The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be ...determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function. In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers in Rptor knockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size of Rptor knockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation.
The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new regulatory axes ...remains in its infancy, the bone‐specific protein, osteocalcin, has been shown to be centrally involved. Undercarboxylated osteocalcin acts as a secretagogue in a feed‐forward loop to stimulate pancreatic β‐cell proliferation and insulin secretion, improve insulin sensitivity, and promote testosterone production. Importantly, dysregulation of insulin signaling in bone causes a reduction in serum osteocalcin levels that is associated with elevated blood glucose and reduced serum insulin levels, suggesting that the skeleton may play a significant role in the development of diet‐induced insulin resistance. Insulin signaling is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) which becomes hyper‐activated in response to nutrient overload. Loss‐ and gain‐of function models suggest that mTORC1 function in bone is essential for normal skeletal development; however, the role of this complex in the regulation of glucose metabolism remains to be determined. This review highlights our current understanding of the role played by osteocalcin in the skeletal regulation of glucose metabolism and fertility. In particular, it examines data emerging from transgenic mouse models which have revealed a pancreas‐bone‐testis regulatory axis and discusses recent human studies which seek to corroborate findings from mouse models with clinical observations. Moreover, we review recent studies which suggest dysregulation of insulin signaling in bone leads to the development of insulin resistance and discuss the potential role of mTORC1 signaling in this process.
The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new skeletal functions remains in its infancy, the bone‐specific protein, osteocalcin, has been shown to be centrally involved in both processes. This review examines recent data emerging from transgenic mouse models and human clinical studies which have revealed a novel pancreas‐bone‐testis regulatory axis, and discusses the potential role of bone specific mTORC1 signaling in the regulation of systemic glucose metabolism.
Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) and differentiation toward either lineage is both mutually exclusive and transcriptionally controlled. Recent ...studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition of mTOR promoting OB differentiation and suppressing AdC differentiation. mTOR functions within two distinct multiprotein complexes, mTORC1 and mTORC2, each of which contains the unique adaptor protein, raptor or rictor, respectively. While compounds used to study mTOR signaling, such as rapamycin and related analogs, primarily inhibit mTORC1, prolonged exposure can also disrupt mTORC2 function, confounding interpretation of inhibitor studies. As a result, the relative contribution of mTORC1 and mTORC2 to MSC fate determination remains unclear. In this study, we generated primary mouse MSCs deficient in either Rptor (RapKO) or Rictor (RicKO) using the Cre/loxP system. Cre‐mediated deletion of Rptor or Rictor resulted in impaired mTORC1 and mTORC2 signaling, respectively. Under lineage‐inductive culture conditions, RapKO MSCs displayed a reduced capacity to form lipid‐laden AdCs and an increased capacity to form a mineralized matrix. In contrast, RicKO MSCs displayed reduced osteogenic differentiation capacity and enhanced adipogenic differentiation potential. Taken together, our findings reveal distinct roles for mTORC1 and mTORC2 in MSC lineage commitment. Stem Cells 2015;33:1359–1365
This is a revision of the previous joint Policy Statement titled "Guidelines for Care of Children in the Emergency Department." Children have unique physical and psychosocial needs that are ...heightened in the setting of serious or life-threatening emergencies. The majority of children who are ill and injured are brought to community hospital emergency departments (EDs) by virtue of proximity. It is therefore imperative that all EDs have the appropriate resources (medications, equipment, policies, and education) and capable staff to provide effective emergency care for children. In this Policy Statement, we outline the resources necessary for EDs to stand ready to care for children of all ages. These recommendations are consistent with the recommendations of the Institute of Medicine (now called the National Academy of Medicine) in its report "The Future of Emergency Care in the US Health System." Although resources within emergency and trauma care systems vary locally, regionally, and nationally, it is essential that ED staff, administrators, and medical directors seek to meet or exceed these recommendations to ensure that high-quality emergency care is available for all children. These updated recommendations are intended to serve as a resource for clinical and administrative leadership in EDs as they strive to improve their readiness for children of all ages.
Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. ...Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells
We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma.
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Abstract Objective Attentional deficits represent a core cognitive impairment in schizophrenia. The distractor condition Sustained Attention Task (dSAT) has been identified by the Cognitive ...Neuroscience Treatment to Improve Cognition in Schizophrenia (CNTRICS) initiative as a promising translational task for assessing schizophrenia-related deficits in attentional selection-control, identifying neuroimaging biomarkers of such deficits, and for preclinical animal research on potential pro-cognitive treatments. Here, we examined whether patients would show specific difficulties in selection-control and in avoiding distraction in the dSAT. Method Selection-control deficits are measured by comparing attentional performance in the Sustained Attention Task (SAT) without distraction to performance on the task when distraction is present (dSAT). The baseline SAT condition can also be used to assess time-on-task or vigilance effects. Patients with schizophrenia, age- and gender-matched healthy controls and, as an additional control, school-aged children were tested on both the SAT and dSAT. Results Compared to healthy controls, patients had reduced performance overall and were differentially vulnerable to distraction. In contrast, patients but not children had preserved vigilance over time. Conclusion These results demonstrate specific input-selection control impairments in schizophrenia and suggest that patients' distraction-related impairments can be distinguished from general performance impairments and from deficits in other attentional processes (e.g., sustaining attention) evident in other groups.
To identify core practices for workforce management of communication and swallowing functions in coronavirus disease 2019 (COVID-19) positive patients within the intensive care unit (ICU).
A modified ...Delphi methodology was used, with 3 electronic voting rounds. AGREE II and an adapted COVID-19 survey framework from physiotherapy were used to develop survey statements. Sixty-six statements pertaining to workforce planning and management of communication and swallowing function in the ICU were included.
Electronic modified Delphi process.
Speech-language pathologists (SLPs) (N=35) from 6 continents representing 12 countries.
Not applicable.
The main outcome was consensus agreement, defined a priori as ≥70% of participants with a mean Likert score ≥7.0 (11-point scale: 0=strongly disagree, 10=strongly agree). Prioritization rank order of statements in a fourth round was also conducted.
SLPs with a median of 15 years of ICU experience, working primarily in clinical (54%), academic (29%), or managerial positions (17%), completed all voting rounds. After the third round, 64 statements (97%) met criteria. Rank ordering identified issues of high importance.
A set of global consensus statements to facilitate planning and delivery of rehabilitative care for patients admitted to the ICU during the COVID-19 pandemic were agreed by an international expert SLP group. Statements focused on considerations for workforce preparation, resourcing and training, and the management of communication and swallowing functions. These statements support and provide direction for all members of the rehabilitation team to use for patients admitted to the ICU during a global pandemic.
To determine congenital and developmental outcomes of children with Unilateral Hearing Loss (UHL) who were admitted to the Neonatal Intensive Care Unit (NICU).
Retrospective, single-site study that ...followed 25 children with permanent congenital UHL
a NICU admission to a NICU of Nottingham University Hospital. Birth and two-year developmental follow-up data were collected. They were compared to matched control group who had a NICU admission but no hearing loss (matched on gestational age, weight and sex).
The median birthweights, gestational ages and number of days spent on the NICU for the UHL population were 2510 g, 36 weeks, and 12 days respectively. Most children (20/25; 80%) with UHL
a NICU admission were diagnosed with a congenital anomaly within the first two years of life. Only half (13/25) of these children were diagnosed with a congenital anomaly at discharge. Children with UHL
a NICU admission were more likely than the matched group (NICU admission only;
< .001) to have multiple congenital anomalies. We found a positive association between multiple congenital anomalies and developmental impairment for the NICU graduates with UHL (
= .019). This UHL-NICU group were also more likely than the matched NICU children to have developmental impairment (7/25 vs. 0/25;
= .01), speech and language therapy (13/25 vs. 1/25;
< .001), inner ear malformations (14/25 vs. 0/25,
< .001) or craniofacial anomalies (12/25 vs. 2/25;
= .004).
Children with UHL
a NICU admission were at high risk of congenital anomalies and certain adverse developmental outcomes. Improved congenital anomaly screening is needed at birth for this population. Having multiple congenital anomalies suggests closer developmental monitoring is needed. This study contributes towards producing clinical screening and management guidelines to ensure consistent high-quality care for this unique population.
Pediatric patients cared for in emergency departments (EDs) are at high risk of medication errors for a variety of reasons. A multidisciplinary panel was convened by the Emergency Medical Services ...for Children program and the American Academy of Pediatrics Committee on Pediatric Emergency Medicine to initiate a discussion on medication safety in the ED. Top opportunities identified to improve medication safety include using kilogram-only weight-based dosing, optimizing computerized physician order entry by using clinical decision support, developing a standard formulary for pediatric patients while limiting variability of medication concentrations, using pharmacist support within EDs, enhancing training of medical professionals, systematizing the dispensing and administration of medications within the ED, and addressing challenges for home medication administration before discharge.
Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Progression of multiple myeloma is accompanied by an increase in bone marrow angiogenesis. Studies from our laboratory suggest ...a role for the CXCL12 chemokine in this process, with circulating levels of CXCL12 correlating with bone marrow angiogenesis in patients with multiple myeloma. While the mechanisms responsible for aberrant plasma cell expression of CXCL12 remain to be determined, studies in other systems suggest a role for hypoxia and hypoxia-inducible transcription factors.
The expression of hypoxia-inducible factor protein was examined in patients' bone marrow biopsy specimens using immunohistochemistry. The hypoxic regulation of CXCL12 was examined in multiple myeloma plasma cell lines using polymerase chain reaction and western blotting. The role of hypoxia-inducible factors-1 and -2 in the regulation of CXCL12 expression was examined using over-expression and short hairpin RNA knockdown constructs, electrophoretic mobility shift assays and chromatin immunoprecipitation. The contribution of CXCL12 to hypoxia-induced angiogenesis was examined in vivo using a subcutaneous murine model of neovascularization.
Strong hypoxia-inducible factor-2 protein expression was detected in CD138(+) multiple myeloma plasma cells in patients' biopsy specimens. Prolonged exposure to hypoxia strongly up-regulated CXCL12 expression in multiple myeloma plasma cells and hypoxia-inducible factor-2 was found to play a key role in this response. Promoter analyses revealed increased hypoxia-inducible factor-2 binding to the CXCL12 promoter under hypoxic conditions. Over-expression of hypoxia-inducible factor in multiple myeloma plasma cells strongly induced in vivo angiogenesis, and administration of a CXCL12 antagonist decreased hypoxia-inducible factor-induced angiogenesis.
Hypoxia-inducible factor-2 is a newly identified regulator of CXCL12 expression in multiple myeloma plasma cells and a major contributor to multiple myeloma plasma cell-induced angiogenesis. Targeting the hypoxic niche, and more specifically hypoxia-inducible factor-2, may represent a viable strategy to inhibit angiogenesis in multiple myeloma and progression of this disease.
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