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Abstract Background Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a complex interplay between genetic and environmental factors, genetics play a role in disease susceptibility. This study used genome-wide association studies (GWAS) and polygenic risk score (PRS) to elucidate the genetic basis for COPD in Taiwanese patients. Results GWAS was performed on a Taiwanese COPD case–control cohort with a sample size of 5,442 cases and 17,681 controls. Additionally, the PRS was calculated and assessed in our target groups. GWAS results indicate that although there were no single nucleotide polymorphisms (SNPs) of genome-wide significance, prominent COPD susceptibility loci on or nearby genes such as WWTR1, EXT1, INTU, MAP3K7CL, MAMDC2, BZW1/CLK1, LINC01197, LINC01894, and CFAP95 (C9orf135) were identified, which had not been reported in previous studies. Thirteen susceptibility loci, such as CHRNA4, AFAP1, and DTWD1, previously reported in other populations were replicated and confirmed to be associated with COPD in Taiwanese populations. The PRS was determined in the target groups using the summary statistics from our base group, yielding an effective association with COPD (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02–1.17, p = 0.011). Furthermore, replication a previous lung function trait PRS model in our target group, showed a significant association of COPD susceptibility with PRS of Forced Expiratory Volume in one second (FEV1)/Forced Vital Capacity (FCV) (OR 0.89, 95% CI 0.83–0.95, p = 0.001). Conclusions Novel COPD-related genes were identified in the studied Taiwanese population. The PRS model, based on COPD or lung function traits, enables disease risk estimation and enhances prediction before suffering. These results offer new perspectives on the genetics of COPD and serve as a basis for future research.

BackgroundGastrodia elata Blume, also called Tian Ma (TM), has been used to treat stroke for centuries. However, its effects on inflammation in acute cerebral ischemic injury and underlying mechanisms involved in microglial polarization remain unknown. The present study explored the effects of the TM extract on the modulation of microglial M1/M2 polarization 2 days after transient cerebral ischemia.MethodsMale Sprague Dawley rats were intracerebroventricularly administered with 1% dimethyl sulfoxide 25 min before cerebral ischemia and subsequently intraperitoneally administered 0.25 g/kg (DO + TM-0.25 g), 0.5 g/kg (DO + TM-0.5 g), or 1 g/kg (DO + TM-1 g) of the TM extract after cerebral ischemia onset.ResultsDO + TM-0.5 g and DO + TM-1 g treatments downregulated the following: phospho-c-Jun N-terminal kinase (p-JNK)/JNK, tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3), TRAF3-interacting JNK-activating modulator (T3JAM), p-nuclear factor-kappa B p65 (p-NF-κB p65)/NF-κB p65, ionized calcium-binding adapter molecule 1 (Iba1), CD86, TNF-α, interleukin (IL)-1β, and IL-6 expression and toll-like receptor 4 (TLR4)/Iba1, CD86/Iba1, and p-NF-κB p65/Iba1 coexpression. These treatments also upregulated IL-10, nerve growth factor, and vascular endothelial growth factor A expression and YM-1/2/Iba1 and IL-10/neuronal nuclei coexpression in the cortical ischemic rim. The JNK inhibitor SP600125 exerted similar treatment effects as the DO + TM-0.5 g and DO + TM-1 g treatments.ConclusionDO + TM-0.5 g and DO + TM-1 g/kg treatments attenuate cerebral infarction by inhibiting JNK-mediated signaling. TM likely exerts the neuroprotective effects of promoting M1 to M2 microglial polarization by inhibiting JNK/TLR4/T3JAM/NF-κB-mediated signaling in the cortical ischemic rim 2 days after transient cerebral ischemia.

Abstract Background Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. Methods We selected 8115 patients with osteoporosis (T-score ≤ − 2.5) and 55,942 healthy individuals (T-score > − 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient’s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. Results The GBA1 gene variant rs11264345 was significantly associated [P

