Availability and stability of palliative care for family members of terminally ill patients in an integrated model of health and social care.

BACKGROUND: Palliative care and the integration of health and social care have gradually become the key direction of development to address the aging of the population and the growing burden of multimorbidity at the end of life in the elderly. AIMS: To explore the benefits/effectiveness of the availability and stability of palliative care for family members of terminally ill patients in an integrated institution for health and social care. METHODS: This prospective observational study was conducted at an integrated institution for health and social care. 230 patients with terminal illness who received palliative care and their family members were included. Questionnaires and scales were administered to the family members of patients during the palliative care process, including quality-of-life (SF-8), family burden (FBSD, CBI), anxiety (HAMA), and distress (DT). We used paired t-tests and correlation analyses to analyze the data pertaining to our research questions. RESULTS: In the integrated institution for health and social care, palliative care can effectively improve quality of life, reduce the family's burden and relieve psychological impact for family members of terminally ill patients. Palliative care was an independent influencing factor on the quality of life, family burden, and psychosocial status. Independently of patient-related and family-related factors, the results are stable and widely applicable. CONCLUSION: The findings underline the availability and stability of palliative care and the popularization of an integrated service model of health and social care for elder adults.

Three Neolignan Glycosides from the Root of Nothopanax davidii.

Three neolignan glycosides, including a new compound (7S,8R)-dihydro-3'-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol-9-O-ß-D-xylopyranoside (1), were isolated from the root of Nothopanax davidii. Their structures were determined by extensive spectroscopic analyses, particularly NMR, HR-ESI-MS, and ECD experiments, and the absolute configuration of 2 was first definitively determined. The anti-tumor activity was assessed on four tumor cells by MTT assay, the anti-inflammatory activity was determined by inhibition of NO production in LPS reduced RAW264.7 cells, and the interaction with iNOS was predicted by molecular docking. At the dose of 100 µM, the three neolignan glycosides showed no cytotoxic activity against HepG2, HCT116, HeLa and A549 human tumor cells, but significantly inhibited LPS induced NO generation in RAW264.7 cells with inhibition rates of 31.53 %, 23.95 %, and 20.79 %, respectively, showing weak anti-inflammatory activity, possibly due to their binding to key residues of iNOs involved in inhibitor binding.

circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop.

BACKGROUND: In recent years, an increasing number of studies have indicated that circular RNA plays crucial roles in regulating tumor development and chemoresistance. Using two high-throughput RNA sequence datasets, we previously found that circEXOC6B was downregulated in colon cancer. However, its role and mechanism in colorectal cancer (CRC) remained unknown. METHODS: Real-time quantitative PCR was used to examine the expression of circEXOC6B in CRC tissues. In vivo and in vitro functional experiments were performed to determine the suppressor role of circEXOC6B in CRC progression. RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, fluorescence in situ hybridization, and immunofluorescence were applied to investigate the possible mechanisms connecting circEXOC6B to CRC growth and 5-fluorouracil-induced apoptosis. Chromatin immunoprecipitation, dual-luciferase assay, western blot, and immunohistochemistry were used to explore the mechanisms underlying the HIF1A regulation of RRAGB transcription. RESULTS: circEXOC6B was downregulated in CRC tissues, and its lower expression was associated with poor prognosis of patients. Functional experiments showed that circEXOC6B inhibited growth and increased the 5-fluorouracil-induced apoptosis of CRC cells in vitro and in vivo. Mechanistically, circEXOC6B inhibited the heterodimer formation of RRAGB by binding to it, thereby suppressing the mTORC1 pathway and HIF1A level. In addition, HIF1A upregulated the transcription of RRAGB by binding to its promoter region. Altogether, the results demonstrated that a HIF1A-RRAGB-mTORC1 positive feedback loop drives tumor progression in CRC, which could be interrupted by circEXOC6B. CONCLUSIONS: circEXOC6B inhibits the progression of CRC and enhances the chemosensitivity of CRC cells to 5-fluorouracil by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop. circEXOC6B is a possible therapeutic target for CRC treatment.

Lifetime pathogen burden, inflammatory markers, and depression in community-dwelling older adults.

