Jun-Hyun Yoo

Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke

Cerebrovascular risk factors, including hypertension, smoking, diabetes mellitus, aging, dyslipidemia, and hyperhomocyst(e)inemia are linked to endothelial dysfunction. Endothelial-derived nitric oxide (NO) has inhibitory effects on key processes in atherothrombosis. Although asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is associated with atherosclerotic disease, there has been no report on association of ADMA with ischemic stroke. Here we investigated the relation of plasma ADMA, stroke, and homocyst(e)inemia in the elderly. Plasma ADMA and homocyst(e)ine concentration was determined using high-performance liquid chromatography and fluorescence detection. Patients with ischemic stroke had significantly higher concentrations of plasma ADMA than controls (1.85+/-1.32 vs. 0.93+/-0.32 micromol/l, P=0.0001). After adjustment for risk factors, elevated ADMA levels, above 90th percentile of normal controls (> or =1.43 micromol/l) was associated with stroke (OR=6.05, 95% CI; 2.77-13.3, P=0.02). ADMA plasma levels were positively correlated to homocyst(e)ine levels (r=0.43, P=0.01). Multiple logistic regression analysis revealed that hyperhomocyst(e)inemia (plasma homocyst(e)ine concentration > or =15.0 micromol/l) was a significant predictor of elevated ADMA level. Altogether, findings indicate that elevated ADMA concentrations are at increased risk for ischemic stroke in the elderly, and may account for increased risk of stroke in patients with hyperhomocyst(e)inemia.

Relation of Plasma Homocyst(e)ine to Cerebral Infarction and Cerebral Atherosclerosis

BACKGROUND AND PURPOSE A number of investigations support the theory that the elevated plasma homocyst(e)ine is associated with occlusive vascular disease. The aim of this study is to examine whether moderate hyperhomocyst(e)inemia is an independent risk factor for cerebral infarction. In addition, we examined the association between plasma homocyst(e)ine and the severity of cerebral atherosclerosis. METHODS We conducted a hospital-based case-control study with 140 male controls and 78 male patients with nonfatal cerebral infarction, aged between 39 and 82 years. Plasma homocyst(e)ine levels were analyzed in 218 subjects. Fifty-five patients were evaluated for cerebral vascular stenosis by MR angiography. RESULTS The mean plasma level of homocyst(e)ine was higher in cases than in controls (11.8+/-5.6 versus 9.6+/-4.1 micromol/L; P=0.002). The proportion of subjects with moderate hyperhomocyst(e)inemia was significantly higher in cases than in controls (16.7% versus 5.0%; P=0.004). Based on the logistic regression model, the odds ratio of the highest 5% of homocyst(e)ine levels in control group was 4.17 (95% confidence interval, 3.71 to 4. 71)(P=0.0001). After additional adjustment for total cholesterol, hypertension, smoking, diabetes, and age, the odds ratio was 1.70 (95% confidence interval, 1.48 to 1.95) (P=0.0001). The plasma homocyst(e)ine levels of patients having vessels with 3 or 2 stenosed sites were significantly higher than those of patients having vessels with 1 stenosed site or normal vessels (14.6+/-1.4, 11.0+/-1.4 versus 7.8+/-1.5, 8.9+/-1.4 micromol/L respectively; P<0. 02). Multiple logistic regression analysis revealed that moderate hyperhomocyst(e)ienemia was significantly associated with the number of stenosed vessels (P=0.001). CONCLUSIONS These findings suggest that moderate hyperhomocyst(e)inemia is an independent risk factor for cerebral infarction and may predict the severity of cerebral atherosclerosis in patients with cerebral infarction.

A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants.

Hyperhomocysteinemia is a condition caused by both genetic and nongenetic factors. To determine whether a common methylenetetrahydrofolate reductase (MTHFR) variant is related to elevated homocysteine concentrations in epileptic patients receiving anticonvulsants, we investigated the plasma total homocysteine (tHcy) level, folate level, and MTHFR 677 C --> T mutation using a polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis with HinfI digestion in 103 patients with epilepsy and 103 normal controls. The prevalence of hyperhomocysteinemia (> or = 11.4 micromol/L, 90th percentile of control group) was higher in patients than in controls (25% v 10.0%, P = .007). The homozygosity for the 677 C --> T mutation of MTHFR was associated with elevated tHcy and low folate levels. The magnitude of hyperhomocysteinemia in MTHFR TT homozygotes was more pronounced in epileptic patients than in controls (18.2 +/- 1.6 v 9.1 +/- 1.2 micromol/L, P = .04). In epileptic patients, hyperhomocysteinemia was more frequent in MTHFR TT genotypes versus CT or CC genotypes (58% v 17% and 16%, P < .001). Multiple logistic regression analysis showed that MTHFR TT genotype was an independent predictor of hyperhomocysteinemia in epileptic patients receiving anticonvulsants (phenytoin and carbamazepine but not valproic acid), suggesting that gene-drug interactions induce hyperhomocysteinemia. These findings indicate that epileptic patients receiving anticonvulsants may have a higher folate requirement to maintain a normal tHcy level, especially homozygotes for MTHFR 677 C --> T mutation.

Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine >/=15 micromol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; P=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively; P=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85; P=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39; P=0.0007), whereas those with a single infarct did not (odds ratio 2.03, P=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine beta-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.

End-of-life communication in Korean older adults: With focus on advance care planning and advance directives.

The present article aimed to provide a comprehensive review of current status of end‐of‐life (EOL) care and sociocultural considerations in Korea, with focus on the EOL communication and use of advance directives (AD) in elderly Koreans. Through literature review, we discuss the current status of EOL care and sociocultural considerations in Korea, and provide a look‐ahead. In Korea, patients often receive life‐sustaining treatment until the very end of life. Advance care planning is rare, and most do‐not‐resuscitate decisions are made between the family and physician at the very end of patients life. Koreans, influenced mainly by Confucian tradition, prefer a natural death and discontinuation of life‐sustaining treatment. Although Koreans generally believe that death is natural and unavoidable, they tend not to think about or discuss death, and regard preparation for death as unnecessary. As a result, AD are completed by just 4.7% of the general adult population. This situation can be explained by several sociocultural characteristics including opting for natural death, wish not to burden others, preference for family involvement and trust in doctor, avoidance of talking about death, and filial piety. Patients often receive life‐sustaining treatment until the very EOL, advance care planning and the use of AD is not common in Korea. This was related to unique sociocultural characteristics of Korea. A more active role of physicians, development of a more deliberate EOL discussion process, development of culturally appropriate AD and promotion of advance care planning might be required to provide good EOL care in Korea. Geriatr Gerontol Int 2016; 16: 407‐415.

Folic Acid Deficiency Increases Delayed Neuronal Death, DNA Damage, Platelet Endothelial Cell Adhesion Molecule-1 Immunoreactivity, and Gliosis in the Hippocampus After Transient Cerebral Ischemia

Folic acid deficiency increases stroke risk. In the present study, we examined whether folic acid deficiency enhances neuronal damage and gliosis via oxidative stress in the gerbil hippocampus after transient forebrain ischemia. Animals were exposed to a folic acid‐deficient diet (FAD) for 3 months and then subjected to occlusion of both common carotid arteries for 5 min. Exposure to an FAD increased plasma homocysteine levels by five‐ to eightfold compared with those of animals fed with a control diet (CD). In CD‐treated animals, most neurons were dead in the hippocampal CA1 region 4 days after ischemia/reperfusion, whereas, in FAD‐treated animals, this occurred 3 days after ischemia/reperfusion. Immunostaining for 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) was performed to examine DNA damage in CA1 neurons in both groups after ischemia, and it was found that 8‐OHdG immunoreactivity in both FAD and CD groups peaked at 12 hr after reperfusion, although the immunoreactivity in the FAD group was much greater than that in the CD group. Platelet endothelial cell adhesion molecule‐1 (PECAM‐1; a final mediator of neutrophil transendothelial migration) immunoreactivity in both groups increased with time after ischemia/reperfusion: Its immunoreactivity in the FAD group was much higher than that in the CD group 3 days after ischemia/reperfusion. In addition, reactive gliosis in the ischemic CA1 region increased with time after ischemia in both groups, but astrocytosis and microgliosis in the FAD group were more severe than in the CD group at all times after ischemia. Our results suggest that folic acid deficiency enhances neuronal damage induced by ischemia.

Intestinal removal of free fatty acids from hosts by Lactobacilli for the treatment of obesity.

