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Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Ureteropelvic junction obstruction (UPJO) is one of the most common urological diseases in children. The etiology can be intrinsic, extrinsic (crossing vessel [CV] or adhesions), or mixed. To date, ultrasonography and scintigraphy are considered gold-standard imaging techniques for the study of UPJO. Functional magnetic resonance urography (fMRU) combines anatomical and functional information and has been recently evaluated for the detection of CVs in UPJO. The objective of the study was to evaluate the concordance between fMRU and surgery in determining the etiology of UPJO and the presence of obstructing/non-obstructing CVs. Patients with unilateral hydronephrosis who underwent surgery after an fMRU were included in the sample. Surgical data regarding the etiology of UPJO were compared with radiological results. The etiology was divided into intrinsic, extrinsic due to CV, extrinsic due to adhesions, and mixed or cicatricial (postoperative). The concordance was calculated by means of the Cohen's kappa coefficient. The observed agreement between fMRU and surgical findings regarding the etiology and the presence of CV were 83.2% and 89.4%, respectively (with substantial Cohen's kappa coefficient). The sensitivity and specificity of fMRU were 0.84 and 0.93, respectively; the positive predictive value (PPV) and negative predictive value (NPV) were 0.889 and 0.897, respectively. The observed agreement regarding the type of vessel was 88.3% with a Cohen's kappa coefficient of 0.787 (substantial). In children with hydronephrosis, it is very important for the surgeon to quantify the extent of dilation, define the etiology of the obstruction, and the presence or absence of CVs. fMRU is a 'one-stop-shop' technique which provides both anatomical and functional information showing a high concordance with surgical findings, avoiding radiation exposure. fMRU should be considered a valid imaging technique in the study of pediatric UPJO, as it provides the surgeon with important information regarding the etiology of the obstruction for the preoperative planning. fMRU image showing the presence of CV as etiologic cause of the obstruction. [ABSTRACT FROM AUTHOR]

Summary: We have recently hypothesized that structural and secretory components of the adult human thyroid gland maintain constant reciprocal and geometrical relationships, even if changes occur in the three-dimensional (3D) architecture of any of these elements. This means that thyroid morphology could be studied from the point of view of a 3D topology. As a consequence, we have investigated anatomical aspects that could support this assumption. In the present study, we show that the presence of a constant relationship can be demonstrated between the vascular arrangement of the gland, including the extension of intraglandular arterial fields, arterial anastomoses and arterial calibers, and the shape as well as volume of the thyroid. Specifically, a statistically significant difference has been found between the network amplitudes of the superior and inferior thyroid arteries in relation to either a conic or an ellipsoidal geometry of the thyroid lobe. In addition, a direct relationship has been implicated between the distribution of arterial anastomoses and the behavior of the lobe as a single hemodynamic unit. Finally, a statistically significant correlation has been observed between average arterial caliber of the inferior thyroid artery and thyroid volume. On the basis of these results, we propose a model of architectural assembly between stromal and parenchymal elements of the adult thyroid that might prove useful in designing a bioartificial gland ex situ. Potential clinical applications of this principle in regenerative medicine of other endocrine organs are highlighted. [Copyright &y& Elsevier]

Our objective was the checking of clinical data obtainable from the assay of some parameters in NID diabetic individuals. To this end, we studied 133 patients--57 males and 76 females, average age 74.36 +/- 1.01 years, 72.6% of which were above 65 years of age. The control population was subdivided as follows: 50 subjects, 26 F and 24 M; average age 71.25 +/- 1.32 years, with normal glucidic tolerance as assessed by OGTT. Current glycemia, average glycemia, fructosamine, glycosylated hemoglobin, triglycerides, LDL-cholesterol and apolipoprotein B were obviously much higher than normal in the individuals admitted to the study. A statistically significant correlation was found between average glycemia, glycosylated hemoglobin, LDL-cholesterol and blood triglycerides (p less than 0.05). No correlation was found between current glycemia, fructosamine and glycosylated hemoglobin. Similarly, serum fructosamine was unrelated to the parameters studied. In our study, fructosamine, glycosylated hemoglobin and current glycemia offered unrelatable data. Hence, in our opinion it is necessary to assay these three parameters contemporaneously for a reliable assessment of metabolic compensation.

