Human Monocyte Chemotaxis: A Quantitative in Vivo Technique

This report describes a new quantitative technique for evaluating monocyte chemotaxis to a site of superficial epidermal abrasion. Micro-acrylic chambers containing 50% Zymosan activated autologous serum were separated from a 5-mm diameter epidermal abrasion by 2 Nucleopore filters which entrapped migrating monocytes but allowed free neutrophil migration. Monocytes were specifically identified by alpha napthyl acetate esterase activity. Monocytes accumulated within the filters by 4 hr and maximized at 16 and 20 hr.This technique is superior to previous skin chamber techniques in the high yield of monocytes and in specific histochemical identification of monocytes. In contrast to the Rebuck window, it does not generate attractants and has greater reproducibility.This technique will be useful in the study of diseases characterized by monocytic infiltrates, in contrasting the function of peripheral blood monocytes to those available in the skin, and in testing the effects of drugs, immunodeficiency and infection on monocyte function in vivo

Self-Rated Health Predicts Healthcare Utilization in Heart Failure

BACKGROUND: Heart failure (HF) patients experience impaired functional status, diminished quality of life, high utilization of healthcare resources, and poor survival. Yet, the identification of patient-centered factors that influence prognosis is lacking. METHODS AND RESULTS: We determined the association of 2 measures of self-rated health with healthcare utilization and skilled nursing facility (SNF) admission in a community cohort of 417 HF patients prospectively enrolled between October 2007 and December 2010 from Olmsted County, MN. Patients completed a 12-item Short Form Health Survey (SF-12). Low self-reported physical functioning was defined as a score ≤ 25 on the SF-12 physical component. The first question of the SF-12 was used as a measure of self-rated general health. After 2 years, 1033 hospitalizations, 1407 emergency department (ED) visits, and 19,780 outpatient office visits were observed; 87 patients were admitted to a SNF. After adjustment for confounding factors, an increased risk of hospitalizations (1.52 [1.17 to 1.99]) and ED visits (1.48 [1.04 to 2.11]) was observed for those with low versus moderate-high self-reported physical functioning. Patients with poor and fair self-rated general health also experienced an increased risk of hospitalizations (poor: 1.73 [1.29 to 2.32]; fair: 1.46 [1.14 to 1.87]) and ED visits (poor: 1.73 [1.16 to 2.56]; fair: 1.48 [1.13 to 1.93]) compared with good-excellent self-rated general health. No association between self-reported physical functioning or self-rated general health with outpatient visits and SNF admission was observed. CONCLUSION: In community HF patients, self-reported measures of physical functioning predict hospitalizations and ED visits, indicating that these patient-reported measures may be useful in risk stratification and management in HF

Coronary atherosclerosis in diabetes mellitus A population-based autopsy study

AbstractObjectivesThe study was conducted to test the hypothesis that the prevalence of coronary atherosclerosis is greater among diabetic than among nondiabetic individuals and is similar for diabetic individuals without clinical coronary artery disease (CAD) and nondiabetics with clinical CAD.BackgroundPersons with diabetes but without clinical CAD encounter cardiovascular mortality similar to nondiabetic individuals with clinical CAD. This excess mortality is not fully explained. We examined the association between diabetes and coronary atherosclerosis in a geographically defined autopsied population, while capitalizing on the autopsy rate and medical record linkage system available via the Rochester Epidemiology Project, which allows rigorous ascertainment of coronary atherosclerosis, clinical CAD, and diabetes.MethodsUsing two measures, namely a global coronary score and high-grade stenoses, the prevalence of atherosclerosis was analyzed in a cohort of autopsied residents of Rochester, Minnesota, age 30 years or older at death, while stratifying on diabetes, clinical CAD diagnosis, age, and gender.ResultsIn this cohort, diabetes was associated with a higher prevalence of atherosclerosis. Among diabetic decedents without clinical CAD, almost three-fourths had high-grade coronary atherosclerosis and more than half had multivessel disease. Without diabetes, women had less atherosclerosis than men, but this female advantage was lost with diabetes. Among those without clinical CAD, diabetes was associated with a global coronary disease burden and a prevalence of high-grade atherosclerosis similar to that observed among nondiabetic subjects with clinical CAD.ConclusionsThese findings provide mechanistic insights into the excess risk of clinical CAD among diabetic individuals, thereby supporting the need for aggressive prevention of atherosclerosis in all diabetic individuals, irrespective of clinical CAD symptoms

