The impact of forearm blood flow limitation on muscle reflex (metaboreflex) activation during exercise was examined in 10 heart failure (HF) (NYHA class III and IV) and 9 control (Ctl) subjects. ...Rhythmic handgrip contractions (25% maximal voluntary contraction, 30 contractions/min) were performed over 5 min under conditions of ambient pressure or with +50 mmHg positive pressure about the exercising forearm. Mean arterial blood pressure (MAP) and venous effluent hemoglobin (Hb) O2 saturation, lactate and H+ concentrations (La and H+, respectively) were measured at baseline and during exercise. For ambient contractions, the increase (Delta) in MAP by end exercise (DeltaMAP; i.e., the exercise pressor response) was the same in both groups (10.1 +/- 1.2 vs. 7.33 +/- 1.3 mmHg, HF vs. Ctl, respectively) despite larger DeltaLa and DeltaH+ for the HF group (P < 0.05). With ischemic exercise, the DeltaMAP for HF (21.7 +/- 2.7 mmHg) exceeded that of Ctl subjects (12.2 +/- 2.8 mmHg) (P < 0.0001). Also, for HF, DeltaLa (2.94 +/- 0.4 mmol) and DeltaH+ (24.8 +/- 2.7 nmol) in the ischemic trial were greater than in Ctl (1.63 +/- 0.4 mmol and 15.3 +/- 2.8 nmol; La and H+, respectively) (P < 0.02). Hb O2 saturation was reduced in Ctl from approximately 43% in the ambient trial to approximately 27% with ischemia (P < 0.0001). O2 extraction was maximized under ambient exercise conditions for HF but not for Ctl. Despite progressive increases in blood perfusion pressure over the course of ischemic exercise, no improvement in Hb O2 saturation or muscle metabolism was observed in either group. These data suggest that muscle reflex activation of the pressor response is intact in HF subjects but the resulting improvement in perfusion pressure does not appear to enhance muscle oxidative metabolism or muscle blood flow, possibly because of associated increases in sympathetic vasoconstriction of active skeletal muscle.
Abstract Objectives Given the sparse evidence for selection of first-line therapy for acute atrial fibrillation (AF) based on clinical factors alone, incorporation of genotype data may improve the ...effectiveness of treatment algorithms and advance the understanding of interpatient heterogeneity. We tested whether candidate nucleotide polymorphisms (SNPs) related to AF physiologic responses are associated with ventricular rate control after intravenous diltiazem in the emergency department (ED). Methods We conducted an analysis within a prospective observational cohort of ED patients with acute symptomatic AF, ventricular rate > 110 beats per minute within the first 2 hours, initially treated with intravenous diltiazem, and who had DNA available for analysis. We evaluated 24 candidate SNPs that were grouped into 3 categories based on their phenotype response (atrioventricular nodal AVN conduction, resting heart rate, disease susceptibility) and calculated 3 genetic scores for each patient. Our primary outcome was maximum heart rate reduction within 4 hours of diltiazem administration. Multivariable regression was used to identify associations with the outcome while adjusting for age, sex, baseline heart rate, and diltiazem dose. Results Of the 142 patients, 127 had complete data for the primary outcome. None of the genetic scores for AVN conduction, resting heart rate, or AF susceptibility showed a significant association with maximal heart rate response. Conclusion Using a candidate SNP approach, screening for genetic variants associated with AVN conduction, resting heart rate, or AF susceptibility failed to provide significant data for predicting successful rate control response to intravenous diltiazem for treating acute AF in the ED.
