Familial tooth agenesis (FTA) is one of the most common craniofacial anomalies in humans. Loss‐of‐function mutations in PAX9 and WNT10A have been known to cause FTA with various expressivity. In this ...study, we identified five FTA kindreds with novel PAX9 disease‐causing mutations: p.(Glu7Lys), p.(Val83Leu), p.(Pro118Ser), p.(Ser197Argfs*23), and c.771+4A>G. Concomitant PAX9 and WNT10A pathogenic variants found in two probands with severe phenotypes suggested an effect of mutational synergism. All overexpressed PAX9s showed proper nuclear localization, excepting the p.(Pro118Ser) mutant. Various missense mutations caused differential loss of PAX9 transcriptional ability. PAX9 overexpression in dental pulp cells upregulated LEF1 and AXIN2 expression, indicating a positive regulatory role for PAX9 in canonical Wnt signaling. Analyzing 176 cases with 63 different mutations, we observed a distinct pattern of tooth agenesis for PAX9‐associated FTA: Maxillary teeth are in general more frequently affected than mandibular ones. Along with all second molars, maxillary bicuspids and first molars are mostly involved, while maxillary lateral incisors and mandibular bicuspids are relatively less affected. Genotypically, missense mutations are associated with fewer missing teeth than frameshift and nonsense variants. This study significantly expands the phenotypic and genotypic spectrums of PAX9‐associated disorders and reveals a molecular mechanism of genetic synergism underlying FTA variable expressivity.
Familial tooth agenesis (FTA) is one of the most common craniofacial anomalies in humans. Loss‐of‐function mutations in PAX9 and WNT10A have been known to cause FTA with various expressivity. In this study, we identified 5 FTA kindreds with novel PAX9 disease‐causing mutations. Concomitant PAX9 and WNT10A pathogenic variants found in two probands with severe phenotypes suggested an effect of mutational synergism.
Hyperuricemia has been proven to be an independent risk factor for chronic kidney disease (CKD). However, the role of hyperuricemia in the progression of CKD remains unclear. Thus, we performed a ...systematic review and meta-analysis to evaluate the efficacy and safety of febuxostat, a first line urate-lowering agent, in CKD patients with hyperuricemia.
We have systematically searched for randomized controlled trials assessing the efficacy and safety of febuxostat versus control in CKD patients with hyperuricemia through MEDLINE, PubMed, EMBASE, and Cochrane databases. All statistical analyses were conducted by using the statistical package Review Manager, version 5.3.5. Heterogeneity was assessed using the Cochrane Q and I tests and summary statistics were reported with 95% confidence interval. Two-tailed test was used for analysis and a P value of <.05 is considered statistically significant.
Eleven eligible trials with 1317 participants were included in the meta-analysis. A significant reduction in serum uric acid was found in the febuxostat treated group. Also, a significant higher eGFR was found in the febuxostat treated group among CKD stage 3 and 4 patients. No significant difference of major complication or death was identified between treatment and control groups.
The meta-analysis showed that other than its urate-lowering effect, febuxostat presented a reno-protective effect in CKD patients. More studies with larger sample sizes and higher quality are required to clarify the role of febuxostat use in the progression of CKD.
Doxorubicin (DOX) is a widely used antitumor drug that causes severe neurotoxicity in patients. Diallyl trisulfide (DATS) is an organosulfur compound with established potent antioxidant and ...anti-inflammatory properties. Herein, we investigated the neuroprotective efficacy of DATS in preventing DOX-induced neurotoxicity in a rat model. Specifically, DATS (40 mg/kg) was administered to rats 24 h after DOX treatment, once a week for 8 weeks. Our results showed that DATS treatment led to a decrease in plasma levels of tumor necrosis factor-alpha (TNF-α) induced by DOX. DATS restored cerebral cortex and hippocampus histopathological architecture and neuronal loss. Immunohistochemical staining indicated that DATS decreased the expression of glial fibrillar acidic protein (GFAP) in DOX treated rats. Components of stress-related inflammatory proteins (TNF-α, phospho nuclear factor kappa B (NF-κB), inducible nitricoxide synthase (iNOS) and cyclooxygenase-2 (COX-2)) were all significantly increased in the DOX group, in comparison with the control group, whereas they were decreased after DATS treatment. In addition, the mRNA of antioxidant enzymes (superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1, 4 (GPx1 and GPx4)) and antioxidant proteins (heme oxygenase-1 (HO-1), superoxide dismutase 1, 2 (SOD1 and SOD2), Γ-glutamylcysteine synthase (Γ-GCSc)) were markedly increased in DOX group compared with the control group, which were significantly attenuated by DATS treatment. The upregulation of antioxidants enzymes in DOX group was probably a compensatory effect against elevated oxidative stress induced by DOX. DATS treatment could ameliorate this oxidative stress in brain. Our results suggested that DATS has potential clinical applications in the prevention of DOX-induced neurotoxicity by ameliorating inflammatory insults and oxidative stress.
Display omitted
•DATS inhibit DOX-induced TNF-α release in peripheral plasma and brain.•DATS decreased DOX-induced the GFAP expression level in cerebral cortex.•DATS has strong anti-inflammatory effects in the brain by inhibiting TNF-α/NFκB/iNOS/COX2 signaling pathway.•DATS ameliorated DOX-induced oxidative stress in brain and achieved brain tissue protection.
Patients with end stage renal disease (ESRD) are at high risk of developing upper tract urothelial carcinoma (UTUC). Due to high recurrence rate of UTUC in contralateral kidney and ureter, and high ...risk of complications related to surgery and anesthesia, whether it’s necessary to remove both kineys and ureters at one time remains in debate. We utilized Taiwanese UTUC Registry Database to valuate the difference of oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving surgical resection. Patients with ESRD and UTUC were divided into three groups, unilateral UTUC, previous history of unilateral UTUC with metachronous contralateral UTUC, and concurrent bilatetral UTUC. Oncological outcomes, perioperative complications, and length of hospital stays were investiaged. We found that there is no diffence of oncological outcomes including overall survival, cancer specific survival, disease free survival and bladder recurrence free survival between these three groups. Complication rate and length of hospital stay are similar. Adverse oncological features such as advanced tumor stage, lymph node involvement, lymphovascular invasion, and positive surgical margin would negatively affect oncological outcomes.
New-onset diabetes after transplantation and increased insulin resistance have both been shown to affect graft performance and survival after kidney transplantation. Thus, we aimed to evaluate the ...predictive roles of different insulin resistance indices on early graft function in kidney transplant recipients.
We conducted a retrospective analysis of non-diabetic patients who received kidney transplantation between January 1, 2018 and December 31, 2021. The primary outcome was the predictive role of different insulin resistance indices on early graft function of serum creatinine level and estimated glomerular filtration rate at 1, 3, 6, and 12 months. The secondary outcome analyzed was the possible clinical predictive factors for poor kidney graft function at 12 months.
Among 123 kidney transplantation patients, stratification with homeostatic model assessment for insulin resistance showed no significant difference in kidney graft function outcome at 1, 3, 6, and 12 months. However, patients with a higher insulin-to-glucose ratio exhibited a significantly higher serum creatinine level at 3 and 6 months and a significantly lower estimated glomerular filtration rate level at 3, 6, and 12 months. Using multivariate logistic regression analysis, patients with a higher insulin-to-glucose ratio were associated with a poorer kidney graft function 12 months after transplantation.
Patients with a higher baseline insulin resistance with an insulin-to-glucose ratio ≥of 0.092 exhibited a significantly worse early kidney graft function. Thus, with the identification of patients with increased insulin resistance, early intervention, and preventive measures can be implemented to enhance graft performance further.
Dyslipidemia is associated with glomerular injury. However, the effect of statins on chronic kidney disease (CKD) progression remains controversial. We aimed to investigate the efficacy of statins ...for renal protection in patients with CKD. The retrospective cohort study comprised 3441 patients diagnosed with CKD in multiple medical centers. We divided the patients into two cohorts based on statin prescription, and compared proportions and risks of CKD progression events between the two groups. CKD progression event was defined as an average annual decline of eGFR >5 mL/min/1.73 m
or advancement to the dialysis stage. The result revealed that among all incident patients with CKD, 28.7% and 30.3% of the users and nonusers demonstrated CKD progression, respectively. The crude odds ratio (OR) of CKD progression was 0.93 95% confidence interval (CI) 0.78-1.10. After adjustment for baseline characteristics, the adjusted OR was 0.80 (95% CI 0.63-1.01). The sensitivity analysis results showed consistent OR for CKD progression, stratification by age, sex, Charlson score, and statins use within 1 year before index date. The effect of statins was significant in patients with CKD stage 3B-5 (OR 0.68, 95% CI 0.48-0.95), but not statistically significant in those with CKD stage 1-3A (OR 0.97, 95% CI 0.68-1.38). The effect of statins was significant in patients with proteinuria ≥1000 mg/day (OR 0.63, 95% CI 0.43-0.92), but not statistically significant in those with proteinuria <1000 mg/day (OR 1.02, 95% CI 0.74-1.41).
