Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity

Febrile-range hyperthermia (FRH) improves survival in experimental infections by accelerating pathogen clearance, but may also increase collateral tissue injury. We hypothesized that FRH would worsen the outcome of inflammation stimulated by a non-replicating agonist and tested this hypothesis in a murine model of pulmonary oxygen toxicity. Using a conscious, temperature-controlled mouse model, we showed that maintaining a core temperature at FRH (39 degrees C to 40 degrees C) rather than at euthermic levels (36.5 degrees C to 37 degrees C) during hyperoxia exposure accelerated lethal pulmonary vascular endothelial injury, reduced the inspired oxygen threshold for lethality, induced expression of granulocyte-colony stimulating factor, and expanded the circulating neutrophil pool. In these same mice, FRH augmented pulmonary expression of the ELR(+) CXC chemokines, KC and LPS-induced CXC chemokine, enhanced recruitment of neutrophils, and changed the histological pattern of lung injury to a neutrophilic interstitial pneumonitis. Immunoblockade of CXC receptor-2 abrogated neutrophil recruitment, reduced pulmonary vascular injury, and delayed death. These combined data demonstrate that FRH may enlist distinct mediators and effector cells to profoundly shift the host response to a defined injurious stimulus, in part by augmenting delivery of neutrophils to sites of inflammation, such as may occur in infections. In certain conditions, such as in the hyperoxic lung, this process may be deleterious.     

Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters

Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Evaluation of a shared decision making program for women suspected to have a genetic predisposition to breast cancer: preliminary results.

BACKGROUND: Women suspected to have a genetic predisposition to breast cancer face the difficult choice between regular breast cancer screening and prophylactic mastectomy. The authors developed a shared decision making program (SDMP) to support this decision. OBJECTIVES: To evaluate the SDMP in terms of practicality, beneficial effects, and patient satisfaction. DESIGN: A one-group pretest-posttest design was used. MEASURES: Decision uncertainty, decision burden, subjective knowledge, and risk comprehension were assessed before and after the SDMP. Additional measures were obtained for concepts related to breast cancer concern, desire to participate in the program, satisfaction, program acceptability, and emotional reaction to the program information. RESULTS: Seventy-two women, most of whom were awaiting the genetic test results, participated. Decision uncertainty (effect size d = 0.37) and decision burden (d = 0.41) were reduced by the SDMP. Subjective knowledge (averaged d = 0.94) and risk comprehension were improved. The women were satisfied with the SDMP and found its rationale acceptable. Women who had strong emotional reactions to the information benefited less from the SDMP, whereas women with strong desires to participate in the decision benefited more. CONCLUSIONS: There is a need to give patients more information, especially about prophylactic mastectomy and among gene carriers. Beneficial effects were observed irrespective of whether genetic status was known, suggesting that information concerning treatment options should be made available as soon as DNA testing begins. The better psychological outcomes of women with stronger desires to participate may arise because the desire to participate is characteristic of emotional stability.     

Demands of Multiple Behavior Change in Type 2 Diabetes Risk Reduction

The purpose of this study was to explore individual experiences of participation in multiple activities recommended for type 2 diabetes risk reduction. Twelve individuals at risk for type 2 diabetes described their experiences regarding risk-reduction activities. A grounded theory method guided data collection and analysis. Data analysis revealed facilitators and inhibitors associated with participation in recommended multiple behavior change for type 2 diabetes risk reduction. Our findings emphasize social and personal factors that increase or decrease the likelihood of adherence to prevention recommendations. Findings suggest that health care providers provide structured yet individualized recommendations to support multiple behavior change efforts.     

