APOE – a genetic marker of comorbidity in subjects with morbid obesity

Background: In population-based studies, the genetic variability of the APOE E alleles have been associated with health outcomes. Health problems are common in subjects with obesity. This study explored associations between the APOE E alleles and comorbidity in subjects with morbid obesity. Methods: The study included consecutive subjects referred for evaluation of bariatric surgery with morbid obesity (defined as BMI > 40 or > 35 kg/m2 with complications related to obesity). The subjects followed a conservative weight loss program for 6 months before surgery and had a follow-up visit 12 months after surgery. Demographic data and a set psychosomatic scores (musculoskeletal pain, WHO-5 Well-Being Index, Rosenberg Self-Esteem Scale, Hopkins Symptom Check-list 10; Epworth Sleepiness Scale, and Fatigue Severity Scale) were collected, and blood samples were analysed for haematological and biochemical parameters and APOE alleles. Results: One hundred and forty subjects (men/women: 32 (23%)/108 (77%) with mean age 43.0 (SD 8.7) years and BMI 42.1 (SD 3.8) kg/m2 were included. One hundred and eight and 92 subjects had data after conservative treatment and 12 months after surgery, respectively. The prevalence of the APOE alleles were: E2E2: 1 (0.7%), E2E3: 13 (9.3%), E2E4: 4 (2.9%), E3E3: 71 (50.7%), E3E4: 47 (33.6%), and E4E4: 4 (2.9%). The prevalence rates were as anticipated in a Norwegian population. The weight loss during conservative treatment and after bariatric surgery was independent of E allele variability. E2 was associated with a significant or clear trend toward improvement of all psychosomatic disorders. There was a significant fall in CRP during the two treatment periods with weight loss. E2 and E4 were significantly associated with high and low CRP, respectively, but no associations were seen between CRP and comorbidity. Conclusions: The most marked finding was the association between E2 and improvement of all psychosomatic disorders. The positive and negative associations between CRP and E2 and E4, respectively, could indicate effects on inflammation and immunological reactions.acceptedVersio

The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmit ters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, ad equate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.publishedVersio

Changes in circulating sirtuin 1 after bariatric surgery

Background and aims: Obesity is associated with chronic inflammation and oxidative stress. Weight loss after bariatric surgery improves the inflammatory state and risk of cardiovascular disease. Improvement in metabolic dysfunction might be associated with changes in the activity of sirtuin 1 (SIRT1) and we aimed to investigate the effect of bariatric surgery on its circulating levels. Methods and results: This is a sub-study of a prospective cohort study, including 110 subjects with morbid obesity. The surgical procedure was either laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Blood was sampled at inclusion and six and 12 months after surgery. SIRT1 was measured in EDTA plasma with an enzyme-linked immunosorbent assay. The mean age in the population was 43 years, 80% were women and mean body mass index (BMI) was 38.8 kg/m2. RYGB and SG were performed in 89 and 21 subjects, respectively. SIRT1 concentration was significantly reduced from baseline to six and 12 months after surgery, with mean values (SD) 156.8 (82.6), 119.5 (65.6) and 94.9 (45.6) ng/mL, respectively, (p 0.002, all), accompanied by significant reductions in C-reactive protein (CRP), BMI and triglycerides from inclusion (p < 0.001, all). Type of surgery did not differently modify SIRT1 levels (p Z 0.09). CRP and tri glycerides were both positively predictive of SIRT1 levels (p 0.001, both). Conclusion: SIRT1 concentration was significantly lower six and 12 months after bariatric surgery. CRP and triglycerides independently predicted SIRT1 levels, suggesting that reduction in SIRT1 levels might not intrinsically be related to weight reduction, but to improvement in metaflammation.publishedVersio

APOE Polymorphism and Endocrine Functions in Subjects with Morbid Obesity Undergoing Bariatric Surgery

Background: Obesity is an interplay between genes and the environment, including lifestyle. The genetics of obesity is insufficiently understood. Apolipoprotein E (APOE) genetic polymorphism has been associated with a wide range of disorders. Knowing that some APOE alleles are associated with obesity and endocrine disorders that are common in obesity, the present study aimed at exploring associations between APOE polymorphisms and endocrine functions in subjects with obesity undergoing bariatric surgery. Methods: Analyses of hormones in blood collected before and one year after bariatric surgery were examined. The APOE alleles were grouped as follows: E2 = ε2ε2 + ε2ε3; E3 = ε3ε3 + ε2ε4; E4 = ε3ε4 + ε4ε4. The APOE groups were analysed as nominal and ordered groups (E2-E3-E4) with a linear mixed model to predict the hormonal effects of the groups. Results: Forty-nine women (79%) and thirteen (21%) men with a mean age of 47.7 (SD 8.5) years were included in the study. The adiponectin level was significantly lower (p < 0.05) in the E2 group compared with the E4 group. Adiponectin and cortisol were positively and negatively associated, respectively, with the ordered APOE groups. Conclusions: The ordered APOE groups E2-E3-E4 were significantly associated with high and low levels of adiponectin and cortisol, respectively. The findings indicate APOE-mediated effects on body weight and metabolic functions in subjects with morbid obesity.publishedVersio