Prevalence of Metabolic Syndrome and Risks of Abnormal Serum Alanine Aminotransferase in Hispanics: A Population-Based Study

Study the prevalence of metabolic syndrome (MS) and risk factors for and association with elevated alanine aminotransferase (ALT) as markers of hepatic injury in a large Hispanic health disparity cohort with high rates of obesity.Analysis of data from a prospective cross-sectional population based study. From 2004-7, we randomly recruited 2000 community participants to the Cameron County Hispanic Cohort collecting extensive socioeconomic, clinical and laboratory data. We excluded 153 subjects due to critical missing data. Pearson chi-square tests and Student's t-tests were used for categorical and continuous variable analysis, respectively. Logistic regression analysis was performed to determine the risk factors for elevated ALT.The mean age of the cohort was 45 years and 67% were females. The majority of the cohort was either overweight (32.4%) or obese (50.7%). Almost half (43.7%) had MS and nearly one-third diabetes. Elevated ALT level was more prevalent in males than females. Obesity was a strong risk for abnormal ALT in both genders. Hypertriglyceridemia, hypercholesterolemia and young age were risks for elevated ALT in males only, whereas increased fasting plasma glucose was associated with elevated ALT in females only.We identified high prevalence of MS and markers of liver injury in this large Mexican American cohort with gender differences in prevalence and risk factors, with younger males at greatest risk

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Auditory Function in the Tc1 Mouse Model of Down Syndrome Suggests a Limited Region of Human Chromosome 21 Involved in Otitis Media

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K+ currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca2+ activated K+ current (IK,f), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active

Ecological and Cultural Understanding as a Basis for Management of a Globally Significant Island Landscape

Islands provide the opportunity to explore management regimes and research issues related to the isolation, uniqueness, and integrity of ecological systems. K’gari (Fraser Island) is an Australian World Heritage property listed based on its outstanding natural value, specifically, the unique wilderness characteristics and the diversity of ecosystem types. Our goal was to draw on an understanding of the natural and cultural environment of K’gari as a foundation on which to build a management model that includes First Nations Peoples in future management and research. Our research involved an analysis of papers in the peer-reviewed scientific literature, original reports, letters, and other manuscripts now housed in the K’gari Fraser Island Research Archive. The objectives of the research were: (1) to review key historical events that form the cultural, social, and environmental narrative; (2) review the major natural features of the island and threats; (3) identify the gaps in research; (4) analyse the management and conservation challenges associated with tourism, biosecurity threats, vegetation management practices, and climate change and discuss whether the requirements for sustaining island ecological integrity can be met in the future; and (5) identify commonalities and general management principles that may apply globally to other island systems and other World Heritage sites listed on the basis of their unique natural and cultural features. We found that the characteristics that contribute to island uniqueness are also constraints for research funding and publication; however, they are important themes that warrant more investment. Our review suggests that K’gari is a contested space between tourist visitation and associated environmental impacts, with an island that has rich First Nations history, extraordinary ecological diversity, and breathtaking aesthetic beauty. This juxtaposition is reflected in disparate views of custodianship and use, and the management strategies are needed to achieve multiple objectives in an environmentally sustainable way whilst creating cultural equity in modern times. We offer a foundation on which to build a co-management model that includes First Nations Peoples in governance, management, research, and monitoring

Comparison of Clinicopathologic Features and Survival of Histopathologically Amelanotic and Pigmented Melanomas: A Population-Based Study

Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathology review, or no adjustment for stage limit interpretation or generalization of results from prior studies

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response