Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

The differences in nurses' willingness to discuss palliative care with patients and their family members.

BACKGROUND: This study aimed to evaluate the differences in nurses' willingness to discuss palliative care with terminally ill patients and their family members. METHODS: The participants were randomly recruited from registered staff nurses ≥20 years of age who were responsible for clinical inpatient care in a tertiary hospital in northern Taiwan. A semi-structured questionnaire was administered to evaluate nurses' experiences of discussing do-not-resuscitate (DNR) decisions and their willingness to discuss palliative care with terminal patients and their family members. The differences in nurses' experiences regarding DNR and willingness to discuss palliative care with terminally ill patients and their family members were compared using the Chi-square test. Logistic regressions were used to analyze factors associated with nurses' willingness to discuss palliative care with patients and their families. RESULTS: More participants had experienced initiating discussions about DNR with patients' families than with patients (72.2% vs 61.9%, p < 0.001). Unadjusted logistic regression analysis showed that the experiences of actively initiating DNR discussions with patients were a significant factor associated with palliative care discussion with patients (odds ratio [OR] = 2.91, 95% confidence interval [CI]: 1.09-7.79). On the other hand, the experiences of actively initiating DNR discussions with patients and with patients' families were significant factors associated with palliative care discussion with patients' families (OR = 3.84, 95% CI: 1.22-12.06 and OR = 3.60, 95% CI: 1.19-10.90, respectively). After adjusting for covariates, no significant factors were found to be independently associated with nurses' willingness to discuss palliative care with patients and their family members. CONCLUSION: There are significant differences in nurses' willingness to discuss palliative care with patients and their family members. Further research is needed to evaluate factors associated with nurses' willingness to discuss palliative care with patients and their families to facilitate these discussions and protect patients' autonomy.

A dual system platform for drug metabolism: Nalbuphine as a model compound.

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450s (CYPs), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs, 10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3'-hydroxylnalbuphine and 4'-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.

Fundamentals of Pharmacokinetics to Assess the Correlation Between Plasma Drug Concentrations and Different Blood Sampling Methods.

PURPOSE: Various blood collection methods were developed and used in the pharmacokinetic evaluation of drugs. However, the influence of different blood sampling methods on plasma drug concentrations has not been clarified. In the present study, we aimed to determine whether the plasma concentration of a target drug changes based on the collection site and elucidate the mechanism responsible for this change. METHODS: We compared three blood sampling methods commonly used in small animals. Eight clinical drugs were selected and administered to rats simultaneously via intracardiac injection or oral gavage. Blood samples were collected from different sites at the same individual, and pharmacokinetic properties of the drugs were then evaluated. RESULTS: Study results showed that the maximum plasma concentration or area under the curve of three study drugs was significantly higher in rats when blood was sampled from the carotid artery than when it was sampled from the caudal vein or by tail snip. CONCLUSIONS: Pharmacokinetics of certain drugs may differ based on the blood sampling site. The acid-base properties of drugs may influence pharmacokinetic evaluation. The rate and extent of drug distribution may also cause such differences and have significant effects on plasma drug levels.

Novel pre-mRNA splicing of intronically integrated HBV generates oncogenic chimera in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatitis B virus (HBV) integration is common in HBV-associated hepatocellular carcinoma (HCC) and may play an important pathogenic role through the production of chimeric HBV-human transcripts. We aimed to screen the transcriptome for HBV integrations in HCCs. METHODS: Transcriptome sequencing was performed on paired HBV-associated HCCs and corresponding non-tumorous liver tissues to identify viral-human chimeric sites. Validation was further performed in an expanded cohort of human HCCs. RESULTS: Here we report the discovery of a novel pre-mRNA splicing mechanism in generating HBV-human chimeric protein. This mechanism was exemplified by the formation of a recurrent HBV-cyclin A2 (CCNA2) chimeric transcript (A2S), as detected in 12.5% (6 of 48) of HCC patients, but in none of the 22 non-HCC HBV-associated cirrhotic liver samples examined. Upon the integration of HBV into the intron of the CCNA2 gene, the mammalian splicing machinery utilized the foreign splice sites at 282nt. and 458nt. of the HBV genome to generate a pseudo-exon, forming an in-frame chimeric fusion with CCNA2. The A2S chimeric protein gained a non-degradable property and promoted cell cycle progression, demonstrating its potential oncogenic functions. CONCLUSIONS: A pre-mRNA splicing mechanism is involved in the formation of HBV-human chimeric proteins. This represents a novel and possibly common mechanism underlying the formation of HBV-human chimeric transcripts from intronically integrated HBV genome with functional impact. LAY SUMMARY: HBV is involved in the mammalian pre-mRNA splicing machinery in the generation of potential tumorigenic HBV-human chimeras. This study also provided insight on the impact of intronic HBV integration with the gain of splice sites in the development of HBV-associated HCC.

