A consensus on the diagnostic criteria for sarcopenia, a common syndrome in the elderly, has not been reached yet. Prevalence rates vary between studies due to the use of different criteria ...encompassing different measures, correction factors and cutoff points.
This study compared prevalence rates of sarcopenia using nine sets of diagnostic criteria applied in two different elderly populations.
The study population encompassed 308 healthy elderly participants (152 males, 156 females; mean age 74 years) and 123 geriatric outpatients (54 males, 69 females; mean age 81 years). Diagnostic criteria included relative muscle mass, absolute muscle mass, muscle strength and physical performance.
Prevalence rates of sarcopenia varied between 0 and 15% in healthy elderly participants and between 2 and 34% in geriatric outpatients.
This study clearly demonstrates the dependency of sarcopenia prevalence rates on the applied diagnostic criteria.
Hereditary spastic paraplegia (HSP) describes a heterogeneous group of inherited neurodegenerative disorders in which the cardinal pathological feature is upper motor neurone degeneration leading to ...progressive spasticity and weakness of the lower limbs. Using samples from a large Omani family we recently mapped a gene for a novel autosomal recessive form of HSP (SPG35) in which the spastic paraplegia was associated with intellectual disability and seizures. Magnetic resonance imaging of the brain of SPG35 patients showed white matter abnormalities suggestive of a leukodystrophy. Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del). Measurement of enzyme activity in vitro revealed significantly reduced enzymatic function of FA2H associated with these mutations. These results demonstrate that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated HSP and radiological features of leukodystrophy.
Purpose
The posterior cornea is rotationally asymmetric, and Descemet membrane endothelial keratoplasty (DMEK) grafts preferentially scroll vertically. This prospective study assessed whether graft ...attachment after DMEK differed depending on the rotational alignment of the donor graft in the recipient eye.
Methods
Pseudo‐randomization and blinding of the graft orientation in the recipient’s eye were possible by procedural separation: (1) The eye bank recorded the position of an orientation marker in the donor cornea; (2) the surgeon preparing the DMEK graft recorded an upside‐down marker relative to the eye bank marker; and (3) the surgeon assessed the position of the upside‐down marker in the recipient after DMEK. Surgeons were masked towards the eye bank marker. Using mixed‐effects models, we assessed graft attachment relative to the rotational alignment of the donor graft.
Results
Postoperatively, the graft was not fully attached in 59 of 179 eyes (33%). A second air fill (rebubbling) was performed in 11%. The graft axis was in line with the recipient cornea axis in 40%, oblique in 28% and orthogonal in 32%. We did not detect an elevated risk of incomplete attachment (odds ratio OR, 1.16; 95% CI, 0.61–2.20), risk of rebubbling (OR, 1.25; 95% CI, 0.47–3.31) or larger areas of graft detachment in non‐aligned grafts compared to aligned grafts.
Conclusion
Rotational alignment was not strongly associated with the risk of incomplete graft attachment, although modestly elevated risks cannot be ruled out. Efforts are needed to reduce the need for rebubbling after DMEK and to identify modifiable risk factors for graft detachment.
Autophagy, a highly conserved intracellular self-digestion process, plays an integral role in maintaining cellular homeostasis. Although emerging evidence indicate that the endocrine system regulates ...autophagy in mammals, there is still a scarcity of information on autophagy in avian (non-mammalian) species. Here, we show that intracerebroventricular administration of leptin reduces feed intake, modulates the expression of feeding-related hypothalamic neuropeptides, activates leptin receptor and signal transducer and activator of transcription (Ob-Rb/STAT) pathway, and significantly increases the expression of autophagy-related proteins (Atg3, Atg5, Atg7, beclin1, and LC3B) in chicken hypothalamus, liver, and muscle. Similarly, leptin treatment activates Ob-Rb/STAT pathway and increased the expression of autophagy-related markers in chicken hypothalamic organotypic cultures, muscle (QM7) and hepatocyte (Sim-CEL) cell cultures as well as in Chinese Hamster Ovary (CHO-K1) cells-overexpressing chicken Ob-Rb and STAT3. To define the downstream mediator(s) of leptin's effects on autophagy, we determined the role of the master energy sensor AMP-activated protein kinase (AMPK). Leptin treatment significantly increased the phosphorylated levels of AMPKα1/2 at Thr172 site in chicken hypothalamus and liver, but not in muscle. Likewise, AMPKα1/2 was activated by leptin in chicken hypothalamic organotypic culture and Sim-CEL, but not in QM7 cells. Blocking AMPK activity by compound C reverses the autophagy-inducing effect of leptin. Together, these findings indicate that AMPK mediates the effect of leptin on chicken autophagy in a tissue-specific manner.
Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the ...causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).
We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio OR per standard deviation 15.4 mm Hg of SBP 95% CI: 0.75 0.62-0.91; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day 95% CI: 0.67 0.51-0.89; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 0.37, 1.33; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.
Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.
BI 1002494 (R)-4-{(R)-1-7-(3,4,5-trimethoxy-phenyl)-1,6napthyridin-5-yloxy-ethyl}pyrrolidin-2-one is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma ...exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.
Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, ...FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9
genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1β levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10
). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (P
= 2.46•10
) whereas no prediction was detected in seronegative patients (P
= 0.36). Although the predictive ability of the model was substantially lower in the replication population (P
= 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.
The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic ...variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles. We define 9 metabolic subnetworks that encapsulate the metabolic differences within MNP from 38 different tissues. Obtained modules reveal that cholesterol synthesis appears particularly active within the migratory dendritic cells, while glutathione synthesis is essential for cysteinyl leukotriene production by peritoneal and lung macrophages.
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•ImmGen monomuclear phagocyte open-source (MNP OS) dataset is introduced (337 samples)•Myeloid mouse scRNA-seq dataset across tissues is assembled based on Tabula Muris•GAM clustering is metabolic network analysis of the large-scale/single-cell data•Tissue-/cell-specific cholesterol, glycolysis, nucleotide, GSH/lipid modules reported
Gainullina et al. describe metabolic variability of the mononuclear phagocytes across 38 mouse tissues using GAM-clustering, a metabolic network analysis approach. The approach is applied to large-scale transcriptional datasets (ImmGen MNP OS and phase 1) and single-cell RNA-seq data (Tabula Muris) and highlights consistent metabolic modules across cells and tissues.
Obsessive–compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in ...underlying genetic architecture. We present the first genome‐wide characterization of the sex‐specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex‐dependent liability threshold, the presence of individual sex‐specific risk variants on the autosomes and the X chromosome, and sex‐specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex‐combined genome‐wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex‐dependent liability threshold model, suggesting that sex‐combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex‐specific genome‐wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene‐based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex‐specific genetic risk factors for OCD.
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