We used whole genome sequencing with epidemiologic data to determine if USA300 methicillin-resistant Staphylococcus aureus (MRSA) transmission networks exist in an urban community. We observed potential MRSA transmission networks and identified community factors or exposures that may facilitate spread of USA300.
Background. In a community, it is unknown what factors account for transmission of methicillin-resistant Staphylococcus aureus (MRSA). We integrated whole genome sequencing (WGS) and epidemiologic data to identify factors associated with MRSA transmission networks in an urban community.
Methods. WGS was performed on colonizing USA300 MRSA isolates from 74 individuals within 72 hours of admission to a public hospital in Chicago, IL. Single nucleotide variants (SNVs) were used to reconstruct the phylogeny of sequenced isolates, and epidemiologic data was overlaid to identify factors associated with transmission networks.
Results. The maximum within-patient SNV difference for an individual with multisite colonization was 41 SNVs, with no systematic divergence among body sites. We observed a minimum of 7 SNVs and maximum of 153 SNVs between isolates from different individuals. We identified 4 pairs of individuals whose isolates were within 40 SNVs of each other. Putting our isolates in the context of previously sequenced USA300 isolates from other communities, we identified a 13-member group and two 4-member groups that represent samples from putative local transmission networks. Individuals in these groups were more likely to be African American, to be human immunodeficiency virus–infected, to reside in high detainee release areas, and to be current users of illicit drugs.
Conclusions. Using WGS, we observed potential transmission networks in an urban community and that certain epidemiologic factors were associated with inclusion in these networks. Future work with contact tracing and advanced molecular diagnostics may allow for identification of MRSA “epicenters” in the community where interventions can be targeted.
MRSA; whole genome sequencing
Knowledge of the duration of colonization with KPC is essential for infection control measures. We found that only 17% of LTACH patients lost colonization within four weeks. Half of the KPC-positive patients were still carriers when readmitted after nine months.
Background. High prevalence of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae has been reported in long-term acute care hospitals (LTACHs), in part because of frequent readmissions of colonized patients. Knowledge of the duration of colonization with KPC is essential to identify patients at risk of KPC colonization upon readmission and to make predictions on the effects of transmission control measures.
Methods. We analyzed data on surveillance isolates that were collected at 4 LTACHs in the Chicago region during a period of bundled interventions, to simultaneously estimate the duration of colonization during an LTACH admission and between LTACH (re)admissions. A maximum-likelihood method was used, taking interval-censoring into account.
Results. Eighty-three percent of patients remained colonized for at least 4 weeks, which was the median duration of LTACH stay. Between LTACH admissions, the median duration of colonization was 270 days (95% confidence interval, 91–∞).
Conclusions. Only 17% of LTACH patients lost colonization with KPC within 4 weeks. Approximately half of the KPC-positive patients were still carriers when readmitted after 9 months. Infection control practices should take prolonged carriage into account to limit transmission of KPCs in LTACHs.
carbapenemase; duration of colonization; KPC; LTACH
Glucocorticoid excess decreases bone mass and strength in part by acting directly on osteoblasts and osteocytes, but the mechanisms remain unclear. Macroautophagy (herein referred to as autophagy) is a lysosome-based recycling pathway that promotes the turnover of intracellular components and can promote cell function and survival under stressful conditions. Recent studies have shown that glucocorticoids stimulate autophagy in osteocytes, suggesting that autophagy may oppose the negative actions of glucocorticoids on this cell type. To address this possibility, we compared the impact of prednisolone administration on the skeletons of adult mice in which autophagy was suppressed in osteocytes, via deletion of Atg7 with a Dmp1-Cre transgene, to their control littermates. In control mice, prednisolone increased autophagic flux in osteocyte-enriched bone as measured by LC3 conversion, but this change did not occur in the mice lacking Atg7 in osteocytes. Nonetheless, prednisolone reduced femoral cortical thickness, increased cortical porosity, and reduced bone strength to similar extents in mice with and without autophagy in osteocytes. Prednisolone also suppressed osteoblast number and bone formation in the cancellous bone of control mice. As shown previously, Atg7 deletion in osteocytes reduced osteoblast number and bone formation in cancellous bone, but these parameters were not further reduced by prednisolone administration. In cortical bone, prednisolone elevated osteoclast number to a similar extent in both genotypes. Taken together, these results demonstrate that although glucocorticoids stimulate autophagy in osteocytes, suppression of autophagy in this cell type does not worsen the negative impact of glucocorticoids on the skeleton.
