Citations

CD4+T cells have a critical role in the development of allergic pulmonary inflammation, including the recruitment of eosinophils to the airway lumen and interstitium. The expression of interleukin (IL)-5 by CD4+cells has, in particular, often been lionized as the central link between allergic inflammation and the concomitant expansion or recruitment of eosinophils. The mechanism(s) by which CD4+T cells mediates eosinophil recruitment was assessed with gene knockout mice deficient for T cells or T cell subtypes and a unique IL-5 transgenic mouse (line NJ.1726) that constitutively overexpresses this cytokine in the lung epithelium. Pulmonary IL-5 expression is significantly attenuated in T cell- and CD4+but not CD8+cell-deficient animals, suggesting an obvious explanation for the lack of eosinophils in the lungs of T cell-deficient and CD4(−/−) mice. However, although the constitutive expression of IL-5 in the lung epithelium of NJ.1726 mice elicited an eosinophilia in the airway lumen of both naive and ovalbumin-treated mice, in the absence of CD4+cells, allergen-mediated eosinophil recruitment to the bronchoalveolar lavage fluid was abolished. Moreover, intranasal instillation of the potent eosinophil-specific chemokine eotaxin-2 was incapable of eliciting eosinophil recruitment in naive and ovalbumin-treated NJ.1726 CD4(−/−) mice, suggesting that eosinophil trafficking during allergic inflammatory responses is a consequence of a CD4+cell-mediated event(s) in addition to IL-5 expression and the establishment of a pulmonary chemokine gradient.

It is currently unclear whether aging alters the perfusion of active muscles during large-muscle dynamic exercise in humans. To study this issue, direct measurements of leg blood flow (femoral vein thermodilution) and systemic arterial pressure during submaximal cycle ergometry (70, 140, and 210 W) were compared between six younger (Y; 22–30 yr) and six older (O; 55–68 yr) chronically endurance-trained men. Whole body O2uptake, ventilation, and arterial and femoral venous samples for blood-gas, catecholamine, and lactate determinations were also obtained. Training duration (min/day), estimated leg muscle mass (dual-energy X-ray absorptiometry; Y, 21.5 ± 1.2 vs. O, 19.9 ± 0.9 kg), and blood hemoglobin concentration (Y, 14.9 ± 0.4 vs. O, 14.7 ± 0.2 g/dl) did not significantly differ ( P > 0.05) between groups. Leg blood flow, leg vascular conductance, and femoral venous O2 saturation were ∼20–30% lower in the older men at each work rate (all P < 0.05), despite similar levels of whole body O2 uptake. At 210 W, leg norepinephrine spillover rates and femoral venous lactate concentrations were more than twofold higher in the older men. Pulmonary ventilation was also higher in the older men at 140 (+24%) and 210 (+39%) W. These results indicate that leg blood flow and vascular conductance during cycle ergometer exercise are significantly lower in older endurance-trained men in comparison to their younger counterparts. The mechanisms responsible for this phenomenon and the extent to which they operate in other groups of older subjects deserve further attention.

