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Nephrocalcinosis often begins on a calcium phosphate deposit, at the tip of the medullo-papillary complex (MPC) known as Randall's plaque (RP). Contextualizing proximally observed biominerals within the MPC has led us to postulate a mechanobiological switch that can trigger interstitial biomineralization at the MPC tip, remote from the intratubular biominerals. Micro X-ray computed tomography scans of human MPCs correlated with transmission and scanning electron micrographs, and X-ray energy dispersive spectrometry demonstrated novel findings about anatomically-specific biominerals. An abundance of proximal intratubular biominerals were associated with emergence of distal interstitial RP. The fundamental architecture of the MPC and mineral densities at the proximal and distal locations of the MPC differed markedly. A predominance of plate-like minerals or radially oriented plate-like crystallites within spheroidal minerals in the proximal intratubular locations, and core-shell type crystallites within spheroidal minerals in distal interstitial locations were observed. Based on the MPC anatomic location of structure-specific biominerals, a biological switch within the mineral-free zone occurring between the proximal and distal locations is postulated. The "on" and "off" switch is dependent on changes in the pressure differential resulting from changes in tubule diameters; the "Venturi effect" changes the "circumferential strain" and culminates in interstitial crystal deposits in the distal tubule wall in response to proximal tubular obstruction. These distal interstitial mineralizations can emerge into the collecting system of the kidney linking nephrocalcinosis with nephrolithiasis.
Tissue engineering approaches for the repair of osteochondral defects using biomaterial scaffolds and stem cells have remained challenging due to the inherent complexities of inducing cartilage-like matrix and bone-like matrix within the same local environment. Members of the transforming growth factor β (TGFβ) family have been extensively utilized in the engineering of skeletal tissues, but have distinct effects on chondrogenic and osteogenic differentiation of progenitor cells. The goal of this study was to develop a method to direct human bone marrow-derived mesenchymal stem cells (MSCs) to deposit either mineralized matrix or a cartilaginous matrix rich in glycosaminoglycan and type II collagen within the same biochemical environment. This differential induction was performed by culturing cells on engineered three-dimensionally woven poly(ɛ-caprolactone) (PCL) scaffolds in a chondrogenic environment for cartilage-like matrix production while inhibiting TGFβ3 signaling through Mothers against DPP homolog 3 (SMAD3) knockdown, in combination with overexpressing RUNX2, to achieve mineralization. The highest levels of mineral deposition and alkaline phosphatase activity were observed on scaffolds with genetically engineered MSCs and exhibited a synergistic effect in response to SMAD3 knockdown and RUNX2 expression. Meanwhile, unmodified MSCs on PCL scaffolds exhibited accumulation of an extracellular matrix rich in glycosaminoglycan and type II collagen in the same biochemical environment. This ability to derive differential matrix deposition in a single culture condition opens new avenues for developing complex tissue replacements for chondral or osteochondral defects.
PURPOSE OF REVIEW - While thinning of the cortices or trabeculae weakens bone, age-related changes in matrix composition also lower fracture resistance. This review summarizes how the organic matrix, mineral phase, and water compartments influence the mechanical behavior of bone, thereby identifying characteristics important to fracture risk.
RECENT FINDINGS - In the synthesis of the organic matrix, tropocollagen experiences various post-translational modifications that facilitate a highly organized fibril of collagen I with a preferred orientation giving bone extensibility and several toughening mechanisms. Being a ceramic, mineral is brittle but increases the strength of bone as its content within the organic matrix increases. With time, hydroxyapatite-like crystals experience carbonate substitutions, the consequence of which remains to be understood. Water participates in hydrogen bonding with organic matrix and in electrostatic attractions with mineral phase, thereby providing stability to collagen-mineral interface and ductility to bone. Clinical tools sensitive to age- and disease-related changes in matrix composition that the affect mechanical behavior of bone could potentially improve fracture risk assessment.