The lack of fiber in the western diet may contribute to the development of several diseases including gastrointestinal disorders; the clinical effects of a new substance (AGIOLAX) made from plantago seeds and senna pods were studied. 100 patients of both sexes, aged from 40 to 60 years (30 with diabetes mellitus, 40 with obesity and 30 with hyperlipidemia) were treated; everyone complained a slowness, of different degree, of normal intestinal transit time or chronic constipation. The experiment was carried out without the use of a control group. Aim of the present study was to investigate the efficacy and tolerability of the product. In addition to the clinical evaluation of the symptoms, laboratory tests were performed. The patients were treated for 3 months with a daily dose of 2 teaspoons every evening. In the majority of the subjects a good clinical response was obtained; 88% of the patients presented a normalization of the gastrointestinal transit time; only 12% of them did not respond satisfactorily to the substance. Further the drug was well tolerated by 86% of the patients. In conclusion the authors report a good efficacy and tolerability of the product; thus they recommend its use in those disorders characterized by slow intestinal transit time and/or constipation.

A one-year clinical trial with pantethine was conducted in 24 patients with established dyslipidemia of Fredrickson's types II A, II B, and IV, alone or associated with diabetes mellitus. The treatment was well tolerated by all patients with no subjective complaints or detectable side effects. Blood lipid assays repeated after 1, 3, 6, 9, and 12 months of treatment revealed consistent and statistically significant reductions of all atherogenic lipid fractions (total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B) with parallel increases of high-density lipoprotein cholesterol and apolipoprotein A. The results were equally good in patients with uncomplicated dyslipidemia and in those with associated diabetes mellitus. The authors conclude that pantethine (a drug entity related to the natural compound, pantetheine) represents a valid therapeutic support for patients with dyslipidemia not amenable to satisfactory correction of blood lipids by diet alone.

After having stressed the importance of fibres in the nutritional field, pointing out the inverse relationship between vegetal fibres consumption in various populations and diffusion of many diseases of the so-called "industrialized" societies (such as obesity, diabetes, dyslipidemias, atherosclerosis, cholelithiasis, cancer of the colon, etc.), the Authors report their experiment on a new experimental product based on glucomannane purified (PRL). The present study was carried out on 24 obese subjects (5 males and 19 females). The patients, normoglycemics in their basic condition, were submitted to OGTT with 75 g of glucose in the morning before eating and were subdivided into two groups, the first (Group A) characterized by the sequence OGTT + placebo; after a few days, by another OGTT + experimental product; the second characterized by the inverse sequence. Four tablets (glucomannane purified 5,2 g) and four tablets of placebo was the posology employed. The evaluation of the possible action of the product in reducing or slowing down the intestinal absorption of glucose was the aim of the research. The results obtained show that the administration of the product under study has led to a sharp decrease of the average glycemic values with variations per cent ranging from 13% to 16% in Group A, from 10% to 11% in Group B and from 7% to 12% in the two groups considered on the whole. In conclusion, the Authors wish an increased diffusion of dietary fibres and particularly of the glucomannanes in all those dysmetabolic forms having at their bases an unbalanced, hypercaloric alimentation, rich in refined aliments and poor in fibres.

Recent investigations have confirmed the effectiveness and the excellent tolerability of pantethine, a derivative of pantetheine, an essential part of the acetylation coenzyme CoA, administered P.O., in normalizing the blood lipid concentrations of patients with hyperlipidemias. A group of 18 patients with hyperlipidemias (9 M, 9 F), with an average age of 52.6 years, was submitted to pantethine parenteral treatment. After a 20 days wash-out, pantethine (400 mg/day; BID) was administered intramuscularly, for 20 days. Total cholesterol, triglycerides, HDL-cholesterol, apo A-1 and B lipoprotein, uric acid in serum, glycemia, CBC, B.U.N., creatininemia, E.S.R., SGOT, SGPT, bilirubinemia, cardiac frequency, blood pressure and body weight were controlled before and after treatment. The drug showed to have a therapeutic effectiveness by a rapid and significant improvement in the blood lipid pattern with reduction of total cholesterol, triglycerides and apo-B lipoprotein and increase of HDL-cholesterol and apo A-1 lipoprotein. The tolerability of pantethine at the stated dosage and mode of administration was invariably excellent, with non complaints or visible side effects imputable to the test drug. BUN, creatininemia, glycemia, SGOT, SGPT, bilirubinemia, E.S.R., CBC, cardiac frequency and blood pressure readings showed no noteworthy changes throughout the study.