autophagy; osteocytes; glucocorticoids
In men, androgens are critical for the acquisition and maintenance of bone mass in both the cortical and cancellous bone compartment. Male mice with targeted deletion of the androgen receptor (AR) in mature osteoblasts or osteocytes have lower cancellous bone mass, but no cortical bone phenotype. We have investigated the possibility that the effects of androgens on the cortical compartment result from AR signaling in osteoprogenitors or cells of the osteoclast lineage; or via estrogen receptor alpha (ERα) signaling in either or both of these two cell types upon conversion of testosterone to estradiol. To this end, we generated mice with targeted deletion of an AR or an ERα allele in the mesenchymal (ARf/y;Prx1-Cre or ERαf/f;Osx1-Cre) or myeloid cell lineage (ARf/y; LysM-Cre or ERαf/f;LysM-Cre) and their descendants. Male ARf/y;Prx1-Cre mice exhibited decreased bone volume and trabecular number, and increased osteoclast number in the cancellous compartment. Moreover, they did not undergo the loss of cancellous bone volume and trabecular number caused by orchidectomy (ORX) in their littermate controls. In contrast, ARf/y;LysM-Cre, ERαf/f; Osx1-Cre, or ERαf/f;LysM-Cre mice had no cancellous bone phenotype at baseline and lost the same amount of cancellous bone as their controls following ORX. Most unexpectedly, adult males of all four models had no discernible cortical bone phenotype at baseline, and lost the same amount of cortical bone as their littermate controls after ORX. Recapitulation of the effects of ORX by AR deletion only in the ARf/y;Prx1-Cre mice indicates that the effects of androgens on cancellous bone result from AR signaling in osteoblasts—not on osteoclasts or via aromatization. The effects of androgens on cortical bone mass, on the other hand, do not require AR or ERα signaling in any cell type across the osteoblast or osteoclast differentiation lineage. Therefore, androgens must exert their effects indirectly by actions on some other cell type(s) or tissue(s).
SEX STEROIDS; GENETIC ANIMAL MODELS; OSTEOBLASTS; OSTEOCLASTS; OSTEOCYTES
Rac1 and Rac2 are thought to have important roles in osteoclasts. Therefore, mice with deletion of both Rac1 and Rac2 in mature osteoclasts (DKO) were generated by crossing Rac1flox/flox mice with mice expressing Cre in the cathepsin K locus and then mating these animals with Rac2−/− mice. DKO mice had markedly impaired tooth eruption. Bone mineral density (BMD) was increased 21% to 33% in 4- to 6-week-old DKO mice at all sites when measured by dual-energy X-ray absorptiometry (DXA) and serum cross-linked C-telopeptide (CTx) was reduced by 52%. The amount of metaphyseal trabecular bone was markedly increased in DKO mice, but the cortices were very thin. Spinal trabecular bone mass was increased. Histomorphometry revealed significant reductions in both osteoclast and osteoblast number and function in 4- to 6-week-old DKO animals. In 14- to 16-week-old animals, osteoclast number was increased, although bone density was further increased. DKO osteoclasts had severely impaired actin ring formation, an impaired ability to generate acid, and reduced resorptive activity in vitro. In addition, their life span ex vivo was reduced. DKO osteoblasts expressed normal differentiation markers except for the expression of osterix, which was reduced. The DKO osteoblasts mineralized normally in vitro, indicating that the in vivo defect in osteoblast function was not cell autonomous. Confocal imaging demonstrated focal disruption of the osteocytic dendritic network in DKO cortical bone. Despite these changes, DKO animals had a normal response to treatment with once-daily parathyroid hormone (PTH). We conclude that Rac1 and Rac2 have critical roles in skeletal metabolism.
RAC1; RAC2; OSTEOCLASTS; OSTEOCYTES
Infection rates have increased in all age groups and settings nationally.
The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections is increasing in the United States. However, few studies have addressed their epidemiology in children. To phenotypically identify CRE isolates cultured from patients 1–17 years of age, we used antimicrobial susceptibilities of Enterobacteriaceae reported to 300 laboratories participating in The Surveillance Network–USA database during January 1999–July 2012. Of 316,253 isolates analyzed, 266 (0.08%) were identified as CRE. CRE infection rate increases were highest for Enterobacter species, blood culture isolates, and isolates from intensive care units, increasing from 0.0% in 1999–2000 to 5.2%, 4.5%, and 3.2%, respectively, in 2011–2012. CRE occurrence in children is increasing but remains low and is less common than that for extended-spectrum β-lactamase–producing Enterobacteriaceae. The molecular characterization of CRE isolates from children and clinical epidemiology of infection are essential for development of effective prevention strategies.
carbapenem-resistant Enterobacteriaceae; CRE; bacteria; antimicrobial resistance; antibacterial agents; children; epidemiology; infections; β-lactamases; Surveillance Network–USA database; United States
This technology-based public health tool can facilitate detection of and communication about these bacteria.
In response to clusters of carbapenem-resistant Enterobacteriaceae (CRE) in Illinois, USA, the Illinois Department of Public Health and the Centers for Disease Control and Prevention Chicago Prevention Epicenter launched a statewide Web-based registry designed for bidirectional data exchange among health care facilities. CRE occurrences are entered and searchable in the system, enabling interfacility communication of patient information. For rapid notification of facilities, admission feeds are automated. During the first 12 months of implementation (November 1, 2013–October 31, 2014), 1,557 CRE reports (≈4.3/day) were submitted from 115 acute care hospitals, 5 long-term acute care hospitals, 46 long-term care facilities, and 7 reference laboratories. Guided by a state and local public health task force of infection prevention specialists and microbiologists and a nonprofit informatics entity, Illinois Department of Public Health deployed a statewide registry of extensively drug-resistant organisms. The legal, technical, and collaborative underpinnings of the system enable rapid incorporation of other emerging organisms.
automated medical records system; drug resistance; microbial; registries; computers; bacteria; antimicrobial resistance; extensively drug-resistant organisms; Illinois; United States
Community-associated methicillin-resistant Staphylococcus aureus (MRSA) has had a significant impact on human immunodeficiency virus (HIV)-infected and incarcerated individuals. We examined electronic medical surveillance data from 2006 to 2011 and observed that even in a population of currently or recently incarcerated individuals, HIV status was a significant risk factor for MRSA infections and Hispanic ethnicity was protective.
HIV; incarceration; MRSA
Parathyroid hormone (PTH) excess stimulates bone resorption. This effect is associated with increased expression of the osteoclastogenic cytokine receptor activator of nuclear factor кB ligand (RANKL) in bone. However, several different cell types, including bone marrow stromal cells, osteocytes, and T lymphocytes, express both RANKL and the PTH receptor and it is unclear whether RANKL expression by any of these cell types is required for PTH-induced bone loss. Here we have used mice lacking the RANKL gene in osteocytes to determine whether RANKL produced by this cell type is required for the bone loss caused by secondary hyperparathyroidism induced by dietary calcium deficiency in adult mice. Thirty days of dietary calcium deficiency caused bone loss in control mice, but this effect was blunted in mice lacking RANKL in osteocytes. The increase in RANKL expression in bone and the increase in osteoclast number caused by dietary calcium deficiency were also blunted in mice lacking RANKL in osteocytes. These results demonstrate that RANKL produced by osteocytes contributes to the increased bone resorption and the bone loss caused by secondary hyperparathyroidism, strengthening the evidence that osteocytes are an important target cell for hormonal control of bone remodeling.
