Enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia.

Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (Alpl) encoding tissue-nonspecific alkaline phosphatase (TNAP). Alpl(-/-) mice exhibit many characteristics seen in infantile HPP including long bone and tooth defects, vitamin B6 responsive seizures and craniosynostosis. Previous reports demonstrated that a mineral-targeted form of TNAP rescues long bone, vertebral and tooth mineralization defects in Alpl(-/-) mice. Here we report that enzyme replacement with mineral-targeted TNAP (asfotase-alfa) also prevents craniosynostosis (the premature fusion of cranial bones) and additional craniofacial skeletal abnormalities in Alpl(-/-) mice. Craniosynostosis, cranial bone volume and density, and craniofacial shape abnormalities were assessed by microscopy, histology, digital caliper measurements and micro CT. We found that craniofacial shape defects, cranial bone mineralization and craniosynostosis were corrected in Alpl(-/-) mice injected daily subcutaneously starting at birth with recombinant enzyme. Analysis of Alpl(-/-) calvarial cells indicates that TNAP deficiency leads to aberrant osteoblastic gene expression and diminished proliferation. Some but not all of these cellular abnormalities were rescued by treatment with inorganic phosphate. These results confirm an essential role for TNAP in craniofacial skeletal development and demonstrate the efficacy of early postnatal mineral-targeted enzyme replacement for preventing craniofacial abnormalities including craniosynostosis in murine infantile HPP.

Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl(-/-) mouse model of infantile hypophosphatasia.

UNLABELLED: Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. OBJECTIVES: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl(-/-) mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. METHODS: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. RESULTS: Alpl(-/-) mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl(-/-) mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. CONCLUSIONS: These findings demonstrate that Alpl(-/-) mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base.

Measuring meaning and peace with the FACIT-spiritual well-being scale: distinction without a difference?

The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp; Peterman, Fitchett, Brady, Hernandez, & Cella, 2002) has become a widely used measure of spirituality; however, there remain questions about its specific factor structure and the validity of scores from its separate scales. Specifically, it remains unclear whether the Meaning and Peace scales denote distinct factors. The present study addresses previous limitations by examining the extent to which the Meaning and Peace scales relate differentially to a variety of physical and mental health variables across 4 sets of data from adults with a number of chronic health conditions. Although a model with separate but correlated factors fit the data better, discriminant validity analyses indicated limited differences in the pattern of associations each scale showed with a wide array of commonly used health and quality-of-life measures. In total, the results suggest that people may distinguish between the concepts of Meaning and Peace, but the observed relations with health outcomes are primarily due to variance shared between the 2 factors. Additional research is needed to better understand the separate and joint role of Meaning and Peace in the quality of life of people with chronic illness.

Music for patients with hematological malignancies undergoing bone marrow biopsy: a randomized controlled study of anxiety, perceived pain, and patient satisfaction.

OBJECTIVE: To examine the impact of random assignment to music versus usual care on anxiety, perceived pain level and patient satisfaction in patients undergoing bone marrow biopsies. METHOD: Patients were randomized to music or usual care after completing a baseline questionnaire. All patients completed a post-procedure questionnaire. RESULTS: Study participants (N=59) had a mean age of 50.9 years (SD = 13.9; range 22-78). Post-procedure state anxiety (STAI) and pain rating (VAS) were not significantly different between groups (STAI p=0.766; VAS p=0.771). However, patient satisfaction with music was high; 66% of these patients said they very much preferred to listen to music at a future biopsy. CONCLUSIONS: While there were no significant group differences for the music intervention compared to standard of care for anxiety or perceived pain, additional feedback indicated that patients found the music intervention beneficial and requested use of music during future procedures.

Restorative yoga for women with breast cancer: findings from a randomized pilot study.

OBJECTIVES: Restorative yoga (RY) is a gentle type of yoga that may be beneficial for cancer patients and post-treatment survivors. Study goals were: to determine the feasibility of implementing a RY intervention for women with breast cancer; and to examine group differences in self-reported emotional, health-related quality of life, and symptom outcomes. METHODS: Women with breast cancer (n=44; mean age 55.8 years) enrolled in this study; 34% were actively undergoing cancer treatment. Study participants were randomized to the intervention (10 weekly 75-minute RY classes) or a waitlist control group. Participants completed questionnaires at Week 0 (baseline) and Week 10 (immediately post-intervention for the yoga group). RESULTS: Group differences favoring the yoga group were seen for mental health, depression, positive affect, and spirituality (peace/meaning). Significant baseline*group interactions were observed for negative affect and emotional well-being. Women with higher negative affect and lower emotional well-being at baseline derived greater benefit from the yoga intervention compared to those with similar values at baseline in the control group. The yoga group demonstrated a significant within-group improvement in fatigue; no significant difference was noted for the control group. CONCLUSIONS: Although limited by sample size, these pilot data suggest potential benefit of RY on emotional outcomes and fatigue in cancer patients. This study demonstrates that a RY intervention is feasible for women with breast cancer; implications for study design and implementation are noted with an emphasis on program adoption and participant adherence.

Restorative yoga for women with ovarian or breast cancer: findings from a pilot study.

Yoga has demonstrated benefit in healthy individuals and those with various health conditions. There are, however, few systematic studies to support the development of yoga interventions for cancer patients. Restorative yoga (RY) is a gentle type of yoga that has been described as "active relaxation." The specific aims of this pilot study were to determine the feasibility of implementing an RY intervention as a supportive therapy for women diagnosed with ovarian or breast cancer and to measure changes in self-reported fatigue, psychological distress and well-being, and quality of life. Fifty-one women with ovarian (n = 37) or breast cancer (n = 14) with a mean age of 58.9 years enrolled in this study; the majority (61%) were actively undergoing cancer treatment at the time of enrollment. All study participants participated in 10 weekly 75-minute RY classes that combined physical postures, breathing, and deep relaxation. Study participants completed questionnaires at baseline, immediately postintervention, and 2 months postintervention. Significant improvements were seen for depression, negative affect, state anxiety, mental health, and overall quality of life. Fatigue decreased between baseline and postintervention follow-up. Health-related quality of life improved between baseline and the 2-month follow-up. Qualitative feedback from participants was predominantly positive; relaxation and shared group experience were two common themes.