Evidence That p-Cresol and IL-6 Are Adsorbed by the HFR Cartridge: Towards a New Strategy to Decrease Systemic Inflammation in Dialyzed Patients?

Introduction

Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate.

Methods

We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UF_in) and at the outlet (UF_out) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD.

Results

p-Cresol and IL-6 were lower in UF_out than in UF_in both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UF_out collected at the end than with UF_in collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro-inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures.

Conclusions

This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01865773","term_id":"NCT01865773"}}NCT01865773     

The “Finger,” a Unique Multicellular Morphology of Candida albicans Induced by CO2 and Dependent upon the Ras1-Cyclic AMP Pathway

Most experiments exploring the basic biology of pathogenic microbes are performed in vitro under conditions that do not usually mimic those of their host niche. Hence, developmental programs initiated by specific host cues may be missed in vitro. We have tested the effects of growing low-density agar cultures of the yeast pathogen Candida albicans in concentrations of CO₂ found in the gastrointestinal tract. It is demonstrated that in physiological concentrations of CO₂ at 37°C, yeast cells form a heretofore undescribed multicellular “finger” morphology distinct from a previously described stalk-like structure induced by high doses of UV irradiation that kills more than 99.99% of cells. The finger extends aerially, is uniform in diameter, and is visible to the naked eye, attaining lengths of 3 mm. It is composed of a basal yeast cell monolayer adhering to a semispherical crater formed in the agar and connected to a basal bulb of yeast cells at a fragile interface. The bulb extends into the long shaft. We propose that a single, centrally located hypha extending the length of the shaft forms buds at compartment junctions that serve as the source of the yeast cells in the shaft. A mutational analysis reveals finger formation is dependent upon the pathway Ras1→Cdc35→cyclic AMP (cAMP) (PDE2—|)→Tpk2→Tec1. Because of the mechanically fragile interface and the compactness of bulb and shaft, we suggest that the finger may function as a multicellular dispersal mechanism produced in host niches containing high levels of CO₂.     

The Chromatin “Landscape” of a Murine Adult β-Globin Gene Is Unaffected by Deletion of Either the Gene Promoter or a Downstream Enhancer

In mammals, the complex tissue- and developmental-specific expression of genes within the β-globin cluster is known to be subject to control by the gene promoters, by a locus control region (LCR) located upstream of the cluster, and by sequence elements located across the intergenic regions. Despite extensive investigation, however, the complement of sequences that is required for normal regulation of chromatin structure and gene expression within the cluster is not fully defined. To further elucidate regulation of the adult β-globin genes, we investigate the effects of two deletions engineered within the endogenous murine β-globin locus. First, we find that deletion of the β2-globin gene promoter, while eliminating β2-globin gene expression, results in no additional effects on chromatin structure or gene expression within the cluster. Notably, our observations are not consistent with competition among the β-globin genes for LCR activity. Second, we characterize a novel enhancer located 3′ of the β2-globin gene, but find that deletion of this sequence has no effect whatsoever on gene expression or chromatin structure. This observation highlights the difficulty in assigning function to enhancer sequences identified by the chromatin “landscape” or even by functional assays.     

“I Don’t See That as a Medical Problem”: Clinicians’ Attitudes and Responses to Requests for Cosmetic Genital Surgery by Adolescents

Labiaplasty is a form of genital surgery to reduce large or protruding labia minora. Internationally, the rates of this surgery among women and girls is increasing and is viewed as a worrying trend. Currently, the main clinical strategy is to reassure adolescents that they are normal by talking about the variation of labia size and appearance and showing pictures demonstrating the wide range of normal female genital appearance. For the most part, policy documents recommend against labiaplasty in adolescents, claiming that it is medically non-essential surgery. In this paper, we contrast findings from our interviews with clinicians with the existing literature and policy documents and we point out areas needing more thought. This is qualitative research using semi-structured interviews. We set out to find out on what basis clinicians decide how to treat or manage adolescent patients seeking labiaplasty. We interviewed clinicians who are likely to be approached by under-eighteens requesting labiaplasty. We use interpretive content analysis and thematic analysis to analyse the data. Our findings support the emphasis on education and reassurance as the first step for all patients, but other issues that have not figured previously in the literature that would alter clinical strategies for managing patients emerge as well. Key findings are that reassurance does not always work and that the distinction between functional and appearance concerns is not a solid foundation in itself for deciding whether surgery is ethically appropriate. We conclude that the distinction between functional and appearance concerns is not ethically relevant. It is open to different interpretations and is not regarded by all clinicians as the definitive factor in relation to surgery. The focus of clinicians should be on relieving distress whatever the cause. Appearance reasons may sometimes justify surgery but, also, functional reasons may sometimes not be sufficient justification for surgery.     

“If You Tell People That You Had Sex with a Fellow Man,It Is Hard to Be Helped and Treated”: Barriers and Opportunities for Increasing Access to HIV Services among Men Who Have Sex with Men in Uganda

Background

Despite the high HIV prevalence among men who have sex with men (MSM) in sub-Saharan Africa, little is known about their access to HIV services. This study assessed barriers and opportunities for expanding access to HIV services among MSM in Uganda.

Methods

In October-December 2013, a cross-sectional qualitative study was conducted in 12 districts of Uganda. Semi-structured in-depth interviews were conducted with 85 self-identified MSM by snowball sampling and 61 key informants including HIV service providers and policy makers. Data were analysed using manifest content analysis and Atlas.ti software.

Results

Three quarters of the MSM (n = 62, 72.9%) were not comfortable disclosing their sexual orientation to providers and 69 (81.1%) felt providers did not respect MSM. Half (n = 44, 51.8%) experienced difficulties in accessing health services. Nine major barriers to access were identified, including: (i) unwelcoming provider behaviours; (ii) limited provider skills and knowledge; (iii) negative community perceptions towards MSM; (iv) fear of being exposed as MSM; (v) limited access to MSM-specific services; (vi) high mobility of MSM, (vii) lack of guidelines on MSM health services; viii) a harsh legal environment; and ix) HIV related stigma. Two-thirds (n = 56, 66%) participated in MSM social networks and 86% of these (48) received support from the networks to overcome barriers to accessing services.

Conclusions

Negative perceptions among providers and the community present barriers to service access among MSM. Guidelines, provider skills building and use of social networks for mobilization and service delivery could expand access to HIV services among MSM in Uganda.     

The Curious Case of “Case Report” of Infections Caused by Human and Animal Fungal Pathogens: An Educational Tool,an Online Archive,or a Format in Need of Retooling

Case reports describe the unusual occurrence and complications of diseases, diagnostic challenges, and notable therapeutic successes. Some journals have discontinued the case reports, while new case report journals have appeared in recent years. During the eightieth anniversary of Mycopathologia, it is fitting to examine the relevance of the case report since the journal continues to traverse the boundaries of basic and clinical sciences. A random sample of recent case reports and other articles were selected from Mycopathologia. Springer Nature individual article download statistics, and Google Scholar and Scopus citations numbers were compared to assess the reader access and bibliometric impact of case reports. Our analysis indicated that the case report format continues to be a vital element of publication in a cross-disciplinary journal such as Mycopathologia. Medical and veterinary case reports covering fungal pathogens are widely read as evident from their download numbers. The download numbers have a positive correlation with the completeness of the report, the topics and geographic origin of reports have a neutral influence, and the recency leads to lower downloads. There is no discernible trend between the download numbers and the citations of case reports as measured by Google Scholar and Scopus. A specially designed checklist for Mycopathologia case reports and new format MycopathologiaIMAGES are being introduced to improve the quality and relevance of case reports further.     

The Rare TXNRD1_v3 (“v3”) Splice Variant of Human Thioredoxin Reductase 1 Protein Is Targeted to Membrane Rafts by N-Acylation and Induces Filopodia Independently of Its Redox Active Site Integrity

The human selenoprotein thioredoxin reductase 1 (TrxR1), encoded by the TXNRD1 gene, is a key player in redox regulation. Alternative splicing generates several TrxR1 variants, one of which is v3 that carries an atypical N-terminal glutaredoxin domain. When overexpressed, v3 associates with membranes and triggers formation of filopodia. Here we found that membrane targeting of v3 is mediated by myristoylation and palmitoylation of its N-terminal MGC motif, through which v3 specifically targets membrane rafts. This was suggested by its localization in cholera toxin subunit B-stained membrane areas and also shown using lipid fractionation experiments. Utilizing site-directed mutant variants, we also found that v3-mediated generation of filopodia is independent of the Cys residues in its redox active site, but dependent upon its membrane raft targeting. These results identify v3 as an intricately regulated protein that expands TXNRD1-derived protein functions to the membrane raft compartment.