osteocyte; osteoclast; RANKL; parathyroid hormone
Since the publication of “A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals” in 2008, prevention of healthcare-associated infections (HAIs) has become a national priority. Despite improvements, preventable HAIs continue to occur. The 2014 updates to the Compendium were created to provide acute care hospitals with up-to-date, practical, expert guidance to assist in prioritizing and implementing their HAI prevention efforts. They are the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Institute for Healthcare Improvement (IHI), the Pediatric Infectious Diseases Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), and the Surgical Infection Society (SIS).
CA-MRSA; extra-nasal colonization
Skeletal aging is accompanied by decreased cancellous bone mass and increased formation of pores within cortical bone. The latter accounts for a large portion of the increase in non-vertebral fractures after age 65 in humans. We selectively deleted Bak and Bax, two genes essential for apoptosis, in two types of terminally differentiated bone cells: the short-lived osteoblasts that elaborate the bone matrix, and the long-lived osteocytes that are immured within the mineralized matrix and choreograph the regeneration of bone. Attenuation of apoptosis in osteoblasts increased their working lifespan and thereby cancellous bone mass in the femur. In long-lived osteocytes, however, it caused dysfunction with advancing age and greatly magnified intracortical femoral porosity associated with increased production of receptor activator of nuclear factor-κB ligand and vascular endothelial growth factor. Increasing bone mass by artificial prolongation of the inherent lifespan of short-lived osteoblasts, while exaggerating the adverse effects of aging on long-lived osteocytes, highlights the seminal role of cell age in bone homeostasis. In addition, our findings suggest that distress signals produced by old and/or dysfunctional osteocytes are the culprits of the increased intracortical porosity in old age.
apoptosis; osteoblasts; osteocytes; bone formation; aging; cortical porosity; RANKL
Apoptotic death of osteocytes was recognized over 15 years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed. This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines. The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength.
osteocytes; apoptosis; RANKL; bone remodeling; mechanical force; ovariectomy; glucocorticoid excess
We examined community-associated methicillin-resistant Staphylococcus aureus extranasal colonization among newly admitted human immunodeficiency virus (HIV)–infected and HIV-negative inpatients. HIV-infected patients had higher colonization burden and more often carried the USA300 strain type. In certain populations, enhanced outpatient community and healthcare-based infection control strategies may be needed.
Background. The epidemic of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has had a disproportionate impact on patients with human immunodeficiency virus (HIV).
Methods. We evaluated CA-MRSA colonization burden (number of colonized sites per total number sampled) among HIV-infected and HIV-negative inpatients within 72 hours of hospitalization. From March 2011 through April 2012, we obtained cultures from nasal and extranasal sites (throat, axilla, inguinal, perirectal, and chronic wound if present) and collected risk factor data.
Results. Of 745 patients (374 HIV-infected, 371 HIV-negative), 15.7% were colonized with CA-MRSA at any site: 20% of HIV and 11% of HIV-negative patients (relative prevalence = 1.8, P = .002). HIV-infected patients had a higher prevalence of nasal, extranasal, and exclusive extranasal colonization as well as higher colonization burden. Perirectal and inguinal areas were the extranasal sites most frequently colonized, and 38.5% of colonized patients had exclusive extranasal colonization. Seventy-three percent of isolates were identified as USA300. Among HIV-infected patients, male sex, younger age, and recent incarceration were positively associated whereas Hispanic ethnicity was negatively associated with higher colonization burden. Among HIV-negative patients, temporary housing (homeless, shelter, or substance abuse center) was the only factor associated with higher colonization burden. Predictors of USA300 included HIV, younger age, illicit drug use, and male sex; all but 1 colonized individual with current or recent incarceration carried USA300.
Conclusions. HIV-infected patients were more likely to have a higher CA-MRSA colonization burden and carry USA300. In certain populations, enhanced community and outpatient-based infection control strategies may be needed to prevent CA-MRSA cross-transmission and infection.