To compare the efficacy and safety of the sandwich method with GreenLight photoselective vaporization (GLPVP) and bipolar transurethral resection (B-TURP) with those of the enucleation method in ...patients with BPH and a prostate volume ≥ 80 g.
Patients with BPH who underwent either the sandwich method with GLPVP and B-TURP or the enucleation method between 2014 and 2021 were included in the analysis. The primary outcome was the comparison of uroflowmetry results between the 2 groups. Safety analysis of the complication rates was also compared.
The cohort included 55 patients in the sandwich group and 41 patients in the enucleation group. In the efficacy analysis, both groups showed comparable uroflowmetry results, except for a higher postoperative average flow rate in the enucleation group. Regarding perioperative parameters, the sandwich method required a longer operating time, and the enucleation group had a higher incidence of manual Foley irrigation. Both groups demonstrated similar postoperative complications.
The sandwich method exhibited comparable efficacy and safety to the enucleation method in patients with BPH with a prostate volume ≥ 80 g. Thus, for surgeons who are familiar with GLPVP and B-TURP, the sandwich method may be an alternative surgical approach for BPH patients with large prostates.
The risk of dialysis following contrast exposure is unclear. We aimed to examine the overall risk of contrast induced nephropathy and the need of dialysis based on a systematic review with ...random-effects meta-analysis.
We searched the electronic database including PubMed, Medline, Embase, and Cochrane Library from inception to 31 October, 2020 with predetermined search term to identify relevant studies. Observational studies investigating the association between contrast induced nephropathy after angiography and the need of dialysis were included, and summary risks were estimated. Two independent reviewers extracted the data, followed with random effects model to calculate the overall pooled incidence of contrast induced nephropathy and the need of dialysis after angiography. Subgroup-analysis and meta-regression were performed to assess heterogeneity of incidence across studies.
Of 2,243 identified articles, 259 met our inclusion criteria were included in the meta-analysis after screening. Pooled effect estimates had the following summary incidence proportion for contrast induced nephropathy after angiography: 9.06% (95% CI: 8.53-9.58%; derived from 120 studies) and 0.52% (95% CI: 0.37-0.70%; derived from 110 studies) for the need of dialysis, respectively. The stratified summary incidence proportion of contrast induced nephropathy after contrast administration
intra-arterial route was 9.60% (95% CI: 9.0-10.2%; derived from 106 studies) and was 0.6% (95% CI: 0.40-0.80%; derived from 100 studies) for the need of dialysis, respectively. Our meta-regressions found that the amount of contrast medium exposure was associated with contrast-induced nephropathy.
The potential risk of dialysis needs to be communicated to patients undergoing procedures requiring contrast, especially
intra-arterial exposure.
https://reurl.cc/8Wrlry, identifier CRD42020170702.
Purpose
Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential therapy for autosomal dominant polycystic kidney disease (ADPKD), but prior studies remained ...controversial about their efficacy. We performed an updated meta-analysis regarding the therapeutic and adverse effects of mTOR inhibitors in patients with ADPKD.
Methods
We systematically searched Cochrane Library, PubMed, EMBASE, and Medline for randomized controlled trials (RCTs) comparing mTOR inhibitors to placebo in ADPKD patients up to August 2019. We calculated weighted mean differences (WMDs) for total kidney volume (TKV), estimated glomerular filtration rates (eGFRs), and weighted odds ratios (ORs) for treatment-related complications between the treatment and the placebo groups, using the random effects model.
Results
We retrieved a total of 9 RCTs enrolling 784 ADPKD patients receiving rapamycin, sirolimus, or everolimus between 2009 and 2016. The WMDs of TKV and eGFR from baseline to the last measurement were − 31.54 mL (95% confidence interval CI − 76.79 to 13.71 mL) and 2.81 mL/min/1.73 m
2
(95% CI − 1.85 to 7.46 mL/min/1.73 m
2
), respectively. Patients receiving mTOR inhibitors had a significantly increased risk of any adverse effects (OR 5.92, 95% CI 3.53–9.94), with the most common ones being aphthous stomatitis (OR 15.45, 95% CI 9.68–24.66) and peripheral edema (OR 3.49, 95% CI 1.31–9.27) compared to placebo users.
Conclusions
mTOR inhibitors did not significantly influence renal progression in patients with ADPKD, but were associated with a higher risk of complications. Whether mTOR inhibitors can be an add-on option or second-line agents remain undetermined.
Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin ...signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.
PDF
