Temporal mechanically-induced signaling events in bone and dorsal root ganglion neurons after in vivo bone loading

Mechanical signals play an integral role in the regulation of bone mass and functional adaptation to bone loading. The osteocyte has long been considered the principle mechanosensory cell type in bone, although recent evidence suggests the sensory nervous system may play a role in mechanosensing. The specific signaling pathways responsible for functional adaptation of the skeleton through modeling and remodeling are not clearly defined. In vitro studies suggest involvement of intracellular signaling through mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR). However, anabolic signaling responses to bone loading using a whole animal in vivo model have not been studied in detail. Therefore, we examined mechanically-induced signaling events at five time points from 0 to 24 hours after loading using the rat in vivo ulna end-loading model. Western blot analysis of bone for MAPK's, PI3K/Akt, and mTOR signaling, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to estimate gene expression of calcitonin gene-related protein alpha (CGRP-α), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), c-jun, and c-fos in dorsal root ganglion (DRG) of the brachial intumescence were performed. There was a significant increase in signaling through MAPK's including extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) in loaded limbs at 15 minutes after mechanical loading. Ulna loading did not significantly influence expression of the genes of interest in DRG neurons. Bone signaling and DRG gene expression from the loaded and contralateral limbs was correlated (SR>0.40, P<0.05). However, bone signaling did not correlate with expression of the genes of interest in DRG neurons. These results suggest that signaling through the MAPK pathway may be involved in load-induced bone formation in vivo. Further characterization of the molecular events involved in regulation of bone adaptation is needed to understand the timing and impact of loading events, and the contribution of the neuronal signaling to functional adaptation of bone

Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial

<p>Abstract</p> <p>Background</p> <p>We compared the healing response of tibial delayed unions between subjects treated with low-intensity pulsed ultrasound (LIPUS) (n = 51) and subjects treated with a sham device (n = 50). Fracture age was ≥ 4 months in all cases. Study personnel and participants were blinded to random treatment assignment throughout the study.</p> <p>Methods</p> <p>This multi-center randomized sham-controlled trial was undertaken at six hospitals in Germany. Adult patients who had sustained a tibial shaft fracture that subsequently showed inadequate progress toward healing (i.e., delayed union) were enrolled and randomized to receive either LIPUS (Exogen 2000/2000+, Smith & Nephew GmbH, Schenefeld, Germany) or an identical nonoperative sham device. The daily treatment duration was 20 minutes, for a period of 16 weeks. Subjects randomly assigned to active treatment had the ultrasound pressure wave signal set at the following parameters: 1.5 MHz frequency, 1 kHz repetition rate, 200 μs pulse duration, 30 mW/cm²spatial intensity. Progress toward healing was estimated from changes in bone mineral density (BMD) and gap area as determined from computed tomography scans. Intention-to-treat analysis was conducted using a multiple imputation methodology.</p> <p>Results</p> <p>Based on log-transformed data, mean improvement in BMD was 1.34 (90% confidence interval (CI) 1.14 to 1.57) times greater for LIPUS-treated subjects compared to sham (p = 0.002). A mean reduction in bone gap area also favored LIPUS treatment (p = 0.014).</p> <p>Conclusions</p> <p>These findings demonstrate significantly greater progress toward bone healing after LIPUS treatment compared to no LIPUS treatment in subjects with established delayed unions of the tibia.</p

Characterization of a rat osteotomy model with impaired healing

<p>Abstract</p> <p>Background</p> <p>Delayed union or nonunion are frequent and feared complications in fracture treatment. Animal models of impaired bone healing are rare. Moreover, specific descriptions are limited although understanding of the biological course of pathogenesis of fracture nonunion is essential for therapeutic approaches.</p> <p>Methods</p> <p>A rat tibial osteotomy model with subsequent intramedullary stabilization was performed. The healing progress of the osteotomy model was compared to a previously described closed fracture model. Histological analyses, biomechanical testing and radiological screening were undertaken during the observation period of 84 days (d) to verify the status of the healing process. In this context, particular attention was paid to a comparison of bone slices by histological and immunohistological (IHC) methods at early points in time, <it>i.e</it>. at 5 and 10 d post bone defect.</p> <p>Results</p> <p>In contrast to the closed fracture technique osteotomy led to delayed union or nonunion until 84 d post intervention. The dimensions of whole reactive callus and the amounts of vessels in defined regions of the callus differed significantly between osteotomized and fractured animals at 10 d post surgery. A lower fraction of newly formed bone and cartilaginous tissue was obvious during this period in osteotomized animals and more inflammatory cells were observed in the callus. Newly formed bone tissue accumulated slowly on the anterior tibial side with both techniques. New formation of reparative cartilage was obviously inhibited on the anterior side, the surgical approach side, in osteotomized animals only.</p> <p>Conclusion</p> <p>Tibial osteotomy with intramedullary stabilisation in rats leads to pronounced delayed union and nonunion until 84 d post intervention. The early onset of this delay can already be detected histologically within 10 d post surgery. Moreover, the osteotomy technique is associated with cellular and vascular signs of persistent inflammation within the first 10 d after bone defect and may be a contributory factor to impaired healing. The model would be excellent to test agents to promote fracture healing.</p

Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study

<p>Abstract</p> <p>Aims</p> <p>To investigate the impact of iron intake on the development of type 1 diabetes (T1DM).</p> <p>Methods</p> <p>Case-control study with self-administered questionnaire among families of children with T1DM who were less than 10 years old at the time of the survey and developed diabetes between age 1 and 6 years. Data on the types of infant feeding in the first 4 months of life was collected from parents of children with T1DM (n = 128) and controls (n = 67) <10 years old. Because some cases had sibling controls, we used conditional logistic regression models to analyze the data in two ways. First we performed a case-control analysis of all 128 cases and 67 controls. Next, we performed a case-control analysis restricted to cases (n = 59) that had a sibling without diabetes (n = 59). Total iron intake was modeled as one standard deviation (SD) increase in iron intake. The SD for iron intake was 540 mg in the total sample and 539 mg in the restricted sample as defined above.</p> <p>Results</p> <p>The median (min, max) total iron intake in the first 4 months of life was 1159 (50, 2399) mg in T1DM cases and 466 (50, 1224) mg among controls (<it>P </it>< 0.001). For each one standard deviation increase in iron intake, the odds ratio (95% confidence interval) for type 1 diabetes was 2.01 (1.183, 3.41) among all participants (128 cases and 67 controls) while it was 2.26 (1.27, 4.03) in a restricted sample of T1 D cases with a control sibling (59 cases and 59 controls) in models adjusted for birth weight, age at the time of the survey, and birth order.</p> <p>Conclusion</p> <p>In this pilot study, high iron intake in the first 4 months of infancy is associated with T1DM. Whether iron intake is causal or a marker of another risk factor warrants further investigation.</p

The Impact of Matching Vaccine Strains and Post-SARS Public Health Efforts on Reducing Influenza-Associated Mortality among the Elderly

Public health administrators do not have effective models to predict excess influenza-associated mortality and monitor viral changes associated with it. This study evaluated the effect of matching/mismatching vaccine strains, type/subtype pattern changes in Taiwan's influenza viruses, and the impact of post-SARS (severe acute respiratory syndrome) public health efforts on excess influenza-associated mortalities among the elderly. A negative binomial model was developed to estimate Taiwan's monthly influenza-associated mortality among the elderly. We calculated three winter and annual excess influenza-associated mortalities [pneumonia and influenza (P&I), respiratory and circulatory, and all-cause] from the 1999–2000 through the 2006–2007 influenza seasons. Obtaining influenza virus sequences from the months/years in which death from P&I was excessive, we investigated molecular variation in vaccine-mismatched influenza viruses by comparing hemagglutinin 1 (HA1) of the circulating and vaccine strains. We found that the higher the isolation rate of A (H3N2) and vaccine-mismatched influenza viruses, the greater the monthly P&I mortality. However, this significant positive association became negative for higher matching of A (H3N2) and public health efforts with post-SARS effect. Mean excess P&I mortality for winters was significantly higher before 2003 than after that year [mean ± S.D.: 1.44±1.35 vs. 0.35±1.13, p = 0.04]. Further analysis revealed that vaccine-matched circulating influenza A viruses were significantly associated with lower excess P&I mortality during post-SARS winters (i.e., 2005–2007) than during pre-SARS winters [0.03±0.06 vs. 1.57±1.27, p = 0.01]. Stratification of these vaccine-matching and post-SARS effect showed substantial trends toward lower elderly excess P&I mortalities in winters with either mismatching vaccines during the post-SARS period or matching vaccines during the pre-SARS period. Importantly, all three excess mortalities were at their highest in May, 2003, when inter-hospital nosocomial infections were peaking. Furthermore, vaccine-mismatched H3N2 viruses circulating in the years with high excess P&I mortality exhibited both a lower amino acid identity percentage of HA1 between vaccine and circulating strains and a higher numbers of variations at epitope B. Our model can help future decision makers to estimate excess P&I mortality effectively, select and test virus strains for antigenic variation, and evaluate public health strategy effectiveness

