The Effect of a Gluten-Free Diet in Children With Difficult-to-Manage Nephrotic Syndrome

Case reports have linked childhood nephrotic syndrome to food sensitivity, including gluten. We report our experience with 8 children (6 boys, 2 girls; age at implementation of special diet 2–14 years) with difficult-to-manage nephrotic syndrome who were placed on a gluten-free diet for 3.4 ± 4.3 years (range, 0.6–14 years) and who had clinical improvement enabling reduction or discontinuation in steroid dosage

Linguistic and maternal genetic diversity are not correlated in Native Mexicans

Mesoamerica, defined as the broad linguistic and cultural area from middle southern Mexico to Costa Rica, might have played a pivotal role during the colonization of the American continent. The Mesoamerican isthmus has constituted an important geographic barrier that has severely restricted gene flow between North and South America in pre-historical times. Although the Native American component has been already described in admixed Mexican populations, few studies have been carried out in native Mexican populations. In this study, we present mitochondrial DNA (mtDNA) sequence data for the first hypervariable region (HVR-I) in 477 unrelated individuals belonging to 11 different native populations from Mexico. Almost all of the Native Mexican mtDNAs could be classified into the four pan-Amerindian haplogroups (A2, B2, C1, and D1); only two of them could be allocated to the rare Native American lineage D4h3. Their haplogroup phylogenies are clearly star-like, as expected from relatively young populations that have experienced diverse episodes of genetic drift (e.g., extensive isolation, genetic drift, and founder effects) and posterior population expansions. In agreement with this observation, Native Mexican populations show a high degree of heterogeneity in their patterns of haplogroup frequencies. Haplogroup X2a was absent in our samples, supporting previous observations where this clade was only detected in the American northernmost areas. The search for identical sequences in the American continent shows that, although Native Mexican populations seem to show a closer relationship to North American populations, they cannot be related to a single geographical region within the continent. Finally, we did not find significant population structure in the maternal lineages when considering the four main and distinct linguistic groups represented in our Mexican samples (Oto-Manguean, Uto-Aztecan, Tarascan, and Mayan), suggesting that genetic divergence predates linguistic diversification in Mexico

Fibroblast Growth Factor 21 Induces Cardiac Hypertrophy

Diabetic cardiomyopathy is a diabetes-associated cardiovascular disease (CVD), which causes heart dysfunction. Left ventricular hypertrophy (LVH) is a key feature of diabetic cardiomyopathy. Molecular mechanisms underlying this condition are largely unknown. Fibroblast growth factor (FGF) 21, an adipokine that regulates metabolism, has been found to be elevated in the circulation of type 2 diabetic patients. This thesis evaluates the long-term effects of increased serum FGF21 levels on the heart. It reveals that FGF21 induces hypertrophy of cardiac myocytes via FGF receptor (FGFR) 4-dependent activation of the pathological and pro-hypertrophic PLCγ/calcineurin/NFAT pathway, but independently of β-klotho, the canonical co-receptor for FGF21 in the liver. FGF21 transgenic mice develop LVH at 6 months of age. 6 weeks of pan-FGFR inhibitor treatment of diabetic ob/ob mice or 24 weeks of FGFR4 specific blockade of diabetic db/db mice inhibits pathological cardiac signaling and LVH development. These results show that FGF21 can induce hypertrophic signaling in the heart independently of β-klotho, that long-term FGF21 elevation may be responsible for the development of diabetic cardiomyopathy, and that FGFR4 blockade might serve as a novel cardio-protective therapy in diabetic patients.</p

Analyse von Ursachen der Sterblichkeit untergewichtiger Saeuglinge - Bezirk Gera 1978-1982

DB Leipzig(101) - Di 1992 B 7182 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice

The liver plays a decisive role in the regulation of systemic inflammation. In chronic kidney disease in particular, the liver reacts in response to the uremic milieu, oxidative stress, endotoxemia and the decreased clearance of circulating proinflammatory cytokines by producing a large number of acute-phase reactants. Experimental tools to study inflammation and the underlying role of hepatocytes are crucial to understand the regulation and contribution of hepatic cytokines to a systemic acute phase response and a prolonged pro-inflammatory scenario, especially in an intricate setting such as chronic kidney disease. Since studying complex mechanisms of inflammation in vivo remains challenging, resource-intensive and usually requires the usage of transgenic animals, primary isolated hepatocytes provide a robust tool to gain mechanistic insights into the hepatic acute-phase response. Since this in vitro technique features moderate costs, high reproducibility and common technical knowledge, primary isolated hepatocytes can also be easily used as a screening approach. Here, we describe an enzymatic-based method to isolate primary murine hepatocytes, and we describe the assessment of an inflammatory response in these cells using ELISA and quantitative real-time PCR

Abstract 455: FGF23-induced Cardiac Hypertrophy is Reversible

Left ventricular hypertrophy (LVH) is a common feature of cardiovascular disease in chronic kidney disease (CKD) and affects up to 90% of patients by the time they reach dialysis. Serum levels of fibroblast growth factor (FGF) 23 continuously rise as patients progress to renal failure. We have previously shown that FGF23 can activate FGF receptor (FGFR) 4 and the PLCgamma/calcineurin/NFAT signaling cascade in cardiac myocytes and induce hypertrophy in vitro and in vivo. Administration of an isoform-specific FGFR4 blocking antibody in the 5/6 nephrectomy rat model of CKD immediately after surgery protects rats from developing LVH, and delivery of a pan-FGFR blocker in CKD rats two weeks after surgery reverses LVH. To further study the reversibility of cardiac FGF23 effects, we elevated serum FGF23 levels in mice by administration of a high phosphate (2%) diet for three months. Animals developed LVH, as evident by significantly increased LV wall thickness and myocyte cross sectional area. When mice were switch from high phosphate to normal chow, the LVH phenotype resolved and cardiac parameters were comparable to those of mice that constantly received a normal diet. Furthermore, isolated cardiac myocytes recovered within 24 hours from FGF23-induced hypertrophy upon removal of FGF23. Finally, the FGFR4 blocking antibody was capable of reversing FGF23-induced hypertrophy in vitro. Our data indicate that FGF23-induced LVH is reversible and treatable. Interfering with FGF23/FGFR4 signaling in the heart might provide a novel therapeutic strategy to tackle cardiac injury in CKD. We propose that progression and reversibility of cardiac injury might depend on the duration of cardiac FGF23/FGFR4 activation

Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment

Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to <i>biochemical</i> resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be <i>physiological</i>, emerging as a consequence of the tumor’s physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an “ion trapping” phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed