Nature Clinical Practice. Cardiovascular Medicine最新文献

Polymorphisms located within the MHC have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of HLA genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical HLA class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with HLA-B showing the highest (∼1.9%), followed by HLA-A (∼1.8%), and HLA-C showing the lowest diversity (∼0.9%). Despite its greater diversity, HLA-B mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of HLA-A or HLA-C reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most HLA-A and -C loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical HLA class I loci.

Background: The prevalence of sensitization varies geographically based on multiple environmental factors including humidity. The aim of this study was to determine the prevalence of atopy in symptomatic adults. More importantly we aimed to obtain a regional statistic of sensitization to common allergens given Saskatchewan's dry climate.

Methods: One thousand consecutive symptomatic adults were screened for atopy via skin prick test over 10 years (2006-2016) in the Division of Respirology. An atopic screen was performed with twenty common aeroallergens by a single investigator, Dr. D. Cockcroft. A positive test was considered to be a wheal ≥3 mm and markedly positive reactions ≥8 mm were also documented.

Results: The prevalence of atopy by means of a positive skin test (≥3 mm) was 45.5%. The prevalence of one or more markedly positive reactions (≥8 mm) was 29.5% of the total population. The most frequent sensitization was to cat dander (58.2%), followed by mixed grass (32.1%), and birch (26.8%). Dust mite sensitization was 22.4% and mouse 6.2%. A positive epidemiology screen for cat/grass/mite would have incorporated 82.0% (n = 373) of subjects with positive skin tests. Those who failed the cat/grass/mite screen were mainly sensitized to trees (n = 34), molds (n = 22), weeds (n = 7), and animals (n = 8).

Conclusions: There is a high prevalence of cat sensitization in Saskatchewan, much higher than recorded in other centers internationally. This is likely due to a high proportion of cat ownership. The prevalence of mite sensitization is lower than those mentioned at other centres likely due to Saskatchewan's dry climate. The significance of the rate of markedly positive reactions (≥8 mm wheal) when compared to humid areas with higher burden of mite is unknown. There is a low prevalence of roach also likely due to the dry climate and mouse sensitization was low but still identified as a significant indoor allergen. A cat/grass/mite screen may be useful with a 82.0% sensitivity.

Objective: Impaired cellular immunity and reduced phagocytic function of polymorphonuclear leukocytes facilitate the development of skin fungal and bacterial infections due to uncontrolled hyperglycemia in diabetic patients. In our study, we aimed to assess onychomycosis and/or tinea pedis frequency in diabetic patients, and effects on the development of chronic complications, particularly foot ulcer.

Methods: We included 227 diabetic patients in the study. Forty-three patients had diabetic foot ulcer. We screened and recorded demographic characteristics, HbA1c levels of patients, and presence of complications We examined patients dermatologically, and collected samples by scalpel from skin between toes, and from sole, toe nail, and area surrounding nails from suspected to have fungal infection.

Results: Native positivity between toes was higher in men compared to women (p<0.05). We obtained significant relation between HbA1c elevation and native positivity between toes (p<0.05). Fungal infection between toes, at sole and toe nail significantly increased in patients with diabetic foot ulcer compared to patients without diabetic foot ulcer (p<0.05). Moreover, native positivity in patients with diabetic foot ulcer correlated with presence of fungal infection examination findings (p<0.05).

Conclusion: Fungal infections were more frequently observed in the presence of poor glycemic control and peripheral vascular disease in diabetic patients in compliance with the literature, and the presence of fungal infection may also responsible for the development of foot ulcers.

Myocardial contrast echocardiography utilizes intravenously injected gas-filled microspheres as acoustically active red blood cell tracers. During ultrasound imaging, unimpeded microsphere transit through the intramyocardial microcirculation causes transient myocardial opacification, which can be mapped and quantified as myocardial perfusion. Ultrasound molecular imaging utilizes similar acoustically active microspheres, which are modified to bear a receptor-specific ligand on the surface, conferring microsphere binding to a disease-specific endothelial epitope. Because the microspheres adhere to the endothelium, ultrasound imaging reveals a persistent, rather than transient, contrast effect, indicating the presence and location of the molecule of interest in real time. Molecular contrast echocardiography has been developed to detect upregulated leukocyte adhesion molecules during microvascular inflammation, such as occurs in cardiac transplant rejection and ischemia-reperfusion. Principles of microsphere targeting and ultrasound imaging of microvascular epitopes have been extended to larger vessels to image molecular markers of atherosclerosis. This Article summarizes the current status of cardiovascular ultrasound molecular imaging. Experimental proofs of concept will be outlined and the clinical extension of these concepts to the molecular imaging of cardiovascular disease using clinical ultrasound technology will be discussed.

