Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of ...karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.
Approaches, tools, and technologies for atrial fibrillation (AF) ablation have evolved significantly since its inception. We sought to characterize secular trends in AF ablation success rates.
We ...performed a systematic review and meta-analysis of AF ablation from January 1, 1990, to August 1, 2016, searching PubMed, Scopus, and Cochrane databases. Major exclusion criteria were insufficient outcome reporting and ablation strategies that were not prespecified and uniform. We stratified treatment arms by AF type (paroxysmal AF; nonparoxysmal AF) and analyzed single-procedure outcomes. Multivariate meta-regressions analyzed effects of study, patient, and procedure characteristics on success rate trends. Registered in PROSPERO (CRD42016036549).
A total of 180 trials and observational studies with 28,118 patients met inclusion. For paroxysmal AF ablation studies, unadjusted success rate summary estimates ranged from 73.1% in 2003 to 77.1% in 2016, increasing by 0.9%/year (95% CI 0.4%-1.4%; P = .001; I2 = 90%). After controlling for study design and patient demographics, rate of improvement in success rate summary estimate increased (1.6%/year; 95% CI 0.9%-2.2%; P = .001; I2 = 87%). For nonparoxysmal AF ablation studies, unadjusted success rate summary estimates ranged from 70.0% in 2010 to 64.3% in 2016 (1.1%/year; 95% CI −1.3% to 3.5%; P = .37; I2 = 85%), with no improvement in multivariate analyses.
Despite substantial research investment and health care expenditure, improvements in AF ablation success rates have been incremental. Meaningful improvements may require major paradigm or technology changes, and evaluation of clinical outcomes such as mortality and quality of life may prove to be important going forward.
Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to ...disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.
Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in ...part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.
Introduction
We performed a systematic review and meta‐analysis of geographic and racial representation and reported success rates of studies of catheter ablation for atrial fibrillation (AF).
...Methods and results
We searched PubMed, Scopus, and Cochrane databases from 1/1/1990 to 8/1/2016 for trials and observational studies reporting AF ablation outcomes. Major exclusion criteria were insufficient reporting of outcomes, non‐English language articles, and ablation strategies that were not prespecified and uniform. We described geographic and racial representation and single‐procedure ablation success rates by country, controlling for patient demographics and study design characteristics. The analysis cohort included 306 studies (49,227 patients) from 28 countries. Over half of the paroxysmal (PAF) and nonparoxysmal AF (NPAF) treatment arms were conducted in 5 and 3 countries, respectively. Reporting of race or ethnicity demographics and outcomes were rare (1 study, 0.3%) and nonexistent, respectively. Unadjusted success rates by country ranged from 63.5% to 83.0% for PAF studies and 52.7% to 71.6% for NPAF studies, with substantial variation in patient demographics and study design. After controlling for covariates, South Korea and the United States had higher PAF ablation success rates, with large residual heterogeneity. NPAF ablation success rates were statistically similar by country.
Conclusions
Studies of AF ablation have substantial variation in patient demographics, study design, and reported outcomes by country. There is limited geographic representation of trials and observational studies of AF ablation and a paucity of race‐ or ethnicity‐stratified results. Future AF ablation studies and registries should aim to have broad representation by race, geography, and ethnicity to ensure generalizability.
Background The objective was to explore the efficacy of ablation lesion sets in addition to pulmonary vein isolation ( PVI ) for paroxysmal atrial fibrillation. The optimal strategy for catheter ...ablation of paroxysmal atrial fibrillation is debated. Methods and Results The SMASH-AF (Systematic Review and Meta-analysis of Ablation Strategy Heterogeneity in Atrial Fibrillation) study cohort includes trials and observational studies identified in PubMed, Scopus, and Cochrane databases from January 1 1990, to August 1, 2016. We included studies reporting single procedure paroxysmal atrial fibrillation ablation success rates. Exclusion criteria included insufficient reporting of outcomes, ablation strategies that were not prespecified and uniform, and a sample size of fewer than 40 patients. We analyzed lesion sets performed in addition to PVI ( PVI plus) using multivariable random-effects meta-regression to control for patient, study, and procedure characteristics. The analysis included 145 total studies with 23 263 patients ( PVI- only cohort: 115 studies, 148 treatment arms, 16 500 patients; PVI plus cohort: 39 studies; 46 treatment arms, 6763 patients). PVI plus studies, as compared with PVI -only studies, included younger patients (56.7 years versus 58.8 years, P=0.001), fewer women (27.2% versus 32.0% women, P=0.002), and were more methodologically rigorous with longer follow-up (29.5 versus 17.1 months, P 0.004) and more randomization (19.4% versus 11.8%, P<0.001). In multivariable meta-regression, PVI plus studies were associated with improved success (7.6% absolute improvement 95% CI, 2.6-12.5%; P<0.01, I
=88%), specifically superior vena cava isolation (4 studies, 4 treatment arms, 1392 patients; 15.1% absolute improvement 95% CI, 2.3-27.9%; P 0.02, I
=87%). However, residual heterogeneity was large. Conclusions Across the paroxysmal atrial fibrillation ablation literature, PVI plus ablation strategies were associated with incremental improvements in success rate. However, large residual heterogeneity complicates evidence synthesis.
Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes ...defined them as "ciliopathies.” However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.
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► Mutations of ZNF423 or CEP164 are causes of retinal-renal ciliopathies ► The gene products colocalize with TIP60 at both centrosomes and nuclear foci ► Knockdown of ZNF423 or CEP164 impairs DNA damage response signaling ► Knockdown of cep164 in zebrafish causes a ciliopathy phenotype and dysregulated DDR
Whole-exome resequencing of individuals with ciliopathies reveals mutations in genes that are involved in DNA damage response signaling, providing new insight into the pathogenic mechanisms behind this class of degenerative disorders.
Introduction:
Treatments for myeloma have evolved over the past several years with resultant improvements in survival. Two new medications, bortezomib (B) and lenalidomide (L), have played a major ...role in this development. Each has received FDA approval in the past 10 years. Both medications are relatively expensive and, due to its teratogenic effects, lenalidomide requires a pt training and education program before pharmacies may fill the prescription. In addition, specialty pharmacies need to be identified and prior approval is required from the insurance carrier. This study addresses whether or not a relatively underinsured, indigent population was able to receive these medications and in a timely fashion.
Methods:
Electronic medical records of all pts diagnosed with myeloma from 1/2005-12/2014 at MetroHealth Medical Center (a large safety net institution in Cleveland, OH) were reviewed.
88 pts were identified. Med age was 59 (35 -87); 50% were African American (AA), 43% caucasian (C), 1% Hispanic and 6% unknown. Health insurance status: 26% private; 35% medicare; 17% medicaid; and 22% were uninsured.
Results:
77% AA received either B or L or both vs 82% C pts (NS).
Overall, 17/88 (19%) never received either L or B. This included: 5 due to pt preference or co-morbidities which precluded treatment,; 2 who died before they could receive any therapy; 3 lost to follow-up before treatment could be started; 6 who received thalidomide and then either transferred care elsewhere, died or did not require another treatment; and 1 who transferred to another facility for stem cell transplant evaluation before treatment was initiated. Therefore, all 71 pts who were candidates and w/treatment data available received B or L. Of the 17 who did not get B or L: 6 were uninsured, 5 private insurance, 4 medicare, and 2 medicaid.
Overall, 66 pts received B; 31 received L.
Ave time from prescription to pt start of medication: 19.1 days for L (med 14.5d, range 0-65d) vs 1.56d for B (med 0d, range 0-20d), p<0.00001. The pts treated with L were not overrepresented from any particular insurance status (29% were uninsured; 19% medicaid; 29% medicare; 23% private). This payor mix was similar for those who received B (21% uninsured; 13% medicaid, 36% medicare and 30% private).
Conclusions:
In this underinsured, indigent population, all appropriate pts with myeloma received at least one of the 2 novel drugs. There was a statistically significant delay in treatment for those pts who were prescribed lenalidomide as compared to bortezomib (19.1 days L vs 1.56 days for B). It is not clear that this is a clinically significant difference but suggests that bortezomib containing regimens may be a better option in cases where urgent therapy is needed, particularly in this population.
No relevant conflicts of interest to declare.
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