Repetitive, negligible force reaching in rats induces pathological overloading of upper extremity bones.

Work-related repetitive motion disorders are costly. Immunohistochemical changes in bones resulting from repetitive reaching and grasping in 17 rats were examined. After 3-6 weeks, numbers of ED1+ macrophages and osteoclasts increased at periosteal surfaces of sites of muscle and interosseous membrane attachment and metaphyses of reach and nonreach forelimbs. These findings indicate pathological overloading leading to inflammation and subsequent bone resorption. INTRODUCTION: Sixty-five percent of all occupational illnesses in U.S. private industry are attributed to musculoskeletal disorders arising from the performance of repeated motion, yet the precise mechanisms of tissue pathophysiology have yet to be determined for work-related musculoskeletal disorders. This study investigates changes in upper extremity bone tissues resulting from performance of a voluntary highly repetitive, negligible force reaching and grasping task in rats. MATERIALS AND METHODS: Seventeen rats reached an average of 8.3 times/minute for 45-mg food pellets for 2 h/day, 3 days/week for up to 12 weeks. Seven rats served as normal or trained controls. Radius, ulna, humerus, and scapula were collected bilaterally as follows: radius and ulna at 0, 3, 4, 5, 6, and 12 weeks and humerus and scapula at 0, 4, and 6 weeks. Bones were examined for ED1-immunoreactive mononuclear cells and osteoclasts. Double-labeling immunohistochemistry was performed for ED1 (monocyte/macrophage lineage cell marker) and TRACP (osteoclast marker) to confirm that ED1+ multinucleated cells were osteoclasts. Differences in the number of ED1+ cells over time were analyzed by ANOVA. RESULTS: Between 3 and 6 weeks of task performance, the number of ED1+ mononuclear cells and osteoclasts increased significantly at the periosteal surfaces of the distal radius and ulna of the reach and nonreach limbs compared with control rats. These cells also increased at periosteal surfaces of humerus and scapula of both forelimbs by 4-6 weeks. These cellular increases were greatest at muscle attachments and metaphyseal regions, but they were also present at some interosseous membrane attachments. The number of ED1+ cells decreased to control levels in radius and ulna by 12 weeks. CONCLUSIONS: Increases in ED1+ mononuclear cells and osteoclasts indicate that highly repetitive, negligible force reaching causes pathological overloading of bone leading to inflammation and osteolysis of periosteal bone tissues.     

Economic Burden of Opioid-Induced Constipation Among Long-Term Opioid Users with Noncancer Pain

Background

Opioid-induced constipation (OIC) can be a debilitating side effect of opioid therapy and may result in increased medical costs. The published data on the economic burden of OIC among long-term opioid users are limited.

Objective

To assess the economic burden of OIC in patients with noncancer pain in a managed care population in the United States.

Methods

This retrospective study used 2007–2011 data from the Truven Health MarketScan Commercial and Medicare databases. The study included adults with ≥12 months of insurance enrollment before and after starting long-term (≥90 days) use of opioids. Patients were excluded if they had cancer or a diagnosis of drug abuse or drug dependence during the study period, or if they had constipation or bowel obstruction within 90 days before starting opioid therapy during the study period. OIC was identified by International Classification of Diseases, Ninth Edition codes for constipation (564.0) or bowel obstruction (560.x) within 12 months of the initiation of an opioid. Patients with OIC were identified in the nonelderly, elderly (age ≥65 years), and long-term care populations. Differences in costs and healthcare resource utilization were calculated using propensity scoring.

Results

A total of 13,808 nonelderly (age, 48.6 ± 10.4 years; female, 50%) and 2958 elderly patients (age, 78.7 ± 8.1 years; female, 70%) met the study inclusion criteria. Of 401 nonelderly and 194 elderly patients with OIC, 85 patients initiated opioid therapy in a long-term care facility (age, 80.7 ± 11.6 years; female, 77%). After matching by key covariates, patients with OIC had significantly more hospital admissions than patients without OIC (nonelderly, 33% vs 22%, respectively; P <.001; elderly, 51% vs 31%, respectively; P <.001) and longer inpatient stays (nonelderly, 3.0 ± 8.4 days vs 1.0 ± 3.0 days, respectively; P <.001; elderly, 5.2 ± 12.2 days vs 2.1 ± 4.0 days, respectively; P <.001). The group with OIC had significantly higher total healthcare costs than the group without OIC in all 3 study cohorts (nonelderly, $23,631 ± $67,209 vs $12,652 ± $19,717, respectively; elderly, $16,923 ± $38,191 vs $11,117 ± $19,525, respectively; long-term care, $16,000 ± $22,897 vs $14,437 ± $25,690, respectively; all P <.05).

Conclusion

To the best of our knowledge, this is the first study to analyze the economic impact of long-term use of opioids among patients with OIC, using real-world data. The findings underscore the significant economic burden associated with long-term opioid use for noncancer pain in a managed care population. Effective therapies for OIC may reduce the associated economic burden and improve quality of life for long-term opioid users.     

Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial)

Drug-eluting stent failures were associated with various clinical factors. However, the clinical impact of stent deployment technique was unknown. This study was designed to evaluate the frequency and impact of suboptimal percutaneous coronary intervention on long-term outcomes of 1,557 patients treated with sirolimus-eluting stents (SESs) in 41 US hospitals. All steps of the interventional procedure were scrutinized by an independent core laboratory to determine the occurrence of geographic miss (GM). GM included longitudinal (LGM; injured or diseased segment not covered by SES) or axial GM (balloon-artery size ratio <0.9 or >1.3) mismatches. Patients with and without GM were stratified (GM vs no-GM group). Patients, investigators, and the independent clinical event adjudication committee were blind to study group assignments. The primary end point was 1-year target-vessel revascularization (TVR) rate. Incidences and predictors of GM and safety outcomes were secondary end points. GM occurred in 943 patients (66.5%): 47.6% had LGM, 35.2% had axial GM, and 16.5% had both. One-year TVR rates were 5.1% in the GM group versus 2.5% in the no-GM group (p=0.025). TVR was 6.1% in the LGM versus 2.6% in the no-LGM subgroups (p=0.001). The association of GM with 1-year TVR was independent of clinical or anatomic factors (hazard ratio 2.0, 95% confidence interval 1.0 to 4.02, p=0.05). There was a 3-fold increase in myocardial infarction rates associated with GM (2.4% vs 0.8%; p=0.04). In conclusion, GM occurred frequently during SES implantation and was associated with increased risk of TVR and myocardial infarction at 1 year. These results emphasized the need for improvement in contemporary percutaneous coronary intervention practices and technologies.     

Mutation in Osteoactivin Decreases Bone Formation in Vivo and Osteoblast Differentiation in Vitro

We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb⁺/SjJ (D2J/Gpnmb⁺)]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb⁺ mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb⁺ osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-β receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-β signaling. These data confirm the anabolic role of OA in postnatal bone formation.Osteoporosis is a growing public health problem, in part because of the increasing numbers of people living beyond the age of 65 years.¹ It is characterized by low bone mass due to increased bone resorption by osteoclasts and decreased bone formation by osteoblasts, with significant deterioration in the bone microarchitecture leading to high bone fragility and increased fracture risk.^1,2 The net effect of osteoporosis is low bone mass.¹ There is an increasing demand for identifying novel bone anabolic factors with potential therapeutic benefits in treating generalized bone loss, such as osteoporosis and/or major skeletal fracture.Osteoactivin is a novel glycoprotein first identified in natural mutant osteopetrotic rats.³ The same protein has been identified and named separately in several other species: as dendritic cell heparan sulfate proteoglycan integrin dependent ligand (DCHIL) in mouse dendritic cells,⁴ as transmembrane glycoprotein NMB (GPNMB) in human melanoma cell lines and melanocytes,⁵ and as hematopoietic growth factor inducible neurokinin (HGFIN) in human tumor cells.⁶ The current recommended name for the protein encoded by Gpnmb in mouse is transmembrane glycoprotein NMB (http://www.ncbi.nlm.nih.gov/protein/Q99P91.2); here, we continue to use osteoactivin (OA) for the protein and Gpnmb for the gene. OA is a type I transmembrane protein that consists of multiple domains, including an extracellular domain, transmembrane domain, and protein sorting signal sequence.⁷ Within the C-terminal domain, OA has an RGD motif, predicting an integrin attachment site.^3,7–9Our research group initially reported on the novel role of OA in osteoblast differentiation and function.^7–10 We demonstrated that OA expression has a temporal pattern during osteoblast differentiation, being highest during matrix maturation and culture mineralization in vitro.^7–11 Using loss-of–function and gain-of–function approaches in osteoblasts, we reported that OA overexpression increases osteoblast differentiation and function and that OA down-regulation decreases nodule formation, alkaline phosphatase (ALP) activity, osteocalcin (OC) production, and matrix mineralization in vitro.⁷ We also reported on the positive role of OA in mesenchymal stem cell (MSCs) differentiation into osteoblasts in vitro.¹² In another study, we showed that recombinant OA protein induces higher osteogenic potential of fetal-derived MSCs, compared with bone marrow–derived MSCs¹³ and its osteogenic effects in the mouse C3H10T1/2 MSC cell line were similar to those of recombinant BMP-2.¹² We also localized OA protein as associated predominately with osteoblasts lining trabecular bones in vivo,¹¹ and showed that local injection of recombinant OA increased bone mass in a rat model.¹⁴ Moreover, in a fracture repair model OA expression increased over time, reaching a maximum 2 weeks after fracture.¹¹ In a parallel study, recombinant OA supported bone regeneration and formation in a rat critical-size calvarial defect model.¹⁵ Others have shown that OA is highly expressed by osteoclasts in vitro, suggesting that it may regulate osteoclast formation and activity.¹⁶There is urgent need for an animal model to fully examine the role of OA in osteogenesis. Interestingly, a natural mutation of the Gpnmb gene has been identified in the DBA/2J (D2J) mouse strain.¹⁷ These mice exhibit high-frequency hearing loss, which begins at the time of weaning and becomes severe by 2 to 3 months of age.^18,19 Aged D2J mice also develop progressive eye abnormalities that closely mimic human hereditary glaucoma. The onset of disease symptoms falls roughly between 3 and 4 months of age, and disease becomes severe by 6 months of age.^5,20 D2J mice are homozygous for a nonsense mutation in the Gpnmb gene sequence that induces an early stop codon, generating a truncated protein sequence of 150 amino acids (aa) instead of the full-length 562-aa OA protein.⁵ The control for the D2J mouse is the wild-type DBA/2J-Gpnmb⁺/SjJ mouse (D2J/Gpnmb⁺), homozygous for the wild-type Gpnmb gene.²¹ These Gpnmb wild-type mice do not develop glaucoma, as D2J mice do, although they exhibit mild iris stromal atrophy.²¹In the present study, we used Gpnmb mutant (D2J) and Gpnmb wild-type (D2J/Gpnmb⁺) mice to gain insight into the role of OA in osteogenesis and in osteoblast differentiation and function. Here, we report that loss-of–function mutation of Gpnmb suppresses bone formation by directly affecting osteoblast proliferation and survival, leading to a decreased number of differentiated osteoblasts with suppressed activity in bone mineralization. Thus, our data point to OA as a novel and positive regulator of postnatal bone formation.     

Association of vitamin D receptor gene polymorphisms with insulin resistance and response to vitamin D

The objectives of the study were to determine associations between single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene and insulin resistance and the effects of these SNPs on changes in insulin sensitivity in response to vitamin D supplementation. The research described here was an extension of the Surya study. Genotyping of the Cdx-2, FokI, BsmI, ApaI, and TaqI SNPs was carried out on 239 South Asian women in New Zealand using polymerase chain reaction-based techniques. Associations of these genotypes and 3' end haplotypes with insulin resistance were determined using multiple regression analysis. Associations between SNP genotypes and responses in insulin sensitivity to vitamin D supplementation (4000 IU vitamin D(3) per day) were also determined for a subset (81) of these women. BsmI BB, ApaI AA, and TaqI tt genotypes were significantly associated with lower insulin resistance compared with BsmI bb, ApaI aa, and TaqI TT, respectively, in the cohort of 239 women. Furthermore, homozygosity of the haplotypes baT and BAt was associated with higher and lower insulin resistance, respectively, compared with no copies of their respective alleles. Of the 81 subjects who were supplemented with vitamin D, women with the FokI Ff genotype showed a significantly greater improvement in insulin sensitivity (increase of 29.4 [2.9, 38.1]) compared with women with the FokI FF genotype (increase of 2.3 [-11.5, 10.1]). This study has highlighted the association of vitamin D responsiveness and insulin resistance with VDR gene polymorphisms. This is the first study to determine associations between all three. Genotyping of the VDR gene may provide a predictive measure for insulin resistance in response to vitamin D intervention.     

Effect of sociodemographic variables on complete denture satisfaction

PURPOSE

The objective of this study was to evaluate the effect of sociodemographic factors on quality of satisfaction towards denture treatment.

MATERIALS AND METHODS

One hundred subjects (filling inclusion criteria) who were wearing a denture for at least two months were enrolled and divided into five groups on the basis of sociodemographic variables (age, gender, literacy level, socio-economic and marital status). Questionnaires consisting of 38 questions (positive and negative attitude towards denture satisfaction) related to patients'' perception of clinical outcome in different domains such as mastication, appearance, speech, comfort, health, denture care and social status were scored by the subjects. Questions reflecting positive attitude were scored as 2, 1, or 0 (yes, uncertain and no, respectively) and reversely for the negative questions. Statistical analysis was done by using Statistical Package for Social Sciences (α = .05).

RESULTS

Level of denture satisfaction was higher in age subgroup belonging to 45 - 65 years of age in relation to comfort, health and denture care. Female and male showed significant priority for denture treatment because of esthetic and function respectively. Level of satisfaction was statistically significant with literacy level. Upper high income group showed significantly higher level of satisfaction only in case of social status. Married group showed significantly higher satisfaction level only with comfort.

CONCLUSION

Patients'' sociodemographic variables were influential factors on denture satisfaction.