The link between pathogen exposure and mental health has long been hypothesized, but evidence remains limited. We investigated the association of seropositivity to common pathogens and total pathogen burden with depression and mental health and explored the role of mediating inflammatory cytokines. We profiled in 884 participants in the Singapore Longitudinal Ageing Studies, mean (SD) age: 67.9 (8.1) years, their seropositivities for 11 pathogens (CMV, HSV 1, HSV 2, HHV-6, EBV, VZV, RSV, Dengue, Chikungunya, H. Pylori and Plasmodium) and pathogen burden, Geriatric Depression Scale (GDS) score at baseline and 3-4 and 6-8 years follow-up, and baseline Mental Component Score (MCS) of 12-Item Short Form Survey (SF-12). Inflammatory markers included CRP, TNF-α, IL-6, MIP-1α, sgp130, sTNF-RI, sTNF-RII, C3a, and MCP-2. Controlling for age, sex, ethnicity, education, marital status, living alone, and smoking status, high pathogen burden (7 + cumulative infections) compared to low pathogen burden (1-5 cumulative infections) was significantly associated with period prevalence (the highest GDS score from baseline and follow-up measurements) of depressive symptoms (OR = 2.36, 95% CI = 1.05-5.33) and impaired mental health (OR = 2.25, 95% CI = 1.18-4.30). CMV seropositivity and HSV1 seropositivity, which are highly prevalent and most widely studied, were associated with estimated 2-fold increased odds of depression, but only HSV1 seropositivity was significantly associated with depression after adjusting for confounders. Notably, adjusted for confounders, RSV, H. pylori and Plasmodium seropositivity were significantly associated with increased odds, and Dengue seropositivity was associated with unexpectedly deceased odds of depressive symptoms and impaired mental health. The association of pathogen exposure with depression and mental health were at least in parts explained by inflammatory markers. Adding certain inflammatory markers to the models attenuated or weakened the association. Bootstrap method showed that MIP-1α significantly mediated the association between pathogen burden and mental health. In conclusion, lifelong pathogen burden and specific infections are associated with depression and impaired mental health in older adults.

Cardiometabolic and Vascular Disease Factors and Mild Cognitive Impairment and Dementia.

INTRODUCTION: There is empirical evidence that cardiovascular risk factors and vascular pathology contribute to cognitive impairment and dementia. METHODS: We profiled cardiometabolic and vascular disease (CMVD) and CMVD burden in community-living older adults in the Singapore Longitudinal Ageing Study cohort and examined the association of CMVD risk markers with the prevalence and incidence of mild cognitive impairment (MCI) and dementia from a median 3.8 years of follow-up. RESULTS: Prevalent MCI and dementia, compared with normal cognition, was associated with higher proportions of persons with any CMVD, hypertension, diabetes, coronary heart disease, atrial fibrillation, or stroke. Diabetes, stroke, and the number of CMVD risk markers remained significantly associated with dementia or MCI after adjusting for age, sex, formal education level, APOE-ε4 genotype, and level of physical, social, or productive activities, with odds ratios ranging from 1.3 to 5.7. Among cognitively normal participants who were followed up, any CMVD risk factor, dyslipidemia, diabetes, or heart failure at baseline predicted incident MCI or its progression to dementia after adjusting for potential confounders. CONCLUSION: Older adults with higher burden of CMVD, driven especially by diabetes, are likely to increase the risk of prevalent and incident MCI and dementia.

Malnutrition Risk and Kidney Function and Decline in Community-Dwelling Older Adults.

OBJECTIVES: The association of malnutrition with chronic kidney disease (CKD) is well established. However, there is a paucity of studies of the effect of malnutrition risk (MR) on kidney function decline among older persons who do not have end-stage or dialyzable CKD. This study aimed to examine the association between MR status and kidney function, and future risks of kidney function decline and CKD progression in community-dwelling older adults. DESIGN AND METHODS: Nutrition Screening Initiative's DETERMINE Your Nutritional Health Checklist and estimated glomerular filtration rate (eGFR) were assessed at baseline among 5,122 participants free of end-stage renal failure or dialyzed CKD in the Singapore Longitudinal Aging Studies (SLAS-1 and SLAS-2). Follow-up eGFR was assessed in a subcohort of SLAS-2 participants without CKD (eGFR > 60 mL/min/1.73 m2) at baseline (N = 786) who were followed up at 3-5 years. RESULTS: In baseline cross-sectional analyses adjusting for other risk factors, low, moderate, and high MR was significantly associated with decreasing eGFR coefficients of -1.5, -3.3, and -5.0 mL/min/1.73 m2 respectively, and increasing CKD odds ratios of 1.81, 2.18, and 3.11 respectively. In longitudinal analysis, low, moderate, and high MR was significantly associated with increased risk of eGFR (>25%) decline (odds ratio of 2.37, 3.34, and 2.18 respectively). CONCLUSIONS: Among older adults without advanced kidney disease, MR is associated with poor kidney function and increased risk of kidney function decline and CKD. Preventive interventions to modify MR may help to reduce the deterioration of renal function in older people.

