persistent (1) AT underwent ablation using CT image integration into the EnSite NavX mapping system with the EnSite Fusion Dynamic Registration software module. In all cases, segmentation of the CT data was accomplished using the EnSite Verismo segmentation tool, although repeat segmentation attempts were required in seven cases. The CT was registered with the NavX‐created geometry using an average of 24 user‐defined fiducial pairs (range 9 to 48). The average distance from NavX‐measured lesion positions to the CT surface was 3.2 ± 0.9 mm (median 2.4 mm). A large, automated, retrospective test using registrations with random subsets of each patient's fiducial pairs showed this average distance decreasing as the number of fiducial pairs increased, although the improvement ceased to be significant beyond 15 pairs. In confirmation, those studies which had used 16 or more pairs had a smaller average lesion‐to‐surface distance (2.9 ± 0.7 mm) than those using 15 or fewer (4.3 ± 0.8 mm, P < 0.02). Finally, for the 13 patients who underwent left atrial circumferential ablation (LACA), there was no significant difference between the circumference computed using NavX‐measured positions and CT surface positions for either the left pulmonary veins (178 ± 64 vs. 177 ± 60 mm; P = 0.81) or the right pulmonary veins (218 ± 86 vs. 207 ± 81 mm; P = 0.08). Conclusion: CT image integration into the EnSite NavX Fusion system was successful in all patients undergoing catheter ablation. A learning curve exists for the Verismo segmentation tool; but once the 3D model was created, the registration process was easily accomplished, with a registration error that is comparable with registration errors using other mapping systems with CT image integration. All patients went on to have subsequent successful ablation procedures. Where LACA was performed (13 patients), only four patients required segmental ostial lesions to achieve electrical isolation.     

The future of proteomics in the study of alcoholism

This article represents the proceedings of a workshop at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The workshop organizers/chairpersons were Chinnaswamy Kasinathan and Paul Manowitz. The presentations were (1) Introduction to the field of proteomics, by Kent Vrana; (2) Use of proteomics in the identification of urinary biomarkers for alcohol intake, by Chinnaswamy Kasinathan, Paul Thomas, and Paul Manowitz; (3) Proteomics screening illuminates ethanol-mediated induction of HDL proteins in macaques, by Kent Vrana, Randy Gooch, Travis Worst, Stephen Walker, Aaron Xu, Peter Pierre, Heather Green, and Kathleen Grant; and (4) Proteomics applied to the study of the liver, by Laura Beretta.     

MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells

MT1-MMP plays a key role in endothelial function, as underscored by the angiogenic defects found in MT1-MMP deficient mice. We have studied the molecular interactions that underlie the functional regulation of MT1-MMP. At lateral endothelial cell junctions, MT1-MMP colocalizes with tetraspanin CD151 (Tspan 24) and its associated partner alpha3beta1 integrin. Biochemical and FRET analyses show that MT1-MMP, through its hemopexin domain, associates tightly with CD151, thus forming alpha3beta1 integrin/CD151/MT1-MMP ternary complexes. siRNA knockdown of HUVEC CD151 expression enhanced MT1-MMP-mediated activation of MMP2, and the same activation was seen in ex vivo lung endothelial cells isolated from CD151-deficient mice. However, analysis of collagen degradation in these experimental models revealed a diminished MT1-MMP enzymatic activity in confined areas around the cell periphery. CD151 knockdown affected both MT1-MMP subcellular localization and its inclusion into detergent-resistant membrane domains, and prevented biochemical association of the metalloproteinase with the integrin alpha3beta1. These data provide evidence for a novel regulatory role of tetraspanin microdomains on the collagenolytic activity of MT1-MMP and indicate that CD151 is a key regulator of MT1-MMP in endothelial homeostasis.     

Recruiting Rural Healthcare Providers Today: a Systematic Review of Training Program Success and Determinants of Geographic Choices

Background

Rural areas have historically struggled with shortages of healthcare providers; however, advanced communication technologies have transformed rural healthcare, and practice in underserved areas has been recognized as a policy priority. This systematic review aims to assess reasons for current providers’ geographic choices and the success of training programs aimed at increasing rural provider recruitment.

Methods

This systematic review (PROSPERO: CRD42015025403) searched seven databases for published and gray literature on the current cohort of US rural healthcare practitioners (2005 to March 2017). Two reviewers independently screened citations for inclusion; one reviewer extracted data and assessed risk of bias, with a senior systematic reviewer checking the data; quality of evidence was assessed using the GRADE approach.

Results

Of 7276 screened citations, we identified 31 studies exploring reasons for geographic choices and 24 studies documenting the impact of training programs. Growing up in a rural community is a key determinant and is consistently associated with choosing rural practice. Most existing studies assess physicians, and only a few are based on multivariate analyses that take competing and potentially correlated predictors into account. The success rate of placing providers-in-training in rural practice after graduation, on average, is 44% (range 20–84%; N = 31 programs). We did not identify program characteristics that are consistently associated with program success. Data are primarily based on rural tracks for medical residents.

Discussion

The review provides insight into the relative importance of demographic characteristics and motivational factors in determining which providers should be targeted to maximize return on recruitment efforts. Existing programs exposing students to rural practice during their training are promising but require further refining. Public policy must include a specific focus on the trajectory of the healthcare workforce and must consider alternative models of healthcare delivery that promote a more diverse, interdisciplinary combination of providers.

