Aging increases metabolic capacity and reduces work efficiency during handgrip exercise in males

Maximal oxygen uptake and exercise performance typically decline with age. However, there are indications of preserved vascular function and blood flow regulation during arm exercise. Yet, it is unknown if this potential physiological preservation with age is mirrored in peripheral metabolic capacity and V̇O2/watt ratio. Thus, to investigate the effects of aging in the arms, we measured metabolic and vascular responses to 6-minute bouts of dynamic handgrip exercise at 40% and 80% of maximal work rate (WRmax) in eleven young (26±2yr) and twelve old (80±6yr) males, applying Doppler-ultrasound combined with blood samples from a deep forearm vein. At baseline, old had a larger arterial diameter compared to young (p<0.001). During exercise, the two groups reached the same WRmax. V̇O2, blood flow, and oxygen supply were higher (40%WRmax; 80%WRmax, all p<0.01), and arterio-venous oxygen-difference lower (80%WRmax, p<0.02), in old compared to young. Old also had a higher oxygen-excess at 80%WRmax (p<0.01) than young, while no difference in muscle diffusion or oxygen-extraction was detected. Only young exhibited an increase in intensity-induced arterial dilation (p<0.05), and they had a lower mean arterial pressure than old at 80%WRmax (p<0.001). V̇O2/watt (40%WRmax; 80%WRmax) was reduced in old compared to young (both p<0.05). In conclusion, in old and young males with a similar handgrip WRmax, old had a higher V̇O2 during 80%WRmax intensity, achieved by an increased blood flow. This may be a result of the available cardiac output reserve, compensating for reduced work efficiency and attenuated vascular response observed in old

Tumor classification and marker gene prediction by feature selection and fuzzy c-means clustering using microarray data

BACKGROUND: Using DNA microarrays, we have developed two novel models for tumor classification and target gene prediction. First, gene expression profiles are summarized by optimally selected Self-Organizing Maps (SOMs), followed by tumor sample classification by Fuzzy C-means clustering. Then, the prediction of marker genes is accomplished by either manual feature selection (visualizing the weighted/mean SOM component plane) or automatic feature selection (by pair-wise Fisher's linear discriminant). RESULTS: The proposed models were tested on four published datasets: (1) Leukemia (2) Colon cancer (3) Brain tumors and (4) NCI cancer cell lines. The models gave class prediction with markedly reduced error rates compared to other class prediction approaches, and the importance of feature selection on microarray data analysis was also emphasized. CONCLUSIONS: Our models identify marker genes with predictive potential, often better than other available methods in the literature. The models are potentially useful for medical diagnostics and may reveal some insights into cancer classification. Additionally, we illustrated two limitations in tumor classification from microarray data related to the biology underlying the data, in terms of (1) the class size of data, and (2) the internal structure of classes. These limitations are not specific for the classification models used

Functions on Irreducible Components of the Emerton-Gee Stack

Let $K / \mathbb{Q}_p$ be a finite unramified extension, and let $\mathcal{X}_n$ denote the Emerton-Gee stack parametrizing \'etale $(\varphi,\Gamma_K)$-modules of rank $n$. It is known since the work of Emerton-Gee that the irreducible components of the reduced special fiber of $\mathcal{X}$ are labeled by Serre weights $\sigma$ of $\operatorname{GL}_n(k)$. If such a component is denoted $\mathcal{X}(\sigma)$, we prove that $\mathcal{O}(\mathcal{X}(\sigma)) \cong \mathbb{F}[x_1,x_2,\dots,x_{n-1},x_n^{\pm 1}]$ when $\sigma$ is sufficiently generic.Comment: Comments welcome

Maximal strength training-induced improvements in forearm work efficiency are associated with reduced blood flow