Circulating Lipoproteins in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy

The efficacy of various bariatric procedures on the mitigation of the obese dyslipidemia remains debated, and the impact of these measures on lipoprotein(a) (Lp(a)) levels is unknown. In this study we aimed to compare the two most commonly used procedures: gastric bypass (RYGB) and sleeve gastrectomy (SG). Adult patients with morbid obesity were assigned to receive either RYGB or SG. The levels of non-HDL cholesterol, LDL/HDL-ratio and Lp(a) at examinations conducted 6 and 12 months postoperatively were determined and compared to preoperative levels to estimate the efficacy of the two surgical methods. All results 6 and 12 months after surgery were used in the comparisons with the preoperative results. A linear mixed regression model for repeated analyses was used. The Lp(a) and the non-HDL cholesterol levels were considerably reduced in the RYGB group, in contrast to the minor changes in the SG group. In addition, the LDL/HDL ratio was significantly more reduced in the RYGB group when compared to the SG group. Conclusively, RYGB was found to be more efficient than SG for the mitigation of obese dyslipidemia, including preoperative high Lp(a)-levels. This might have important individual and societal implications, especially regarding the potential to reduce the risk of cardiovascular disease and the related societal costs.publishedVersio

Reply to Paredes et al. Comment on "Aaseth et al. Circulating Lipoproteins in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients 2022, 14, 2381"

Hereby, we thank Silvia Paredes et al. [...].publishedVersio

Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study

<p>Abstract</p> <p>Background</p> <p>Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2^ndgeneration CTLA4-Ig) or cyclosporine (CsA).</p> <p>Methods</p> <p>Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two <it>IMPDH </it>isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.</p> <p>Results</p> <p>The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC_{0–9 h}and C₀) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for <it>IMPDH1 </it>expression, starting at week 1. Higher MPA exposure was associated with larger elevations of <it>IMPDH1 </it>(r = 0.81, P = 0.023, n = 7 for MPA and <it>IMPDH1 </it>AUC_{0–9 h}at week 1). The maximum <it>IMPDH1 </it>expression was 52 (13–177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor <it>IMPDH1 </it>expression. No difference was observed in T cell subsets between treatment groups.</p> <p>Conclusion</p> <p>The significant influence of MPA on <it>IMPDH1 </it>expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.</p

Hippocampal volumes are important predictors for memory function in elderly women

<p>Abstract</p> <p>Background</p> <p>Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).</p> <p>Methods</p> <p>Brain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.</p> <p>Results</p> <p>APOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.</p> <p>Conclusion</p> <p>Gender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.</p

Nicotinic Receptor Gene CHRNA4 Interacts with Processing Load in Attention

Background: Pharmacological studies suggest that cholinergic neurotransmission mediates increases in attentional effort in response to high processing load during attention demanding tasks [1]. Methodology/Principal Findings: In the present study we tested whether individual variation in CHRNA4, a gene coding for a subcomponent in a4b2 nicotinic receptors in the human brain, interacted with processing load in multiple-object tracking (MOT) and visual search (VS). We hypothesized that the impact of genotype would increase with greater processing load in the MOT task. Similarly, we predicted that genotype would influence performance under high but not low load in the VS task. Two hundred and two healthy persons (age range = 39–77, Mean = 57.5, SD = 9.4) performed the MOT task in which twelve identical circular objects moved about the display in an independent and unpredictable manner. Two to six objects were designated as targets and the remaining objects were distracters. The same observers also performed a visual search for a target letter (i.e. X or Z) presented together with five non-targets while ignoring centrally presented distracters (i.e. X, Z, or L). Targets differed from non-targets by a unique feature in the low load condition, whereas they shared features in the high load condition. CHRNA4 genotype interacted with processing load in both tasks. Homozygotes for the T allele (N = 62) had better tracking capacity in the MOT task and identified targets faster in the high load trials of the VS task. Conclusion: The results support the hypothesis that the cholinergic system modulates attentional effort, and that commo

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p