High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients

l-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and l-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] mu M vs. 2.78 [2.89-3.35] mu M (P <0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA

Urinary Oxalate Excretion and Long-Term Outcomes in Kidney Transplant Recipients

Epidemiologic studies have linked urinary oxalate excretion to risk of chronic kidney disease (CKD) progression and end-stage renal disease. We aimed to investigate whether urinary oxalate, in stable kidney transplant recipients (KTR), is prospectively associated with risk of graft failure. In secondary analyses we evaluated the association with post-transplantation diabetes mellitus, all-cause mortality and specific causes of death. Oxalate excretion was measured in 24-h urine collection samples in a cohort of 683 KTR with a functioning allograft >= 1 year. Mean eGFR was 52 +/- 20 mL/min/1.73 m(2). Median (interquartile range) urinary oxalate excretion was 505 (347-732) mu mol/24-h in women and 519 (396-736) mu mol/24-h in men (p = 0.08), with 302 patients (44% of the study population) above normal limits (hyperoxaluria). A consistent and independent inverse association was found with all-cause mortality (HR 0.77, 95% CI 0.63-0.94, p = 0.01). Cause-specific survival analyses showed that this association was mainly driven by an inverse association with mortality due to infection (HR 0.56, 95% CI 0.38-0.83, p = 0.004), which remained materially unchanged after performing sensitivity analyses. Twenty-four-hour urinary oxalate excretion did not associate with risk of graft failure, post-transplant diabetes mellitus, cardiovascular mortality, mortality due to malignancies or mortality due to miscellaneous causes. In conclusion, in KTR, 24-h urinary oxalate excretion is elevated in 44% of KTR and inversely associated with mortality due to infectious causes

Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality in the general population:results from the prospective Lifelines-MINUTHE study

Background: Methylmalonic acid (MMA) is best known for its use as a functional marker of vitamin B12 deficiency. However, MMA concentrations not only depend on adequate vitamin B12 status, but also relate to renal function and endogenous production of propionic acid. Hence, we aimed to investigate to what extent variation in MMA levels is explained by vitamin B12 and eGFR and whether MMA levels are associated with mortality if vitamin B12 and eGFR are taken into account. Methods: A total of 1533 individuals (aged 60–75 years, 50% male) were included from the Lifelines Cohort and Biobank Study. Individuals were included between 2006 and 2013, and the total follow-up time was 8.5 years. Results: Median [IQR] age of the study population was 65 [62–69] years, 50% was male. At baseline, median MMA concentration was 170 [138–216] nmol/L, vitamin B12 290 [224–362] pmol/L, and eGFR 84 [74–91] mL/min/1.73 m2. Log 2 vitamin B12, log 2 eGFR, age, and sex were significantly associated with log 2 MMA in multivariable linear regression analyses (model R 2 = 0.22). After a total follow-up time of 8.5 years, 72 individuals had died. Log 2 MMA levels were significantly associated with mortality (hazard ratio [HR] 1.67 [95% CI 1.25–2.22], P < 0.001). Moreover, we found a significant interaction between MMA and eGFR with respect to mortality (P interaction < 0.001). Conclusions: Only 22% of variation in MMA levels was explained by vitamin B12, eGFR, age, and sex, indicating that a large part of variation in MMA levels is attributable to other factors (e.g., catabolism, dietary components, or gut microbial production). Higher MMA levels are associated with an increased risk for mortality, independent of vitamin B12, eGFR, and sex. This association was more pronounced in individuals with impaired renal function

Association of Plasma Concentration of Vitamin B-12 With All-Cause Mortality in the General Population in the Netherlands

