Abstract Both bone density and quality are important determinants of bone strength. Bone quality is prescribed by matrix characteristic including collagen cross-linking and bone structural ...characteristics and is important in reinforcement of bone strength. We investigated the effects of alfacalcidol (ALF), a prodrug of calcitriol, and alendronate (ALN), a bisphosphanate, on the mechanical properties and content of enzymatic cross-links in femoral bone using a fracture repair rat model. Forty 3-month-old female Wistar–Imamichi rats were randomized into 4 groups: SHAM (sham-operated+vehicle), OVX (ovariectomy+vehicle), ALF (ovariectomy+ALF, 0.1 μg/kg/d, p.o.) and ALN (ovariectomy+ALN, 10 μg/kg/d, s.c.). Treatment began immediately after SHAM or OVX surgery. Three weeks later, all animals underwent transverse osteotomies at the midshaft of the left femur. Treatment was continued and rats were sacrificed at 12 weeks post-fracture for evaluation by X-ray radiography, micro-CT, pQCT, biomechanical testing and bone histomorphometry. In the ALN group, no new cortical shell appeared and the callus diameter was significantly larger than in the OVX group ( p < 0.05). Stiffness of fractured callus in the ALF group, but not in the ALN group, was significantly higher than in the OVX group. Young's modulus in the ALN group was significantly decreased compared to the OVX group. Moreover, micro-CT analysis showed that ALN treatment increased the lowly mineralized bone in the callus by, resulting in the highest content of woven bone area and lowest content of lamellar bone. The total amount of enzymatic cross-links in both the ALF and ALN groups was significantly higher than in the OVX control group. Of particular interest, the Pyr-to-Dpyr ratio was significantly decreased by ALF administration, suggesting that ALF but not ALN normalized the enzymatic cross-link patterns in fractured bone to the control level. In conclusion, ALN and ALF treatment increased bone strength via the distinctive effect on bone mass and quality. ALN formed larger calluses and increased enzymatic cross-links despite delayed woven bone remodeling into lamellar bone, whereas ALF treatment induced lamellar bone formation coincided with increasing in the enzymatic cross-linking and normalizing the cross-link pattern in callus to native bone pattern.
Background and Objectives: Naldemedine is a peripherally acting μ-opioid receptor antagonist that improves opioid-induced constipation. Although clinical trials have excluded patients with poor ...performance status (PS) and those started on naldemedine early after opioid initiation, clinical practice has used naldemedine for the same patients. Therefore, we investigated the treatment patterns of naldemedine in a real-world setting. Materials and Methods: This was a multicenter, retrospective chart review study of opioid-treated patients with cancer receiving naldemedine. Adverse events that occurred within 7 days of naldemedine initiation were evaluated in those who received one or more doses of the same. Effectiveness was assessed in patients who used naldemedine for more than 7 days. Results: A total of 296 patients satisfied the eligibility criteria, among whom 129 (43.6%) had a PS of ≥3 and 176 (59.5%) started naldemedine within 2 weeks of opioid initiation. Moreover, 203 (79.6%) patients had ≥3 bowel movements per week. Incidences of all grades of diarrhea and abdominal pain were 87 (29.4%) and 12 (4.1%), respectively. No patient had grade 4 or higher adverse events. Conclusions: Although nearly half of the patients receiving naldemedine in clinical practice belonged to populations that were not included in the clinical trials, our results suggested that naldemedine in clinical practice had the same efficacy and safety as that in clinical trials.
Aim
We speculated that low back pain, which is the most common ailment in older adults, is associated with frailty and/or sarcopenia and contributes to the progression of either condition. Our ...objective was to evaluate the relationship between low back pain, sarcopenia and frailty in rural Japanese community‐dwelling older adults.
Methods
We recruited 730 participants aged ≥65 years who underwent a comprehensive health examination between November 2016 and December 2018. The Oswestry Disability Index (ODI) was used to assess low back pain quantitatively, and scores were compared for the frail groups determined by the Japanese version of Cardiovascular Health Study, and the sarcopenia groups as determined by the Asian Working Group for Sarcopenia 2019.
Results
Among 730 participants, the prevalence of low back pain was 57.8%. There were significant differences in the ODI scores between the robust, prefrail and frail groups (P < 0.001). In contrast, there were no significant differences in the ODI scores among the robust, low appendicular skeletal muscle and sarcopenia groups. Logistic regression analysis showed that the prevalence of low back pain and the ODI scores were significantly associated with frailty after adjustment for age, sex and body mass index (odds ratio 3.41, 95% confidence interval 1.39–8.39, P = 0.008, and odds ratio 1.06, 95% confidence interval 1.04–1.09, P < 0.001, respectively).
Conclusions
To the best of our knowledge, this study is the first to show the close association between low back pain and frailty, and suggests that not only the decline in physical function but also neuropsychiatric factors, including chronic pain, constitute a vicious cycle of frailty in community‐dwelling older adults. Geriatr Gerontol Int 2021; 21: 54–59.
Abstract Two case–control studies were designed to investigate the contribution of the geometry and bone mineral density (BMD) of the proximal femur to bone strength in Japanese elderly women. We ...also investigated whether clinical CT is useful to assess the risk of hip fracture. Subjects in the neck fracture study included 20 Japanese women with neck fracture (age: mean ± SD; 80.1 ± 4.5 years old) and 20 age-matched control women (79.2 ± 2.6 years old). Subjects in the trochanteric fracture study included 16 Japanese women with trochanteric fracture (82.6 ± 5.0 years old) and 16 age-matched control women (80.8 ± 3.8 years old). CT examination of the proximal femur was performed between the date of admission and the date of surgery. The CT scanners used were an Aquillion 16 (Toshiba) and Somatom 64 (Siemens); the scanning conditions including spatial resolution and scanning energy were adjusted, and the same type of reference phantom containing hydroxyapatite was used. QCT PRO software (Mindways) was used to analyze data for BMD, geometry, and biomechanical parameters. Both the neck and trochanteric fracture cases had significantly lower total and cortical BMD, a significantly smaller cortical cross-sectional area (CSA), and a larger trabecular CSA. Both had significantly thinner cortex and smaller distance to center of bone mass, and women with trochanteric fracture had a significantly smaller cortical perimeter in the cross-sectional femoral neck. Women with neck fracture had a longer hip axis length (HAL) and women with trochanteric fracture had a significantly larger neck-shaft angle (NSA). Both groups had significantly lower cross-sectional moment of inertia (CSMI), and only women with neck fracture had a significantly higher buckling ratio (BR) compared to their respective controls. According to the multiple logistic regression analysis, women with neck fracture had a significantly longer HAL, lower CSMI, and higher BR, and women with trochanteric fracture had a significantly smaller cortical CSA of the femoral neck. We conclude that clinical CT may be useful for the assessment of the risk of neck and trochanteric fracture.
Caloric restriction (CR) extends the lifespan of various organisms and slows the onset of age-related disorders; however, little is known about the long-term effects of CR per se on bone. In the ...present study, we have examined the effects of life-long CR vs. ad libitum (AD) feeding, mainly on the trabecular bone of proximal tibiae in male C57BL/6 mice and F344 rats. Micro-computed tomography scanning of tibiae revealed that CR for 3–9 months caused a substantial decrease in three-dimensional bone volume with structural derangements. Bone histomorphometry revealed the reduced bone mass was due mainly to suppression of bone formation. In db/db mice with defective leptin receptor, CR was unable to decrease bone mass and suppress bone formation. The effect of CR on bone mass was inhibited by administration of a β-adrenergic blocker, propranolol. Thus, CR may regulate bone formation through leptin signaling and elevated sympathetic nervous tone. Interestingly, the difference in bone volume between the CR and AD groups disappeared after 1 yr of age, and mice and rats on an additional extension of CR to natural death maintained higher bone mass than the AD groups, with reduced bone turnover, suggesting that CR slows skeletal aging by regulating the rate of bone turnover. This is the first report, to our knowledge, that has examined the effects of lifelong CR on bone metabolism and trabecular microstructure and documents its contrasting effects during maturation vs. the postmaturational, involutional period.
Highlights • Probabilities of preterm EEG envelopes were distributed lognormally at ages of 38 weeks or less. • The probabilities were better described by gamma distribution at the end of the ...neonatal period. • The distribution transitioned from lognormal to gamma as its skewness decreased. • The scale parameter, skewness, and mode were indicators of how the preterm EEG activity matures.
Mutations of Filamin genes, which encode actin-binding proteins, cause a wide range of congenital developmental malformations in humans, mainly skeletal abnormalities. However, the molecular ...mechanisms underlying Filamin functions in skeletal system formation remain elusive. In our screen to identify skeletal development molecules, we found that Cfm (Fam101) genes, Cfm1 (Fam101b) and Cfm2 (Fam101a), are predominantly co-expressed in developing cartilage and intervertebral discs (IVDs). To investigate the functional role of Cfm genes in skeletal development, we generated single knockout mice for Cfm1 and Cfm2, as well as Cfm1/Cfm2 double-knockout (Cfm DKO) mice, by targeted gene disruption. Mice with loss of a single Cfm gene displayed no overt phenotype, whereas Cfm DKO mice showed skeletal malformations including spinal curvatures, vertebral fusions and impairment of bone growth, showing that the phenotypes of Cfm DKO mice resemble those of Filamin B (Flnb)-deficient mice. The number of cartilaginous cells in IVDs is remarkably reduced, and chondrocytes are moderately reduced in Cfm DKO mice. We observed increased apoptosis and decreased proliferation in Cfm DKO cartilaginous cells. In addition to direct interaction between Cfm and Filamin proteins in developing chondrocytes, we showed that Cfm is required for the interaction between Flnb and Smad3, which was reported to regulate Runx2 expression. Furthermore, we found that Cfm DKO primary chondrocytes showed decreased cellular size and fewer actin bundles compared with those of wild-type chondrocytes. These results suggest that Cfms are essential partner molecules of Flnb in regulating differentiation and proliferation of chondryocytes and actin dynamics.
Bcl2 subfamily proteins, including Bcl2 and Bcl-X(L), inhibit apoptosis. As osteoblast apoptosis is in part responsible for osteoporosis in sex steroid deficiency, glucocorticoid excess, and aging, ...bone loss might be inhibited by the upregulation of Bcl2; however, the effects of Bcl2 overexpression on osteoblast differentiation and bone development and maintenance have not been fully investigated. To investigate these issues, we established two lines of osteoblast-specific BCL2 transgenic mice. In BCL2 transgenic mice, bone volume was increased at 6 weeks of age but not at 10 weeks of age compared with wild-type mice. The numbers of osteoblasts and osteocytes increased, but osteoid thickness and the bone formation rate were reduced in BCL2 transgenic mice with high expression at 10 weeks of age. The number of BrdU-positive cells was increased but that of TUNEL-positive cells was unaltered at 2 and 6 weeks of age. Osteoblast differentiation was inhibited, as shown by reduced Col1a1 and osteocalcin expression. Osteoblast differentiation of calvarial cells from BCL2 transgenic mice also fell in vitro. Overexpression of BCL2 in primary osteoblasts had no effect on osteoclastogenesis in co-culture with bone marrow cells. Unexpectedly, overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteocytes, which had a reduced number of processes, gradually died with apoptotic structural alterations and the expression of apoptosis-related molecules, and dead osteocytes accumulated in cortical bone. These findings indicate that overexpression of BCL2 in osteoblasts inhibits osteoblast differentiation, reduces osteocyte processes, and causes osteocyte apoptosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report the occurrence of neuronal cytoplasmic inclusions (NCIs) in the external cuneate nucleus of humans. The NCIs appeared as accumulations of eosinophilic rod‐like structures in the neuronal ...somata in 20 (9.5%) of 211 consecutive autopsy cases. Histochemically, the NCIs were stained bright red with Gomori trichrome, Azan‐Mallory and methyl green‐pyronin, indicating that they contain protein and RNA. Immunohistochemically, the NCIs were positive for stress granule marker proteins, including Hu‐antigen R, eukaryotic translation initiation factor 3 and poly(A)‐binding protein 1, but negative for ubiquitin‐ and autophagy‐related proteins. Ultrastructurally, the NCIs were composed of randomly oriented arrays of parallel fibrillar crystalline material with a well‐defined substructure consisting of longitudinal striations, and were often associated with ribosome‐like granules. These NCIs are morphologically, immunohistochemically and topographically distinct from any other inclusions previously described. Their incidence was found to increase with age. A high incidence was also observed in individuals with noninfectious inflammatory disease. These findings suggest that eosinophilic NCIs in the external cuneate nucleus are novel inclusions and might be formed under stress conditions.
Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has ...recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover.
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