Background The Menstrual Distress Questionnaire (MDQ) is a commonly used questionnaire that assesses various symptoms and distress associated with the menstrual cycle in women. However, the questionnaire has not been completely translated into Chinese with rigorous reliability and validity testing.Methods This study translated the Menstrual Distress Questionnaire Form Cycle (MDQC) from English into Chinese: MDQCC in two stages. First, it was translated forward and backward using Jones’ model; second, to test the validity and reliability, 210 Chinese-speaking women were recruited through online announcements and posters posted between June 2019 and May 2020. Expert validity, construct validity, convergent validity, and factorial validity were determined using content validity index (CVI), intraclass correlation coefficient (ICC), composite reliability (CR), and exploratory factor analysis, respectively. For concurrent criterion validity, MDQCC score was compared with three existing pain scales. Reliability was evaluated using internal consistency across items and two-week test-retest reliability over time.Results The CVI for content validity was .92. Item-CVI for expert validities among the 46 items ranged from .50 − 1; scale-CVI for the eight subscales, from .87 − 1; ICC, from .650 − .897; and CRs, from .303 − .881. Pearson correlation coefficients between MDQCC and short-form McGill pain questionnaire, present pain intensity, and visual analog scale scores were .640, .519, and .575, respectively. Cronbach’s α for internal consistency was satisfactory (.932). ICC for test-retest reliability was .852 for the entire MDQCC.Conclusion MDQCC was valid and reliable for Mandarin Chinese-speaking women. It can be used to evaluate female psychiatric symptoms related to the menstrual cycle in future work.

Background and purpose: Acupuncture exerts an anti-inflammatory effect and is recommended by the World Health Organization as a complementary therapy for stroke. This study investigated the improvement in neurological function outcome in acute-stage intervention of acute ischemic stroke (AIS), and the anti-inflammatory effect of early acupuncture. Methods: Fifty patients with AIS were randomly assigned to either a control group (CG, 25 patients, received sham acupuncture) or treatment group (TG, 25 patients, received acupuncture treatment). Acupuncture intervention was administered twice a week for a total of 8 sessions over 4 consecutive weeks. The primary outcome was the changes in the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Barthel Index (BI) scores. The secondary outcome was the changes in serum inflammation-related biomarker levels.(ANAIS trial) Results: A total of 35 patients (18 patients in the CG and 17 patients in the TG) completed the trial. The reduction in NIHSS scores was greater in the TG than in the CG between V2 (second assessment administered after acupuncture intervention) and V1 (first assessment administered before acupuncture intervention; 4.33 ± 1.91 vs. 2.68 ± 1.42, p = 0.005) and between V3 (third assessment administered 28 days after last acupuncture intervention) and V1 (6.00 ± 2.53 vs. 3.83 ± 2.31, p = 0.012). The increase in BI scores was greater in the TG than in the CG between V2 and V1 (28.89 ± 15.39 vs. 14.21 ± 19.38, p = 0.016) and between V3 and V1 (39.41 ± 20.98 vs. 25.00 ± 18.47, p = 0.038). Among participants with high inflammation, the increase in serum IL-12p70 level between V2 and V1 was greater in the TG than in the CG (0.20 ± 0.19 vs. −0.14 ± 0.30, pg/mL p = 0.006). Conclusions: Acupuncture improved the neurological function of patients with AIS, and the relationship between acupuncture improving neurological function and anti-inflammatory effect needs further study. In addition, studies with larger sample sizes and longer follow-ups as well as multicenter clinical trials are expected in the future.

Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured mean spherical equivalent (SE), genetic, and demographic data were included. The myopia PRS was generated based on genome-wide association study (GWAS) outcomes in a Taiwanese population and previously published GWAS reports. The results demonstrated that the inclusion of age and sex in the PRS had an area under the curve (AUC) of 0.80, 0.78, and 0.73 (p < 0.001) for participants aged >18 years with high (SE < −6.0 diopters (D); n = 1089), moderate (−6.0 D < SE ≤ −3.0 D; n = 3929), and mild myopia (−3.0 D < SE ≤ −1.0 D; n = 2241), respectively. Participants in the top PRS quartile had a 1.30-fold greater risk of high myopia (95% confidence interval = 1.09–1.55, p = 0.003) compared with that in the remaining participants. Further, a higher PRS significantly increased the risk of high myopia (SE ≤ −2.0 D) in children ≤6 years of age (p = 0.027). In conclusion, including the PRS, age, and sex improved the prediction of high myopia risk in the Taiwanese population.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The prevalence and phenotypes of AMD differ among populations, including between people in Taiwan and other regions. We performed a genome-wide association study to identify genetic variants and to develop genetic models to predict the risk of AMD development and progression in the Taiwanese population. In total, 4039 patients with AMD and 16,488 non-AMD controls (aged ≥ 65 years) were included. We identified 31 AMD-associated variants (p < 5 × 10−8) on chromosome 10q26, surrounding PLEKHA1-ARMS2-HTRA1. Two genetic models were constructed using the clump and threshold method. Model 1 included the single nucleotide polymorphism rs11200630 and showed a 1.31-fold increase in the risk of AMD per risk allele (95% confidence interval (CI) = 1.20–1.43, p < 0.001). In model 2, 1412 single-nucleotide polymorphisms were selected to construct a polygenic risk score (PRS). Individuals with the top 5% PRS had a 1.40-fold higher AMD risk compared with that of individuals with a PRS in the bottom quartile (95% CI = 1.04–1.89, p = 0.025). Moreover, the PRS in the upper quartile was related to a decreased age at AMD diagnosis by 0.62 years (95% CI = −1.15, −0.09, p = 0.023). Both genetic models provide useful predictive power for populations at high risk of AMD, affording a basis for identifying patients requiring close follow-up and early intervention.

