Long-term effects of luteolin in a mouse model of nephropathic cystinosis.

In infantile nephropathic cystinosis, variants of the CTNS gene cause accumulation of cystine in lysosomes, causing progressive damage to most organs. Patients usually present before 1 year of age with signs of renal Fanconi syndrome. Cysteamine therapy allows cystine clearance from lysosomes and delays kidney damage but does not prevent progression to end-stage kidney disease, suggesting that pathways unrelated to cystine accumulation are also involved.

Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis.

Key Points: Ketogenic diet can change the metabolism in the body and helped restore the function of altered pathways in nephropathic cystinosis. Ketogenic diet had significant benefits for preventing kidney damage, even when initiated after the onset of kidney impairment. Ketogenic diet may provide a partial therapeutic alternative in countries where cysteamine therapy is too expensive.

Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys.

The Potential of Endoscopic Spring Ligament Repair in Flatfoot Reconstruction.

Background: Spring ligament fulfills 2 main important functions: one, supporting the head of the talus and stabilizing the talonavicular joint, and the other, maintaining the longitudinal arch by acting as a static support. In this preliminary report, we describe an endoscopic repair for spring ligament injuries with modified portals.

Methods: We performed a retrospective case series study from February 2019 to January 2022.

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.

Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence.

Defective Cystinosin, Aberrant Autophagy-Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle.

Epithelial cells that form the kidney proximal tubule (PT) rely on an intertwined ecosystem of vesicular membrane trafficking pathways to ensure the reabsorption of essential nutrients-a key requisite for homeostasis. The endolysosome stands at the crossroads of this sophisticated network, internalizing molecules through endocytosis, sorting receptors and nutrient transporters, maintaining cellular quality control via autophagy, and toggling the balance between PT differentiation and cell proliferation. Dysregulation of such endolysosome-guided trafficking pathways might thus lead to a generalized dysfunction of PT cells, often causing chronic kidney disease and life-threatening complications.

Multisystem involvement, defective lysosomes and impaired autophagy in a novel rat model of nephropathic cystinosis.

Recessive mutations in the CTNS gene encoding the lysosomal transporter cystinosin cause cystinosis, a lysosomal storage disease leading to kidney failure and multisystem manifestations. A Ctns knockout mouse model recapitulates features of cystinosis, but the delayed onset of kidney manifestations, phenotype variability and strain effects limit its use for mechanistic and drug development studies. To provide a better model for cystinosis, we generated a Ctns knockout rat model using CRISPR/Cas9 technology.

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis.

Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others.

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis.

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels.

Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood-testis barrier and a subtherapeutic effect of cysteamine in testis.

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment.

Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis.

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis.

Minimally invasive neurectomy for Morton's neuroma with interdigital approach. Long term results.

Background: "Morton's Neuroma" is a frequent cause of chronic forefoot pain. It can affect general population, including athletes, and can lead to progressive foot pain and discomfort for daily life activities and sports.

Hypothesis/purpose: Our objective is to evaluate the long-term results in a series of 85 feet, operatively treated with minimally invasive interdigital approach for neurectomy.

Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis.

Background: Mutations in the gene that encodes the lysosomal cystine transporter cystinosin cause the lysosomal storage disease cystinosis. Defective cystine transport leads to intralysosomal accumulation and crystallization of cystine. The most severe phenotype, nephropathic cystinosis, manifests during the first months of life, as renal Fanconi syndrome.

Flatfoot Deformity Due to Isolated Spring Ligament Injury.

Patients with acquired flatfoot deformity due to isolated injury of the spring ligament, with healthy posterior tibialis tendon, are rarely identified. Between December 2004 and September 2011 (6 years and 9 months), we treated 10 patients with acquired flatfoot deformity due to spring ligament injury without tibialis posterior tendon tear. One patient (10%) was lost to follow-up.

NLRP2 Regulates Proinflammatory and Antiapoptotic Responses in Proximal Tubular Epithelial Cells.

Nod-like Receptor Pyrin domain containing proteins (NLRPs) expressed by resident renal cells may contribute to the pathogenesis of multiple renal diseases. Cystinosis is a genetic disorder that affects kidney and particularly proximal tubular epithelial cells (PTEC). Here, we investigated the expression of NLRP family members in human control and cystinotic conditionally immortalized PTEC.

Intrinsic Bone Defects in Cystinotic Mice.

Cystinosis is a rare lysosomal storage disorder caused by loss-of-function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. Approximately 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets. In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism.

Molecular determinants of ER-Golgi contacts identified through a new FRET-FLIM system.