Maximal strength training (MST) improves work efficiency. However, since blood flow is greatly dictated by muscle contractions in arms during exercise, and vascular conductance is lower, it has been indicated that arms rely more upon adapting oxygen extraction than legs in response to the enhanced work efficiency. Thus, to investigate if metabolic and vascular responses are arm-specific, we utilized Doppler-ultrasound and a catheter placed in the subclavian vein to measure blood flow and a-vO2diff during steady state work in seven young males (24{plus minus}3(SD) years) following six-weeks of handgrip MST. As expected, MST improved maximal strength (49{plus minus}9 to 62{plus minus}10kg) and rate of force development (923{plus minus}224 to 1086{plus minus}238N·s-1), resulting in a reduced submaximal V̇O2 (30{plus minus}9 to 24{plus minus}10ml·min-1) and concomitantly increased work efficiency (9.3{plus minus}2.5 to 12.4{plus minus}3.9%) (all p<0.05). In turn, the work efficiency improvement was associated with a reduced blood flow (486{plus minus}102 to 395{plus minus}114ml·min-1), mediated by a lower blood velocity (43{plus minus}8 to 32{plus minus}6cm·s-1) (all p<0.05). Conduit artery diameter and a-vO2diff remained unaltered. The maximal work test revealed increased time to exhaustion (949{plus minus}239 to 1102{plus minus}292seconds) and maximal work rate (both p<0.05), but no change in peak oxygen uptake. In conclusion, despite prior indications of metabolic and vascular limb-specific differences, these results reveal that improved work efficiency following small muscle mass strength training in the upper extremities is accompanied by a blood flow reduction, and coheres with what has been documented for lower extremities.publishedVersio

Maximal strength training : the impact of eccentric overload

The search for the most potent strength training intervention is continuous. Maximal strength training (MST) yields large improvements in force-generating capacity (FGC), largely attributed to efferent neural drive enhancement. However, it remains elusive whether eccentric overload, before the concentric phase, may augment training-induced neuromuscular adaptations. A total of 53 23 ± 3 (SD)-yr-old untrained males were randomized to either a nontraining control group (CG) or one of two training groups performing leg press strength training with linear progression, three times per week for 8 wk. The first training group carried out MST with four sets of four repetitions at ~90% one-repetition maximum (1RM) in both action phases. The second group performed MST with an augmented eccentric load of 150% 1RM (eMST). Measurements were taken of 1RM and rate of force development (RFD), countermovement jump (CMJ) performance, and evoked potentials recordings [V-wave (V) and H-reflex (H) normalized to M-wave (M) in musculus soleus]. 1RM increased from 133 ± 16 to 157 ± 23 kg and 123 ± 18 to 149 ± 22 kg and CMJ by 2.3 ± 3.6 and 2.2 ± 3.7cm for MST and eMST, respectively (all P < 0.05). Early, late, and maximal RFD increased in both groups [634–1,501 N/s (MST); 644–2,111 N/s (eMST); P < 0.05]. These functional improvements were accompanied by increased V/M-ratio (MST: 0.34 ± 0.11 to 0.42 ± 14; eMST: .36 ± 0.14 to 0.43 ± 13; P < 0.05). Resting H/M-ratio remained unchanged. Training-induced improvements did not differ. All increases, except for CMJ, were different from the CG. MST is an enterprise for large gains in FGC and functional performance. Eccentric overload did not induce additional improvements, suggesting firing frequency and motor unit recruitment during MST may be maximal.publishedVersio

Association between metformin use and risk of esophageal squamous cell carcinoma in a population-based cohort study

Objectives: Esophageal cancer is a highly fatal malignant neoplasm, with two etiologically different histological types. A large prospective study is expected to elucidate the specific risk of the 90% subtype of esophageal cancer, esophageal squamous cell carcinoma, with metformin therapy. This study aims to determine the association between metformin use and incident esophageal squamous cell carcinoma risk. Methods: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005-2015. Among 8.4 million participants identified in the cohort, 411,603 (5%) were metformin users. The users were compared with 10 times as many frequency-matched non-users of metformin (n=4,116,030) by age and sex. Metformin use was treated as a time-varying variate and multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for esophageal squamous cell carcinoma, adjusted for age, sex, calendar year, residence area, tobacco smoking, alcohol overconsumption, and use of non-steroidal anti-inflammatory drugs or statins. Results: The incidence rates of esophageal squamous cell carcinoma were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the non-users. Metformin users overall were at a decreased risk of esophageal squamous cell carcinoma compared with non-users (HR 0.68, 95% CI 0.54-0.85). The decrease in risk was more pronounced in new metformin users (HR 0.44, 95% CI 0.28-0.64) and participants aged 60-69 years (HR 0.45, 95% CI 0.31-0.66). Conclusions: Metformin use decreases the risk of developing esophageal squamous cell carcinoma.Swedish Research CouncilSwedish Cancer SocietyUnited European Research PrizeManuscrip

