Human Placental Arterial Distensibility, Birth Weight, and Body Size Are Positively Related to Fetal Homocysteine Concentration

Methionine demethylation during metabolism generates homocysteine (Hcy) and its remethylation requires folate and cobalamin. Elevated Hcy concentrations are associated with vascular-related complications of pregnancy, including increased vascular stiffness, predictive of clinical vascular disease. Maternal and fetal total Hcy (tHcy) concentrations are positively related, yet the influence of Hcy on fetoplacental vascular function in normal pregnancy has not been examined. We hypothesized that Hcy alters fetoplacental vascular characteristics with influences on fetal growth outcomes. We investigated (1) placental chorionic plate artery distensibility and neonatal blood pressure in relation to umbilical plasma tHcy; (2) relationships between cord venous (CV) and cord arterial (CA) plasma tHcy, folate, and cobalamin concentrations; and (3) tHcy associations with birth weight and anthropometric measurements of body size as indices of fetal growth in normal pregnancies with appropriate weight-for-gestational age newborns. Maternal plasma tHcy, folate, and cobalamin concentrations were consistent with published data. Placental chorionic plate artery distensibility index (β; measure of vessel stiffness) was inversely related to CA tHcy, yet neonatal blood pressure was not significantly affected. CV and CA tHcy concentrations were positively related and CV tHcy negatively related to CV cobalamin but not folate. CV tHcy concentration positively related to birth weight, corrected birth weight per-centile, length, head circumference, and mid-arm circumference of newborns. CV cobalamin was inversely related to fetal growth indices but not to folate concentration. Our study demonstrates a potential relationship between fetal tHcy and placental artery distensibility, placing clinical relevance to cobalamin in influencing Hcy concentration and maintaining low vascular resistance to facilitate nutrient exchange favorable to fetal growth

Pkd2 Mesenteric Vessels Exhibit a Primary Defect in Endothelium-Dependent Vasodilatation Restored by Rosiglitazone

Patients with autosomal dominant polycystic kidney disease have a high prevalence of hypertension and structural vascular abnormalities, such as intracranial aneurysms. Hypertension can develop in childhood and often precedes a significant reduction in the glomerular filtration rate. The major aim of this study was to investigate whether a primary endothelial defect or a vascular smooth muscle (VSM) defect was present in murine polycystic kidney disease (Pkd)2 heterozygous mesenteric vessels before the development of renal failure or hypertension. Using pressure myography, we observed a marked defect in ACh-stimulated endothelium-dependent vasodilatation in Pkd2 arterioles. In contrast, Pkd2 vessels responded normally to sodium nitroprusside, phenylephrine, KCl, and pressure, indicating unaltered VSM-dependent responses. Pretreatment with the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone significantly restored ACh-dependent vasodilation in Pkd2 mice. Isolated heterozygous Pkd2 endothelial cells displayed normal ACh-stimulated Ca2+ and nitric oxide production. However, isolated Pkd2 heterozygous VSM cells displayed basal increases in superoxide and sodium nitroprusside-stimulated peroxynitrite formation, which were both suppressed by rosiglitazone. Furthermore, we observed a defective response of Pkd2 mesenteric venules to ACh in vivo, which was more marked after ischemia-reperfusion injury. In conclusion, the results of our study suggest that the defect in vasodilatation in Pkd2 heterozygous vessels is primarily due to a reduction in nitric bioavailability secondary to increased vascular oxidative stress. The ability of rosiglitazone to correct this phenotype suggests that this defect is potentially reversible in patients with autosomal dominant polycystic kidney disease

Validation of RNA Extraction Methods and Suitable Reference Genes for Gene Expression Studies in Developing Fetal Human Inner Ear Tissue

\ua9 2024 by the authors.A comprehensive gene expression investigation requires high-quality RNA extraction, in sufficient amounts for real-time quantitative polymerase chain reaction and next-generation sequencing. In this work, we compared different RNA extraction methods and evaluated different reference genes for gene expression studies in the fetal human inner ear. We compared the RNA extracted from formalin-fixed paraffin-embedded tissue with fresh tissue stored at −80 \ub0C in RNAlater solution and validated the expression stability of 12 reference genes (from gestational week 11 to 19). The RNA from fresh tissue in RNAlater resulted in higher amounts and a better quality of RNA than that from the paraffin-embedded tissue. The reference gene evaluation exhibited four stably expressed reference genes (B2M, HPRT1, GAPDH and GUSB). The selected reference genes were then used to examine the effect on the expression outcome of target genes (OTOF and TECTA), which are known to be regulated during inner ear development. The selected reference genes displayed no differences in the expression profile of OTOF and TECTA, which was confirmed by immunostaining. The results underline the importance of the choice of the RNA extraction method and reference genes used in gene expression studies

