Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Metabolic Profiling Analysis Reveals the Potential Contribution of Barley Sprouts against Oxidative Stress and Related Liver Cell Damage in Habitual Alcohol Drinkers.

Chronic excessive alcohol consumption is associated with multiple liver defects, such as steatosis and cirrhosis, mainly attributable to excessive reactive oxygen species (ROS) production. Barley sprouts (Hordeum vulgare L.) contain high levels of polyphenols that may serve as potential antioxidants. This study aimed to investigate whether barley sprouts extract powder (BSE) relieves alcohol-induced oxidative stress and related hepatic damages in habitual alcohol drinkers with fatty liver. In a 12-week randomized controlled trial with two arms (placebo or 480 mg/day BSE; n = 76), we measured clinical markers and metabolites at the baseline and endpoint to understand the complex molecular mechanisms. BSE supplementation reduced the magnitude of ROS generation and lipid peroxidation and improved the glutathione antioxidant system. Subsequent metabolomic analysis identified alterations in glutathione metabolism, amino acid metabolism, and fatty acid synthesis pathways, confirming the role of BSE in glutathione-related lipid metabolism. Finally, the unsupervised machine learning algorithm indicated that subjects with lower glutathione reductase at the baseline were responders for liver fat content, and those with higher fatigue and lipid oxidation were responders for γ-glutamyl transferase. These findings suggest that BSE administration may protect against hepatic injury by reducing oxidative stress and changing the metabolism in habitual alcohol drinkers with fatty liver.

Dental management of patients with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is a hereditary metabolic disease caused by the loss of phosphate through the renal tubules into the urine, and an associated decrease in serum calcium and potassium phosphate. Its dental features include spontaneous dental abscesses that occur in the absence of trauma or dental caries. The aim of this case report was to describe the dental problems of XLH patients and to evaluate limitations in their treatment. A 14 year old male and a 38 year old female with XLH were referred to the Department of Conservative Dentistry for endodontic treatment. The dental findings were periapical abscesses without obvious trauma or caries. Conservative endodontic treatment was performed in teeth with pulp necrosis and abscess. In case 1, the treated teeth showed improvements in bone healing, without clinical symptoms. However, in case 2, the implants and the treated tooth showed hypermobility, and the final restoration was therefore postponed. Early diagnosis, periodic examinations, and communication with the patient's pediatrician are important in the dental management of patients with XLH.

Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development.

Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease characterized by the formation of multiple fluid-filled cysts in bilateral kidneys. Although mutations in polycystic kidney disease 1 (PKD1) are predominantly responsible for ADPKD, the focal and sporadic property of individual cystogenesis suggests another molecular mechanism such as epigenetic alterations. To determine the epigenomic alterations in ADPKD and their functional relevance, ADPKD and non-ADPKD individuals were analyzed by unbiased methylation profiling genome-wide and compared with their expression data. Intriguingly, PKD1 and other genes related to ion transport and cell adhesion were hypermethylated in gene-body regions, and their expressions were downregulated in ADPKD, implicating epigenetic silencing as the key mechanism underlying cystogenesis. Especially, in patients with ADPKD, PKD1 was hypermethylated in gene-body region and it was associated with recruitment of methyl-CpG-binding domain 2 proteins. Moreover, treatment with DNA methylation inhibitors retarded cyst formation of Madin-Darby Canine Kidney cells, accompanied with the upregulation of Pkd1 expression. These results are consistent with previous studies that knock-down of PKD1 was sufficient for cystogenesis. Therefore, our results reveal a critical role for hypermethylation of PKD1 and cystogenesis-related regulatory genes in cyst development, suggesting epigenetic therapy as a potential treatment for ADPKD.

Herniated Nucleus Pulposus during Pregnancy / 대한주산의학회잡지

A herniated nucleus pulposus (HNP) during pregnancy has been a rare occurrence with a reported incidence of 1:10,000 case. It is hard to diagnose because of the potentially hazardous effect of ionizing radiation to the fetus when complaining back pain during pregnancy. In this case, magnetic resonance imaging (MRI) provide safe and useful modality and in general, back pain usually respond readily to conservative treatment. Cauda equina syndrome or severe and/or progressive neurologic deficit is a medical emergency that necessitates prompt surgery during pregnancy. She admitted at 31 weeks gestation for sudden development of right leg paresthesia and ankle motor weakness, an MRI showing compression on right nerve root at the level of L5~S1. After 4 weeks treated with bed rest and analgesics, we delivered by cesarean section and laminectomy at the same time. We have experienced a pregnancy with HNP, so report of this case with brief review of literature.

Perinatal Outcomes of Twin-Twin Transfusion Syndrome according to Clinical Stage based on Sonographic findings / 대한산부인과학회지

OBJECTIVE: After classifing the twin-twin transfusion syndrome (TTTS) according to clinical stage by Quintero, we reviewed effectiveness and usefulness of clinical stage by Quintero in diagnosis and treatment of TTTS. METHODS: Twelve cases (16%) were diagnosed as TTTS among 75 examples (31.3%) of monochorionic twin pregnancy out of 240 cases of twin pregnancy born in our hospital between Mach 2000 and June 2004. For TTTS, the clinical stage was decided at the time of initial diagnosis, and any changes of it were observed according to the developments of pregnancy. Neonate was regarded as alive when 5 minutes Apgar score was above 7 after birth. Also we observed the vascular anastomosis of placenta, and classified the method of treatments and its results according to each clinical stage. RESULTS: Two cases were classified into the clinical stage 1 through 4 each, and 4 cases in the clinical stage 5. The higher the clinical stage, the shorter the duration between diagnosis and delivery (p<0.05). In cases of both survivors, compared to no survivors, the interval between diagnosis and delivery were long (p<0.05). In the clinical stage 4 and 5, we found many cases that didn't have placental vascular anastomosis between artery and artery, and in this case, there revealed poor perinatal outcomes. For 4 cases that fell in the clinical stage 1 and 2 and 4, we performed amnioreduction and for one case in the clinical stage 2, we did amnioseptostomy at the same time. In 4 cases with amnioreduction or amnioseptostomy, survival rate was 38%. CONCLUSION: The clinical classification system of TTTS by ultrasound would be helpful for planning treatments and also for predicting the outcomes.