Medullary Volume Research Articles

Osteoblastgenic and Osteogenic Effects of KY-273 with CDK8/19 Inhibitory Activity in Bone Marrow Mesenchymal Stem Cells and Female Rats.

Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells). In female rat femur, ovariectomy decreased metaphyseal trabecular bone volume (Tb.BV), mineral content (Tb.BMC), yet had no effect on metaphyseal and diaphyseal cortical bone volume (Ct.BV), mineral content (Ct.BMC) and strength parameters (BSPs). In ovaries-intact and ovariectomized rats, oral administration of KY-273 (10 mg/kg/d) for 6 weeks increased metaphyseal and diaphyseal Ct.BV, Ct.BMC, and BSPs without affecting medullary volume (Med.V), but did not affect Tb.BV and Tb.BMC. In ovariectomized rats, alendronate (3 mg/kg/d) caused marked restoration of Tb.BV, Tb.BMC and structural parameters after ovariectomy, and increased metaphyseal but not diaphyseal Ct.BV, Ct.BMC, and BSPs. In ovaries-intact and ovariectomized rats, by the last week, KY-273 increased bone formation rate/bone surface at the periosteal but not the endocortical side. These findings indicate that KY-273 causes osteogenesis in cortical bone at the periosteal side without reducing Med.V. In conclusion, KY-273 has cortical-bone-selective osteogenic effects by osteoblastogenesis via CDK8/19 inhibition in ovaries-intact and ovariectomized rats, and is an orally active drug candidate for bone diseases such as osteoporosis in monotherapy and combination therapy.

Quantification of enlarged deep medullary vein volumes in Sturge-Weber syndrome.

Enlarged deep medullary veins (EDMVs) in patients with Sturge-Weber syndrome (SWS) may channel venous blood from the surface to the deep vein system in brain regions affected by the leptomeningeal venous malformation. Thus, the quantification of EDMV volume may provide an objective imaging marker for this vascular compensatory process. The present study proposes a novel analytical method to quantify enlarged EDMV volumes in the affected hemisphere of patients with unilateral SWS. Twenty young subjects, including 10 patients with unilateral SWS and 10 healthy siblings (age 14.5±6.7 and 16.0±7.0 years, respectively) underwent 3T brain MRI scanning using susceptibility-weighted imaging (SWI) and volumetric T1-weighted sequences. The proposed image analytic steps segmented EDMVs in white matter regions, defined on the volumetric T1-weighted images, by statistically associating the likelihood of intensity, location, and tubular shape on SWI. The volumes of the segmented EDMVs, calculated in each hemisphere, were compared between affected and unaffected hemispheres. EDMV volumes were also correlated with visually assessed EDMV scores, hemispheric white matter volumes, and cortical surface areas. Parametric tests including Pearson's correlation, unpaired and paired t-tests, were used. A P value <0.05 was considered statistically significant. It was found that EDMVs were identified well in SWS-affected hemispheres while calcified regions were excluded. Mean EDMV volumes in the SWS-affected hemispheres were 10-12-fold greater than in the unaffected or healthy control hemispheres; while white matter volumes and cortical surface areas were lower. EDMV volumes in the SWS-affected hemispheres showed a strong positive correlation with the visual EDMV scores (r=0.88, P=0.001) and an inverse correlation with cortical surface area ratios (r=-0.65, P=0.04) but no correlation with white matter volume ratios. EDMVs were detected in the SWS-affected atrophic hemispheres reliably while avoiding calcified regions. The approach can be used to quantify enlarged deep cerebral veins in the human brain, which may provide a potential marker of cerebral venous remodeling.