Limited information exists on the anatomically-specific early stage events leading to clinically detectable mineral aggregates in the renal papilla. In this study, quantitative multiscale correlative maps of structural, elemental and biochemical properties of whole medullo-papillary complexes from human kidneys were developed. Correlative maps of properties specific to the uriniferous and vascular tubules using high-resolution X-ray computed tomography, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, and immunolocalization of noncollagenous proteins (NCPs) along with their association with anatomy specific biominerals were obtained. Results illustrated that intratubular spherical aggregates primarily form at the proximal regions distant from the papillary tip while interstitial spherical and fibrillar aggregates are distally located near the papillary tip. Biominerals at the papillary tip were closely localized with 10 to 50 μm diameter vasa recta immunolocalized for CD31 inside the medullo-papillary complex. Abundant NCPs known to regulate bone mineralization were localized within nanoparticles, forming early pathologic mineralized regions of the complex. Based on the physical association between vascular and urothelial tubules, results from light and electron microscopy techniques suggested that these NCPs could be delivered from vasculature to prompt calcification of the interstitial regions or they might be synthesized from local vascular smooth muscle cells after transdifferentiation into osteoblast-like phenotypes. In addition, results provided insights into the plausible temporal events that link the anatomically specific intratubular mineral aggregates with the interstitial biomineralization processes within the functional unit of the kidney.
Context - Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology.
Objective - To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR).
Design, Setting, Participants - Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression.
Main Outcome Measure - Serum FGF23.
Results - FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity.
Conclusion - In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.
Copyright © 2017 by the Endocrine Society
OBJECTIVES - To describe a new hypothesis for the initial events leading to urinary stones. A biomechanical perspective on Randall's plaque formation through form and function relationships is applied to functional units within the kidney, we have termed the 'medullo-papillary complex' - a dynamic relationship between intratubular and interstitial mineral aggregates.
METHODS - A complete MEDLINE search was performed to examine the existing literature on the anatomical and physiological relationships in the renal medulla and papilla. Sectioned human renal medulla with papilla from radical nephrectomy specimens were imaged using a high resolution micro X-ray computed tomography. The location, distribution, and density of mineral aggregates within the medullo-papillary complex were identified.
RESULTS - Mineral aggregates were seen proximally in all specimens within the outer medulla of the medullary complex and were intratubular. Distal interstitial mineralisation at the papillary tip corresponding to Randall's plaque was not seen until a threshold of proximal mineralisation was observed. Mineral density measurements suggest varied chemical compositions between the proximal intratubular (330 mg/cm ) and distal interstitial (270 mg/cm ) deposits. A review of the literature revealed distinct anatomical compartments and gradients across the medullo-papillary complex that supports the empirical observations that proximal mineralisation triggers distal Randall's plaque formation.
CONCLUSION - The early stone event is initiated by intratubular mineralisation of the renal medullary tissue leading to the interstitial mineralisation that is observed as Randall's plaque. We base this novel hypothesis on a multiscale biomechanics perspective involving form and function relationships, and empirical observations. Additional studies are needed to validate this hypothesis.
© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.
BACKGROUND - The evidence base for effects of nutritional interventions for malnourished HIV-infected patients starting antiretroviral therapy (ART) is limited and inconclusive.
OBJECTIVE - We hypothesized that both vitamin and mineral deficiencies and poor appetite limit weight gain in malnourished patients starting ART and that vitamin and mineral supplementation would improve appetite and permit nutritional recovery.
DESIGN - The randomized controlled Nutritional Support for Africans Starting Antiretroviral Therapy trial was conducted in Mwanza, Tanzania, and Lusaka, Zambia. ART-naive adults referred for ART and with body mass index <18.5 kg/m received lipid-based nutritional supplements either without (LNS) or with added vitamins and minerals (LNS-VM), beginning before ART initiation. Participants were given 30 g/d LNS from recruitment until 2 weeks after starting ART and 250 g/d from weeks 2 to 6 of ART.
RESULTS - Of 1815 patients recruited, 365 (20%) died during the study and 813 (45%) provided data at 12 weeks. Controlling for baseline values, anthropometric measures were consistently higher at 12-week ART in the LNS-VM than in the LNS group but statistically significant only for calf and mid-upper arm circumferences and triceps skinfold. Appetite did not differ between groups. Using piecewise mixed-effects quadratic models including all patients and time points, the main effects of LNS-VM were seen after starting ART and were significant for weight, body mass index, and mid-upper arm circumference.
