Hematopoietic cytoplasmic adaptor protein Hem1 promotes osteoclast fusion and bone resorption in mice.

Hem1 (hematopoietic protein 1), a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins, is essential for lymphopoiesis and innate immunity as well as for the transition of hematopoiesis from the fetal liver to the bone marrow. However, the role of Hem1 in bone cell differentiation and bone remodeling is unknown. Here, we show that deletion of Hem1 resulted in a markedly increase in bone mass because of defective bone resorption in mice of both sexes. Hem1-deficient osteoclast progenitors were able to differentiate into osteoclasts, but the osteoclasts exhibited impaired osteoclast fusion and decreased bone-resorption activity, potentially because of decreased mitogen-activated protein kinase and tyrosine kinase c-Abl activity. Transplantation of bone marrow hematopoietic stem and progenitor cells from wildtype into Hem1 knockout mice increased bone resorption and normalized bone mass. These findings indicate that Hem1 plays a pivotal role in the maintenance of normal bone mass.

Ionizing Radiation Activates Mitochondrial Function in Osteoclasts and Causes Bone Loss in Young Adult Male Mice.

The damaging effects of ionizing radiation (IR) on bone mass are well-documented in mice and humans and are most likely due to increased osteoclast number and function. However, the mechanisms leading to inappropriate increases in osteoclastic bone resorption are only partially understood. Here, we show that exposure to multiple fractions of low-doses (10 fractions of 0.4 Gy total body irradiation [TBI]/week, i.e., fractionated exposure) and/or a single exposure to the same total dose of 4 Gy TBI causes a decrease in trabecular, but not cortical, bone mass in young adult male mice. This damaging effect was associated with highly activated bone resorption. Both osteoclast differentiation and maturation increased in cultures of bone marrow-derived macrophages from mice exposed to either fractionated or singular TBI. IR also increased the expression and enzymatic activity of mitochondrial deacetylase Sirtuin-3 (Sirt3)-an essential protein for osteoclast mitochondrial activity and bone resorption in the development of osteoporosis. Osteoclast progenitors lacking Sirt3 exposed to IR exhibited impaired resorptive activity. Taken together, targeting impairment of osteoclast mitochondrial activity could be a novel therapeutic strategy for IR-induced bone loss, and Sirt3 is likely a major mediator of this effect.

Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice.

Space is a high-stress environment. One major risk factor for the astronauts when they leave the Earth's magnetic field is exposure to ionizing radiation from galactic cosmic rays (GCR). Several adverse changes occur in mammalian anatomy and physiology in space, including bone loss. In this study, we assessed the effects of simplified GCR exposure on skeletal health in vivo. Three months following exposure to 0.5 Gy total body simulated GCR, blood, bone marrow and tissue were collected from 9 months old male mice. The key findings from our cell and tissue analysis are (1) GCR induced femoral trabecular bone loss in adult mice but had no effect on spinal trabecular bone. (2) GCR increased circulating osteoclast differentiation markers and osteoclast formation but did not alter new bone formation or osteoblast differentiation. (3) Steady-state levels of mitochondrial reactive oxygen species, mitochondrial and non-mitochondrial respiration were increased without any changes in mitochondrial mass in pre-osteoclasts after GCR exposure. (4) Alterations in substrate utilization following GCR exposure in pre-osteoclasts suggested a metabolic rewiring of mitochondria. Taken together, targeting radiation-mediated mitochondrial metabolic reprogramming of osteoclasts could be speculated as a viable therapeutic strategy for space travel induced bone loss.

Risk-reducing salpingo-oophorectomy among diverse patients with BRCA mutations at an urban public hospital: a mixed methods study.