Importance: Higher plasma concentrations of vitamin B12 have been associated with mortality in elderly and hospitalized populations, including patients with chronic kidney disease, but the association of plasma concentrations of vitamin B12 with mortality in the general population remains unclear. Objective: To investigate the association of plasma concentrations of vitamin B12 with all-cause mortality. Design, Setting, and Participants: This longitudinal cohort study used post hoc analysis to examine data from participants of the Prevention of Renal and Vascular End-stage Disease Study in Groningen, the Netherlands. Participants included individuals who completed the second screening visit beginning January 1, 2001, excluding those who were missing values of vitamin B12 plasma concentrations or used vitamin B12 supplementation. Follow-up time was defined between the beginning of the second screening round to end of follow-up on January 1, 2011. Data analysis was conducted from October 2, 2018, to February 22, 2019. Exposures: Plasma vitamin B12 concentration level. Main Outcomes and Measures: Death as recorded by the Central Bureau of Statistics of Groningen, the Netherlands. Results: A total of 5571 participants (mean [SD] age, 53.5 [12.0] years; 2830 [50.8%] men) were included in analyses. Median (interquartile range) plasma concentration of vitamin B12 was 394.42 (310.38-497.42) pg/mL. During the median (interquartile range) of 8.2 (7.7-8.9) years of follow-up, 226 participants (4.1%) died. According to quartiles of the distribution of plasma vitamin B12 concentration levels, mortality rates were 33.8 deaths per 10 000 person-years for the quartile with the lowest plasma concentration of vitamin B12 and 65.7 deaths per 10 000 person-years for the quartile with the highest plasma concentration of vitamin B12. After adjustment for multiple clinical and laboratory variables, Cox regression analyses found a significant association between higher vitamin B12 plasma concentration level and increased risk of all-cause mortality (hazard ratio per 1-SD increase, 1.25 [95% CI, 1.06-1.47]; P = .006). Conclusions and Relevance: These findings suggest that higher levels of plasma concentrations of vitamin B12 were associated with increased risk of all-cause mortality after adjusting for age, sex, renal function, and other clinical and laboratory variables. The mechanisms underlying this association remain to be established

Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism:Results from an Elderly Sample of the LifeLines Cohort Study

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60-75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of alpha-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of gamma-tocopherol were often opposite to those of alpha-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for alpha-tocopherol and gamma-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied

4 modalities of periodontal treatment compared over 5 years *

The purpose of the present study was to assess in a clinical trial over 5 years the results following 4 different modalities of periodontal therapy (pocket elimination or reduction surgery, modified Widman flap surgery, subgingival curettage, and scaling and root planing). 90 patients were treated. The treatment methods were applied on a random basis to each of the 4 quadrants of the dentition. The patients were given professional tooth cleaning and oral hygiene instructions every 3 months. Pocket depth and attachment levels were scored once a year. 72 patients completed the 5 years of observation. Both patient means for pocket depth and attachment level as well as % distribution of sites with loss of attachment ≥2 mm and ≥3 mm were compared. For 1-3 mm probing depth, scaling and root planing, as well as subgingival curettage led to significantly less attachment loss than pocket elimination and modified Widman flap surgery. For 4 6 mm pockets, scaling and root planing and curettage had better attachment results than pocket elimination surgery. For the 7-12 mm pockets, there was no statistically significant difference among the results following the various procedures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72788/1/j.1600-051X.1987.tb02249.x.pd

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in similar to 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.Peer reviewe

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

The randomized shortened dental arch study (RaSDA): design and protocol

<p>Abstract</p> <p>Background</p> <p>Various treatment options for the prosthetic treatment of jaws where all molars are lost are under discussion. Besides the placement of implants, two main treatment types can be distinguished: replacement of the missing molars with removable dental prostheses and non-replacement of the molars, i.e. preservation of the shortened dental arch. Evidence is lacking regarding the long-term outcome and the clinical performance of these approaches. High treatment costs and the long time required for the treatment impede respective clinical trials.</p> <p>Methods/design</p> <p>This 14-center randomized controlled investigator-initiated trial is ongoing. Last patient out will be in 2010. Patients over 35 years of age with all molars missing in one jaw and with at least both canines and one premolar left on each side were eligible. One group received a treatment with removable dental prostheses for molar replacement (treatment A). The other group received a treatment limited to the replacement of all missing anterior and premolar teeth using fixed bridges (treatment B). A pilot trial with 32 patients was carried out. Two hundred and fifteen patients were enrolled in the main trial where 109 patients were randomized for treatment A and 106 for treatment B. The primary outcome measure is further tooth loss during the 5-year follow-up. The secondary outcome measures encompassed clinical, technical and subjective variables. The study is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG WA 831/2-1, 2-2, 2-3, 2-4, 2-5).</p> <p>Discussion</p> <p>The particular value of this trial is the adaptation of common design components to the very specific features of complex dental prosthetic treatments. The pilot trial proved to be indispensable because it led to a number of adjustments in the study protocol that considerably improved the practicability. The expected results are of high clinical relevance and will show the efficacy of two common treatment approaches in terms of oral health. An array of secondary outcome measures will deliver valuable supplementary information. If the results can be implemented in the clinical practice, the daily dental care should strongly profit thereof.</p> <p>Trial registration</p> <p>The trial is registered at ClinicalTrials.gov under ISRCTN68590603 (pilot trial) and ISRCTN97265367 (main trial).</p