Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.

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).

Blood triacylglycerols: a lipidomic window on diet and disease.

Although the measurement of triacylglycerols (TAGs) by clinical chemistry has been used in the diagnosis of a range of metabolic diseases, such approaches ignore the different species of TAGs that contribute to the total concentration. With the advent of LC and direct infusion forms of MS it is now possible to profile the individual TAGs in blood plasma or tissue extracts. This mini review surveys the information that is obtainable from the lipidomic profiling of TAGs in following metabolic diseases such as type 2 diabetes (T2DM), cardiovascular disease (CVD) and non-alcoholic fatty liver disease, as well as the development of insulin resistance and obesity.

Amniotic membrane transplantation: structural and biological properties, tissue preparation, application and clinical indications.

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.

Treatment of Diabetic Macular Edema or Macular Edema Following Retinal Vein Occlusion Based on Repeated Injection of the Dexamethasone Intravitreal Implant: A Retrospective Real-World Analysis.

Purpose: To assess the "real world" utility of repeated injection with the dexamethasone intravitreal implant (DEX) in routine practice. Methods: This was a retrospective, single-center analysis of consecutive patients with diabetic macular edema, or macular edema following retinal vein occlusion, treated with DEX. None had received prior intravitreal steroid treatment. DEX was implanted as per the manufacturer's instructions. Results: Seventy-eight individuals (95 eyes) were included (50.0% female; mean age: 68.1 ± 12.4 years; mean duration of macular edema: 13.2 ± 12.9 months). Thirty-three eyes (34.7%) had received previous treatment with an anti-vascular endothelial growth factor (anti-VEGF) and/or laser. Thirty eyes (31.6%) underwent one round of DEX implantation; the remainder received 2-5 cycles (total: 225 cycles). Initial DEX treatment led to significant increases in visual acuity (VA) at 6 weeks (mean change: 4.6 letters; P=0.004). Greater VA improvements during the first treatment cycle were associated with inferior baseline VA (P=0.02), borderline associated with baseline central macular thickness (CMT; P=0.06), and independent of prior anti-VEGF treatment (P=0.39). In an analysis of all DEX injections, VA improvements were robust across cycles 1 and 2 but reduced in cycle 3 (P=0.03). CMT improvements did not differ based on injection number (P=0.20). Increases in intraocular pressure (IOP) were largest over the first 6 weeks (but rebounded towards baseline more rapidly) in cycle 1 versus cycles 2 and 3 (P<0.001). IOP rises were typically manageable with topical medications. Conclusion: This analysis confirms the broad utility of DEX and may inform decision-making in routine practice.

Comparison of Two Main Orthokeratology Lens Designs in Efficacy and Safety for Myopia Control.

Purpose: 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. Methods: 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. Results: 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 P < 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 P < 0.05). A lower incidence of total adverse events was found with the CRT lenses compared with the VST lenses (P < 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 P > 0.05). Conclusions: 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.

Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.

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.

Rhabdomyolysis caused by carnitine palmitoyltransferase 2 deficiency: A case report and systematic review of the literature.

Carnitine palmitoyltransferase 2 deficiency is an inherited metabolic disorder involving a deficiency in a mitochondrial enzyme necessary for long chain fatty acid oxidation, and therefore decreased utilisation of fatty acids. The adult form of this condition leads to recurrent rhabdomyolysis triggered by exercise, fasting and infection. It is a very rare condition with only a few hundred reported cases worldwide. Here we present a case of severe rhabdomyolysis in the context of carnitine palmitoyltransferase 2 deficiency in which major organ involvement was avoided, and organ support was not needed. This prompted us to perform a systematic review of the existing case reports in the literature to ascertain the most frequent patterns of organ involvement and assess the outcomes that are seen in these patients. Our findings suggest that these patients most frequently develop isolated renal failure, often requiring renal replacement therapy; however, the outcomes following this are very good, supporting the early involvement of intensive care teams.

A matched case-control study of the clinical, economic, and patient-reported outcomes of cystoid macular edema complicating phacoemulsification surgery.

PURPOSE: 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. SETTING: West Suffolk Hospital NHS Foundation Trust, United Kingdom. DESIGN: Matched case-control study. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The use of pan-retinal photocoagulation to treat recurrent vitreous haemorrhage with neovascularisation in the context of Epstein syndrome: an MYH9-related disorder.

A female patient presented with stable chronic thrombocytopaenia with large platelets, sensorineuronal deafness and renal impairment. Her treatment was refractory to intravenous immunoglobulins (IVIG) and steroids for a putative diagnosis of immune thrombocytopaenic purpura (ITP). She underwent genetic testing which revealed a MYH9 mutation in-keeping with a diagnosis of Epstein Syndrome. Subsequently to this she developed globally constricted fields on Goldmann visual field testing. MRI pituitary was unremarkable but she was diagnosed with a pituitary microprolactinoma secondary to raised prolactin in the blood responsive to carbegoline therapy. She subsequently developed retinal haemorrhages and recurrent vitreous haemorrhages due to neovascularisation. Fluorescein angiography revealed the extent of the neovascularisation and microvascular ischaemia. She underwent pan-retinal photocoagulation (PRP) to treat the ischaemic stimulus which resulted in regression of the new vessels and cessation of vitreous haemorrhages. There are no previous reported cases of microvascular retinal disease in the literature in the context of Epstein Syndrome, and this is the first report of successful treatment with PRP.

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.

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.

Toxic interactions of metal ions (Cd2+ , Pb2+ , Zn2+ and Sb3- ) on in vitro biomass production of ectomycorrhizal fungi.

