Yen-Ting Lai

Deficiency of CPEB2-Confined Choline Acetyltransferase Expression in the Dorsal Motor Nucleus of Vagus Causes Hyperactivated Parasympathetic Signaling-Associated Bronchoconstriction.

Cytoplasmic polyadenylation element binding protein 2 (CPEB2) is an RNA-binding protein and translational regulator. To understand the physiological function of CPEB2, we generated CPEB2 knock-out (KO) mice and found that most died within 3 d after birth. CPEB2 is highly expressed in the brainstem, which controls vital functions, such as breathing. Whole-body plethysmography revealed that KO neonates had aberrant respiration with frequent apnea. Nevertheless, the morphology and function of the respiratory rhythm generator and diaphragm neuromuscular junctions appeared normal. We found that upregulated translation of choline acetyltransferase in the CPEB2 KO dorsal motor nucleus of vagus resulted in hyperactivation of parasympathetic signaling-induced bronchoconstriction, as evidenced by increased pulmonary acetylcholine and phosphorylated myosin light chain 2 in bronchial smooth muscles. Specific deletion of CPEB2 in cholinergic neurons sufficiently caused increased apnea in neonatal pups and airway hyper-reactivity in adult mice. Moreover, inhalation of an anticholinergic bronchodilator reduced apnea episodes in global and cholinergic CPEB2-KO mice. Together, the elevated airway constriction induced by cholinergic transmission in KO neonates may account for the respiratory defect and mortality. SIGNIFICANCE STATEMENT This study first generated and characterized cpeb2 gene-deficient mice. CPEB2-knock-out (KO) mice are born alive but most die within 3 d after birth showing no overt defects in anatomy. We found that the KO neonates showed severe apnea and altered respiratory pattern. Such respiratory defects could be recapitulated in mice with pan-neuron-specific or cholinergic neuron-specific ablation of the cpeb2 gene. Further investigation revealed that cholinergic transmission in the KO dorsal motor nucleus of vagus was overactivated because KO mice lack CPEB2-suppressed translation of the rate-limiting enzyme in the production of acetylcholine (i.e., choline acetyltransferase). Consequently, increased parasympathetic signaling leads to hyperactivated bronchoconstriction and abnormal respiration in the KO neonates.

Statins Reduces the Risk of Dementia in Patients with Late-Onset Depression: A Retrospective Cohort Study

Objective Patients with late-onset depression (LOD) have been reported to run a higher risk of subsequent dementia. The present study was conducted to assess whether statins can reduce the risk of dementia in these patients. Methods We used the data from National Health Insurance of Taiwan during 1996–2009. Standardized Incidence Ratios (SIRs) were calculated for LOD and subsequent dementia. The criteria for LOD diagnoses included age ≥65 years, diagnosis of depression after 65 years of age, at least three service claims, and treatment with antidepressants. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients for validation studies. Kaplan-Meier curve estimate was used to measure the group of patients with dementia living after diagnosis of LOD. Results Totally 45,973 patients aged ≥65 years were enrolled. The prevalence of LOD was 12.9% (5,952/45,973). Patients with LOD showed to have a higher incidence of subsequent dementia compared with those without LOD (Odds Ratio: 2.785; 95% CI 2.619–2.958). Among patients with LOD, lipid lowering agent (LLA) users (for at least 3 months) had lower incidence of subsequent dementia than non-users (Hazard Ratio = 0.781, 95% CI 0.685–0.891). Nevertheless, only statins users showed to have reduced risk of dementia (Hazard Ratio = 0.674, 95% CI 0.547–0.832) while other LLAs did not, which was further validated by Kaplan-Meier estimates after we used the propensity scores with the one-to-one nearest-neighbor matching model to control the confounding factors. Conclusions Statins may reduce the risk of subsequent dementia in patients with LOD.

Glycogen synthase kinase 3 beta in somites plays a role during the angiogenesis of zebrafish embryos.

