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Background Galantamine has been approved for the treatment of Alzheimer’s disease (AD). However, there are few studies which have reported the association between cognitive responses and galantamine plasma concentration. The aim of this study was to determine the correlation between galantamine plasma concentration and the subsequent cognitive response following treatment in AD patients. Methods AD sufferers who continuously took 8 mg/d galantamine for at least 6 months without previous exposure to other kinds of AChEI such as donepezil, rivastigmine, or memantine were included in this cohort study. The assessments included the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR) and the Cognitive Assessment Screening Instrument (CASI). Each subdomain of the CASI assessment was conducted at baseline and after 6 months of galantamine. The plasma concentrations of galantamine were measured by capillary electrophoresis after 6 months of the treatment. Logistic regression was performed to adjust for age, gender, apolipoprotein E ε4 genotype status, and baseline score to investigate the association between galantamine plasma concentrations and the cognitive response. Results The total sample consisted of 33 clinically diagnosed AD patients taking galantamine 8 mg/d for 6 months. There was no linear correlation between galantamine concentration and cognitive response in patients. However, 22 patients were responsive to the treatment in the long-term memory domain. In CASI subset domain, concentration improved during the 6 months follow up. Conclusions In the limited samples study, galantamine mostly benefitted the cognitive domain of long-term memory. The benefits were not related to the galantamine plasma concentration. Objective intra-individual evaluation of therapeutic response should be encouraged.

Aim The presence of cerebral white matter changes (WMC) has been reported as an important predictor of the rapidity of cognitive decline in Alzheimer's disease (AD). The association between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and WMC in AD is yet to be elucidated. The present study aimed to examine the association between the ACE I/D polymorphism and WMC among AD patients in Taiwan. Methods A total of 403 patients clinically diagnosed with AD were recruited in a cross-sectional study carried out in an area hospital in Kaohsiung, Taiwan. The ACE I/D polymorphism was genotyped, and cerebral white matter rating was carried out using the visual rating scale for age-related white matter changes. Results The I allele was associated with a significantly lower total age-related white matter changes scale score compared with the D allele (4.83 vs 5.93, P = 0.013). The total age-related white matter changes scale score was significantly lower for the I/I genotype than for the I/D (4.37 vs 5.87, P = 0.009) and I/D + D/D genotypes (4.37 vs 5.91, P = 0.006), with no differences observed between the I/I + I/D and the D/D genotypes (5.08 vs 6.09, P = 0.373), after adjustment for age and hypertension. A stratified analysis by sex demonstrated that the I/I genotype was associated with significant lower WMC than other genotypes in women, but not in men. Conclusions The present study supports the hypothesis that the ACE I/D polymorphism is associated with the severity of WMC in patients with AD. Patients with AD who are homozygous for the I allele might be less likely to develop WMC, especially women. Geriatr Gerontol Int 2017; 17: 945-950.

Background Patients with heart failure rarely engage in adequate self-care. Greater emphasis on self-care discharge readiness is needed. Purpose This study examined the effects of a predischarge educational program combined with 1 year of postdischarge follow-up on self-care behaviors, readmission, sleep quality, and depression in patients with heart failure. Methods A longitudinal, nonequivalent two-group pretest-posttest design was used. The intervention group received tailored education and follow-ups, whereas the control group received routine predischarge heart-failure education from direct care nurses only. Measurements included the self-care maintenance and self-care management subscales of the Self-Care of Heart Failure Index, Pittsburg Sleep Quality Index, Patient Health Questionnaire-9, and readmission rate. Data obtained at baseline and at 1, 3, 6, and 12 months postdischarge were analyzed using linear mixed models with both intention-to-treat and per-protocol approaches. The propensity score was used to adjust for the confounding effects of the New York Heart Association functional class and left ventricular ejection fraction. Results Of the 62 patients with heart failure (28 in the intervention group and 34 in the control group) who were sampled at baseline, 47 (n = 25 vs. n = 22) provided data over the entire course of this 1-year study (76% retention rate). The per-protocol analysis did not find significant differences for any variables. However, the intention-to-treat analysis showed that the intervention group significantly improved in self-care maintenance at 6 months and self-care management at 12 months after hospital discharge, with fewer, albeit not significantly fewer, first and subsequent hospital readmissions than the control group. Conclusions/implications for practice The effect of this intervention was not found to be substantial, indicating a need to design more efficacious and powerful interventions. Hospitalized patients must receive patient education before discharge to foster their self-care knowledge and skills regarding self-care at home. Strategies are needed to help nurses provide patient education in a time-efficient manner.

