Conceptualisation of severe and enduring anorexia nervosa : a qualitative meta-synthesis

Background: Severe and enduring anorexia nervosa (SE-AN) is amongst the most impairing of all mental illnesses. Collective uncertainties about SE-AN nosology impacts treatment refinement. Qualitative research, particularly lived experience literature, can contribute to a process of revision and enrichment of understanding the SE-AN experience and further develop treatment interventions. Poor outcomes to date, as evidenced in clinical trials and mortality for people with SE-AN (1 in 20) demonstrate the need for research that informs conceptualisations and novel treatment directions. This interpretative, meta-ethnographic meta-synthesis aimed to bridge this gap. Methods: A systematic search for qualitative studies that explored the AN experiences of people with a duration of greater than 3 years was undertaken. These studies included those that encompassed phenomenology, treatment experiences and recovery. Results: 36 papers, comprising 382 voices of SE-AN experiences informed the meta-ethnographic findings. Four higher order constructs were generated through a synthesis of themes and participant extracts cited in the extracted papers: (1) Vulnerable sense of self (2) Intra-psychic processes (3) Global impoverishment (4) Inter-psychic temporal processes. Running across these meta-themes were three cross cutting themes (i) Treatment: help versus harm, (ii) Shifts in control (iii) Hope versus hopelessness. These meta-themes were integrated into conceptualisations of SE-AN that was experienced as a recursive process of existential self-in-relation to other and the anorexia nervosa trap. Conclusions: The alternative conceptualisation of SE-AN proposed in this paper poses a challenge to current conceptualisations of AN and calls for treatments to engage with the complex intra and inter-psychic processes of the SE-AN, more fully. In doing so, clinicians and researchers are asked to continue to be bold in testing novel ideas that may challenge our own rigidity and attachment to dominant paradigms to best serve the individual person with SE-AN. The ‘global impoverishment of self’, found in this synthesis of AN experiences, should inform proposed diagnostic criteria for SE-AN

Conceptualising specialist supportive clinical management (SSCM) : current evidence and future directions

Background: Current evidence-based treatments for adult anorexia nervosa (AN) have limitations, with high attrition, very poor outcomes for 20% of people, and no clearly superior manualised therapy for adults with AN. Specialist Supportive Clinical Management (SSCM) was designed as a control treatment but has evolved as a valid first line treatment. The present paper aims to provide an overview of the evidence base for SSCM and a pedagogical reconceptualization with expansion by theoretical integration (TI). Body: A secondary meta-analysis endorses SSCM as a promising treatment. This paper positions SSCM as a manualised therapy for adult AN with six unique features, namely (1) a philosophy which is person-centred, non-prescriptive, and informed by the person’s strengths and values, (2) a focus on the person through inclusion of supportive psychotherapy and problem (clinical management), within target symptoms as defined in relation to AN, (3) a flexible and responsive therapy that could be delivered by a variety of clinicians with experience treating AN (4) a commitment to reversing starvation though a directional approach and a defined yet flexible stance on dietetic intervention (5) a commitment to the therapeutic relationship within all three phases of treatment, and (6) a therapy ‘uncluttered’ by specific mandates. In addition, this paper positions SSCM as a treatment that may be strengthened by other modalities and may also be adapted to the treatment of other eating disorders (ED), not just AN. The level of therapist sophistication to deliver upon the supportive psychotherapy component is explored and future directions are offered. Conclusion: SSCM is a unique and valid first line treatment for AN and would benefit from further expansion in line with emerging understandings of AN to strengthen it as a treatment. Speculation on aspects of potency would benefit from further testing. The proposed re-conceptualisation of SSCM in the context of its evidence may strengthen it as a treatment overall, position it as adaptable for treatment of other eating disorders and make it more accessible to clinicians

Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle.

