Intravenous lipid emulsions designed to meet preterm infant requirements increase plasma and tissue levels of docosahexaenoic acid and arachidonic acid in mice.

BACKGROUND & AIMS: Intravenous lipid emulsions used in preterm infants contain insufficient docosahexaenoic acid (DHA) and arachidonic acid (ARA) to support normal development, resulting in deficiencies that contribute to complications of prematurity and cognitive delay. We sought to investigate the effects of new intravenous lipid emulsions designed to contain sufficient DHA and ARA to meet preterm needs, while avoiding liver toxicity. METHODS: Three new lipid emulsions (NLE A-C) were laboratory-generated using high pressure homogenization. First, a long-term experiment evaluated the impact on plasma, liver, and frontal cortex fatty acid composition compared to commercially available lipid emulsions. Lipid emulsions were administered via daily orogastric gavage to four-week-old C57Bl/6 J mice. Next, liver toxicity was evaluated in a murine model of parenteral nutrition-induced hepatosteatosis. Mice were provided an ad lib fat-free high carbohydrate diet, with intravenous lipid emulsion administration every other day for 19 days. RESULTS: Administration of commercially available lipid emulsions (soybean oil, mixed oil, or fish oil) resulted in decreased plasma and tissue levels of DHA and/or ARA compared to a chow control. The new lipid emulsions demonstrated a dose-response effect in plasma and tissue concentration of DHA and ARA. NLE C (with an approximately even DHA:ARA ratio), compared to chow, maintained similar DHA (19.2 ± 0.3 vs. 19.3 ± 0.3%, P = 1.00) and ARA (10.4 ± 0.2 vs. 9.9 ± 0.2% ARA, P = 0.75) content in frontal cortex tissue. All three new lipid emulsions prevented biochemical liver injury and pathologist-assessed hepatosteatosis; soybean oil lipid emulsion and mixed oil lipid emulsion treatment resulted in hepatosteatosis in both experiments. CONCLUSION: Long-term treatment with the new lipid emulsions in juvenile mice resulted in increased plasma and tissue DHA and/or ARA content compared to currently available lipid emulsions. The new lipid emulsions also prevented hepatosteatosis and biochemical liver injury with enteral and parenteral administration.

Incidence and development of cholestasis in surgical neonates receiving an intravenous mixed-oil lipid emulsion.

BACKGROUND: Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. METHODS: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). RESULTS: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. CONCLUSION: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

The longitudinal association between coffee and tea consumption and the risk of metabolic syndrome and its component conditions in an older adult population.

The present study aimed to assess the longitudinal associations of coffee and tea consumption with metabolic syndrome and its component conditions in a group of Australian older adults who participated in the Blue Mountains Eye Study (n 2554, mean age: 64 years, 43 % female). Participants' coffee and tea intake were measured using a validated food frequency questionnaire. Hazard ratios (HRs) over a 10-year period were estimated using Cox hazard regression models adjusting for lifestyle factors. Results showed that coffee consumption was not associated with the incidence of metabolic syndrome, high fasting glucose, high triglycerides, central obesity, high blood pressure and low HDL-cholesterol (HDL-C). Tea consumption was not associated with incidence of metabolic syndrome and the component conditions except for the risk of having low HDL-C, in which a nominally inverse association was observed (multivariate-adjusted HR at 2-3 cups/d: 0⋅48, 95 % CI 0⋅26, 0⋅87, P = 0⋅016; 4 cups/d or more: 0⋅50, 95 % CI 0⋅27, 0⋅93, P = 0⋅029). After stratifying for fruit consumption (P interaction between tea and fruit = 0⋅007), consuming four cups of tea per day was nominally associated with lower incidence of metabolic syndrome among those with high fruit consumption (multivariable-adjusted HR: 0⋅44, 95 % CI 0⋅20, 0⋅93, P = 0⋅033). Our results did not support a significant association between tea and coffee consumption and metabolic syndrome. Tea consumption may be associated with a lower risk of having low HDL-C, while high tea and fruit consumption together may be associated with a lower risk of developing metabolic syndrome.

Histone Deacetylase Inhibition by Gut Microbe-Generated Short-Chain Fatty Acids Entrains Intestinal Epithelial Circadian Rhythms.