Proctor, David N., Kenneth C. Beck, Peter H. Shen, Tamara J. Eickhoff, John R. Halliwill, and Michael J. Joyner. Influence of age and gender on cardiac output-V˙o2relationships during submaximal cycle ergometry. J. Appl. Physiol. 84(2): 599–605, 1998.—It is presently unclear how gender, aging, and physical activity status interact to determine the magnitude of the rise in cardiac output (Q˙c) during dynamic exercise. To clarify this issue, the present study examined theQ˙c-O2uptake (V˙o2) relationship during graded leg cycle ergometry in 30 chronically endurance-trained subjects from four groups ( n = 6–8/group): younger men (20–30 yr), older men (56–72 yr), younger women (24–31 yr), and older women (51–72 yr). Q˙c (acetylene rebreathing), stroke volume (Q˙c/heart rate), and whole bodyV˙o2were measured at rest and during submaximal exercise intensities (40, 70, and ∼90% of peakV˙o2). Baseline resting levels of Q˙c were 0.6–1.2 l/min less in the older groups. However, the slopes of theQ˙c-V˙o2relationship across submaximal levels of cycling were similar among all four groups (5.4–5.9 l/l). The absolute Q˙c associated with a given V˙o2(1.0–2.0 l/min) was also similar among groups. Resting and exercise stroke volumes (ml/beat) were lower in women than in men but did not differ among age groups. However, older men and women showed a reduced ability, relative to their younger counterparts, to maintain stroke volume at exercise intensities above 70% of peakV˙o2. This latter effect was most prominent in the oldest women. These findings suggest that neither age nor gender has a significant impact on theQ˙c-V˙o2relationships during submaximal cycle ergometry among chronically endurance-trained individuals.

Estimates of calf blood flow with venous occlusion plethysmography vary widely between studies, perhaps due to the use of different plethysmographs. Consequently, we compared calf blood flow estimates at rest and during reactive hyperemia in eight healthy subjects (four men and four women) with two commonly used plethysmographs: the mercury-in-silastic (Whitney) strain gauge and Dohn air-filled cuff. To minimize technical variability, flow estimates were compared with a Whitney gauge and a Dohn cuff on opposite calves before and after 10 min of bilateral femoral arterial occlusion. To account for any differences between limbs, a second trial was conducted in which the plethysmographs were switched. Resting flows did not differ between the plethysmographs (P = 0.096), but a trend toward lower values with the Whitney was apparent. Peak flows averaged 37% lower with the Whitney (27.8 +/- 2.8 ml.dl-1.min-1) than with the Dohn plethysmograph (44.4 +/- 2.8 ml.dl-1.min-1; P < 0.05). Peak flow expressed as a multiple above baseline was also lower with the Whitney (10-fold) than with the Dohn plethysmograph (14.5-fold; P = 0.02). Across all flows at rest and during reactive hyperemia, estimates were highly correlated between the plethysmographs in all subjects (r2 = 0.96-0.99). However, the mean slope for the Whitney-Dohn relationship was only 60 +/- 2%, indicating that over a wide range of flows the Whitney gauge estimate was 40% lower than that for the Dohn cuff. These results demonstrate that the same qualitative results can be obtained with either plethysmograph but that absolute flow values will generally be lower with Whitney gauges.

BackgroundPatients with heart failure (HF) have increased risk for thromboembolic events. Real‐world incidences of efficacy and safety outcomes of direct oral anticoagulants (DOACs) in patients with left ventricular systolic dysfunction (LVSD) are of growing clinical interest.HypothesisReal‐world efficacy and safety outcomes of DOACs in patients with LVSD will be similar to those of LVSD or HF subgroups in the RE‐LY, ROCKET‐AF, and ARISTOTLE trials.MethodsWe performed a retrospective review of adult patients with LVSD (left ventricular ejection fraction ≤40%) on DOAC therapy between 2010 and 2016. Incidences of safety and efficacy outcomes of anticoagulation with DOACs were extracted from primary and secondary hospital discharge diagnoses.ResultsDOACs were prescribed to 287 patients with LVSD over a mean follow‐up of 313.3 ± 52.3 days. Many patients had moderate and severe chronic kidney disease (28.9% and 10.1%, respectively) and indications for anticoagulation therapy other than atrial fibrillation (19.9%). For efficacy outcomes, the calculated incidence rates of ischemic stroke and systemic embolism were 1.2 (95% confidence interval [CI]: 0.25‐3.56) and 0.81 (95% CI: 0.10‐2.94) events per 100 person‐years, respectively. For the safety outcomes, incidence rates of GI bleeding and intracranial hemorrhage were 2.4 (95% CI: 0.8‐5.3) and 0.41 (95% CI: 0.1‐2.2) events per 100 patient‐years, respectively.ConclusionsOur findings are largely compatible with the results of LVSD or HF subgroups in RE‐LY, ROCKET‐AF, and ARISTOTLE trials and add to increasing confidence that DOACs can be safely used for stroke and systemic embolism prevention in patients with LVSD.