     

Prediction of mortality in community-living frail elderly people with long-term care needs

OBJECTIVES: To develop and validate a prognostic index for mortality in community‐living, frail elderly people. DESIGN: Cohort study of Program of All‐Inclusive Care for the Elderly (PACE) participants enrolled between 1988 and 1996. SETTING: Eleven PACE sites, a community‐based long‐term care program that cares for frail, chronically ill elderly people who meet criteria for nursing home placement. PARTICIPANTS: Three thousand eight hundred ninety‐nine PACE enrollees. The index was developed in 2,232 participants and validated in 1,667. MEASUREMENTS: Time to death was predicted using risk factors obtained from a geriatric assessment performed by the PACE interdisciplinary team at the time of enrollment. Risk factors included demographic characteristics, comorbid conditions, and functional status. RESULTS: The development cohort had a mean age of 79 (68% female, 40% white). The validation cohort had a mean age of 79 (76% female, 65% white). In the development cohort, eight independent risk factors of mortality were identified and weighted, using Cox regression, to create a risk score: male sex, 2 points; age (75–79, 2 points; 80–84, 2 points; ≥85, 3 points); dependence in toileting, 1 point; dependence in dressing (partial dependence, 1 point; full dependence, 3 points); malignant neoplasm, 2 points; congestive heart failure, 3 points; chronic obstructive pulmonary disease, 1 point; and renal insufficiency, 3 points. In the development cohort, respective 1‐ and 3‐year mortality rates were 6% and 21% in the lowest‐risk group (0–3 points), 12% and 36% in the middle‐risk group (4–5 points), and 21% and 54% in the highest‐risk group (>5 points). In the validation cohort, respective 1‐ and 3‐year mortality rates were 7% and 18% in the lowest‐risk group, 11% and 36% in the middle‐risk group, and 22% and 55% in the highest‐risk group. The area under the receiver operating characteristic curve for the point score was 0.66 and 0.69 in the development and validation cohorts, respectively. CONCLUSION: A multidimensional prognostic index was developed and validated using age, sex, functional status, and comorbidities that effectively stratifies frail, community‐living elderly people into groups at varying risk of mortality.     

Effects of chronic iodine excess in a cohort of long-term American workers in West Africa

A cross-sectional survey of 102 Peace Corps volunteers in Niger, West Africa, in 1998 had previously demonstrated a high rate of thyroid dysfunction and goiter attributable to excess iodine from their water filters. The Peace Corps volunteers were followed-up a mean of 30 wk after they ceased using iodine-based water filtration systems. Goiter was present in 44% of subjects during excess iodine ingestion and in 30% after removal of excess iodine. Mean serum iodine decreased from 293 micro g/liter during excess iodine ingestion to 84 micro g/liter after cessation of excess iodine. Mean total serum T(4) values increased from 100.4 to 113.3 nmol/liter (7.8 to 8.8 micro g/dl). Mean serum free T(4) increased from 32.2 to 34.7 pmol/liter (2.5 to 2.7 ng/dl). Mean serum TSH decreased from 4.9 to 1.8 mU/liter. Mean serum thyroid peroxidase antibody levels decreased from 33,000 to 22,000 IU/liter (33 to 22 IU/ml). We found that during prolonged excess iodine exposure there were marked increases in serum total iodine concentrations, and the prevalence of goiter, elevated serum TSH values, and elevated serum thyroid peroxidase antibody values increased. The prevalence of all abnormalities decreased after removal of excess iodine from the drinking water system.     

Flow cytometric analysis of intestinal intraepithelial lymphocytes in the diagnosis of refractory celiac sprue

The etiology of refractory celiac sprue (RCS) is unclear. In a high proportion of cases, the clonal nature of intestinal intraepithelial lymphocytes (IEL) can be demonstrated and a pathogenetic implication of intestinal IEL has been postulated. The prognosis of this subgroup of RCS is poor, with a high risk to develop an overt lymphoma and uncontrolled malabsorption despite steroid/immunosuppressive therapy. Cases with a relatively indolent clinical course, however, exist and their early diagnosis may be difficult. To gain insight into the pathogenic implication of intestinal IEL in refractory celiac sprue, we have performed an extensive phenotypic and functional characterization of clonal intestinal IEL in a patient with an indolent form of refractory celiac sprue, using multiparametric flow cytometry. The abnormal lymphocyte infiltrate lacked surface membrane expression of CD3/T-cell receptor (TCR) complexes (TCR(-), CD4(-), CD8(-), sCD3(-)), but contained intracellular CD3(epsilon) (CyCD3(+)) and surface CD103(+) and CD7(+). In particular, these cells showed a unique spontaneous ex-vivo cytokine secretion profile with an increased percentage of CD3(-) IEL containing TNF-alpha and IL-10, in the absence of IL-2, IL-4 and IFN-gamma. Altogether our results suggest that flow cytometry immunophenotyping of intestinal IEL, in cases suspected of celiac disease and their complicated forms, could be of great help in the correct diagnosis of RCS and the understanding of the immunopathogenic mechanisms of the disease and their clinical and/or therapeutical implications.