Obesity cardiomyopathy and systolic function: Obesity is not independently associated with dilated cardiomyopathy

Obesity is a growing worldwide problem and the prevalence of heart failure is also on the rise. Obesity itself is an independent risk factor for the development of heart failure and the case of obesity-related heart failure is thought to be multifactorial. Obesity leads to increased central and total blood volumes along with decreased systemic arterial resistance resulting in high cardiac output state related adaptations in the cardiac structure. Persistence of these hemodynamic changes ultimately results in diastolic dysfunction, however, whether these changes progress to significant systolic dysfunction or not is doubtful. Some MUGA (Multi Gated Acquisition) scan-based studies had shown mild degree of left ventricular systolic dysfunction in the obese, however, these findings could not be confirmed with recent echocardiogram-based studies. Using extensive literature review, we found no evidence of obesity-related cardiomyopathy leading to significant systolic dysfunction fulfilling criterion for the diagnosis of dilated cardiomyopathy (LVEF <35 %). Therefore, any obese patient presenting with severe LV dysfunction should prompt further investigations to evaluate for the underlying etiology.     

Tackling metabolic syndrome by functional foods

The metabolic syndrome is one of the most vibrant and widely prevailing health concerns worldwide. It is characterized by several metabolic abnormalities, which involve obesity, insulin resistance, dyslipidemia, enhanced oxidative stress; hypertension and increased pro-inflammatory state that ultimate contribute towards poor health. The prevalence of metabolic syndrome in Pakistan according to different definitions is reported to be from 18 % to 46 %. Fifty percent of Pakistani population is at high risk of metabolic syndrome as being hypertensive. In studying dyslipidemia in Pakistan, hypertriglyceridemia is found in 27–54 % of the population, whereas 68–81 % has low levels of high-density lipoprotein (HDL). Population likes to eat healthier diet without changing their fundamental dietary pattern. Nutrition science has moved on from the classical concepts of avoiding nutrient deficiencies and basic nutritional adequacy to the concept of positive or optimal nutrition. Many traditional food products including fruits, vegetables, flaxseed, oat, barley, whole grains, soy and milk have been found to contain component with potential health benefits. Nowadays, functional foods are used in the prevention and amelioration of several chronic diseases, such as the metabolic syndrome. The relation of the consumption of certain functional foods and the improvement in health status is regulated through health claims. This review focuses on the different features of the metabolic syndrome and the influence of functional foods on these aspects, involving dyslipidemia, improvement of insulin sensitivity, serum lipid profile, antioxidant status, anti-inflammatory status and weight management of humans.     

The Stanford/PAVA data collection form for coding J waves on routine screening 10 second ECGs

The study of J waves and slurs and their association with cardiovascular death is clouded by the lack of a standardized coding or classification methodology. Over the past three years of studying these ECG patterns, we have evolved a Data Entry Form that is designed to resolve some of the key issues. These issues include the effect of other ECG findings, whether the QRS–ST junction occurs before or after the J waves, if contiguous leads are required and rules to distinguish J waves from fragmented QRS complexes. This form is now being used to code the ECGs of 44,000 VA patients and the follow up is being extended to 15 years to resolve these issues.     

Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes

The advent of novel genomic sequencing technologies has aided the identification of somatically acquired genetic abnormalities up to 80% of myelodysplastic syndrome (MDS) patients. Novel recurrent genetic mutations in pathways such as RNA splicing, DNA methylation and histone modification and cohesion complexes, underscore the molecular heterogeneity seen in this clinically varied disease. Functional studies to establish a causative link between genomic aberrations and MDS biogenesis are still in their infancy. The deluge of this molecular information, once validated on a larger cohort, will be incorporated into prognostic systems and clinical practise, and also hopefully aid in MDS therapeutics, especially in guiding targeted therapy.     

