Computer-directed rational design enhanced the thermostability of carbonyl reductase LsCR for the synthesis of ticagrelor precursor.

Carbonyl reductases are useful for producing optically active alcohols from their corresponding prochiral ketones. Herein, we applied a computer-assisted strategy to increase the thermostability of a previously constructed carbonyl reductase, LsCRM4 (N101D/A117G/F147L/E145A), which showed an outstanding activity in the synthesis of the ticagrelor precursor (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol. The stability changes introduced by mutations at the flexible sites were predicted using the computational tools FoldX, I-Mutant 3.0, and DeepDDG, which demonstrated that 12 virtually screened mutants could be thermally stable; 11 of these mutants exhibited increased thermostability. Then a superior mutant LsCRM4-V99L/D150F was screened out from the library that was constructed by iteratively combining the beneficial sites, which showed a 78% increase in activity and a 17.4°C increase in melting temperature compared to LsCRM4. Our computer-assisted design and combinatorial strategy dramatically increased the efficiency of thermostable enzyme production.

Development of a new chemo-enzymatic catalytic route for synthesis of (S)- 2-chlorophenylglycine.

(S)-2-chlorophenylglycine ((S)-CPG) is a key chiral intermediate for the synthesis of clopidogrel. Herein, a novel, efficient and environmentally friendly chemo-enzymatic route for the preparation of optically pure (S)-CPG was developed. A straightforward chemical synthesis of the corresponding prochiral keto acid substrate (2-chlorophenyl)glyoxylic acid (CPGA) was developed with 91.7% yield, which was enantioselectively aminated by leucine dehydrogenase (LeuDH) to (S)-CPG. Moreover, protein engineering of LeuDH was performed via directed evolution and semi-rational design. A beneficial variant EsLeuDH-F362L with enlarged substrate-binding pocket and increased hydrogen bond between K77 and substrate CPGA was constructed, which exhibited 2.1-fold enhanced specific activity but decreased thermal stability. Coupled with a glucose dehydrogenase from Bacillus megaterium (BmGDH) for NADH regeneration, EsLeuDH-F362L completely converted up to 0.5 M CPGA to (S)-CPG in 8 h at 40 °C.

[Effect of Fu's subcutaneous needling on thickness and elasticity of affected muscles in shoulder neck pain based on ultrasonic elastography].

OBJECTIVE: To observe the effect of Fu's subcutaneous needling on thickness and elasticity of affected muscles in subjects with shoulder neck pain by ultrasonic elastography. METHODS: A total of 30 subjects with upper trapezius pain and local tenderness, or stiffness and funicular nodules were observed randomly, right shoulders were as observation group and left shoulders were as control group. Simple resistance training was adopted in the control group. At the same time of the resistance training, sweeping technique of Fu's subcutaneous needling was adopted at the local tenderness or the stiffness and funicular nodules of upper trapezius in the observation group. The treatment was given once in both groups. Before and immediately after treatment, thickness and elasticity of bilateral upper trapezius and supraspinatus were observed by ultrasonic elastography, and the variations of visual analogue scale (VAS) score were observed in the two groups. RESULTS: Compared before treatment, the elasticity of upper trapezius and supraspinatus were decreased after treatment in both groups (P<0.05), and those in the observation group were lower than the control group (P<0.05). Compared before treatment, the VAS scores after treatment were decreased in both groups (P<0.05), and that in the observation group was lower than the control group (P<0.05). CONCLUSION: Fu's subcutaneous needling can increase the elasticity and release the muscular tension of affected muscles, and relieve pain in subjects with shoulder neck pain.

Postinfectious inflammatory response syndrome in HIV-uninfected and nontransplant men after cryptococcal meningitis.

Aim: The aim of our study was to describe the characteristics of postinfectious inflammatory response syndrome (PIIRS) in HIV-uninfected and nontransplant men after cryptococcal meningitis (CM). Patients & methods: A case-control study was designed to compare HIV-uninfected and nontransplant male CM patients with and without PIIRS. Results: CM-PIIRS patients had increased rates of hearing loss, V-P shunt placement, amphotericin B treatment, higher cerebrospinal fluid pressures and Cryptococcus counts in the first CM episode. CM-PIIRS episode was characterized by higher frequencies of headache and fever, higher C-reactive protein, erythrocyte sedimentation rate, cerebrospinal fluid white blood cell (WBC) counts and modified Rankin Score. Brain MRI scans revealed the high signal lesions on axial flair imaging. Receipt of corticosteroid therapy was associated with lower rates of fever and better modified Rankin Score scores at 1 month after treatment. Conclusion: CM-PIIRS episode differs to the initial presentation, may help to identify which patients are at risk to develop PIIRS. Steroids therapy could be beneficial.

