Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare fatal autorecessive disease. Halter et al. report outcomes from all known haematopoietic stem cell transplantations worldwide from sibling or unrelated donors for MNGIE between 2005 and 2011. In some of the recipients, correction of the underlying metabolic defect results in gradual clinical improvemen

Spironolactone for adult female acne (SAFA): protocol for a double-blind, placebo-controlled, phase III randomised study of spironolactone as systemic therapy for acne in adult women

Introduction: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. Methods and analysis: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator’s Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants. Ethics and dissemination: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact. Trial registration number ISRCTN12892056;Pre-results

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor

Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK-DC crosstalk

Natural killer (NK) cells play a critical role in antitumor immunity, their activation being regulated through NK cell receptors. Although the endogenous ligands for these receptors are largely unknown, viral ligands have been identified. We investigated the ability of an activating NK receptor ligand derived from the mumps virus, haemagglutinin-neuraminidase (HN) to enhance NK activation against tumor cells. HN-expressing B16.OVA tumor cells induced stronger activation of NK cells compared with B16.OVA cells and also promoted dendritic cell (DC) activation toward a DC1 phenotype, in vitro. Moreover, incubation of DCs, NK cells and HN-expressing B16-OVA cells further enhanced NK cell activation through the NK-DC crosstalk, in a cell-to-cell contact- and IL-12-dependent fashion. Immunization of mice with HN-expressing B16-OVA cells resulted in &gt; 85% survival rate after subsequent challenge with parental B16 or B16.OVA tumor cells. Tumor rejection was dependent on both NK and CD8+ T cells but not on CD4+ T cells, demonstrating induction of an effective adaptive immune response through innate immune cell activation. Our data indicate the potential of using robust NK cell activation, which through the NK-DC crosstalk stimulates effective antitumor responses, providing an alternate vaccine strategy

The feeding and reproductive strategies of Acartidae in Southampton Water

This work looked at some of the environmental and biological aspects of the reproductive effort in Southampton Water Acartidae. Adult Acartia congeners A. bifilosa, A. clausi, A. discaudata and A. tonsa have distinct seasonal and spatial distribution patterns in Southampton Water, governed by temperature and salinity respectively. The effect of these factors on other life stages, hatch success and naupliar survival, was investigated by exposing the congeners to a range of salinity (15.5-33.3) and temperature (5-20°C). Acartia clausi is known to prefer more saline waters (Lance 1963, 1964) and showed highest hatch success at 33.3 salinity. Acartia tonsa is more tolerant to dilution and at 15.5 salinity it had the highest hatch success of all of the congeners. Hatch success in both Acartia bifilosa and A. discaudata was similar over the range of salinities investigated, confirming that they are intermediate species in terms of spatial distribution. However, nauplii of all species survived well at the higher salinities and best at 33.3, which allows for differential transport of the poor-swimming nauplii to the mouth of the estuary until size and swimming ability increase when they can then return to regions of preferred salinity (Villante et al. 1993). The summer species, A. clausi and A. tonsa showed higher hatch success at 20°C, whereas A. discaudata which is present in the water column all year round showed no significant differences in hatch success at the three temperatures. Acartia bifilosa, which diapauses over summer showed significantly (P&lt;0.05) higher hatch success at 10°C than 20°C. The physiological relationship between temperature and development time was clear with naupliar survival of all species highest at 20°C and all congeners reached CI significantly faster at 20°C, but no consistent pattern was seen for salinity. Reflecting hatch and nauplii parameters, Acartia bifilosa Scope for Growth (SfG) at 10°C is twice that at 5°C and 20°C and since there is less energy available to it at 20°C the ultimate reason behind its oversummering in the egg phase is to avoid higher temperatures which decrease its competitive ability.</p

The feeding and reproductive strategies of Acartidae in Southampton Water

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Photoperiod and temperature regulation of diapause egg production in Acartia bifilosa from Southampton Water

In Southampton Water the copepod Acartia bifilosa presents a diapause reproductive strategy, where there is a switch from subitaneous to diapause egg production around May, prior to the species' disappearance from the water column between June and October. The effect of temperature and photoperiod on the production of diapause eggs by A. bifilosa was studied in an attempt to determine the primary cues for its summer diapause. A parallel study on the effect of temperature on metabolic efficiency of A. bifilosa and the non-diapause species A. discaudata, defined by the species' 'scope for growth' (SfG), was examined as a potential, ultimate reason behind the diapause stage. Photoperiod was identified as the primary proximate cue that induced diapause in A. bifilosa, and this response was temperature-mediated. Diapause was triggered by a 13:11 h light:dark photoperiod (day length), corresponding to a late-April photoperiodic regime, and resting eggs were produced even at temperatures as low as 5°C. A very low number of diapause eggs were, however, also produced after 6 d at a 12:12 h light:dark photoperiod at elevated temperatures between 14 and 20°C, but the mean percentage produced was significantly less (p &lt; 0.05) than under the longer day lengths. The ultimate cause of the over-summering strategy of A. bifilosa is currently unknown, but the SfG assay indicated that at 10°C, SfG was twice that at 20 or 5°C, and so it may diapause to avoid the higher temperatures in summer. This pattern contrasted with the SfG of A. discaudata, which suggested a simple, positive relationship with temperature. In the field, competition is greatly reduced in the winter months, so A. bifilosa has a better chance of survival, even with its lower SfG

Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells

Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2. Moreover, hESCs cultured at atmospheric O2 levels expressed significantly less OCT4, SOX2 and NANOG than those maintained at 5% O2. To determine whether this difference in metabolism was a reflection of the pluripotent state, hESCs were cultured at 5% O2 in the absence of FGF2 for 16 hours leading to a significant reduction in the expression of SOX2. In addition, these cells consumed less glucose and produced significantly less lactate compared to those cultured in the presence of FGF2. hESCs maintained at 5% O2 were found to consume significantly less O2 than those cultured in the absence of FGF2, or at 20% O2. GLUT1 expression correlated with glucose consumption and using siRNA and chromatin immunoprecipitation was found to be directly regulated by hypoxia inducible factor (HIF)-2? at 5% O2. In conclusion, highly pluripotent cells associated with hypoxic culture consume low levels of O2, high levels of glucose and produce large amounts of lactate, while at atmospheric conditions glucose consumption and lactate production are reduced and there is an increase in oxidative metabolism. These data suggest that environmental O2 regulates energy metabolism and is intrinsic to the self-renewal of hESCs

Bimekizumab for treating active psoriatic arthritis: a single technology appraisal

This report is a critique of the company’s submission (CS) to NICE from UCB Pharma on the clinical effectiveness and cost effectiveness of bimekizumab for treating psoriatic arthritis. It identifies the strengths and weaknesses of the CS