Bisphosphonate Treatment Modifies Canine Bone Mineral and Matrix Properties and their Heterogeneity

Bone loss and alterations in bone quality are major causes leading to bone fragility in postmenopausal women. Although bisphosphonates are well known to reduce bone turnover and prevent bone loss in postmenopausal osteoporosis, their effects on other bone properties are not fully characterized. Changes in bone mineral and matrix properties may contribute to the anti-fracture efficacy observed with bisphosphonate treatments. The aim of this work was to analyze the effect of a 1-year treatment with either alendronate or risedronate, at low and high doses, on spatially resolved bone material and compositional properties that could contribute to the fracture efficacy of these agents. Distal tibias from 30 normal beagles that had been treated daily for 1 year with oral doses of vehicle (Veh), alendronate (Aln) at 0.2 or 1 mg/kg, and risedronate (Ris) at 0.1 or 0.5 mg/kg were analyzed by Fourier Transform Infrared imaging (FTIRI) to assess the changes in both mineral and matrix properties in discrete bone areas. The widths at half maximum of the pixel histograms for each FTIRI parameter were used to assess the heterogeneity of the bone tissue. Aln and Ris increased the mineral content and the collagen maturity mainly in cancellous bone and at the endocortical surface. Significant differences were observed in the mineral content and in the hydroxyapatite crystallinity distribution in bone tissue, which can contribute to reduced ductility and micro-crack accumulation. No significant differences were observed between low and high dose nor between Aln and Ris treatments. These results show that pharmacologic suppression of bone turnover increases the mineral and matrix bone tissue maturity in normal cancellous and endocortical bone areas where bone turnover is higher. These positive effects for decreased fracture risk are also associated with a loss of bone heterogeneity that could be one factor contributing to increased bone tissue brittleness and micro-crack accumulation

Minor Physical Anomalies in Patients with Schizophrenia, Unaffected First-Degree Relatives, and Healthy Controls: A Meta-Analysis

Background: Minor physical anomalies (MPAs) have been found to be more prevalent in schizophrenia than control participants in numerous studies and may index a potential endophenotype for schizophrenia.</p

A systematic review and meta-analysis of neurological soft signs in relatives of people with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Neurological soft signs are subtle but observable impairments in motor and sensory functions that are not localized to a specific area of the brain. Neurological soft signs are common in schizophrenia. It has been established that soft signs meet two of five criteria for an endophenotype, namely: association with the illness, and state independence. This review investigated whether soft signs met a further criterion for an endophenotype, namely familial association. It was hypothesized that if familial association were present then neurological soft signs would be: (a) more common in first-degree relatives of people with schizophrenia than in controls; and (b) more common in people with schizophrenia than in their first-degree relatives.</p> <p>Method</p> <p>A systematic search identified potentially eligible studies in the EMBASE (1980-2011), OVID - MEDLINE (1950-2011) and PsycINFO (1806-2011) databases. Studies were included if they carried out a three-way comparison of levels of soft signs between people with schizophrenia, their first-degree relatives, and normal controls. Data were extracted independently by two reviewers and cross-checked by double entry.</p> <p>Results</p> <p>After screening 8678 abstracts, seven studies with 1553 participants were identified. Neurological soft signs were significantly more common in first-degree relatives of people with schizophrenia than in controls (pooled standardised mean difference (SMD) 1.24, 95% confidence interval (c.i) 0.59-1.89). Neurological soft signs were also significantly more common in people with schizophrenia than in their first-degree relatives (SMD 0.92, 95% c.i 0.64-1.20). Sensitivity analyses examining the effects of age and group blinding did not significantly alter the main findings.</p> <p>Conclusions</p> <p>Both hypotheses were confirmed, suggesting that the distribution of neurological soft signs in people with schizophrenia and their first-degree relatives is consistent with the endophenotype criterion of familial association.</p

Morphological features in a Xhosa schizophrenia population

BACKGROUND: Demonstrating an association between physical malformation and schizophrenia could be considered supportive of a neurodevelopmental origin of schizophrenia and may offer insights into a critical period for the development of this illness. The aim of our study was to investigate whether differences in the presence of minor physical anomalies could be demonstrated between schizophrenia sufferers and normal controls in a Xhosa population with a view to identifying a means of subtyping schizophrenia for use in future genetic studies. METHODS: Sixty-three subjects with schizophrenia (21 sibling pairs, 1 sibship of four and a group of probands with an affected non-participating sibling (n = 17)), 81 normal controls (37 singletons and 22 sibling pairs) of Xhosa ethnicity were recruited. Each participant was then examined for minor physical anomalies using the Modified Waldrop scale. The relationship between each of the morphological features and the presence of an affected sib was examined using the Chi-squared test, followed by an intra-pair concordance analysis in the sibling pairs. RESULTS: Gap between first and second toes was significantly more common in the affected sib pair group when compared to the non-affected sib pair group (p = 0.019) and non-affected singleton control group (p = 0.013). Concordance analysis also revealed increased concordance for this item in the affected sib pair group. CONCLUSION: These findings offer an intriguing possibility that in the Xhosa population, affected sib pair status may be linked to a neurodevelopmental insult during a specific period of the fetal developmental

Novel European free-living, non-diazotrophic Bradyrhizobium isolates from contrasting soils that lack nodulation and nitrogen fixation genes - a genome comparison

The slow-growing genus Bradyrhizobium is biologically important in soils, with different representatives found to perform a range of biochemical functions including photosynthesis, induction of root nodules and symbiotic nitrogen fixation and denitrification. Consequently, the role of the genus in soil ecology and biogeochemical transformations is of agricultural and environmental significance. Some isolates of Bradyrhizobium have been shown to be non-symbiotic and do not possess the ability to form nodules. Here we present the genome and gene annotations of two such free-living Bradyrhizobium isolates, named G22 and BF49, from soils with differing long-term management regimes (grassland and bare fallow respectively) in addition to carbon metabolism analysis. These Bradyrhizobium isolates are the first to be isolated and sequenced from European soil and are the first free-living Bradyrhizobium isolates, lacking both nodulation and nitrogen fixation genes, to have their genomes sequenced and assembled from cultured samples. The G22 and BF49 genomes are distinctly different with respect to size and number of genes; the grassland isolate also contains a plasmid. There are also a number of functional differences between these isolates and other published genomes, suggesting that this ubiquitous genus is extremely heterogeneous and has roles within the community not including symbiotic nitrogen fixation

Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function

MRI Study of Minor Physical Anomaly in Childhood Autism Implicates Aberrant Neurodevelopment in Infancy

Background: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. Methods: We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Results: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Conclusions: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. © 2011 Cheung et al.published_or_final_versio

Methylobacterium Genome Sequences: A Reference Blueprint to Investigate Microbial Metabolism of C1 Compounds from Natural and Industrial Sources

Methylotrophy describes the ability of organisms to grow on reduced organic compounds without carbon-carbon bonds. The genomes of two pink-pigmented facultative methylotrophic bacteria of the Alpha-proteobacterial genus Methylobacterium, the reference species Methylobacterium extorquens strain AM1 and the dichloromethane-degrading strain DM4, were compared. Methodology/Principal Findings The 6.88 Mb genome of strain AM1 comprises a 5.51 Mb chromosome, a 1.26 Mb megaplasmid and three plasmids, while the 6.12 Mb genome of strain DM4 features a 5.94 Mb chromosome and two plasmids. The chromosomes are highly syntenic and share a large majority of genes, while plasmids are mostly strain-specific, with the exception of a 130 kb region of the strain AM1 megaplasmid which is syntenic to a chromosomal region of strain DM4. Both genomes contain large sets of insertion elements, many of them strain-specific, suggesting an important potential for genomic plasticity. Most of the genomic determinants associated with methylotrophy are nearly identical, with two exceptions that illustrate the metabolic and genomic versatility of Methylobacterium. A 126 kb dichloromethane utilization (dcm) gene cluster is essential for the ability of strain DM4 to use DCM as the sole carbon and energy source for growth and is unique to strain DM4. The methylamine utilization (mau) gene cluster is only found in strain AM1, indicating that strain DM4 employs an alternative system for growth with methylamine. The dcm and mau clusters represent two of the chromosomal genomic islands (AM1: 28; DM4: 17) that were defined. The mau cluster is flanked by mobile elements, but the dcm cluster disrupts a gene annotated as chelatase and for which we propose the name “island integration determinant” (iid).Conclusion/Significance These two genome sequences provide a platform for intra- and interspecies genomic comparisons in the genus Methylobacterium, and for investigations of the adaptive mechanisms which allow bacterial lineages to acquire methylotrophic lifestyles.Organismic and Evolutionary Biolog