CONCLUSIONS - Provision of high levels of vitamins and minerals to patients referred for ART, delivered with substantial macronutrients, increased nutritional recovery but did not seem to act through treatment group differences in appetite.
This work examines the fate of synthetic growth promoters (trenbolone acetate, melengestrol acetate, and zeranol) in sterilized soil systems, focusing on their sorption to organic matter and propensity for mineral-promoted reactions. In organic-rich soil matrices (e.g., Pahokee Peat), the extent and reversibility of sorption did not generally correlate with compound hydrophobicity (e.g., K(ow) values), suggesting that specific binding interactions (e.g., potentially hydrogen bonding through C17 hydroxyl groups for the trenbolone and melengestrol families) can also contribute to uptake. In soils with lower organic carbon contents (1-5.9% OC), evidence supports sorption occurring in parallel with surface reaction on inorganic mineral phases. Subsequent experiments with pure mineral phases representative of those naturally abundant in soil (e.g., iron, silica, and manganese oxides) suggest that growth promoters are prone to mineral-promoted oxidation, hydrolysis, and/or nucleophilic (e.g., H2O or OH(-)) addition reactions. Although reaction products remain unidentified, this study shows that synthetic growth promoters can undergo abiotic transformation in soil systems, a previously unidentified fate pathway with implications for their persistence and ecosystem effects in the subsurface.
Recent work has shown that solid-state (1) H and (31) P MRI can provide detailed insight into bone matrix and mineral properties, thereby potentially enabling differentiation of osteoporosis from osteomalacia. However, (31) P MRI of bone mineral is hampered by unfavorable relaxation properties. Hence, accurate knowledge of these properties is critical to optimizing MRI of bone phosphorus. In this work, (31) P MRI signal-to-noise ratio (SNR) was predicted on the basis of T1 and T2 * (effective transverse relaxation time) measured in lamb bone at six field strengths (1.5-11.7 T) and subsequently verified by 3D ultra-short echo-time and zero echo-time imaging. Further, T1 was measured in deuterium-exchanged bone and partially demineralized bone. (31) P T2 * was found to decrease from 220.3 ± 4.3 µs to 98.0 ± 1.4 µs from 1.5 to 11.7 T, and T1 to increase from 12.8 ± 0.5 s to 97.3 ± 6.4 s. Deuteron substitution of exchangeable water showed that 76% of the (31) P longitudinal relaxation rate is due to (1) H-(31) P dipolar interactions. Lastly, hypomineralization was found to decrease T1, which may have implications for (31) P MRI based mineralization density quantification. Despite the steep decrease in the T2 */T1 ratio, SNR should increase with field strength as B0 (0.4) for sample-dominated noise and as B0 (1.1) for coil-dominated noise. This was confirmed by imaging experiments.
Copyright © 2013 John Wiley & Sons, Ltd.
BACKGROUND - Calcium has been implicated in carcinogenesis and linked to the risk of several cancers in epidemiologic studies; however, few studies have investigated the association of calcium intake with lung cancer risk, particularly among nonsmokers.
METHODS - We evaluated the association of intakes of calcium and related minerals, assessed through a food frequency questionnaire, with lung cancer risk among 71,267 female nonsmokers who were cancer free at baseline in the Shanghai Women's Health Study, a population-based, prospective cohort study. Multivariate Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI).
RESULTS - During follow-up through December 2009 (median follow-up time: 11.2 years), 428 incident lung cancer cases accrued. The median intakes of dietary calcium, magnesium, and phosphorus were 441, 266, and 935 mg/d, respectively. Intakes of calcium, phosphorus, and the calcium-to-magnesium (Ca:Mg) ratio were inversely associated with lung cancer risk. The corresponding HRs (95% CIs) for the highest compared with the lowest quartile were 0.66 (0.48, 0.91) for calcium, 0.55 (0.36, 0.85) for phosphorus, and 0.62 (0.47, 0.82) for the Ca:Mg ratio. No association was observed for dietary magnesium intake or the use of calcium- or vitamin D-containing supplements.
CONCLUSIONS AND IMPACT - Our study provides some of the first evidence suggesting a possible role for increasing dietary calcium intake in lung cancer prevention among female nonsmokers, especially in populations with relatively low calcium intake.