Total, phasic, and regional myocardial blood flow in aortic stenosis.

The effect of aortic stenosis on total, phasic, and regional myocardial flow was studied in 16 anesthetized, open-chested dogs. An adjustable catheter device was used to produce increasing aortic obstruction, the severity of which was judged from the left ventricular aortic peak systolic gradient as mild (< 25 mm. Hg), moderate (26 to 50 mm. Hg) and severe (> 50 mm. Hg). The supply/demand index was estimated from the ratio of diastolic pressure time index to systolic pressure time index ($\text{DPTI}\text{SPTI}$). The ratio of diastolic to systolic coronary blood flow ($\text{DIAS}\text{SYS}$) was determined from the flow tracings. Total myocardial flow and endocardial/epicardial flow ratios ($\text{ENDO}\text{EPI}$) were determined by injecting four differently-labeled 7 to 9 micron microspheres in the left atrium during control, mild, moderate, and severe aortic stenosis.The supply/demand ($\text{DPTI}\text{SPTI}$) index decreased significantly at all levels of aortic stenosis because of a decrease in DPTI and an increase in SPTI. The $\text{DIAS}\text{SYS}$ coronary flow ratio and the $\text{ENDO}\text{EPI}$ myocardial flow ratio were not significantly changed during aortic stenosis. The total myocardial flow was significantly higher than control only during severe aortic stenosis.The results indicate that, for all degrees of experimental aortic stenosis, there were significant decreases in $\text{DPTI}\text{SPTI}$ but no significant changes in $\text{DIAS}\text{SYS}$ coronary flow ratio or the distribution of myocardial perfusion. Thus, in acute, experimental aortic stenosis, there is evidence of increased myocardial oxygen demand, but endocardial perfusion is not changed significantly.     

ER,PR, and Her2 immunocytochemistry on cell‐transferred cytologic smears of primary and metastatic breast carcinomas: A Comparison Study With Formalin‐Fixed Cell Blocks and Surgical Biopsies

The use of formalin‐fixed cell blocks (CBs) for detection of ER, PR, and Her2 status of primary and metastatic breast carcinomas sampled by fine‐needle aspiration (FNA) has been extensively used in clinical practice; however, CBs sometimes lack adequate cellularity even when direct smears are cellular. The aim of this study is to assess the reliability of ER, PR, and Her2 status as demonstrated by immunocytochemical staining (ICC) on alcohol‐fixed direct smears using the cell transfer (CT) technique. FNA cases diagnosed as primary or metastatic breast carcinoma in which the status of ER, PR, and Her2 had been determined either on CB or concurrent biopsy were identified over a period of 18 months. ICC for ER, PR, and Her2 was performed on alcohol‐fixed direct smears using the CT technique. Results were compared with those reported for the corresponding formalin‐fixed tissue. A total of 47 FNA specimens from 46 patients were included in this study. ICC results were excluded from analysis if the CT smear contained fewer than 50 cells. Correlation between the ICC performed on the CT smears and the corresponding CB or biopsy revealed a sensitivity rate for ER, PR, and Her2 of 95%, 90%, and 88%, respectively with a specificity of 100% for all three markers. ICC performed on the FNA smears using the CT technique is a reliable method for assessment of the ER, PR, and Her2 status of breast carcinomas, especially when the direct smears are highly cellular and the CB lacks adequate cellularity. Diagn. Cytopathol. 2013. © 2012 Wiley Periodicals, Inc.     

Predictors of Health Behavior Change After an Integrative Medicine Inpatient Program

Background

Health behavior change can improve physical and psychosocial outcomes in internal medicine patients.

Purpose

This study aims to identify predictors for health behavior change after an integrative medicine inpatient program.

Method

German internal medicine patients' (N?=?2,486; 80 % female; 53.9?±?14.3 years) practice frequency for aerobic exercise (e.g., walking, running, cycling, swimming), meditative movement therapies (e.g., yoga, tai ji, qigong), and relaxation techniques (e.g., progressive relaxation, mindfulness meditation, breathing exercises, guided imagery) was assessed at admission to a 14-day integrative medicine inpatient program, and 3, 6, and 12 months after discharge. Health behavior change was regressed to exercise self-efficacy, stage of change, and health locus of control (internal, external-social, external-fatalistic).