Objective: We aimed to identify biomarkers of Alzheimer's disease (AD) in order to improve diagnostic accuracy at mild stage. Methods: AD patients aged >50 years were included in the disease group. We evaluated the relationship between potential blood and cerebrospinal fluid inflammatory biomarkers, cognitive status, temporal lobe atrophy and disease severity. Inflammatory biomarkers including interleukin 6 (IL-6), IL-18, fractalkine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels were measured. APOE genotypes were determined. Results: We enrolled 41 subjects in the disease group and 40 subjects in the normal control group. The majority (88.9%) of subjects in the disease group had mild AD. Elevated levels of plasma IL-6 and decreased levels of plasma TRAIL in the disease group were noted. Plasma levels of IL-6 and TRAIL were significantly correlated with their cerebrospinal fluid levels. Conclusion: Plasma IL-6 and TRAIL were identified as potential biomarkers of AD at an early stage.

Background: Excessive daytime sleepiness can increase heart failure (HF) mortality, cause poor medication adherence, and worsen quality of life in people with HF. Recognition of excessive daytime sleepiness can help improve HF management outcomes. Purpose: This study was designed to identify the determinants of daytime sleepiness in patients with HF in Taiwan. Methods: A cross-sectional and correlational study design was employed. We used nonprobability sampling to recruit 133 participants during their regular visits to a cardiovascular outpatient department of a medical center. Instruments used included the Epworth Sleepiness Scale, Symptom Subscale of Kansas City Cardiomyopathy Questionnaire, and Pittsburgh Sleep Quality Index. Results: Excessive daytime sleepiness occurred in 23.3% of study participants. Significant determinants of excessive daytime sleepiness were daytime dysfunction, body mass index, and HF symptom frequency. Use of angiotensin-converting enzyme inhibitors was correlated with excessive daytime sleepiness but was not identified as a determinant. Conclusions/Implications for Practice: Approximately one quarter of participants reported subjective excessive daytime sleepiness, suggesting that recognition of this symptom should be incorporated into HF management. Interventions for improving daytime dysfunction, decreasing body mass index, and ameliorating HF symptoms may help improve excessive daytime sleepiness. Habitual daytime napping may assist Taiwanese patients with chronic HF to overcome poor nocturnal sleep and restore energy. However, extra daytime sleep and changes in the duration and pattern of daytime napping during the HF trajectory should be recognized early to maintain daytime functioning. Medical treatments may help control HF symptoms. Optimizing medications to minimize adverse effects may help patients maintain better treatment adherence.

Rivastigmine has been widely used in mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A dose-dependent effect has been suggested, but the plasma concentration of rivastigmine and its metabolite, NAP 226-90, were not measured in previous studies. The influencing factors of therapeutic response are complicated and discordant in various studies among different ethnic groups. Hence, we analyzed the therapeutic responses of rivastigmine, measured by neuropsychological assessments, among 63 clinically diagnosed AD patients taking a daily dosage of 6–9 mg in relation to their plasma concentration of rivastigmine and NAP 226-90, apolipoprotein E (APOE) genotype and demographic characteristics. Our reports revealed that 41.3% of recruited AD patients had improvement in cognition, measured by Mini-Mental Status Examination (MMSE), and 63.5% in global status, by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. In cognition, the clinically improving group had a significantly higher rivastigmine concentration [p = 0.049, odds ratio (OR) = 1.029, 95%CI = 1.000–1.058], lower initial MMSE score (p = 0.010, OR = 0.708, 95%CI = 0.546–0.920), and lower initial CDR-SB score (p = 0.003, OR = 0.552, 95%CI = 0.372–0.817). The patients with APOE ε4 allele had worsening cognition (p = 0.037, OR = 3.870, 95%CI = 1.082–13.840). In global status, only higher education (p = 0.043, OR = 1.222, 95%CI = 1.007–1.484) was significantly associated with clinical improvement. In conclusion, high concentrations of rivastigmine may benefit cognitive function of AD patients, especially in APOE ε4 (−) carriers.