Nematode-naive sheep and sheep immunised by truncated infections with Trichostrongylus colubriformis were fitted with intestinal cannulae to allow administration of challenge infection and collection ...of intestinal fluids. Sheep were slaughtered at various times after challenge and the distribution of larvae along the small intestine was determined. Results showed that immune sheep had significantly fewer larvae in their intestines and that some sheep could expel the challenge infection within 2 h. Mucus samples from immune sheep contained increased parasite-specific antibody, histamine and anti-parasite activity as measured by larval migration inhibition assay. Higher levels of antibody and histamine were seen in intestinal fluids of immune sheep after challenge. Immunisation of sheep by truncated infections stimulated serum IgE and resulted in significantly higher numbers of IgE-positive cells in gut tissue sections before challenge and at 2 h and 24 h after challenge. Immune sheep also had greater numbers of mucosal mast cells and globule leucocytes after challenge, compared with naive sheep. When challenge larvae were mixed with mucus from immune sheep and infused back into naive recipient sheep, there was a distinct displacement of the larval population towards the distal part of the intestine, compared with the profile of larval establishment after infusion with mucus from naive sheep. These results are further evidence for an immediate hypersensitivity reaction in the intestine of immune sheep, where challenge larvae are expelled within 2 h and confirm the direct anti-larval properties of mucus. The cannulated-sheep challenge model described here will be a useful tool to unravel the mechanism of larval rejection from immune sheep and could lead to novel therapies.
We have investigated the use of a cationic lipid preparation to enhance antisense oligonucleotide activity in human umbilical vein endothelial cells. A liposomal preparation containing the cationic ...lipid N-1-(2,3-dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA) was found to increase by at least 1000-fold the potency of an antisense oligonucleotide (ISIS 1570) that hybridizes to the AUG translation initiation codon of human intercellular adhesion molecule-1. In the presence of 8 microM DOTMA, 6-15-fold more 35S-ISIS 1570 associated with cells, at oligonucleotide concentrations from 0.01 to 5 microM, than did in the absence of DOTMA. Both 35S-ISIS 1570 association with cells and antisense activity were increased as a function of DOTMA concentration and with increasing time of incubation with the cationic lipid. Fluorescein-labeled ISIS 1570 was used to assess the intracellular distribution of the oligonucleotide in the presence and absence of DOTMA. In the absence of DOTMA, the oligonucleotide localized to discrete structures in the cytoplasm of the cell, resulting in a punctate fluorescence pattern. In the presence of DOTMA, cellular fluorescence markedly increased and the oligonucleotide localized within the nucleus, as well as to discrete structures in the cytoplasm. Accumulation of the oligonucleotide in the nucleus in the presence of DOTMA was time and temperature dependent. Nuclear accumulation was inhibited by preincubation of the cells with monensin but not chloroquine, NH4Cl, nocodazole, colcemid, or brefeldin A. These data demonstrate that cationic lipids increase antisense activity by increasing the amount of oligonucleotide associated with cells and altering intracellular distribution of the oligonucleotide.
Abstract Background Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study ...aimed to assess the impact of AF on ventricular T1 at the time of CMRI. Methods Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. Results One hundred fifty-seven patients were studied (32% women; median age, 61 years interquartile range {IQR}, 55–67, 50% persistent AF episodes>7 days or requiring electrical or pharmacologic cardioversion, 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381–428). AF at the time of CMRI was associated with a 4.4% shorter T1 ( p =0.000) com p ared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate<60). A post-hoc multivariate model adjusted for heart rate suggested that heart rate elevation ( p =0.009) contributes to the reduction in T1 observed in patients with AF at the time of CMRI. No association between ventricular T1 and AF recurrence after ablation was demonstrated. Conclusion AF at the time of CMRI was associated with lower post-contrast ventricular T1 compared with sinus rhythm. This effect was at least partly due to elevated heart rate. T1 was not associated with the recurrence of AF after ablation.