Phosphorylation of the CENP-A amino-terminus in mitotic centromeric chromatin is required for kinetochore function

The role of the mitotic phosphorylation of the amino (NH₂) terminus of Centromere Protein A (CENP-A), the histone variant epigenetic centromeric marker, remains elusive. Here, we show that the NH₂ terminus of human CENP-A is essential for mitotic progression and that localization of CENP-C, another key centromeric protein, requires only phosphorylation of the CENP-A NH₂ terminus, and is independent of the CENP-A NH₂ terminus length and amino acid sequence. Mitotic CENP-A nucleosomal complexes contain CENP-C and phosphobinding 14-3-3 proteins. In contrast, mitotic nucleosomal complexes carrying nonphosphorylatable CENP-A–S7A contained only low levels of CENP-C and no detectable 14-3-3 proteins. Direct interactions between the phosphorylated form of CENP-A and 14-3-3 proteins as well as between 14-3-3 proteins and CENP-C were demonstrated. Taken together, our results reveal that 14-3-3 proteins could act as specific mitotic “bridges,” linking phosphorylated CENP-A and CENP-C, which are necessary for the platform function of CENP-A centromeric chromatin in the assembly and maintenance of active kinetochores.Histone variants are nonallelic isoforms of conventional histones. It is widely accepted that the incorporation of histone variants generally confers novel structural and functional properties to the nucleosome (1). Centromere Protein A (CENP-A) is a histone variant, which replaces the canonical histone H3 at the centromere (2) and marks epigenetically the centromeres and the kinetochores (for reviews see refs. 3 and 4). The presence of CENP-A is required for the assembly of active kinetochores and its depletion results in numerous mitotic problems, such as chromosome misalignments and segregation defects, generation of chromosome bridges, aneuploidy, etc. (5). The resulting mitotic defects, following CENP-A depletion, were associated also with notable alterations in the composition and organization of the kinetochore, including the delocalization of the inner kinetochore proteins CENP-C, CENP-I, and CENP-H as well as the outer kinetochore components Highly Expressed in Cancer protein 1 (HEC1), Mitotic Arrest Deficient 2-like protein (Mad2), and CENP-E (5).During recent years, the studies of CENP-A were focused mainly on its histone-fold domain. The NH₂ terminus of CENP-A, which is not required for centromeric targeting (6, 7) appeared, however, to play an important role in both mitosis and meiosis. In yeast, the NH₂ tail of Chromosome Segregation Protein 4 (Cse4p) (the homolog of mammalian CENP-A) has an essential function distinct from that of the histone-fold domain in chromosome assembly and segregation (8). The reported data in Arabidopsis thaliana suggested the existence of a meiosis-specific loading pathway for CENP-A, requiring its NH₂ terminus (9). In addition, human CENP-A is phosphorylated in its NH₂ terminus at serine 7 in mitosis but the role of this phorphorylation is far from being clear (10, 11).Sequence alignments of the NH₂ termini of CENP-A from different species show very low sequence conservation in terms of amino acid composition, sequence, and length (Fig. 1A). However, expression of CENP-A with its NH₂ terminus deleted is lethal in yeast (12) and plants (13). These data create a paradox because on one hand, the NH₂ terminus of CENP-A, in certain organisms, is required for their survival and on the other hand, it appears to be nonessential because there is no evolutionary pressure to conserve at least some specific sequence elements.Open in a separate windowFig. 1.The NH₂ tail of CENP-A is required for mitosis and the H3 swapped NH₂ tail CENP-A chimera rescues the CENP-A null cell phenotype. (A) Sequence alignment of CENP-A NH₂ termini from different species. Names of species are indicated at Left. Serine residues are indicated in blue. Conservation between different species is shown (Lower). (B) Cell cycle visualization, after CENP-A suppression by siRNA treatment of naïve HeLa cells (second row) or HeLa cells stably expressing siRNA-resistant full-length GFP–CENP-A (third row) or tailless GFP–ΔN–CENP-A (fourth row) or GFP–H3–CENP-A swapped tail mutant (fifth row). First row shows naïve cells not treated with siRNA. A CREST antibody was used to visualize the centromeres in naïve cells; GFP fluorescence was used to visualize CENP-A in GFP fusion-expressing cells. An antibody against inner centromere protein (INCENP) and antilamina antibody were used to detect the midbody during cytokinesis and the nuclear envelope in interphase cells (shown in red). Blue, DNA; white arrowheads point to misaligned or lagging chromosomes and to chromatin bridges. (Scale bar, 5 µm.) (C) Detection of the GFP–CENP-A fusions and endogenous CENP-A in control (−) and siRNA treated (+) cells at 72 h posttransfection by Western blot. Cells used are indicated (Upper). Arrows indicate the positions of the GFP–CENP-A fusions or endogenous CENP-A. (D) Histograms showing the percentage of mitotic defects at 72 h posttransfection with siRNA against CENP-A in the indicated cell lines. HeLa, naïve cell line. (E) Same as D, but showing the percentage of multinucleate cells. For each experiment, at least 400 cells were counted. Data are means and SEM of five independent experiments.Here, we have analyzed the mitotic function of the NH₂ terminus of human CENP-A and its phosphorylation. We show the mere phosphorylation of CENP-A, but not its length and amino acid sequence, is required for the localization of CENP-C, a key mediator between centromeric chromatin and the outer kinetochore components. Our data reveal that in mitosis, the phosphorylated CENP-A nucleosomes are “bridged” to CENP-C via the phosphobinding 14-3-3 proteins. These 14-3-3 mitotic bridges are essential for the assembly of active kinetochores.     

