RIFLE classification in geriatric patients with acute kidney injury in the intensive care unit

Background

The RIFLE classification is widely used to assess the severity of acute kidney injury (AKI), but its application to geriatric AKI patients complicated by medical problems has not been reported.

Methods

We investigated 256 geriatric patients (≥65 years old; mean age, 74.4 ± 6.3 years) who developed AKI in the intensive care unit (ICU) according to the RIFLE classification. Etiologic, clinical, and prognostic variables were analyzed.

Results

They were categorized into RIFLE-R (n = 53), RIFLE-I (n = 102), and RIFLE-F (n = 101) groups. The overall in-hospital mortality was 39.8 %. There were no significant differences in RIFLE category between survivors and non-survivors. Survivors had significantly less needs for a ventilator and vasopressor, and lower number of failing organs. Survivors had higher systolic blood pressure, hemoglobin level, and serum albumin levels. We performed a logistic regression analysis to identify the independent predictors of in-hospital mortality. In a univariate analysis, hypertension, chronic kidney disease, RIFLE classification, number of failing organs, need for a ventilator and vasopressor, systolic blood pressure, hemoglobin level, and serum albumin levels were identified as prognostic factors of in-hospital mortality. However, in a multivariate analysis, hypertension, chronic kidney disease, number of failing organs, and serum albumin levels were independent risk factors, with no significant difference for in-hospital mortality with the RIFLE classification.

Conclusion

The RIFLE classification might not be associated with mortality in geriatric AKI patients in the ICU. In geriatric patients with AKI, various factors besides severity of AKI should be considered to predict mortality.

     

Involvement of Na+-Ca2+ exchanger on metabotropic glutamate receptor 1-mediated [Ca2+]i transients in rat cerebellar Purkinje neurons

Cerebellar Purkinje neurons have intracellular regulatory systems including Ca2+-binding proteins, intracellular Ca2+ stores, Ca2+-ATPase and Na+-Ca2+ exchanger (NCX) that keep intracellular Ca2+ concentration ([Ca2+]i) in physiological range. Among these, NCX interacts with AMPA receptors, activation of which induces cerebellar synaptic plasticity. And the activation of metabotropic glutamate receptor 1 (mGluR1) is also involved in the induction of cerebellar long-term depression. The interaction of NCX with mGluR1 is not known yet. Thus, in this study, the functional relationship between NCX and mGluR1 in modulating the [Ca2+]i in rat Purkinje neurons was investigated. The interaction between NCX and mGluR1 in Purkinje neurons was studied by measuring intracellular Ca2+ transients induced by an agonist of group I mGluRs, 3,5-dihydroxyphenylglycine (DHPG). The DHPG-induced Ca2+ transient was significantly reduced by treatments of NCX inhibitors, bepridil and KB-R7943. When cells were pretreated with antisense oligodeoxynucleotides of NCX, the DHPG-induced Ca2+ transient was also inhibited. These results suggest that NCX modulates the activity of mGluR1 in cerebellar Purkinje neurons. Therefore, NCX appears to play an important role in the physiological function of cerebellar Purkinje neurons such as synaptic plasticity.     

Activation of non-canonical NF-kappaB pathway mediated by STP-A11, an oncoprotein of Herpesvirus saimiri

Although Saimiri Transforming Protein (STP)-A11, an oncoprotein of Herpesvirus saimiri, has been known to activate NF-kappaB signaling pathway, the detailed mechanism has not been reported yet. We herein report that STP-A11 activates non-canonical NF-kappaB pathway, resulting in p100 processing to p52. In addition, translocation of p52 protein (NF-kappaB2) into the nucleus is observed by the expression of STP-A11. STP-A11-mediated processing of p100 to p52 protein requires proteosome-mediated proteolysis because MG132 treatment clearly blocked p52 production in spite of the expression of STP-A11. Analysis of STP-A11 mutants to activate NF-kappaB2 pathway discloses the requirement of TRAF6-binding site not Src-binding site for STP-A11-mediated NF-kappaB2 pathway. Blockage of STP-A11-mediated p52 production using siRNA against p52 enhanced a chemotherapeutic drug-mediated cell death, suggesting that p52 production induced by the expression of STP-A11 would contribute to cellular transformation, which results from a resistance to cell death.     

