Increased telomere attrition following renal transplantation: impact of anti-metabolite therapy

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. Results: Non-CKD patients had significantly (P <= 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003). Conclusions: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Adenovirus-36 Is Associated with Obesity in Children and Adults in Sweden as Determined by Rapid ELISA

Background Experimental and natural human adenovirus-36 (Adv36) infection of multiple animal species results in obesity through increasing adipogenesis and lipid accumulation in adipocytes. Presence of Adv36 antibodies detected by serum neutralization assay has previously been associated with obesity in children and adults living in the USA, South Korea and Italy, whereas no association with adult obesity was detected in Belgium/the Netherlands nor among USA military personnel. Adv36 infection has also been shown to reduce blood lipid levels, increase glucose uptake by adipose tissue and skeletal muscle biopsies, and to associate with improved glycemic control in non-diabetic individuals. Principal Findings Using a novel ELISA, 1946 clinically well-characterized individuals including 424 children and 1522 non-diabetic adults, and 89 anonymous blood donors, residing in central Sweden representing the population in Stockholm area, were studied for the presence of antibodies against Adv36 in serum. The prevalence of Adv36 positivity in lean individuals increased from ~7% in 1992–1998 to 15–20% in 2002–2009, which paralleled the increase in obesity prevalence. We found that Adv36-positive serology was associated with pediatric obesity and with severe obesity in females compared to lean and overweight/mildly obese individuals, with a 1.5 to 2-fold Adv36 positivity increase in cases. Moreover, Adv36 positivity was less common among females and males on antilipid pharmacological treatment or with high blood triglyceride level. Insulin sensitivity, measured as lower HOMA-IR, showed a higher point estimate in Adv36-positive obese females and males, although it was not statistically significant (p = 0.08). Conclusion Using a novel ELISA we show that Adv36 infection is associated with pediatric obesity, severe obesity in adult females and lower risk of high blood lipid levels in non-diabetic Swedish individuals

Ovary transplantation method resulting in high reproductive performance in mice

There are mutant and transgenic mouse strains which lack the ability to breed, but where the females have functional ovaries. Ovary transplantation is an important tool for maintaining and producing crosses with these non-breeding strains.We have evaluated an ovary transplantation method by transplanting ovaries from females belonging to a non-reproduetive BALB/cByJ mutant mouse strain, All transplanted mice, 10 BALB/c.C57BL/6By, produced offspring and 94% of the progeny originated from the transplanted ovaries. The mean litter size and the mating period needed for productive mating to occur were similar to what is observed for corresponding control mice

CLOCK is suggested to associate with comorbid alcohol use and depressive disorders

<p>Abstract</p> <p>Background</p> <p>Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol.</p> <p>Methods</p> <p>32 SNPs in 19 circadian clockwork related genes were analyzed using DNA from 76 individuals with comorbid depression and AUD, 446 individuals with AUD and 517 healthy controls with no psychiatric diagnosis. The individuals participated in a nationwide health examination study, representative of the general population aged 30 and over in Finland.</p> <p>Results</p> <p>The <it>CLOCK </it>haplotype TTGC formed by SNPs rs3805151, rs2412648, rs11240 and rs2412646, was associated with increased risk for comorbidity (OR = 1.65, 95% CI = 1.14-2.28, P = 0.0077). The SNPs of importance for this suggestive association were rs2412646 and rs11240 indicating location of the functional variation in the block downstream rs2412648. There was no indication for association between <it>CLOCK </it>and AUD.</p> <p>Conclusion</p> <p>Our findings suggest an association between the <it>CLOCK </it>gene and the comorbid condition of alcohol use and depressive disorders. Together with previous reports it indicates that the <it>CLOCK </it>variations we found here may be a vulnerability factor to depression given the exposure to alcohol in individuals having AUD.</p

The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder

<p>Abstract</p> <p>Background</p> <p>Cognitive behavioral therapy (CBT) represents a learning process leading to symptom relief and resulting in long-term changes in behavior. CBT for panic disorder is based on exposure and exposure-based processes can be studied in the laboratory as extinction of experimentally acquired fear responses. We have recently demonstrated that the ability to extinguish learned fear responses is associated with a functional genetic polymorphism (COMTval158met) in the <it>COMT </it>gene and this study was aimed at transferring the experimental results on the COMTval158met polymorphism on extinction into a clinical setting.</p> <p>Methods</p> <p>We tested a possible effect of the COMTval158met polymorphism on the efficacy of CBT, in particular exposure-based treatment modules, in a sample of 69 panic disorder patients.</p> <p>Results</p> <p>We present evidence that panic patients with the COMTval158met met/met genotype may profit less from (exposure-based) CBT treatment methods as compared to patients carrying at least one val-allele. No association was found with the 5-HTTLPR/rs25531 genotypes which is presented as additional material.</p> <p>Conclusions</p> <p>We were thus able to transfer findings on the effect of the COMTval158met polymorphism from an experimental extinction study obtained using healthy subjects to a clinical setting. Furthermore patients carrying a COMT val-allele tend to report more anxiety and more depression symptoms as compared to those with the met/met genotype. Limitations of the study as well as possible clinical implications are discussed.</p> <p>Trial registration</p> <p>Clinical Trial Registry name: Internet-Versus Group-Administered Cognitive Behavior Therapy for Panic Disorder (IP2). Registration Identification number: NCT00845260, <url>http://www.clinicaltrials.gov/ct2/show/NCT00845260</url></p