Abstract Background There is a critical period for visual development, conventionally considered to be the first 6 years of life. Children aged 7 years and older are significantly less responsive to amblyopia treatment. This study investigated the efficacy of binocular vision therapy in amblyopic children aged 7–10 years. Methods This retrospective study enrolled 36 children with unilateral amblyopia who were divided into a case group (receiving vision therapy, optical correction, and part-time patching of the weaker eye) and a control group (receiving optical correction and part-time patching of the weaker eye). Visual acuity (VA) was measured at baseline, at the 3-month, 6-month, and 9-month visits, and 3 months after cessation of treatment. Results There were 19 subjects in the case group and 17 subjects in the control group. Mean VA in the case group improved from 0.39 ± 0.24 logMAR at baseline to 0.10 ± 0.23 logMAR at the endpoint of treatment (p

Patients with chronic spontaneous urticaria (CSU) have a higher risk of developing hypertension. This study aimed to determine whether acupuncture could decrease the risk of hypertension in patients with CSU. We enrolled patients newly diagnosed with CSU between 1 January 2008, and 31 December 2018, from the Taiwanese National Health Insurance Research Database. The claims data were assessed from the index date to 31 December 2019. A Cox regression model was used to compare the hazard ratios (HRs) of the two cohorts. The cumulative incidence of hypertension was estimated using the Kaplan–Meier method. After propensity score matching with a 1:1 ratio, 43,547 patients with CSU who received acupuncture were matched with 43,547 patients with CSU who did not receive acupuncture in this study. After considering potential confounding factors, patients who received acupuncture had a significantly lower risk of hypertension than those in the control group (adjusted hazard ratio = 0.56, 95% confidence interval = 0.54–0.58). Patients who received medications combined with acupuncture tended to have the lowest risk of hypertension. This study revealed that acupuncture decreases the risk of hypertension in patients with CSU in Taiwan. The detailed mechanisms can be further clarified through prospective studies.

Abstract Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with oestrogen receptor-positive, early-stage, and metastatic breast cancer. Although effective, the risk of falls due to AI-associated knee joint pain significantly increased. The aim of this study was to evaluate the therapeutic effects of yoga and massage on AI-associated knee joint pain. Breast cancer survivors were randomly assigned to a 6-week yoga intervention-2-week rest-6-week massage exposure (Yoga first, n = 30) or a 6-week massage intervention-2-week rest-6-week yoga exposure (Massage first, n = 30). Evaluations of the treatment efficacy were made at baseline, post-intervention, and post-exposure using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, plasma cytokine levels, and changes in meridian energy. The results showed that yoga, superior to massage intervention, significantly reduced AI-associated knee joint pain, as demonstrated by the WOMAC pain score. The yoga intervention improvements were also associated with changes in plasma cytokine levels and meridian energy changes. In conclusion, this study provides scientific evidence that yoga was more effective than massage for reducing AI-associated knee joint pain. Meridian energy changes may provide another scientific, objective, non-invasive way to monitor the therapeutic effects of yoga and investigate another alternative, complementary medicine.

