Causal Effects of Homocysteine,Folate, and Cobalamin on Kidney Function: A Mendelian Randomization Study

Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change −0.95 (−1.21, −0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (−0.11 (−0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.     

Brain Multimodality Monitoring: Updated Perspectives

The challenges posed by acute brain injury (ABI) involve the management of the initial insult in addition to downstream inflammation, edema, and ischemia that can result in secondary brain injury (SBI). SBI is often subclinical, but can be detected through physiologic changes. These changes serve as a surrogate for tissue injury/cell death and are captured by parameters measured by various monitors that measure intracranial pressure (ICP), cerebral blood flow (CBF), brain tissue oxygenation (PbtO₂), cerebral metabolism, and electrocortical activity. In the ideal setting, multimodality monitoring (MMM) integrates these neurological monitoring parameters with traditional hemodynamic monitoring and the physical exam, presenting the information needed to clinicians who can intervene before irreversible damage occurs. There are now consensus guidelines on the utilization of MMM, and there continue to be new advances and questions regarding its use. In this review, we examine these recommendations, recent evidence for MMM, and future directions for MMM.     

Preventive Effect of the Flavonoid, Wogonin, Against Ethanol-Induced Gastric Mucosal Damage in Rats

Whether wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of Scutellaria baicalensis Georgi, which has been shown to have antiinflammatory and antitumor activities in various cell types, possesses a gastric cytoprotective effect was investigated in an ethanol-induced gastric damage model in rats. Ethanol administration alone induced evident gastric damage including gastric hemorrhages and edema, while this gastric damage was significantly attenuated by wogonin pretreatment (30 mg/kg B.W.) 1 hr before ethanol administration. As major protective mechanisms of wogonin on ethanol-induced gastric damage, we found that wogonin showed either antiinflammatory effects through dual actions on arachidonic acid metabolism, i.e., induction of prostaglandin D2 and suppression of 5S-hydroxyeicosatetraenoic acid (5S-HETE), or preventive induction of profuse apoptosis in the stomach. Conclusively, the flavonoid wogonin could be used as a preventive agent of alcohol-induced gastropathy, whose actions were proven to be strong antiinflammation and apoptosis induction.     

Comparisons of changes in the two-point discrimination test following muscle fatigue in healthy adults

[Purpose] This study aimed to examine the effects of muscle fatigue on skin sensation by looking at changes in two-point discrimination (2PD) after inducing muscle fatigue. [Subjects] Thirty-four young and healthy adults with no pathological symptoms (17 males; 17 females) participated in this study. [Methods] Continuous isometric contraction was applied to the upper and lower extremities with an intensity of 50% of the maximal muscle strength to trigger muscle fatigue, and then the 2PD test was conducted on the 3 cm medial area of the elbow and 5 cm area of the knee bone. [Results] After muscle fatigue was induced, the 2PD distance significantly increased in the upper and lower extremities of both males and females. Before triggering muscle fatigue, the 2PD distance was longer in males than females, but after causing muscle fatigue, there was no difference between males and females. The increase in 2PD distance after the experiment was more significant in females than males. [Conclusion] Muscle fatigue has an effect of reducing the skin’s sensory faculty by increasing the 2PD distance in the skin. There is a difference in the response of the skin according to body area and gender; therefore, caution is needed to avoid triggering fatigue during exercise.Key words: Muscle fatigue, Skin sensation, Two-point discrimination     

Catalpol protects against 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin‐induced cytotoxicity in osteoblastic MC3T3‐E1 cells

2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is a well‐known environmental contaminant that produces a wide variety of adverse effects in humans. Catalpol, a major bioactive compound enriched in the dried root of Rehmannia glutinosa, is a major iridoid glycoside that alleviates bone loss. However, the detailed mechanisms underlying the effects of catalpol remain unclear. The present study evaluated the effects of catalpol on TCDD‐induced cytotoxicity in osteoblastic MC3T3‐E1 cells. Catalpol inhibited TCDD‐induced reduction in cell viability and increases in apoptosis and autophagic activity in osteoblastic MC3T3‐E1 cells. Additionally, pretreatment with catalpol significantly decreased the nitric oxide and nitrite levels compared with a control in TCDD‐treated cells and significantly inhibited TCDD‐induced increases in the levels of cytochrome P450 1A1 and extracellular signal‐regulated kinase. Pretreatment with catalpol also effectively restored the expression of superoxide dismutase and extracellular signal‐regulated kinase 1 and significantly enhanced the expression of glutathione peroxidase 4 and osteoblast differentiation markers, including alkaline phosphatase and osterix. Taken together, these findings demonstrate that catalpol has preventive effects against TCDD‐induced damage in MC3T3‐E1 osteoblastic cells.     

Unidirectionally aligned line patterns driven by entropic effects on faceted surfaces

A simple, versatile approach to the directed self-assembly of block copolymers into a macroscopic array of unidirectionally aligned cylindrical microdomains on reconstructed faceted single crystal surfaces or on flexible, inexpensive polymeric replicas was discovered. High fidelity transfer of the line pattern generated from the microdomains to a master mold is also shown. A single-grained line patterns over arbitrarily large surface areas without the use of top-down techniques is demonstrated, which has an order parameter typically in excess of 0.97 and a slope error of 1.1 deg. This degree of perfection, produced in a short time period, has yet to be achieved by any other methods. The exceptional alignment arises from entropic penalties of chain packing in the facets coupled with the bending modulus of the cylindrical microdomains. This is shown, theoretically, to be the lowest energy state. The atomic crystalline ordering of the substrate is transferred, over multiple length scales, to the block copolymer microdomains, opening avenues to large-scale roll-to-roll type and nanoimprint processing of perfectly patterned surfaces and as templates and scaffolds for magnetic storage media, polarizing devices, and nanowire arrays.     

Dolichoectasia: a brain arterial disease with an elusive treatment

Neurological Sciences - Dolichoectasia is a form of brain large artery disease associated with a high risk of mortality and morbidity. Progressive enlargement of arterial size is a predictor of...     

Causal mediation analysis with multiple mediators in the presence of treatment noncompliance

Randomized experiments are often complicated because of treatment noncompliance. This challenge prevents researchers from identifying the mediated portion of the intention‐to‐treated (ITT) effect, which is the effect of the assigned treatment that is attributed to a mediator. One solution suggests identifying the mediated ITT effect on the basis of the average causal mediation effect among compliers when there is a single mediator. However, considering the complex nature of the mediating mechanisms, it is natural to assume that there are multiple variables that mediate through the causal path. Motivated by an empirical analysis of a data set collected in a randomized interventional study, we develop a method to estimate the mediated portion of the ITT effect when both multiple dependent mediators and treatment noncompliance exist. This enables researchers to make an informed decision on how to strengthen the intervention effect by identifying relevant mediators despite treatment noncompliance. We propose a nonparametric estimation procedure and provide a sensitivity analysis for key assumptions. We conduct a Monte Carlo simulation study to assess the finite sample performance of the proposed approach. The proposed method is illustrated by an empirical analysis of JOBS II data, in which a job training intervention was used to prevent mental health deterioration among unemployed individuals.     

Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation

Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation.