In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the ...interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target.
This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome.
This IRB-approved retrospective observational study included 133 NB ...patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses.
A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001).
Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.
Abstract Background This study analyzed presentation and management of hemorrhage after pancreaticoduodenectomy (PD) to determine the respective role of surgery and embolization. Methods From January ...1992 to March 2005, 411 patients underwent PD and were analyzed with regard to postoperative hemorrhage. Results Hemorrhage occurred in 27 patients (7%), either within the first 3 postoperative days (“early” hemorrhage, n = 11) or after day 8 (“delayed” hemorrhage, n = 16, including 4 with “sentinel” bleeding). At the time of bleeding, 12 patients (44%) (all with delayed hemorrhage) had associated abdominal complications. Two patients had successful conservative treatment. Two stable patients with pseudoaneurysm, diagnosed by computed tomography scan, underwent successful embolization. Four patients with active bleeding underwent unsuccessful angiography. Overall, 23 patients were reoperated on without any completion pancreatectomy, 3 rebled, and 3 (11%) died (including 2 with delayed hemorrhage). Conclusions Both embolization and surgery have a role in the management of hemorrhage after PD. For early hemorrhage, reoperation is appropriate. In case of sentinel bleeding, pseudoaneurysms can be detected by computed tomography scan and treated by embolization. For delayed active hemorrhage, reoperation is still indicated.
Congenital nephron number varies widely in the human population and individuals with low nephron number are at risk of developing hypertension and chronic kidney disease. The development of the ...kidney occurs via an orchestrated morphogenetic process where metanephric mesenchyme and ureteric bud reciprocally interact to induce nephron formation. The genetic networks that modulate the extent of this process and set the final nephron number are mostly unknown. Here, we identified a specific isoform of MITF (MITF-A), a bHLH-Zip transcription factor, as a novel regulator of the final nephron number. We showed that overexpression of MITF-A leads to a substantial increase of nephron number and bigger kidneys, whereas Mitfa deficiency results in reduced nephron number. Furthermore, we demonstrated that MITF-A triggers ureteric bud branching, a phenotype that is associated with increased ureteric bud cell proliferation. Molecular studies associated with an in silico analyses revealed that amongst the putative MITF-A targets, Ret was significantly modulated by MITF-A. Consistent with the key role of this network in kidney morphogenesis, Ret heterozygosis prevented the increase of nephron number in mice overexpressing MITF-A. Collectively, these results uncover a novel transcriptional network that controls branching morphogenesis during kidney development and identifies one of the first modifier genes of nephron endowment.
Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of ...gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis.
Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone AMH), and ultrasound of penis/testes.
In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 ± 4.06 ng/mL 12.15 ± 14.09 nmol/L), SPL (from 13.8 ± 4.5 to 42.6 ± 5 mm; p < 0.0001), inhibin B (from 94.8 ± 74.9 to 469.4 ± 282.5 pg/mL, p = 0.04), and AMH (from 49.6 ± 30.6 to 142 ± 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm.
Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long-term follow-up is needed to assess the impact, if any, on future fertility and reproduction. .
Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice ...carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as SREBP1, PPARG, and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1.
Robotic-assisted laparoscopic pyeloplasty is increasingly being used in children. This prospective case series demonstrates the feasibility and safety of day surgery in children undergoing ...retroperitoneal robot-assisted laparoscopic pyeloplasty, obviating the need for routine inpatient care. Excellent results can be achieved by careful patient selection, a clear clinical pathway, and a dedicated and experienced team.
Robot-assisted pyeloplasty is the most frequently performed robotic procedure in children. A retroperitoneal approach limits surgical trauma and avoids peritoneal irritation. This led to the establishment of the criteria for day surgery (DS) and a related clinical care pathway.
To assess the feasibility and safety of DS in children undergoing retroperitoneal robot-assisted laparoscopic pyeloplasty (R-RALP).
We performed a bicentric prospective study (NCT03274050) over 2 yr involving the two major paediatric urology teaching hospitals in Paris. A clinical pathway and a prospective research protocol were specifically established.
DS in selected children undergoing R-RALP.
The primary outcomes were DS failure, 30-d complications, and readmission rates. The secondary outcomes included preoperative characteristics, perioperative parameters, and surgical outcomes. Quantitative variables were expressed as medians with interquartile ranges.
Thirty-two children fulfilled specific inclusion criteria and were consecutively selected for DS following R-RALP. The median patient age was 7.6 yr (4.1–11.8) and weight 25 kg (14–45). The median console time was 137 min (108–167). There were no intraoperative complications or conversions. Six children were kept under observation overnight and discharged the following day due to persistent pain (n = 3), parental anxiety (n = 2), or a prolonged procedure (n = 1). The median duration of hospital stay of the 26 children in the DS setting was 12.7 h (12.2–13.2). During the 30-d period, there were four emergency room visits (15%) resulting in two patients requiring readmission (8%): one for febrile urinary tract infection (Clavien-Dindo II) and one child with no JJ stent for urinoma (Clavien-Dindo IIIb). Radiological studies confirmed improvement in dilatation for all cases with no recurrence (median follow-up: 15 mo).
This prospective case series is the first to demonstrate the feasibility and safety of DS in children undergoing R-RALP, obviating the need for routine inpatient care. Excellent results can be achieved by careful patient selection, a clear clinical pathway, and a dedicated team. Further evaluation is warranted to assess the cost effectiveness.
This study shows that day surgery after robotic pyeloplasty is both safe and effective in selected children.
Purpose:
Cystinuria is a genetic disorder characterized by a defective reabsorption of cystine and dibasic amino acids leading to development of urinary tract calculi from childhood onward. Cystine ...lithiasis is known to be resistant to fragmentation. The aim was to evaluate our long-term experience with extracorporeal shockwave lithotripsy (ESWL) used as first-line urological treatment to treat cystine stones in children.
Methods:
We retrospectively reviewed the charts of all children who underwent ESWL for cystine stone. We assessed the 3-month stone-free rate, according to age, younger (group 1) or older (group 2) than 2 years old.
Results:
Between 2003 and 2016, 15 patients with a median (IQR) age at first treatment of 48 (15–108) months underwent ESWL in monotherapy. Median age was, respectively, 15 and 108 months in each group. The median (IQR) stone burden was 2,620 (1,202–8,265) mm
3
in group I and 4,588 (2,039–5,427) mm
3
in group II (
p
= 0.96). Eleven patients had bilateral calculi. ESWL was repeated on average 2.4 times, with a maximum of 4 for patients of group I, and 4.8 times, with a maximum of 9 for group II (
p
> 0.05). ESWL in monotherapy was significantly more efficient to reach stone-free status for children under 2 years of age: 83% vs. 6.2% (
p
= 0.040). The median (IQR) follow-up of the study was 69 (42–111) months.
Conclusion:
ESWL appears as a valid urological option for the treatment of cystine stones, in young children. Even if cystine stones are known to be resistant to fragmentation, we report 83% of stone-free status at 3 months with ESWL used in monotherapy in children under 2 years old with cystinuria. In older children, the success rate is too low to recommend ESWL as a first line approach.
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