ER-TGN contact sites (ERTGoCS) have been visualized by electron microscopy, but their location in the crowded perinuclear area has hampered their analysis via optical microscopy as well as their mechanistic study. To overcome these limits we developed a FRET-based approach and screened several candidates to search for molecular determinants of the ERTGoCS. These included the ER membrane proteins VAPA and VAPB and lipid transfer proteins possessing dual (ER and TGN) targeting motifs that have been hypothesized to contribute to the maintenance of ERTGoCS, such as the ceramide transfer protein CERT and several members of the oxysterol binding proteins.

The activity of Sac1 across ER-TGN contact sites requires the four-phosphate-adaptor-protein-1.

Phosphatidylinositol-4-phosphate (PI4P), a phosphoinositide with key roles in the Golgi complex, is made by Golgi-associated phosphatidylinositol-4 kinases and consumed by the 4-phosphatase Sac1 that, instead, is an ER membrane protein. Here, we show that the contact sites between the ER and the TGN (ERTGoCS) provide a spatial setting suitable for Sac1 to dephosphorylate PI4P at the TGN. The ERTGoCS, though necessary, are not sufficient for the phosphatase activity of Sac1 on TGN PI4P, since this needs the phosphatidyl-four-phosphate-adaptor-protein-1 (FAPP1).

Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis.

Background & Aims: Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy.

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells.

Background: Nephropathic cystinosis is a lysosomal storage disease that is caused by mutations in the CTNS gene encoding a cystine/proton symporter cystinosin and an isoform cystinosin-LKG which is generated by an alternative splicing of exon 12. We have investigated the physiological role of the cystinosin-LKG that is widely expressed in epithelial tissues.

Methods: We have analyzed the intracellular localization and the function of the cystinosin-LKG conjugated with DsRed (cystinosin-LKG-RFP) in Madin-Darby canine kidney cells (MDCK II) and in proximal tubular epithelial cells carrying a deletion of the CTNS gene (cystinotic PTEC), respectively.

Carboxyl-Terminal SSLKG Motif of the Human Cystinosin-LKG Plays an Important Role in Plasma Membrane Sorting.

Cystinosin mediates an ATP-dependent cystine efflux from lysosomes and causes, if mutated, nephropathic cystinosis, a rare inherited lysosomal storage disease. Alternative splicing of the last exon of the cystinosin sequence produces the cystinosin-LKG isoform that is characterized by a different C-terminal region causing changes in the subcellular distribution of the protein. We have constructed RFP-tagged proteins and demonstrated by site-directed mutagenesis that the carboxyl-terminal SSLKG sequence of cystinosin-LKG is an important sorting motif that is required for efficient targeting the protein to the plasma membrane, where it can mediate H+ coupled cystine transport.

Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells.

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease characterized by accumulation of cystine into lysosomes secondary to mutations in the cystine lysosomal transporter, cystinosin. The defect initially causes proximal tubular dysfunction (Fanconi syndrome) which in time progresses to end-stage renal disease. Cystinotic patients treated with the cystine-depleting agent, cysteamine, have improved life expectancy, delayed progression to chronic renal failure, but persistence of Fanconi syndrome.

Rheolityc thrombectomy in acute myocardial infarction: Effect on microvascular obstruction, infarct size, and left ventricular remodeling.

Objectives: We sought to analyze whether rheolytic thrombectomy (RT) in comparison with manual thrombus aspiration (MTA) may reduce microvascular obstruction (MVO), infarct size (IS), and left ventricular (LV) remodeling in ST-elevation myocardial infarction (STEMI).

Background: Conflicting results have been reported as to whether MTA reduces MVO and IS.

Methods And Results: Eighty STEMI reperfused by primary angioplasty and abciximab were randomly allocated (1:1) to RT or MTA.

Endoplasmic reticulum-Golgi complex membrane contact sites.

Although they were identified as long ago as the 1960s, there are still many unknowns regarding the functions and composition of membrane contact sites between the endoplasmic reticulum (ER) and the trans-Golgi (TG). While it seems to be fairly well established that they facilitate lipid exchange between the two organelles, much less is known about how they are regulated. A bottleneck in the study of the ER-TG contact sites has been the absence of methods for their biochemical isolation and visualization by light microscopy.

Paradoxical embolization in TIPS: take a closer look to the heart.

No definitive indications are provided in the literature for pre-TIPS patient workup, which is often limited to prevent the incidence of refractory hepatic encephalopathy or unacceptable deterioration of liver function. Concerning cardiologic workup, efforts are generally limited at excluding ventricular failure or porto pulmonary hypertension. The cases presented herein focus the attention of the readers on the possible occurrence of post-TIPS paradoxical embolization in the presence of a patent foramen ovale, frequently recognized in adult population.