Light Chain Podocytopathy Mimicking Recurrent Focal Segmental Glomerulosclerosis.

Kidney injury related to paraproteinemia is common and typically occurs after the fourth decade of life in association with an underlying plasma cell dyscrasia or other lymphoproliferative disease. Kidney transplantation in paraprotein-related kidney disease can be successful in conjunction with treatment of the underlying hematopoietic process; however, when hematologic response to therapy is not achieved, recurrent kidney injury is frequently seen. We describe a young male patient who presented at the age of 23 years with end-stage kidney disease thought to be secondary to focal segmental glomerulosclerosis; this patient ultimately received two kidney allografts. He experienced recurrent proteinuria in both kidneys, with a biopsy from his second allograft showing kappa-restricted crystalline light chain podocytopathy, which was identified in both his native and first allograft kidneys upon retrospective review. Recurrent light chain podocytopathy has not been previously reported but poses a diagnostic challenge as it can mimic focal segmental glomerulosclerosis, particularly in young patients in whom paraprotein-related kidney injury is usually not suspected.

Hydroxymethylation as a Novel Environmental Biosensor.

Beyond the genome, epigenetics has become a promising approach in understanding the interactions between the gene and the environment. Epigenetic regulation includes DNA methylation, histone modifications, and non-coding RNAs. Among these, DNA methylation, which is the addition of a methyl group to the fifth base of cytosine to produce 5-methylcytosine (5-mC), is most commonly studied. Epigenetic regulation has changed given the discovery of 5-hydroxymethylcytosine (5-hmC), considered the "sixth base", and the nature of TET proteins to catalyze 5-mC oxidation to 5-hmC. 5-hydroxymethylation has been proposed to be a stable intermediate between methylation and demethylation and has raised questions about the functions of 5-hmC in gene regulation in cells, tissues, and organs in response to environmental exposure. Herein, we have provided an introduction to the chemistry of 5-hydroxymethylation, and the techniques for detection of 5-hydroxymethylation. In addition, we have reviewed current reports describing how 5-hmC responds to environmental factors, leading to the development of disease. And finally, we have discussed the potential use of 5-hmC in the study of disease development. All in all, it is our goal to provide innovative and convincing epigenetic studies for understanding the etiology of environmentally-related human disease, and translate these epigenetic findings into lifestyle recommendations and clinical practices to prevent and cure disease.

Cyclin D3 action in androgen receptor regulation and prostate cancer.

Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a ligand-dependent transcription factor. AR activation controls G1-S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa.

Impact of differential cyclin D1 expression and localisation in prostate cancer.

Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21Cip1. These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

Comparison of the biodistribution of free or liposome-entrapped Crotalus durissus terrificus (South American rattlesnake) venom in mice.

The local absorption rate, clearance and tissue distribution of Crotalus durissus terrificus venom, (Cdt) were examined using a two-antibody sandwich ELISA assay. We compared the biodistribution of both free or encapsulated Cdt in mice. Following subcutaneous injection of 10 microg/mouse of free Cdt (0.8 LD50), venom was detected in serum after 15 min, showed its highest level at 30 min (45+/-5 ng/ml) and was cleared from the circulation after 6 h. After 2 h of inoculation, venom was detected in the kidney (57+/-9 ng/g of tissue), spleen (18+/-4 ng/g of tissue) and brain (14+/-6 ng/g of tissue). For both subcutaneous or intravenous injection of free Cdt, venom was firstly detected in the kidney. No Cdt appeared either in the kidney, spleen, brain, or other tissues after subcutaneous inoculation of encapsulated venom even though a higher dose was used, 25 microg/mouse (2 LD50). Venom remained at the site of injection for a period of 1 week. Following intravenous injection of encapsulated venom (5 microg/mouse, 2 LD50), venom was detected in liver and spleen tissues. The biodistribution of encapsulated venom is discussed in relation to the effects of reduction of toxicity and increase of adjuvanticity.

Body distribution of Tityus serrulatus scorpion venom in mice and effects of scorpion antivenom.

In the present study we report the distribution of Tityus serrulatus scorpion venom in serum and various tissues of CFI mice and the efficacy of antivenom in reducing venom concentration. The animals were injected s.c. with 10 micrograms of scorpion venom, divided into groups of four animals and killed at different times from 15 min to 24 hr. Blood samples and samples of different tissues (heart, lung, liver, kidney, spleen, brain and injection site) were collected. Maximum venom levels occurred at 15 min in the kidney and liver and at 30 min in serum, lung, heart and spleen. After 2 hr the venom decreased rapidly in serum and in all other organs until venom levels were no longer detectable after 8 hr. No venom was detected in the central nervous system. In another experiment, 10 microliters of scorpion antivenom was injected i.v. together with the venom, and a rapid reduction of venom concentration was observed in the blood and tissues. In the third experiment, anti-scorpion venom was injected i.v. 1 hr after venom administration, and partial reduction of venom concentration was detected in tissues (lung and kidney). These studies contribute to the elaboration of more objective treatment that may result in a more economic, efficient and controlled use of scorpion antivenom in stings involving humans.

[Lupic nephropathy in childhood: morphologic analysis of 18 cases]. / Nefropatia lúpica na infância: estudo morfológico de 18 casos.

The present study describes 21 cases (17 females and 01 male) of 12 year old patients, or younger, with diagnosis of SLE, that were submitted to renal biopsy. The histologic study demonstrated 10 cases of membranoproliferative glomerulonephritis (Class IV-WHO); 4 cases of focal proliferative glomerulonephritis (Class III-WHO; 2 cases of mesangial proliferative glomerulonephritis (Class II-WHO) and 2 cases of membranous glomerulonephritis (Class V-WHO). Three cases were excluded. In this study the incidence of lupus nephritis in children was small, similar to what has been described by other authors, and presenting unfavorable histologic patterns.