BACKGROUND & AIMS: The circadian clock orchestrates ∼24-hour oscillations of gastrointestinal epithelial structure and function that drive diurnal rhythms in gut microbiota. Here, we use experimental and computational approaches in intestinal organoids to reveal reciprocal effects of gut microbial metabolites on epithelial timekeeping by an epigenetic mechanism. METHODS: We cultured enteroids in media supplemented with sterile supernatants from the altered Schaedler Flora (ASF), a defined murine microbiota. Circadian oscillations of bioluminescent PER2 and Bmal1 were measured in the presence or absence of individual ASF supernatants. Separately, we applied machine learning to ASF metabolomics to identify phase-shifting metabolites. RESULTS: Sterile filtrates from 3 of 7 ASF species (ASF360 Lactobacillus intestinalis, ASF361 Ligilactobacillus murinus, and ASF502 Clostridium species) induced minimal alterations in circadian rhythms, whereas filtrates from 4 ASF species (ASF356 Clostridium species, ASF492 Eubacterium plexicaudatum, ASF500 Pseudoflavonifactor species, and ASF519 Parabacteroides goldsteinii) induced profound, concentration-dependent phase shifts. Random forest classification identified short-chain fatty acid (SCFA) (butyrate, propionate, acetate, and isovalerate) production as a discriminating feature of ASF "shifters." Experiments with SCFAs confirmed machine learning predictions, with a median phase shift of 6.2 hours in murine enteroids. Pharmacologic or botanical histone deacetylase (HDAC) inhibitors yielded similar findings. Further, mithramycin A, an inhibitor of HDAC inhibition, reduced SCFA-induced phase shifts by 20% (P < .05) and conditional knockout of HDAC3 in enteroids abrogated butyrate effects on Per2 expression. Key findings were reproducible in human Bmal1-luciferase enteroids, colonoids, and Per2-luciferase Caco-2 cells. CONCLUSIONS: Gut microbe-generated SCFAs entrain intestinal epithelial circadian rhythms by an HDACi-dependent mechanism, with critical implications for understanding microbial and circadian network regulation of intestinal epithelial homeostasis.

Dietary Fibre Intake and the 10-Year Incidence of Tinnitus in Older Adults.

Tinnitus is the phantom perception of sound in the ears or head that increases in prevalence as age increases. With strong evidence supporting the benefits of dietary fibre for vascular health and hearing loss, intake of dietary fibre may also have a role in the prevention of tinnitus symptoms. This longitudinal study aims to determine the association between the intake of dietary fibre and other carbohydrate nutrition variables including glycaemic index (GI), glycaemic load (GL) and total carbohydrate intakes, and incident tinnitus over 10 years. Of the 1730 participants (aged ≥50 years) from the Blue Mountains Hearing Study with complete baseline data on tinnitus symptoms and carbohydrate intakes, 536 (31%) cases of tinnitus were identified and excluded from further incidence analysis. Dietary data were collected using a validated semi-quantitative food frequency questionnaire to determine intakes of total dietary fibre and fibre contributions from cereals, vegetables, and fruit. A purpose-built database based on Australian GI values was used to calculate mean GI. Lower versus higher intakes of fruit fibre (≤3.6 g/day vs. >3.6 g/day) and cereal fibre (≤4.2 g/day vs. >4.2 g/day) were significantly associated with a 65% (HR = 1.65; 95% CI: 1.15-2.36) and 54% (HR = 1.54; 95% CI: 1.07-2.22) increased risk of developing tinnitus over 10 years, respectively. Associations between intake of other carbohydrate nutrients and incident tinnitus were mostly non-significant. In summary, our study showed modest associations between intake of dietary fibre and incident tinnitus. The protective effects of fibre, particularly insoluble fibre, could underlie observed associations by reducing the risk of tinnitus via vascular risk factors such as cardiovascular disease. Further longitudinal studies evaluating different types and sources of fibre and tinnitus risk are needed to confirm our study findings.

Perspectives of people with late age-related macular degeneration on mental health and mental wellbeing programmes: a qualitative study.