SAT644 Gender Affirming Hormone Therapy (GHAT) In Adult Male-to-female Mice Increases Cortical And Trabecular Bone, Resulting In An Increase In Bone Strength

Abstract Disclosure: J.D. Zajac: None. T. Nie: None. V. Venkatesh: None. S. Golub: None. K. Stok: None. R. Desai: None. D.J. Handelsman: None. R.A. Davey: None. There are conflicting reports of the effects of GAHT on bone health and fracture risk in adult transgender women, and the underlying changes are poorly understood. We aimed to determine the effects of GAHT administered during adulthood on bone microarchitecture and strength in a mouse model of male-to-female transition. To model male-to-female transition in adults, C57BL/6 male mice aged 16 weeks that had reached peak bone mass were administered an estradiol-filled silastic implant (∼1.3mg) intraperitoneally for 12 weeks. Controls included vehicle treated intact males and females, n=9-10/group. At study end, serum sex steroids were determined by LCMS/MS, femoral bone microarchitecture by μ-CT, and strength by 3-point bending. Mean serum estradiol was 4.7-fold higher in males treated with estradiol (91.8±10.4 pg/mL) than the peak estradiol levels observed during the proestrus stage of the estrus cycle in adult female mice (19.4±13.5 pg/mL, Handelsman, 2020). Estradiol treatment in males increased the endocortical deposition of bone evidenced by an increase in cortical thickness (mm)(P&amp;lt;0.05) and a decrease in medullary volume (mm3)(P&amp;lt;0.05) compared to male and female controls. Periosteal circumference was not effected by estradiol treatment in males compared to controls. Trabecular bone volume/tissue volume (%) was 4-fold higher in estradiol treated males compared to male controls and 12-fold higher than female controls due to an increase in trabecular number (μm)(P&amp;lt;0.0001). The increase in both cortical and trabecular bone contributed to increased bone strength, as the maximum force (N) the bone could withstand prior to fracture was 2-fold higher in males treated with estradiol compared to both male and female controls (P&amp;lt;0.0001). Measurement of the material properties of the femur showed an increase in ultimate stress (MPa)(P&amp;lt;0.001) and elastic modulus (MPa)(P&amp;lt;0.01) in males following estradiol treatment compared to male controls, indicative of increased rigidity. In this model of adult male-to-female transition, supraphysiological levels of estradiol in male mice increases cortical and trabecular bone mass leading to increased bone strength. The increased rigidity of the femur following estradiol treatment suggests increased bone mineral content. It may be possible therefore, to preserve bone health and prevent fractures in trans women treated with GAHT, however a dose of estradiol that protects the bone without adverse side effects needs to be identified. Presentation: Saturday, June 17, 2023

Osteogenic Effects of KY-054, a Novel Coumarin Derivative on Femur Cortical Bone in Ovariectomized Female Rats.

Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, a 4,6-substituted coumarin derivative, and found that it potently promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity at 0.01-1 µM in mouse-derived mesenchymal stem cells (ST2 cells) and rat bone marrow-derived mesenchymal stem cells (BMSCs). In the ovariectomized (OVX) rats, KY-054 (10 mg/kg/d, 8 weeks) increased plasma bone-type ALP activity, suggesting in vivo promoting effects on osteoblast differentiation and/or activation. In dual-energy X-ray absorption (DEXA) scanning, KY-054 significantly increased the distal and diaphyseal femurs areal bone mineral density (aBMD) that was decreased by ovariectomy, indicating its beneficial effects on bone mineral contents (BMC) and/or bone volume (BV). In micro-computed tomography (micro-CT) scanning, KY-054 had no effect on metaphysis trabecular bone loss and microarchitecture parameters weakened by ovariectomy, but instead increased metaphysis and diaphysis cortical bone volume (Ct.BV) and cortical BMC (Ct.BMC) without reducing medullary volume (Med.V), resulting in increased bone strength parameters. It is concluded that KY-054 preferentially promotes metaphysis and diaphysis cortical bone osteogenesis with little effect on metaphysis trabecular bone resorption, and is a potential orally active osteogenic anti-osteoporosis drug candidate.

The Number and Size of Individual Kidney Medullary Pyramids is Associated with Clinical Characteristics, Kidney Biopsy Findings, and CKD Outcomes among Kidney Donors.