MAOA haplotypes associated with thrombocyte-MAO activity

BACKGROUND: The aim was to ascertain whether thrombocyte MAO (trbc-MAO) activity and depressed state are genetically associated with the MAO locus on chromosome X (Xp11.3 – 11.4). We performed novel sequencing of the MAO locus and validated genetic variants found in public databases prior to constructing haplotypes of the MAO locus in a Swedish sample (N = 573 individuals). RESULTS: Our results reveal a profound SNP desert in the MAOB gene. Both the MAOA and MAOB genes segregate as two distinct LD blocks. We found a significant association between two MAOA gene haplotypes and reduced trbc-MAO activity, but no association with depressed state. CONCLUSION: The MAO locus seems to have an effect on trbc-MAO activity in the study population. The findings suggest incomplete X-chromosome inactivation at this locus. It is plausible that a gene-dosage effect can provide some insight into the greater prevalence of depressed state in females than males

OTHR-02. One-year follow-up of the new ERN PaedCan CNS tumor board: lessons learnt and future prospects [Abstract]

BACKGROUND European Reference Networks (ERN) are collaborative networks connecting healthcare professionals across Europe. A virtual tumor board for pediatric patients with central nervous system (CNS) tumors was established within the ERN for pediatric oncology (ERN PaedCan) in September 2022. We report the feasibility, the implementation of recommendations and satisfaction of the participants. METHODS A web-based questionnaire was distributed to physicians presenting cases between November 2022 and November 2023. Questions addressed the implementation of recommendations, satisfaction and basic information about the local institution. Basic data of the presented cases were taken from anonymized tumor board protocols. RESULTS In the first year, 19 patients from 11 institutions located in nine European countries were discussed in 21 tumor boards. Median age at diagnosis was 10 (1-17) years. Demonstration of MRI findings by the German national reference center for neuroradiology was conducted in 19/21 conferences. 18/21 questionnaires (86%) were answered by physicians from eight countries. Main reason to request the discussion were questions about therapy (78%, n=14/18). Inquiring institutions treated a median of 10 (5-150) neuro-oncological pediatric patients per year. All hospitals conducted own institutional tumor boards. National central review was available in 3/8 countries (38%). Recommendations were followed, at least partly, in all cases except for one patient experiencing unexpected clinical deterioration. Recommendations were deemed helpful in 89%. All participants would recommend the tumor board to colleagues. Technical issues regarding data provision were reported as the main obstacle in 50 %. CONCLUSIONS A European virtual tumor board for pediatric patients with CNS tumors is feasible and perceived as useful by the participating institutions. Recommendations were followed frequently. Optimization of privacy-compliant data exchange is crucial for continuance of the format. This project has been supported by ERN PaedCan, which is funded by the European Union within the EU4Health Program 2021-2027. Funded by EU-grant 101085543

A truncated Kv1.1 protein in the brain of the megencephaly mouse: expression and interaction

BACKGROUND: The megencephaly mouse, mceph/mceph, is epileptic and displays a dramatically increased brain volume and neuronal count. The responsible mutation was recently revealed to be an eleven base pair deletion, leading to a frame shift, in the gene encoding the potassium channel Kv1.1. The predicted MCEPH protein is truncated at amino acid 230 out of 495. Truncated proteins are usually not expressed since nonsense mRNAs are most often degraded. However, high Kv1.1 mRNA levels in mceph/mceph brain indicated that it escaped this control mechanism. Therefore, we hypothesized that the truncated Kv1.1 would be expressed and dysregulate other Kv1 subunits in the mceph/mceph mice. RESULTS: We found that the MCEPH protein is expressed in the brain of mceph/mceph mice. MCEPH was found to lack mature (Golgi) glycosylation, but to be core glycosylated and trapped in the endoplasmic reticulum (ER). Interactions between MCEPH and other Kv1 subunits were studied in cell culture, Xenopus oocytes and the brain. MCEPH can form tetramers with Kv1.1 in cell culture and has a dominant negative effect on Kv1.2 and Kv1.3 currents in oocytes. However, it does not retain Kv1.2 in the ER of neurons. CONCLUSION: The megencephaly mice express a truncated Kv1.1 in the brain, and constitute a unique tool to study Kv1.1 trafficking relevant for understanding epilepsy, ataxia and pathologic brain overgrowth