血管内皮生长因子与运动的相关性

目的:血管内皮生长因子是一种广泛存在于机体组织的细胞因子,与运动密切相关,是近来运动人体科学界和运动医学界研究的焦点。对近来血管内皮生长因子与运动的相关研究进行综述,以能够找到提高训练质量乃至运动水平的方法。资料来源:应用计算机检索Medscape.net1996-01/2006-12的相关文章,并根据相关的参考文献检索了部分文章,检索词“vascular endothelial growth factor,exercise”,限定语言种类为English;同时计算机检索中国知识资源总库1996-01/2006-12的相关文献,限定语言种类为中文,检索词“血管内皮生长因子,运动”。资料选择:纳入条件:①随机对照试验研究。②试验包括对照组和干预组。同时排除综述和重复的研究。资料提炼:共找到相关研究47篇,排除17篇,30篇符合标准。通过30个实验对运动中血管内皮生长因子在机体中的表达、作用及含量和动态变化进行了相关的分析和研究。资料综合:①血管内皮生长因子与运动的关系密切相关,现在仍然是运动医学界的研究焦点之一,研究的方向为运动对机体血管内皮生长因子的影响,目的是发现运动对机体的影响。②不同的运动方式对机体的血管内皮生长因子的表达不同,目前采用的训练方式多为极限运动或运动与其他因素相结合,如低压强 运动。③观察部位多集中在大脑、肌肉、心血管、血液等,不同部位的表达不同。④运动对血管内皮生长因子表达有动态变化的规律。结论:血管内皮生长因子与运动的关系密切相关,不同的运动方式会造成血管内皮生长因子在机体不同部位不同表达。运动对血管内皮生长因子表达的影响呈现出规律性。     

Comparative Efficacy and Bioequivalence of Novel H1-Antihistamine Bepotastine Salts (Nicotinate and Salicylate)

Bepotastine salts (nicotinate and salicylate) were investigated for their physicochemical properties to develop novel salt forms of bepotastine, bioequivalent to the bepotastine besilate-loaded tablet (Talion). These bepotastine salts of either nicotinate- or salicylate-loaded tablets were prepared by conventional wet granulation method, and dissolution profiles and pharmacokinetics in beagle dogs were compared to those of Talion. A novel bepotastine nicotinate has a higher solubility at varying pH levels (1.2, 4, or 6.8) than salicylate-loaded or besilate-loaded salt. In addition, those bepostastine salt forms (nicotinate and salicylate) are stable in heat, light, and water. Further, the novel nicotinate- and salicylate-loaded tablets showed similar dissolution rates to Talion in several selected dissolution media and were bioequivalent to Talion in beagle dogs in terms of area under the concentration–time curve (AUC) and maximum observed concentration (C_max). A pharmacokinetic study performed in beagle dogs demonstrated that test and reference products were found to be bioequivalent in terms of safety, efficacy, and pharmacokinetic properties. These results suggest that bepostastine nicotinate and salicylate formulations are considered applicable candidates and are well tolerated versus the conventional bepostastine besilate formulation.     

Impact of positive surgical margins and their locations after radical prostatectomy: comparison of biochemical recurrence according to risk stratification and surgical modality

Purpose

We investigated the influence of positive surgical margins (PSMs) and their locations on biochemical recurrence (BCR) according to risk stratification and surgical modality.

Methods

A total of 1,874 post-radical-prostatectomy (RP) patients of pT2–T3a between 2000 and 2010 at three tertiary centers, and who did not receive neoadjuvant/adjuvant therapy, were included in this study. Patients were stratified according to BCR risk: low risk (PSA <10, pT2a-b, and pGS ≤6), intermediate risk (PSA 10–20 and/or pT2c and/or pGS 7), and high risk (PSA >20 or pT3a or pGS 8–10). The median follow-up was 43 months.

Results

PSMs were a significant predictor of BCR in both the intermediate- and high-risk-disease groups (P = .001, HR 2.1, 95 % CI 1.3–3.4; P < .001, HR 2.8, 95 % CI 2.0–4.1). Positive apical margin was a significant risk factor for BCR in high-risk disease (P = .003, HR 2.0, 95 % CI 1.2–3.3), but not in intermediate-risk disease (P = .06, HR 1.7, 95 % CI 0.9–3.1). Positive bladder neck margin was a significant risk factor for BCR in both intermediate- and high-risk disease (P < .001, HR 5.4, 95 % CI 2.1–13.8; P = .001, HR 4.5, 95 % CI 1.8–11.4). In subgroup analyses, robotic RP provided comparable BCR-free survival regardless of risk stratification. Patients with PSMs showed similar BCR-free survival between open and robotic RP (log-rank, P = .897).

