The Role of a Neurovascular Signaling Pathway Involving Hypoxia-Inducible Factor and Notch in the Function of the Central Nervous System

In the neurovascular unit, the neuronal and vascular systems communicate with each other. O2 and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O2 and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson’s disease, and Alzheimer’s disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

Diastolic dysfunction and acute kidney injury in elderly patients with femoral neck fracture

BACKGROUND: Femoral neck fracture is common in the elderly population. Acute kidney injury (AKI) is an important risk factor for mortality in patients who have had such fracture. We evaluated the incidence of AKI in patients who had femoral neck fracture and identified risk factors for AKI and mortality. METHODS: This was an observational cohort study including 285 patients who were ≥ 65 years of age and who underwent femoral neck fracture surgery between 2013 and 2017. RESULTS: The mean age was 78.63 ± 6.75 years. A total of 67 (23.5%) patients developed AKI during the hospital stay: 57 (85.1%), 5 (7.5%), and 5 (7.5%) patients were classified as having stage 1, 2, and 3 AKI, respectively. Patients with AKI had a lower baseline estimated glomerular filtration rate and higher left atrial dimension, left ventricular mass index, pulmonary artery pressure, and the ratio of early mitral inflow velocity to early diastolic mitral annulus velocity (E/e’) and were more likely to have diabetes or hypertension (HTN) (P < 0.05). The presence of HTN (odds ratio [OR], 4.570; 95% confidence interval [CI], 1.632–12.797) higher E/e’ (OR, 1.105; 95% CI, 1.019–1.198), and lower hemoglobin (OR, 0.704; 95% CI, 0.528–0.938) were independently associated with a higher risk for developing AKI. Severe AKI (OR, 24.743; 95% CI, 2.822–212.401) was associated with a higher risk of mortality. CONCLUSION: Elderly patients with femoral neck fracture had a high incidence of AKI. Diastolic dysfunction was associated with AKI. Severe AKI was associated with in-hospital mortality.

Retroperitoneal fibrosis in the era of immunoglobulin G4-related disease

BACKGROUND: Retroperitoneal fibrosis (RPF) is a rare disease characterized by fibroinflammatory tissue in the periaortic or periiliac retroperitoneum, where it frequently encases ureters. There is emerging evidence that a subset of this disease is part of a spectrum of multisystemic autoimmune diseases collectively referred to as “immunoglobulin G4 (IgG4)-related disease”. METHODS: We retrospectively analyzed 27 idiopathic RPF patients and identified a subset as IgG4-related RPF, which we categorized according to recently published comprehensive diagnostic criteria. We compared clinical and laboratory characteristics and response to treatment between the two groups. RESULTS: Of 27 total patients, 16 (59.3%) were diagnosed as having IgG4-related RPF, and these were predominantly male. They were also significantly older and more likely to have other organ involvement, hydronephrosis, and postrenal acute kidney injury (AKI) compared to those with idiopathic RPF. However, there was no difference in response rate to systemic steroid treatment. CONCLUSION: IgG4-related RPF accounts for a substantial portion of RPF cases previously identified as “idiopathic RPF” in Korea. Clinical and laboratory characteristics of IgG4-related RPF are similar to those of idiopathic RPF except for a striking male predominance, older age, and higher incidence of postrenal AKI in IgG4-related RPF. More comprehensive, prospective studies are needed to clearly distinguish IgG4-related RPF from idiopathic RPF based on clinical manifestation and to further assess treatment response and long-term prognosis.

Role of Carbon Monoxide in Neurovascular Repair Processing

Carbon monoxide (CO) is a gaseous molecule produced from heme by heme oxygenase (HO). Endogenous CO production occurring at low concentrations is thought to have several useful biological roles. In mammals, especially humans, a proper neurovascular unit comprising endothelial cells, pericytes, astrocytes, microglia, and neurons is essential for the homeostasis and survival of the central nervous system (CNS). In addition, the regeneration of neurovascular systems from neural stem cells and endothelial precursor cells after CNS diseases is responsible for functional repair. This review focused on the possible role of CO/HO in the neurovascular unit in terms of neurogenesis, angiogenesis, and synaptic plasticity, ultimately leading to behavioral changes in CNS diseases. CO/HO may also enhance cellular networks among endothelial cells, pericytes, astrocytes, and neural stem cells. This review highlights the therapeutic effects of CO/HO on CNS diseases involved in neurogenesis, synaptic plasticity, and angiogenesis. Moreover, the cellular mechanisms and interactions by which CO/HO are exploited for disease prevention and their therapeutic applications in traumatic brain injury, Alzheimer’s disease, and stroke are also discussed.

Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the eNOS mRNA 3′-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3′-UTR activity of eNOS mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and N-acetylcysteine prevented H₂O₂-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.

Black Raspberry Improved Lipid Profiles and Vascular Endothelial Function in Patients with Metabolic Syndrome: A Subgroup Analysis of Statin Naïve Participants

OBJECTIVE: Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects and for improving vascular endothelial function in patients at high-risk for cardiovascular disease. We investigated short-term effects of black raspberry on lipid profiles, vascular endothelial function and circulating endothelial progenitor cells in statin naïve participants with metabolic syndrome. METHODS: Patients with metabolic syndrome (n=51) without lipid lowering medications were prospectively randomized into the black raspberry group (n=26, 750 mg/day) and placebo group (n=25) during the 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD) and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, sVCAM-1 were measured at baseline and at 12-week follow-up. Central blood pressure and augmentation index were also measured at baseline and at 12-week follow-up. RESULTS: Decreases from baseline in total cholesterol levels (-22.7±34.3 mg/dL vs. 0.0±34.7mg/dL, p<0.05, respectively) and total cholesterol/HDL ratio (-0.34±0.68 vs. 0.17±0.56, p<0.05, respectively) were significantly greater in the black raspberry group when compared to the placebo group. Decreases from baseline in IL-6 (-0.5±1.4 pg/mL vs. -0.1±1.1 pg/mL, p<0.05, respectively) and TNF-α levels (-5.4±4.5 pg/mL vs. -0.8±4.0 pg/mL, p<0.05, respectively) were significantly greater in the black raspberry group. Increases from the baseline in adiponectin levels (2.9±2.1 µg/mL vs. -0.2±2.5 µg/mL, p<.05) were significant in the black raspberry group. Increases in baFMD at 12-week follow-up were significantly greater in the black raspberry group when compared to the placebo group (2.9±3.6 mm vs. 1.0±3.9 mm, p<0.05, respectively). Radial augmentation indexes were significantly decreased in the black raspberry group when compared to the placebo group (-2±10% vs. 4±13%, p<0.05). CONCLUSION: The use of black raspberry significantly decreased serum total cholesterol levels, inflammatory cytokines, and augmentation index, thereby improving vascular endothelial function in statin naïve participants with metabolic syndrome during the 12-week follow-up.

Involvement of Heme Oxygenase-1 in Orexin-A-induced Angiogenesis in Vascular Endothelial Cells

The cytoprotective enzyme heme oxygenase-1 (HO-1) influences endothelial cell survival, proliferation, inflammatory response, and angiogenesis in response to various angiogenic stimuli. In this study, we investigate the involvement of HO-1 in the angiogenic activity of orexin-A. We showed that orexin-A stimulates expression and activity of HO-1 in human umbilical vein endothelial cells (HUVECs). Furthermore, we showed that inhibition of HO-1 by tin (Sn) protoporphryin-IX (SnPP) reduced orexin-A-induced angiogenesis in vivo and ex vivo. Orexin-A-stimulated endothelial tube formation and chemotactic activity were also blocked in SnPP-treated vascular endothelial cells. Orexin-A treatment increased the expression of nuclear factor erythroid-derived 2 related factor 2 (Nrf2), and antioxidant response element (ARE) luciferase activity, leading to induction of HO-1. Collectively, these findings indicate that HO-1 plays a role as an important mediator of orexin-A-induced angiogenesis, and provide new possibilities for therapeutic approaches in pathophysiological conditions associated with angiogenesis.

AKAP12 regulates vascular integrity in zebrafish

The integrity of blood vessels controls vascular permeability and extravasation of blood cells, across the endothelium. Thus, the impairment of endothelial integrity leads to hemorrhage, edema, and inflammatory infiltration. However, the molecular mechanism underlying vascular integrity has not been fully understood. Here, we demonstrate an essential role for A-kinase anchoring protein 12 (AKAP12) in the maintenance of endothelial integrity during vascular development. Zebrafish embryos depleted of akap12 (akap12 morphants) exhibited severe hemorrhages. In vivo time-lapse analyses suggested that disorganized interendothelial cell-cell adhesions in akap12 morphants might be the cause of hemorrhage. To clarify the molecular mechanism by which the cell-cell adhesions are impaired, we examined the cell-cell adhesion molecules and their regulators using cultured endothelial cells. The expression of PAK2, an actin cytoskeletal regulator, and AF6, a connector of intercellular adhesion molecules and actin cytoskeleton, was reduced in AKAP12-depleted cells. Depletion of either PAK2 or AF6 phenocopied AKAP12-depleted cells, suggesting the reduction of PAK2 and AF6 results in the loosening of intercellular junctions. Consistent with this, overexpression of PAK2 and AF6 rescued the abnormal hemorrhage in akap12 morphants. We conclude that AKAP12 is essential for integrity of endothelium by maintaining the expression of PAK2 and AF6 during vascular development.

