Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.
The synthesis of an array of 5-phenyloxazole derivatives bearing a variety of hydroxyalkyl groups at the C-2 position of the heterocyclic nucleus and possessing a formyl or a carboxyl function at C-4 is reported. These bifunctionalized compounds have been efficiently prepared by addition of carbonylated electrophiles to the 2-lithio derivative of 5-phenyloxazole preliminarily equipped with an oxazoline unit at the 4-position of the oxazole nucleus. It is demonstrated that this protocol offers a double advantage since it suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline ring system.
Vinblastine-C4 acyl derivatives were synthesized by linking alkyl maleoyl or amino acid maleoyl compounds through an ester linkage at C4 position of the Vindoline moiety of Vinblastine. To target these derivatives selectively to hepatoma, conjugates were prepared with a neoglycoprotein i.e. lactosaminated human albumin, as a specific carrier. The method of preparation of lactosaminated albumin and of coupling to Vinca alkaloid derivatives is described and the mechanism of addition of the protein to the derivative is discussed. The experimental antitumor activity of these conjugates has been screened against the experimental P-388 Leukemia. The activity of the best conjugate has been evaluated in several human tumor xenografts. Further, the therapeutic potential of this type of conjugate has been demonstrated in a model of hepatoma xenograft developed in our laboratory, the HepG2 carcinoma.
The 17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17β-HSD type 1 enzyme (17β-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure−activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17β-HSD1 and is selective for 17β-HSD1 over 17β-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17β-HSD1 reported to date. These amides are also selective for 17β-HSD1 over 17β-HSD2.
Abstract BACKGROUND AND AIMS Little is known about the long-term outcome during adulthood of childhood onset idiopathic nephrotic syndrome (INS). We aimed to determine which patients require long-term follow up after transition, to identify risk factors of relapse and to analyze treatment strategies. METHOD In this monocentric retrospective study, we included all patients admitted in our adult nephrology department with INS diagnosed during childhood. Patients who reached kidney failure during childhood were excluded. Data regarding the outcome at adult age were obtained through clinical database and medical charts. RESULTS Eighty-two patients (male/female = 2/1) were included, with a median age at diagnosis of 3.9 years (1.2–16.5). Sixty-eight patients had steroid-sensitive INS, including 52 with steroid-dependent nephrotic syndrome or frequently relapsing nephrotic syndrome. Fourteen patients had steroid-resistant nephrotic syndrome. A total of 89% of patients received corticosteroid sparing treatment during childhood. Median follow-up during adulthood was 6.2 (0.3–25) years. A total of 71% of patients experienced at least one relapse during adulthood. The total number of relapses during childhood and the number of relapses per year during childhood, reflecting disease activity, were significantly higher in patients who experienced relapses during adulthood than in patients who did not (Figure 1). The risk of relapse during adulthood was also significantly associated with the need for immunosuppressive regimen at the time of the transition visit (P = 0.002). To promote the successful transition of young people, we propose to organize a transition visit where the adolescent/young adult is seen jointly by pediatric and adult nephrologists, as it was done for 68% of patients in this study. The relapse rate was significantly lower (50%) in the subgroup of patients who had such a transition visit. We also found that relapse during the first two-years of adulthood follow-up was significantly associated with the risk of further relapse, highlighting the need for a close follow-up during the transition period. A total of 45% of patients received corticosteroid sparing treatment during adulthood, mainly mycophenolate mofetil (N = 23), calcineurin inhibitors (N = 21) and rituximab (N = 12). The main complications were high blood pressure (20/82, 26%) and osteopenia (19/26, 73% when bone densitometry was performed). Only one thrombo-embolic event and three severe infections were reported. At last follow-up, median eGFR was 87.1 (23.4–150.8) mL/min/1.73 m². CONCLUSION The incidence of relapses in adulthood is high in patients with active disease during childhood. A long-term follow-up is mandatory in these patients. Whereas renal function remained normal in most patients, high blood pressure and osteopenia were frequent and should be carefully monitored during adulthood. Transition visit should be carefully coordinated to prevent the risk of nonadherence.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)