CA-MRSA; HIV; extranasal colonization
Glucocorticoid administration is the most common cause of secondary osteoporosis and the leading cause of nontraumatic osteonecrosis. In patients receiving long-term therapy, glucocorticoids induce fractures in 30 to 50% and osteonecrosis in 9 to 40%. This article reviews glucocorticoid-induced osteoporosis and osteonecrosis addressing the risk factors, pathogenesis, evaluation, treatment, and uncertainties in the clinical management of these disorders.
glucocorticoid-induced apoptosis; bone strength; osteoblasts; osteocytes; osteoclasts; bone vascularity; bisphosphonates; teriparatide; denosumab; glucocorticoid-associated litigation
Awareness of the need for prevention of glucocorticoid- induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid- induced osteonecrosis develops in 9–40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte–lacunar–canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.
Glucocorticoids; Osteonecrosis; Avascular necrosis; Apoptosis; Osteoblasts; Osteocytes; Bisphosphonates
Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis.
We examined the epidemiology of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) nasal colonization among human immunodeficiency virus (HIV)–infected and HIV-negative outpatients. We identified at-risk outpatients with high levels of CA-MRSA colonization. In certain populations, community exposures may be more important for predicting CA-MRSA colonization than HIV status.
Background. We examined the epidemiology of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) nasal colonization among 3 groups of human immunodeficiency virus (HIV)–infected and 1 group of HIV-negative outpatients.
Methods. We determined prevalence and risk factors associated with MRSA colonization among women, recently incarcerated, and Hispanic HIV-infected patients and HIV-negative patients; isolates were typed by pulsed-field gel electrophoresis. Relative prevalence was calculated using Poisson regression, and logistic regression was used for multivariate analysis.
Results. Of 601 patients, 9.3% were colonized with MRSA; 11% of HIV-infected and 4.2% of HIV-negative patients were colonized (relative prevalence, 2.6; 95% confidence interval [CI], 1.12–6.07; P = .03). Among HIV-infected patients, recently incarcerated patients had the highest colonization prevalence (15.6%) followed by women (12%); Hispanic patients had the lowest (2.8%). Eighty percent of confirmed MRSA isolates were identified as USA300.
On multivariate analysis, history of incarceration or residence in alternative housing (odds ratio [OR], 2.3; 95% CI, 1.1–4.7; P = .03) was associated with MRSA colonization; Hispanic ethnicity was negatively associated (OR, 0.3; 95% CI, .11–.98; P = .045). There was a trend (OR, 1.6; 95% CI, .9–3.0; P = .097) toward geographic location of residence being associated with colonization. After controlling for incarceration, residence, and geography, HIV status was no longer significantly associated with colonization.
Conclusions. The CA-MRSA and HIV epidemics have intersected. Examination of networks of individuals released from incarceration, both HIV positive and negative, is needed to assess the role of social networks in spread of CA-MRSA and inform prevention strategies.
Previous work has shown that daily skin cleansing with chlorhexidine gluconate (CHG) is effective in preventing infection in the medical intensive care unit (MICU).
A colorimetric, semi-quantitative indicator was used to measure CHG concentration on skin (neck, antecubital fossae, inguinal areas) of patients bathed daily with CHG during MICU stay and after discharge from MICU, when CHG bathing stopped. Skin sites were also cultured quantitatively. The relationship between CHG concentration and microbial density on skin was explored in a mixed effects model using gram-positive colony forming unit (CFU) counts.
For 20 MICU patients studied (240 measurements), lowest CHG concentrations (0–18.75μg/mL) and highest gram-positive CFUs were on the neck (median 1.07log10CFU, p=0.014). CHG concentration increased post-bath and decreased over 24h(p<0.001). In parallel, median log10CFUs decreased pre- to post-bath (0.78 to 0) and then increased over 24h to baseline of 0.78 (p=0.001). A CHG concentration >18.75μg/mL was associated with decreased gram-positive CFU(p=0.004). In all but 2 instances, CHG was detected on patient skin during entire inter-bath (~24h) period (18/20(90%) patients). In 11 patients studied after MICU discharge (80 measurements), CHG skin concentrations fell below effective levels after 1–3 days.