Four New Triterpenoid Saponins from the Root of Ilex centrochinensis.

One new siaresinolic acid saponin (1) and three new rotundic acid saponins (2-4) were isolated from the roots of Ilex centrochinensis. Their structures were confirmed by detailed analysis of standard spectroscopic data (IR, MS, 1D and 2D NMR). Compounds 1-4 exhibited anti-inflammatory activity by inhibiting nitric oxide production in a lipopolysaccharide-induced RAW264.7 cell inflammatory model. However, they showed no significant lipid-lowering activity against the production of triglycerides in the lipid-accumulation model of HepG2 cells induced by oleic acid.

Interrelationship between myoglobin oxidation and lipid oxidation during the processing of Cantonese sausage with d-sodium erythorbate.

BACKGROUND: Pork is used as raw material to produce Cantonese sausage, and 0.5 or 1 g kg-1 of d-sodium erythorbate is added to the pork meat. In this study the myoglobin oxidation rate, relative metmyoglobin content, heme iron content, redness, pH, free radical content and thiobarbituric acid reactive substance (TBARS) value were measured at different processing times and different content of d-sodium erythorbate. RESULTS: It was found that d-sodium erythorbate significantly reduced the free radical content and myoglobin and lipid oxidation rates and increased heme iron levels. When d-sodium erythorbate was added to the sausage, the absorption peak of myoglobin porphyrin shifted left, migrating from 414 to 405 nm. At 72 h, with an increase in the d-sodium erythorbate content, a significant negative correlation was identified between heme iron and the degree of redness (P < 0.01). CONCLUSION: During sausage processing, there are strong correlations among TBARS values, free radical content, metmyoglobin levels, heme iron levels, a* and pH at the same d-sodium erythorbate level. At the same processing time, adding d-sodium erythorbate can slow the rate of myoglobin and lipid oxidation and prevent the discoloration of sausage. © 2019 Society of Chemical Industry.

Hallmarks of improved immunological responses in the vaccination of more physically active elderly females.

Physical inactivity is one of the leading contributors to worldwide morbidity and mortality. The elderly are particularly susceptible since the features of physical inactivity overlap with the outcomes of natural aging - including the propensity to develop cardiovascular diseases, cancer, diabetes mellitus, sarcopenia and cognitive impairment. The age-dependent loss of immune function, or immunosenescence, refers to the progressive depletion of primary immune resources and is linked to the development of many of these conditions. Immunosenescence is primarily driven by chronic immune activation and physical activity interventions have demonstrated the potential to reduce the risk of complications in the elderly by modulating inflammation and augmenting the immune system. Since poor vaccination outcome is a hallmark of immunosenescence, the assessment of vaccine efficacy provides a window to study the immunological effects of regular physical activity. Using an accelerator-based study, we demonstrate in a Singaporean Chinese cohort that elderly women (n=56) who walk more after vaccination display greater post-vaccination expansion of monocytes and plasmablasts in peripheral blood. Active elderly female participants also demonstrated lower baseline levels of IP-10 and Eotaxin, and the upregulation of genes associated with monocyte/macrophage phagocytosis. We further describe postive correlations between the monocyte response and the post-vaccination H1N1 HAI titres of participants. Finally, active elderly women reveal a higher induction of antibodies against Flu B in their 18-month second vaccination follow-up. Altogether, our data are consistent with better immunological outcomes in those who are more physically active and highlight the pertinent contribution of monocyte activity.

Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7.