Recent findings on the association of gut microbiota with various diseases, including obesity, prompted us to investigate the possibility of using a certain type of gut bacteria as a safe therapeutic for obesity. Lactobacillus mutants with enhanced capacity in absorption of free fatty acids (FFAs) were isolated to show reduced absorption of FFAs by the administered host, attributing to inhibition of body weight gain and body fat accumulation as well as amelioration of blood profiles. Consequently, high throughput screening of natural FFAs‐absorbing intestinal microbes led to the isolation of Lactobacillus reuteri JBD30 l. The administration of Lactobacillus JBD30l lowered the concentration of FFAs in the gut fluid content of small intestine, thus reducing intestinal absorption of FFAs whereas promoting fecal excretion of FFAs. Animal data also confirmed that the efficacy of Lactobacillus JBD30l on body weight similar to that of orlistat, an FDA‐approved pharmaceutical for long‐term use to treat obesity. In a subsequent random, double‐blind, placebo‐controlled clinical trial (KCT0000452 at Clinical Research Information Service of Korea), there was a statistically significant difference in the percentage change in body weight between the Lactobacillus JBD301 and the placebo group (P = 0.026) as well as in the BMI (P = 0.036) from the 0‐week assessment to the 12‐week assessment. Our results show that FFA‐absorbing Lactobacillus JBD301 effectively reduces dietary fat absorption, providing an ideal treatment for obesity with inherent safety.

Deletion polymorphism in the gene for angiotensin-converting enzyme is associated with essential hypertension in men born during the Pacific War.

Age is a strong risk factor for hypertension in relation to vascular aging. Additional etiological factors include: lifestyle, genetic factors, and their interactions. The aim of this study is to examine whether an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene is associated with essential hypertension in Korean born during the Pacific War. A total of 13,914 healthy subjects (8261 men, 5653 women) aged 20-79 years were examined. Subjects with abnormal renal, thyroid dysfunction, or electrolyte levels were excluded. Logistic regression analysis showed increased risk (OR=1.15; 95% CI, 1.01-1.31) in men, but not in women (OR, 1.06; 95% CI, 0.89-1.26). However, after adjustment for age, obesity, cholesterol, alcohol consumption, and diabetes mellitus, increased risk in men was not significant (OR, 1.13; 95% CI, 0.98-1.42). Analyzed according to birth-year, DD genotype showed increased risk for hypertension in only a subgroup of men (adjusted OR, 1.56; 95% CI, 1.16-2.09; p = 0.001), born during the Pacific War (1941-1945 year). Findings suggest that the ACE DD genotype plays a role in the pathogenesis of essential hypertension, in conjunction with adverse environmental conditions in early life, with sex-related difference.

Safety and tolerability of Korean Red Ginseng in healthy adults: a multicenter, double-blind, randomized, placebo-controlled trial

Background Korean Red Ginseng (KRG) has been used in Asia for its various biological effects, but no studies have investigated the safety of its long-term intake. Therefore, the present study evaluated the safety of KRG intake for 24 weeks. Methods We randomized 1,000 participants in a 1:1 ratio into two groups, which were treated daily with 2 g of KRG or a placebo for 24 weeks. The primary endpoint was all adverse events and adverse drug reactions (ADRs) that occurred after KRG or placebo administration, which were reported at week 4, 12, and 24 after the baseline visit. Results In total, 192 and 211 participants experienced adverse events in the KRG and placebo groups (39.2% and 42.0%, respectively; p = 0.361), and 59 and 57 KRG- and placebo-treated individuals reported ADRs (12.0% and 11.4%, respectively; p = 0.737). The frequently occurring ADRs were pruritus (2.0%), headache (1.6%), diarrhea (1.4%), and dizziness (1.2%) in the KRG group and pruritus (2.0%), headache (1.8%), dizziness (1.6%), rash (1.4%), and diarrhea (1.2%) in the placebo group. Discontinuation of drug administration due to ADRs was reported in 13 participants, six (1.2%) and seven (1.4%) in the KRG and placebo groups, respectively (p = 0.814). No significant abnormal changes were revealed by anthropometric, laboratory, and vital sign measurements in the KRG group compared with those in the placebo group. Conclusion The present study confirms the safety and tolerability of daily intake of 2 g of KRG for 24 weeks by healthy adults.

Comment on “Asian collaboration to establish a provisional system to provide high-quality end-of-life care by promoting advance care planning for the elderly”: Letters to the Editor

We read with keen interest the Letter to the Editor by Senda et al., entitled “Asian collaboration to establish a provisional system to provide high-quality end-of-life care by promoting advance care planning for the elderly”, which provided excellent comments on our previous article. Here, we update the Korean situation, and provide our comments regarding the letter.As of January 2016, a legal bill regarding the hospice-palliative care and life-sustaining treatment (LST) decision for dying patients was passed in Korean congress. The following are the major points of the passed bill: