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.     

Ageing appearance in China: biophysical profile of facial skin and its relationship to perceived age

Background Perceived age is important to women and is a primary driver for topical product use and facial cosmetic surgery. Changes in facial features and biophysical skin parameters with chronological age and their associations with perceived age have not been described in Asian populations. Objective To investigate the relationship between biophysical properties of the skin, visual features of skin ageing and perceived facial age in Chinese women. Methods Facial photographs were collected of 250 Chinese women, aged 25–70 years in Shanghai, China. The perceived facial age was determined and related to the chronological age for each participant and to a range of visual assessments of skin appearance and objective biophysical measurements of the skin. The profile of changes in these parameters with age was investigated together with the differences in those parameters for women judged to look younger than their chronological age and those judged to look older than their chronological age. Results Large discrepancies in perceived age (up to 29 years) were found in women of the same chronological age. Each objective skin measure and visual assessment parameter had a stronger correlation with perceived age than with chronological age. The strongest relationships to perceived age were for wrinkles and hyperpigmentation. Skin colour, hydration and trans‐epidermal water loss (TEWL) had weaker associations with perceived age. Women judged to look older than their chronological age had significantly higher scores than those judged to look younger for coarse wrinkles and hyperpigmentation across all age groups. The appearance differences between these groups were evident in composite facial images of the same average chronological age. Conclusions We have identified the skin attributes which differ with perceived age in Chinese women. Perceived age is a better measure of the biological age of facial skin than is chronological age in this population.     

Effects of patient deaths by suicide on clinicians working in mental health: A survey

In the UK, at least a quarter of suicides occurs in patients whilst under the care of mental health services. This study investigated the effects of such deaths on non-medical mental health clinicians. An online survey was conducted within a single NHS mental health Trust to elicit both quantitative and qualitative responses from staff across a range of professions. The survey focused on personal and professional impacts and available support. Participants reported significant negative emotional and professional effects that were long-lasting for some. These included mental health difficulties, loss of confidence regarding clinical responsibilities, and actual or contemplated career change. However, there was also some evidence of positive effects and professional growth. Support from colleagues and line managers is clearly important following deaths of patients by suicide. Clinicians' experiences of the support they had received in the workplace were polarized, suggesting that there is no single nor ideal approach that will meet everyone's needs. Participants made recommendations for the types of support that may be helpful. Most commonly, clinicians desired opportunities for focused reflection and support and help with the formal processes following the death. Sensitivity around how clinicians are notified about the death was highlighted as being particularly important. Conclusions are drawn as to how training institutions and employers can help staff to be better prepared for the potential occurrence of patient suicides and the formal processes that follow, with a view to mitigating risks of more serious harm to staff and hence indirectly to patients, and potential loss of highly trained clinicians to the workforce.     

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.