Excess thyroid hormones have complex metabolic effects, particularly hyperthyroidism, and are associated with various cardiovascular risk factors. Previous candidate gene studies have indicated that genetic variants may contribute to this variable response. Electronic medical record (EMR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform the disease comorbidity development. In this study, we combined electronic medical record (EMR) -derived phenotypes and genotype information to conduct a genome-wide analysis of hyperthyroidism in a 35,009-patient cohort in Taiwan. Diagnostic codes were used to identify 2,767 patients with hyperthyroidism. Our genome-wide association study (GWAS) identified 44 novel genomic risk markers in 10 loci on chromosomes 2, 6, and 14 (P < 5 × 10–14), including CTLA4, HCP5, HLA-B, POU5F1, CCHCR1, HLA-DRA, HLA-DRB9, TSHR, RPL17P3, and CEP128. We further conducted a comorbidity analysis of our results, and the data revealed a strong correlation between hyperthyroidism patients with thyroid storm and stroke. In this study, we demonstrated application of the PheWAS using large EMR biobanks to inform the comorbidity development in hyperthyroidism patients. Our data suggest significant common genetic risk factors in patients with hyperthyroidism. Additionally, our results show that sex, body mass index (BMI), and thyroid storm are associated with an increased risk of stroke in subjects with hyperthyroidism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Background This study aims to identify the age trajectories of disability in instrumental activities of daily life (IADLs) over 11 years and their correlates, and to estimate disability-free life expectancy for identified trajectory groups in middle-aged and older adults. Methods We included 3118 participants aged 50 and over without IADL limitations at baseline from the Taiwan Longitudinal Study in Aging, followed across 1996–2007. We used group-based trajectory models to identify age trajectories of IADL disability, and multiple logistic regressions to examine their correlates. Sullivan method was used to compute IADL disability-free life expectancy for trajectory groups at different ages. Results We identified two trajectories groups: 67.7% of participants classified as the late-onset group and 32.3% as the early-onset group. Female (adjusted odds ratio [aOR]: 1.93, 95% confidence interval [95% CI]: 1.54, 2.41), not being employed (aOR: 1.30, 95% CI: 1,08, 1,56), poor/fair self-rated health (aOR: 1.31, 95% CI:1.09, 1.58), hypertension (aOR: 1.32, 95% CI: 1.07, 1.63), diabetes mellitus (aOR: 2.29, 95% CI: 1.72, 3.07), arthritis (aOR: 1.42, 95% CI: 1.11, 1.81), stroke (aOR: 2.21, 95% CI: 1.04, 4.70), and one-point increase in a 10-item depression scale (aOR: 1.04, 95% CI: 1.02, 1.06) were associated with early-onset of disability, whereas higher education (aOR: 0.59, 95% CI: 0.42, 0.81), regular exercise (aOR: 0.76, 95% CI: 0.62, 0.93), and participating voluntary or club activities (aOR: 0.78, 95% CI: 0.65, 0.93) related to the late-onset. IADL disability-free life expectancies at 65 years old in the late-onset group were 15.6 years for women and 14.4 for men, respectively, comprising 56.6 and 64.2% of their remaining life, whereas those of the early-onset group were 4.8 and 4.6 years for women and men respectively, comprising 22.5 and 27.2% of remaining life. Conclusions Early-onset of IADLs disability may correlate to chronic conditions, and engagement in employment, exercise, and social participation were associated with a reduced risk of early disability in IADLs.

Hyperthyroidism is a prevalent endocrine disorder, and genetics play a major role in the development of thyroid-associated diseases. In particular, the inheritance of HLA has been demonstrated to induce the highest susceptibility to Graves’ disease (GD). However, thus far, no studies have reported the contribution of HLA to the development of GD and the complications that follow. Thus, in the present study, to the best of our knowledge, for the first time, a powerful imputation method, HIBAG, was used to predict the HLA subtypes among populations with available genome-wide SNP array data from the China Medical University Hospital (CMUH). The disease status was extracted from the CMUH electronic medical records; a total of 2,998 subjects with GD were identified as the cases to be tested and 29,083 subjects without any diagnosis of thyroid disorders were randomly selected as the controls. A total of 12 HLA class I genotypes (HLA-A*02:07-*11:01, HLA-B*40:01-*46:01 and *46:01-*46:01, and HLA-C*01:02-*01:02, *01:02-*03:04, and *01:02-*07:02) and 17 HLA class II genotypes (HLA-DPA1*02:02-*02:02, HLA-DPB1*02:01-*05:01, *02:02-*05:01, and *04:01-*05:01, HLA-DQA1*03:02, HLA-DRB1*09:01-*15:01, and *09:01-*09:01) were found to be associated with GD in the Taiwanese population. Moreover, the HLA subtypes HLA-A*11:01, HLA-B*46:01, HLA-DPA1*01:03, and HLA-DPB1*05:01 were found to be associated with heart disease, stroke, diabetes, and hypertension among subjects with GD. Our data suggest that several HLA alleles are markedly associated with GD and its comorbidities, including heart disease, hypertension, and diabetes.

