The impact of cytokines on the expression of drug transporters,cytochrome P450 enzymes and chemokine receptors in human PBMC

Background and purpose:

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.

Experimental approach:

Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.

Key results:

We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-γ (IFNγ) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNγ respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r² = 0.545).

Conclusions and implications:

These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.     

Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

What are the qualitative experiences of people affected by kidney failure receiving haemodialysis?

Background

People affected by kidney failure receiving haemodialysis experience complexity within their health condition unlike any other chronic illness or condition. Kidney failure impacts the individual in all areas of their life including relationships and activities of daily living.

Objective

To conduct a meta-aggregation of studies about the lived experiences of people with kidney failure receiving haemodialysis.

Design

Using PRISMA Guidelines, six databases (CINAHL, ClinicalTrials.gov , Cochrane Library, MEDLINE, PsycINFO, and Scopus) were comprehensively searched using keywords and subject headings from January 1990 to October 2021. Articles were assessed according to prespecified eligibility criteria. Data extraction and quality appraisal was conducted. A meta-aggregation of qualitative findings was conducted using the Joanna Briggs Institute methodology for meta-aggregation.

Results

Of the 9409 articles screened, 55 studies were included. This represented a total of 188 findings across 45 categories representing a range of unmet supportive care needs. The meta-aggregation identified 11 synthesised findings broadly related to psychological/emotional needs, physical needs, social needs, interpersonal/intimacy needs, patient-clinician communication needs, family related needs, health system/information needs, spiritual needs, daily living needs, practical needs and daily living needs.

Conclusions

This meta-aggregation has identified that people affected by kidney failure can experience a range of unmet supportive care needs. It was evident that living with kidney failure and receiving haemodialysis impacted a person's sense of self, introduced practical needs and other complex needs which were not being addressed in existing services. This review has highlighted important implications for clinical practice and future research directions.     

The use of lingual mucosal graft in adult anterior urethroplasty: surgical steps and short-term outcome

OBJECTIVES: Investigate the tolerability, safety, and efficacy of using the lingual mucosal graft (LMG) for anterior urethroplasty. METHODS: Ten patients (average age, 41 yr) underwent substitution urethroplasty LMG. Harvesting the graft from the tongue was performed by either the oral surgeon or the urologist. In five patients with penile urethral strictures, the grafts were placed on the dorsal urethral surface as a "dorsal inlay." In five patients with bulbar urethral strictures, the grafts were used as a "dorsal inlay" (3 cases) or "ventral onlay" (2 cases). The average follow-up was 5 mo (range: 3-12 mo). RESULTS: Nine cases (90%) were successful and one (10%) was a failure. Three patients who underwent bulbar urethroplasty showed prior failed repair using buccal mucosal grafts harvested from a single cheek (1 case), from both cheeks (1 case), or from the lip (1 case). The length of the lingual grafts was 4-6cm (mean: 4.5cm) with a width of 2.5cm. No patient developed early or late postoperative complications on the harvest site related to the tongue surgery. No difference was observed in patients in whom the graft harvesting was performed by the oral surgeon compared to the patients in whom the procedure was performed by the urologist. CONCLUSIONS: The surgical technique for harvesting a graft from the tongue is simple and safe. The tongue may be the best alternative donor site to the lip when a thin graft is required for urethroplasty or when the cheek harvesting is not possible.     

Health screening for people with learning disabilities by a community learning disability nursing service in Northern Ireland

Over the last 30 years there has been a considerable increase in the life expectancy of people with learning disabilities. This has resulted in changing patterns of morbidity and mortality and an increasing recognition of the health needs of people with learning disabilities. Major strides forward have been made in the reduction of preventable illnesses among the general population. However, among people with learning disabilities such illnesses have received only limited health promotion attention until recently. In the last decade major gaps have been identified in the ability of current primary health services to respond to the needs of people with learning disabilities. The need to respond effectively to this situation has been identified as a priority by the current United Kingdom Government. Following an overview of the literature in relation to the changing health profile of people with learning disabilities and the need for health screening, consideration is given to some of the key difficulties which may be encountered when attempting to utilize current primary health services. The analysis of data derived from the health screening of 373 people with learning disabilities by a community nursing service in Down and Lisburn Health and Social Services Trust reveals the need for further action in relation to cardiovascular status, sensory deficits, mobility and aspects of sexual health.     

Poverty and health promotion in primary health care: professionals' perspectives

This paper examines the effectiveness of current strategies for health promotion in the UK in the light of knowledge about the links between health, illness and poverty. The implications of recent policies which target health promotion within primary health care (PHC) settings are examined. The results of an exploratory study undertaken during 1993/94 in a city in South West England are discussed. This qualitative study used semi-structured interviews to investigate the perceptions of a range of PHC professionals. Fifty-four interviews were carried out amongst staff in 16 PHC practices. This paper reports on professionals' views and practice in relation to promoting health in areas of poverty and with low-income clients. These findings are discussed in relation to the literature and the constraints on effective health promotion in PHC are explored particularly in relation to issues of poverty and deprivation.