Glycogen synthase kinase 3 beta (Gsk3b) acts as a negative modulator in endothelial cells through the Wnt/β–catenin/PI3K/AKT/Gsk3b axis in cancer‐induced angiogenesis. However, the function of Gsk3b during embryonic angiogenesis remains unclear. Here, either gsk3b knockdown by morpholino or Gsk3b loss of activity by LiCl treatment had serious phenotypic consequences, such as defects in the positioning and patterning of intersegmental blood vessels and reduction of vegfaa121 and vegfaa165 transcripts. In embryos treated with the phosphatidylinositol 3‐kinase inhibitor, angiogenesis was severely inhibited, along with reduced Wnt, phosphorylated AKT and phosphorylated Gsk3b, suggesting that the remaining Gsk3b in somites could still degrade β–catenin, resulting in decreased vascular endothelial growth factor Aa(VegfAa) expression. However, in gsk3b‐mRNA‐overexpressed embryos, intersegmental vessels ectopically sprouted by the increase in phosphorylated‐Gsk3b which prevented the degradation of β–catenin and promoted the increase in phosphorylated AKT activity, thus increasing VegfAa expression in somites. Interestingly, the Gsk3b‐dependent cross‐talk between PI3K/AKT and Wnt/β–catenin suggests that Wnt/β–catenin and PI3K/AKT interaction controls embryonic angiogenesis by a positive feedback loop rather than a hierarchical framework such as that found in cancer‐induced angiogenesis. Thus, both active and inactive forms of Gsk3b mediate the cooperative signaling between Wnt/β–catenin and PI3K/AKT to control VegfAa expression in somites during angiogenesis in zebrafish embryos.

The Effects of Upper Limb Exercise Through Yoga on Limb Swelling in Chinese Breast Cancer Survivors – A Pilot Study

Purpose: Breast cancer is the most common female cancer. The aim of this study was to assess the impact of yoga on lymphedema in breast cancer survivors. Design: Repeated measures before and after the intervention. We enrolled 15 women with breast cancer who had not previously worn elastic clothing to treat lymphedema. Methods: The program was led by a certified trainer and consisted of 60-minute sessions, three times a week for 12 weeks. The volumes of the affected and normal limbs were measured. A self-assessed edema score was also recorded. Findings: Fifteen patients completed the program, none of whom suffered from complications related to exercise. There was no significant edema after exercise. No significant differences were noted in subgroup analysis by age or the affected arm. Conclusions: Yoga does not induce lymphedema. Clinical Relevance: Lymphedema is usually treated with uncomfortable elastic clothing, and high-resistance exercise may induce edema. Yoga may be suitable for these patients.

Shift from darbepoetin-α to continuous erythropoietin receptor activator decreases serum aluminium concentration in patients on hemodialysis.

OBJECTIVE The response of erythropoietic stimulating agents (ESA) in uremic patients may be associated with the changes of biochemical parameters, metal elements and inflammation status during the shift from one ESA to another. METHOD We compared changes in above mentioned factors after switching from darbepoetin-α (DPO) 20μg weekly for 10 weeks to continuous erythropoietin receptor activator (CERA) 100μg monthly for 10 weeks in uremic patients on hemodialysis. The haematocrit (Hct), metal elements and inflammation status are the primary outcome. Subjects included 54 patients without transfusion or bleeding or additional ESAs. Responders (IR, n=36) were defined as patients with an increase in Hct after the swtich. RESULT Although there was no significant difference in overall mean Hct after the switch (p=0.135), there are significantly greater mean number of red blood cells (RBC) (p=0.006), higher platelet numbers (p=0.001), larger RBCs (p=0.017) and higher creatinine (p=0.04) and total cholesterol (T-CHOL) (p=0.003) levels. Mean overall aluminium (Al) level decreased significantly (p=0.001). C-reactive protein (CRP) also decreased (p=0.016). The overall LDH increased (p=0.049) and potassium decreased significantly (p=0.036), which indicating active erythropoiesis. The calcium (Ca) level was significantly higher (p=0.034) and phosphate was significantly lower (p=0.028) after the shift. Although there was no significant increase in overall levels of parathyroid hormone (PTH) after the shift (p=0.061), but the pre-shift and post-shift PTH level was significantly higher in IRs than in non-IRs (p=0.003 and p=0.027, respectively). IRs had a significantly lower initial T-CHOL (p=0.03) and initial CRP (p=0.012) than non-responders, which may be related to lower inflammation. CONCLUSION We found the shift from DPO to CERA results in lower Al levels, a reduced inflammatory response, and an increase in RBC number and PTH level in uremic patients on hemodialysis.

