Severe Acute Kidney Injury and Double Tubulopathy Due to Dual Toxicity Caused by Combination Antiretroviral Therapy.

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Cellular Variant of Focal Segmental Glomerulosclerosis Treated with Plasma Exchange

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disease in nephrotic patients in the United States, frequently leading to end stage renal disease (ESRD). The cellular variant is a rare form of FSGS commonly associated with poor outcome. We report a case of cellular variant FSGS with progressive kidney dysfunction successfully treated with plasma exchange (PE). A 49-year-old Caucasian female presented with two days of ankle edema and hypertension. Laboratory findings showed serum creatinine (SCr) 1.6 mg/dL, urine albumin/creatinine ratio (uACR) 2.8 g/g, haematuria 3+ and no immunological abnormalities. Kidney biopsy revealed a cellular FSGS variant with segmental endocapillary proliferation on light microscopic, negative immunofluorescence and widespread foot process effacement by electronic microscopic. Prednisolone 1 mg/Kg was started. Four days later the SCr worsened (3.6 mg/dL) and the patient became severely nephrotic with uACR of6.8g/g, quickly attaining a maximum of 24.6 g/g in a short time and albumin of 2.15g/dL. Pulsed methyl prednisolone was started. Despite a 10 course of steroids, no clinical improvement was observed. Considering the rapidly worsening renal function and severe nephrotic syndrome, PE was begun in association with mycophenolate mofetil and tacrolimus. Kidney function recovered after one week. Complete remission was achieved at 3rd week and remains in complete remission at 27 months follow-up. Prolonged remission is a challenge in primary FSGS. PE associated with combined immunosuppression was effective in the present case. The short and long-term effects of plasma exchange in primary FSGS should be evaluated in prospective studies.info:eu-repo/semantics/publishedVersio

Kidney biopsy in Lupus Nephritis: still essential in clinical practice

Renal involvement in Systemic Lupus Erythematous is common and its management remains a daily challenge for clinical providers. Percutaneous kidney biopsy remains the gold standard for diagnosis of lupus nephritis. More recently, we have seen the role of the biopsy being challenged, considering the widespread use of corticosteroids and mycophenolate mofetil for all forms of lupus nephritis. We present a review of published evidence regarding first and repeat kidney biopsies for patients with lupus nephritis. Based on the available literature, we recommend a kidney biopsy to guide treatment and determine prognosis and we also suggest an algorithm for kidney rebiopsy in lupus nephritis.info:eu-repo/semantics/publishedVersio

Severe Systemic Lupus Erythematosus presentation in patient with alternative complement pathway mutations

Systemic lupus erythematosus (SLE) is an autoimmune disease which can involve almost any organ, making its difficult therapeutic approach. Immune complex deposition can often activate complement, accounting for many of SLE clinical manifestations and laboratory findings. We present a case of a patient who presented with acute pancreatitis and acute kidney injury as onset manifestations of SLE, later developing neurological manifestations, who was successfully treated with rituximab, plasma exchange and steroids as induction therapy. Persistently low C3 level led to a genetic analysis of the complement system components. We found three polymorphisms in the alternative pathway of complement regulators (complement factor H c2669 G>T, p.Ser890Ile and c3019 G>T, p.Val1007Leu and complement factor I c.482+6 G>T), two of which have been correlated with atypical haemolytic uraemic syndrome and dense deposit disease and also complement factor H -related protein (CFHR1 and CFHR3) mutations by deletion. This raises the question whether these polymorphisms and mutations played any role in our patient’s clinical course.info:eu-repo/semantics/publishedVersio

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Perception of Vibrotactile Cues in Musical Performance

We suggest that studies on active touch psychophysics are needed to inform the design of haptic musical interfaces and better understand the relevance of haptic cues in musical performance. Following a review of the previous literature on vibrotactile perception in musical performance, two recent experiments are reported. The first experiment investigated how active finger-pressing forces affect vibration perception, finding significant effects of vibration type and force level on perceptual thresholds. Moreover, the measured thresholds were considerably lower than those reported in the literature, possibly due to the concurrent effect of large (unconstrained) finger contact areas, active pressing forces, and long-duration stimuli. The second experiment assessed the validity of these findings in a real musical context by studying the detection of vibrotactile cues at the keyboard of a grand and an upright piano. Sensitivity to key vibrations in fact not only was highest at the lower octaves and gradually decreased toward higher pitches; it was also significant for stimuli having spectral peaks of acceleration similar to those of the first experiment, i.e., below the standard sensitivity thresholds measured for sinusoidal vibrations under passive touch conditions

Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data

<p>Abstract</p> <p>Background</p> <p>We introduce Glaucoma Discovery Platform (GDP), an online environment for facile visualization and interrogation of complex transcription profiling datasets for glaucoma. We also report the availability of Datgan, the suite of scripts that was developed to construct GDP. This reusable software system complements existing repositories such as NCBI GEO or EBI ArrayExpress as it allows the construction of searchable databases to maximize understanding of user-selected transcription profiling datasets.</p> <p>Description</p> <p>Datgan scripts were used to construct both the underlying data tables and the web interface that form GDP. GDP is populated using data from a mouse model of glaucoma. The data was generated using the DBA/2J strain, a widely used mouse model of glaucoma. The DBA/2J-<it>Gpnmb⁺</it>strain provided a genetically matched control strain that does not develop glaucoma. We separately assessed both the retina and the optic nerve head, important tissues in glaucoma. We used hierarchical clustering to identify early molecular stages of glaucoma that could not be identified using morphological assessment of disease. GDP has two components. First, an interactive search and retrieve component provides the ability to assess gene(s) of interest in all identified stages of disease in both the retina and optic nerve head. The output is returned in graphical and tabular format with statistically significant differences highlighted for easy visual analysis. Second, a bulk download component allows lists of differentially expressed genes to be retrieved as a series of files compatible with Excel. To facilitate access to additional information available for genes of interest, GDP is linked to selected external resources including Mouse Genome Informatics and Online Medelian Inheritance in Man (OMIM).</p> <p>Conclusion</p> <p>Datgan-constructed databases allow user-friendly access to datasets that involve temporally ordered stages of disease or developmental stages. Datgan and GDP are available from <url>http://glaucomadb.jax.org/glaucoma</url>.</p

Paradoxes in carcinogenesis: New opportunities for research directions

<p>Abstract</p> <p>Background</p> <p>The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored.</p> <p>Discussion</p> <p>Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1) the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2) the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3) spontaneous regression, (4) higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5) lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6) cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7) the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8) the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena.</p> <p>Summary</p> <p>The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril.</p

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.info:eu-repo/semantics/publishedVersio

Selection of reliable biomarkers from PCR array analyses using relative distance computational model: Methodology and proof-of-concept study

10.1371/journal.pone.0083954PLoS ONE812-POLN