Caregivers play a major role in providing care for patients with Alzheimer's disease (AD) and are themselves at higher risk of health comorbidities.
To address the impact of neuropsychiatric symptoms ...of patients in different stages of AD on their caregivers' burden.
This prospective study enrolled 260 AD patients with clinical dementia rating (CDR) of 0.5, 1 and 2 at a tertiary medical center.
All patients were tested using the mini-mental state examination (MMSE), the cognitive abilities screening instrument (CASI), the neuropsychiatric inventory (NPI) and the CDR scale. Data regarding therapeutic outcomes of anti-Alzheimer's drugs were also collected. Caregivers were tested using NPI.
The mean follow-up interval was 25.0 ± 12.2 months, and two patients died during follow-up. NPI-burden was positively correlated with NPI-sum ( r = 0.822, P < 0.001) but negatively correlated with years of education ( r = -0.140, P = 0.024), CASI score ( r = -0.259, P < 0.001) and MMSE score ( r = -0.262, P <0.001). Multiple linear regression analysis showed that only NPI-sum was independently associated with mean NPI-burden. Both higher mean CASI and MMSE scores had better therapeutic outcome of anti-Alzheimer's drugs ( P = 0.001 and P = 0.005, respectively).
The severity of neuropsychiatric symptoms in patients with AD was positively associated with caregiver's stress, and patients with better cognitive functions, under treatment with anti-Alzheimer's drugs, had better therapeutic outcomes. To reduce the impact of neuropsychiatric symptoms, it is crucial to detect dementia in its early phases and provide early intervention with anti-Alzheimer's drugs, which might help decrease the caregiver burden, thereby improving their quality of life.
Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic ...pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5β1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5β1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.
This study investigated seasonal variations in the mass concentration and chemical composition of ambient aerosols observed at three stations (coastal, mountainous, and downtown sites) in northern ...Taiwan from March 2009 to February 2012. The results show that the major aerosol components include ammonium, sulfate, nitrate, sea salt, dust, organic carbon, and elemental carbon, whereas the mass fraction of each species depends on the sampling location and season. A significant correlation (r = 0.7–0.8) was observed in aerosol concentrations measured at the respective stations, indicating that aerosol concentrations were dominated by regional‐scale factors. Ammonium, sulfate, and nitrate consistently reached respective peak values in the spring in conjunction with dust particle levels. This shows that the transport of dust and particulate air pollutants from the Asian continent has affected the atmospheric environment in this area. Distinct seasonality was observed for sea salt and secondary organic carbon (SOC): sea salt levels peaked in the autumn, whereas SOC levels peaked in the summer, implying that their sources were regulated by independent seasonal factors. Correlation between sea salt concentration and surface wind speed was derived from coastal measurements and showed a high value for the wind speed sensitivity parameter of around 0.37 for our location. In addition, it was revealed that the SOC concentration in aerosols was positively correlated with oxidant photolysis index (Ox × UVB), suggesting that the SOC seasonality was dominated by hydroxyl radical production.
Key Points
Inorganic particulate pollutants and dust consistently peaked in the spring due to Asian outflow effects
Ambient concentrations of sea salt particles were exponentially correlated with surface wind speeds
The production of secondary organic aerosols was dominated by the photolysis of total oxidants
Summary
Background
Cirrhotic patients admitted to intensive care units (ICUs) have high mortality rates. The Chronic Liver Failure–Sequential Organ Failure Assessment (CLIF‐SOFA) score, a modified ...Sequential Organ Failure Assessment (SOFA) score, is a newly developed scoring system exclusively for patients with end‐stage liver disease.
Aim
To externally validate the efficacy of the CLIF‐SOFA score and evaluate other scoring systems for 6‐month mortality in critically ill cirrhotic patients.
Methods
This study prospectively recorded and analysed the data for 30 demographical parameters and some clinical characteristic variables on day 1 of 250 cirrhotic patients admitted to a 10‐bed specialised hepatogastroenterology ICU in a 2000‐bed tertiary care referral hospital during the period from September 2010 to August 2013.