Background: Functional impairment is frequently seen in patients with stroke. Although the progression of functional recovery after stroke has been proposed, the recovery profile after acute stroke is not well described. The objective of this study is to investigate functional recovery in stroke patients entering post-acute rehabilitation care. Methods: A retrospective cohort study collected the data of patients who entered the stroke Post-acute Care (PAC) programs. Ninety-five patients after stroke with a modified Ranking Scale (mRS) score of 3–4 who were referred to a post-acute care unit for intensive rehabilitation were recruited. The patients underwent functional, quality of life, and neuropsychological evaluation tests at admission and before discharge. The test scores before discharge were used as outcome variables and were compared with the test scores at admission to show functional recovery. Results: The average length of stay was 58.15 days. After an intensive rehabilitation intervention, significant improvements were observed in all test scores. Additionally, a significant removal rate for nasogastric tubes (p = 0.000) and Foley catheters (p = 0.003) was found at discharge. Conclusion: This study showed that the PAC rehabilitation unit was beneficial for patients with acute stroke who had functional impairments. The study results may call for further investigation to identify and develop better models for the delivery of rehabilitation in the stroke PAC unit. Keywords: Post-acute care, Rehabilitation, Stroke, Modified ranking scale

Abstract Background Genetic factors, dysregulation in the endocrine system, cytokine and paracrine factors are implicated in the pathogenesis of familial short stature (FSS). Nowadays, the treatment choice for FSS is limited, with only recombinant human growth hormone (rhGH) being available. Methods Herein, starting from the identification of 122 genetic loci related to FSS, we adopted a genetic-driven drug discovery bioinformatics pipeline based on functional annotation to prioritize crucial biological FSS-related genes. These genes were suggested to be potential targets for therapeutics. Results We discovered five druggable subnetworks, which contained seven FSS-related genes and 17 druggable targerts. Conclusions This study provides a valuable drug repositioning accompanied by corresponding targetable gene clusters for FSS therapy.

The stemness and metastasis of cancer cells are crucial features in determining cancer progression. Argonaute-2 (AGO2) overexpression was reported to be associated with microRNA (miRNA) biogenesis, supporting the self-renewal and differentiation characteristics of cancer stem cells (CSCs). Ursolic acid (UA), a triterpene compound, has multiple biological functions, including anticancer activity. In this study, we find that UA inhibits the proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines using the CCK-8 assay. UA induced a significant decrease in the fraction of CSC in which it was examined by changes in the expression of stemness biomarkers, including the Nanog and Oct4 genes. UA altered invasion and migration capacities by significant decreases in the levels of epithelial-to-mesenchymal transition (EMT) proteins of slug and vimentin. Furthermore, the co-reduction in oncogenic miRNA levels (miR-9 and miR-221) was a result of the down-modulation in AGO2 in breast cancer cells in vitro. Mechanically, UA increases PTEN expression to inactivate the FAK/PI3K/Akt/mTOR signaling pathway and the decreased level of c-Myc in quantitative RT-PCR and Western blot imaging analyses. Our current understanding of the anticancer potential of UA in interrupting between EMT programming and the state of CSC suggests that UA can contribute to improvements in the clinical practice of breast cancer.

