Surgical trauma causes immune impairment, but it is largely unknown whether surgery for cancer and benign diseases instigate comparable levels of immune inhibition. Here, we compared the impact of ...laparoscopic surgery on immunological biomarkers in patients with colorectal cancer (CRC) and ventral hernia (VH).
Natural Killer cell activity (NKA), leukocyte subsets, and soluble programmed death ligand 1 (sPD-L1) were measured in blood samples collected from CRC (n = 29) and VH (n = 9) patients preoperatively (PREOP) and on postoperative day (POD) 1, 3-6, 2 weeks and 3 months. NKA was evaluated by the NK Vue assay that uses the level of IFNγ as a surrogate marker of NKA. Normal NKA was defined as IFNγ > 250 pg/mL and low NKA was defined as IFNγ < 250 pg/mL.
The CRC cohort was classified into either PREOPLOW having preoperative low NKA or PREOPHIGH having preoperative normal NKA. The median NKA of the PREOPLOW subset was only in the normal range in the POD3 months sample, whereas median NKA of the PREOPHIGH subset and the VH cohort were only low in the POD1 sample. While PREOPLOW differed from VH in the PREOP-, POD1-, and POD3-6 samples (P =.0006, P = .0181, and P = .0021), NKA in PREOPHIGH and VH differed in the POD1 samples (P = .0226). There were no apparent differences in the distribution of leukocyte subsets in the perioperative period between the cohorts.
CRC patients with preoperative normal NKA and VH patients showed the same pattern of recovery in NKA, while the CRC subset with preoperative low NKA seemed to experience prolonged NK cell impairment. As low NKA is associated with recurrence, preoperative level of NKA may identify patients who will benefit from immune-enhancing therapy in the perioperative period.
The study explored the immunosuppressive effect of surgery. Colorectal cancer (CRC) patients with preoperative normal Natural Killer cell activity (NKA) and ventral hernia patients showed the same pattern of NKA recovery, while CRC patients with preoperative low NKA seemed to experience prolonged NKA impairment. Low preoperative NKA may identify patients who will benefit from perioperative immunostimulatory therapy.
The three common alleles of the APOE gene, ɛ2/ɛ3/ɛ4, have been linked to human spatial orientation. We investigated the genetic role of APOE in developmental topographical disorientation (DTD), a ...lifelong condition that results in topographical disorientation. We genotyped the APOE ɛ2/ɛ3/ɛ4 alleles in a cohort of 20 unrelated DTD probands, and found allele frequencies not statistically different from the those seen in the population as a whole. Therefore, we found no evidence that DTD occurs preferentially on a genetic background containing any particular APOE allele, making it unlikely that these APOE alleles are contributing to the development of DTD.
Introduction & Objective: Low birth weight (BW) is associated with increased type 2 diabetes (T2D) severity and high plasma leptin levels in people without diabetes. In a cross-sectional study of ...6402 people recently diagnosed with T2D, we examined if BW is associated with plasma leptin and if leptin is associated with clinical characteristics reflecting disease severity. Methods: Plasma leptin levels were measured using a Meso Scale Discovery U-plex assay. The association between BW (exposure) and plasma leptin levels and then between leptin (exposure) and clinical T2D severity, at T2D diagnosis were assessed. We used linear regression to estimate continuous outcomes and log-binomial/robust Poisson regression to determine prevalence ratios (PRs) in categorical analyses. Analyses were first adjusted for sex, age, and T2D family history, then + BMI, and + BW. Results: A 1kg lower BW was only associated with a 12.0% (95% CI: 8.0, 15.9) higher plasma leptin level when adjusted for BMI. A 20% increase in leptin was associated with 0.52kg/m2 (95% CI: 0.5, 0.54) higher BMI, 1.7% (95% CI: 1.5, 1.9) higher triglyceride, 3.8% (95% CI: 3.6, 4.0) higher plasma C-peptide, 6.0% (95% CI: 5.5, 6.5) higher hsCRP, 2.4% (95% CI: 2.2, 2.7) higher HOMA2-insulin secretion, and 3.7% (95% CI: 3.5, 3.9) lower HOMA2-insulin sensitivity. Having a plasma leptin level within the top 25% (>34ng/ml) was associated with increased use of glucose-lowering medications (PR for insulin-and-oral/insulin only: 1.27 95% CI: 1.01, 1.59), Charlson Comorbidity Index score (PR ≥ 3, 1.57 95% CI: 1.22, 2.00), macro- (PR 1.25 95% CI: 1.10, 1.42) -and-microvascular (PR 1.22 95% CI: 1.02, 1.45) complications, compared to having the middle 50% leptin (6-34ng/ml). The associations remained robust when further adjusted for BMI and then BW. Conclusion: Low BW is associated with elevated plasma leptin levels, potentially contributing to disease severity in people recently diagnosed with T2D. Disclosure P.A. Obeng: None. A. Lühr Hansen: None. L.M. Engelhard: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. V. Hirschberg Jensen: None. T. Hansen: None. N. Jessen: None. P. Vestergaard: None. J.S. Nielsen: None. K. Hojlund: None. M. Olsen: Other Relationship; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Other Relationship; Teva Pharmaceutical Industries Ltd. R.W. Thomsen: None. A.A. Vaag: None. Funding Danish Agency for Science (09-067009 and 09-075724), the Danish Health and Medicines Authority, the Danish Diabetes Association, the Region of Southern Denmark, and the Novo Nordisk Foundation (NNF17SA0030962-2, NNF20O0063292, and NNF17SA0030364).This study was conducted during Prince's scholarship period at Lund University, funded by the Swedish Institute.
Introduction & Objective: Low birthweight (BW), a proxy for an adverse intrauterine environment, has been associated with risk of type 2 diabetes (T2D) and chronic kidney disease (CKD) later in life. ...The extent to which lower birthweight among people with T2D increases risk of CKD is unknown. Methods: Original midwife records were reviewed for 5979 people recently diagnosed with T2D in the Danish Center for Strategic Research in T2D (DD2) cohort. Individuals were followed for the incidence of CKD, defined by 1) two eGFR values <60ml/min per 1.73m2, 90 to 365 days apart, or 2) two urine albumin/creatinine ratios >30mg/g, 90 to 365 days apart. Ten-year standardized risks of CKD were estimated by the parametric G-formula using the Aalen-Johansen estimator, considering death as a competing risk. Adjusted hazard ratios (aHRs) were computed using Cox regression analysis. Continuous relations between BW and incident CKD were assessed with linear and restricted cubic spline regression. All models were standardized or adjusted for sex, age, calendar year at birth, family history of diabetes, and born-at-term status. Results: A total of 1443 incident CKD outcomes occurred in people with T2D during median follow-up of 8.5 years. Spline models showed progressively increasing aHRs of CKD with successively lower BW. The 10-year standardized risk of CKD was 39.9% in people with low BW <2500 g, compared with 33.5% in people with a BW of 2500-4500 g, yielding a CKD risk difference of 6.4% (95% CI: -0.3, 13.3) and an aHR of 1.25 (95% CI: 0.99, 1.58). People with T2D and a high BW >4500 g, compared with a BW of 2500-4500 g, had similar 10-year standardized CKD risks of 31.7% vs. 33.5%, respectively, corresponding to an aHR of 0.93 (95% CI: 0.59, 1.47). Conclusion: Lower birthweight is associated with elevated risk of CKD among people with type 2 diabetes. Disclosure A. Lühr Hansen: None. C. Christiansen: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. L.M. Engelhard: None. T. Hansen: None. J.S. Nielsen: None. P. Vestergaard: None. K. Hojlund: None. N. Jessen: None. M. Olsen: Other Relationship; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Other Relationship; Teva Pharmaceutical Industries Ltd. H.T. Sørensen: Other Relationship; See text. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. R.W. Thomsen: None. A.A. Vaag: None. Funding Danish Agency for Science (09-067009 and 09-075724); Novo Nordisk Foundation ( NNF17SA0030962-2, NNF20O0063292, NNF17SA0030364)
AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia
Studies of Metabolic Traits in 7,683 White Danish Subjects
Gitte Andersen 1 ,
Kristoffer Sølvsten Burgdorf 1 ,
...Thomas Sparsø 1 ,
Knut Borch-Johnsen 1 2 3 ,
Torben Jørgensen 2 ,
Torben Hansen 1 and
Oluf Pedersen 1 3
1 Steno Diabetes Center, Gentofte, Denmark
2 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
3 Faculty of Health Science, University of Aarhus, Aarhus, Denmark
Corresponding author: Gitte Andersen, MSc, PhD, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820 Gentofte, Denmark.
E-mail: gtta{at}steno.dk
Abstract
OBJECTIVE— The gene encoding the α2 Heremans-Schmid glycoprotein ( AHSG ) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts
to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven
frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia.
RESEARCH DESIGN AND METHODS— The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted
laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous
findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association.
Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 ( IRS1 ) and β-2-adrenergic receptor polymorphisms were investigated.
RESULTS— The −469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes ( P = 0.007 and P = 0.006, respectively, or P corr = 0.04 and P corr = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and
a previous study −469T>G remained significant (odds ratio 0.90 95% CI 0.84–0.97; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia ( P = 0.003 and P corr = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post–oral glucose tolerance test serum insulin release
( P = 0.02, P corr = 0.1 for fasting and P = 0.04, P corr = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of
insulin resistance (9.0 vs. 8.6 mmol · l −1 · pmol −1 · l −1 ; P = 0.01, P corr = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations.
CONCLUSIONS— Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
ADRB2, β-2-adrenergic receptor
AHSG, α2 Heremans-Schmid glycoprotein
IRS1, insulin receptor substrate-1
LD, linkage disequilibrium
MAF, minor allele frequency
SNP, single nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 3 March 2008. DOI: 10.2337/db07-0558.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0558 .
G.A. holds stock in Novo Nordisk.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 7, 2008.
Received April 25, 2007.
DIABETES
Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue ...remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.
•Probiotics reduced depressive-like behaviour in one set of rats, but failed to do so in another.•The responding and non-responding set of rats had profoundly different gut microbiota ...composition.•The relative faecal abundance of the probiotics was higher in responders than in non-responders.•The cohabiting microbiota may potentially modulate the behavioural response to probiotics.
Numerous studies have been published describing the effect of various probiotics (PRO) on behaviours related to psychiatric disease. We have previously shown a robust antidepressant-like effect of PRO in rats, but over time, the treatment effect seems to vary significantly between different sets of rats from the same commercial vendor. Therefore, we hypothesised that the antidepressant-like response may be modulated by the cohabiting gut microbiota.
The aims of the present study were (1) to investigate any differences in the gut microbiota composition between responders (Resp) and non-responders (Non-resp) to PRO with regards to depressive-like behaviour, and (2) to evaluate the effects of PRO on the microbiota composition.
Two sets of 20 male Sprague-Dawley rats each were treated with multi-species PRO (nine Bifidobacterium, Lactococcus and Lactobacillus species) for eight weeks and subjected to a behavioural assessment. Faecal samples were collected for 16 s rRNA (VR4) gene amplicon sequencing (Illumina MiSeq).
As previously reported, PRO-treated Resp animals showed a marked decrease in depressive-like behaviour, whereas no such response was seen in Non-resp. We observed profound differences in the gut microbiota composition between the two sets of rats, and the relative faecal abundance of the genera that comprised PRO was higher in Resp than in Non-resp although treated with the same dose of PRO. Particularly, the relative abundance of the Lactobacillus genus was not increased in PRO-treated Non-resp animals.
In conclusion, the cohabiting microbiota and the faecal abundance of PRO may modulate the antidepressant-like effect of PRO in rats.
The authors and journal apologize for an error in the above paper above which appeared in 160 (4) 603–609. The twelfth author's name should have appeared as Oluf Pedersen, as shown correctly above.
The clinical advantage of telemetric intracranial pressure (ICP) monitoring has previously been limited by issues with inaccuracy and zero-drift. Today, 2 comparable telemetric ICP monitoring systems ...are available performing adequately in these parameters. The objective of this study is to identify appropriate uses of each system.
The 2 telemetric ICP monitoring systems from Raumedic (implant: Neurovent-P-tel) and Miethke (implant: Sensor Reservoir) are compared in terms of fundamental differences, sensor survival, monitoring possibilities, complications, and cost/benefit. Two illustrative cases are presented highlighting clinical advantages and disadvantages of each system.
Both systems provide transdermal (telemetric) ICP measurements through external application of a reader unit cabled to a portable data sampler. Thereby, they allow several ICP monitoring sessions without multiple surgical insertions of a cabled ICP sensor. The Miethke implant has a high sampling frequency (40 Hz) and a long CE (Conformité Européenne) approval (3 years) but cannot be used for long-duration monitoring sessions. In comparison, the Raumedic implant has a lower sampling frequency (5 Hz) and shorter CE approval (90 days) but can be used for long-duration monitoring sessions. The standard 3-year cost for a patient with a Neurovent-P-tel is 17,380 €, and for the Sensor Reservoir it is 15,790 €.
The Miethke system is useful in outpatient clinics where patients have sequential point measurements of ICP performed, whereas the Raumedic system is ideal for long-duration ICP monitoring outside the hospital. When choosing between the 2 systems, it must primarily be decided if the clinical situation requires long-duration monitoring sessions or continuous repeated ambulatory follow-up sessions.
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