PURPOSE: People with age-related macular degeneration (AMD) experience high rates of depression, but rarely engage in or have access to tailored mental wellbeing programmes. This qualitative study investigated the perspectives of those primarily with late AMD on mental health and mental wellbeing programmes. METHODS: Twenty-eight people with late AMD in at least one eye, and one person with early AMD in both eyes, aged 56-87 years (mean age 78 years) attending a private eye clinic between December 2019 and January 2020 in Sydney, New South Wales, Australia, participated. Individual semi-structured interviews were conducted and analysed deductively using content analysis, following the individual level factors for health promotion interventions in the behaviour change wheel: Capability (Physical & Psychological), Opportunity (Physical & Social), and Motivation (Reflective & Automatic). RESULTS: Six major themes were identified: Capability: (1) Impact of vision loss on mobility and leisure pursuits; (2) Adjustment to living with vision loss; Opportunity: (3) Program considerations for those with AMD; (4) Stigma and self-perception of vision loss and mental health; Motivation: (5) Accumulation of vision-related issues as a barrier to participation; (6) Examples of others living with vision loss. General personal factors relevant to delivery of a programme in this age group were also identified: Comorbidities; Limitations using technology; Isolation; Financial concerns and Beliefs that undesired effects of aging are inevitable. CONCLUSIONS: Complex individual, environmental and social factors influence the perspectives of people with late AMD on mental health, and potential participation in mental wellbeing programmes. These factors should be considered when developing and implementing mental wellbeing programmes to improve the emotional and functional rehabilitation outcomes for people with AMD.

One-year Experience With Composite Intravenous Lipid Emulsion in Children on Home Parenteral Nutrition.

BACKGROUND: Composite lipid emulsion (CLE) composed of soybean oil, medium-chain triglycerides, olive oil, and fish oil is approved in the US for parenterally fed adults. For stable children discharged on home parenteral nutrition (HPN) without cholestasis (direct bilirubin > 2.0 mg/dL), CLE has theoretical benefits over soybean-based intravenous lipid emulsion due to reduced phytosterol exposure with higher calorie support to permit reduced glucose infusion rates (GIRs), omega-3 supplementation, and supplemental α-tocopherol. METHODS: In this prospective, single-center open-label research study, safety and efficacy outcomes were evaluated in patients on HPN younger than 18 years treated with CLE at 1 to 3 g ·â€Škg-1 ·â€Šday-1 over 12 months. The primary outcome was change in anthropometrics and GIRs compared with baseline. Secondary outcomes were changes in fatty acid profiles and liver function and enzyme tests compared with baseline. RESULTS: Fifty-seven subjects were treated with a median age of 7 years. The diagnosis was short bowel syndrome in 72%. Change in practice was associated with a decrease in mean GIRs from 17 to 14 mg ·â€Škg-1 ·â€Šh-1 at 4 to 6 months postbaseline and beyond with a coincidental decline in mean arachidonic acid and stable growth parameters. No significant adverse events were noted. CONCLUSIONS: CLE was safe and well-tolerated in stable children on HPN at 1 year, but further studies are needed in this population to appreciate long-term outcomes.

Growth in Infants and Children With Intestinal Failure-associated Liver Disease Treated With Intravenous Fish Oil.

BACKGROUND: Infants with intestinal failure (IF) and IF-associated liver disease (IFALD) are at risk for poor somatic growth because of increased metabolic demands, inadequate intake, intestinal malabsorption, chronic liver disease and other comorbidities. There are limited data on the nutritional adequacy of intravenous fish oil lipid emulsion (FOLE) compared with standard soybean oil lipid emulsion (SOLE) in the setting of intestinal failure. AIMS: To describe growth patterns in a large cohort of infants with IFALD treated with FOLE. METHODS: We compared growth data from infants enrolled in a single-center, prospective FOLE study to published norms, as well as to a multicenter, historical cohort of infants with IF treated with SOLE. RESULTS: One hundred thirty-eight infants with IFALD were treated with FOLE and 108 with SOLE. Compared with normative growth curves from WHO and published preterm data, infants in both groups from 6 to 11 months postmenstrual age exhibited declines in mean weight- and length-for-age z scores. At 24 months postmenstrual age compared with WHO growth data, infants treated with FOLE had a mean (95% confidence interval [CI]) weight-for-age z-score of 0.13 (-0.18 to 0.45) and length-for-age z-score of 0.07 (-0.33 to 0.47). In comparison, at 24 months postmenstrual age, infants treated with SOLE had a mean weight for age z-score of -0.93 (-1.20 to -0.67) and mean length for age z-score of -2.33 (-2.75 to -1.91). Independent predictors of higher weight, length and head circumference z-scores included older postmenstrual age at baseline, fewer central line-associated blood stream infections, resolution of cholestasis, type of intravenous fat emulsion (FOLE vs SOLE) and female sex. CONCLUSIONS: Infants with IFALD treated with FOLE showed comparable somatic growth to those treated with SOLE in early infancy, and improved somatic growth up to 24 months of age, supporting its wider use in this patient population.