OBJECTIVES: To assess the association of socioeconomic demographics with recommendation for and uptake of risk-reducing bilateral salpingo-oophorectomy (rrBSO) in patients with BRCA1 and BRCA2 (BRCA1/2) mutations. DESIGN: Retrospective cohort, semistructured qualitative interviews. SETTING AND PARTICIPANTS: BRCA1/2 mutation carriers at an urban, public hospital with a racially and socioeconomically diverse population. INTERVENTION: None. PRIMARY AND SECONDARY OUTCOMES: The primary outcomes were rate of rrBSO recommendation and completion. Secondary outcomes were sociodemographic variables associated with rrBSO completion. RESULTS: The cohort included 167 patients with BRCA1/2 mutations of whom 39% identified as black (n=65), 35% white (n=59) and 19% Hispanic (n=32). Over 95% (n=159) received the recommendation for age-appropriate rrBSO, and 52% (n=87) underwent rrBSO. Women who completed rrBSO were older in univariable analysis (p=0.05), but not in multivariable analysis. Completion of rrBSO was associated with residence in zip codes with lower unemployment and documented recommendation for rrBSO (p<0.05). All subjects who still received care in the health system (n=79) were invited to complete interviews regarding rrBSO decision-making, but only four completed surveys for a response rate of 5.1%. Themes that emerged included menopause, emotional impact and familial support. CONCLUSIONS: In this understudied population, genetic counselling and surrogates of financial health were associated with rrBSO uptake, highlighting genetics referrals and addressing social determinants of health as opportunities to improve cancer prevention and reduce health inequities. Our study demonstrates a need for more culturally centred recruiting methods for qualitative research in marginalised communities to ensure adequate representation in the literature regarding rrBSO.

Incidence, Contributing Factors, and Implications for Clinical Management of Polycythemia in Transmasculine Patients on Testosterone.

Purpose: The goal of this study was to evaluate contributing factors and management strategies for polycythemia in transmasculine patients on testosterone therapy. Methods: A retrospective analysis of medical records was performed for transmasculine patients on testosterone for at least 12 months. Data collected from each patient included age, body mass index (BMI), nicotine dependence, pulmonary disease status, obstructive sleep apnea (OSA) status, oophorectomy status, and testosterone route of administration. For patients who developed polycythemia, polycythemia management strategy data were collected. Results: Five-hundred-eleven patients were evaluated and 113 (22%) experienced an episode of polycythemia. Within the polycythemia group, 77% of patients were younger than age 40, 56% had a BMI >30.0, 44% had current or former nicotine dependence, 12% had a pulmonary disease, 12% had OSA, and 47% had received an oophorectomy. The polycythemia group had a significantly higher average age, BMI, and dose of testosterone, and also had a higher proportion of patients with OSA and an oophorectomy. Conclusion: These results revealed that polycythemia is a common side effect for transmasculine patients on testosterone. Importantly, previous oophorectomy may be associated with polycythemia which appears to be a novel finding. This finding requires further research but provides the potential to be an important screening consideration for transmasculine patients after oophorectomy. Polycythemia will continue to be a major concern for patients on testosterone therapy, and this study provided important information for clinical practice and future research that will lead to improved outcomes.

Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults With Cancer: Society for Integrative Oncology-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations to health care providers on integrative approaches to managing anxiety and depression symptoms in adults living with cancer. METHODS: The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, methodology, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2023. Outcomes of interest included anxiety or depression symptoms as measured by validated psychometric tools, and adverse events. Expert panel members used this evidence and informal consensus with the Guidelines into Decision Support methodology to develop evidence-based guideline recommendations. RESULTS: The literature search identified 110 relevant studies (30 systematic reviews and 80 randomized controlled trials) to inform the evidence base for this guideline. RECOMMENDATIONS: Recommendations were made for mindfulness-based interventions (MBIs), yoga, relaxation, music therapy, reflexology, and aromatherapy (using inhalation) for treating symptoms of anxiety during active treatment; and MBIs, yoga, acupuncture, tai chi and/or qigong, and reflexology for treating anxiety symptoms after cancer treatment. For depression symptoms, MBIs, yoga, music therapy, relaxation, and reflexology were recommended during treatment, and MBIs, yoga, and tai chi and/or qigong were recommended post-treatment. DISCUSSION: Issues of patient-health care provider communication, health disparities, comorbid medical conditions, cost implications, guideline implementation, provider training and credentialing, and quality assurance of natural health products are discussed. While several approaches such as MBIs and yoga appear effective, limitations of the evidence base including assessment of risk of bias, nonstandardization of therapies, lack of diversity in study samples, and lack of active control conditions as well as future research directions are discussed.Additional information is available at www.asco.org/survivorship-guidelines.

