Medical Comorbidities of Dementia: Links to Caregivers’ Emotional Difficulties and Gains

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154268/1/jgs16244_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154268/2/jgs16244.pd

Novel application and validation of in vivo micro‐CT to study bone modelling in 3D

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149362/1/ocr12265.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149362/2/ocr12265_am.pd

Validity of new child-specific thoracic gas volume prediction equations for air-displacement plethysmography

BACKGROUND: To determine the validity of the recently developed child-specific thoracic gas volume (TGV) prediction equations for use in air-displacement plethysmography (ADP) in diverse pediatric populations. METHODS: Three distinct populations were studied: European American and African American children living in Birmingham, Alabama and European children living in Lisbon, Portugal. Each child completed a standard ADP testing protocol, including a measured TGV according to the manufactures software criteria. Measured TGV was compared to the predicted TGV from current adult-based ADP proprietary equations and to the recently developed child-specific TGV equations of Fields et al. Similarly, percent body fat, derived using the TGV prediction equations, was compared to percent body fat derived using measured TGV. RESULTS: Predicted TGV from adult-based equations was significantly different from measured TGV in girls from each of the three ethnic groups (P < 0.05), however child-specific TGV estimates did not significantly differ from measured TGV in any of the ethnic or gender groups. Percent body fat estimates using adult-derived and child-specific TGV estimates did not differ significantly from percent body fat measures using measured TGV in any of the groups. CONCLUSION: The child-specific TGV equations developed by Fields et al. provided a modest improvement over the adult-based TGV equations in an ethnically diverse group of children

Current and emerging treatment of osteoporosis

The goal of treating a patient with recent fragility fracture should not only be to treat the patient in the acute phase but also to prevent further fractures. Interventions to increase bone mass to preventing further fragility fractures can be classified as non-pharmacological and pharmacological. All European and international guidelines base the need for treatment, not on the diagnosis of osteoporosis (based on the T-score), but on the risk of fracture, which is strongly influenced by the presence of a fragility fracture, especially vertebral or femoral fractures. Before treatment, it is important to make a differential diagnosis between primary and secondary osteoporosis because anti-osteoporotic drug treatment would be useless if the primary illness causing osteoporosis is not treated too. Some studies show that anti-osteoporotic drugs are frequently interrupted within 1 month of their prescription; this happens not so much due to the occurrence of adverse events but mostly because patients have not been sufficiently informed about the importance of taking the drug and because are not receiving personalised treatment. All data confirm that, in older people, vitamin D deficiency is highly prevalent and calcium intake is often not adequate. So, osteoporosis guidelines recommend calcium and vitamin D for all patients in association with antiosteoporotic therapy. We have many drugs for the treatment of patients at high risk of fracture, but we should use drugs based on evidence of their efficacy and safety in older-age subgroups, provided by targeted studies or extrapolated data. In this chapter, we describe efficacy, route of administration, adverse events and recent technical remarks of current antiresorptive and anabolic osteoporosis therapies. Furthermore, we describe emerging therapies, such as Abaloparatide and Romosozumab

Bone Degeneration and Recovery after Early and Late Bisphosphonate Treatment of Ovariectomized Wistar Rats Assessed by In Vivo Micro-Computed Tomography

Bisphosphonates are antiresorptive drugs commonly used to treat osteoporosis. It is not clear, however, what the influence of the time point of treatment is. Recently developed in vivo micro-computed tomographic (CT) scanners offer the possibility to study such effects on bone microstructure in rats. The aim of this study was to determine the influence of early and late zoledronic acid treatment on bone in ovariectomized rats, using in vivo micro-CT. Twenty-nine female Wistar rats were divided into the following groups: ovariectomy (OVX, n = 5), OVX and zoledronic acid (ZOL) at week 0 (n = 8), OVX and ZOL at week 8 (n = 7), and sham (n = 9). CT scans were made of the proximal tibia at weeks 0, 2, 4, 8, 12, and 16; and bone structural parameters were determined in the metaphysis. Two fluorescent labels were administered to calculate dynamic histomorphometric parameters. At week 16, all groups were significantly different from each other in bone volume fraction (BV/TV), connectivity density, and trabecular number (Tb.N), except for the early ZOL and control groups which were not significantly different for any structural parameter. After ZOL treatment at week 8, BV/TV, structure model index, Tb.N, and trabecular thickness significantly improved in the late ZOL group. The OVX and ZOL groups showed, respectively, higher and lower bone formation rates than the control group. Early ZOL treatment inhibited all bone microstructural changes seen after OVX. Late ZOL treatment significantly improved bone microstructure, although the structure did not recover to original levels. Early ZOL treatment resulted in a significantly better microstructure than late treatment. However, late treatment was still significantly better than no treatment

Assessment of soy phytoestrogens' effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial

BACKGROUND: Osteoporosis is the gradual declining in bone mass with age, leading to increased bone fragility and fractures. Fractures in hip and spine are known to be the most important complication of the disease which leads in the annual mortality rate of 20% and serious morbidity rate of 50%. Menopause is one of the most common risk factors of osteoporosis. After menopause, sex hormone deficiency is associated with increased remodeling rate and negative bone balance, leading to accelerated bone loss and micro-architectural defects, resulting into increased bone fragility. Compounds with estrogen-like biological activity similar to "Isoflavones" present in plants especially soy, may reduce bone loss in postmenopausal women as they are similar in structure to estrogens. This research, therefore, was carried out to study the effects of Iranian soy protein on biochemical indicators of bone metabolism in osteopenic menopausal women. MATERIALS AND METHODS: This clinical trial of before-after type was carried out on 15 women 45–64 years of age. Subjects were given 35 g soy protein per day for 12 weeks. Blood and urine sampling, anthropometric measurement and 48-h-dietary recalls were carried out at zero, 6 and 12 weeks. Food consumption data were analyzed using Food Proccessor Software. For the study of bone metabolism indicators and changes in anthropometric data as well as dietary intake, and repeated analyses were employed. RESULTS: Comparison of weight, BMI, physical activity, energy intake and other intervening nutrients did not reveal any significant changes during different stages of the study. Soy protein consumption resulted in a significant reduction in the urinary deoxypyridinoline and increasing of total alkaline phosphatase (p < 0.05), although the alterations in osteocalcin, c-telopeptide, IGFBP3 and type I collagen telopeptide were not significant. CONCLUSION: In view of beneficial effect of soy protein on bone metabolism indicators, inclusion of this relatively inexpensive food in the daily diet of menopausal women, will probably delay bone resorption, thereby preventing osteoporosis

Cthrc1 Is a Positive Regulator of Osteoblastic Bone Formation

Bone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream target of bone morphogenetic protein-2 (BMP2) in osteochondroprogenitor-like cells by PCR-based suppression subtractive hybridization followed by differential hybridization, and found that Cthrc1 was expressed in bone tissues in vivo. To investigate the role of Cthrc1 in bone, we generated Cthrc1-null mice and transgenic mice which overexpress Cthrc1 in osteoblasts (Cthrc1 transgenic mice). Microcomputed tomography (micro-CT) and bone histomorphometry analyses showed that Cthrc1-null mice displayed low bone mass as a result of decreased osteoblastic bone formation, whereas Cthrc1 transgenic mice displayed high bone mass by increase in osteoblastic bone formation. Osteoblast number was decreased in Cthrc1-null mice, and increased in Cthrc1 transgenic mice, respectively, while osteoclast number had no change in both mutant mice. In vitro, colony-forming unit (CFU) assays in bone marrow cells harvested from Cthrc1-null mice or Cthrc1 transgenic mice revealed that Cthrc1 stimulated differentiation and mineralization of osteoprogenitor cells. Expression levels of osteoblast specific genes, ALP, Col1a1, and Osteocalcin, in primary osteoblasts were decreased in Cthrc1-null mice and increased in Cthrc1 transgenic mice, respectively. Furthermore, BrdU incorporation assays showed that Cthrc1 accelerated osteoblast proliferation in vitro and in vivo. In addition, overexpression of Cthrc1 in the transgenic mice attenuated ovariectomy-induced bone loss.Our results indicate that Cthrc1 increases bone mass as a positive regulator of osteoblastic bone formation and offers an anabolic approach for the treatment of osteoporosis

Early changes in biochemical markers of bone turnover and their relationship with bone mineral density changes after 24 months of treatment with teriparatide

Summary We report the changes in biochemical markers of bone formation during the first 6 months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6 months of treatment. Introduction The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24 months of teriparatide. Methods We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n = 181 treatment-naïve) who had at least one post-baseline bone marker determination. Teriparatide (20 μg/day) was administered for up to 24 months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6 months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24 months. Results Significant increases in formation markers occurred after 1 month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1 month was lower in previously treated versus treatment-naïve patients, but after 6 months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24 months. Conclusions This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs

Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals

Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design

<p>Abstract</p> <p>Background</p> <p>Empirical scoring functions have proven useful in protein structure modeling. Most such scoring functions depend on protein side chain conformations. However, backbone-only scoring functions do not require computationally intensive structure optimization and so are well suited to protein design, which requires fast score evaluation. Furthermore, scoring functions that account for the distinctive relative position and orientation preferences of residue pairs are expected to be more accurate than those that depend only on the separation distance.</p> <p>Results</p> <p>Residue pair scoring functions for fixed backbone protein design were derived using only backbone geometry. Unlike previous studies that used spherical harmonics to fit 2D angular distributions, Gaussian Mixture Models were used to fit the full 3D (position only) and 6D (position and orientation) distributions of residue pairs. The performance of the 1D (residue separation only), 3D, and 6D scoring functions were compared by their ability to identify correct threading solutions for a non-redundant benchmark set of protein backbone structures. The threading accuracy was found to steadily increase with increasing dimension, with the 6D scoring function achieving the highest accuracy. Furthermore, the 3D and 6D scoring functions were shown to outperform side chain-dependent empirical potentials from three other studies. Next, two computational methods that take advantage of the speed and pairwise form of these new backbone-only scoring functions were investigated. The first is a procedure that exploits available sequence data by averaging scores over threading solutions for homologs. This was evaluated by applying it to the challenging problem of identifying interacting transmembrane alpha-helices and found to further improve prediction accuracy. The second is a protein design method for determining the optimal sequence for a backbone structure by applying Belief Propagation optimization using the 6D scoring functions. The sensitivity of this method to backbone structure perturbations was compared with that of fixed-backbone all-atom modeling by determining the similarities between optimal sequences for two different backbone structures within the same protein family. The results showed that the design method using 6D scoring functions was more robust to small variations in backbone structure than the all-atom design method.</p> <p>Conclusions</p> <p>Backbone-only residue pair scoring functions that account for all six relative degrees of freedom are the most accurate and including the scores of homologs further improves the accuracy in threading applications. The 6D scoring function outperformed several side chain-dependent potentials while avoiding time-consuming and error prone side chain structure prediction. These scoring functions are particularly useful as an initial filter in protein design problems before applying all-atom modeling.</p