Trends of INR and Fecal Excretion of Vitamin K During Cholestasis Reversal: Implications in the Treatment of Neonates With Intestinal Failure-Associated Liver Disease.

BACKGROUND: Vitamin K is a fat-soluble compound that plays important roles in coagulation. In children with intestinal failure-associated liver disease (IFALD), the disrupted enterohepatic circulation can lead to intestinal loss of vitamin K. Fish oil-based lipid emulsion (FOLE) has proven effective in treating IFALD. As biliary excretion is restored during cholestasis reversal, the accelerated vitamin K loss can pose a risk for deficiency. METHODS: Ten neonates with IFALD and receiving FOLE monotherapy were prospectively enrolled in the study from 2016 to 2018. In addition to weekly measurements of international normalized ratio (INR) and direct bilirubin (DB), ostomy output was collected for determination of fecal concentrations of phylloquinone (PK). Trends of DB, INR, and fecal PK concentrations were summarized with locally estimated scatterplot smoothing. RESULTS: The median time (interquartile range) from FOLE initiation to cholestasis reversal was 59 (19-78) days. During cholestasis reversal, INR remained relatively unchanged, whereas the mean (95% confidence interval) daily fecal excretion of PK increased from 25.1 (5.0-158.5) ng at the time of FOLE initiation to 158.5 (31.6-1000.0) ng at complete reversal. Examination of individual trends in fecal PK excretion and INR revealed little correlation between the 2 measurements (r = -0.10; P = 0.50). CONCLUSION: Children with IFALD are at risk for vitamin K deficiency during cholestasis reversal. Close monitoring and quantified supplementation of vitamin K may be warranted during this period. However, this should not be guided by INR alone, as it is a poor indicator of vitamin K status.

Metabolic and Inflammatory Effects of an ω-3 Fatty Acid-Based Eucaloric Ketogenic Diet in Mice With Endotoxemia.

BACKGROUND: Dietary strategies can aid in the management of critically ill patients. Very-low-carbohydrate diets have been shown to improve glucose control and the inflammatory response. We aimed to determine the effects of a eucaloric ketogenic diet (EKD) enriched with ω-3 fatty acids (O3KD) on glucose levels and inflammation in mice with endotoxemia. METHODS: Adult mice were fed 1 of 3 diets (control diet [CD], EKD, or O3KD). After 4 weeks, each group received saline or Escherichia coli lipopolysaccharide (LPS) (5 mg/kg) intraperitoneally during the postprandial (PPP) or postabsorptive (PAP) periods. Blood glucose was measured at 0, 15, 30, 60, 90, 120, 180, and 240 minutes. Serum tumor necrosis factor (TNF)-α and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay. Distribution of serum fatty acids was determined by gas liquid chromatography. Hepatic expression of genes involved in inflammation, as well as glucose and lipid metabolism, were determined by quantitative polymerase chain reaction. RESULTS: During the PPP, glucose curves were comparable among the experimental groups. During the PAP, EKD showed a more pronounced increase in glucose levels at the first hour after LPS challenge compared with the CD-LPS group. During the PAP, IL6 was lower in O3KD-LPS compared with CD-LPS and EKD-LPS groups. These differences disappeared in the PPP. Similarly, TNF-α was lower in the O3KD-LPS group compared with the EKD-LPS group. The O3KD significantly increased the serum levels of the ω-3 eicosapentaenoic and docosahexaenoic acids and decreased the ω-6 arachidonic acid. CONCLUSION: An O3KD leads to reduced inflammation and maintains glucose homeostasis in mice with endotoxemia.

Omega-3 fatty acids are protective in hepatic ischemia reperfusion injury in the absence of GPR120 signaling.

BACKGROUND: A single dose of IV fish oil (FO) before hepatic ischemia reperfusion injury (HIRI) increases hepatocyte proliferation and reduces necrosis in wild type (WT) mice. It has been suggested that the GPR120 receptor on Kupffer cells mediates FO's ability to reduce HIRI. The purpose of this study was to determine whether GPR120 is required for FO to reduce HIRI. METHODS: Sixty-four (n = 8/group) adult male WT (C57BL/6) and GPR120 knockout (KO) mice received IV FO (1 g/kg) or saline 1 h prior to HIRI or sham operation. Mice were euthanized 24 h postoperatively for analysis of hepatic histology, NFκB activity, and serum alanine transaminase (ALT) levels. RESULTS: FO pretreated livers had less necrosis after HIRI than saline pretreated livers in both WT (mean ±â€¯SEM 25.9 ±â€¯7.3% less, P = 0.007) and KO (36.6 ±â€¯7.3% less, P < 0.0001) mice. There was no significant difference in percent necrosis between WT-FO and KO-FO groups. Sham groups demonstrated minimal necrosis (0-1.9%). Mean [95% CI] ALT after HIRI was significantly higher (P = 0.04) in WT-Saline mice (1604 U/L [751-3427]) compared to WT-FO (321 U/L [150-686]) but was not significantly higher in KO-Saline mice compared to KO-FO. There were no differences in ALT between WT-FO and KO-FO mice who underwent HIRI or between groups who underwent sham surgery. There were no differences in NFκB or IKKß activation among groups as measured by Western blot analysis. CONCLUSIONS: IV FO pretreatment was able to reduce HIRI in GPR120 KO mice, suggesting the hepatoprotective effects of FO are not mediated by GPR120 alone.

Fish oil protects the liver from parenteral nutrition-induced injury via GPR120-mediated PPARγ signaling.

Intravenous fish oil lipid emulsions (FOLE) can prevent parenteral nutrition (PN)-induced liver injury in murine models and reverse PN-induced cholestasis in pediatric patients. However, the mechanisms by which fish oil protects the liver are incompletely characterized. Fish oil is rich in omega-3 fatty acids, which are ligands for the G-protein coupled receptor 120 (GPR120), expressed on hepatic Kupffer cells. This study tested the hypothesis that FOLE protects the liver from PN-induced injury through GPR120 signaling. Utilizing a previously described murine model of PN-induced liver injury in which mice develop steatosis in response to an oral parenteral nutrition diet, FOLE was able to preserve normal hepatic architecture in wild type mice, but not in congenic GPR120 knockout (gpr120-/-) mice. To further characterize the requirement of intact GPR120 for FOLE-mediated hepatic protection, gene expression profiles of key regulators of fat metabolism were measured. PPARγ was identified as a gene that is up-regulated by the PN diet and normalized with the addition of FOLE in wild type, but not in gpr120-/- mice. This was confirmed at the protein expression level. A PPARγ expression array further identified CD36 and SCD1, both down-stream effectors of PPARγ, to be up-regulated in PN-fed wild type mice yet normalized upon FOLE administration in wild type but not in gpr120-/- mice. Together, these results suggest that FOLE protects the liver, in part, through activation of GPR120 and the downstream effectors PPARγ and CD36. Identification of key genetic determinants of FOLE-mediated hepatic protection may provide targets for small molecule-based hepatic protection strategies.

Essential Fatty Acid Status in Surgical Infants Receiving Parenteral Nutrition With a Composite Lipid Emulsion: A Case Series.

Infants requiring prolonged parenteral nutrition (PN) may receive intravenous (IV) lipid in the form of soybean oil, fish oil, or a composite lipid emulsion (CLE) (i.e., SMOFlipid®). Soybean oil lipid-dose restriction is a popular method of treating and reducing the risk of intestinal failure-associated liver disease (IFALD) that may influence dosing strategies of other IV fat emulsions. Here we present 4 infants receiving PN with SMOFlipid® as their IV lipid source and examine trends in essential fatty-acid status, triglycerides, and dosing strategy. The infants on restricted doses of CLE developed biochemical essential fatty-acid deficiency (EFAD) that resolved with a dosage increase or by transition to a pure fish-oil lipid emulsion. Three of the 4 infants originally prescribed CLE were diagnosed with IFALD and started a pure fish-oil lipid emulsion after treatable causes of cholestasis were excluded. One of the 4 infants presented with hypertriglyceridemia that resolved upon transition to pure fish-oil lipid emulsion. Misapplication of lipid restriction protocols to CLE regimens render infants at risk for EFAD. CLE should be dosed within recommended ranges to prevent EFAD. Restricted protocols warrant close monitoring of essential fatty-acid status in infants receiving prolonged PN, particularly in those with minimal or no enteral intake. Hypertriglyceridemia and cholestasis are known adverse effects of CLE and require monitoring.

The Victorian Comprehensive Cancer Centre lung cancer clinical audit: collecting the UK National Lung Cancer Audit data from hospitals in Australia.

BACKGROUND: Clinical audit may improve practice in cancer service provision. The UK National Lung Cancer Audit (NLCA) collects data for all new cases of thoracic cancers. AIM: To collect similar data for our Victorian patients from six hospitals within the Victorian Comprehensive Cancer Centre and associated Western and Central Melbourne Integrated Cancer Service. METHODS: We conducted a retrospective audit of all newly diagnosed patients with lung cancer and mesothelioma in 2013 across the six Victorian Comprehensive Cancer Centre/Western and Central Melbourne Integrated Cancer Service hospitals. The objectives were to adapt the NLCA data set for use in the Australian context, to analyse the findings using descriptive statistics and to determine feasibility of implementing a routine, ongoing audit similar to that in the UK. Individual data items were adapted from the NLCA by an expert steering committee. Data were collated from the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited for missing data. RESULTS: Eight hundred and forty-five patients were diagnosed across the sites in 2013. Most were aged 65-80 (55%) and were male (62%). Most had non-small-cell lung cancer (81%) with 9% diagnosed with small cell lung cancer and 2% with mesothelioma. Data completeness varied significantly between fields. For those with higher levels of completeness, headline indicators of clinical care were comparable with NLCA data. The Victorian population seem to lack access to specialist lung cancer nurse services. CONCLUSION: Lung cancer care at participating hospitals appeared to be comparable with the UK in 2013. In future, prospective data collection should be harmonised across sites and correlated with survival outcomes. One area of concern was a lack of documented access to specialist nursing services.

Age-related macular degeneration.

Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.

Vascular Endothelial Growth Factor Enhances Compensatory Lung Growth in Piglets.

BACKGROUND: Vascular endothelial growth factor has been found to accelerate compensatory lung growth after left pneumonectomy in mice. The aim of this study was to determine the natural history and the effects of vascular endothelial growth factor on compensatory lung growth in a large animal model. METHODS: To determine the natural history of compensatory lung growth, female Yorkshire piglets underwent a left pneumonectomy on days of life 10-11. Tissue harvest and volume measurement of the right lung were performed at baseline (n = 5) and on postoperative days 7 (n = 5), 14 (n = 4), and 21 (n = 5). For pharmacokinetic studies, vascular endothelial growth factor was infused via a central venous catheter, with plasma vascular endothelial growth factor levels measured at various time points. To test the effect of vascular endothelial growth factor on compensatory lung growth, 26 female Yorkshire piglets underwent a left pneumonectomy followed by daily infusion of vascular endothelial growth factor at 200 µg/kg or isovolumetric 0.9% NaCl (saline control). Lungs were harvested on postoperative day 7 for volume measurement and morphometric analyses. RESULTS: Compared with baseline, right lung volume after left pneumonectomy increased by factors of 2.1 ± 0.6, 3.3 ± 0.6, and 3.6 ± 0.4 on postoperative days 7, 14, and 21, respectively. The half-life of VEGF ranged from 89 to 144 minutes. Lesser doses of vascular endothelial growth factor resulted in better tolerance, volume of distribution, and clearance. Compared with the control group, piglets treated with vascular endothelial growth factor had greater lung volume (P < 0.0001), alveolar volume (P = 0.001), septal surface area (P = 0.007) and total alveolar count (P = 0.01). CONCLUSION: Vascular endothelial growth factor enhanced alveolar growth in neonatal piglets after unilateral pneumonectomy.

Characterization of Fatty Acid Profiles in Infants With Intestinal Failure-Associated Liver Disease.