Lower urinary tract and bowel dysfunction in spinocerebellar ataxias

Background: Little information is available in spinocerebellar ataxias (SCAs) regarding pelvic organ symptoms. The aim of this study was to characterize the lower urinary tract (LUT) and bowel dysfunction in autosomal dominant spinocerebellar ataxias. Methods: Patients with confirmed SCAs attending a tertiary care service were approached about LUT and bowel complaints, and completed validated questionnaires: urinary symptom profile (USP), QualiveenShort form, International Prostate Symptom Score, and Neurogenic Bowel Dysfunction Score. SCA3 and SCA7 patients with urological complaints additionally underwent urodynamic studies (UDS). Patients’ characterization included demographic, clinical (Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS)), and genetic variables. Descriptive and comparative analyses were performed. Results: Fifty-one patients participated: SCA1 (n = 4), SCA2 (n = 11), SCA3 (n = 13), SCA6 (n = 17), and SCA7 (n = 6). The prevalence of self-reported LUT symptoms was 60.8% (n = 31), whereas LUT symptoms was reported in 86.3%(n = 44) using the USP. Both storage and voiding symptoms were reported, urinary frequency and urgency being the most frequent (n = 34, 68%). Although LUT symptoms were most often classed as mild (n = 27, 61.4%), they impacted QoL in 38 patients (77.6%). Of these, 21 (55.3%) were not on pharmacological treatment for urinary dysfunction. Most common abnormalities in UDS (n = 14) were detrusor overactivity (storage phase) and detrusor underactivity (voiding phase). Bowel symptoms were less common (31.4%, n = 16) and of mild severity. Conclusion: LUT symptoms are prevalent in SCA patients and impact QoL, whereas bowel symptoms tend to be mild. These symptoms are overlooked by patients and physicians due to the complexity of neurological involvement in SCA, and therefore a multidisciplinary management approach should be adopted

Leukocyte telomere length variability as a potential biomarker in patients with polyQ diseases

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies

2D sodium MRI of the human calf using half-sinc excitation pulses and compressed sensing

PURPOSE: Sodium MRI can be used to quantify tissue sodium concentration (TSC) in vivo; however, UTE sequences are required to capture the rapidly decaying signal. 2D MRI enables high in-plane resolution but typically has long TEs. Half-sinc excitation may enable UTE; however, twice as many readouts are necessary. Scan time can be minimized by reducing the number of signal averages (NSAs), but at a cost to SNR. We propose using compressed sensing (CS) to accelerate 2D half-sinc acquisitions while maintaining SNR and TSC. METHODS: Ex vivo and in vivo TSC were compared between 2D spiral sequences with full-sinc (TE = 0.73 ms, scan time ≈ 5 min) and half-sinc excitation (TE = 0.23 ms, scan time ≈ 10 min), with 150 NSAs. Ex vivo, these were compared to a reference 3D sequence (TE = 0.22 ms, scan time ≈ 24 min). To investigate shortening 2D scan times, half-sinc data was retrospectively reconstructed with fewer NSAs, comparing a nonuniform fast Fourier transform to CS. Resultant TSC and image quality were compared to reference 150 NSAs nonuniform fast Fourier transform images. RESULTS: TSC was significantly higher from half-sinc than from full-sinc acquisitions, ex vivo and in vivo. Ex vivo, half-sinc data more closely matched the reference 3D sequence, indicating improved accuracy. In silico modeling confirmed this was due to shorter TEs minimizing bias caused by relaxation differences between phantoms and tissue. CS was successfully applied to in vivo, half-sinc data, maintaining TSC and image quality (estimated SNR, edge sharpness, and qualitative metrics) with ≥50 NSAs. CONCLUSION: 2D sodium MRI with half-sinc excitation and CS was validated, enabling TSC quantification with 2.25 × 2.25 mm2 resolution and scan times of ≤5 mins

Patterns of inflammation, microstructural alterations, and sodium accumulation define multiple sclerosis subtypes after 15 years from onset

INTRODUCTION: Conventional MRI is routinely used for the characterization of pathological changes in multiple sclerosis (MS), but due to its lack of specificity is unable to provide accurate prognoses, explain disease heterogeneity and reconcile the gap between observed clinical symptoms and radiological evidence. Quantitative MRI provides measures of physiological abnormalities, otherwise invisible to conventional MRI, that correlate with MS severity. Analyzing quantitative MRI measures through machine learning techniques has been shown to improve the understanding of the underlying disease by better delineating its alteration patterns. METHODS: In this retrospective study, a cohort of healthy controls (HC) and MS patients with different subtypes, followed up 15 years from clinically isolated syndrome (CIS), was analyzed to produce a multi-modal set of quantitative MRI features encompassing relaxometry, microstructure, sodium ion concentration, and tissue volumetry. Random forest classifiers were used to train a model able to discriminate between HC, CIS, relapsing remitting (RR) and secondary progressive (SP) MS patients based on these features and, for each classification task, to identify the relative contribution of each MRI-derived tissue property to the classification task itself. RESULTS AND DISCUSSION: Average classification accuracy scores of 99 and 95% were obtained when discriminating HC and CIS vs. SP, respectively; 82 and 83% for HC and CIS vs. RR; 76% for RR vs. SP, and 79% for HC vs. CIS. Different patterns of alterations were observed for each classification task, offering key insights in the understanding of MS phenotypes pathophysiology: atrophy and relaxometry emerged particularly in the classification of HC and CIS vs. MS, relaxometry within lesions in RR vs. SP, sodium ion concentration in HC vs. CIS, and microstructural alterations were involved across all tasks