Expression of key metabolic genes and proteins involved in mRNA translation, energy sensing, and glucose metabolism in liver and skeletal muscle were investigated in a late-gestation fetal sheep model of placental insufficiency intrauterine growth restriction (PI-IUGR). PI-IUGR fetuses weighed 55% less; had reduced oxygen, glucose, isoleucine, insulin, and IGF-I levels; and had 40% reduction in net branched chain amino acid uptake. In PI-IUGR skeletal muscle, levels of insulin receptor were increased 80%, whereas phosphoinositide-3 kinase (p85) and protein kinase B (AKT2) were reduced by 40%. Expression of eukaryotic initiation factor-4e was reduced 45% in liver, suggesting a unique mechanism limiting translation initiation in PI-IUGR liver. There was either no change (AMP activated kinase, mammalian target of rapamycin) or a paradoxical decrease (protein phosphatase 2A, eukaryotic initiation factor-2 alpha) in activation of major energy and cell stress sensors in PI-IUGR liver and skeletal muscle. A 13- to 20-fold increase in phosphoenolpyruvate carboxykinase and glucose 6 phosphatase mRNA expression in the PI-IUGR liver was-associated with a 3-fold increase in peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mRNA and increased phosphorylation of cAMP response element binding protein. Thus PI-IUGR is-associated with reduced branched chain amino acid uptake and growth factors, yet up-regulation of proximal insulin signaling and a marked increase in the gluconeogenic pathway. Lack of activation of several energy and stress sensors in fetal liver and skeletal muscle, despite hypoxia and low energy status, suggests a novel strategy for survival in the PI-IUGR fetus but with potential maladaptive consequences for reduced nutrient sensing and insulin sensitivity in postnatal life

Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep.

Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA and phosphorylation of cAMP response element binding protein at Ser(133) were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4alpha, or CCAAT enhancer binding protein-beta. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

Negative Modulation of Macroautophagy by Stabilized HERPUD1 is Counteracted by an Increased ER-Lysosomal Network With Impact in Drug-Induced Stress Cell Survival

Macroautophagy and the ubiquitin proteasome system work as an interconnected network in the maintenance of cellular homeostasis. Indeed, efficient activation of macroautophagy upon nutritional deprivation is sustained by degradation of preexisting proteins by the proteasome. However, the specific substrates that are degraded by the proteasome in order to activate macroautophagy are currently unknown. By quantitative proteomic analysis we identified several proteins downregulated in response to starvation independently of ATG5 expression. Among them, the most significant was HERPUD1, an ER membrane protein with low expression and known to be degraded by the proteasome under normal conditions. Contrary, under ER stress, levels of HERPUD1 increased rapidly due to a blockage in its proteasomal degradation. Thus, we explored whether HERPUD1 stability could work as a negative regulator of autophagy. In this work, we expressed a version of HERPUD1 with its ubiquitin-like domain (UBL) deleted, which is known to be crucial for its proteasome degradation. In comparison to HERPUD1-WT, we found the UBL-deleted version caused a negative role on basal and induced macroautophagy. Unexpectedly, we found stabilized HERPUD1 promotes ER remodeling independent of unfolded protein response activation observing an increase in stacked-tubular structures resembling previously described tubular ER rearrangements. Importantly, a phosphomimetic S59D mutation within the UBL mimics the phenotype observed with the UBL-deleted version including an increase in HERPUD1 stability and ER remodeling together with a negative role on autophagy. Moreover, we found UBL-deleted version and HERPUD1-S59D trigger an increase in cellular size, whereas HERPUD1-S59D also causes an increased in nuclear size. Interestingly, ER remodeling by the deletion of the UBL and the phosphomimetic S59D version led to an increase in the number and function of lysosomes. In addition, the UBL-deleted version and phosphomimetic S59D version established a tight ER-lysosomal network with the presence of extended patches of ER-lysosomal membrane-contact sites condition that reveals an increase of cell survival under stress conditions. Altogether, we propose stabilized HERPUD1 downregulates macroautophagy favoring instead a closed interplay between the ER and lysosomes with consequences in drug-cell stress survival