Results

Short-term increases in practice frequency were found for aerobic exercise: short- and long-term increases for meditative movement therapies and relaxation techniques (all p?p?p?Conclusion Health behavior change after an integrative medicine inpatient program was predicted by self-efficacy, stage of change, and health locus of control. Considering these aspects might improve adherence to health-promoting behavior after lifestyle modification programs.     

Do greater rates of body heat storage precede the accelerated reduction of self-paced exercise intensity in the heat?

Aim

To reevaluate the previous hypothesis that greater reductions in self-paced exercise intensity in the heat are mediated by early differences in the rate of body heat storage (S).

Methods

Eight trained volunteers cycled in 19 °C/1.8 kPa (COOL), 25 °C/1.2 kPa (NORM), and 34 °C/1.6 kPa (HOT), while maintaining an RPE of 16. Potential differences in S following the onset of exercise were assessed by comparing rates of esophageal temperature change (ΔT _es/Δt); and estimated S values using a traditional two-compartment thermometric model (S _therm) of changes in rectal (T _re) and skin (T _sk) temperature, and partitional calorimetry (S _cal).

Results

After 15 min of exercise, workload decreased more in HOT vs. COOL (P = 0.03), resulting in a shorter time (HOT: 40.7 ± 14.9 min; COOL: 53.5 ± 18.7 min; P = 0.04) to 70 % of initial workload. However, there were no preceding differences in ΔT _es/Δt between conditions (P = 0.18). S _therm values were different between HOT and COOL during the first 5 min of exercise (P < 0.05), primarily due to negative S _therm values (?32 ± 15 kJ min^?1) in COOL, which according to partitional calorimetric measurements, required improbably high (~56 kJ min^?1) rates of evaporation when no sweating on the back and thigh was observed until after 7.6 ± 1.5 min and 4.8 ± 1.7 min of exercise, respectively. S _cal values in the first 5 min of exercise confirmed S was actually positive in COOL (+21 ± 8 kJ min^?1) and not negative. Different S _therm values following the onset of exercise at different environmental temperatures are simply due to transient differences in the rate of change in T _sk.

Conclusion

Reductions in self-paced exercise intensity in the heat are not mediated by early differences in S following the onset of exercise.     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Pride in all Who Served: Development,Feasibility, and Initial Efficacy of a Health Education Group For LGBT Veterans

ABSTRACT

Many of the more than 1 million military veterans who identify as lesbian, gay, bisexual, and/or transgender (LGBT) have encountered “rejecting experiences in the military” and stigma from prior “Don’t Ask Don’t Tell” policies. Associated minority stress and social isolation have been linked to a disproportionate risk for depression and suicide, as well as a reluctance to seek medical care at Veterans Health Administration (VHA) facilities. This paper describes feasibility and preliminary outcomes of the newly developed, Pride in All Who Served Health Education Group created to meet the unique needs of sexual and gender minority veterans. The 10-week, closed, health education group (e.g., continuums of identity, military culture) enables open dialogue, fosters social connectedness, and empowers veterans to be more effective self-advocates within the healthcare system. Feedback from formative evaluations (n = 29 LGBT veterans and n = 25 VHA stakeholders) was incorporated before conducting a small scale, non-randomized pilot. Preliminary pre-post surveys (n = 18) show promise (i.e., Cohen’s d range ± 0.40 to 1.59) on mental health symptoms (depression/anxiety, suicidal ideation), resilience indicators (identity affirmation, community involvement, problem-focused coping), and willingness to access care within the VA system (satisfaction with VA services, perception of staff competence). Results suggest that the 10-week Pride Group may be an effective tool for addressing minority-related stress in LGBT veterans. A full-scale, randomized clinical trial of this intervention is needed to determine short and long-term impacts on clinical and healthcare access-related outcomes.     

FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.