Segmentation of multiple structures in cross-sectional imaging is time-consuming and impractical to perform manually, especially if the end goal is clinical implementation. In this study, we developed, validated, and demonstrated the capability of a deep learning algorithm to segment individual medullary pyramids in a rapid, accurate, and reproducible manner. The results demonstrate that cortex volume, medullary volume, number of pyramids, and mean pyramid volume is associated with patient clinical characteristics and microstructural findings and provide insights into the mechanisms that may lead to CKD. The kidney is a lobulated organ, but little is known regarding the clinical importance of the number and size of individual kidney lobes. After applying a previously validated algorithm to segment the cortex and medulla, a deep-learning algorithm was developed and validated to segment and count individual medullary pyramids on contrast-enhanced computed tomography images of living kidney donors before donation. The association of cortex volume, medullary volume, number of pyramids, and mean pyramid volume with concurrent clinical characteristics (kidney function and CKD risk factors), kidney biopsy morphology (nephron number, glomerular volume, and nephrosclerosis), and short- and long-term GFR <60 or <45 ml/min per 1.73 m 2 was assessed. Among 2876 living kidney donors, 1132 had short-term follow-up at a median of 3.8 months and 638 had long-term follow-up at a median of 10.0 years. Larger cortex volume was associated with younger age, male sex, larger body size, higher GFR, albuminuria, more nephrons, larger glomeruli, less nephrosclerosis, and lower risk of low GFR at follow-up. Larger pyramids were associated with older age, female sex, larger body size, higher GFR, more nephrons, larger glomerular volume, more nephrosclerosis, and higher risk of low GFR at follow-up. More pyramids were associated with younger age, male sex, greater height, no hypertension, higher GFR, lower uric acid, more nephrons, less nephrosclerosis, and a lower risk of low GFR at follow-up. Cortex volume and medullary pyramid volume and count reflect underlying variation in nephron number and nephron size as well as merging of pyramids because of age-related nephrosclerosis, with loss of detectable cortical columns separating pyramids.

Neurodevelopmental Outcomes and Brain Volumetric Analysis of Low-Grade Intraventricular Hemorrhage

Purpose: Extremely preterm infants are prone to brain injury and underdevelopment. Intraventricular hemorrhage (IVH) is the most common cause of brain injury and a significant risk factor for neurodevelopmental delay in preterm infants. Severe IVH is known to have a poor outcome; however, the outcomes of low-grade IVH remain controversial. This study aimed to evaluate neurodevelopmental outcomes and brain segmental volumes of preterm infants with low-grade IVH.Methods: This retrospective cohort study included 109 extremely preterm infants who underwent term equivalent age-magnetic resonance imaging and neurodevelopmental evaluation at a corrected age of 18 to 24 months. We compared infants with and without low-grade IVH.Results: Among the 109 extremely preterm infants, 25 had low-grade IVH and 84 had no IVH. There were no significant differences in the neurodevelopmental outcomes between the low-grade and no IVH groups. In multivariate analysis, low-grade IVH was associated with a smaller medullary volume (adjusted odds ratio, 0.575; 95% confidence interval, 0.346 to 0.957; &lt;i&gt;P&lt;/i&gt;=0.034).Conclusion: We found no significant differences in the neurodevelopmental outcomes of extremely preterm infants at a corrected age of 18 to 24 months between those with low-grade IVH and those without IVH. Low-grade IVH was associated with a smaller medullary volume.

Fabricating Stiffness-Matched Three Dimensional -Printed Metal Implants for Total Wrist Arthroplasty.

Total wrist arthroplasty (TWA) is a motion-sparing treatment for pancarpal arthritis; however, complication rates up to 50% have limited widespread use. Implant micromotion, stress shielding, and periprosthetic osteolysis result in implant failure and revision to arthrodesis. Metal 3-dimensional (3D) printing allows for more accurate matching of surrounding bone biomechanical properties, theoretically reducing periprosthetic osteolysis. Herein, we use computed tomography to characterize the relationship of relative stiffness along the length of the distal radius with patient demographic factors. After institutional review, wrist computed tomography scans at a single institution between 2013 and 2021 were identified. Exclusion criteria were history of radius or carpal trauma or fracture. Collected demographics included age, sex, and comorbidities (including osteoporosis/osteopenia). Scans were analyzed using Materialize Mimics Innovation Suite 24.0 (Leuven, Belgium). Distal radius cortical density (in Hounsfield units) and medullary volume (in cubic millimeters) with relation to distance from the radiocarpal joint were recorded. Average values for each variable were used to 3D-printed distal radius trial components with stiffness matched to bone density by length. Thirty-two patients met inclusion criteria. Distal radius cortical bone density progressively increased proximal to the radiocarpal joint, whereas medullary volume decreased; changes in both plateaued 20 mm proximal to the joint. Distal radius material properties differed by age, sex, and comorbidities. Total wrist arthroplasty implants were fabricated to match these variables as proof of concept. Distal radius material properties vary along the bone length; conventional implants do not account for this variance. This study showed 3D-printed implants can be created to match bone properties along the length of the implant.