Circular RNAs (circRNAs) are significantly dysregulated in various cancer types. However, the roles and mechanisms of circRNAs in cancer remain largely unknown. In this study, we demonstrated that a novel circRNA (circITGA7) and its linear host gene ITGA7 are both significantly downregulated in colorectal cancer (CRC) tissues and cell lines. These decreased expression levels correlated with CRC progression. Functional assays demonstrated that ectopic circITGA7 expression suppressed the growth and metastasis of CRC cells in vitro and in vivo. Knockdown of circITGA7 or ITGA7 promoted the proliferation and migration of CRC cells in vitro, and enhanced CRC growth in vivo. Mechanistically, by using RNA-sequencing and KEGG enrichment analysis, we found that circITGA7 is a negative regulator of the Ras signalling pathway, and that ITGA7 is associated with cytokine-related signalling pathways. In addition, circITGA7 binds to miR-370-3p to antagonise its suppression of neurofibromin 1, which is a well-known negative regulator of the Ras pathway. Finally, circITGA7 upregulates the transcription of ITGA7 by suppressing RREB1 via the Ras pathway. In conclusion, our findings indicate a suppressor role of circITGA7 and ITGA7 in CRC, and reveal that circITGA7 inhibits the proliferation and metastasis of CRC cells by suppressing the Ras signalling pathway and promoting the transcription of ITGA7, suggesting that circITGA7 is a potential target for CRC treatment. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A new derivatization method for the determination of valproic acid in serum using tetramethylammonium hydroxide as a catalyst.

Valproic acid (VPA) pharmacokinetics is highly variable and monitoring of blood levels is necessary to determine its appropriate dosage. This study aimed to establish and validate a novel derivatization method for the determination of VPA. The method was based on the catalytic effect of tetramethylammonium hydroxide using 2,4'-dibromoacetophenone as a derivatization reagent. After derivatization, samples were injected into the HPLC system for analysis. The method showed a good linearity in the range of 1.0-200.7 µg mL-1 , and the limit of quantification was 1 µg mL-1 . All values of the accuracy and relative standard deviations were acceptable for the analyses of biological samples. The recoveries were in the range from 91.6 to 97.4% for VPA with RSD <3.9%. A novel and high conversion-rate derivatization method has been developed and validated for the determination of VPA in human serum. It can be applied to the analysis of VPA in clinic serum samples.

Neoadjuvant chemotherapy in combination with surgery in the treatment of local advanced breast cancer.

OBJECTIVE: To investigate the effect of neoadjuvant chemotherapy combined with surgery on locally advanced breast cancer and its prognosis. METHODS: One hundred and fifty-four patients with locally advanced breast cancer who were admitted to our hospital from February 2014 to April 2015 were selected as the study subjects. They were divided into an observation group and a control group according to the principle of random equalization, 77 each group. The observation group was treated with TAC scheme, neoadjuvant chemotherapy combined with modified radical resection, and continuously treated with the same scheme after operation until the end of the course of treatment. The control group was treated with modified radical resection and TAC scheme. The clinical efficacy of the two groups was observed, and the perioperative indications, prognosis and occurrence of adverse reactions were compared between the two groups. RESULTS: The total effective rate of the observation group was 76.62%, significantly higher than that of the control group (55.84%, P<0.05). The observation group had shorter operation time and hospitalization time and less bleeding amount compared to the control group (P<0.05). The metastasis rate and recurrence rate of the observation group were significantly lower than those of the control group (P<0.05); there was a significant difference between the two groups (P<0.05). The one-year and three-year survival rates of the observation group were significantly higher than those of the control group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups after operation (P>0.05). CONCLUSION: Preoperative neoadjuvant chemotherapy in combination with TAC scheme can reduce the difficulty of operation, improve the curative effect of patients, significantly improve the prognosis of patients and prolong the survival time, which is worth clinical application.

CDCA3 promotes cell proliferation by activating the NF-κB/cyclin D1 signaling pathway in colorectal cancer.

Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF-κB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC.

Correlation of MACC1/c-Myc Expression in Endometrial Carcinoma with Clinical/Pathological Features or Prognosis.

BACKGROUND Endometrial carcinoma (EC) is a type of female reproductive malignant tumor, the incidence of which is generally 20~30%. Multiple factors and genes are involved in the regulation of EC occurrence and progression. This study aimed to measure the expressions of MACC1 and c-Myc in EC patients to analyze their correlation with pathological features of EC. MATERIAL AND METHODS A total of 60 EC patients were recruited in the experimental group, while another cohort of 30 people with endometrial inflammatory hyperplasia was enrolled in the control group. The levels of serum MACC1 and c-Myc were measured by ELISA, and the protein expressions in EC cancer tissues, tumor-adjacent tissues, and controlled endometrial tissues were detected by immunohistochemistry (IHC). The correlation between gene expression and clinical/pathological features was then determined. RESULTS Our data indicate that the level of serum MACC1 and c-Myc in the experimental group was 1.67±0.08 ng/ml and 1.78±0.07 ng/ml, respectively, both of which were significantly higher than that of the control group (p<0.05). However, no significant difference was found among levels of serum MACC1 or c-Myc at different TNM stages (p>0.05). In cancer tissues, the positive rate of MACC1 or c-Myc was 73.3% and 78.3%, respectively, which were significantly higher than that in adjacent or control tissues (p<0.05). MACC1/c-Myc expression was correlated with TNM stage, primary infiltration grade, lymph node metastasis, and distal metastasis (p<0.05). CONCLUSIONS MACC1 and c-Myc are highly expressed in serum and tumor tissues of EC patients. Both are correlated with TNM stage, primary infiltration, and lymph node or distal metastasis, which provides a scientific basis for the development of new biomarkers for the diagnosis of endometrial carcinoma.

