Obesity is rampant across the spectrum of age, gender, and race in the Unites States. Paralleling this epidemic, kidney stone prevalence is also rising, affecting nearly 1 in 11 individuals. Bariatric surgical procedures, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), are the most effective weight loss options for morbidly obese or severely obese individuals with comorbidities. A number of studies have linked kidney stone development to bariatric surgical history, particularly RYGB, which portends up to a threefold increase in calcium oxalate stone risk compared with age-matched, obese controls. Stone development after malabsorptive (RYGB) and restrictive (SG) bariatric procedures are driven primarily by alterations in 24-h urine profiles, such as increased urinary oxalate, decreased urine volume, and reduced urinary citrate levels-all of which have been linked to increased kidney stone risk. What clinical recommendations, if any, can be given to reduce kidney stone risk in bariatric kidney stone patients? This review provides not only updated stone incidence and 24-h urine data in this population, but also reassurance-the metabolic alterations that result from bariatric surgery can be successfully mitigated by increased provider awareness, patient education, and a combination of dietary and pharmacological adjustments.
Alongside Pdx1 and Beta2/NeuroD, the transcription factor MafA has been shown to be instrumental in the maintenance of the beta cell phenotype. Indeed, a combination of MafA, Pdx1 and Ngn3 (an upstream regulator of Beta2/NeuroD) was recently reported to lead to the effective reprogramming of acinar cells into insulin-producing beta cells. These experiments set the stage for the development of new strategies to address the impairment of glycemic control in diabetic patients. However, the clinical applicability of reprogramming in this context is deemed to be poor due to the need to use viral vehicles for the delivery of the above factors. Here we describe a recombinant transducible version of the MafA protein (TAT-MafA) that penetrates across cell membranes with an efficiency of 100% and binds to the insulin promoter in vitro. When injected in utero into living mouse embryos, TAT-MafA significantly up-regulates target genes and induces enhanced insulin production as well as cytoarchitectural changes consistent with faster islet maturation. As the latest addition to our armamentarium of transducible proteins (which already includes Pdx1 and Ngn3), the purification and characterization of a functional TAT-MafA protein opens the door to prospective therapeutic uses that circumvent the use of viral delivery. To our knowledge, this is also the first report on the use of protein transduction in utero.
Our knowledge of organ ontogeny is largely based on loss-of-function (knockout) or gain-of-function (transgenesis) approaches. However, developmental modulators such as proteins, mRNAs, microRNAs(miRNAs), small interfering RNAs, and other small molecules may complement the above DNA-modifying technologies in a much more direct way. Unfortunately, their use is often limited by the ability of these compounds to cross the placenta and reach physiologically relevant concentrations when administered systemically to the mother. The design of safe and effective techniques to deliver these compounds into the embryo is therefore an area of great scientific potential. In this article we report a new method for introducing developmental modulators into murine embryos by means of direct injection into the heart. Unlike other reported methods that require surgical exposure of the uterus, our percutaneous ultrasound-guided approach allows for the intracardial injection of mouse embryos as early as embryonic day 10.5 (e10.5) and throughout gestation in a minimally invasive manner that largely preserves embryo viability. This system offers a critical advantage over in vitro settings because the effects of any given treatment can be observed without disturbing the native environment of the developing organ. Procedures are described for the delivery and detection of transducible proteins as well as morpholinos designed to block the expression of specific miRNAs within the living embryo.
RESULTS: DM tolerated 3 hours of constant CO2 anesthesia in combination with X-ray radiation exposure throughout the uCT acquisition, during which the optimal scanning protocol achieved DM survival and minimal image-noise. With this method, successful 3D reconstruction and visualization of DM adults were reproduced at 5.72 um isotropic voxel spacing, with stones clearly present (Fig. 1). Analysis of the impact of BS168 on stone formation is ongoing.CONCLUSIONS: We have demonstrated that using CO2 gas during uCT imaging of live DM induces safe, repeatable, temporary fullbody immobilization without motion artefacts, for the purpose of visualizing stones. DM could fully recover after scans and we demonstrated the capability of this tool in time-course studies, as the same individuals were repeatedly scanned throughout the experiment. Currently this technique is being applied to characterize the effect of stone-modulating treatments such as probiotic bacteria with future potential in evaluating pharmaceuticals.
