Examination of the Non-linear V̇O2p Response to Exercise: Non-invasive Evidence of Linear Systems Control Using V̇O2p Kinetic Analyses

The pulmonary O2 uptake (V̇O2p) response to exercise has been characterized by exponential kinetics that remain constant regardless of the exercise protocol used to force the change in V̇O2p (kinetics are invariant). A system that responds in this way is classified as “dynamically linear”, implying that a first-order rate reaction controls V̇O2 at the muscle level (V̇O2m). However, slowed V̇O2p kinetics when initiating exercise from raised baseline intensities challenges this notion. The purpose of this thesis was to characterize the rate (τV̇O2p) and magnitude (gain) of adjustment of V̇O2p in response to step-transitions initiated from a wide range of exercise intensities to examine whether V̇O2 kinetics at the muscle level function as a dynamically linear system. In silico experiments were included to corroborate responses measured in vivo. Using breath-by-breath V̇O2p during step- and ramp-incremental exercise it was demonstrated that: 1) V̇O2p kinetics were invariant and fast (τV̇O2p ~20s) when transitions of varying ∆WR were initiated from a common WR (Chapter III); and 2) the V̇O2p response to ramp exercise was linearly related to WR and well described by a mono-exponential (Chapter IV) – consistent with dynamically linear control. However, it was also demonstrated in the same groups of participants that τV̇O2p and gain increased as a function of baseline intensity (Chapters III and IV) – refuting this notion. Modelling the summed influence of muscle compartments based on in vivo measurements in Chapter III revealed that τV̇O2p could appear fast (20s) despite being derived from τV̇O2m values ranging 15-40s and τQ̇m ranging 20-45s. Additionally, it was demonstrated that the V̇O2p response to ramp exercise in Chapter IV could also be characterized by an exponential function with τV̇O2p and gain parameters that vary as a function of WR. Collectively, these data suggest that V̇O2p kinetics are slowed dependent on WR and may be strongly influenced by muscle metabolic and circulatory heterogeneity. Therefore, it is proposed that at the muscle level V̇O2 kinetics operate as a linear system and that non-linear V̇O2p responses to exercise may reflect a “heterogeneity of linear responses” within the range of muscle fibres recruited to address the exercise challenge

Effect of heavy-intensity 'priming' exercise on oxygen uptake and muscle deoxygenation kinetics during moderate-intensity step-transitions initiated from an elevated work rate

We examined the effect of heavy-intensity ‘priming’ exercise on the rate of adjustment of pulmonary O2 uptake (τ 2p) initiated from elevated intensities. Fourteen men (separated into two groups: τ 2p≤25s [Fast] or τ 2p>25s [Slow]) completed step-transitions from 20W-to- 45%lactate threshold (LT; lower-step, LS) and 45%-to-90%LT (upper-step, US) performed (i) without; and (ii) with US preceded by heavy-intensity exercise (HUS). Breath-by-breath 2p and near-infrared spectroscopy-derived muscle deoxygenation ([HHb+Mb]) were measured. Compared to LS, τ 2p was greater (p0.05) from LS or Fast group US. In Slow, τ[HHb+Mb] increased (p<0.05) in US relative to HUS; this finding coupled with a reduced τ 2p indicates a priming-induced improvement in matching of muscle O2 delivery-to-O2 utilization during transitions from elevated intensities in those with Slow but not Fast 2p kinetics

Influence of Sex and Age on Muscle Sympathetic Nerve Activity of Healthy Normotensive Adults

As with blood pressure, age-related changes in muscle sympathetic nerve activity (MSNA) may differ nonlinearly between sexes. Data acquired from 398 male (age: 39±17; range: 18-78 years [mean±SD]) and 260 female (age: 37±18; range: 18-81 years) normotensive healthy nonmedicated volunteers were analyzed using linear regression models with resting MSNA burst frequency as the outcome and the predictors sex, age, MSNA, blood pressure, and body mass index modelled with natural cubic splines. Age and body mass index contributed 41% and 11%, respectively, of MSNA variance in females and 23% and 1% in males. Overall, changes in MSNA with age were sigmoidal. At age 20, mean MSNA of males and females were similar, then diverged significantly, reaching in women a nadir at age 30. After 30, MSNA increased nonlinearly in both sexes. Both MSNA discharge and blood pressure were lower in females until age 50 (17±9 versus 25±10 bursts·min-1; P\u3c1×10-19; 106±11/66±8 versus 116±7/68±9 mm Hg; P\u3c0.01) but converged thereafter (38±11 versus 35±12 bursts·min-1; P=0.17; 119±15/71±13 versus 120±13/72±9 mm Hg; P\u3e0.56). Compared with age 30, MSNA burst frequency at age 70 was 57% higher in males but 3-fold greater in females; corresponding increases in systolic blood pressure were 1 (95% CI, -4 to 5) and 12 (95% CI, 6-16) mm Hg. Except for concordance in females beyond age 40, there was no systematic change with age in any resting MSNA-blood pressure relationship. In normotensive adults, MSNA increases after age 30, with ascendance steeper in women

