Office or home versus 24-hour blood pressure measurement in stable kidney transplant recipients.

BACKGROUND AND HYPOTHESIS: The aim of this study was to quantify hypertension control and evaluate concordance between all commonly available blood pressure modalities in kidney transplant recipients (KTR). METHODS: For this prospective cross-sectional study 89 stable KTR were recruited at the Charité Transplant Outpatient Clinic. For each study participant office (manual office blood pressure 'MOBP' and automated office blood pressure 'AOBP'), 7-day home (HBPM) and 24-hour ambulatory blood pressure measurement (24h-ABPM) were performed. RESULTS: 80 of the 89 patients recruited had sufficient blood pressure recordings. Mean blood pressure for MOBP, AOBP, HBPM and 24h-ABPM was 129/73, 126/71, 131/85 and 130/81 mmHg, respectively. Uncontrolled hypertension, as defined by 24h-ABPM (mean ≥ 130/80 mmHg), was present in 53 (66%) patients. MOBP, AOBP and HBPM classified 19 (24%), 22 (28%) and 41 (51%) patients respectively as 'uncontrolled hypertensive'. The Bland-Altman plot showed good agreement between systolic MOBP, AOBP, HBPM and Daytime-ABPM (mean bias ± SD: -1 ± 13 mmHg, -4 ± 13 mmHg, 1 ± 10 mmHg, respectively). Uncontrolled nighttime hypertension was present in 74 (93%) KTR, with 71 (89%) patients showing a non-physiological dipping pattern. Moderate positive correlation between Daytime-ABPM/HBPM and Nighttime-ABPM (Pearson Correlation Coefficients: 0.62-0.73), followed by MOBP/AOBP (Pearson Correlation Coefficients: 0.49-0.59) was noted. eGFR and proteinuria displayed weak correlation with 24h-, Daytime- and Nighttime-ABPM (absolute values of Pearson Correlation Coefficients: 0.04-0.41). No robust association with either 24h-, Daytime- or Nighttime-ABPM was observed for volume status exams. CONCLUSIONS: Masked hypertension is highly prevalent in KTR, especially due to high rates of uncontrolled nighttime hypertension. HBPM shows the narrowest limits of agreement with Daytime-ABPM. Daytime-ABPM and HBPM show the highest, albeit clinically insufficient, correlation with Nighttime-ABPM. Systematic integration of 24h-ABPM into clinical practice, as proposed by the '2023 ESH Guidelines for the Management of arterial hypertension', should not be withheld for the KTR population. Clinical trials evaluating treatment of hypertension in KTR are urgently needed.

Myelin-associated oligodendrocyte basic protein rs616147 polymorphism as a risk factor for Parkinson's disease.

BACKGROUND: The rs616147 polymorphism of the myelin-associated oligodendrocyte basic protein (MOBP) gene locus has been associated with amyotrophic lateral sclerosis (ALS). ALS and Parkinson's disease (PD) are two common neurodegenerative disorders that share features regarding their etiology, pathophysiology, and genetic backgrounds. While the MOBP rs616147 polymorphism has been associated with ALS, little is known about its role in PD. OBJECTIVE: To assess the role of MOBP rs616147 on PD risk. METHODS: This case-control comparison study consists of 358 PD-affected cases and 358 controls from the Neurology Clinic of the University Hospital of Larissa, University of Thessaly, Faculty of Medicine, in Greece. The diagnosis of PD was made by a specialist neurologist according to the UK Parkinson's Disease Society Brain Bank's clinical criteria. All the participants were genotyped for the MOBP rs616147. Furthermore, in order to validate our results, we genotyped 327 patients with Alzheimer's disease (AD) for MOBP rs616147 and compared them with the control group. RESULTS: According to the univariate analysis, there was a significant association between rs616147 and PD in the dominant (OR [95% C.I.] = 0.70 [0.52-0.94], p = .018), the overdominant (OR [95% C.I.] = 0.68 [0.50-0.92], p = .011), and in the codominant (G/A VS G/G; OR [95% C.I.] = 0.66 [0.48-0.91], p = .035) modes of inheritance. In contrast, there was no association between the MOBP rs616147 polymorphism and AD. CONCLUSIONS: We provide preliminary results associating MOBP rs616147 genetic variant with PD.

Latent trait modeling of tau neuropathology in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10-5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

MOBP rs616147 Polymorphism and Risk of Amyotrophic Lateral Sclerosis in a Greek Population: A Case-Control Study.

Background and Objectives: To date, only one study has investigated the association between the rs616147 polymorphism of the Myelin-associated Oligodendrocyte Basic Protein (MOBP) locus and Amyotrophic Lateral Sclerosis (ALS). Materials and Methods: A case-control study was performed. Patients with definite sporadic ALS were prospectively and consecutively recruited from the inpatient and outpatient clinics of the Neurology Department of the General University Hospital of Larissa, Central Greece. Community based, age and sex matched healthy individuals with a free personal and family history constituted the control group. Results: A total of 155 patients with definite sporadic ALS and an equal number of healthy controls were genotyped. The power of our sample size was slightly above 80% and MOBP rs616147 was determined to be in Hardy-Weinberg Equilibrium among healthy participants (p = 1.00). According to the univariate analysis, there was no significant relationship between rs616147 and ALS [log-additive OR = 0.85 (0.61, 1.19), over-dominant OR = 0.73 (0.46, 1.15), recessive OR = 1.02 (0.50, 2.09), dominant OR = 0.74 (0.47, 1.16), co-dominant OR1 = 0.71 (0.44, 1.14) and co-dominant OR2 = 0.88 (0.42, 1.84). Additionally, the effect of rs616147 on the age of ALS onset was determined insignificant using both unadjusted and adjusted (sex, site of onset) cox-proportional models. Finally, rs616147 was not related to the site of ALS onset. Conclusions: Our study is the first to report the absence of an association between MOBP rs616147 and ALS among individuals of Greek ancestry. Additional, larger nationwide and multi-ethnic studies are warranted to shed light on the connection between rs616147 and ALS.

MOBP levels are regulated by Fyn kinase and affect the morphological differentiation of oligodendrocytes.

Oligodendrocytes are the myelinating glial cells of the central nervous system (CNS). Myelin is formed by extensive wrapping of oligodendroglial processes around axonal segments, which ultimately allows a rapid saltatory conduction of action potentials within the CNS and sustains neuronal health. The non-receptor tyrosine kinase Fyn is an important signaling molecule in oligodendrocytes. It controls the morphological differentiation of oligodendrocytes and is an integrator of axon-glial signaling cascades leading to localized synthesis of myelin basic protein (MBP), which is essential for myelin formation. The abundant myelin-associated oligodendrocytic basic protein (MOBP) resembles MBP in several aspects and has also been reported to be localized as mRNA and translated in the peripheral myelin compartment. The signals initiating local MOBP synthesis are so far unknown and the cellular function of MOBP remains elusive. Here, we show, by several approaches in cultured primary oligodendrocytes, that MOBP synthesis is stimulated by Fyn activity. Moreover, we reveal a new function for MOBP in oligodendroglial morphological differentiation.

The Fulcrum of Demyelination in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), including the brain, spinal cord, and optic nerves. The symptoms can vary from muscle weakness to vision loss. In the case of MS, the immune system attacks the myelin sheath, which protects the nerve fiber and causes inflammation resulting in demyelination. The myelin sheath has the composition of various proteins including membrane proteins and glycoproteins. The four main proteins namely Myelin Basic Protein (MBP), Myelin associated Oligodendrocyte Basic protein (MOBP), Myelin Proteolipid Protein (PLP) and Myelin Associated Glycoprotein (MAG) are known to be critical auto-antigens in causing demyelination in CNS leading to MS. Three out of these four proteins are intrinsically disordered proteins and in this review, we attempted to understand how these proteins play a crucial role in maintaining the integrity of myelin, by exploring its structural and functional aspects and also their auto-antigenicity leading to multiple sclerosis.

Common genetic variation is associated with longitudinal decline and network features in behavioral variant frontotemporal degeneration.

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP -) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression.

Integrated analysis of miRNA and mRNA expression profiles in the brains of BTBR mice.

The BTBR T+  Itpr3tf (BTBR) mouse has developmental disorders in brain and many aberrant neuroanatomical structures and brain dysfunction. However, identification of the pathological mechanisms underlying abnormal brain development in the brains of BTBR mice is still lacking. Increasingly evidence showed that epigenetics plays an important role in the processes of brain development. In this study, we analyzed microRNA (miRNA) and mRNA expression profiles in the cortical brain tissue from BTBR mice, using RNA sequencing. As compared to C57BL/6J (B6) mice, 1,271 differentially expressed genes (DEGs) and 36 known differentially expressed miRNAs (DEMs) were found in the brain from BTBR mice. The functional annotation and categories of DEGs and DEMs were analyzed. Integration analysis identified 103 known miRNA-mRNA interaction pairs. We further verified selected several genes and miRNAs which may be associated with brain development using quantitative RT-PCR (qRT-PCR). Finally, we speculate that reduced myelin-associated oligodendrocytic basic protein and transmembrane proteins 260 may be linked with abnormal brain development in BTBR mice.

Involvement of MeCP2 in Regulation of Myelin-Related Gene Expression in Cultured Rat Oligodendrocytes.

Methyl CpG binding protein 2 (MeCP2) is a multifunctional protein which binds to methylated CpG, mutation of which cause a neurodevelopmental disorder, Rett syndrome. MeCP2 can function as both transcriptional activator and repressor of target gene. MeCP2 regulate gene expression in both neuron and glial cells in central nervous system (CNS). Oligodendrocytes, the myelinating cells of CNS, are required for normal functioning of neurons and are regulated by several transcription factors during their differentiation. In current study, we focused on the role of MeCP2 as transcription regulator of myelin genes in cultured rat oligodendrocytes. We have observed expression of MeCP2 at all stages of oligodendrocyte development. MeCP2 knockdown in cultured oligodendrocytes by small interference RNA (siRNA) has shown increase in myelin genes (myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), and myelin-associated oligodendrocyte basic protein (MOBP)), neurotrophin (brain-derived neurotrophic factor (BDNF)), and transcriptional regulator (YY1) transcripts level, which are involved in regulation of oligodendrocyte differentiation and myelination. Further, we also found that protein levels of MBP, PLP, DM-20, and BDNF also significantly upregulated in MeCP2 knockdown oligodendrocytes. Our study suggests that the MeCP2 acts as a negative regulator of myelin protein expression.