Inhibitory brainstem reflexes under external emotional-stimuli in bipolar I and II disorders.

BACKGROUND: Bipolar disorder types I (BD I) and II (BD II) might present different dysfunctions of the cortex and brainstem, as reflected by the second exteroceptive suppression period of temporalis muscle activity (ES2) under different stimuli of external emotions. METHODS: This study included 30 BD I and 20 BD II patients, and 40 healthy volunteers. All participants were invited to answer the Mood Disorder Questionnaire, the Hypomania Checklist-32, and the Plutchik-van Praag Depression inventory, as well as to undergo the ES2 test under external emotional-stimuli (emotional pictures plus sounds) of Disgust, Erotica, Fear, Happiness, and Sadness. RESULTS: The scale scores were elevated in both patient groups, but were not correlated with ES2 parameters. Compared to healthy controls, BD I showed prolonged ES2 latency under Erotica, and their perceived happiness and sadness intensities were negatively correlated with the respective ES2 durations, while BD II showed prolonged ES2 latencies under Disgust and Happiness, and shortened ES2 durations under Disgust, Happiness and Sadness. Moreover, ES2 duration under Sadness was significantly shorter in BD II than that in BD I. CONCLUSIONS: The cortico-brainstem inhibitory dysfunctions in BD I and BD II was different, and this difference was independent of the patient's ongoing emotions. Our study thus provides some hints to distinguish the two types of bipolar disorders.

Overexpression of miR-335 confers cell proliferation and tumour growth to colorectal carcinoma cells.

The involvement of miR-335 in csolorectal cancer (CRC) development remains controversial. Here, we found that miR-335 was highly up-regulated in CRC specimens relative to normal mucosa, and high miR-335 expression level was markedly associated with the tumour size and differentiation of CRC. The overexpression of miR-335 in CRC cells facilitated cell proliferation in vitro and tumour growth in vivo. RASA1 was validated as a target of miR-335 that was downregulation in CRC. Forced expression of miR-335 silenced RASA1 and triggered Ras/ERK cascade in CRC. Together, miR-335-RASA1 contributes to cell growth in CRC, and elucidation of downstream pathway will provide new insights into the molecular mechanisms of CRC progression.

Waking-hour cerebral activations in nightmare disorder: A resting-state functional magnetic resonance imaging study.

AIM: The purpose of the current study was to explore the cerebral areas involved in nightmare disorder. METHODS: Fifteen nightmare disorder patients and 15 healthy volunteers were invited to undergo resting-state functional magnetic resonance imaging and to complete the Nightmare Experience Questionnaire. RESULTS: The nightmare disorder patients scored higher on the Physical Effect and Horrible Stimulation scales, had higher values of regional homogeneity in clusters within the left anterior cingulate cortex and right inferior parietal lobule, and lower regional homogeneity values within the left superior and inferior frontal gyri and bilateral middle occipital gyri. Physical Effect was negatively correlated with regional homogeneity values in anterior cingulate cortex and inferior parietal lobule in the nightmare disorder group, and was positively correlated with regional homogeneity value in the inferior frontal gyrus in the healthy control group. CONCLUSION: To our best knowledge, this is the first neuroimaging study on nightmare disorder, and we have characterized the cerebral activities underlying altered hyperarousal and emotion regulation in nightmare disorder at resting-state.

MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer.

BACKGROUND: Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood. METHODS: A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC. RESULTS: We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour-initiating cell capacity endowed CRC cells with the potential of resistance to irradiation. CONCLUSIONS: These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC.

Obesity, asthma prevalence and IL-4: Roles of inflammatory cytokines, adiponectin and neuropeptide Y.

BACKGROUND: Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association. METHODS: We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-α, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data. RESULTS: Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-α (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-α (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up. CONCLUSIONS: The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes.

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients.

AIM: To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication. METHODS: A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, p.o.) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check. RESULTS: A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus. CONCLUSION: Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.