Resting heart rate,heart rate variability and functional decline in old age

Background:

Heart rate and heart rate variability, markers of cardiac autonomic function, have been linked with cardiovascular disease. We investigated whether heart rate and heart rate variability are associated with functional status in older adults, independent of cardiovascular disease.

Methods:

We obtained data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). A total of 5042 participants were included in the present study, and mean follow-up was 3.2 years. Heart rate and heart rate variability were derived from baseline 10-second electrocardiograms. Heart rate variability was defined as the standard deviation of normal-to-normal RR intervals (SDNN). Functional status in basic (ADL) and instrumental (IADL) activities of daily living was measured using Barthel and Lawton scales, at baseline and during follow-up.

Results:

The mean age of the study population was 75.3 years. At baseline, higher heart rate was associated with worse ADL and IADL, and lower SDNN was related to worse IADL (all p values < 0.05). Participants in the highest tertile of heart rate (range 71–117 beats/min) had a 1.79-fold (95% confidence interval [CI] 1.45–2.22) and 1.35-fold (95% CI 1.12–1.63) higher risk of decline in ADL and IADL, respectively (p for trend < 0.001 and 0.001, respectively). Participants in the lowest tertile of SDNN (range 1.70–13.30 ms) had 1.21-fold (95% CI 1.00–1.46) and 1.25-fold (95% CI 1.05–1.48) higher risk of decline in ADL and IADL, respectively (both p for trends < 0.05). All associations were independent of sex, medications, cardiovascular risk factors and comorbidities.

Interpretation:

Higher resting heart rate and lower heart rate variability were associated with worse functional status and with higher risk of future functional decline in older adults, independent of cardiovascular disease. This study provides insight into the role of cardiac autonomic function in the development of functional decline.Elevated heart rate and reduced heart rate variability — the beat-to-beat variation in heart rate intervals — both reflect an altered balance of the autonomic nervous system tone characterized by increased sympathetic and/or decreased parasympathetic activity.^1–3 Sympathetic overactivity has been linked to a procoagulant state and also to risk factors for atherosclerosis, including metabolic syndrome, obesity and subclinical inflammation.^2–4 Moreover, increased heart rate is related to atherosclerosis, not only as an epiphenomenon of sympathetic overactivity, but also through hemodynamic mechanisms, such as high pulsatile shear stress, which leads to endothelial dysfunction.⁵Atherosclerosis has been linked to increased risk of functional decline in older people via cardiovascular events.⁶ As the world population is aging, the burden of functional disability is expected to increase.⁶ It has been hypothesized that heart rate and heart rate variability are markers of frailty, an increased vulnerability to stressors and functional decline.⁷ However, the direct link between these 2 parameters and risk of functional decline has not been fully established, and it is uncertain whether this association is independent of cardiovascular comorbidities.In this study, we examined whether heart rate and heart rate variability were cross-sectionally and longitudinally associated with functional status in older adults at high risk of cardiovascular disease, independent of cardiovascular risk factors and comorbidities.     

Formulation and In Vitro,In Vivo Evaluation of Effervescent Floating Sustained-Release Imatinib Mesylate Tablet

Introduction

Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets.

Methodology

Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO₃) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted.

Results and Discussion

Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO₃ produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower C_max and higher T_max compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours.

Conclusion

In conclusion, in order to suggest a better drug delivery system with constant favorable release, resulting in optimized absorption and less side effects, formulated CP-HPMC-SA based imatinib mesylate floating sustained-release tablets can be a promising candidate for cancer chemotherapy.     

Phenotype and genotype relationship of glutathione peroxidase1 (GPx1) and rs 1800668 variant: the homozygote effect on kinetic parameters

GPx1 is one of the most important enzymes involved in oxidative balance so that, we studied the phenotype and genotype relationship of GPx1 activity and rs 1800668 (C/T) site and also evaluated the changes of GPx1 kinetic parameters in the rs 1800668 homozygotes. One hundred fifty eight subjects were recruited after clinical exams. The rs 1800668 (C/T) genotype distribution was identified using RFLP-PCR method. The hemolysate GPx1 activity was spectrophotometrically measured in a reaction coupled with glutathione reductase (GR). The GPx1 enzyme was purified using gel filtration chromatography with Sephacryl S-300 column and, Km(app) was studied in the rs 1800668 TT and CC homozygotes. The results showed that the GPx1 activity is significantly associated to the rs 1800668 (C/T) genotype distribution (P<0.05) so that, the GPx1 activity was high among the CC homozygotes (P<0.03). In addition, Km(app) for TBHP substrate in the TT homozygote (8.48 μM) was higher than the CC homozygote (5.74 μM). We concluded that the C allele within rs 1800668 position is related to the GPx1 activity and may be a potential factor involved in development of inflammatory events.     

