ABSTRACT
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl‐CoA subunits that are produced from a number of different pathways within the cell, most ...commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non‐alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance.
Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of ...saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates.
We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis.
A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.
The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to ...prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.
The amniotic membrane is a single epithelial layer of the placenta. It has anti-inflammatory, anti-scarring, anti-angiogenic and possibly bactericidal properties. The basement membrane of the ...amniotic membrane acts as a substrate to encourage healing and re-epithelialisation. It has been used in many ocular surface diseases including persistent epithelial defects (corneal or conjunctival), chemical or thermal burns, limbal stem cell deficiency, cicatrising conjunctivitis, ocular graft versus host disease, microbial keratitis, corneal perforation, bullous keratopathy, dry eye disease, corneal haze following refractive surgery and cross-linking, band keratopathy, ocular surface neoplasia, pterygium surgery, and ligneous conjunctivitis. This review provides an up-to-date overview of amniotic membrane transplantation including the structural and biological properties, preparation and application, clinical indications, and commercially available products.
Aims/Purpose: To assess the real‐world effectiveness of idebenone in a heterogenous group of patients with LHON treated with idebenone in Wales. This provides insight into the national outcomes of.
...Methods: Patients were identified from the ophthalmic genetics service based at Cardiff Eye Unit. Clinical notes were reviewed and details were collated on: demographics of patients, genetic mutation ascribed to be causative of LHON, visual acuity from diagnosis through to March 2023. Visual acuity was analysed for clinically relevant recovery (CRR) defined as improvement from “off‐chart” to at least 5 letters “on‐chart” or “on‐chart” improvement of at least 10 letters.
Results: 11 patients with LHON were identified as being treated with Idebenone 300 mg TDS. Currently 45.9 ± 20.3 years of age (range 22–73). 8 male and 3 female patients. 6 patients had the m11778G > A mutation and 4 patients had the m14484T>C. Disease duration at treatment onset ranged from 2 to 216 months with a mean of 35.8 months. Patients had a mean duration of treatment of 14 months (range 6–20). 2 eyes in one patient demonstrated CRR improving from a nadir of 6/60 and counting fingers acuity to 6/6 and 6/7.5 respectively. All other patients demonstrated no CRR at the time of data collection.
Conclusions: Idebenone has mixed results in a heterogenous group of patients with LHON providing significant benefit for one patient out of a cohort of 12, meanwhile others demonstrated limited improvements, albeit prior to a full two‐year course of treatment. It remains to be seen what the long‐term outcomes will be with sustained treatment with idebenone.
To assess the visual outcomes of pseudophakic cystoid macular edema (CME) as compared with age- and copathology-matched control subjects, the costs of treatment and follow-up, and the ...patient-reported outcomes using the new Cat-patient-reported outcome measures (PROM) 5 questionnaire.
West Suffolk Hospital NHS Foundation Trust, United Kingdom.
Matched case-control study.
Fifty-two eyes of 49 patients developed CME over an 18-month period. Age- and copathology-matched patients were identified from clinical records over the same time period in a 2:1 ratio (90 eyes). Postoperative clinical outcomes were recorded including treatments received, costs of treatments, and patient-reported outcome measures using the Cat-PROM5.
Patients with CME reported a significantly worse outcome from surgery than control subjects. Furthermore, patients with CME had significantly worse visual acuity postoperatively than control subjects (CME: logarithm of the minimum angle of resolution 0.40 ± 0.33, n = 37; control subjects: 0.30 ± 0.33; P < .05) despite there being no difference in preoperative visual acuity. In patients with epiretinal membrane (ERM), notably those with CME had worse patient-reported outcomes than control subjects with ERM, and only 18% received prophylactic corticosteroid injection at surgery compared with 63.6% of control subjects. CME resulted in an excess of 266 outpatient appointments, with 388 weeks of topical therapy, 18 orbital floor injections, 6 intravitreal steroid injections, 5 intravitreal antivascular endothelial growth factor injections, and 1 intravitreal dexamethasone implant with an excess expenditure of £216.81 per case.
Patients developing CME after cataract surgery had reduced visual acuity at 4 to 6 weeks, patient-reported visual outcomes, and increased number of hospital appointments, treatments, and costs.
Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver ...for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)
This study aimed to compare the efficacy and safety of corneal refractive therapy (CRT) lenses and vision shaping treatment (VST) lenses for myopia control in children.
Medical records of 1,001 ...children (2,002 eyes) who had been fitted with orthokeratology lenses for over 1.5 years were retrospectively reviewed. We collected the clinical data of four types of orthokeratology (OK) lenses available: one CRT lens (brand: CRT) and three VST lenses (brands: Euclid, Alpha, and Hiline) over 1.5 years. Results were compared and analyzed using a one-way ANOVA and Pearson's chi-square test.
Axial length elongation in the CRT lens group was 0.13 ± 0.02 mm faster than that in the Euclid lens, 0.1 ± 0.02 mm faster in the Alpha lens, and 0.08 ± 0.02 mm faster in the Hiline lens over the 1.5-year period (all
< 0.05). Among the subjects, 37.3% of them using the CRT lens experienced more than 1 D of refractive growth, compared with 20.2-30.8% of subjects wearing the three groups of VST lenses (all
< 0.05). A lower incidence of total adverse events was found with the CRT lenses compared with the VST lenses (
< 0.05), especially corneal staining. No difference was found in axial length elongation, refraction growth, and incidence of adverse events among the three types of VST lenses (all
> 0.05).
Compared with the VST lenses, CRT lenses demonstrated a weaker effect on myopia control but with a better safety profile. Different types of VST lenses had similar efficacy and safety in the context of controlling myopia progression.
Aims/Purpose: Inherited retinal dystrophies (IRD) are a group of predominantly monogenic disorders which have genetically heterogeneous origins and display wide clinical phenotypic heterogeneity. The ...current study aims to describe the clinical diagnoses, demographics, and genetic aetiology of patients in an adult cohort of Welsh patients to provide insight into the rates of genetic diagnosis of IRD. This will help inform patient prognosis and counselling in future clinical encounters.
Methods: A comprehensive database of patients attending the tertiary referral clinic from 2011 to 2022 was compiled contemporaneously. Demographic data were collated from patients' clinical records. Subjects underwent genetic screening, including targeted gene sequencing, next‐generation sequencing‐based gene panel, or whole exome sequencing, to investigate the causative mutations.
Results: A total of 365 probands (191 men and 174 women). The median age at which the patients developed visual symptoms related to IRD was 42 ± 17.7 years (range, 1–86 years). Retinitis pigmentosa (176; 48.2%), Macular Dystrophy (49; 13.4%), and Cone Rod Dystrophy (41; 11.2%) were the most common clinical diagnoses in this cohort. Among all the subjects, a genetic mutation was identified in 193 (52.9%) patients and the genetic aetiology of diseases was confirmed in 147 (40.3%) patients. Pathogenic mutations were identified in 48 retinal genes with the most commonly affected genes being ABCA4, USH2A and GUCY2D with 78, 44 and 13 mutations identified overall.
Conclusions: The establishment of a molecular genetic diagnosis in this group of patients serves as a basis for genetic counselling and will allow patients to enrol in current and future gene‐based clinical trials, and benefit from any future gene‐based treatments.
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