Fetal growth restriction followed by very preterm birth is associated with smaller kidneys but preserved kidney function in adolescence

BackgroundPreterm birth and fetal growth restriction (FGR) are associated with structural and functional kidney changes, increasing long-term risk for chronic kidney disease and hypertension. However, recent studies in preterm children are conflicting, indicating structural changes but normal kidney function. This study therefore assessed kidney structure and function in a cohort of adolescents born very preterm with and without verified FGR.MethodsAdolescents born very preterm with FGR and two groups with appropriate birthweight (AGA) were included; one matched for gestational week at birth and one born at term. Cortical and medullary kidney volumes and T1 and T2* mapping values were assessed by magnetic resonance imaging. Biochemical markers of kidney function and renin–angiotensin–aldosterone system (RAAS) activation were analyzed.ResultsSixty-four adolescents were included (13–16 years; 48% girls). Very preterm birth with FGR showed smaller total (66 vs. 75 ml/m2; p = 0.01) and medullary volume (19 vs. 24 ml/m2; p < 0.0001) compared to term AGA. Corticomedullary volume ratio decreased from preterm FGR (2.4) to preterm AGA (2.2) to term AGA (1.9; p = 0.004). There were no differences in T1 or T2* values (all p ≥ 0.34) or in biochemical markers (all p ≥ 0.12) between groups.ConclusionsFGR with abnormal fetal blood flow followed by very preterm birth is associated with smaller total kidney and medullary kidney volumes, but not with markers of kidney dysfunction or RAAS activation in adolescence. Decreased total kidney and medullary volumes may still precede a long-term decrease in kidney function, and potentially be used as a prognostic marker.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Vasculogenic gene therapy: No role for revitalization of structural bone allografts.

Segmental bone defects are often performed with cryopreserved allografts. They provide immediate stability, but risk nonunion, infection and late stress fracture. Improving the rate and extent of bone revitalization may improve results. Angiogenesis from surgically placed arteriovenous (AV) bundles improves bone blood flow and vitality in cryopreserved rat femora, augmented by vasculogenic growth factors. This study tests the same principal in Yucatan mini-pigs with a tibial diaphyseal defect, combining surgical angiogenesis with angiogenic gene therapy within cryopreserved orthotopically-placed allografts. Tibial diaphyseal defects were reconstructed with cryopreserved allografts and rigid internal fixation in 16 mini pigs. Half of the cranial tibial AV bundles placed within the allograft medullary canal were transfected with an adeno-associated virus containing vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) genes (AAV9.VEGF.PDGF). Bone remodeling, angiogenesis, and allograft healing were assessed. During the postoperative survival period 5 of 8 transfected animals developed cutaneous benign vascular lesions at sites remote from the operated hindlimb, causing excessive bleeding. Within the allograft, both medullary (p = 0.013) and cortical (p = 0.009) vascular volumes were higher and vessels more mature than nontransfected allografts. Bone turnover (p = 0.013), bone mineralization (p = 0.018), bone healing (p = 0.008) and graft incorporation (p = 0.006) were all significantly higher in the gene therapy group. In a large animal tibial defect model, gene therapy of implanted AV bundles improved revascularization, remodeling and healing of cryopreserved allografts used for limb reconstruction. However, benign vascular lesions causing excessive bleeding developed in 5 out of 8 pigs transfected with AAV containing genes for VEGF and PDGF. This unforeseen complication makes vasculogenic gene therapy unacceptable for clinical use.