Background: Recognition of rates and causes of hard, patient-centered outcomes of death and cerebrovascular events (CVEs) after heart rhythm disorder management (HRDM) procedures is an essential step for the development of quality improvement programs in electrophysiology laboratories. Our primary aim was to assess and characterize death and CVEs (stroke or transient ischemic attack) after HRDM procedures over a 17-year period. Methods: We performed a retrospective cohort study of all patients undergoing HRDM procedures between January 2000 and November 2016 at the Mayo Clinic. Patients from all 3 tertiary academic centers (Rochester, Phoenix, and Jacksonville) were included in the study. All in-hospital deaths and CVEs after HRDM procedures were identified and were further characterized as directly or indirectly related to the HRDM procedure. Subgroup analysis of death and CVE rates was performed for ablation, device implantation, electrophysiology study, lead extraction, and defibrillation threshold testing procedures. Results: A total of 48 913 patients (age, 65.7±6.6 years; 64% male) who underwent a total of 62 065 HRDM procedures were included in the study. The overall mortality and CVE rates in the cohort were 0.36% (95% confidence interval [CI], 0.31–0.42) and 0.12% (95% CI, 0.09–0.16), respectively. Patients undergoing lead extraction had the highest overall mortality rate at 1.9% (95% CI, 1.34–2.61) and CVE rate at 0.62% (95% CI, 0.32–1.07). Among patients undergoing HRDM procedures, 48% of deaths directly related to the HDRM procedure were among patients undergoing device implantation procedures. Overall, cardiac tamponade was the most frequent direct cause of death (40%), and infection was the most common indirect cause of death (29%). The overall 30-day mortality rate was 0.76%, with the highest being in lead extraction procedures (3.08%), followed by device implantation procedures (0.94%). Conclusions: Half of the deaths directly related to an HRDM procedure were among the patients undergoing device implantation procedures, with cardiac tamponade being the most common cause of death. This highlights the importance of the development of protocols for the quick identification and management of cardiac tamponade even in procedures typically believed to be lower risk such as device implantation.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta = 2.95, p < 2.0 × 10 −16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10 −16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Abstract Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1–3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2–M arrest in vitro. In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide (P = 0.005), 11 days placebo (P &lt; 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide (P = 0.93), 14 days with placebo, P &lt; 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp−/− versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, P &lt; 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood–brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. Mol Cancer Ther; 16(12); 2735–46. ©2017 AACR.

AbstractMonte Carlo (MC) simulation has been used to generate commissioning data for the beam modeling of treatment planning system (TPS). We have developed a method called radial projection (RP) for postprocessing of MC‐simulation‐generated data. We used the RP method to reduce the statistical uncertainty of the lateral profile of proton pencil beams with axial symmetry. The RP method takes advantage of the axial symmetry of dose distribution to use the mean value of multiple independent scores as the representative score. Using the mean as the representative value rather than any individual score results in substantial reduction in statistical uncertainty. Herein, we present the concept and step‐by‐step implementation of the RP method, as well as show the advantage of the RP method over conventional measurement methods for generating lateral profile. Lateral profiles generated by both methods were compared to demonstrate the uncertainty reduction qualitatively, and standard error comparison was performed to demonstrate the reduction quantitatively. The comparisons showed that statistical uncertainty was reduced substantially by the RP method. Using the RP method to postprocess MC data, the corresponding MC simulation time was reduced by a factor of 10 without quality reduction in the generated result from the MC data. We concluded that the RP method is an effective technique to increase MC simulation efficiency for generating lateral profiles for axially symmetric pencil beams.