Background: In this study we aim to determines the effect of our vision therapy program for 7- to 10-year-old patients who exhibit bilateral amblyopia that is no longer responsive to conventional treatment. Methods: Children with bilateral amblyopia between the ages of 7 and 10 treated with vision therapy at the China Medical University Hospital between 2016 and 2019 were retrospectively reviewed. Age and visual acuity-matched bilateral amblyopes are included as a control group. The visual acuity for both groups showed no improvement for more than 3 months with part-time patching and full refraction correction. The initial and final visual acuity, stereopsis, and refractive status were analyzed. Results: Here, 15 cases were included as the treatment group and 16 cases as a control group. At the endpoint, the study group shows a significant improvement in BCVA, with a mean of 0.32 ± 0.15 logMAR (3 lines improvement) versus 0.003 ± 0.19 logMAR (nearly no improvement) for the control group (p < 0.001). The benefits of treatment are most obvious in the first 3 months after treatment (p < 0.001) and last until the end point. Stereoacuity also improves from 190.00 ± 163.34 to 85.00 ± 61.24 arc seconds, which is a 55.26% improvement. Conclusions: Vision therapy, comprising orthoptic therapy, perceptual learning and dichoptic training, is a successful program for increasing visual acuity and stereoacuity in 7- to 10-year-old children with bilateral amblyopia that is unresponsive to conventional treatment.

ObjectiveDiabetic nephropathy (DN) and diabetic retinopathy (DR) comprise major microvascular complications of diabetes that occur with a high concordance rate in patients and are considered to potentially share pathogeneses. In this case-control study, we sought to investigate whether DR-related single nucleotide polymorphisms (SNPs) exert pleiotropic effects on renal function outcomes among patients with diabetes.Research design and methodsA total of 33 DR-related SNPs were identified by replicating published SNPs and via a genome-wide association study. Furthermore, we assessed the cumulative effects by creating a weighted genetic risk score and evaluated the discriminatory and prediction ability of these genetic variants using DN cases according to estimated glomerular filtration rate (eGFR) status along with a cohort with early renal functional decline (ERFD).ResultsMultivariate logistic regression models revealed that the DR-related SNPs afforded no individual or cumulative genetic effect on the nephropathy risk, eGFR status or ERFD outcome among patients with type two diabetes in Taiwan.ConclusionOur findings indicate that larger studies would be necessary to clearly ascertain the effects of individual genetic variants and further investigation is also required to identify other genetic pathways underlying DN.

Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. Methods: The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. Results: We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). Conclusion: Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.

Background and Objectives: To regain the ability of community ambulation is a meaningful goal for stroke patients. Recent research recommended that the distance accomplished during the six-minute walk test (≥205 m in 6MWT) is the fittest for defining community ambulation. Until now, there are few studies that have used the updated definition to investigate the related predictors. The aim of this study was to investigate the association between the admission clinical parameters and community ambulation measured by the 6MWT at discharge. The other aim was to find the admission Berg Balance Scale (BBS) cut-off score to discriminate between household or community ambulators. Materials and Methods: This cohort study collected the data of patients who entered the post-acute Care Cerebrovascular Diseases program. Multivariate logistic regression was used to identify significant predictors measured at admission that are associated with community ambulation, and a receiver operating characteristic was adopted to calculate the cut-off value for admission status. There were 120 participants included in this study, and 25% (n = 30) of them regained the ability of community ambulation at discharge. The BBS on admission was identified as the only significant predictor for community ambulation (odds ratio 1.06). Results: The optimal cut-off score for the BBS at admission was 29, and the area under the curve for BBS scores on admission when discriminating between household and community ambulators at discharge was 0.74. Conclusions: The admission BBS scores could be used to predict household and community ambulators at discharge in stroke patients. The results of this study could help clinical physicians set appropriate discharge goals early.

Abstract Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p

Our objective was to determine how docosahexaenoic acid (DHA) proportions in human milk are modulated by maternal FADS gene variants and dietary intake in Taiwanese women. Inclusion criteria included being healthy, 20–40 y old, having had a full-term baby that they intended to breast feed for at least 1 month, and willingness to participate in this study. Intake of DHA was assessed by food frequency questionnaire and fatty acids were analyzed in human milk samples collected 3–4 weeks postpartum. Based on multiple linear regression of data from 164 mothers that completed this study, there was 0.28% (FA%) reduction in milk DHA in high versus low genetic risk (stratified by whether minor allele numbers were ≥ 3 in rs1535 and rs174448) and 0.45% reduction in low versus high intake (stratified by whether DHA intake reached 200 mg/d). There was a significant gene–diet interaction; mothers with low genetic risk only had high milk DHA proportions with high DHA intake, whereas for mothers with high genetic risk, dietary effects were quite limited. Therefore, for FADS single nucleotide polymorphism in Taiwanese women, increasing DHA intake did not correct low milk DHA proportions in those with a high-risk genotype. Diet only conferred benefits to those with a low-risk genotype. Trial registration: This trial was retrospectively registered (Feb 12, 2019) in ClinicalTrials.gov (No. NCT03842891, https://clinicaltrials.gov/ct2/show/NCT03842891).

The anti-tumor activity of diosgenin, a new steroidal constituent present in fenugreek, on two human breast cancer cell lines, MCF-7 and Hs578T, was studied. Diosgenin treatment resulted in cell growth inhibition, cell cycle arrest, and apoptosis in concentration- and time-dependent manners in both cell lines. Western blot analyses of whole cell lysates for cell cycle proteins showed that diosgenin altered phosphorylated cyclin checkpoint1 (p-Chk1Ser345) and cyclin B expression, which resulted in G2/M phase blockade. Mechanistically, Cdc25C-Cdc2 signaling was involved in inactivating Chk1Ser345 by p53-dependence in MCF-7 cells and p21-dependence in Hs578T cells that are p53-deficient. Moreover, diosgenin induced a significant loss of the mitochondrial membrane potential in breast cancer cells, and prominently affected cell death through down-regulation of the anti-apoptotic protein, Bcl-2. This released cytochrome c and activated the caspase signaling cascade. Taken together, these findings reveal that the anti-proliferative activity of diosgenin involves the induction of G2/M phase arrest via modulating the Cdc25C-Cdc2-cyclin B pathway and mitochondria-mediated apoptosis in human breast cancer cell lines. This suggests the potential usefulness of diosgenin in treating breast cancer.

Diabetic nephropathy (DN) is one of the most common complications in diabetic patients. New noninvasive markers are still needed for the early detection of DN before identifiable alternations in kidney function or urine albumin excretion occurs. A C18 plate and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were used to compare the urinary protein profiles of 238 subjects from the following 4 groups: patients with type 2 diabetic (T2D) with microalbuminuria, patients with DM without micro- or macroalbuminuria, patients with micro- or macroalbuminuria due to nondiabetic disease, and healthy controls. β2-microglobulin (B2M) and Clara-cell protein (CC16) were found to be highly released in the urine of patients with proteinuria due to nondiabetic or diabetic diseases. In differentiating nephropathy from healthy subject, the B2M and CC16 markers have a combined sensitivity and specificity of 77.3% and 91.8%, respectively. In distinguishing T2D with microalbuminuria from T2D patients, the combined markers have sensitivity and specificity of 66% and 73%, respectively. The predictive ability of B2M and CC16 for early renal functional decline (ERFD) was validated in 125 T2D patients with a follow-up times. The odds ratio (OR) of combined B2M and CC16 markers for developing ERFD was 7.59 (95% CI: 1.97-29.24). The detection of B2M and CC16 with the C18 plate-MALDI-TOF MS approach could be an attractive and practical assay for rapid diagnosis of nephropathy in nondiabetic/diabetic patients and as a predictor of ERFD among T2D patients who had not manifested significant kidney disease at baseline.

Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Leprdb/ + Leprdb, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis.

Benign paroxysmal positional vertigo (BPPV), the most common type of vertigo in the general population, is thought to be caused by dislodgement of otoliths from otolithic organs into the semicircular canals. In most cases, however, the cause behind the otolith dislodgement is unknown. Dental procedures, one of the most common medical treatments, are considered to be a possible cause of BPPV, although this has yet to be proven. This study is the first nationwide population-based case-control study conducted to investigate the correlation between BPPV and dental manipulation.Patients diagnosed with BPPV between January 1, 2007 and December 31, 2012 were recruited from the National Health Insurance Research Database in Taiwan. We further identified those who had undergone dental procedures within 1 month and within 3 months before the first diagnosis date of BPPV. We also identified the comorbidities of the patients with BPPV, including head trauma, osteoporosis, migraine, hypertension, diabetes, hyperlipidemia and stroke. These variables were then compared to those in age- and gender-matched controls.In total, 768 patients with BPPV and 1536 age- and gender-matched controls were recruited. In the BPPV group, 9.2% of the patients had undergone dental procedures within 1 month before the diagnosis of BPPV. In contrast, only 5.5% of the controls had undergone dental treatment within 1 month before the date at which they were identified (P = 0.001). After adjustments for demographic factors and comorbidities, recent exposure to dental procedures was positively associated with BPPV (adjusted odds ratio 1.77; 95% confidence interval 1.27-2.47). This association was still significant if we expanded the time period from 1 month to 3 months (adjusted odds ratio 1.77; 95% confidence interval 1.39-2.26).Our results demonstrated a correlation between dental procedures and BPPV. The specialists who treat patients with BPPV should consider dental procedures to be a risk factor, and dentists should recognize BPPV as a possible complication of dental treatment.

Background: Gastrodia elata Blume, also called Tian Ma (TM), has been used to treat stroke for centuries. However, its effects on inflammation in acute cerebral ischemic injury and underlying mechanisms involved in microglial polarization remain unknown. The present study explored the effects of the TM extract on the modulation of microglial M1/M2 polarization 2 days after transient cerebral ischemia. Methods: Male Sprague Dawley rats were intracerebroventricularly administered with 1% dimethyl sulfoxide 25 min before cerebral ischemia and subsequently intraperitoneally administered 0.25 g/kg (DO + TM-0.25 g), 0.5 g/kg (DO + TM0.5 g), or 1 g/kg (DO + TM-1 g) of the TM extract after cerebral ischemia onset. Results: DO + TM-0.5 g and DO + TM-1 g treatments downregulated the following: phospho-c-Jun N-terminal kinase (p-JNK)/JNK, tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3), TRAF3-interacting JNKactivating modulator (T3JAM), p-nuclear factor-kappa B p65 (p-NF-κB p65)/ NF-κB p65, ionized calcium-binding adapter molecule 1 (Iba1), CD86, TNF-α, interleukin (IL)-1β, and IL-6 expression and toll-like receptor 4 (TLR4)/Iba1, CD86/ Iba1, and p-NF-κB p65/Iba1 coexpression. These treatments also upregulated IL10, nerve growth factor, and vascular endothelial growth factor A expression and YM-1/2/Iba1 and IL-10/neuronal nuclei coexpression in the cortical ischemic rim. The JNK inhibitor SP600125 exerted similar treatment effects as the DO + TM0.5 g and DO + TM-1 g treatments. Conclusion: DO + TM-0.5 g and DO + TM-1 g/kg treatments attenuate cerebral infarction by inhibiting JNK-mediated signaling. TM likely exerts the neuroprotective effects of promoting M1 to M2 microglial polarization by inhibiting JNK/TLR4/T3JAM/NF-κB-mediated signaling in the cortical ischemic rim 2 days after transient cerebral ischemia. [ABSTRACT FROM AUTHOR]

Background/Aim: Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management. Patients and Methods: We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020. Results: Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years. Conclusion: Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background/Aim: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a major cause of blindness in working-age adults. Diosgenin (DG), a natural steroidal sapogenin extracted from fenugreek seeds and wild yam roots, has hypolipidemic, hypoglycemic, anticancer, and anti-inflammatory properties. Given its pharmacological effects, we speculated that DG may be a promising treatment for DR. Therefore, this study was aimed at evaluating the effectiveness of DG in preventing or slowing DR progression in a mouse model (+Leprdb/+Leprdb strain) of type 2 diabetes (T2D). Materials and Methods: DG (5.0 mg/kg body weight) or phosphatebuffered saline (PBS) was administered to 8-week-old T2D mice via oral gavage daily for 24 weeks. Paraffin-embedded eye tissues from the mice were collected and stained with hematoxylin and eosin to evaluate retinal histopathology. Apoptosis-related proteins BCL2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 were evaluated by western blotting of mouse retinas. Results: Body weight was slightly reduced in the DG-treated group; however, glucose levels were not markedly different between the DGand PBS-treated groups. Total retinal thickness, thickness of the photoreceptor and outer nuclear layers, and loss of ganglion cells significantly improved in the retina of the DGtreated T2D mice compared with those in the PBS-treated T2D mice. Cleaved caspase-3 level significantly decreased in the retina of the DG-treated T2D mice. Conclusion: DG alleviates DR pathology and exerts a protective effect on the T2D mouse retina. The inhibitory effects of DG on DR may involve mechanisms of the anti-apoptotic pathway. [ABSTRACT FROM AUTHOR]