Discrepancy in Mandibular Medullary Cavity on Different Sides: More Hints Towards Understanding Hemifacial Microsomia

The authors attempt to approach hemifacial microsomia with macroscopic techniques and look for a link between clinical manifestations with pathogenesis. In this study, for the first time mandibular medullary cavities as essential parts of the mandible were intravitally measured based on the 3-dimensional models. A total of 153 patients were included. The 3-dimensional models of patients' mandibles were reconstructed and medullary cavity volumes (mm 3 ) were measured. The ratio of medullary cavity volume to mandible volume was calculated to determine the proportion of the marrow in the bone. Statistical significance was found in mandible volumes ( P <0.001) and medullary cavity volumes ( P <0.001) on different sides. Medullary cavity volumes were significantly related to mandible volumes on both sides (both P <0.001). Medullary cavity volumes on the nonaffected and affected side were both in correlation with age but in different degrees ( r =0.214, P =0.008 versus r =0.170, P =0.036). The ratios of medullary cavity volume and the mandible were significantly different ( P <0.001) on 2 sides. The volume ratio on the nonaffected side correlated to age while this correlation did not exist on the affected side ( r =0.195, P =0.016 versus r =0.129, P =0.112). A smaller medullary cavity found on the affected side could lead to a reduced amount of bone marrow cells and consequently reduced osteogenic and hematopoietic potential. This could result in abnormal bone formation on the affected side of mandible. Proportions of marrow in bone on the affected side irrelevant to patients' ages signify a poorer potential of expansion. This may explain a higher reluctancy of growth in affected mandibular sides.

MO061: Mri-Based Segmentation of Kidneys in Participants of the German National Cohort (NAKO/GNC) Study

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) affects around 10% of adults worldwide and an estimated 13–17% in Germany1. Imaging is a novel, promising approach to identify additional markers of kidney function and CKD2. Within a large, population-based cohort study, the German National Cohort study (NAKO/GNC), 30 000 participants underwent a whole-body MRI protocol3. The goal of our project was to develop an automated kidney segmentation workflow and to examine distributions of the segmented kidneys and kidney sub-compartments. METHOD Data from the first 11 207 participants were used to develop a robust image processing pipeline for kidney segmentation and apply it to participants’ abdominal MRI images. After importing 3D gradient echo and 2D haste images into the imaging platform NORA (www.nora-imaging.org), an in-house ‘patchwork’-framework (https://bitbucket.org/reisert/patchwork) based on deep-learning convolutional neural networks was trained on data from 300 persons to automatically segment different kidney compartments (cortex, hilus, medulla and cysts). After an initial training round, the model was improved over four iterations by a loop of prediction, manual correction and retraining. The final model was then applied to the full dataset of 11 207 abdominal MR images, followed by manual quality control prior to statistical analysis. Volumetric parameters for total kidney volume [TKV, defined as cortex + medulla] and compartments were calculated from the segmentations. Values were calculated in absolute units of mL and normalized to body-surface-area (BSA) defined as sqrt(weight in kg*height in cm)/3600. RESULTS TKV and the kidney compartments cortex, medulla and hilus could be segmented robustly with the trained network (Fig. 1A). After exclusion of approximately 10% of images because of insufficient segmentation quality due to initial imaging artifacts or poor image quality, the mean (SD) TKV was 364 (±60) mL for men and 290 (±51) mL for women. This difference was markedly attenuated after normalisation to BSA (Fig. 1B). The right kidney was systematically smaller than the left kidney by approximately 5% (Fig. 1C). There was a strong association between participants’ BSA with TKV (Fig. 1D). The normalized kidney sub-compartment volumes showed different patterns across age, with medullary volume decreasing and hilus increasing (Fig. 2). CONCLUSION The developed framework enables robust segmentation of kidneys in abdominal MRI data from a nonspecific clinical routine protocol of a large cohort study. Basic parameters such as TKV and sub-compartment volumes of the kidney show correlations with participants’ height, weight, sex and age that are consistent with prior knowledge and may enable an estimation of ‘kidney age’. This is an optimal starting point to identify more advanced imaging biomarkers of kidney function and CKD.

Non-contrast-enhanced magnetic resonance imaging can be used to assess renal cortical and medullary volumes-A validation study.

