The importance of genetic testing in adolescent-onset steroid-resistant nephrotic syndrome - Case report

Approximately 10-20% of children and 40% of adults with idiopathic nephrotic syndrome are steroid resistant and progress to end-stage renal disease requiring dialysis or renal transplantation. In these cases, renal histology typically shows focal segmental glomerulosclerosis. Mutations in NPHS1, NPHS2, WT1, CD2AP and ACTN4 genes located on different chromosomes, expressed by glomerular podocytes, have been identified in patients with steroid-resistant nephrotic syndrome. The authors report two cases of adolescent-onset steroid-resistant nephrotic syndrome. Both cases had similar clinical and histopathological manifestations, with different prognosis and evolution due to different mechanisms leading to proteinuria: an acquired and a genetic form. The first case, a 16 year old girl presented the onset of the disease with massive, generalized edema, secondary hypothyroidism and high blood pressure. Evolution was favorable under cyclosporine therapy. The second case, a 13-years-old adolescent girl, presented an insidious onset of the disease with mild edema. Genetic testing revealed a mutation in the WT1 gene. The patient developed end-stage kidney failure eight months after the onset of the disease and following kidney transplant had a favorable evolution. Histological examination of the renal biopsy specimen showed focal segmental glomerulosclerosis in both cases. Conclusions: Genetic forms of nephrotic syndrome do not respond to immunosuppressive therapy and may progress to end-stage renal disease, but after kidney transplantation relapse is not expected, in contrast to the immune form. The early genetic diagnosis in steroid-resistant nephrotic syndrome is time-consuming, but is important for proper clinical management of the patients, prognosis and genetic counseling of the families

Evolution of the Early-Type Galaxy Fraction in Clusters since z = 0.8

We study the morphological content of a large sample of high-redshift clusters to determine its dependence on cluster mass and redshift. Quantitative morphologies are based on bulge+disk decompositions of cluster and field galaxies on deep VLT/FORS2 images of 18 optically-selected clusters at 0.45 < z < 0.80 from the ESO Distant Cluster Survey (EDisCS). Morphological content is given by the early-type galaxy fraction f_et, and early-type galaxies are selected based on their bulge fraction and image smoothness. A set of 158 SDSS clusters is analyzed exactly as the EDisCS sample to provide a robust local comparison. Our main results are: (1) f_et values for the SDSS and EDisCS clusters exhibit no clear trend as a function of sigma. (2) Mid-z EDisCS clusters around sigma = 500 km/s have f_et ~= 0.5 whereas high-z EDisCS clusters have f_et ~= 0.4 (~25% increase over 2 Gyrs). (3) There is a marked difference in the morphological content of EDisCS and SDSS clusters. None of the EDisCS clusters have f_et greater than 0.6 whereas half of the SDSS clusters lie above this value. This difference is seen in clusters of all velocity dispersions. (4) There is a strong correlation between morphology and star formation in SDSS and EDisCS clusters. This correlation holds independent of sigma and z even though the fraction of [OII] emitters decreases from z~0.8 to z~0.06 in all environments. Our results pose an interesting challenge to structural transformation and star formation quenching processes that strongly depend on the global cluster environment and suggest that cluster membership may be of lesser importance than other variables in determining galaxy properties. (ABRIDGED)Comment: 22 pages, 10 figures, accepted for publication in A&

Dietary factors impact on the association between CTSS variants and obesity related traits.

Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology--this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors--increased by high protein, glycemic index and energy diets

Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles

Release of membrane vesicles, a process conserved in both prokaryotes and eukaryotes, represents an evolutionary link, and suggests essential functions of a dynamic extracellular vesicular compartment (including exosomes, microparticles or microvesicles and apoptotic bodies). Compelling evidence supports the significance of this compartment in a broad range of physiological and pathological processes. However, classification of membrane vesicles, protocols of their isolation and detection, molecular details of vesicular release, clearance and biological functions are still under intense investigation. Here, we give a comprehensive overview of extracellular vesicles. After discussing the technical pitfalls and potential artifacts of the rapidly emerging field, we compare results from meta-analyses of published proteomic studies on membrane vesicles. We also summarize clinical implications of membrane vesicles. Lessons from this compartment challenge current paradigms concerning the mechanisms of intercellular communication and immune regulation. Furthermore, its clinical implementation may open new perspectives in translational medicine both in diagnostics and therapy

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes

Injectable local anaesthetic agents for dental anaesthesia

Background: Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to dentists. / Objectives: Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention. Our secondary objective was to report on patients' experience of the procedures carried out. / Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research. / Selection criteria: We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or cross‐over design. / Data collection and analysis: We used standard Cochrane methodological approaches for data collection and analysis. / Main results: We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for meta‐analysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing. We assessed the included studies as having low risk of bias in most domains. Seventy‐three studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion. We reported results for the eight most important comparisons. / Success of anaesthesia: When the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; low‐quality evidence). When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderate‐quality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; low‐quality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine. Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very low‐quality evidence). Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 cross‐over studies; 37 participants; low‐quality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 cross‐over studies; 31 participants; low‐quality evidence) on success of anaesthesia for teeth requiring extraction are uncertain. Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 cross‐over study; 110 participants; low‐quality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; low‐quality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain. For remaining outcomes, assessing success of dental local anaesthesia via meta‐analyses was not possible. / Onset and duration of anaesthesia: For comparisons assessing onset and duration, no clinical studies met our outcome definitions. Adverse effects (continuous pain measured on 170‐mm Heft‐Parker visual analogue scale (VAS)) Differences in post‐injection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI ‐1.98 to 11.46 mm; 3 cross‐over studies; 314 interventions; moderate‐quality evidence). Lidocaine probably resulted in slightly less post‐injection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 cross‐over studies; 309 interventions; moderate‐quality evidence) on the same VAS. For remaining comparisons assessing local and systemic adverse effects, meta‐analyses were not possible. Other adverse effects were rare and minor. / Patients' experience: Patients' experience of procedures was not assessed owing to lack of data. / Authors' conclusions: For success (absence of pain), low‐quality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderate‐quality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed. Adverse events were rare. Moderate‐quality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection. Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible. Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow meta‐analysis. Once assessed, results of the 34 ‘Studies awaiting classification (full text unavailable)’ may alter the conclusions of the review

NMR and MS urinary metabolic phenotyping in kidney diseases is fit-for-purpose in the presence of a protease inhibitor

Nephrotic syndrome with idiopathic membranous nephropathy as a major contributor, is characterized by proteinuria, hypoalbuminemia and oedema. Diagnosis is based on renal biopsy and the condition is treated using immunosuppressive drugs; however nephrotic syndrome treatment efficacy varies among patients. Multi-omic urine analyses can discover new markers of nephrotic syndrome that can be used to develop personalized treatments. For proteomics, a protease inhibitor (PI) is sometimes added at sample collection to conserve proteins but its impact on urine metabolic phenotyping needs to be evaluated. Urine from controls (n = 4) and idiopathic membranous nephropathy (iMN) patients (n = 6) were collected with and without PI addition and analysed using 1H NMR spectroscopy and UPLC-MS. PI-related data features were observed in the 1H NMR spectra but their removal followed by a median fold change normalisation, eliminated the PI contribution. PI-related metabolites in UPLC-MS data had limited effect on metabolic patterns specific to iMN. When using an appropriate data processing pipeline, PI-containing urine samples are appropriate for 1H NMR and MS metabolic profiling of patients with nephrotic syndrome

Rumination, anxiety, depressive symptoms and subsequent depression in adolescents at risk for psychopathology:a longitudinal cohort study

BACKGROUND: A ruminative style of responding to low mood is associated with subsequent high depressive symptoms and depressive disorder in children, adolescents and adults. Scores on self-report rumination scales correlate strongly with scores on anxiety and depression symptom scales. This may confound any associations between rumination and subsequent depression. METHODS: Our sample comprised 658 healthy adolescents at elevated risk for psychopathology. This study applied ordinal item (non-linear) factor analysis to pooled items from three self-report questionnaires to explore whether there were separate, but correlated, constructs of rumination, depression and anxiety. It then tested whether rumination independently predicted depressive disorder and depressive symptoms over the subsequent 12 months, after adjusting for confounding variables. RESULTS: We identified a single rumination factor, which was correlated with factors representing cognitive symptoms of depression, somatic symptoms of depression and anxiety symptoms; and one factor representing adaptive responses to low mood. Elevated rumination scores predicted onset of depressive disorders over the subsequent year (p = 0.035), and levels of depressive symptoms 12 months later (p < 0.0005), after adjustment for prior levels of depressive and anxiety symptoms. CONCLUSION: High rumination predicts onset of depressive disorder in healthy adolescents. Therapy that reduces rumination and increases distraction/problem-solving may reduce onset and relapse rates of depression