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Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20–50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment.

BackgroundAmygdala is considered as the core pathogenesis of generalized social anxiety disorder (GSAD). However, it is still unclear whether effective group cognitive behavioral therapy (CBT) could modulate the function of amygdala-related network. We aimed to examine the resting-state functional connectivity (rsFC) of the amygdala before and after group CBT.MethodsFifteen patients with GSAD were scanned on a 3T MR system before and after 8 weeks of group CBT. For comparison, nineteen healthy control participants also underwent baseline fMRI scanning. We used bilateral amygdala as seed regions and the rsFC maps of the right and left amygdala were created separately in a voxel-wise way. Clusters survived two-tailed Gaussian Random Field (GRF) correction at p <0.05 (voxel z value >2.3).ResultsCompared with baseline, patients with CBT showed significantly decreased connectivity of the left amygdala with the right putamen, the left dorsal medial prefrontal cortex (dmPFC) and the right dorsal anterior cingulate cortex (dACC). Especially, the changes of the connectivity between the left amygdala and the dACC positively correlated with changes of the anxiety symptom in patients. Furthermore, in relative to controls, patients showed higher connectivity of left amygdala with dmPFC and dACC at baseline, while normal after CBT.ConclusionsShort-term group CBT could down-regulate the abnormal higher connectivity of prefrontal-amygdala network, along with clinical improvement. This may provide a potential biomarker to monitor the treatment effect of CBT in GSAD patients.

Type I collagen (Col I) is a main component of extracellular matrix (ECM). Its safety, biocompatibility, hydrophilicity and pyrogen immunogenicity make it suitable for tissues engineering applications. Mg2+ also control a myriad of cellular processes, including the bone development by enhancing the attachment and differentiation of osteoblasts and accelerating mineralization to enhance bone healing. In our studies, Mg2+ bind collagen to promote the proliferation and differentiation of osteoblasts through the expression of integrins and downstream signaling pathways. In order to clarify the biological behavior effect of 10 mM Mg2+/Col I coating, we performed 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), alkaline phosphatase (ALP), 4′6-diamidino-2-phenylindole (DAPI), Alizarin red staining and Rhodamine B-isothiocyanate (RITC)-labeled phalloidin experiments and found that 10 mM Mg2+ group, Col I-coating group, 10 mM Mg2+/Col I-coating group, respectively, promoted the proliferation and differentiation of osteoblasts, especially 10 mM Mg2+/Col I-coating group. We detected the mRNA expression of osteogenic-related genes (Runx2, ALP and OCN, OPN and BMP-2) and the protein expression of signaling pathway (integrin α2, integrin β1, FAK and ERK1/2), these results indicated that 10 mM Mg2+/Col I coating play an critical role in up-regulating the MC3T3-E1 cells activity. The potential mechanisms of this specific performance may be through activating via integrin α2β1-FAK-ERK1/2 protein-coupled receptor pathway.

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BackgroundStudies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160.MethodsWe identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model.ResultsWe identified two compound-heterozygous NUP160 mutations, NUP160R1173× and NUP160E803K. We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160R1173× completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160E803K rescued only nuclear pore complex and nuclear lamin localization defects.ConclusionsMutations in NUP160 are implicated in SRNS. Our findings indicate that NUP160 should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause SRNS.

The aim of this study was to explore white-matter disruption in social anxiety disorder (SAD) patients by using diffusion tensor imaging (DTI) and to investigate the relationship between cerebral abnormalities and the severity of the symptoms. Eighteen SAD patients and age- and gender-matched healthy controls were recruited. DTI scans were performed to measure fractional anisotropy (FA) and apparent diffusion coefficient (ADC) for each subject. We used voxel-based analysis to determine the differences of FA and ADC values between the two groups with two-sample t-tests. The SAD patient showed significantly decreased FA values in the white matter of the left insula, left inferior frontal gyrus, left middle temporal gyrus, and left inferior parietal gyrus and increased ADC values in the left insula, bilateral inferior frontal gyrus, bilateral middle temporal gyrus, and left inferior parietal gyrus. In SAD patients, we observed a significant negative correlation between FA values in the left insula and the total LSAS scores and a positive correlation between the ADC values in the left inferior frontal gyrus and the total LSAS scores. Above results suggested that white-matter microstructural changes might contribute to the neuropathology of SAD.

In the long-wavelength limit, a periodic array of bottom-mounted vertical cylinders may be used as a homogeneous medium for liquid surface waves and their effective parameters, such as their refractive index, depending on the filling fraction of the cylinders. Based on this effective medium theory, a gradient index (GRIN) lens for the focusing of liquid surface waves has been designed and fabricated here through the gradual modification of the cylinder filling fraction along a direction perpendicular to the lens axis. Their focusing performance and the transmission properties for liquid surface waves are then studied both experimentally and numerically. Both the wave patterns and spatial intensities obtained by experiment and numerical calculation demonstrate that the GRIN lens is able to focus planar liquid surface waves within a certain frequency region.