BackgroundMagnetic resonance imaging (MRI) biomarkers can diagnose and prognosticate kidney disease. Renal volume validation studies are however scarce, and measurements are limited by use of contrast agent or advanced post-processing.PurposeTo validate a widely available non-contrast-enhanced MRI method for quantification of renal cortical and medullary volumes in pigs; investigate observer variability of cortical and medullary volumes in humans; and present reference values for renal cortical and medullary volumes in adolescents.Materials and MethodsCortical and medullary volumes were quantified from transaxial in-vivo water-excited MR images in six pigs and 15 healthy adolescents (13–16years). Pig kidneys were excised, and renal cortex and medulla were separately quantified by the water displacement method. Both limits of agreement by the Bland-Altman method and reference ranges are presented as 2.5–97.5 percentiles.ResultsAgreement between MRI and ex-vivo quantification were -7 mL (-10–0 mL) for total parenchyma, -4 mL (-9–3 mL) for cortex, and -2 mL (-7–2 mL) for medulla. Intraobserver variability for pig and human kidneys were <5% for total parenchyma, cortex, and medulla. Interobserver variability for both pig and human kidneys were ≤4% for total parenchyma and cortex, and 6% and 12% for medulla. Reference ranges indexed for body surface area and sex were 54–103 mL/m2 (boys) and 56–103 mL/m2 (girls) for total parenchyma, 39–62 mL/m2 and 36–68 mL/m2 for cortex, and 16–45 mL/m2 and 17–42 mL/m2 for medulla.ConclusionThe proposed widely available non-contrast-enhanced MRI method can quantify cortical and medullary renal volumes and can be directly implemented clinically.

Effect of Age on Bone Structure Parameters in Laying Hens.

Simple SummaryLaying hens supply calcium to their eggshells via a process of dynamic bone formation and resorption called remodeling. As hens age, their bone becomes weak and brittle due to an imbalance in remodeling, resulting in bone disorders. Osteoporosis, characterized by bone mass loss and increased risk of fractures, is a serious problem in the egg industry, affecting both productivity and animal welfare. Nonetheless, the mechanisms of age-related osteoporosis remain unknown. We evaluated differences in bone structure between age groups, using microscopy and 3D imaging. Bone quality was reduced by an increase in porosity, with loss of volume, contributing to age-related osteoporosis.Changes in medullary and cortical bone structure with age remain unclear. Twenty Hy-Line W36 hens, 25 or 52 weeks of age, were euthanized, and both tibiae were collected when an egg was present in the magnum. Serial cross sections of the tibiae were stained with Alcian blue. The bones were scanned using micro-computed tomography. Trabecular width (Tb.Wi) was significantly higher (p < 0.05) in 25-week-old hens, whereas medullary bone tissue volume (TV) was significantly higher (p < 0.01) in 52-week-old hens. 25-week-old hens had significantly higher (p < 0.01) bone volume fraction (BVF = calcified tissue / TV). Moreover, the cortical bone parameters were significantly higher (TV and bone mineral content (BMC) at p < 0.05, and bone volume (BV) and BVF at p < 0.01) in younger hens. Open porosity and total porosity, which indicate less density, were significantly higher (p < 0.01) in older hens. Older hens showed significantly higher (p < 0.01) tibial diaphysis TV than younger hens. Younger hens had significantly higher (p < 0.01) BV, BVF and bone mineral density (BMD) of the tibial diaphysis. These findings reveal that reductions in medullary bone quality might be associated with age-related low estrogen levels and stimulation of osteoclastic bone resorption by parathyroid hormone. Cortical bone quality decreased with enlargement of the Haversian canals and loss of volume, with a longer egg-laying period leading to osteoporosis.

Role of long-term supplementation of 25-hydroxyvitamin D3 on laying hen bone 3-dimensional structural development