Thawing plateau time indicating the duration of phase transition from ice to water is the strongest predictor for long-term durable pulmonary vein isolation after cryoballoon ablation for atrial fibrillation—Data from the index and repeat procedures

Introduction: This study aimed to clarify the relationship between the durability of pulmonary vein (PV) isolation and the time of phase transition from ice to water indicated by thawing plateau time in a cryoballoon ablation for atrial fibrillation (AF). Methods and results: In this retrospective study, 241 PVs from 71 patients who underwent a repeat AF ablation 526 (IQR: 412, 675) days after a cryoballoon ablation were analyzed. Reconnection was observed in 101 (41.9%) PVs of 53 patients (74.6%). Thawing plateau time (TimeTP) was defined as the time from 0°C to 10°C inside the balloon in the thawing period. Durable PV isolation was associated with significantly longer TimeTP compared with PV reconnection (26.0 vs. 11.0 s, P 25 s with a positive predictive value of 84.6% (sensitivity = 55.0%, specificity = 86.1%). In the analysis of multivariable logistic regression, location of PV reconnection (P < 0.01), TimeTP (P < 0.05) and thawing plateau integral (P < 0.01) were shown as independent predictors for durable PV isolation. Conclusion: TimeTP is an independent predictor for the durability of PV isolation, and it presents in a dose-proportional manner. TimeTP 25 s predicts durable PV isolation.publishedVersio

The impacts of contact force, power and application time on ablation effect indicated by serial measurements of impedance drop in both conventional and high-power short-duration ablation settings of atrial fibrillation

Background: This study aimed to clarify the interrelationship and additive effects of contact force (CF), power and application time in both conventional and high-power short-duration (HPSD) settings. Methods: Among 38 patients with paroxysmal atrial fibrillation who underwent first-time pulmonary vein isolation, 787 ablation points were collected at the beginning of the procedure at separate sites. Energy was applied for 60 s under power outputs of 25, 30 or 35 W (conventional group), or 10 s when using 50 W (HPSD group). An impedance drop (ID) of 10 Ω was regarded as a marker of adequate lesion formation. Results: ID ≥ 10 Ω could not be achieved with CF < 5 g under any power setting. With CF ≥ 5 g, ID could be enhanced by increasing power output or prolonging ablation time. ID for 30 and 35 W was greater than for 25 W (p < 0.05). Ablation with 35 W resulted in greater ID than with 30 W only when CF of 10–20 g was applied for 20–40 s (p < 0.05). Under the same power output, ID increased with CF level at different time points. The higher the CF, the shorter the time needed to reach ID of 10 Ω and maximal ID. ID correlated well with ablation index under each power, except for lower ID values at 25 W. ID with 50 W for 10 s was equivalent to that with 25 W for 40 s, but lower than that with 30 W for 40 s or 35 W for 30 s. Conclusions: CF of at least 5 g is required for adequate ablation effect. With CF ≥ 5g, CF, power output, and ablation time can compensate for each other. Time to reach maximal ablation effect can be shortened by increasing CF or power. The effect of HPSD ablation with 50 W for 10 s is equivalent to conventional ablation with 25 W for 40 s and 30–35 W for 20–30 s in terms of ID.publishedVersio

Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease

Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.</p

A stitch in time: Efficient computation of genomic DNA melting bubbles

Background: It is of biological interest to make genome-wide predictions of the locations of DNA melting bubbles using statistical mechanics models. Computationally, this poses the challenge that a generic search through all combinations of bubble starts and ends is quadratic. Results: An efficient algorithm is described, which shows that the time complexity of the task is O(NlogN) rather than quadratic. The algorithm exploits that bubble lengths may be limited, but without a prior assumption of a maximal bubble length. No approximations, such as windowing, have been introduced to reduce the time complexity. More than just finding the bubbles, the algorithm produces a stitch profile, which is a probabilistic graphical model of bubbles and helical regions. The algorithm applies a probability peak finding method based on a hierarchical analysis of the energy barriers in the Poland-Scheraga model. Conclusions: Exact and fast computation of genomic stitch profiles is thus feasible. Sequences of several megabases have been computed, only limited by computer memory. Possible applications are the genome-wide comparisons of bubbles with promotors, TSS, viral integration sites, and other melting-related regions.Comment: 16 pages, 10 figure