Dynamic Hyperinflation Correlates with Exertional Oxygen Desaturation in Patients with Chronic Obstructive Pulmonary Disease

Background

Dynamic hyperinflation (DH) causes exercise limitation and exertional dyspnea in patients with chronic obstructive pulmonary disease (COPD). Exertional desaturation (ED) also occurs commonly in COPD but neither routine physiologic parameters nor imaging predict ED accurately. In this study we evaluated the relationship between DH and ED during 6-min walk testing (6MWT).

Methods

We measured ED and DH in patients with stable COPD. SpO₂ was measured by continuous pulse oximetry during 6MWT. ED was defined as a decline in SpO₂ (ΔSpO₂) ≥4 %. DH was determined by measuring inspiratory capacity (IC) before and after the 6MWT using a handheld spirometer. DH was defined as ΔIC >0.0 L. We correlated DH and ED with clinical and pulmonary physiologic variables by regression analysis, χ ², and receiver operator curve (ROC) analysis.

Results

Thirty males [age = 65 ± 9.4 years, FEV₁ % predicted = 48 ± 14 %, and DLCO % predicted = 50 ± 21 % (mean ± SD)] were studied. ΔSpO₂ correlated with ΔIC (r = 0.49, p = 0.005) and age (r = 0.39, p = 0.03) by univariate analysis; however, only ΔIC correlated on multivariate regression analysis (p = 0.01). ΔSpO₂ did not correlate with FEV₁, FVC, FEF_25–75, RV, DLCO % predicted, BMI, smoking, BORG score, or distance covered in 6MWT. DH strongly correlated with ED (p = 0.001). On ROC analysis, DH had an area under the curve of 0.92 for the presence of ED (sensitivity = 90 %; specificity = 77 %, p < 0.001).

Conclusion

Routine pulmonary function test results and clinical variables did not correlate with ED in patients with stable COPD. Dynamic hyperinflation strongly correlates with exertional desaturation and could be a reason for this desaturation.     

Same-day or historical ESR for disease activity score measurement: does it matter?

Several guidelines recommended routine use of Disease Activity Score-28 (DAS28) to monitor disease and the response to treatment for rheumatoid arthritis (RA). In practice, it may be appropriate to use historical erythrocyte sedimentation rate (ESR) values in place of same-day ESR, thereby preventing unnecessary delay in adjusting intervention. We asked whether ESR blood samples taken up to 3 months prior to the clinic appointment were adequate to accurately assess RA disease activity using the DAS28. RA patients (N?=?66) who met the inclusion criteria were assessed at baseline and ESR obtained on the day of review to calculate the DAS28 and compared with the DAS28 derived from the latest previous ESR (mean interval, 38.6 days; range, 6–99 days). Limits of agreement (LoA) were used to assess the agreement between the DAS28 pairs. The mean age of the participants was 61.5 years (range, 20–83 years), with mean disease duration of 11.0 years (range, 0.1–40 years). Comparing the DAS28 using same-day ESR versus pre-recorded historical ESR showed a small statistical difference (mean, ?0.09; 95 %CI, ?0.1602 to ?0.017) in the DAS28 score. The calculated LoA (?0.66 and 0.48) demonstrated acceptable agreement between DAS28 pairs, with 7.6 % of patients residing outside the LoA, all of whom had a significant treatment change. Disease misclassification occurred in 9.1 % of patients who were close to disease activity boundaries. Our results indicate that differences in the DAS28 due to a previous or same-day ESR are unlikely to be clinically significant for RA patients with established disease. A decision to adjust treatment therefore may be confidently made for most patients using the most recent ESR for calculating the DAS28, provided there was no major change in treatment since the last ESR measurement.