SUMMARY
In an accompanying paper we show that antibodies in intestinal mucus that recognize a 35‐kDa antigen from the surface of the L3 stage of the sheep intestinal nematode parasite, ...Trichostrongylus colubriformis, are strongly associated with immune rejection of L3 in a truncated infection model of immunity in sheep. Monoclonal antibody PAB‐1 was used to immunopurify this antigen from T. colubriformis L3. The antigen is resistant to digestion with a range of proteases including proteinase K and does not stain on gels or blots treated with protein‐detecting reagents but does stain with carbohydrate‐detecting reagents. The antigen is also resistant to degradation by the action of lipases and is not soluble in organic solvents, suggesting that lipid components are not present or not accessible. Treatment with glycosidases does not affect the antigen, indicating either that sialic acid and N‐linked or O‐linked sugars are not present or that they are not accessible to enzyme attack. The antigen is not destroyed by harsh alkaline degradation with up to 8 m NaOH with or without borohydride reducing agent, or by extensive hydrazinolysis. Strong acid hydrolysis with trifluoroacetic acid or boiling in hydrochloric acid for 20 min does destroy the antigen. The antigen migrates as a poorly defined high molecular weight complex on native electrophoresis gels, but is detected as a major band at 35 kDa on SDS PAGE either by carbohydrate staining or by immunoblotting with antibody from immune sheep intestinal mucus and with mAb PAB‐1. Proteinase K digestion and alkaline degradation of extracts from L3 of 10 other parasitic nematode species revealed that L3 of each species contained a carbohydrate staining molecule which can be detected by mAb PAB‐1 and by mucus antibody from immune sheep. Because antibodies in intestinal mucus are directed against these antigens and may be responsible for protective immunity, carbohydrate larval antigens (CarLA) could represent a new family of molecules with potential as targets for stimulating host immunity.
Preoperative injection of radiocolloid for axillary sentinel node biopsy in breast cancer is uncomfortable for patients. This study evaluated the reliability of radiocolloid injection as determined ...by sentinel node identification rate and positive sentinel node biopsy rate, after the patient has been anesthetized in the operating room as compared with preoperative injection.
After institutional review board approval, a retrospective cohort of patients with breast cancer who underwent sentinel node biopsy from January 2005 through December 2010 was evaluated for analysis. Patients who received intraoperative injection of radiocolloid were compared with those who received their injection preoperatively. Patients with incomplete pathologic staging or having received neoadjuvant chemotherapy were excluded. All patients received radiocolloid injections into the retroareolar tissue; some also received intradermal injection directly over the tumor. All injections contained 37 MBq (1 mCi) in 0.5 mL of filtered (0.22-μm) (99m)Tc-sulfur colloid.
Over the 6-y study period there were 904 sentinel node biopsy procedures, and 165 patients were excluded from analysis. Of the 739 sentinel node biopsies that were analyzed, 647 had preoperative injection of radiocolloid and 92 had intraoperative injection. The overall sentinel lymph node identification rates were similar for the 2 groups: 93.5% for the preoperative injection group and 94.6% for the intraoperative injection group (not statistically significant). The identification rates remained comparable for both groups when analyzed by T stage of the tumor. The average number of sentinel lymph nodes removed was similar between preoperative and intraoperative injection: 2.60 and 2.70 nodes, respectively. The overall rates of positive sentinel nodes were comparable for the 2 groups: 25.6% for the preoperative injection group and 26.4% for the intraoperative injection group (not statistically significant). When analyzed by T stage, the positive sentinel node rates remained similar between the 2 groups.
The sentinel lymph node identification rate of 94.6% for the intraoperative injection group was similar to other published sentinel lymph node identification rates (96%-100%). The positive sentinel lymph node rate was also comparable to that of published series. Intraoperative injection of radiocolloid for axillary sentinel node biopsy appears equivalent to preoperative injection and is a less painful experience for breast cancer patients.
The workshop Dawn VI: Next Generation Observatories took place online over three days, 5-7 October, 2021. More than 200 physicists and astronomers attended to contribute to, and learn from, a ...discussion of next-generation ground-based gravitational-wave detectors. The program was centered on the next generation of ground-based gravitational-wave observatories and their synergy with the greater landscape of scientific observatories of the 2030s. Cosmic Explorer (CE), a concept developed with US National Science Foundation support, was a particular focus; Einstein Telescope (ET), the European next generation concept, is an important complement and partner in forming a network. The concluding summary of the meeting expressed the sentiment that the observational science accessible to CE and ET, also in combination with data from other non-GW observatories, will stimulate a very broad community of analysts and yield insights which are exciting given the access to GWs from the entire universe. The need, and desire, for closer collaboration between ET and CE was expressed; a three-detector network is optimal for delivering much of the science. The science opportunities afforded by CE and ET are broad and compelling, impacting a wide range of disciplines in physics and high energy astrophysics. There was a consensus that CE is a concept that can deliver the promised science. A strong endorsement of Cosmic Explorer, as described in the CE Horizon Study, is a primary outcome of DAWN VI.
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