To study the metabolic and functional changes that occur during training with inspiratory flow resistive loads, a chronically instrumented unanesthetized sheep preparation was used. Sheep were exposed to resistances ranging from 50 to 100 cmH2O.l-1.s, for 2-4 h/day, 5-6 days/wk, for a total of 3 wk. Load intensity was adjusted to maintain arterial Po2 (PaO2) above 60 Torr and arterial PCO2 (PaCO2) below 45 Torr. Training produced significant (P less than 0.05) increases in citrate synthase, 3-hydroxyacyl-CoA dehydrogenase, and cytochrome oxidase in the costal and crural diaphragm of the trained sheep (n = 9) compared with control sheep (n = 7). Phosphofructokinase did not increase. In the quadriceps, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase, and phosphofructokinase did not change with training but cytochrome oxidase increased significantly (P less than 0.01). Function of the diaphragm was assessed in a subset of five sheep exposed to the same severe load 1 wk before and 2 days after the final training session. After training, sheep had a lower PaCO2 (10-40%), generated a higher transdiaphragmatic pressure (20-40%), and could sustain this level of transdiaphragmatic pressure for 0.5-2 h longer. The respiratory duty cycle was 10-15% lower, whereas minute ventilation and tidal volume were 20-30% higher in the posttraining test. We conclude that 1) training with inspiratory flow resistive loads improves the performance of the respiratory neuromuscular system and 2) the shift in enzyme profile of the diaphragm is at least in part responsible for this improvement.

Two brothers had nonobstructive hypertrophic cardiomyopathy, mental retardation, and vacuolar myopathy, and their mother died of cardiopathy at age 31. Seven families with this syndrome have been described; heredity appears to be X-linked dominant or autosomal dominant, with different expressivity in males and females. The biochemical cause of this lysosomal storage disease is unknown.

Background Biomarkers represent a potential tool to identify individuals at risk for anthracycline-induced cardiotoxicity (AICT) prior to symptom onset or left ventricular dysfunction. Methods This study examined the levels of cardiac and noncardiac biomarkers before, after the last dose of, and 3–6 months after completion of doxorubicin chemotherapy. Cardiac biomarkers included 5th generation high-sensitivity cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide, growth/differentiation factor-15 (GDF-15), and soluble suppression of tumorigenesis-2 (sST2). Noncardiac biomarkers included activated caspase-1 (CASP-1), activated caspase-3, C-reactive protein, tumor necrosis factor-α, myeloperoxidase (MPO), galectin-3, and 8-hydroxy-2’-deoxyguanosine. Echocardiographic data (LVEF and LVGLS) were obtained at pre- and post-chemotherapy. Subanalysis examined interval changes in biomarkers among high (cumulative doxorubicin dose ≥ 250 mg/m2) and low exposure groups. Results The cardiac biomarkers cTnT, GDF-15, and sST2 and the noncardiac biomarkers CASP-1 and MPO demonstrated significant changes over time. cTnT and GDF-15 levels increased after anthracycline exposure, while CASP-1 and MPO decreased significantly. Subanalysis by cumulative dose did not demonstrate a larger increase in any biomarker in the high-dose group. Conclusions The results identify biomarkers with significant interval changes in response to anthracycline therapy. Further research is needed to understand the clinical utility of these novel biomarkers.

Background: It is now recognized that stroke is a systemic stressor that triggers profound changes throughout the body, leading to alterations in the immune system and response. In the CNS, cell death from ischemic stroke activates glial cells, leading to trafficking of leukocytes into the brain and subsequent inflammation. Chemokines play an active role in modulating this recruitment process. Monocyte chemotactic protein-3 (MCP-3), also known as CCL7, is a chemokine that attracts a broad spectrum of immune cells. Although secreted at lower levels than the better-understood monocyte chemotactic protein-1, MCP-3 is released after injury and regulates migration of leukocytes, thus facilitating inflammation. As neuroinflammation is a well-documented complication after ischemic stroke, we hypothesized that MCP-3 levels would be elevated after stroke. In light of the fact that age is the principle risk factor for stroke, and that a chronic pro-inflammatory milieu is associated with aging, we also hypothesized that MCP-3 would increase with age. Methods: Young (10 weeks) and aged (18 months) male C57B16 mice were subjected to transient (60 minute) middle cerebral artery occlusion (MCAO) or a sham surgery. MCP-3 protein levels in brain tissue and serum samples from these stroked mice, as well as from cohorts of young and aged naïve mice, were analyzed with an ELISA. Results: The comparisons of naïve aged (n=4, mean=0.042±0.005 pg/μg) to naïve young (n=4, mean=0.017±0.009 pg/μg) mice showed a significant increase (p<.01) in MCP-3 in aged brain tissue. Additionally, when comparing aged MCAO to young MCAO (n=3, mean=0.01±0.007 pg/μg), MCP-3 was significantly elevated (p<.01) in the aged group. In comparing aged MCAO (n=6, mean=0.31±0.11 pg/ug ) to aged sham (n=6, mean=0.03±0.006 pg/μg), MCP-3 was significantly elevated (p<.05). No significant differences in MCP-3 levels in serum or between young stroke and young sham brain were seen. Conclusions: We demonstrated that levels of MCP-3 are increased post-stroke in aged mice, but not in young mice. Given what is known about the role of MCP-3 in immune cell trafficking, our data imply that MCP-3 plays a role in inflammation post-stroke, and that it also primes the aged brain for a greater inflammatory response post-stroke.

Backgrounds: An acute ischemic stroke (AIS) triggers rapid infiltration of circulating immune cells in the brain. P2X4R, a receptor for adenosine triphosphate ATP, regulate activation of circulating monocytes after stroke injury. Over-stimulation of P2X4R contributes to ischemic injury. CD14 ++ CD16 – classical, CD14 ++ CD16 + intermediate, and CD14 + CD16 ++ non-classical monocytes are three primary subsets of monocytes. Alterations in activity of circulating monocyte subsets may independently predict pathogenesis of AIS, however, the role of P2X4R in the activation of these monocyte subsets is not known. Methods: Consecutive AIS patients (60-90 years) undergoing endovascular clot retrieval and healthy control subjects both young (18-45 years) and aged (60-90 years) of both sexes were recruited and informed consent obtained. Flow cytometric analysis of whole blood derived monocytes at 0-2 days (acute, n=10), 3-7 days (subacute, n=9), and 65±20 days (chronic, n=7) after stroke onset were compared with healthy subjects (n=9-10/ age group). Results: Both number of total monocyte counts and P2X4R intensity significantly increase with age when compared between healthy young and aged control (P<0.05). Total monocyte count progressively increased during recovery in AIS patient (P<0.05). No. of CD14 ++ CD16 + intermediate monocytes were significantly reduced after stroke ( p <0.05). Both CD14 ++ CD16 + intermediate, and CD14 + CD16 ++ non-classical monocytes showed a significant increased median fluorescent intensity (P<0.01) of P2X4R at subacute and chronic time after AIS. Conclusions: P2X4R expression increases with age and after stroke. Disappearance of the CD14 + CD16 ++ non-classical monocyte subpopulation from circulation during stroke recovery suggests potential migration of these cells to the site of injury, consistent with their potential role in inflammation/phagocytosis. Increased P2X4R expression in intermediate and non-classical monocytes subpopulation suggest its specific role in selective activation of these monocytes subtype. Detailed molecular characterization of P2X4R response in intermediate and non-classical monocyte subpopulations may provide novel insights into P2X4R’s therapeutic potential during AIS.