The correlation between SNPs within the gene of adrenergic receptor and neuropeptide Y and risk of cervical vertigo

Background

The current investigation was aimed to explore the potential associations of SNPs within ADRB2, ADRB1, NPY, and ADRA1A with risk and prognosis of cervical vertigo.

Methods

Altogether 216 patients with cervical vertigo and 204 healthy controls were gathered, and their DNAs were extracted utilizing the whole‐blood DNA extraction kit. Besides, the PCR reactions were conducted using the TaqMan^R single nucleotide polymorphism (SNP) genotyping assays, and the SNPs were detected on the 7900HT real‐time fluorogenic quantitative polymerase chain reaction (PCR) instrument. Finally, the severity of cervical vertigo was classified according to the JOA scoring, and the recovery rate (RR) of cervical vertigo was calculated in light of the formula as:

Results

The SNPs within ADRA1A [rs1048101 (T>C) and rs3802241 (C>T)], NPY [rs16476 (A>C), rs16148 (T>C), and rs5574 (C>T)], ADRB1 [rs28365031 (A>G)] and ADRB2 [rs2053044 (A>G)] were all significantly associated with regulated risk of cervical vertigo (all P < .05). Haplotypes of ADRA1A [CT and TC] and NPY [CCT and ATT] were also suggested as the susceptible factors of cervical vertigo in comparison with other haplotypes. Furthermore, the SNPs within ADRA1A [rs1048101 (T>C)], NPY [rs16476 (A>C), rs16148 (T>C)], as well as ADRB1 [rs28365031 (A>G)] all appeared to predict the prognosis of cervical vertigo in a relatively accurate way (all P < .05). Ultimately, the haplotypes of ADRA1A (CC) and NPY (CCT) tended to decrease the RR.

Conclusions

The SNPs within ADRB2, ADRB1, NPY, and ADRA1A might act as the diagnostic biomarkers and treatment targets for cervical vertigo.

     

Sunitinib–ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain,liver, and kidney in male and female mice differently

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC_0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC_0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC_0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue‐to‐plasma AUC_0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6‐fold higher liver‐to‐plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue‐to‐plasma partial AUC ratio, the drug tissue targeting index, and the tissue‐plasma hysteresis‐like plots also showed sex‐based ibuprofen–sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender‐based P450 and efflux/transporters differences.     

Evaluating the evolution and function of the dynamic Venom Y protein in ectoparasitoid wasps

Venom of the parasitoid wasp Nasonia vitripennis changes the metabolism and gene expression in its fly host Sarcophaga bullata to induce developmental arrest, suppression of the immune response and various other venom effects. Yet, the venom of ectoparasitoid wasps has not been fully characterized. A major component of N. vitripennis venom is an uncharacterized, high‐expressing protein referred to as Venom Y. Here we describe the evolutionary history and possible functions of this venom protein. We found that Venom Y is a relatively young gene that has duplicated to form two distinct paralogue groups. A copy of Venom Y has been recruited as a venom protein in at least five wasp species. Functional analysis found that Venom Y affects detoxification and immunity genes in envenomated fly hosts. Many of these genes are fat‐body specific, suggesting that Venom Y may have a targeted effect on fat body tissue. We also show that Venom Y may mitigate negative effects of other venom proteins. Finally, protein sequencing indicates that Venom Y is post‐translationally modified. This study contributes to elucidating parasitoid venom by using RNA interference knockdown to investigate venom protein function in the context of the whole venom cocktail.     

A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal‐induced triglyceride turnover in healthy subjects

Non‐alcoholic steatohepatitis (NASH) is a liver disease in which fatty infiltration is accompanied by liver inflammation. GSK3008356 is under development as a selective inhibitor of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme involved in the formation of triglyceride (TG). Decreased DGAT1 activity can reduce circulating TG and liver TG, and therefore could potentially prevent or treat NASH. The aim of the current study was to develop a population pharmacokinetic–pharmacodynamic (PKPD) model that characterizes the PK disposition of GSK3008356 and its relation to the changes in blood TG. Drug concentrations were measured in 104 healthy adults receiving various single (SD) and repeat doses (RD) in a first time in human (FiH) study. A 30% fat meal was given at hour 2 postdose, and blood postprandial TG concentrations were measured at various time points. The population PKPD model consists of several parts including a PK model, drug effect model, meal effect model, and a turnover model. The pharmacokinetic data were described using a 3‐compartment model. Drug effect was described by an inhibitory sigmoidal Emax model. Since TG levels change with the introduction of a meal, a bi‐exponential meal effect model was utilized. The total change in TG was fitted using a turnover model with drug and meal effects on the TG production rate. The current analysis presents a PKPD modeling strategy of time‐varying TG data coming from both endogenous and exogenous sources. In general, the presented model could be utilized in the model‐based drug development of drugs that influence TG levels in blood.     