The aim of this small pilot study was to evaluate the association between plasma concentrations of rivastigmine and its metabolite, NAP 226-90, and cognitive function in patients with Alzheimer's disease (AD). Rivastigmine-treated AD patients, who had been maintained on a fixed regimen of twice daily rivastigmine (6 to 12 mg/d) for ≥6 months, were eligible for evaluation. The assessments included cognitive assessment screening instrument (CASI) and clinical dementia rating scale, conducted at baseline and at 6-month follow-up. The 9 subdomains of CASI at baseline and follow-up were analyzed in relation to the plasma concentrations of rivastigmine and NAP 226-90, as measured by capillary electrophoresis. Logistic regression was performed to adjust for age, gender, education level, apolipoprotein E ε4 genotype status, and baseline CASI score to investigate the association between plasma rivastigmine and NAP 226-90 concentrations and the cognitive response. The total sample consisted of 53 clinically diagnosed AD patients taking rivastigmine only at doses of 6 mg to 9 mg/d because of intolerability at 12 mg/d. Higher rivastigmine concentration was significantly associated with improved or preserved short-term memory and worsened abstraction/judgment (p0.05), but not with changes in other domains (p0.05). Higher NAP 226-90 concentration was significantly associated with worsened abstraction/judgment (p0.05), but not with changes in other domains. Higher plasma rivastigmine concentration was significantly associated with improved or preserved short-term memory but worsened abstraction/judgment. An optimal concentration of rivastigmine should be quantified for each patient because of differential cognitive responses.

Angiotensin II stimulates the formation of reactive oxygen species by increased NADPH oxidase activity, which contributes to proapoptotic and profibrotic mechanisms critical in renal injury. Here we determine if apocynin, an inhibitor of NADPH oxidase, interferes with the action of the intrarenal renin-angiotensin system to minimize the progression of renal disease. Transgenic mice that overexpress rat angiotensinogen in their proximal tubule cells were given either apocynin, perindopril, or hydralazine while untreated or apocynin-treated non-transgenic littermates served as controls. Untreated transgenic mice had significant elevations of their systolic blood pressure, albuminuria, reactive oxygen species production, NADPH oxidase activity, tubular apoptosis, active caspase-3, Bax, transforming growth factor-beta1, plasminogen activator inhibitor-1, extracellular matrix proteins, collagen type IV, and phosphorylated p47phox expression compared to untreated non-transgenic mice. Apocynin and perindopril blunted these changes; however, apocynin had no effect on the systolic blood pressure whereas hydralazine prevented hypertension and tubulointerstitial fibrosis but not proximal tubule cell apoptosis. Our study shows that the intrarenal renin-angiotensin system stimulates proximal tubule cell apoptosis and tubulointerstitial fibrosis, in part, by enhanced NADPH oxidase activity and reactive oxygen species generation independent of systemic hypertension.

BQ chewing may produce significant amounts of reactive oxygen species (ROS), resulting in oral mucosa damage, and ROS may be metabolized by CYP26 families. Because the CYP26 polymorphisms associated with malignant oral disorders are not well known, we conducted an association study on the associations between the single nucleotide polymorphisms (SNP) of CYP26 families and the risks of malignant oral disorders. BQ chewers with the CYP26A1 rs4411227 C/C+C/G genotype and C allele showed an increased risk of oral and pharyngeal cancer (adjusted odds ratio (aOR) = 2.30 and 1.93, respectively). The CYP26B1 rs3768647 G allele may be associated with oral and pharyngeal cancer (aOR = 3.12) and OPMDs (aOR = 2.23). Subjects with the rs9309462 CT genotype and C allele had an increased risk of oral and pharyngeal cancer (aOR = 9.24 and 8.86, respectively) and OPMDs (aOR = 8.17 and 7.87, respectively). The analysis of joint effects between the CYP26A1 rs4411227 and CYP26B1 rs3768647/rs9309462 polymorphisms revealed statistical significance (aOR = 29.91 and 10.03, respectively). Additionally, we observed a significant mRNA expression of CY26A1 and CYP26B1 in cancerous tissues compared with adjacent noncancerous tissues. Our findings suggest that novel CYP26 polymorphisms are associated with an increased risk of malignant oral disorders, particularly among BQ chewers.

OBJECTIVE: Polymorphisms of the angiotensinogen (AGT) gene, especially in the promoter region, are in linkage concordance and are associated with hypertension. In this study, we examined the role of AGT promoter polymorphisms, including G-217A, A-6G and M235T variants, and their promoter function in essential hypertension in Taiwanese populations. DESIGN: An association study was conducted to assess the genotype distribution between hypertensive patients and normotensive subjects. We also used a transient transfection assay to examine basal transcriptional activity of G-217A and A-6G variants in a mammalian cell system. METHODS: Hypertensive subjects (390) and normotensive controls (388) of Taiwanese ethnicity were genotyped for the AGT G-217A, A-6G and M235T variants. Promoter activity was studied by cloning the promoter region (-614 to +41 bp) of AGT into the pSEAP2-Basic reporter vector and performing a transient transfection assay in HuH7 and HepG2 cells. RESULTS: The G-217A variant of the AGT gene was significantly associated with hypertension (P = 0.0047), but the A-6G and M235T polymorphisms were not (P = 0.17 and P = 0.33, respectively). Furthermore, the recessive model of homozygous genotype (-217AA) conferred a high risk for hypertension (odds ratio 3.64) in this population. The -217A variant expressed higher transcriptional activity than -217G in vitro. CONCLUSIONS: Our study showed a significant association between the -217A variant of the AGT gene and hypertension. This variant plays a functional role in basal transcription of AGT, and may confer a risk for hypertension in Taiwanese populations.

