Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma

PURPOSE. To assess the level of plasma glutathione in patients with untreated primary open-angle glaucoma. METHODS. Twenty-one patients with newly diagnosed primary open-angle glaucoma and 34 age- and gender-matched control subjects were subjected to a blood analysis to detect the level of circulating glutathione in its reduced and oxidized forms. The effect of age, gender, and systemic blood pressure on circulating glutathione levels was also analyzed. RESULTS. Age had a negative effect on the level of both reduced and total glutathione (P = 0.002, r = -0.52 and P = 0.002, r = -0.52, respectively) in control subjects but not in patients with glaucoma (P > 0.05, r = 0.27, and P > 0.05, r = 0.22, respectively). In the control group, men demonstrated higher levels of both reduced and total glutathione than did women (P = 0.024 and P = 0.032, respectively). After correction for age and gender influences on blood glutathione levels, patients with glaucoma exhibited significantly lower levels of reduced and total glutathione than did control subjects (P = 0.010, F = 7.24 and P = 0.006, F = 8.38, respectively). No differences between study groups were observed in either oxidized glutathione levels or redox index (P > 0.05, F = 0.50; and P > 0.05, F = 0.30, respectively). CONCLUSIONS. Patients with glaucoma exhibit low levels of circulating glutathione, suggesting a general compromise of the antioxidative defense. Copyright © Association for Research in Vision and Ophthalmology

From pelvic radiation to social isolation: a qualitative study of survivors’ experiences of chronic bowel symptoms after pelvic radiotherapy

\ua9 2024, The Author(s).Purpose: We explored survivors’ experiences of chronic bowel symptoms following pelvic radiotherapy, strategies employed in living with these symptoms, effects on daily activities, and roles at home and in the workplace. Methods: Semi-structured interviews were conducted with 28 individuals (10 gynaecological, 14 prostate, four anal/rectal cancer survivors) who had completed pelvic radiotherapy at least six months prior to data collection and who had experience of bowel symptoms during this post-treatment period. Reflexive thematic analysis was undertaken. Results: We propose four themes describing a process leading from experience of symptoms to withdrawal from activities and roles. These are (1) losing control (the experience of unintended anal leakage or discharge); (2) experiencing embarrassment and fear (the experience of embarrassment or fear of embarrassment as a result of discharge becoming public); (3) managing and reacting (acting to reduce the likelihood of discharge or to prevent this becoming public); and (4) restriction and withdrawal (avoiding specific activities or situations so as to reduce or remove the risk of embarrassment). Returning to the workplace presented additional challenges across these themes. Conclusions: Impacts of chronic bowel symptoms can be severe. Survivors employ a variety of methods and strategies in living with their symptoms. Some of these support continued role fulfilment but some constitute a withdrawal from pre-treatment roles. Current healthcare provision and statutory protections fail to fully meet needs following pelvic radiotherapy. Implications for cancer survivors. There is a need to develop and implement evidence-based services and supported self-management programmes for survivors experiencing chronic bowel problems post-radiotherapy

Ferredoxin 1b deficiency leads to testis disorganization, impaired spermatogenesis and feminization in zebrafish

The roles of steroids in zebrafish sex differentiation, gonadal development and function of the adult gonad are poorly understood. Herein, we have employed a ferredoxin 1b (fdx1b) mutant zebrafish to explore such processes. Fdx1b is an essential electron-providing cofactor to mitochondrial steroidogenic enzymes, which are crucial for glucocorticoid and androgen production in vertebrates. Fdx1b-/- zebrafish mutants develop into viable adults, in which concentrations of androgens and the glucocorticoid, cortisol, are significantly reduced. Adult fdx1b-/- mutant zebrafish display predominantly female secondary sex characteristics but may possess either ovaries or testes, confirming that androgen signaling is dispensable for testicular differentiation in this species, as previously demonstrated in androgen receptor mutant zebrafish. Adult male fdx1b-/- mutant zebrafish do not exhibit characteristic breeding behaviors, and sperm production is reduced, resulting in infertility in standard breeding scenarios. However, eggs collected from wild-type females can be fertilized by the sperm of fdx1b-/- mutant males by IVF. The testes of fdx1b-/- mutant males are disorganized and lack defined seminiferous tubule structure. Expression of several pro-male and spermatogenic genes is decreased in the testes of fdx1b-/- mutant males, including pro-male transcription factor SRY-box 9a (sox9a) and spermatogenic genes insulin-like growth factor 3 (igf3) and insulin-like 3 (insl3). This study establishes an androgen- and cortisol-deficient fdx1b zebrafish mutant as a model for understanding the impacts of steroid deficiency on sex development and reproductive function. This model will be particularly useful for further investigation of the roles of steroids in spermatogenesis, gonadal development and regulation of reproductive behavior, thus enabling further elucidation of the physiological consequences of endocrine disruption in vertebrates

Expanding global distribution of rotavirus serotype G9: detection in Libya, Kenya, and Cuba.

Serotype G9 may be the fifth most common human rotavirus serotype, after serotypes G1 to G4. In three cross-sectional studies of childhood diarrhea, we have detected serotype G9 rotaviruses for the first time in Libya, Kenya, and Cuba. Serotype G9 constituted 27% of all rotaviruses identified, emphasizing the reemergence of serotype G9 and suggesting that future human rotavirus vaccines will need to protect against disease caused by this serotype

Gap-filling carbon dioxide, water, energy, and methane fluxes in challenging ecosystems - Comparing between methods, drivers, and gap-lengths

Eddy covariance serves as one the most effective techniques for long-term monitoring of ecosystem fluxes, however long-term data integrations rely on complete timeseries, meaning that any gaps due to missing data must be reliably filled. To date, many gap-filling approaches have been proposed and extensively evaluated for mature and/or less actively managed ecosystems. Random forest regression (RFR) has been shown to be stable and perform better in these systems than alternative approaches, particularly when filling longer gaps. However, the performance of RFR gap filling remains less certain in more challenging ecosystems, e.g., actively managed agri-ecosystems and following recent land-use change due to management disturbances, ecosystems with relatively low fluxes due to low signal to noise ratios, or for trace gases other than carbon dioxide (e.g., methane). In an extension to earlier work on gap filling global carbon dioxide, water, and energy fluxes, we assess the RFR approach for gap filling methane fluxes globally. We then investigate a range of gap-filling methodologies for carbon dioxide, water, energy, and methane fluxes in challenging ecosystems, including European managed pastures, Southeast Asian converted peatlands, and North American drylands. Our findings indicate that RFR is a competent alternative to existing research standard gap-filling algorithms. The marginal distribution sampling (MDS) is still suggested for filling short ( 30 days) gaps in carbon dioxide fluxes and also for gap filling other fluxes (e.g. sensible heat, latent energy and methane). In addition, using RFR with globally available reanalysis environmental drivers is effective when measured drivers are unavailable. Crucially, RFR was able to reliably fill cumulative fluxes for gaps > 3 moths and, unlike other common approaches, key environment-flux responses were preserved in the gap-filled data

Hitting the target but missing the point: recent progress towards adenovirus-based precision virotherapies

More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field. View Full-Text Keywords: adenovirus; oncolytic; virotherapy; targeting; immunotherapy; immunogenic cell death; αvβ6 integri

Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants

Background Histo–blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants Methods A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus–specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. Results In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20–0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03–0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04–0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4–7.2). Conclusions Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi

Individual leader to interdependent leadership: A case study in leadership development and tripartite evaluation

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 Sage Publications.The Problem - In this case study we see a move away from orthodox views of school leadership as “headship” to a more contemporary model of educational leadership wherein we note a departure from functional, curricula-based school leadership toward more human resource development (HRD) approaches. The aim of this study was to consider the effectiveness of an educational development program for middle leaders within an educational establishment. The Solution - We examined the impact of a bespoke higher education leadership development intervention in Leadership (and Change) on the formation and cohesiveness of a newly formed innovative leadership structure. The Stakeholders - The leadership development intervention was designed through a tripartite collaboration including a university, senior school leaders, and staff. The intervention was designed to shift leadership from individual leader agency to interdependent human leadership agency. Through tripartite evaluation we uncover leadership development praxis that transcends the boundaries of conventional educational leadership and reemphasizes the benefits of bridging the academic/practitioner divide and the application of theory to praxis

Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy applications

Oncolytic virotherapies (OV) based on human adenoviral (HAdV) vectors hold significant promise for the treatment of advanced ovarian cancers where local, intraperitoneal delivery to tumour metastases is feasible, bypassing many complexities associated with intravascular delivery. The efficacy of HAdV-C5-based OV is hampered by a lack of tumour selectivity, where the primary receptor, hCAR, is commonly downregulated during malignant transformation. Conversely, folate receptor alpha (FRα) is highly expressed on ovarian cancer cells, providing a compelling target for tumour selective delivery of virotherapies. Here, we identify high-affinity FRα-binding oligopeptides for genetic incorporation into HAdV-C5 vectors. Biopanning identified a 12-mer linear peptide, DWSSWVYRDPQT, and two 7-mer cysteine-constrained peptides, CIGNSNTLC and CTVRTSAEC that bound FRα in the context of the phage particle. Synthesised lead peptide, CTVRTSAEC, bound specifically to FRα and could be competitively inhibited with folic acid. To assess the capacity of the elucidated FRα-binding oligopeptides to target OV to FRα, we genetically incorporated the peptides into the HAdV-C5 fiber-knob HI loop including in vectors genetically ablated for hCAR interactions. Unfortunately, the recombinant vectors failed to efficiently target transduction via FRα due to defective intracellular trafficking following entry via FRα, indicating that whilst the peptides identified may have potential for applications for targeted drug delivery, they require additional refinement for targeted virotherapy applications