A Randomized Trial of Specialty Mental Health Probation: Measuring Implementation and Effectiveness Outcomes

Although the research on specialty mental health probation (SMHP) is promising, there have been no randomized controlled trials (RCT) of the prototypical model advanced in the research literature and little focus on SMHP implementation. This study assesses the adoption of SMHP in two counties and examines its impact on mental health and criminal justice outcomes. Researchers conducted a RCT within a hybrid implementation-effectiveness study to examine intervention adoption as well as mental health treatment engagement and criminal justice outcomes for 100 individuals with serious mental illnesses on probation in one rural and one urban county in a southeastern state. Randomization produced equivalent treatment (n?=?47) and control (n?=?53) groups with no statistically significant differences between groups on demographic or background characteristics. Compared to standard probation officers, SMHP officers addressed the mental health needs of individuals with serious mental illness (i.e., adoption) at higher rates (p?<?0.001). Compared to individuals on standard caseloads, individuals on SMHP had a higher rate of mental health engagement (e.g., mental health assessment, attending treatment appointment; p?<?0.050); however, more individuals on SMHP caseloads had a new crime violation during follow-up compared with individuals on standard caseloads (p?<?0.01). In conclusions, results suggest successful adoption of the intervention and increased mental health engagement among those on SMHP caseloads. Results are consistent with the mixed findings on the impact of SMHP on improving criminal justice outcomes.

     

Physiologic Pulsatile Flow Bioreactor Conditioning of Poly(ethylene glycol)-based Tissue Engineered Vascular Grafts

Mechanical conditioning represents a potential means to enhance the biochemical and biomechanical properties of tissue engineered vascular grafts (TEVGs). A pulsatile flow bioreactor was developed to allow shear and pulsatile stimulation of TEVGs. Physiological 120 mmHg/80 mmHg peak-to-trough pressure waveforms can be produced at both fetal and adult heart rates. Flow rates of 2 mL/sec, representative of flow through small diameter blood vessels, can be generated, resulting in a mean wall shear stress of ∼6 dynes/cm² within the 3 mm ID constructs. When combined with non-thrombogenic poly(ethylene glycol) (PEG)-based hydrogels, which have tunable mechanical properties and tailorable biofunctionality, the bioreactor represents a flexible platform for exploring the impact of controlled biochemical and biomechanical stimuli on vascular graft cells. In the present study, the utility of this combined approach for improving TEVG outcome was investigated by encapsulating 10T-1/2 mouse smooth muscle progenitor cells within PEG-based hydrogels containing an adhesive ligand (RGDS) and a collagenase degradable sequence (LGPA). Constructs subjected to 7 weeks of biomechanical conditioning had significantly higher collagen levels and improved moduli relative to those grown under static conditions. These authors contributed equally to this work     

Extracellular Vesicles Released From Articular Chondrocytes Play a Major Role in Cell–Cell Communication

The purpose of this investigation was to determine the role of extracellular vesicles (EVs), released from articular chondrocytes in a physiological or pathological state, in cell–cell communication with other articular chondrocytes or chondrocyte precursor cells. The conditioned medium from interleukin-1β (IL-1β)-treated human articular chondrocytes stimulated catabolic events and inhibited type II collagen expression in articular chondrocytes to a much greater degree than medium from IL-1β-treated chondrocytes after complete removal of EVs. The vehicle-treated and IL-1β-treated human articular chondrocytes released EVs of similar size; however, the number of EVs released by IL-1β-treated chondrocytes was markedly higher than the number of EVs released from the vehicle-treated cells. Furthermore, our findings demonstrate that similar to medium from IL-1β-treated chondrocytes containing EVs, EVs isolated from medium of IL-1β-treated chondrocytes stimulated catabolic events in articular chondrocytes, whereas EVs isolated from the medium of vehicle-treated chondrocytes inhibited catabolic events and increased messenger RNA levels of aggrecan and type II collagen in IL-1β-treated chondrocytes. Furthermore, the medium containing EVs from vehicle-treated articular chondrocytes or EVs isolated from this medium stimulated chondrogenesis of C3H10T1/2 cells, whereas medium containing EVs from IL-1β-treated chondrocytes or EVs isolated from this medium inhibited chondrogenesis. Our findings suggest that EVs released by articular chondrocytes play a key role in the communication between joint cells and ultimately in joint homeostasis, maintenance, pathology, and repair. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:731-739, 2020