Variability in school closure decisions in response to 2009 H1N1: a qualitative systems improvement analysis

<p>Abstract</p> <p>Background</p> <p>School closure was employed as a non-pharmaceutical intervention against pandemic 2009 H1N1, particularly during the first wave. More than 700 schools in the United States were closed. However, closure decisions reflected significant variation in rationales, decision triggers, and authority for closure. This variability presents the opportunity for improved efficiency and decision-making.</p> <p>Methods</p> <p>We identified media reports relating to school closure as a response to 2009 H1N1 by monitoring high-profile sources and searching Lexis-Nexis and Google news alerts, and reviewed reports for key themes. News stories were supplemented by observing conference calls and meetings with health department and school officials, and by discussions with decision-makers and community members.</p> <p>Results</p> <p>There was significant variation in the stated goal of closure decision, including limiting community spread of the virus, protecting particularly vulnerable students, and responding to staff shortages or student absenteeism. Because the goal of closure is relevant to its timing, nature, and duration, unclear rationales for closure can challenge its effectiveness. There was also significant variation in the decision-making authority to close schools in different jurisdictions, which, in some instances, was reflected in open disagreement between school and public health officials. Finally, decision-makers did not appear to expect the level of scientific uncertainty encountered early in the pandemic, and they often expressed significant frustration over changing CDC guidance.</p> <p>Conclusions</p> <p>The use of school closure as a public health response to epidemic disease can be improved by ensuring that officials clarify the goals of closure and tailor closure decisions to those goals. Additionally, authority to close schools should be clarified in advance, and decision-makers should expect to encounter uncertainty disease emergencies unfold and plan accordingly.</p

Cardiovascular and hormonal responses to static handgrip in young and older healthy men

The purpose of this study was to investigate the effect of age on cardiovascular changes and plasma concentrations of adrenomedullin (ADM), catecholamines, endothelin-1 (ET-1) and plasma renin activity (PRA) in healthy men. A total of 15 young (21 ± 0.3 years) and 15 older (64 ± 0.7 years) healthy men performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. During exercise heart rate (HR), blood pressure (BP), stroke volume (SV) and pre-ejection period (PEP) and left ventricle ejection time (LVET) were measured. Blood samples were taken before exercise, at the end of both exercise bouts and in the fifth minute of the recovery period. The handgrip-induced increases in HR and cardiac output were significantly smaller in older than in young men (p < 0.01). SV decreased only in older men (p < 0.001). There were no differences between groups in BP increases. The baseline plasma ADM and catecholamines were higher in older man compared to young subjects. Handgrip caused increases in plasma ADM, ET-1 and PRA only in older men (p < 0.05). The increases in plasma ADM correlated positively with those of noradrenaline (NA), PRA, ET-1 and LVET and negatively with changes in total peripheral resistance (TPR), SV, PEP and PEP/LVET ratio. The increases in plasma ET-1 correlated positively with those of NA, PRA, TPR, mean BP and SV. These results revealed that ADM, ET-1 and angiotensin II can contribute to maintain vascular tone during static exercise in older but not in younger men

Governing through choice: Food labels and the confluence of food industry and public health discourse to create ‘healthy consumers’

Food industry and public health representatives are often in conflict, particularly over food labelling policies and regulation. Food corporations are suspicious of regulated labels and perceive them as a threat to free market enterprise, opting instead for voluntary labels. Public health and consumer groups, in contrast, argue that regulated and easy-to-read labels are essential for consumers to exercise autonomy and make healthy choices in the face of food industry marketing. Although public health and food industry have distinct interests and objectives, I argue that both contribute to the creation of the food label as a governmental strategy that depends on free-market logics to secure individual and population health. While criticism of ‘Big Food’ has become a growth industry in academic publishing and research, wider critique is needed that also includes the activities of public health. Such a critique needs to address the normalizing effect of neoliberal governmentality within which both the food industry and public health operate to reinforce individuals as ‘healthy consumers’. Drawing on Michel Foucault’s lectures at the Collège de France, I examine the food label through the lens of governmentality. I argue that the rationale operating through the food label combines nutrition science and free-market logics to normalize subjects as responsible for their own health and reinforces the idea of consumption as a means to secure population health from diet-related chronic diseases