Contribution of Thymidylate Synthase Enhancer Region (TSER) Polymorphism to Total Plasma Homocysteine Levels in Korean Patients with Recurrent Spontaneous Abortion / 대한불임학회지

OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) mutation are commonly associated with hyperhomocysteinemia, and through their defects in homocysteine metabolism, they have been implicated as a risk factor for recurrent spontaneous abortion. Recent report describe that 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) that influence enzyme activity would affect plasma homocysteine level. We have investigated the relationship between TSER genotype and plasma homocysteine level in 54 patients with recurrent spontaneous abortion. METHODS: Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutation (C677T and A1298C) was identified by PCR-restriction fragment length polymorphism assay and TSER mutation was analyzed by PCR method. The data were analyzed using the program SAS 8.2 for Windows. RESULTS: Total homocysteine level was significantly higher in MTHFR 677TT genotype (9.80+/-3.87 mumol/L) than MTHFR 677CC genotype (8.14+/-1.74 mumol/L) in Korean patients with unexplained recurrent spontaneous abortion (p=0.0143). However, the plasma homocysteine level was not significantly different in the MTHFR 1298AA (8.42+/-2.65 mumol/L) and 1298CC (6.09+/-0.32 mumol/L; p=0.2058) and, TSER 2R2R (8.61+/-1.68 mumol/L) and 3R3R (8.05+/-2.81 mumol/L; p=0.9319) mutant genotypes, respectively. In this study, we found the combination effects of TSER and MTHFR C677T genotypes. Plasma homocysteine levels were the highest (11.47+/-4.66 mumol/L) in individuals with TSER 3R3R (8.05+/-2.81 mumol/L) and MTHFR 677TT (9.80+/-3.87 mumol/L) genotypes. Individuals with a combination of both TSER 2R2R/2R3R and MTHFR 677CC/CT genotypes (7.69+/-1.77 mumol/L) had lower plasma homocysteine levels than TSER 2R2R (8.61+/-1.68 mumol/L) and MTHR 677CC (8.14+/-1.74 mumol/L) genotypes, respectively. The effect of MTHFR polymorphism in the homocysteine metabolism appears to be stronger than that of TSER polymorphism. CONCLUSION: Although statistically not significant, we found the elevated level of plasma homocysteine in combined genotypes with TSER and MTHFR (C677T and A1298C) in Korean patients with unexplained habitual abortion. In this study, we reported the possibility that TSER polymorphism is a genetic determinant of plasma homocysteine levels in the Korean patients as well as MTHFR C677T polymorphism. A large prospective study is needed to verify our findings.

A case of gastrointestinal stromal tumor of ileum preoperatively diagnosed as extrauterine myoma / 대한산부인과학회잡지

Gastrointestinal stromal tumor (GIST) of ileum is a rare tumor of gastrointestial tract that arise from primitive mesenchymal cells. GIST occur predominantly in persons over 40 years of age with an equal sex incidence. GIST expresses a heterogenous clinical course and the most important prognostic factors are tumor size, site, degree of mitotic activity, tumor necrosis. We report a case of GIST of ileum, which was misdiagnosed as extrauterine leiomyoma preoperatively.

A Case of Acardiac Parabiotic Twin / 대한산부인과학회잡지

Acardia is a very rare congenital anomaly occurring in less than 1 in 35,000 deliveries. Acardiac parabiotic twin has been reported only in multiple, monochronic pregnancies. This anomalous fetus is sustained in utero by parasitic anastomoses to the circulation of its usually normal co-twin and is therefore not compatible with extrauterine survival. A case of an acardiac parabiotic twin is described, and the literature concerning the incidence, classification and etiology of acardiac is reviewed.

A Study On The Stress, Copying and General well-being of Medical Students / 한국의학교육

The mental health of medical students deserves attention because the problems in students may negatively influence learning ability and create consequences for later adjustment to doctor's role. The purpose of this study is to understand the stress, copying, self-esteem and subjective general well-being of medical students and compare them with other students group (students of law, science and humanities). The results was as follows : First, medical students did not report more stress but they use less copying strategy than other students group. Second, there was no differences in stress, copying, self-esteem and general well-being between high and low academic achievement group in medical students. Futhermore, study-related stress had more close relationship with self-esteem, general well-being. Third, the preparatory course students showed lower score in general well-being, especially health, cheerful-depressive mood domain. These results imply that mental health promotion programmes focused in guiding adjustment for the preparatory course students are helpful. And psychiatric, academic counseling should be made available to them. It can lead to an improvement in our health care delivery system. The need of additional longitudinal research is discussed.

A Case of Internalization of Thracoamniotic Shunt of Fatal Bilateral Chylothorax / 대한주산의학회잡지

Using 3D ultrasound, bilateral chylothorax was diagnosed antenatally in the second trimester. Apparently stable, bilateral pleural effusion progressed rapidly to severe hydrops with facial edema during observation, and then we decided bilateral pleural-amniotic shunt operation. Here we present a case where drainage of pleural effusion by a double reverse pig tail stent made by ourself was achieved, although placement of the thoracoamniotic shunt resulted in near complete drainage of bilateral pleural effusion with normalization of intrathoracic anatomic relationships, subsequent resolution of fetal hydrops, but the ultimate outcome was unsuccessful due to the internalization of one catheter and unknown sudden death. We think that ongoing research is required to further evaluation about complications associated with this procedure, specifically failure of function due to obstruction, migration of the catheter,