In MICU patients bathed daily with CHG, CHG concentration was inversely associated with microbial density on skin; residual antimicrobial activity on skin persisted up to 24h. Determination of CHG concentration on patients’ skin may be useful in monitoring adequacy of skin cleansing by healthcare workers.
The detection of estrogen receptor-α (ERα) in osteoblasts and osteoclasts over 20 years ago suggested that direct effects of estrogens on both of these cell types are responsible for their beneficial effects on the skeleton, but the role of ERα in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ERα in osteoclasts can only account for the protective effect of estrogens on the cancellous, but not the cortical, bone compartment that represents 80% of the entire skeleton. Here, we deleted ERα at different stages of differentiation in murine osteoblast lineage cells. We found that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues.
Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of NFκB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors. However, RANKL is expressed by a variety of cell types and it is unclear which of them are essential sources for osteoclast formation. Here we have used a conditional mouse RANKL allele and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.
Programs to reduce central line–associated bloodstream infections (CLABSIs) have improved the safety of hospitalized patients. Efforts are underway to disseminate these successes broadly to reduce other types of hospital-acquired infectious and noninfectious preventable harms. Unfortunately, the ability to broadly measure and prevent other types of preventable harms, especially infectious harms, needs enhancement. Moreover, an overarching research framework for creating and integrating evidence will help expedite the development of national prevention programs. This article outlines a 5-phase translational (T) framework to develop robust research programs that reduce preventable harm, as follows: phase T0, discover opportunities and approaches to prevent adverse health care events; phase T1, use T0 discoveries to develop and test interventions on a small scale; phase T2, broaden and strengthen the evidence base for promising interventions to develop evidence-based guidelines; phase T3, translate guidelines into clinical practice; and phase T4, implement and evaluate T3 work on a national and international scale. Policy makers should use this framework to fill in the knowledge gaps, coordinate efforts among federal agencies, and prioritize research funding.
Sustained parathyroid hormone (PTH) elevation stimulates bone remodeling (ie, both resorption and formation). The former results from increased RANKL synthesis, but the cause of the latter has not been established. Current hypotheses include release of osteoblastogenic factors from osteoclasts or from the bone matrix during resorption, modulation of the production and activity of osteoblastogenic factors from cells of the osteoblast lineage, and increased angiogenesis. To dissect the contribution of these mechanisms, 6-month-old Swiss-Webster mice were infused for 5 days with 470 ng/h PTH(1-84) or 525 ng/h soluble RANKL (sRANKL). Both agents increased osteoclasts and osteoblasts in vertebral cancellous bone, but the ratio of osteoblasts to osteoclasts and the increase in bone formation was greater in PTH-treated mice. Cancellous bone mass was maintained in mice receiving PTH but lost in mice receiving sRANKL, indicating that maintenance of balanced remodeling requires osteoblastogenic effects beyond those mediated by osteoclasts. Consistent with this contention, PTH, but not sRANKL, decreased the level of the Wnt antagonist sclerostin and increased the expression of the Wnt target genes Nkd2, Wisp1, and Twist1. Furthermore, PTH, but not sRANKL, increased the number of blood vessels in the bone marrow. Weekly injections of the RANKL antagonist osteoprotegerin at 10 µg/g for 2 weeks prior to PTH infusion eliminated osteoclasts and osteoblasts and prevented the PTH-induced increase in osteoclasts, osteoblasts, and blood vessels. These results indicate that PTH stimulates osteoclast-dependent as well as osteoclast-independent (Wnt signaling) pro-osteoblastogenic pathways, both of which are required for balanced focal bone remodeling in cancellous bone. © 2010 American Society for Bone and Mineral Research.
parathyroid hormone; sRANKL; osteoblasts; osteoclasts; bone remodeling; hyperparathyroidism