Systematic symptom management in the IMPACT Consortium: rationale and design for 3 effectiveness-implementation trials.

Cancer and its treatment produce deleterious symptoms across the phases of care. Poorly controlled symptoms negatively affect quality of life and result in increased health-care needs and hospitalization. The Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium was created to develop 3 large-scale, systematic symptom management systems, deployed through electronic health record platforms, and to test them in pragmatic, randomized, hybrid effectiveness and implementation trials. Here, we describe the IMPACT Consortium's conceptual framework, its organizational components, and plans for evaluation. The study designs and lessons learned are highlighted in the context of disruptions related to the COVID-19 pandemic.

Effects of Euphorbia esula L. (leafy spurge) on cattle and sheep in vitro fermentation and gas production.

BACKGROUND: Euphorbia esula L. (leafy spurge) is indigenous to Eurasia and has been known to cause grazing aversion in ruminant species. As a result, E. esula encroachment has negatively impacted rangelands in the Northern Great Plains and Intermountain West of the USA, as well as southern Canada. Our objectives were to evaluate the effect of increasing concentrations of E. esula on in vitro dry matter digestibility (DMD) and gas production. Two ruminally-cannulated cows and ewes were used as rumen inoculum donors. To accomplish objectives, two studies were conducted. In study 1, animals were fed exclusively a barley hay (12% crude protein (CP), 55.4% neutral detergent fiber (NDF), DM basis) diet; whereas in study 2, animals were fed a diet of 15% E. esula (21.9% CP, 48% NDF, DM basis) and 85% barley hay based on previous day intake. RESULTS: The 24 and 48 h in vitro and 96 h gas production indicate that, regardless of inoculum source or substrate fermented, DMD was not influenced. Differences, however, were consistently observed across studies for NDF disappearance. CONCLUSION: Regardless of inoculum source NDF disappearance was greater when substrate being fermented contained 0%, 80%, or 100% E. esula.

Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency.

Altered mitochondria activity in osteoblasts and osteoclasts has been implicated in the loss of bone mass associated with aging and estrogen deficiency - the 2 most common causes of osteoporosis. However, the mechanisms that control mitochondrial metabolism in bone cells during health or disease remain unknown. The mitochondrial deacetylase sirtuin-3 (Sirt3) has been earlier implicated in age-related diseases. Here, we show that deletion of Sirt3 had no effect on the skeleton of young mice but attenuated the age-related loss of bone mass in both sexes. This effect was associated with impaired bone resorption. Osteoclast progenitors from aged Sirt3-null mice were able to differentiate into osteoclasts, though the differentiated cells exhibited impaired polykaryon formation and resorptive activity, as well as decreased oxidative phosphorylation and mitophagy. The Sirt3 inhibitor LC-0296 recapitulated the effects of Sirt3 deletion in osteoclast formation and mitochondrial function, and its administration to aging mice increased bone mass. Deletion of Sirt3 also attenuated the increase in bone resorption and loss of bone mass caused by estrogen deficiency. These findings suggest that Sirt3 inhibition and the resulting impairment of osteoclast mitochondrial function could be a novel therapeutic intervention for the 2 most important causes of osteoporosis.

Sex and pairing status explain variations in the activation of nonapeptide receptors in song and motivation regions.