Conclusions

Post-RP PSMs were a significantly independent predictor of disease progression in high-risk disease as well as intermediate-risk disease. Both positive apical and bladder neck margins are also significant risk factors of BCR in high-risk disease. Patients with PSMs showed similar BCR-free survival between open and robotic surgery.     

Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney

Na⁺/H⁺ exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3^−/−) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3^−/− mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.Assembly of protein complexes by adaptor proteins with PSD-95/discs large/ZO-1 (PDZ) domains plays an important role in the regulation of many membrane proteins, especially in epithelial and neuronal tissues.^1,2 For example, PDZ-based adapter proteins in epithelia, such as Shank2, synaptic scaffolding molecule (S-SCAM), and Na⁺/H⁺ exchanger regulatory factors (NHERFs), are known to be involved in the regulation of cell surface expression and the activity of many membrane transporters and receptors in the respiratory, digestive, urinary, and reproductive organs.^3–6 The four members of the NHERF proteins (NHERF1 to 4) contain either two or four PDZ domains and were the first family of PDZ-containing proteins shown to be involved in epithelial transport. NHERF3, also known as PDZK1 or CAP70, has four PDZ domains and is normally localized to the apical microdomains of gastrointestinal and kidney epithelia. Each PDZ domain of NHERF3 has been proposed to bind independently to the PDZ binding motif of various membrane proteins, such as the cystic fibrosis transmembrane conductance regulator (CFTR), the Na⁺/H⁺ exchanger 3, the urate transporter, and the organic anion transporter 4.^7–10 However, Nherf3 knockout (Nherf3^−/−) mice do not have a discernible phenotype except mild hypercholesterolemia,¹¹ and, consequently, the in vivo role of NHERF3 in transepithelial transport remains poorly understood.Transporters belonging to either the ATP binding cassette (ABC) or the solute-linked carrier superfamilies of membrane proteins play diverse roles in the pharmacokinetic and pharmacodynamic pathways of drugs and their metabolites.¹² Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the C subfamily of ABC transporters and mediates the efflux of a group of organic molecules using energy generated from the binding and hydrolysis of ATP.¹³ Cumulative evidence suggests that MRP4 pumps out purine compounds and plays an important role in the renal elimination of purine-based antiviral and antineoplastic agents.^14,15 However, the regulatory mechanisms for MRP4 expression and function have not been extensively studied.The COOH terminus of MRP4 contains a class 1 PDZ interaction motif (-S/T-X-Ф, where Ф is a hydrophobic amino acid),¹⁶ indicating that MRP4 may interact with PDZ-based adaptors in epithelia. In preliminary studies using a yeast two-hybrid assay, MRP4 was found to strongly interact with NHERF3 among several PDZ adaptor proteins expressed in epithelial tissues. The aim of the present study was to identify the physiologic and pharmacologic roles of the interaction of NHERF3 with MRP4 using a variety of in vitro and in vivo experimental approaches. The results obtained provide strong evidence that NHERF3 is a key regulator of organic transport in the kidney, particularly the MRP4-mediated clearance of purine-based drug molecules.     

Static Langer's line and wound contraction rates according to anatomical regions in a porcine model

This study investigated wound contraction rates according to anatomical regions and wound morphology according to skin tension line in a micropig porcine model. Of the four animals used, skin tension morphology was determined in one pig. In the remaining three pigs, six pairs of full‐thickness skin excisions were created on the dorsum (six square and six circular). The wounds were grouped, Wounds #1 through #5, according to the skin tension line and anatomical regions: Wounds #1 and #2, cephalic; Wounds #4 and #5, caudal; and Wound #3, center. Wound sizes and contraction rates were calculated for 28 days. A static tension topography of the micropig dorsum was obtained. Excisional wounds deformed along the local tension vector and healed in this fashion. Wound contraction rates were significantly higher for cephalic wounds (p = 0.004). No significant difference in wound contraction rates were observed between square and circular wounds. Final wound morphology was related to the local tension vector and initial wound shape. Cephalic wounds contracted more quickly. Further studies are needed to characterize scar formation after primarily closed surgical wounds in relation to the newly established skin tension topography and to elucidate the mechanism behind the variable wound contraction rates in the cephalocaudal gradient.