Egg-laying hens have a unique bone development pattern due to the medullary bone formation and high bone turnover rate. The role of long-term supplementation of an intermediate form of vitamin D3, 25-hydroxyvitamin D3 (25OHD), on skeletal development of pullets and laying hens is not well established. Exploring its effects on layer bone development will help develop a strategy for preventing laying hen osteoporosis. The purpose of this study was to investigate the role of long-term supplementation of 25OHD in layer diets on bone 3-dimensional structural development. A total of 390 1-day-old Hy-Line W36 pullets were randomly allocated to 3 treatments with 10 replicate cages and 13 birds/cage. Dietary treatments were 1) vitamin D3 at 2,760 IU/kg, 2) vitamin D3 at 5,520 IU/kg, and 3) vitamin D3 at 2,760 IU/kg plus 25OHD at 2,760 IU (69 μg)/kg. The level of 25OHD in the serum was tested throughout the whole experimental period (0–95 wk). Bone growth rate (BGR) was measured at 10 wk using a calcein injection technique. Femurs were scanned using Micro-CT for 3D structural analysis, and the whole-body composition analysis was performed using a dual-energy x-ray absorptiometry method at 17, 60, and 95 wk. Dietary supplementation of 25OHD significantly increased 25OHD level in the serum from 0 to 95 wk. During the rearing period (0–17 wk), 25OHD increased BGR, cortical tissue volume, and bone marrow area at 17 wk, simultaneously. 25OHD created more pores in cortical bone, which resulted in a lower cortical bone mineral density (BMD) but without alerting bone mineral content (BMC). This effect allowed more space for mineral deposition in bones during the later egg-laying period. At 60 wk, the 25OHD group had significantly greater BMD, which led to the highest total BMC, cortical volume, and trabecular bone connectivity. At 95 wk, the birds fed 25OHD had significantly higher cortical bone volume and lower porosity. The 25OHD group also had higher total BMD and medullary bone volume but a lower BMC and volume of trabecular bone than vitamin D3 or double dosage vitamin D3 treatment. This indicated that the bone resorption rate was lower in cortical bone than that in trabecular bone in the late laying period. In conclusion, supplementation with dietary 25OHD could stimulate bone growth and increase bone volume in pullets to provide more space for mineral deposition during the laying period with positive effects on laying hen bone quality.

MRI and pathology correlations in the medulla in sudden unexpected death in epilepsy (SUDEP): a postmortem study.

Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P<0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P<0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P<0.05). Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.

Topical application of Heparanase-1 facilitates bone remodeling during the healing of bone defects in a mouse model.

Although previous studies have suggested a stimulatory role of heparanase in physiological bone turnover, the potential therapeutic role of heparanase in bone healing has not been elucidated. The purpose of this study was to assess the effect of topical application of heparanase-1 on bone healing. Two different dosages of recombinant mouse heparanase-1 and vehicle control were prepared and delivered via an osmotic pump to provide continuous topical infusion of the therapeutic reagent in a mouse bone defect model at the distal femoral metaphysis. The bone healing progress was evaluated by micro-computed tomography and histological examination at 7, 14, and 21 days after the bone defect was created. The peak of trabecular bone generation was achieved earlier than anticipated with the use of heparanase as measured by medullary bone volume fraction and trabecular number observed in micro-computed tomography, while the remodeling of trabecular bone to cortical bone was also achieved earlier than anticipated with the use of heparanase as measured by connectivity density. Histopathological observation revealed a higher frequency of the presence of cartilaginous tissue in the heparanase-treated groups. Both bone mineral density and cortical bone volume fraction showed the best healing outcome with low-dose heparanase, implying a biphasic effect of its mode of action. These results indicated that with the appropriate dose of topical heparanase-1, the progress of bone healing could be accelerated in vivo.

Kidney Structural Features from Living Donors Predict Graft Failure in the Recipient.

Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft's "intrinsic quality" at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Variations of Mandibular First Molar Root Canal in School Children: An Observational Study.