The nonapeptides oxytocin and vasopressin have been implicated in a variety of social behaviors. In zebra finches, oxytocin antagonists decrease pairing in both sexes, and pairing, in turn, increases expression of both mesotocin (the avian homologue of oxytocin) and vasotocin (the avian homologue of vasopressin). Increases in mesotocin and vasotocin mRNA are correlated with the amount of directed singing by males. Thus, in the present study, we examined the hypothesis that activation of cells containing nonapeptide receptors in song-related regions (ventral tegmental area, lateral septum, and medial preoptic nucleus) would also be correlated with directed singing in males. To rule out the possibility that these regions are involved in general pairing motivation, we also included females as subjects. In the ventral tegmental area, males had higher ZENK and V1aR than females and paired animals (regardless of sex) had higher ZENK and V1aR than did unpaired animals. In the medial preoptic nucleus, paired animals had higher ZENK than did unpaired animals, and there were no sex or pairing effects in the lateral septum. Only ZENK + V1aR in the medial preoptic nucleus was correlated with singing in males. These findings suggest that pairing is associated activation of nonapeptide receptors in the ventral tegmental area and the medial preoptic nucleus, but there is only partial evidence that courtship singing accounts for these findings. (PsycINFO Database Record

Cognitive performance of current methamphetamine and cocaine abusers.

Forty currently using methamphetamine (MA) abusers, 40 currently using cocaine (COC) abusers, and 80 comparison participants who did not use psychostimulants received a cognitive battery and questionnaires covering medical history and stimulant use patterns. Forty comparison participants were matched to the 40 MA users on age, education, ethnicity, and gender. The other 40 comparison participants were matched to the cocaine users on the same variables. This design was chosen because there were significant differences in age and ethnicity between COC and MA users that precluded a direct comparison between the groups. The COC group was older and predominantly African American compared to the predominantly Caucasian MA group. When compared to their matched non-using control groups, both MA and COC abusers were impaired on cognitive measures, but the type and degree of impairments were somewhat different.

Cognitive deficits among methamphetamine users with attention deficit hyperactivity disorder symptomatology.

Understanding the association between attention deficit hyperactivity disorder (ADHD) and substance abuse, specifically methamphetamine (MA) abuse, is challenging, partly because little is known about the specific constellation of cognitive impairments produced by MA. The present investigation serves to address this relationship by comparing the cognitive performance of MA abusers with ADHD symptomatology (n = 28) and MA abusers without ADHD symptomatology (n = 41) on tests of attention, memory and general intellectual functioning, executive functioning, problem solving, verbal fluency, and abstract thinking. Both MA samples had deficiencies in measures of memory and learning function, psychomotor speed and abstract thinking when compared to a control group (n = 40). Additional deficits were noted on tasks involving executive functioning, attention, and general intellectual functioning in MA abusers with ADHD symptomatology. The preliminary data suggests that executive function deficits and some of the symptoms associated with long-term MA use may be due to the fact that a large proportion of MA addicts had ADHD symptomatology as children.

A comparison of patterns of methamphetamine and cocaine use.

Typical use patterns of methamphetamine (MA) users were examined using self-report measures from 120 MA and 63 cocaine users. Twenty (14 MA and 6 cocaine) of the participants also took part in structured interviews designed to provide more specific descriptions of their drug use. The typical MA user uses more than 20 days a month. Use is evenly spaced throughout the day, and although the amount of drug used per day is not different, MA users use fewer times per day than do cocaine users. Fewer of the cocaine users are continuous users, and they use in the evening rather than the daytime. The cocaine pattern of fewer days of use, evening use, and more frequent doses per day fits a picture of recreational use, whereas the all-day-most-days methamphetamine pattern does not.

Identifying predictors of treatment outcome in a drug court program.

Drug courts are popular for dealing with drug-abusing offenders. However, relatively little is known about participant characteristics that reliably predict either success or failure in these treatment settings. In this article, we report on 99 individuals who were enrolled in a drug court program (approximately one-half of whom successfully completed the program). Using, logistic regression techniques we identified 2 significant predictors of outcome. First, individuals who were employed at the time of their enrollment into the drug court program were more likely to successfully complete the treatment program. Second, individuals with a history of illicit intravenous drug use were less likely to complete the program.