BACKGROUND: The purpose of this study was to characterize fatty acid profiles (FAPs) in parenteral nutrition (PN)-dependent infants with intestinal failure-associated liver disease (IFALD) receiving soybean oil-based lipid emulsion (SO) doses of ∼3 and ∼1 g/kg/d. METHODS: Prospectively collected data were retrospectively reviewed. Serum FAPs of patients <1 year old who experienced development of IFALD while receiving standard PN with SO were examined before transitioning to a fish oil-based lipid emulsion for IFALD treatment. Time on SO, dose, gestational age, and weight- and length-for-age z scores were also reviewed. RESULTS: Among the 49 patients analyzed, there were no differences in demographics or anthropometrics between patients who received standard SO (SO-S) (n = 14, range of dosage 2.06-3.31 g/kg/d) and reduced SO (SO-R) (n = 35, range of dosage 0.90-1.34 g/kg/d). Patients received SO for a median of 53 days (interquartile range 39, 73) before FAP measurement. Patients who received SO-R had significantly higher Mead acid and lower α-linolenic, eicosapentaenoic, linoleic, stearic, total ω-3, and total ω-6 fatty acid levels than patients who received SO-S (P < .01). Triene:tetraene ratios were higher in patients who received SO-R (P = .0009), and no patients experienced biochemical essential fatty acid deficiency (EFAD). CONCLUSION: PN-dependent infants with IFALD receiving SO-R have different FAPs than patients receiving SO-S. No patients in either group had biochemical EFAD.

Pretreatment with intravenous fish oil reduces hepatic ischemia reperfusion injury in a murine model.

BACKGROUND: Ischemia reperfusion injury is a barrier to liver surgery and transplantation, particularly for steatotic livers. The purpose of this study was to determine if pretreatment with a single dose of intravenous fish oil decreases hepatic ischemia reperfusion injury and improves recovery of injured livers. METHODS: Sixty adult male C57BL/6 mice received 1 g/kg intravenous fish oil (Omegaven, Fresenius Kabi) or isovolumetric 0.9% NaCl (saline) via tail vein 1 hour before 30 minutes of 70% hepatic ischemia. Animals were killed 4, 8, or 24 hours postreperfusion, and livers were harvested for histologic analysis. RESULTS: Four hours postreperfusion, saline-treated livers demonstrated marked ischemia diffusely around the central veins, while intravenous fish oil-treated livers demonstrated only patchy necrosis with intervening normal parenchyma. Eight hours postreperfusion, all livers demonstrated pale areas of cell loss with surrounding regenerating hepatocytes. Ki67 staining confirmed 14.4/10 high-powered field (95% confidence interval, 3.2-25.6) more regenerating hepatocytes around areas of necrosis in intravenous fish oil-treated livers. Twenty-four hours postreperfusion, all livers demonstrated patchy areas of necrosis, with an 89% (95% confidence interval, 85-92) decrease in the area of necrosis in intravenous fish oil-treated livers. CONCLUSION: Intravenous fish oil treatment prior to hepatic ischemia reperfusion injury decreased the area of hepatic necrosis and increased hepatocyte regeneration compared to saline treatment in a mouse model.

Parenteral Soybean Oil Induces Hepatosteatosis Despite Addition of Fish Oil in a Mouse Model of Intestinal Failure-Associated Liver Disease.

BACKGROUND: Replacement of parenteral soybean oil (SO) with fish oil (FO) is an effective therapy for intestinal failure-associated liver disease (IFALD) in children. However, practitioners remain concerned about the risk of essential fatty acid deficiency (EFAD) and sometimes treat IFALD with a combination of 50% SO and 50% FO emulsions. The purpose of this study was to determine if mixing 50% SO and 50% FO emulsions would prevent hepatosteatosis in a murine model of parenteral nutrition (PN)-induced hepatosteatosis. METHODS: C57BL/6 mice were randomized to receive oral PN with parenteral saline, FO, SO, or a mixture of 50% FO and 50% SO for 19 days. Fatty acid analysis, histologic evaluation, Nonalcoholic Steatohepatitis Clinical Research Network (NSCRN) scores, and reverse-transcriptase polymerase chain reaction for key lipogenic genes were performed. RESULTS: The PN + saline group was the only group with EFAD, with a serum and hepatic triene/tetraene ratio of 0.53. NSCRN scores were highest in the PN + SO group (5.5; 95% confidence interval [CI], 4.9-6.1), followed by the PN + FO/SO (4.5; 95% CI, 3.5-5.5) group, with the lowest score in the PN + FO (2.0; 95% CI, 1.1-2.9) group. Acetyl CoA carboxylase α and acetyl CoA carboxylase ß expression was lower in the PN + FO group than in the PN + FO/SO or PN + SO groups. CONCLUSIONS: Our data demonstrate that a mixed fat emulsion of 50% SO and 50% FO is inferior to 100% FO in reducing hepatosteatosis in this model. These data suggest that use of parenteral SO with parenteral FO, in a 1:1 ratio, may still contribute to liver injury, although it is less hepatotoxic than pure SO.