The ratio of AGE to sRAGE independently associated with albuminuria in hypertensive patients

Background

Soluble receptor for advanced glycation end-products (sRAGE) and advanced glycation end-products (AGE) have been associated with risks of cardiovascular disease. Because sRAGE is regarded as a scavenger to AGE, we hypothesized that the ratio of AGE to sRAGE (AGE/sRAGE) is associated with albuminuria in hypertensive patients.

Methods

In this cross-sectional study, a total of 104 patients with essential hypertension were recruited. Hypertension was defined as a systolic blood pressure?≥?140 mmHg, a diastolic blood pressure?≥?90 mmHg, or use of antihypertensive treatment. Albuminuria was defined as albumin excretion rate ≧ 20 μg/min. Multivariate logistic regression analyses were performed to evaluate the association between AGE/sRAGE and albuminuria.

Results

Among the 104 patients, 30 (28.8%) patients had albuminuria and 74 (71.2%) patients did not. Patients with albuminuria had higher AGE (2.15 vs. 1.71 μg/mL), lower sRAGE (424.5 vs. 492.5 pg/ml) and higher AGE/sRAGE (3.79 vs. 3.29 μg/pg) than those without albuminuria. Multivariate logistic regression model revealed that AGE/sRAGE (OR?=?1.131, 95% CI?=?1.001–1.278, P?=?0.048) was independently associated with albuminuria. There was no significant relationship between AGE and sRAGE alone with albuminuria.

Conclusion

This study suggests that the ratio of AGE to sRAGE may be a surrogate biomarker for microvascular injury. Further prospective studies of the prognostic value of the ratio in relation to microvasular injury are needed.

     

<Emphasis Type="Italic">CER1</Emphasis>gene variations associated with bone mineral density,bone markers,and early menopause in postmenopausal women

Background

Osteoporosis has a multifactorial pathogenesis characterized by a combination of low bone mass and increased fragility. In our study, we focused on the effects of polymorphisms in CER1 and DKK1 genes, recently reported as important susceptibility genes for osteoporosis, on bone mineral density (BMD) and bone markers in osteoporotic women. Our objective was to evaluate the effect of CER1 and DKK1 variations in 607 postmenopausal women. The entire DKK1 gene sequence and five selected CER1 SNPs were amplified and resequenced to assess whether there is a correlation between these genes and BMD, early menopause, and bone turnover markers in osteoporotic patients.

Results

Osteoporotic women seem to suffer menopause 2 years earlier than the control group. The entire DKK1 gene sequence analysis revealed six variations. There was no correlation between the six DKK1 variations and osteoporosis, in contrast to the five common CER1 variations that were significantly associated with BMD. Additionally, osteoporotic patients with rs3747532 and rs7022304 CER1 variations had significantly higher serum levels of parathyroid hormone and calcitonin and lower serum levels of osteocalcin and IGF-1.

Conclusions

No significant association between the studied DKK1 variations and osteoporosis was found, while CER1 variations seem to play a significant role in the determination of osteoporosis and a potential predictive role, combined with bone markers, in postmenopausal osteoporotic women.

     

Gelatin microspheres containing calcitonin gene-related peptide or substance P repair bone defects in osteoporotic rabbits

Objectives

To investigate the therapeutic effect of gelatin microspheres containing different concentrations of calcitonin gene-related peptide (CGRP) or substance P on repairing bone defects in a rabbit osteoporosis model.

Results

Gelatin microspheres containing different concentrations of CGRP or substance P promoted osteogenesis after 3 months in a rabbit osteoporotic bone defective model. From micro-computed tomography imaging results, 10 nM CGRP was optimal for increasing the trabecular number and decreasing the trabecular bone separation degree; similar effects were observed with the microspheres containing 1 µM substance P. Histological analysis showed that the gelatin microspheres containing CGRP or substance P, regardless of the concentration, effectively promoted osteogenesis, and the highest effect was achieved in the groups containing 1 µM CGRP or 1 µM substance P.

Conclusions

Gelatin microspheres containing CGRP or substance P effectively promoted osteogenesis in a rabbit osteoporotic bone defect model dose-dependently, though their effects in repairing human alveolar ridge defects still need further investigation.