Results
The overall in‐hospital and 6‐month mortality rate were 58.8% (147/250) and 78.0% (195/250), respectively. Liver diseases were mostly attributed to hepatitis B virus infection (32%). Multiple Cox logistic regression hazard analysis revealed that Glasgow coma scale, both the CLIF‐SOFA and Acute Physiology and Chronic Health Evaluation III (ACPACHE III) scores determined on the first day of ICU admission were independent predictors of 6‐month mortality. Analysis of the area under the receiver operating characteristic curve revealed that the CLIF‐SOFA score had the best discriminatory power (0.900 ± 0.020). Moreover, the cumulative 6‐month survival rates differed significantly for patients with a CLIF‐SOFA score ≤11 and those with a CLIF‐SOFA score >11 on the ICU admission day.
Conclusion
Both CLIF‐SOFA and APACHE III scores are excellent prognosis evaluation tools for critically ill cirrhotic patients.
Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its ...stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2(-)/FLT3-ITD(+) genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this ...study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.
Summary
Background Hand‐foot skin reaction is a distinctive cutaneous side‐effect of antineoplastic kinase inhibitor‐targeted therapy. Severe hand‐foot skin reaction requires postponement of ...treatment or dose reduction. Histopathological studies of skin toxicity associated with kinase inhibitors are currently unavailable.
Objectives To report the clinical and histopathological findings of hand‐foot skin reaction produced by the multikinase inhibitor sorafenib.
Methods Nine patients with metastatic carcinoma—seven with renal cell carcinoma (RCC), one with melanoma and one with hepatocellular carcinoma (HCC)—received continuous, oral sorafenib 400 mg twice daily. Hand‐foot skin reaction was defined and graded according to National Cancer Institute Common Toxicity Criteria 3.0. Biopsies from lesions of erythematous scaly or blistering skin were obtained from five cases (four RCC and one HCC).
Results Seven of the nine (78%) patients developed hand‐foot skin reaction characterized by well‐demarcated, tender, erythematous papules and plaques with greyish blisters or hyperkeratotic, callus‐like formations on palmoplantar surfaces and distal phalanges. Skin biopsy of hand‐foot skin reaction lesions revealed epidermal acanthosis, papillomatosis, parakeratosis, dispersed dyskeratotic cells and keratinocyte vacuolar degeneration. Other skin toxicities included angular cheilitis, seborrhoeic dermatitis and perianal dermatitis.
Conclusions The clinical manifestations and histopathological features of sorafenib‐induced skin reactions are unique. The most relevant histopathological findings of hand‐foot skin reaction include keratinocyte vacuolar degeneration, the presence of intracytoplasmic eosinophilic bodies, and intraepidermal blisters in the stratum malpighii. Further studies are warranted to elucidate the mechanisms of this novel multitargeted kinase inhibitor‐associated skin reaction.
Metabolic connectivity as showed by 18F fluorodeoxyglucose (FDG) positron emission tomography (FDG‐PET) reflects neuronal connectivity. The aim of this study was to investigate the genetic impact on ...metabolic connectivity in default mode subnetworks and its clinical‐pathological relationships in patients with Alzheimer's disease (AD). We separately investigated the modulation of 2 default mode subnetworks, as identified with independent component analysis, by comparing APOE‐ε4 carriers to noncarriers with AD. We further analyzed the interaction effects of APOE (APOE‐ε4 carriers vs noncarriers) with PICALM (rs3851179‐GG vs rs3851179‐A‐allele carriers) on episodic memory (EM) deficits, reduction in cerebral metabolic rate for glucose (CMRgl) and decreased metabolic connectivity in default mode subnetworks. The metabolic connectivity in the ventral default mode network (vDMN) was positively correlated with EM scores (β =0.441, P < .001). The APOE‐ε4 carriers had significantly lower metabolic connectivity in the vDMN than the APOE‐ε4 carriers (t(96) = −2.233, P = .028). There was an effect of the APOE‐PICALM (rs3851179) interactions on reduced CMRgl in regions of vDMN (P < .001), and on memory deficits (F3,93 =5.568, P = .020). This study identified that PICALM may modulates memory deficits, reduced CMRgl and decreased metabolic connectivity in the vDMN in APOE‐ε4 carriers. 18F FDG‐PET‐based metabolic connectivity may serve a useful tool to elucidate the neural networks underlying clinical‐pathological relationships in AD.