Fixed dose of long-acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis

Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 μg once monthly for 2 months, 50 μg twice monthly for 2 months and then 100 μg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)‐α, interleukin (IL)‐1, IL‐6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty‐seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF‐α (30.71 vs 35.67 ng/mL, P=.007), IL‐6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 106/mm3, P=.025) and a lower IL‐1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD‐related anaemia.

Associations between perfluorinated chemicals and serum biochemical markers and performance status in uremic patients under hemodialysis

Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) are commonly used perfluorinated chemicals (PFCs). PFCs are mainly excreted by urine. Uremic patients tend to accumulate toxins in their body and have poor functional status. We investigated the associations between PFCs and the clinical profile of uremic patients under hemodialysis (HD). Liquid chromatography tandem mass spectrometry coupled with isotope dilution was used to quantify PFOA and PFOS. We enrolled 126 patients under regular HD. Compared with previous research, the concentration of PFOA was lower, but that of PFOS was higher in uremic patients than in the general population. The levels of PFOA and PFOS in uremic patients before dialysis were 0.52 (ng/ml) and 21.84 (ng/ml) respectively. The PFOA level remained unchanged but that of PFOS decreased to1.85 ng/mL after dialysis. PFOS can be removed by HD. Patients using hypertensive medication had a lower PFOS then those who did not. The PFOS level was negatively correlated with the duration of the HD session and patient performance status, but positively correlated with levels of cholesterol, chloride (an indicator of acidemia), ferritin, and total protein. (p<0.05). The association with serum protein may explain the long half-life of PFCs in humans. This is the first study which investigated PFCs in uremic patients and showed PFCs are associated with adverse effects in this population.

Far-infrared ray patches relieve pain and improve skin sensitivity in myofascial pain syndrome: A double-blind randomized controlled study

OBJECTIVE Myofascial pain syndrome (MPS) is a common disorder characterized by muscle pain if myofascial trigger points (MTrP) are stimulated. This study evaluated the effectiveness of far-infrared ray (FIR) patches in reducing the severity of pain in patients with MPS. METHODS A double-blind, randomized controlled study involving 125 patients with MPS and 201 MTrPs located in the trapezius muscle. A FIR patch was applied to 98 MTrPs for 24h in the intervention group (61 patients) and a placebo patch was applied to 91 MTrPs in the control group (57 patients) at the end. Pain intensity was measured using the visual analogue scale (V) while pressure pain threshold (P) and maximal pain tolerance (T) were measured using an algometer before and after treatment. RESULTS The mean age of the patients was 37.16 years old and 67% were female. There was a positive correlation between P and T (p<0.001). Older Age was associated with higher P and T due to poor skin sensitivity (p<0.001). V improved significantly in both groups to a similar extent, but only in the intervention group, P and T decreased significantly (which implied better skin sensitivity) (p<0.05). P and T decreased the most in the female group aged over 35, probably due to thinner skin in this subgroup. CONCLUSIONS FIR and placebo patches were equally effective at relieving pain (with decreased V), but P and T dropped only in the intervention group with FIR patches. This probably resulted from FIR penetrated only to the skin layer and improved skin sensitivity with more blood circulation, but the muscle remained unaffected. Further studies should investigate the effect of longer exposure or higher energy applications.

An Introduction to the Tendency of Online Cosmetic Advertisement Design

With the increasing popularity of the Internet, purchase patterns of the public have shown some innovations. This has encouraged advertising industry to march towards the web market, and establish models of communication with consumers. This study is intended to understand the focuses and elements of cosmetic web ads by widely collecting such advertising contents. Typically, in a cosmetic ad, the product endorser is often the subject of the advertisement. Therefore, this study is investigating such points as what role to choose, how demonstration of the difference role is distinguished, and how validity of the difference role is integrated. The current study is expecting to discover the classification of variables that contributed to the design tendency through surveys, and further provide cosmetics and advertising industry with introduction as reference. It is also expected that general rules of cosmetic web ads should be set out for visual designers of web pages, for preference of consumers, and even for applications in the teaching of webpage design.