Left ventricular remodeling is a key determinant of the clinical course and outcome of systolic heart failure. The myocardial renin-angiotensin system (RAS) has been closely linked to the major maladaptive cellular and molecular changes that accompany left ventricular remodeling. Direct inhibition of various components of the RAS, such as the angiotensin-converting enzyme, angiotensin II type 1 receptor, and aldosterone, has resulted in favorable clinical responses in heart failure. Many questions, however, remain unanswered regarding the timing of initiation, optimum doses, need for simultaneous use of RAS inhibitors, and proper monitoring of RAS blockade. Additionally, significant variation has been noted in individual responses to RAS blockade as a result of genetic differences. Answering these questions requires direct access to the myocardial component of RAS, which is largely independent of its systemic component. Molecular imaging using radiotracers with high affinities for myocardial angiotensin-converting enzyme and angiotensin II type 1 receptors can provide direct access to tissue RAS and thus provide a better understanding of the pathophysiology of left ventricular remodeling in individual patients. This Article briefly reviews the potential for evaluating the tissue expression of angiotensin in heart failure by targeted RAS imaging.

Individuals with systolic dysfunction congestive heart failure may have decreased neuronal density, decreased neuronal function (reuptake or retention of norepinephrine), or a combination of these, plus reduction in postsynaptic beta-receptor density. Cardiac neuronal distribution and function can be imaged with standard gamma cameras and PET using radiolabeled analogs of norepinephrine. Postsynaptic beta-adrenergic receptor distribution and density can be determined using PET. Multiple imaging studies of the presynaptic component have reported that those individuals with the lowest retention or fastest washout of the radiolabeled analogs have a much greater annual mortality than do those with greater retention or slower washout rate. The results of some studies have suggested that the image abnormalities are better predictors of death than are more common predictors of outcome such as ejection fraction, heart rate variability, and microvolt T-wave alternans. The variability between these studies makes it unclear which measure of presynaptic dysfunction is the most predictive. beta-Receptor imaging has not been evaluated as extensively as a prognostic tool as has presynaptic imaging. Preliminary data suggest that regional mismatch between beta-receptors and presynaptic norepinephrine transporter function may serve as a marker for adverse outcome.

Targeted imaging and therapeutics is becoming a field of prime importance in the study and treatment of cardiovascular disease; it promises to enable early diagnosis, promote improved understanding of pathology, and offer a way to improve therapeutic efficacy. Agents, particularly for cardiovascular disease, have been reported to permit the in vivo imaging, by multiple modalities, of macrophages, vascular targets such as vascular cell adhesion molecule 1, and markers for angiogenesis such as alpha(v)beta(3) integrin. In this Article, we first discuss the general concept of multimodality nanoparticles and then focus in greater depth on their clinical application for molecular imaging and therapy. Lastly, several examples of cardiovascular applications are discussed, including combined imaging and therapy approaches.

Sudden cardiac death and acute myocardial infarction often occur as the first manifestation of coronary artery disease. Otherwise asymptomatic individuals with subclinical atherosclerosis almost always have a classic risk-factor profile and it is essential that they are identified before the occurrence of an acute coronary event. The ability to recognize such individuals requires the development of strategies that can localize unstable atherosclerotic lesions. Plaques that are vulnerable to rupture demonstrate distinct histological characteristics, including large plaque and necrotic core volumes, extensive remodeling of the vessel at the lesion site, and attenuated fibrous caps. Precise metrics of typical vulnerable atherosclerotic plaque dimensions will need to be defined to facilitate their identification by noninvasive imaging modalities.

Magnetic resonance spectroscopy (MRS) utilizes magnetic resonance signals from nuclei, such as phosphorus-31, to provide information regarding the biochemical composition and metabolic state of cardiac muscle. This technique is the only method available for noninvasive assessment of cardiac metabolism without the need for the application of external radioactive tracers. MRS provides insights into the role of cardiac energetics in ischemic heart disease, heart failure, hypertrophy, and valve disease. Furthermore, response to therapeutic intervention can be monitored using this method. At present, this technique is used as a research tool, because low spatial and temporal resolution, as well as low reproducibility, precludes its diagnostic use in clinical practice; however, higher-field magnetic resonance systems-using, for example, 7 T-will enable improvements in resolution and reproducibility that may take cardiac MRS into the clinical realm.