1. Possible mechanisms responsible for the increases in intracellular calcium ([Ca2+]i) and sodium ([Na+]i) levels seen during metabolic inhibition were investigated by continuous [Ca2+]i and [Na+]i measurement in cultured rat cerebellar granule cells. An initial small mitochondrial Ca2+ release was seen, followed by a large influx of extracellular Ca2+. A large influx of extracellular Na+ was also seen. 2. The large [Ca2+]i increase was not due to opening of voltage-dependent or voltage-independent calcium channels, activation of NMDA/non-NMDA channels, activation of the Na+i-Ca2+o exchanger, or inability of plasmalemmal Ca2+-ATPase to extrude, or mitochondria to take up, calcium. 3. The large [Na+]i increase was not due to activation of the TTX-sensitive Na+ channel, the Na+i-Ca2+o exchanger, the Na+-H+ exchanger, or the Na+-K+-2Cl- cotransporter, or an inability of Na+-K+-ATPase to extrude the intracellular sodium. 4. Phospholipase A2 (PLA2) activation may be involved in the large influx, since both were completely inhibited by PLA2 inhibitors. Moreover, melittin (a PLA2 activator) or lysophosphatidylcholine or arachidonic acid (both PLA2 activation products) caused similar responses. Inhibition of PLA2 activity may help prevent the influx of these ions that may result in serious brain injury and oedema during hypoxia/ischaemia.

Background.It is unclear if the prevalence of Kawasaki disease (KD) correlates with the degree of urbanization. We hypothesized that the prevalence of KD is more pronounced in urban versus rural environments.Methods.The National Health Insurance (NHI) program was implemented in Taiwan in 1995 and covers most of the population (>99%). We used the NHI database to investigate the epidemiological features of KD. A total of 115 diagnosed patients with KD from 1997 to 2010 were included, together with 1,150 matched controls without KD. Chi-square analyses were performed to investigate the difference between modern city and rural environments.Results.Of the 1265 sampled subjects (claims data from 1,000,000 random subjects), the mean age of the KD study group and control group was 2.08 ± 1.66 and 2.08 ± 1.64 years, respectively. After matching for age, sex, and same index date, no statistically significant differences in urbanization level and geographical location of the patients' residence were observed.Conclusion.Urbanization did not appear to be an important effect modifier of Kawasaki disease in Taiwan.

The identification of blood biomarkers for Alzheimer’s disease (AD) could contribute for improvement in early diagnosis. To define AD biomarkers, we compared serum/plasma levels of amyloid β (Aβ), tau, cytokines, and biometals between AD and non-AD groups. Cognitive impairment was assessed by Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating scales. Plasma concentrations of total Aβ, Aβ42, tumor necrosis factor α (TNF-α), and interleukin 6 were quantified by immunoassays. Serum biometal concentrations were determined using flame atomic absorption spectrometry. We found that serum zinc (Zn) was lower in patients with AD. After controlling for age, the MMSE score correlated with both TNF-α and total Aβ levels in the AD group, while the MMSE score correlated with iron only in the non-AD group. Our finding that blood Zn, TNF-α, and total Aβ are possible biomarkers for AD diagnosis and prognosis validates the pervious publication on potential biomarker in the Taiwanese population.

Rationale: Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation. Objective: Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling. Methods and Results: We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant patients with acute VR ( n =16) compared to ATIR ( n =16) and normal graft function ( n =32, P =0.004). In patients with acute VR, graft loss was associated with elevated LG3 levels. Increasing LG3 serum levels in aortic allograft recipients significantly increased neointima formation. LG3 injection fostered accumulation of α-smooth muscle actin–positive cells and decreased the number of CD31 positive EC. LG3 increased the migration of VSMC through extracellular signal-regulated kinases 1/2-dependent pathways. Conclusion: These results indicate that LG3 is a novel regulator of obliterative vascular remodeling during rejection.

Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS) has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) through serum starvation (SS). After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT) was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE) mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II) were found in a serum-free medium conditioned by HUVECs (SSC). The increased Ang II was suppressed using lisinopril (an ACE inhibitor) treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.