ABSTRACTBackground:Root canal (RC) treatment is most common and effective method for treatment of diseases related to periapical area and pulp of teeth. With the increase in age, the formation of secondary dentin, calcification of canals, and reduction of medullary cavity volume, it becomes increasingly difficult to accomplish a perfect RC treatment, hence the understanding of RC variation and changes in variation with increasing age improves the success rates.Aim:The aim of this study was to study the RC variation in the age-group of 10–14 years and to find if the gradual increase in age plays a role in increasing the complexity of RC variation.Materials and Methods:This study was carried out in Government Medical College, Patna, Bihar, India, from January 2018 to April 2019. Subjects within the age range of 10–14 years were selected conferring to predetermined inclusion and exclusion criteria. The subjects were divided into the groups according to age—Group I: 10–11 years, Group II: 11–12 years, Group III: 12–13 years, and Group IV: 13–14 years. The subjects were further divided into Group A and B according to sex to study if there is any significant difference in RC variation. Three intraoral periapical (IOPA) radiography with radiovisiography (RVG) of each subject were taken from three different predetermined angles and these IOPAs were then analyzed by three independent observers and the most agreed on value was included. The IOPAs were analyzed for the number of roots, the number of canals in each root and the variation of each RC were classified according to Vertucci’s Classification.Results:The most common T of RC variation in mesial root of mandibular first molar was T IV succeeded by T II and T I. For distal canal of mandibular first molar, the most common variation was T I, followed by T II and T III. In our study we found that 98.88% of mandibular molars were having two roots. No significant difference was found in the variation of canal according to age or sex in our study.Conclusion:Hence, we conclude that no significant difference is seen in RC variation according to sex and age. As the groups we included in our study were not wide apart enough in age, a further long-term study is needed to ascertain if the complexity of RC increases with age.

The protective effect of curcumin on the diabetic rat kidney: A stereological, electron microscopic and immunohistochemical study

The prevalence of diabetes in the world is increasing rapidly. Kidney diseases are among the most common medical disorders. The aim of this study was to investigate the effect of curcumin on the diabetic kidney. Thirty-five female Wistar albino rats were divided into seven groups. No procedure was performed on the Cont group. The Sham group received corn oil via gavage for 14 days. The curcumin (Curc) group received 30-mg/kg curcumin for 14 days, while the diabetes mellitus (DM) group received 50-mg/kg streptozotocin (STZ) in a single dose intraperitoneally. The DM + curcumin 1 (DC1) group received 30 mg/kg curcumin for 14 days, seven days after the application of STZ, while the DM + curcumin 2 (DC2) received 30 mg/kg curcumin for 14 days, 21 days after the application of STZ, and the DM + curcumin 3 (DC3) group received single-dose STZ at the same time as the application of 30 mg/kg curcumin for 14 days. Medulla, cortex, tubule, and glomerulus volume ratios were calculated using stereological techniques. Cortex volumes in the Sham and DM groups were significantly lower than in the Cont group (p < 0.05). The cortex volume in the DC3 group was also significantly lower than in the Curc group (p < 0.05). Medullary volume was significantly higher in the DC3 group compared to the DM group (p < 0.05). Curcumin was determined to exhibit a protective effect on the diabetic kidney since the glomerulus in the curcumin-exposed group exhibited a well-protected structure following experimentally induced diabetes based on light and electron microscopic analysis findings. These findings suggest that curcumin used following experimentally induced diabetes exhibits protective effects on the diabetic kidney.

Клиническое значение КТ-перфузии у пациентов с камнями мочеточника

Urinary stone disease is one of the most significant urologic diseases, since its prevalence increases annually, which makes it necessary to study and improve effective preventive measures, diagnostic methods and to implement new treatment interventions. to study changes in blood flow in the renal cortex and medulla in patients with ureteral stones using CT perfusion. From 2017 to 2019, a total of 53 patients with upper ureteric stones were evaluated at the Russian-Japanese Center for Imaging and the Institute of Urology and Reproductive Health of the FGAOU VO I.M. Sechenov First Moscow State Medical University. Preoperatively, all patients underwent CT perfusion. The study was performed on a Toshiba Aquilion One 640 in volume mode with a slice thickness of 0.5 mm. In this study, blood flow changes were evaluated depending on the degree of dilatation of collecting system. In patients without dilatation of the collecting system, the average values of cortical and medullary blood flow and blood volume were within normal values. In patients with a dilatation of collecting system, there were significant differences cortical and medullary blood flow between the affected renal unit and contralateral side (27% and 34%, respectively). A decrease in cortical and medullar perfusion by 55% and 58%, respectively, in patients with the dilatation of calyxes was more pronounced in comparison with a decrease in perfusion in patients with the dilatation of only the ureter and pelvis. CT perfusion performed on the 640-slice CT scan allows an objective assessment of changes in renal blood flow in patients with ureteric stones.