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

Effectiveness of Denitrifying Bioreactors on Water Pollutant Reduction from Agricultural Areas

HighlightsDenitrifying woodchip bioreactors treat nitrate-N in a variety of applications and geographies.This review focuses on subsurface drainage bioreactors and bed-style designs (including in-ditch).Monitoring and reporting recommendations are provided to advance bioreactor science and engineering. Denitrifying bioreactors enhance the natural process of denitrification in a practical way to treat nitrate-nitrogen (N) in a variety of N-laden water matrices. The design and construction of bioreactors for treatment of subsurface drainage in the U.S. is guided by USDA-NRCS Conservation Practice Standard 605. This review consolidates the state of the science for denitrifying bioreactors using case studies from across the globe with an emphasis on full-size bioreactor nitrate-N removal and cost-effectiveness. The focus is on bed-style bioreactors (including in-ditch modifications), although there is mention of denitrifying walls, which broaden the applicability of bioreactor technology in some areas. Subsurface drainage denitrifying bioreactors have been assessed as removing 20% to 40% of annual nitrate-N loss in the Midwest, and an evaluation across the peer-reviewed literature published over the past three years showed that bioreactors around the world have been generally consistent with that (N load reduction median: 46%; mean ±SD: 40% ±26%; n = 15). Reported N removal rates were on the order of 5.1 g N m-3 d-1 (median; mean ±SD: 7.2 ±9.6 g N m-3 d-1; n = 27). Subsurface drainage bioreactor installation costs have ranged from less than $5,000 to$27,000, with estimated cost efficiencies ranging from less than $2.50 kg-1 N year-1 to roughly$20 kg-1 N year-1 (although they can be as high as $48 kg-1 N year-1). A suggested monitoring setup is described primarily for the context of conservation practitioners and watershed groups for assessing annual nitrate-N load removal performance of subsurface drainage denitrifying bioreactors. Recommended minimum reporting measures for assessing and comparing annual N removal performance include: bioreactor dimensions and installation date; fill media size, porosity, and type; nitrate-N concentrations and water temperatures; bioreactor flow treatment details; basic drainage system and bioreactor design characteristics; and N removal rate and efficiency

Mapping male circumcision for HIV prevention efforts in sub-Saharan Africa

Background HIV remains the largest cause of disease burden among men and women of reproductive age in sub-Saharan Africa. Voluntary medical male circumcision (VMMC) reduces the risk of female-to-male transmission of HIV by 50–60%. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries for VMMC campaigns and set a coverage goal of 80% for men ages 15–49. From 2008 to 2017, over 18 million VMMCs were reported in priority countries. Nonetheless, relatively little is known about local variation in male circumcision (MC) prevalence. Methods We analyzed geo-located MC prevalence data from 109 household surveys using a Bayesian geostatistical modeling framework to estimate adult MC prevalence and the number of circumcised and uncircumcised men aged 15–49 in 38 countries in sub-Saharan Africa at a 5 × 5-km resolution and among first administrative level (typically provinces or states) and second administrative level (typically districts or counties) units. Results We found striking within-country and between-country variation in MC prevalence; most (12 of 14) priority countries had more than a twofold difference between their first administrative level units with the highest and lowest estimated prevalence in 2017. Although estimated national MC prevalence increased in all priority countries with the onset of VMMC campaigns, seven priority countries contained both subnational areas where estimated MC prevalence increased and areas where estimated MC prevalence decreased after the initiation of VMMC campaigns. In 2017, only three priority countries (Ethiopia, Kenya, and Tanzania) were likely to have reached the MC coverage target of 80% at the national level, and no priority country was likely to have reached this goal in all subnational areas. Conclusions Despite MC prevalence increases in all priority countries since the onset of VMMC campaigns in 2008, MC prevalence remains below the 80% coverage target in most subnational areas and is highly variable. These mapped results provide an actionable tool for understanding local needs and informing VMMC interventions for maximum impact in the continued effort towards ending the HIV epidemic in sub-Saharan Africa