     

Weekly oral alendronate in mevalonate kinase deficiency

Background

Mevalonate kinase deficiency (MKD) is caused by mutations in the MVK gene, encoding the second enzyme of mevalonate pathway, which results in subsequent shortage of downstream compounds, and starts in childhood with febrile attacks, skin, joint, and gastrointestinal symptoms, sometimes induced by vaccinations.

Methods

For a history of early-onset corticosteroid-induced reduction of bone mineral density in a 14-year-old boy with MKD, who also had presented three bone fractures, we administered weekly oral alendronate, a drug widely used in the management of osteoporosis and other high bone turnover diseases, which blocks mevalonate and halts the prenylation process.

Results

All of the patient’s MKD clinical and laboratory abnormalities were resolved after starting alendronate treatment.

Conclusions

This observation appears enigmatic, since alendronate should reinforce the metabolic block characterizing MKD, but is crucial because of the ultimate improvement shown by this patient. The anti-inflammatory properties of bisphosphonates are a new question for debate among physicians across various specialties, and requires further biochemical and clinical investigation.

     

Is sleep apnea underdiagnosed in adult patients with osteogenesis imperfecta? –a single-center cross-sectional study

Background

Patients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77?years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype.

Results

We found obstructive sleep apnea (apnea hypopnea index ≥5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference.

Conclusions

Seeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.

     

The role of bone marrow mononuclear cell-conditioned medium in the proliferation and migration of human dermal fibroblasts

Background

Several recent studies have demonstrated the great potential of bone marrow cells in regenerative medicine, not only for their ability to differentiate to match a damaged cell type, but also because they synthesize and release various growth factors and cytokines.We examined the effect of bone marrow cell-conditioned medium in the healing process, especially in terms of fibroblast proliferation and migration.

Methods

These in vitro studies consisted of co-culture (without direct contact) of dermal fibroblasts with mononuclear bone marrow cells and the use of conditioned medium obtained from these cultures in a scratch wound model.

Results

Mononuclear cells were found to increase the proliferation of fibroblasts, and the conditioned medium showed a stimulatory effect on the migration of fibroblasts.

Conclusion

When considered together with the observed increase in growth factor levels in conditioned medium, it appears that these cells act through a paracrine mechanism.

     

Could martial arts fall training be safe for persons with osteoporosis?: a feasibility study

Background

Osteoporosis is a well-established risk factor for fall-related hip fractures. Training fall arrest strategies, such as martial arts (MA) fall techniques, might be useful to prevent hip fractures in persons with osteoporosis, provided that the training itself is safe. This study was conducted to determine whether MA fall training would be safe for persons with osteoporosis extrapolated from the data of young adults and using stringent safety criteria.

Methods

Young adults performed sideways and forward MA falls from a kneeling position on both a judo mat and a mattress as well as from a standing position on a mattress. Hip impact forces and kinematic data were collected. For each condition, the highest hip impact force was compared with two safety criteria based on the femoral fracture load and the use of a hip protector.

Results

The highest hip impact force during the various fall conditions ranged between 1426 N and 3132 N. Sideways falls from a kneeling and standing position met the safety criteria if performed on the mattress (max 1426 N and 2012 N, respectively) but not if the falls from a kneeling position were performed on the judo mat (max 2219 N). Forward falls only met the safety criteria if performed from a kneeling position on the mattress (max 2006 N). Hence, forward falls from kneeling position on a judo mat (max 2474 N) and forward falls from standing position on the mattress (max 3132 N) did not meet both safety criteria.

Conclusions

Based on the data of young adults and safety criteria, the MA fall training was expected to be safe for persons with osteoporosis if appropriate safety measures are taken: during the training persons with osteoporosis should wear hip protectors that could attenuate the maximum hip impact force by at least 65%, perform the fall exercises on a thick mattress, and avoid forward fall exercises from a standing position. Hence, a modified MA fall training might be useful to reduce hip fracture risk in persons with osteoporosis.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

A school-curriculum-based exercise intervention program for two years in pre-pubertal girls does not influence hip structure

Background

It is known that physical activity during growth has a positive influence on bone mineral accrual, and is thus possibly one strategy to prevent osteoporosis. However, as bone geometry, independent of areal bone mineral density (aBMD), influences fracture risk, this study aimed to evaluate whether hip structure in pre-pubertal girls is also affected by a two-year exercise intervention program.

Methods

Forty-two girls aged 7–9 years in a school-curriculum-based exercise intervention program comprising 40 minutes of general physical activity per school day (200 minutes per week) were compared with 43 age-matched girls who participated in the general Swedish physical education curriculum comprising a mean of 60 minutes per week. The hip was scanned by dual energy X-ray absorptiometry (DXA) and the hip structural analysis (HSA) software was applied to evaluate bone mineral content (BMC, g), areal bone mineral density (aBMD, g/cm²), periosteal diameter, cross-sectional area (CSA, cm²), section modulus (Z, cm³) and cross-sectional moment of inertia (CSMI, cm⁴) of the femoral neck (FN). Annual changes were compared. Subjective duration of physical activity was estimated by questionnaire and objective level of everyday physical activity at follow-up by means of accelerometers worn for four consecutive days. All children remained at Tanner stage 1 throughout the study. Group comparisons were made by independent student's t-test between means and analyses of covariance (ANCOVA).

Results

At baseline, the two groups did not differ with regard to age, anthropometrics or bone parameters. No between-group differences were observed for annual changes in the FN variables measured.

Conclusion

A two-year school-based moderately intense general exercise program for 7–9-year-old pre-pubertal girls does not influence structural changes in the FN.

     

Novel mutation G324C in <Emphasis Type="Italic">WNT1</Emphasis> mapped in a large Pakistani family with severe recessively inherited <Emphasis Type="Italic">Osteogenesis Imperfecta</Emphasis>

Introduction

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease with skeletal fragility and variable extra-skeletal manifestations. To date several point mutations in 18 different genes causing different types of OI have been identified. Mutations in WNT1 compromise activity of the osteoblasts leading to disturbed bone mass accrual, fragility fractures and progressive skeletal abnormalities. The present study was conducted to determine the underlying genetic cause of an autosomal recessive skeletal dysplasia in a large consanguineous family from Chinute, Pakistan.

Materials and methods

Blood was collected from 24 individuals of affected family along with clinical data. Homozygosity mapping was performed to confirm consanguinity. SNPs were identified, followed by whole exome and Sanger sequencing. In silico characterization of WNT1 mutation was performed using multiple platforms.

Results

Nine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments >?1 Mb in length accounting for 2.1–12.7% of the genome in affected individuals and their siblings and a single 6,344,821 bp homozygous region in all affected individuals on chromosome 12q12-q13. This region includes two potential OI candidate genes WNT1 and VDR. We did whole-exome sequencing for both genes in two patients and identified a novel damaging missense mutation in exon 4 of WNT1: c.1168G?>?T (NM_005430) resulting in p.G324C. Sanger sequencing confirmed segregation of mutation with the disease in family.

Conclusion

We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Experimental research into the potential therapeutic effect of GYY4137 on Ovariectomy-induced osteoporosis

Background

Evidence has shown that endogenous H₂S plays an important role in the physiological and pathophysiological processes of many organs. The study aimed to explore whether exogenous H₂S has a potential therapeutic effect on a rat ovariectomy-induced model of osteoporosis.

Methods

The OVX osteoporosis model was established in female Sprague-Dawley rats by full bilateral ovariectomy. The rats were randomly divided into four groups, with the two experimental groups receiving an intraperitoneal injection of GYY4137 or sodium alendronate. The level of H₂S in the plasma was determined and common laboratory indicators to diagnose osteoporosis, such as alkaline phosphatase (ALP) activity and the levels of osteocalcin (OCN), calcitonin, parathyroid hormone and leptin were measured. The bone mineral density (BMD) of the 4th and 5th lumbar vertebrae was measured using dual-energy X-ray absorptiometry. The maximum stress of femoral fracture was obtained through a three-point bending test of the femur.

Results

The OVX osteoporosis model was successfully established. GYY4137 was injected to increase the level of H₂S in the plasma in one group, designated OVX-GYY during the observation period (p?<?0.05). At 12 weeks, the BMD value of the fourth lumbar vertebra in the OVX-GYY group had increased (p?<?0.05). The BMD femur value in the OVX-vehicle group had decreased (p?<?0.05). Bilateral ovariectomy leads to biochemical disorders related to bone metabolism and hormone levels in rat plasma (all p?<?0.05). Ovariectomy also reduced blood calcium, blood phosphate and calcitonin, and increased parathyroid hormone and leptin. The opposite results were obtained for the groups with alendronate sodium or GYY4137 treatment (all p?<?0.05).

Conclusions

Through the slow release of H₂S, GYY4137 did an excellent job of simulating endogenous neuroendocrine gaseous signaling molecules. Exogenous H₂S had a regulatory effect on osteoporosis in ovariectomized rats, showing potential value for the treatment of human postmenopausal osteoporosis.

     

Methodological reflections on using pilot data from fracture patients to develop a qualitative study

Background

Qualitative studies are particularly valued for their exploratory nature but, like other research methods, they do require careful planning to ensure rigorous study design. Our objective was to undertake a pilot study to inform the development of a larger qualitative study.

Results

We conducted a series of brief interviews with out-patients in a hospital setting. The interviews were designed to elicit superficial information about whether (and how) post-fracture osteoporosis investigation and/or treatment were being initiated among patients receiving treatment or follow-up for a current or recent fracture. We used thematic analysis to identify key themes in the data that related to the broader research questions.We analysed data obtained from 11 out of a total of 12 interviews conducted. Participants were male and female, aged 19-83 years of age (median age 57 years). Participants attended 2-8 medical appointments to seek treatment and follow up for a current or recent fracture. The following four overarching themes emerged from thematic analysis of the data: fracture event, referral pathway, osteoporosis investigation and/or treatment, and communication by health practitioners and staff.

Conclusions

This pilot study was necessarily tentative and exploratory in nature, but provided a helpful snapshot of some typical experiences in the public health system following fracture. Several themes emerged for consideration in the design of the main study.Despite its critics, theoretical sampling and saturation continue to provide sustainable methods for ensuring that relevant themes and categories are covered in sufficient depth and breadth, appropriate to the needs of the study.

     

Long-term potentiation in bone – a role for glutamate in strain-induced cellular memory?

Background

The adaptive response of bone cells to mechanical strain is a primary determinant of skeletal architecture and bone mass. In vivo mechanical loading induces new bone formation and increases bone mineral density whereas disuse, immobilisation and weightlessness induce bone loss. The potency of mechanical strain is such that a single brief period of loading at physiological strain magnitude is able to induce a long-lasting osteogenic response that lasts for days. Although the process of mechanotransduction in bone is incompletely understood, observations that responses to mechanical strain outlast the duration of stimulation necessitate the existence of a form of cellular memory through which transient strain episodes are recorded, interpreted and remembered by bone cells. Recent evidence supports the existence of a complex multicellular glutamate-signalling network in bone that shares functional similarities to glutamatergic neurotransmission in the central nervous system. In neurones, these signalling molecules coordinate synaptic communication required to support learning and memory formation, through a complex process of long-term potentiation.

Presentation of the hypothesis

We hypothesise that osteoblasts use a cellular mechanism similar or identical to neuronal long-term potentiation in the central nervous system to mediate long-lasting changes in osteogenesis following brief periods of mechanical strain.

Testing the hypothesis

N-methyl-D-aspartate (NMDA) receptor antagonism should inhibit the saturating response of mechanical strain and reduce the enhanced osteogenicity of segregated loading to that of an equivalent period of uninterrupted loading. Changes in α-amino-3-hydroxy-5-methyl-isoxazole propionate (AMPA) receptor expression, localisation and electrophysiological responses should be induced by mechanical strain and inhibited by modulators of neuronal long-term potentiation.

Implications of the hypothesis

If true, this hypothesis would provide a mechanism through which the skeleton could be pharmacologically primed to enhance or retrieve the normal osteogenic response to exercise. This would form a basis through which novel therapies could be developed to target osteoporosis and other prevalent bone disorders associated with low bone mass.

     

A methodology for elucidating regulatory mechanisms leading to changes in lipid profiles

Introduction

It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.

Objectives

This work simplifies this process.

Methods

A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.

Results

The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.

Conclusion

This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.

     

Phosphorus availability from bone char in a P-fixing soil influenced by root-mycorrhizae-biochar interactions

Aims

The objectives of this study were to evaluate (1) the fertilizer potential of bone char, (2) the effects of wood biochar on plant-available phosphorus (P), and (3) the role of root-mycorrhizae-biochar interactions in plant P acquisition from a P-fixing soil.

Methods

Incubation and pot experiments were conducted with a P-fixing soil and maize with or without root hairs and arbuscular mycorrhizae (AM) inoculation. Olsen-, resin-P and plant P accumulation were used to estimate P availability from bone char, co-pyrolyzed bone char-wood biochar, and separate bone char and wood biochar additions produced at 60, 350 and 750 °C, and Triple Superphosphate (TSP).

Results

Maize inoculated with AM showed similar P accumulation when fertilized with either 750 °C bone char or TSP. Pyrolyzing bone did not increase extractable P in soil in comparison to unpyrolyzed bone, apart from a 67 % increase in resin-extractable P after additions of bone char pyrolyzed at 350 °C. Despite greater Olsen-P extractability, co-pyrolysis of bone with wood reduced maize P uptake. Wood biochars reduced resin-P from bone char by 14–26 %, whereas oven-dried wood increased resin-P by 23 %.

Conclusions

Bone char is an effective P fertilizer, especially if root-AM interactions are simultaneously considered. Biochar influences plant access to soil P and requires careful management to improve P availability.

     

KniMet: a pipeline for the processing of chromatography–mass spectrometry metabolomics data

Introduction

Data processing is one of the biggest problems in metabolomics, given the high number of samples analyzed and the need of multiple software packages for each step of the processing workflow.

Objectives

Merge in the same platform the steps required for metabolomics data processing.

Methods

KniMet is a workflow for the processing of mass spectrometry-metabolomics data based on the KNIME Analytics platform.

Results

The approach includes key steps to follow in metabolomics data processing: feature filtering, missing value imputation, normalization, batch correction and annotation.

Conclusion

KniMet provides the user with a local, modular and customizable workflow for the processing of both GC–MS and LC–MS open profiling data.

     

Untargeted metabolomics suffers from incomplete raw data processing

Introduction

Untargeted metabolomics is a powerful tool for biological discoveries. To analyze the complex raw data, significant advances in computational approaches have been made, yet it is not clear how exhaustive and reliable the data analysis results are.

Objectives

Assessment of the quality of raw data processing in untargeted metabolomics.

Methods

Five published untargeted metabolomics studies, were reanalyzed.

Results

Omissions of at least 50 relevant compounds from the original results as well as examples of representative mistakes were reported for each study.

Conclusion

Incomplete raw data processing shows unexplored potential of current and legacy data.

     

Lanthanum phosphate/chitosan scaffolds enhance cytocompatibility and osteogenic efficiency via the Wnt/β-catenin pathway

Background

Fabrication of porous scaffolds with great biocompatibility and osteoinductivity to promote bone defect healing has attracted extensive attention.

Methods

In a previous study, novel lanthanum phosphate (LaPO₄)/chitosan (CS) scaffolds were prepared by distributing 40- to 60-nm LaPO₄ nanoparticles throughout plate-like CS films.

Results

Interconnected three dimensional (3D) macropores within the scaffolds increased the scaffold osteoconductivity, thereby promoting cell adhesion and bone tissue in-growth. The LaPO₄/CS scaffolds showed no obvious toxicity and accelerated bone generation in a rat cranial defect model. Notably, the element La in the scaffolds was found to promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through the Wnt/β-catenin signalling pathway and induced high expression of the osteogenesis-related genes alkaline phosphatase, osteocalcin and Collagen I (Col-I). Moreover, the LaPO₄/CS scaffolds enhanced bone regeneration and collagen fibre deposition in rat critical-sized calvarial defect sites.

Conclusion

The novel LaPO₄/CS scaffolds provide an admirable and promising platform for the repair of bone defects.

     

Pseudo current density maps of electrophysiological heart,nerve or brain function and their physical basis

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.