VEGF regulates local inhibitory complement proteins in the eye and kidney

10.1172/JCI86418Journal of Clinical Investigation1271199-21

Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis

Background & AimsEtrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did.MethodsWe performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1.ResultsColon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell−associated genes than patients who did not respond (P < .05). Colonic CD4+ integrin αE+ cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4+ αE− cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMAhigh vs 19% GZMAlow and 44% ITGAEhigh vs 19% ITGAElow). Compared with ITGAElow and GZMAlow patients, patients with ITGAEhigh and GZMAhigh had higher baseline numbers of epithelial crypt-associated integrin αE+ cells (P < .01 for both), but a smaller number of crypt-associated integrin αE+ cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%−80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline.ConclusionsLevels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarkerhigh patients. Larger, prospective studies of markers are needed to assess their clinical value

Costa Rica Rift hole deepened and logged

During Leg 111 of the Ocean Drilling Program, scientists on the drilling vessel JOIDES Resolution studied crustal structure and hydrothermal processes in the eastern equatorial Pacific. Leg 111 spent 43 days on its primary objective, deepening and logging Hole 5048, a deep reference hole in 5.9-million-year-old crust 200 km south of the spreading axis of the Costa Rica Rift. Even before Leg 111 , Hole 5048 was the deepest hole drilled into the oceanic crust, penetrating 274.5 m of sediments and 1,075.5 m of pillow lavas and sheeted dikes to a total depth of 1,350 m below sea floor (mbsf). Leg 111 deepened the hole by 212.3 m to a total depth of 1,562.3 mbsf (1,287.8 m into basement), and completed a highly successful suite of geophysical logs and experiments, including sampling of borehole waters

The influence of metabolic and circulatory heterogeneity on the expression of pulmonary oxygen uptake kinetics in humans

New Findings What is the central question of this study? The finding that pulmonary oxygen uptake (inline image) kinetics on transition to moderate exercise is invariant and exponential is consistent with a first-order reaction controlling inline image. However, slowed inline image kinetics when initiating exercise from raised baseline intensities challenges this notion. What is the main finding and its importance? Here, we demonstrate how a first-order system can respond with non-first-order response dynamics. Data suggest that progressive recruitment of muscle fibre populations having progressively lower mitochondrial density and slower microvascular blood flow kinetics can unify the seemingly contradictory evidence for the control of inline image on transition to exercise. We examined the relationship amongst baseline work rate (WR), phase II pulmonary oxygen uptake (inline image) time constant (inline image) and functional gain inline image during moderate-intensity exercise. Transitions were initiated from a constant or variable baseline WR. A validated circulatory model was used to examine the role of heterogeneity in muscle metabolism (inline image) and blood flow (inline image) in determining inline image kinetics. We hypothesized that inline image and GP would be invariant in the constant baseline condition but would increase linearly with increased baseline WR. Fourteen men completed three to five repetitions of ∆40 W step transitions initiated from 20, 40, 60, 80, 100 and 120 W on a cycle ergometer. The ∆40 W step transitions from 60, 80, 100 and 120 W were preceded by 6 min of 20 W cycling, from which the progressive ΔWR transitions (constant baseline condition) were examined. The inline image was measured breath by breath using mass spectrometry and a volume turbine. For a given ΔWR, both inline image (22–35 s) and GP (8.7–10.5 ml min−1 W−1) increased (P < 0.05) linearly as a function of baseline WR (20–120 W). The inline image was invariant (P < 0.05) in transitions initiated from 20 W, but GP increased with ΔWR (P < 0.05). Modelling the summed influence of multiple muscle compartments revealed that inline image could appear fast (24 s), and similar to in vivo measurements (22 ± 6 s), despite being derived from inline image values with a range of 15–40 s and inline image with a range of 20–45 s, suggesting that within the moderate-intensity domain phase II inline image kinetics are slowed dependent on the pretransition WR and are strongly influenced by muscle metabolic and circulatory heterogeneity

Serum S100B in primary progressive multiple sclerosis patients treated with interferon-beta-1a

S100B belongs to a family of calcium-binding proteins implicated in intracellular and extracellular regulatory activities. This study of serum S100B in primary progressive multiple sclerosis (PPMS) is based on data obtained from a randomized, controlled trial of Interferon β-1a in subjects with PPMS. The key questions were whether S100B levels were associated with either disability or MRI findings in primary progressive MS and whether Interferon β-1a has an effect on their S100B levels. Serial serum S100B levels were measured using an ELISA method. The results demonstrated that serum S100B is not related to either disease progression or MRI findings in subjects with primary progressive MS given Interferon β-1a. Furthermore there is no correlation between S100B levels and the primary and secondary outcome measures

Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies