Regulation and enzymatic basis of bone resorption by human osteoclasts

Although much has been learned recently of the mechanisms that regulate osteoclastic differentiation, much less is known of the means through which their resorptive activity is controlled. This is especially so for human osteoclasts. We have recently developed an assay that allows us to measure resorptive activity while minimizing confounding effects on differentiation by optimizing osteoclastogenesis, so that measurable resorption occurs over a short period, and by relating resorption in each culture during the test period to the resorption that had occurred in the same culture in a prior control period. In the present study, we found that RANKL (receptor activator of nuclear factor kappaB ligand) strongly stimulated the release of CTX-I (C-terminal telopeptide degradation product of type I collagen) by osteoclasts over a similar range to that over which it induces osteoclastic differentiation, consistent with a distinct action on osteoclastic function. CT (calcitonin) dose-dependently inhibited bone resorption, whereas PTH (parathyroid hormone), IL (interleukin)-1, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-8, VEGF (vascular endothelial growth factor), MCP-1 (monocyte chemoattractant protein-1), MIP-1gamma (macrophage inflammatory protein-1gamma), IFN (interferon)-gamma and dibutyryl cGMP had no significant effect. Ca(2+), cyclosporin A, IFN-beta and dibutyryl cAMP all strongly suppressed resorption. Bone resorption was also strongly suppressed by alendronate, the cysteine protease inhibitor E64 and the cathepsin K inhibitor MV061194. Inhibitors of MMPs (matrix metalloproteinases) had no effect on CTX-I release. Moreover, the release of the MMP-derived collagen fragment ICTP (C-terminal cross-linked telopeptide of type I collagen) represented less that 0.01% of the quantity of CTX-I released in our cultures. This suggests that MMPs make, at most, a very small contribution to the bone-resorptive activity of osteoclasts.     

An abnormal urinary excretion of glycine betaine may persist for years

OBJECTIVES: Does abnormal betaine excretion persist? DESIGN AND METHODS: Patients (10) with abnormal excretion in 1998 were recalled in 2005. Subsequent urine samples were collected on 4 days from persistently abnormal subjects. RESULTS: Half the 1998 abnormal patients were abnormal in 2005. Only 1/20 controls was abnormal (p=0.015). All patients with abnormal excretion in 1998 and 2005 had abnormal excretion on successive days while no controls did. CONCLUSIONS: High betaine excretion may be chronic and a health risk.     

Tailored use of belatacept in adolescent kidney transplantation

Adolescent transplant recipients are at risk for nonadherence, development of de novo donor‐specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor‐based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid‐free belatacept and sirolimus for two patients. One patient was initially maintained steroid‐free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy‐proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m² at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid‐responsive acute cellular rejection. Belatacept‐based regimens can be tailored for adolescent recipients with good short‐term clinical outcomes.     

Identifying wound prevalence using the Mobile Wound Care program

Measuring the prevalence of wounds within health care systems is a challenging and complex undertaking. This is often compounded by the clinicians' training, the availability of the required data to collect, incomplete documentation and lack of reporting of this type of data across the various health care settings. To date, there is little published data on wound prevalence across regions or states. This study aims to identify the number and types of wounds treated in the Gippsland area using the Mobile Wound Care (MWC?) program. The MWC program has enabled clinicians in Gippsland to collect data on wounds managed by district nurses from four health services. The main outcomes measured were patient characteristics, wound characteristics and treatment characteristics of wounds in Gippsland. These data create several clinical and research opportunities. The identification of predominant wound aetiologies in Gippsland provides a basis on which to determine a regional wound prospective and the impact of the regional epidemiology. Training that incorporates best practice guidelines can be tailored to the most prevalent wound types. Clinical pathways that encompass the Australian and New Zealand clinical practice guidelines for the management of venous leg ulcers can be introduced and the clinical and economical outcomes can be quantitatively measured. The MWC allows healing times (days) to be benchmarked both regionally and against established literature, for example, venous leg ulcers.     

Appraisal of guidelines developed by the World Health Organization

Objective

To appraise the quality of guidelines developed by the World Health Organization (WHO) that were approved by its Guidelines Review Committee (GRC) and identify strengths and weaknesses in the guideline development process.

Study design

Cross-sectional.

Methods

Three individuals independently assessed GRC-approved WHO guidelines using the Appraisal of Guidelines for Research and Evaluation II instrument (AGREE II). Scores were standardized across domains and overall quality was determined through consensus.

Results

124 guidelines met inclusion criteria and were assessed. 58 guidelines were recommended for use, 58 were recommended with modifications and eight were not recommended. The highest scoring domains across guidelines were scope and purpose, and clarity of presentation. The recommended guidelines had higher rigor of development and applicability domain scores in comparison to other guidelines. 77% of the guidelines referenced an underlying evidence review and 49% used GRADE to assess the body of evidence or the strength of the recommendation. The domains in need of improvement included stakeholder engagement, editorial independence, and applicability. Guidelines not recommended for use were generally insufficient in their rigor of development.

Conclusions

WHO guidelines need further improvement, most importantly in the rigor of their development (i.e., use of evidence reviews). Other areas for improvement include increased stakeholder engagement, a more explicit process for recommendation formulation and disclosure of interests, discussion of the facilitators, barriers, resource implications, and criteria for monitoring the outcomes of guideline implementation. WHO guidelines can improve through increased transparency, adherence to the WHO Handbook for Guideline Development, and better oversight by the GRC.