Metabolic connectivity in ventral default mode network (vDMN) was related to episodic memory performance in patients with mild Alzheimer's disease. APOE‐ε4 carrier genotype has a detrimental effect on metabolic connectivity in the vDMN.
To establish an ideal microenvironment for regenerating maxillofacial defects, recent research interests have concentrated on developing scaffolds with intricate configurations and manipulating the ...stiffness of extracellular matrix toward osteogenesis. Herein, we propose to infuse a degradable RGD-functionalized alginate matrix (RAM) with osteoid-like stiffness, as an artificial extracellular matrix, to a rigid 3D-printed hydroxyapatite scaffold for maxillofacial regeneration. The 3D-printed hydroxyapatite scaffold was produced by microextrusion technology and showed good dimensional stability with consistent microporous detail. RAM was crosslinked by calcium sulfate to manipulate the stiffness, and its degradation was accelerated by partial oxidation using sodium periodate. The results revealed that viability of bone marrow stem cells was significantly improved on the RAM and was promoted on the oxidized RAM. In addition, the migration and osteogenic differentiation of bone marrow stem cells were promoted on the RAM with osteoid-like stiffness, specifically on the oxidized RAM. The in vivo evidence revealed that nonoxidized RAM with osteoid-like stiffness upregulated osteogenic genes but prevented ingrowth of newly formed bone, leading to limited regeneration. Oxidized RAM with osteoid-like stiffness facilitated collagen synthesis, angiogenesis, and osteogenesis and induced robust bone formation, thereby significantly promoting maxillofacial regeneration. Overall, this study supported that in the stabilized microenvironment, oxidized RAM with osteoid-like stiffness offered requisite mechanical cues for osteogenesis and an appropriate degradation profile to facilitate bone formation. Combining the 3D-printed hydroxyapatite scaffold and oxidized RAM with osteoid-like stiffness may be an advantageous approach for maxillofacial regeneration.
Hyperuricemia (HUA) is associated with the prevalence of metabolic syndrome (MetS) and cardiovascular risks in various populations. HUA is also able to induce cardiomyocyte hypertrophy in mouse ...models. However, the dose-response effects of serum uric acid (SUA) on the prevalence of MetS and electrocardiographic left ventricular hypertrophy (LVH) are unclear.
We retrospectively collected data from 18,932 individuals who underwent an annual health examination between 1/1/2016 and 12/31/2016. We excluded those with systemic diseases or missing questionnaires. The primary study endpoints were the prevalence of MetS and LVH, which were defined by the criteria for the Taiwanese population and the “SPRINT” trial. The cohort consisted of 17,913 individuals with a mean age of 31.2 years (SD 7.4) and a mean body mass index of 24.6 kg/m2 (SD 3.6); 87.1% of the individuals were men. The prevalence rates of HUA, MetS, and LVH were 29.5%, 9.4%, and 0.32%, respectively, in the overall study population. The HUA group was predominantly male and had significantly poorer lifestyle choices and greater laboratory cardiometabolic biomarker values than did the normouricemic group. However, the frequencies of physical activity were comparable between the two groups. After adjusting for confounders, SUA was associated with MetS (OR:1.473, 95% CI:1.408–1.540, P < 0.001) and LVH (OR:1.301, 95% CI:1.064–1.591, P = 0.01).
We demonstrated that the dose-response effects of SUA are associated with the prevalence of MetS and electrocardiographic LVH in healthy individuals from Taiwan. Based on this evidence, future studies should investigate urate-lowering therapy and cardiovascular benefits in individuals with HUA (ClinicalTrials.gov number NCT03473951).
•Serum uric acid (SUA) was associated with the prevalence of metabolic syndrome and LVH.•The association is independent of life style choice and physical activity.•The association did not change with adjustment for kidney function.•Future studies might evaluate urate-lowering effects on the improvement of metabolic syndrome and LVH.
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