New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers.

Medullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET\u2013GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers

Time behaviour of new passive anchors on unstable slope monitored via optical fiber

Composite anchors are a new type of self-drilling reinforcements recently developed for the slope stabilization. They consist in hollow bars equipped with some tendons, inserted and cemented in their inner hole after installation. Compared to traditional self-drilling anchors, they offer a higher tensile strength with small increments of cost. This aspect, combined with a high execution flexibility, has favoured their rapid diffusion in the last years. Similar to soil-nailing bars, they are passive reinforcements, but thanks to strand presence, they can be also used as active anchors. The bond strength at the soil-anchor interface is crucial for their design, because it controls the pull-out resistance and the long-term stabilization effects; however, the in-situ bond strength measurements performed in the past with traditional sensors have not always produced satisfactory outcomes. The paper presents some preliminary results obtained using distributed optical fibre sensors (DFOS) exploiting the optical frequency domain reflectometry (OFDR) to measure the strain of a fibre embedded with the tendons inside the bar. This allows to reconstruct the interface action profile of three anchors installed on an active landslide. Upon an extensive validation, the system may become a standard practice to evaluate the effectiveness of these anchors with time

Very low levels of vitamin D in systemic sclerosis patients

Vitamin D displays many extraosseous immunomodulatory effects. The aim of the study was to evaluate the level of vitamin D in patients with systemic sclerosis (SSc) and to analyze the associations between the concentration of the vitamin and clinical manifestations. In March-April 2009, 65 consecutive SSc patients underwent evaluation of vitamin D concentrations by the LIAISON immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency, while concentrations <10 ng/ml as vitamin D deficiency. None of the patients were receiving vitamin D supplementation at the time of or during the year prior to study entry. The mean level of vitamin D was 15.8 +/- 9.1 ng/ml. Only three cases showed normal values; vitamin D insufficiency and deficiency were found in 43 and 19 cases, respectively. Patients with vitamin D deficiency showed longer disease duration (13.1 +/- 6.8 versus 9.4 +/- 5.5 years, P = 0.026), lower diffusing lung capacity for carbon monoxide (63.7 +/- 12.4 versus 76.4 +/- 20.2, P = 0.014), higher estimated pulmonary artery pressure (28.9 +/- 9.9 versus 22.8 +/- 10.4, P = 0.037) and higher values of ESR (40 +/- 25 versus 23 +/- 13 mm/h, P = 0.001) and of CRP (7 +/- 7 and 4 +/- 2 mg/l, P = 0.004) in comparison with patients with vitamin D insufficiency; moreover, late nailfold videocapillaroscopic pattern was more frequently found (52.6% versus 18.6%, P = 0.013). None of the patients showed evidence of overt mal-absorption. Low levels of vitamin D are very frequent in patients with SSc. Intestinal involvement is not likely the cause of vitamin D deficit; other factors such as skin hyperpigmentation and reduced sun exposition for psychological and social reasons may be implicated. Patients with vitamin D deficiency showed more severe disease in comparison with patients with vitamin D insufficiency, above all concerning lung involvement. Further trials are awaited to determine whether vitamin D could represent a modifiable factor able to interfere with SSc evolution

Aberrantly Methylated DNA Regions Lead to Low Activation of CD4+ T Cells in IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. In this setting, also the DNA methylation could be an important factor influencing this disease. We performed a genome-wide screening for DNA methylation in CD4+ T cells from IgAN patients and found three regions aberrantly methylated influencing genes involved in the response and proliferation of CD4+ T cells. Two hypomethylated regions codified genes involved in the T cell receptor (TCR) signalling, TRIM27 and DUSP3,and an hypermethylated region included the VTRNA2-1 non-coding RNA, also known as miR-886 precursor. We showed that the aberrant methylation influence the expression of these genes in IgAN patients. Moreover, we demonstrated that the hypermethylation of miR-886 precursor led to a decreased CD4+ T cell proliferation following TCR stimulation and to the over-expression of TGF\u3b2. Finally, we found a Th1/Th2 imbalance in IgAN patients. The IL-2/IL-5 ratio was notably higher in IgAN patients and clearly indicated a Th1 shift. In conclusion, we identified for the first time some specific DNA regions abnormally methylated in IgAN patients that led to the reduced TCR signal strength of the CD4+ T cells and to their anomalous response and activation that could explain the T helper cell imbalance. This study reveals new molecular mechanisms underlying the abnormal CD4+ T cell response in IgAN patients

Proteomic-based research strategy identified laminin subunit alpha 2 as a potential urinary-specific biomarker for the medullary sponge kidney disease.

Medullary sponge kidney (MSK) disease, a rare kidney malformation featuring recurrent renal stones and nephrocalcinosis, continues to be diagnosed using expensive and time-consuming clinical/instrumental tests (mainly urography). Currently, no molecular diagnostic biomarkers are available. To identify such we employed a proteomic-based research strategy utilizing urine from 22 patients with MSK and 22 patients affected by idiopathic calcium nephrolithiasis (ICN) as controls. Notably, two patients with ICN presented cysts. In the discovery phase, the urine of 11 MSK and 10 controls, were randomly selected, processed, and analyzed by mass spectrometry. Subsequently, several statistical algorithms were undertaken to select the most discriminative proteins between the two study groups. ELISA, performed on the entire patients' cohort, was used to validate the proteomic results. After an initial statistical analysis, 249 and 396 proteins were identified exclusive for ICN and MSK, respectively. A Volcano plot and ROC analysis, performed to restrict the number of MSK-associated proteins, indicated that 328 and 44 proteins, respectively, were specific for MSK. Interestingly, 119 proteins were found to differentiate patients with cysts (all patients with MSK and the two ICN with renal cysts) from ICN without cysts. Eventually, 16 proteins were found to be common to three statistical methods with laminin subunit alpha 2 (LAMA-2) reaching the higher rank by a Support Vector Machine, a binary classification/prediction scheme. ELISA for LAMA-2 validated proteomic results. Thus, using high-throughput technology, our study identified a candidate MSK biomarker possibly employable in future for the early diagnosis of this disease