Expression of measles virus nucleocapsid protein in osteoclasts induces Paget's disease-like bone lesions in mice.

We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. INTRODUCTION: Paget's disease (PD) of bone is the second most common bone disease. Both genetic and viral factors have been implicated in its pathogenesis, but their exact roles in vivo are unclear. We previously reported that transfection of normal human osteoclast (OCL) precursors with the measles virus nucleocapsid (MVNP) or measles virus (MV) infection of bone marrow cells from transgenic mice expressing a MV receptor results in formation of pagetic-like OCLs. MATERIALS AND METHODS: Based on these in vitro studies, we determined if the MVNP gene from either an Edmonston-related strain of MV or a MVNP gene sequence derived from a patient with PD (P-MVNP), when targeted to cells in the OCL lineage of transgenic mice with the TRACP promoter (TRACP/MVNP mice), induced changes in bone similar to those found in PD. RESULTS: Bone marrow culture studies and histomorphometric analysis of bones from these mice showed that their OCLs displayed many of the features of pagetic OCLs and that they developed bone lesions that were similar to those in patients with PD. Furthermore, IL-6 seemed to be required for the development of the pagetic phenotype in OCLs from TRACP/MVNP mice. CONCLUSIONS: These results show that persistent expression of the MVNP gene in cells of the OCL lineage can induce pagetic-like bone lesions in vivo.     

The Role of Exercise in Cardiac Rehabilitation: A Nursing Perspective

A crucial component of cardiac rehabilitation programs is exercise therapy. The purpose of this paper is to describe the benefits of exercise and the role of nursing within these programs. Rehabilitation programs must be individualized by identifying different patient populations and appropriate nursing diagnoses. Thereby, benefits of the program are maximized in order to improve the individual's quality of life.     

Sex differences in the risk of stroke and HbA1c among diabetic patients

Aims/hypothesis

Sex differences in macrovascular disease, especially in stroke, are observed across studies of epidemiology. We studied a large sample of patients with type 2 diabetes to better understand the relationship between glycaemic control and stroke risk.

Methods

We prospectively investigated the sex-specific association between different levels of HbA_1c and incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes.

Results

During a mean follow-up of 6.7 years, 2,949 incident cases of stroke were identified. The multivariable-adjusted HRs of stroke associated with different levels of HbA_1c at baseline (HbA_1c <6.0% [<42 mmol/mol], 6.0–6.9% [42–52 mmol/mol] [reference group], 7.0–7.9% [53–63 mmol/mol], 8.0–8.9% [64–74 mmol/mol], 9.0–9.9% [75–85 mmol/mol] and ≥10.0% [≥86 mmol/mol]) were 0.96 (95% CI 0.80, 1.14), 1.00, 1.04 (0.85, 1.28), 1.11 (0.89, 1.39), 1.10 (0.86, 1.41) and 1.22 (0.92, 1.35) (p for trend?=?0.66) for men, and 1.03 (0.90, 1.18), 1.00, 1.09 (0.94, 1.26), 1.19 (1.00, 1.42), 1.32 (1.09, 1.59) and 1.42 (1.23, 1.65) (p for trend <0.001) for women, respectively. The graded association between HbA_1c during follow-up and stroke risk was observed among women (p for trend?=?0.066). When stratified by race, whether with or without glucose-lowering agents, this graded association of HbA_1c with stroke was still present among women. When stratified by age, the adjusted HRs were significantly higher in women older than 55 years compared with younger women.

Conclusions/interpretation

The current study suggests a graded association between HbA_1c and the risk of stroke among women with type 2 diabetes. Poor control of blood sugar has a stronger effect in diabetic women older than 55 years.     

Increasing prevalence of hypertension in low income residents within Louisiana State University Health Care Services Division Hospital System

BackgroundHypertension risk in local areas may vary from national estimates; however, the data on the prevalence of hypertension in some local areas are limited. We investigate the trend in the prevalence of hypertension in Louisiana from 2000 to 2009.MethodsWe conducted a retrospective study among the subjects aged ≥ 20 years who received medical care from the Louisiana State University Health Care Services Division (LSUHCSD) hospital system during 2000–2009. Hypertensive cases were identified by using ICD-9 codes. The annual hypertension prevalence was calculated as the number of unique hypertensive individuals during the year divided by the number of unique individuals visiting the LSUHCSD hospital during the year.ResultsThe age-standardized prevalence of hypertension in LSUHCSD hospital patients aged ≥ 20 years increased by 49.4% during 2000–2009, from 24.1% in 2000 to 36.0% in 2009. The rise in age-standardized prevalence of hypertension from 2000 to 2009 occurred in both men (from 20.1% to 32.8%) and women (from 26.8 % to 38.3%), and in White (from 20.1% to 33.0%), African (from 27.4% to 37.6%) and other race Americans (from 14.9% to 22.3%). The age-standardized prevalence of hypertension was higher in women than in men, and higher in African Americans than in White and other race Americans.ConclusionThe annual prevalence of hypertension has dramatically increased from 2000 to 2009 in both men and women and in all races of the population served by the LSUHCSD hospitals.     

Gendered Members of Alcoholics Anonymous: Varieties of Spiritual Experiences in Recovery

Women and men share similar as well as different strategies in developing their spirituality as part of their overall 12-Step experience. Special attention is paid to gender differences to account for a variety of spiritual experiences in recovery. The language and use of metaphors as women and men work the 12 Steps in achieving a “spiritual awakening” is explored, recognizing the predominantly male ethos of Alcoholics Anonymous since its inception. The influence of age in expressions of spirituality, distinguishing between young adults, middle-age adults, and older adults, is referenced. Need for further understanding of gender differences, with a focus on the spiritual dimensions of recovery, is recommended.     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.     

Increased IL‐6 Expression in Osteoclasts Is Necessary But Not Sufficient for the Development of Paget's Disease of Bone

Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin‐6 (IL‐6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL‐6^–/– mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF‐κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25‐dihydroxyvitamin D₃ (1,25‐(OH)₂D₃), nor produce elevated levels of IL‐6. We previously generated p62^P394L knock‐in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL‐6 in PD and determine if MVNP mediates its effects primarily through elevation of IL‐6, we generated transgenic mice that overexpress IL‐6 driven by the tartrate‐resistant acid phosphatase (TRAP) promoter (TIL‐6 mice) and produce IL‐6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL‐6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL‐6 mice formed greater numbers of OCLs than either p62KI or TIL‐6 OCL precursors in response to 1,25‐(OH)₂D₃. Histomorphometric analysis of bones from p62KI/TIL‐6 mice revealed increased OCL numbers per bone surface area compared to wild‐type (WT) mice. However, micro‐quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL‐6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL‐6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25‐(OH)₂D₃ and increased OCL numbers, but is not sufficient to induce Paget's‐like OCLs or bone lesions in vivo. © 2014 American Society for Bone and Mineral Research.