Utility of ultrasonography for predicting indications for tolvaptan in patients with autosomal dominant polycystic kidney disease.

PURPOSE: Tolvaptan is the first approved treatment for autosomal dominant polycystic kidney disease (ADPKD) that targets a mechanism directly contributing to the development and growth of renal cysts. We investigated the ability of ultrasonography to predict total kidney volume (TKV) of 750 mL or more, which is an indication for tolvaptan therapy in patients with ADPKD. METHODS: A total of 46 patients with ADPKD were evaluated. The most statistically appropriate measurement based on ultrasonography for predicting TKV determined by computed tomography (CT) was assessed. RESULTS: TKV determined by CT was 796.8 (508.8-1,560.3) mL. The median length, anteroposterior distance, and mediolateral distance determined using ultrasonography were 15.7 cm, 7.6 cm, and 7.6 cm in the left kidney, and 13.4 cm, 6.9 cm, and 7.2 cm in the right kidney, respectively. Multivariate regression analysis showed that total kidney length (left and right) [variance inflation factor (VIF), 9.349] and total mediolateral distance (left and right) (VIF, 3.988) were independently associated with TKV. The correlation (r) between the logarithm of TKV determined by CT and total mediolateral distance determined using ultrasonography was 0.915 (p < 0.001). The linear regression equation was log (total kidney volume) = 1.833 + 0.075 × total mediolateral distance (left and right) based on ultrasonography. The area under the receiver operating characteristic curve for total mediolateral distance determined using ultrasonography to predict TKV of 750 mL or more was 0.989. Using the total mediolateral distance cut-off value of 14.2 cm, the sensitivity and specificity were 96.0% and 100.0%, respectively. CONCLUSION: Total mediolateral distance determined using ultrasonography can predict TKV in patients with ADPKD.

Overexpression of GSH1 gene mimics transcriptional response to low temperature during seed vernalization treatment of Arabidopsis.

Keeping imbibed seeds at low temperatures for a certain period, so-called seed vernalization (SV) treatment, promotes seed germination and subsequent flowering in various plants. Vernalization-promoting flowering requires GSH. However, we show here that increased GSH biosynthesis partially mimics SV treatment in Arabidopsis thaliana. SV treatment (keeping imbibed seeds at 4°C for 24 h) induced a specific pattern of gene expression and promoted subsequent flowering in WT A. thaliana. A similar pattern was observed at 22°C in transgenic (35S-GSH1) plants overexpressing the γ-glutamylcysteine synthetase gene GSH1, coding for an enzyme limiting GSH biosynthesis, under the control of the cauliflower mosaic virus 35S promoter. This pattern of gene expression was further strengthened at 4°C and indistinguishable from the WT pattern at 4°C. However, flowering in 35S-GSH1 plants was less responsive to SV treatment than in WT plants. There was a difference in the transcript behavior of the flowering repressor FLC between WT and 35S-GSH1 plants. Unlike other genes responsive to SV treatment, the SV-dependent decrease in FLC in WT plants was reversed in 35S-GSH1 plants. SV treatment increased the GSSG level in WT seeds while its level was high in 35S-GSH1 plants, even at a non-vernalizing temperature. Taking into consideration that low temperatures stimulate GSH biosynthesis and cause oxidative stress, GSSG is considered to trigger a low-temperature response, although enhanced GSH synthesis was not enough to completely mimic the SV treatment.

Fetuin A, a serum component, promotes growth and biofilm formation by Aspergillus fumigatus.

Aspergillus fumigatus is an all-important pathogenic fungus and is known for its angiotropism. When it invades human organs, A. fumigatus makes direct contact with blood and its components by causing inflammation and invading vascular structures. To learn the effect of its contact with blood on the development of infection, we examined the effect of serum on A. fumigatus growth. In Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, hyphal tip growth was accelerated, forming a thickened and well-networked biofilm associated with extracellular matrix, and fetuin A was identified as the active component in the serum that accelerates fungal growth leading to formation of a community. These results suggest that fetuin A is a novel accelerator of the growth of A. fumigatus and that it participates in the formation of thick biofilm.

[Strategy of Aspergillus fumigatus to evade attacks from host--projectile weapons and armor].

Humans are continually inhaling environmental fungi. When the host immune system is competent, the inhaled fungi are cleared away from the lung by host defense mechanisms. But in immunocompromised individuals, the environmental fungi (e.g., Aspergillus fumigatus) sometimes cause infection. Pathogenic fungi possess various mechanisms to invade the host. A. fumigatus is no exception in possessing several virulence factors and defense mechanisms against host immune attack.One of the virulence factors is secondary metabolite. A. fumigatus produces a variety of secondary metabolites, and the fungal products in culture supernatant have a strong apoptosis-inducing activity to macrophages and alveolar epithelial cells. These data suggest that A. fumigatus is equipped with special projectile weapons for destroying host physical barriers and immunological barriers in lung.The fungal cell wall is an easy target for the host to recognize the pathogen. One of the fungal cell wall components, beta- (1,3) -glucan, is a major fungal PAMP (pathogen-associated molecular pattern), which is recognized by one of the pattern recognition receptors, dectin-1. The interaction induces activation of transcription factors and production of proinflammatory cytokines in the host cell. However, beta-glucan of A. fumigatus is strongly exposed to the surface only during the "swollen-conidia" phase. In the hyphal phase, the fungus is covered with "armor", i.e., other cell wall components to minimize the exposure of the beta-glucan structure. These findings suggest that A. fumigatus evades the recognition and the attack from host by masking beta-glucan. A. fumigatus has clever mechanisms to defend itself and to attack the host immune system.

Level of glutathione is regulated by ATP-dependent ligation of glutamate and cysteine through photosynthesis in Arabidopsis thaliana: mechanism of strong interaction of light intensity with flowering.

Glutathione (GSH) is associated with flowering in Arabidopsis thaliana, but how GSH biosynthesis is regulated to control the transition to flowering remains to be elucidated. Since the key reaction of GSH synthesis is catalyzed by gamma-glutamylcysteine synthetase (gamma-ECS) and all the gamma-ECS cDNAs examined contained extra sequences for plastid targeting, we investigated the relationships among GSH levels, photosynthesis and flowering. The GSH level in Arabidopsis increased with the light intensity. The ch1 mutants defective in a light-harvesting antenna in photosystem II showed reduced GSH levels with accumulation of the GSH precursor cysteine, and introduction of the gamma-ECS gene GSH1 under the control of the cauliflower mosaic virus 35S promoter (35S-GSH1) into the ch1 mutant altered the GSH level in response to the gamma-ECS mRNA level. These indicate that photosynthesis limits the gamma-ECS reaction to regulate GSH biosynthesis. Like the glutathione-biosynthesis-defective cad2-1 mutant, the ch1 mutants flowered late under weak-light conditions, and this late-flowering phenotype was rescued by supplementation of GSH. Introduction of the 35S-GSH1 construct into the ch1 mutant altered flowering in response to the gamma-ECS mRNA and GSH levels. These findings indicate that flowering in A. thaliana is regulated by the gamma-ECS reaction of GSH synthesis that is coupled with photosynthesis.