A number of ectomycorrhizal (ECM) fungi, from sites uncontaminated by toxic metals, were investigated to determine their sensitivity to Cd2+ , Pb+2 , Zn2+ and Sb3- , measured as an inhibition of fungal biomass production, Isolates were grown in liquid media amended with the metals, Individually (over a range of concentrations) and in combination (at single concentrations) to determine any significant interactions between the metals. Significant interspecific variation in sensitivity to Cd2+ and Zn2+ was recorded, while Pb2+ and Sb3- individually had little effect. The presence of Pb2+ and Sb3- in the media did however, amcliorate Cd2+ and Zn2+ toxicity in some circumstances. Interactions between Cd+2 and Zn+2 were investigated further over a range of concentrations. Zn2+ was found to significantly ameliorate the toxicity of Cd2+ to three of the four isolates tested. The influence of Zn2+ varied between ECM species and with the concentrations of metals tested.

Anatomy and function of the ptychoid defensive mechanism in the mite Euphthiracarus cooki (Acari: Oribatida).

Ptychoidy is a defensive adaptation of several groups of oribatid mites in which legs and coxisternum can be fully retracted into the opisthosoma and protected by a ventrally deflected prodorsum, resulting in a seed-like appearance. Using Euphthiracarus cooki as a model, we examined details of exoskeletal and muscular anatomy in combination with studies of live individuals to provide the first functional analysis of ptychoidy. There are two main functional components: the first is a set of exoskeletal and muscular adaptations, mostly of the podosoma and prodorsum, that combine to effect leg withdrawal and prodorsal deflection; the second comprises adaptations of the opisthosoma that allow control of hydrostatic pressure during the large hemocoel volume adjustments associated with ptychoidy. Adaptations important in the closing process (enptychosis) are found in four body regions. Much of the podosomal exoskeleton (especially pleural) is unsclerotized, which facilitates leg retraction and prodorsal deflection during enptychosis. The coxisternum has several flexible furrows along which it folds in order to bring legs into a tightly parallel arrangement. The prodorsum has specialized attachment surfaces (manubrium and inferior retractor process) for retractor muscles and a paired bothridial scale that participates in prodorsal alignment during enptychosis. The subcapitulum has a prominent capitular apodeme on which important retractor muscles insert. The mineralized notogaster has an anterior "collar" that accommodates the retracted prodorsum; it includes paired notches and receptacles that accommodate the bothridial scales, thereby creating a temporary fixed axis for rotation of the prodorsum in a "lazy hinge" mechanism. Specialized muscles form the retractor system; most conspicuous are the large coxisternal retractors and prodorsal retractors, both of which originate on the notogaster. Other components have adjustor roles; among them are muscles of the endosternal system that control retraction of the subcapitulum and assist leg retraction, and the dorsoventral muscles which adjust the folded coxisternum. Hemolymph pressure control is a function of the opisthosoma, where the principle exoskeletal elements form a pleated venter, having a cross-sectional shape like an inverted "W." Paired holoventral plates (each representing fused genital, aggenital, anal, and anal plates) form the inner angle and are flanked by paired plicature plates. The holoventral plates are connected medially in two ways : 1) by three permanent bridges of sclerotized cuticle that include an anterior phragmatal bridge and two widely spaced, hollow apodemes (preanal, postanal); 2) by temporary zipper-like closures of two different types. Lateral compression of the pleats is effected by a series of transversely arranged, lateral compressor muscles that run from plicature to holoventral plate edges, and from holoventral plate edges to the medial apodemes. Compression increases hydrostatic pressure in the opisthosoma and stores energy in both the slightly deformed, mineralized notogaster and in the three holoventral bridges. During normal activity the compressor system is active and the inflated podosomal region provides support for the extended legs. When the mite is irritated, the prodorsum is hydraulically ejected from its active position in the notogastral collar, then relaxation of the compressors causes a fall in hemolymph pressure and return of the notogaster to an undeformed condition. Muscles of the retractor system then act in specific sequence to retract and adjust the coxisternum and prodorsum until they are precisely positioned at the completion of enptychosis. The process takes between 0.5 and 1 sec. When irritation ceases, partial opening allows sensory leg hairs to "test" the environment. Resumption of normal, active posture (ecptychosis) involves activation of the lateral compressor system and hydraulic inflation of the podosoma, through which legs are extended and the prodorsum is reflected.

Hybrid weakness controlled by the dosage-dependent lethal (DL) gene system in common bean (Phaseolus vulgaris) is caused by a shoot-derived inhibitory signal leading to salicylic acid-associated root death.

Certain crosses of common bean (Phaseolus vulgaris) result in temperature-dependent hybrid weakness associated with a severe root phenotype. This is controlled by the interaction of the root- and shoot-expressed semidominant alleles dosage-dependent lethal 1 (DL(1)) and DL(2), which communicate via long-distance signaling. Previously, apparent reciprocal effects on root growth and the restoration of normal root growth by exogenous sucrose led to the hypothesis that the dosage-dependent lethal (DL) system may control root-shoot carbon partitioning. Here, recombinant inbred lines were used to map the DL loci and physiological and biochemical analysis, including metabolite profiling, was used to gain new insights into the signaling interaction and the root phenotype. It is shown that the DL system does not control root-shoot carbon partitioning and that roots are unlikely to die from carbon starvation. Instead, root death likely occurs by defense-related programmed cell death, as indicated by salicylic acid accumulation. DL(2)-expressing cotyledons supply a potent inhibitory signal that is sufficient to cause such death in DL(1)-expressing roots. These data implicate the DL system in defense-related signaling and provide support for the recent hypothesis of defense-related autoimmunity as a potential isolating mechanism in plant speciation, in particular, setting a precedence for the potential roles of long-distance signaling and temperature dependence.