[Community structure of planktonic rotifers in the Pearl River Delta].

Four ecological investigations were carried out on planktonic rotifers in Pearl River Delta in 2012. The community structure, including spatial and temporal patterns of species composition, dominant species, biomass and biodiversity, was investigated. The correlation between the community structure of rotifers and the environmental factors was discussed. Moreover, the aggregation structures of rotifers were analyzed. A total of 53 rotifer species were found. Dominant species changed markedly with season and space. Polyarthra trigla had higher dominance. In terms of seasonal changes, the density and biomass were higher in dry season than in wet season, while the biodiversity and evenness indices were vice versa. The biomass and biodiversity of rotifers showed highly significant differences among seasons. In terms of spatial distribution, the average density and the average biomass showed an increase from the southwest to the northeast. The highest density and biomass were recorded in Shiqiao. The biodiversity and evenness indices had an opposite spatial distribution, with the highest values being recorded in Qingqi. The rotifer density was significantly different among the investigated sites, while the biomass and biodiversity were not significantly different. Correlation analysis demonstrated a highly significant positive correlation between rotifer density and biomass, as well as between biodiversity and evenness indices, and a highly negative correlation between biodiversity and biomass. The biodiversity and evenness indices both decreased markedly with the increase of biomass. Principal component analysis indicated that the rotifer density was closely correlated with environment factors, such as water temperature, pH, dissolved oxy- gen, chlorophyll a content, total phosphorus, and total nitrogen, in different seasons. Aggregation analysis based on rotifer density revealed five aggregation structures in the investigated sites, indicating significant differences in water quality among the investigated sites.

Biomolecular recognition with a sensitivity-enhanced nanowire transistor biosensor.

In applications of silicon nanowire field-effect transistors (SiNW-FETs) as biosensors, the SiNW-FETs conventionally are all area modified (AAM), with receptors covering not only the minute SiNW surface area but also the relatively large surrounding substrate area. In this study, using a bottom-up technique, we successfully fabricated selective surface modified (SSM) SiNW-FETs with the receptors on the SiNW sensing surface only. In this approach, the strategy was to modify the SiNWs with a chemical linker of 3-aminopropyltrimethoxysilane (APTMS) prior to photolithographic fabrication of the device. The APTMS molecules modifying the SiNWs survived the harsh photolithographic processes, including coating with photoresist, washing with organic solvent, and thermal annealing. These SSM SiNW-FETs also exhibited desirable electrical characteristics such as ohmic contact and high transconductance. Using the biotin-avidin binding system, we showed that the faster response time and smaller sample requirements of the SSM SiNW-FETs, relative to the conventional AAM SiNW-FETs, clearly show that restricting the surface modification of the SiNW-FETs substantially improves their detection sensitivity. Detection with a SSM boronic acid-modified SiNW-FET of the dopamine released under high-K(+) buffer stimulation from living PC12 cells also demonstrates that SiNW-FETs can serve as highly sensitive biosensors for biomedical diagnosis. In binding affinity measurements with SiNW-FETs, the dissociation constants (Kd) of the biotin-avidin and dopamine-boronic acid complexes were determined to be 15 ± 1 fM and 33 ± 8 fM, respectively.

[The role and mission of nurses in hospice care].

The concept of "hospice care" was first institutionalized in Taiwan 19 years ago. Today, 30 hospitals in the country provide hospice care, with healthcare teams actively providing humane and compassionate care to those in the last phases of incurable disease so that they may live out their remaining time as fully and as comfortably as possible. Typical therapeutic approaches to hospice care include meaning/existential, nostalgia, environmental and spiritual. Aside from managing symptoms, healthcare teams should address proactively the spiritual needs of a patient's spouse and family in order to create meaning and value by helping them look beyond grief and death to appreciate the warmth of life. This study used a number of clinical cases as examples to illustrate how nurses in an interdisciplinary team setting collaborate to perform their responsibilities and integrate with one another. Ultimately, the healthcare team works to improve the living quality of patients and their families so that all can 'rest in peace'