Involvement of NF-κB and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A

The plant Artocarpus obtusus is a tropical plant that belongs to the family Moraceae. In the present study a xanthone compound Pyranocycloartobiloxanthone A (PA) was isolated from this plant and the apoptosis mechanism was investigated. PA induced cytotoxicity was observed using MTT assay. High content screening (HCS) was used to observe the nuclear condensation, cell permeability, mitochondrial membrane potential (MMP) and cytochrome c release. Reactive oxygen species formation was investigated on treated cells by using fluorescent analysis. Human apoptosis proteome profiler assays were performed to investigate the mechanism of cell death. In addition mRNA levels of Bax and Bcl2 were also checked using RT-PCR. Caspase 3/7, 8 and 9 were measured for their induction while treatment. The involvement of NF-κB was analyzed using HCS assay. The results showed that PA possesses the characteristics of selectively inducing cell death of tumor cells as no inhibition was observed in non-tumorigenic cells even at 30μg/ml. Treatment of MCF7 cells with PA induced apoptosis with cell death-transducing signals, that regulate the MMP by down-regulation of Bcl2 and up-regulation of Bax, triggering the cytochrome c release from mitochondria to cytosol. The release of cytochrome c triggered the activation of caspases-9, then activates downstream executioner caspase-3/7 and consequently cleaved specific substrates leading to apoptotic changes. This form of apoptosis was found closely associated with the extrinsic pathway caspase (caspase-8) and inhibition of translocation of NF-κB from cytoplasm to nucleus. The results demonstrated that PA induced apoptosis of MCF7 cells through NF-κB and Bcl2/Bax signaling pathways with the involvement of caspases.     

A straightforward DOPE (double labeling of oligonucleotide probes)-FISH (fluorescence in situ hybridization) method for simultaneous multicolor detection of six microbial populations

Fluorescence in situ hybridization (FISH) with rRNA-targeted oligonucleotide probes is an essential tool for the cultivation-independent identification of microbes within environmental and clinical samples. However, one of the major constraints of conventional FISH is the very limited number of different target organisms that can be detected simultaneously with standard epifluorescence or confocal laser scanning microscopy. Recently, this limitation has been overcome via an elegant approach termed combinatorial labeling and spectral imaging FISH (CLASI-FISH) (23). This technique, however, suffers compared to conventional FISH from an inherent loss in sensitivity and potential probe binding biases caused by the competition of two differentially labeled oligonucleotide probes for the same target site. Here we demonstrate that the application of multicolored, double-labeled oligonucleotide probes enables the simultaneous detection of up to six microbial target populations in a straightforward and robust manner with higher sensitivity and less bias. Thus, this newly developed technique should be an attractive option for all researchers interested in applying conventional FISH methods for the study of microbial communities.     

Detecting Memory and Structure in Human Navigation Patterns Using Markov Chain Models of Varying Order

One of the most frequently used models for understanding human navigation on the Web is the Markov chain model, where Web pages are represented as states and hyperlinks as probabilities of navigating from one page to another. Predominantly, human navigation on the Web has been thought to satisfy the memoryless Markov property stating that the next page a user visits only depends on her current page and not on previously visited ones. This idea has found its way in numerous applications such as Google''s PageRank algorithm and others. Recently, new studies suggested that human navigation may better be modeled using higher order Markov chain models, i.e., the next page depends on a longer history of past clicks. Yet, this finding is preliminary and does not account for the higher complexity of higher order Markov chain models which is why the memoryless model is still widely used. In this work we thoroughly present a diverse array of advanced inference methods for determining the appropriate Markov chain order. We highlight strengths and weaknesses of each method and apply them for investigating memory and structure of human navigation on the Web. Our experiments reveal that the complexity of higher order models grows faster than their utility, and thus we confirm that the memoryless model represents a quite practical model for human navigation on a page level. However, when we expand our analysis to a topical level, where we abstract away from specific page transitions to transitions between topics, we find that the memoryless assumption is violated and specific regularities can be observed. We report results from experiments with two types of navigational datasets (goal-oriented vs. free form) and observe interesting structural differences that make a strong argument for more contextual studies of human navigation in future work.