The ABCs of CRISPR in Tephritidae: developing methods for inducing heritable mutations in the genera Anastrepha,Bactrocera and Ceratitis

Tephritid fruit flies are destructive agricultural pests that are the targets of expensive population eradication and suppression efforts. Genetic pest management is one of the strategies for reducing or eliminating tephritid populations, relying upon the genetic manipulation of insects to render them sterile or capable of transmitting deleterious traits through gene drive. Currently, radiation, chemical mutagenesis, and transgenic techniques are employed to generate agents for genetic pest management, but new methods must be explored and developed for all tephritid pest species. Targeted mutagenesis induced by nonhomologous end join repair of clustered regularly interspaced short palindromic repeats and the CRISPR associated protein 9 (Cas9) (commonly known as CRISPR/Cas9) has been demonstrated to be an efficient method for creating knock‐out mutants and can be utilized to create germline mutations in Tephritidae. In this paper, we describe detailed methods to knockout the white gene in three tephritid species in the genera Anastrepha, Bactrocera and Ceratitis, including the first demonstration of CRISPR/Cas9 induced mutations in the genus Anastrepha. Lastly, we discuss the variables in tephritid systems that directed method development as well as recommendations for performing injections in remote containment facilities with little molecular biology capabilities. These methods and recommendations combined can serve as a guide for others to use in pursuit of developing CRISPR/Cas9 methods in tephritid systems.     

Psychometric properties of The Hospital Anxiety and Depression Scale and The General Health Questionnaire‐20 in COPD inpatients

Aim: To compare the psychometric properties between the Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire–version 20 (GHQ‐20) in detecting psychological distress in COPD patients referred to pulmonary rehabilitation, and to examine the factor structure of GHQ‐20. Methods: The study comprised 161 consecutive patients with mild to very severe COPD. For comparison of mean scores between the HADS and GHQ‐20, one sample t‐test was used. Potential differences in the detection of possible and normal cases were analysed using Pearson Chi square test. We report Pearson's correlations within and between the questionnaires, and internal consistency was assessed through Chronbach's alpha. The factor structure of the GHQ‐20 was examined through principal axis factoring (PAF) with oblique rotation and eigenvalue >1. Results: There were no differences in mean scores of psychological distress between HADS and GHQ‐20 (12.03 vs. 24.73, p = 0.000), as well as no differences in the prevalence of possible cases of psychological distress (34.6 vs. 36.9, p = 0.000) and normal cases (65.4 vs. 63.1, p = 0.000). The observed difference between HADS and GHQ‐20 regarding internal consistency was marginal, with Chronbach's alpha coefficients of 0.91 and 0.94, respectively. The PAF analysis resulted in a three‐factor solution for GHQ‐20, notably with only two items loading on the third factor, giving an internal consistency <0.70. A two‐factor solution, comprising anxiety/depression and coping, may therefore be more appropriate. Conclusions: This study demonstrates no significant differences between the HADS and GHQ‐20 in their ability to detect possible cases of psychological distress in a rehabilitation setting for COPD patients. Although the HADS and GHQ‐20 are measuring different concepts of psychological distress, both questionnaires can be recommended as screening tools for detection of psychological distress in COPD inpatients. The GHQ‐20 appears to be two‐dimensional, comprising anxiety/depression as one dimension, and coping as the other dimension.     

A case‐control study and meta‐analysis reveal the association between COX‐2 G‐765C polymorphism and primary end‐stage hip and knee osteoarthritis

Background

Osteoarthritis (OA) is a popular arthrosis featured as pain, limited joint activity, and deformity. Cyclooxygenase‐2 (COX‐2) has been reported to be up‐regulated in arthritic tissues and is integral to the progression of osteoarthritis (OA). Previous studies showed the COX‐2 promoter G‐765C polymorphism could influence COX‐2 expression. However, the relationship between the variant and OA risk is contrasting.

Methods

We conducted a case‐control study with 196 primary end‐stage hip and knee OA cases and 196 controls in a Chinese Han population. Subsequently, we integrated this case‐control study in a meta‐analysis to acquire greater statistical power. The results from our case‐control study using MassARRAY genotyping technology and binary logistic regression statistical methods.

Results

The variant carriers in the Chinese Han population had a lower primary end‐stage hip and knee OA susceptibility (C vs G: OR = 0.350, 95%CI: 0.154‐0.797, P = .012; GC vs GG: adjusted OR = 0.282, 95%CI: 0.118‐0.676, P = .005). Stratification studies indicated that a higher GC frequency in women decreased not only knee OA susceptibility but also unilateral knee OA risk. The meta‐analysis showed that the variant exhibited a significantly decreased OA risk through comparisons involving allelic, homozygous, heterozygous, and dominant models.

Conclusion

Our findings suggest that the COX‐2 G‐765C polymorphism exerts a protective effect against primary end‐stage knee osteoarthritis in a female Chinese Han population.