INTRODUCTION AND OBJECTIVE: Patients with type 2 primary hyperoxaluria (PH2) have a defect in Glyoxylate reductase (GR) resulting in excessive urinary oxalate excretion. These patients do not respond to pyridoxine therapy and some may require combined liver/ renal transplantation. We have recently reported that the metabolism of trans-4-hydroxy-L-proline (Hyp), an amino acid derived predominantly from collagen metabolism, is a significant source of oxalate production in individuals with PH2. Hydroxyproline dehydrogenase (HYPDH) is the initial enzyme in the metabolism of Hyp to glyoxylate, the immediate precursor to oxalate. Herein, we describe the phenotypes of the Prodh2 knock out (KO), a HYPDH knock out mouse model, a GR KO (Grhpr) which mimics PH2, and a double KO mouse, Prodh2 /Grhpr.METHODS: These KO mice were created using CRISPR/Cas methodology. Male mice, 12-16 weeks of age, were singly housed in metabolic cages for collection of three consecutive 24-hour urines. Mice had free access to water and a calcium-deficient, high-sucrose basal diet to which calcium chloride was added at 5 mg per gram dry diet. This custom diet contains a very low background oxalate content (12.9 AE 1.1 µg oxalate per gram diet) and is devoid of Hyp. The diet contains 19.6% protein, 57.7% carbohydrate, 6.6% fat, and 10.3% cellulose. Ion chromatography coupled with mass spectroscopy was used.RESULTS: In the HYPDH KO mice (n[9), the plasma Hyp and urinary Hyp excretion levels were significantly elevated as compared to WT animals (n[13); 760 AE 193 µM vs 14.7 AE 3.1 (p<0.001) and 808 AE 532 µg vs <19 µg (p<0.001), respectively. Prodh2 KO mice had an 18% lower urinary oxalate excretion as compared with WT mice (102 AE 4.1 vs 83.7 AE 3.7 µg/mg creatinine, p [ 0.002) and a 20% lower urinary glycolate excretion (p [ 0.014). Prodh2 /Grhpr KO mice (n[9) had reduced urinary oxalate excretion, 30% lower as compared to the Grhpr KO mice (n[8) (178 AE 9 vs 255 AE 16 µG/mg creatinine, p<0.003).CONCLUSIONS: Hydroxyproline dehydrogenase represents a promising therapeutic target for reducing urinary oxalate excretion in PH2 individuals.
Right ventricular (RV) metastasis from an upper tract urothelial carcinoma without inferior vena cava or right atrial involvement is an extremely rare event which highlights the heterogeneity of this disease process. We report a case of a 43-year-old man presenting for long-standing hematuria and left flank pain. Computed tomography revealed a left renal mass with para-aortic lymphadenopathy, in addition to a potential mass in the RV. The mass involving the RV was confirmed on subsequent cardiac evaluation with magnetic resonance imaging (MRI) and echocardiography. After discussion in a multidisciplinary tumor board, the patient underwent a left nephrectomy, regional lymphadenectomy, and excision of metastatic RV tumor with bovine patch reconstruction. Final pathology reported invasive urothelial carcinoma in the left kidney with involvement of regional para-aortic lymph nodes and metastatic tumor in the RV (T4N3M1, AJCC 8 th edition). The patient did well postoperatively and completed adjuvant Cisplatin-Gemcitabine systemic chemotherapy. This is an important addition to the literature as it highlights the aggressive and heterogeneous nature of urothelial carcinoma and the utility of cardiac MRI in surgical planning.
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