Ultrasonographic diagnosis of early unruptured tubal pregnancy in a community hospital.

OBJECTIVE: To investigate ultrasonographic characteristics and diagnostic approaches of unruptured tubal pregnancy (UTP). METHODS: One hundred forty-six cases of early tubal pregnancy, which were confirmed surgically, were analyzed. RESULTS: Among 146 cases of UTP, 130 were diagnosed by ultrasonography. Furthermore, 16 cases of UTP were missed by ultrasonography. A total of 130 patients had a mass detected by ultrasonography, among whom the mass and ipsilateral ovary were distinguishable in 102. The embryo sac type was found in 40.00% (52/130), while the heterogeneous mass type was found in 60.00% (78/130) of patients. The maximum length and diameter of the ectopic pregnancy mass ranged from 10 to 68 mm (mean size, 26.42 ± 11.39 mm). No blood flow was observed in or around the mass in 67.69% (88/130) of patients. Lateral tubal thickening of the mass was found in 47.69% (62/130) of patients. Endometrial thickness was ≤10 mm in 67.80% (99/146) of patients. The intima was mostly hyperechoic in 72.60% (106/146) of patients. CONCLUSION: A paraovarian mass, thickened fallopian tube, uterine endometrium with a thickness of ≤10 mm, and high echo are important indicators of early UTP. Ultrasound examinations should focus on these indicators to help improve detection of early tubal pregnancy.

Histological subtype remains a prognostic factor for survival in nasopharyngeal carcinoma patients.

OBJECTIVES: There is currently no consensus on the prognostic significance of the histological subtype of nasopharyngeal carcinoma (NPC). The aim of the current study was to evaluate the impact of histological subtype on survival in NPC patients based on the Surveillance, Epidemiology, and End Results (SEER) Program. METHODS: Patients with NPC were identified within the SEER database (2004-2015). The effects of histological subtype on cause-specific survival (CSS) in NPC patients were evaluated using univariate and multivariate Cox regression analyses. Subgroup analysis according to histological subtype in NPC patients was carried out by 1:1 propensity score matching (PSM). RESULTS: A total of 4085 NPC patients were selected from the SEER database, including 1929 with keratinizing squamous cell carcinoma (KSCC), 2203 with nonkeratinizing carcinoma (NKC), and 53 with basaloid squamous cell carcinoma (BSCC). The 3-year and 5-year CSS rates were 61.76% and 55.07% for KSCC patients, 79.57% and 72.09% for NKC patients, and 77.55% and 74.03% for BSCC patients, respectively. Multivariate analysis identified sex, age, marital status, race, T stage, N stage, M stage, radiotherapy, chemotherapy, and histological subtype as significant prognostic factors for CSS in NPC patients. KSCC was found to be associated with worse CSS than NKC on Kaplan-Meier analysis and subgroup analysis after 1:1 PSM. CONCLUSIONS: Histological subtype determines the long-term survival outcomes of patients with NPC. Moreover, the NKC subtype has the best prognosis, while the KSCC subtype has the worst prognosis. LEVEL OF EVIDENCE: NA Laryngoscope, 130:E83-E88, 2020.

Effect of 's subcutaneous needling on thickness and elasticity of affected muscles in shoulder neck pain based on ultrasonic elastography / 中国针灸

OBJECTIVE@#To observe the effect of 's subcutaneous needling on thickness and elasticity of affected muscles in subjects with shoulder neck pain by ultrasonic elastography.@*METHODS@#A total of 30 subjects with upper trapezius pain and local tenderness, or stiffness and funicular nodules were observed randomly, right shoulders were as observation group and left shoulders were as control group. Simple resistance training was adopted in the control group. At the same time of the resistance training, sweeping technique of 's subcutaneous needling was adopted at the local tenderness or the stiffness and funicular nodules of upper trapezius in the observation group. The treatment was given once in both groups. Before and immediately after treatment, thickness and elasticity of bilateral upper trapezius and supraspinatus were observed by ultrasonic elastography, and the variations of visual analogue scale (VAS) score were observed in the two groups.@*RESULTS@#Compared before treatment, the elasticity of upper trapezius and supraspinatus were decreased after treatment in both groups (<0.05), and those in the observation group were lower than the control group (<0.05). Compared before treatment, the VAS scores after treatment were decreased in both groups (<0.05), and that in the observation group was lower than the control group (<0.05).@*CONCLUSION@#'s subcutaneous needling can increase the elasticity and release the muscular tension of affected muscles, and relieve pain in subjects with shoulder neck pain.

Estimating the subgroup and testing for treatment effect in a post-hoc analysis of a clinical trial with a biomarker.

We consider the problem of estimating a biomarker-based subgroup and testing for treatment effect in the overall population and in the subgroup after the trial. We define the best subgroup as the subgroup that maximizes the power for comparing the experimental treatment with the control. In the case of continuous outcome and a single biomarker, both a non-parametric method of estimating the subgroup and a method based on fitting a linear model with treatment by biomarker interaction to the data perform well. Several procedures for testing for treatment effect in all and in the subgroup are discussed. Cross-validation with two cohorts is used to estimate the biomarker cut-off to determine the best subgroup and to test for treatment effect. An approach that combines the tests in all patients and in the subgroup using Hochberg's method is recommended. This test performs well in the case when there is a subgroup with sizable treatment effect and in the case when the treatment is beneficial to everyone.

A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer.

Background Antibody drug conjugates (ADC) offer the potential of maximizing efficacy while minimizing systemic toxicity. ASG-5ME, an SLC44A4-targeting antibody carrying monomethyl auristatin E (MMAE), a microtubule-disrupting agent, was investigated in men with metastatic castration resistant prostate cancer. Methods The primary objective of this phase I study was to determine maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives were safety, antitumor activity, pharmacokinetic properties, immunogenicity, and the detection of SLC44A4 on circulating tumor cells. Patients (pts) were treated among 7 dose levels every 21 days. A dose expansion phase enrolled 20 additional pts. at the MTD. Results Twenty-six and 20 pts. were treated in dose escalation and dose expansion cohorts respectively. The MTD was 2.7 mg/kg. Dose-limiting toxicities occurred in 4 pts.: grade 3 fatigue (n = 1); grade 3 abdominal pain, diarrhea and fatigue (n = 1); grade 4 neutropenia and hyponatremia and grade 3 maculopapular rash, constipation and hypoxia (n = 1); grade 3 troponin elevation without cardiac sequelae (n = 1). Fatigue and diarrhea were the most prevalent adverse events (AEs) across all cycles. Two grade 5 AEs occurred in the dose expansion cohort, each after 1 dose: 1 pt. developed grade 3 hyperglycemia, renal insufficiency and leukopenia; 1 pt. developed grade 3 hyperglycemia complicated by bacteremia. Free MMAE levels did not accumulate with repeat dosing. Of evaluable pts., 52% had either stable disease or a partial response. Conclusions Further development of ASG-5ME is not being pursued due to its narrow therapeutic index. Some toxicities were potentially related to on-target effects on normal tissue expressing the SLC44A4 protein. However, other toxicities were consistent with studies of previous MMAE-containing ADCs. Unconjugated MMAE is a less likely etiology based on prior data.

Features of Gait Festination for Patients with Parkinson's Disease: A Three-Dimensional Gait Analysis / 中国康复理论与实践

Objective:To investigate the characteristics of gait festination in patients with Parkinson's disease. Methods:From January, 2016 to January, 2018, 20 Parkinson's disease patients with festination (festination group), other 20 Parkinson's disease patients without festination (non-festination group) (all in ON stage) and 20 healthy controls were tested BTS Motion Capture System and analyzed with SmartAnalyzer. Results:The stride time, swing time of left side and maximum ankle dorsiflexion angle of left side decreased in the festination group compared with those in the non-festination group, while the first peak of ankle appeared earlier (P < 0.05). The stance phase increased in the festination group compared with those in the controls (P < 0.05), while the swing phase, stride length, step length and velocity decreased, as well as the maximum ankle plantar flexion (P < 0.05), and the first peak of ankle appeared earlier (P < 0.05). Conclusion:Festination is characterized as less step length, faster step cadence and slower velocity. The first peak of ankle appeared earlier for the center of mass moving foreward. The maximum plantar flexion angle of the ankle reduces for the poor balance function.

Downregulation of microRNA-21 inhibited radiation-resistance of esophageal squamous cell carcinoma.

BACKGROUND: MicroRNA-21 (miR-21) was previously reported being dysregulated in many kinds of cancer including esophageal squamous cell carcinoma (ESCC). In the present study, we aimed to investigate the role of miR-21 in ESCC, especially in its effects on radiation-sensitivity of ESCC. METHODS: Expression of miR-21 was detected in 63 pairs ESCC tumor and adjacent non-tumoral tissues using qRT-PCR, correlation between miR-21 and clinicopathological feature of ESCC was analyzed. The role of miR-21 in the proliferation, cell cycle and apoptosis of ESCC cells during irradiation were studied. RESULTS: MicroRNA-21 expression was significantly increased in ESCC tumor tissues. Expression of miR-21 was positively associated with advanced clinical stage. Under irradiation, overexpression of miR-21 increased cell proliferation and cells in S phase, and inhibited cell apoptosis of ESCC cells. In contrast, knockdown of miR-21 had an opposite effect. CONCLUSIONS: Downregulation of miR-21 inhibited the radiation-resistance of ESCC, whereas overexpression of miR-21 increased the radiation-resistance. MiR-21 is a potential novel target for developing specific treatment interventions in ESCC in future.

Anxiety, happiness and self-esteem of western Chinese left-behind children.

China's unprecedented economic boom has led a massive number of children left-behind by their peasant parents who have immigrated to urban areas in search of work. In current study, we explored how being left behind is associated with children's positive emotions and negative psychological traits by examining the differences in levels of happiness, self-esteem and anxiety between left-behind children (LBC) and non-LBC. A total of 448 students (aged 7-16) from three schools in Sichuan Province in China responded to the questionnaire. Fourteen teachers of LBC were invited to one-to-one interviews for in depth responses to LBC's behaviors and psychological well-being. The results revealed that non-LBC showed a higher level of happiness (t=-0.21, df=258, p<0.01) and a lower level of anxiety (t=1.41, df=406, p<0.05) than LBC children. Among LBC, low grade children (primary school grades 3 and 4) reported a lower level of happiness (t=-0.73, df=216, p<0.01) and self-esteem (t=-0.24, df=191, p<0.01) than their older counterparts (primary school grades 5 and 6). The teachers' accounts confirmed the statistical results that LBC suffered from the deprivation of parental care. According to the teachers, as LBC grew older, they developed an understanding of their own circumstances and came to appreciate their parents' decisions. With appropriate and adequate support provided to both LBC and the caretakers around them such as relatives and teachers, it may be possible to reduce the adverse impacts of parental deprivation on LBC.

Safety and efficacy of nimotuzumab combined with chemoradiotherapy in Chinese patients with locally advanced cervical cancer.

OBJECTIVE: To evaluate efficacy and safety of nimotuzumab combined with chemotherapy and radiotherapy in women with locally advanced cervical cancer. MATERIALS AND METHODS: Women with locally advanced cervical cancer (stage IIB, III, or IVA) who experienced relapse after first-line chemoradiotherapy and one or more lines of palliative chemotherapy were enrolled. All patients received nimotuzumab weekly at 200 mg/m2 as single agent for 4 weeks (induction phase), then concurrent with 6 cycles (21-day per cycle) of gemcitabine (800 mg/m2) or cisplatin (50 mg/m2) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Overall response rate (ORR) was assessed after 4 weeks of induction therapy and then every 3 months according to response evaluation criteria in solid tumors version 1.1 (primary end point). Secondary end points include progression-free survival (PFS), overall survival (OS), and drug toxicity. Descriptive statistics was used for ORR, and Kaplan-Meier curves were generated for OS and PFS. RESULTS: A total of 80 women with locally advanced cervical cancer were enrolled and evaluated for safety and efficacy. Our results demonstrated that none of the patients had a complete response (0%), 11 patients had a partial response (14%), and 10 patients had progressive disease (13%), giving a tumor response rate of 14%. A total of 59 patients had stable disease (74%), giving a disease control rate of 88% (70/80). Median PFS was 8.21 months (95% confidence interval [CI]: 5.09-12.45). Median OS was 11.96 months (95% CI: 8.11-23.95). The most common adverse events were mucositis, myelosuppression, and gastrointestinal disturbance. CONCLUSION: Our study results suggested that nimotuzumab in combination with chemotherapy and radiotherapy is well tolerated, and could be a better treatment alternative in patients with locally advanced cervical cancer.

Mitotic arrest-induced phosphorylation of Mcl-1 revisited using two-dimensional gel electrophoresis and phosphoproteomics: nine phosphorylation sites identified.

Microtubule targeting agents (MTAs) characteristically promote phosphorylation and degradation of Mcl-1, and this represents a critical pro-apoptotic signal in mitotic death. While several phosphorylation sites and kinases have been implicated in mitotic arrest-induced Mcl-1 phosphorylation, a comprehensive biochemical analysis has been lacking. Contrary to previous reports suggesting that T92 phosphorylation by Cdk1 regulates Mcl-1 degradation, a T92A Mcl-1 mutant expressed in HeLa cells was phosphorylated and degraded with the same kinetics as wild-type Mcl-1 following vinblastine treatment. Similarly, when Mcl-1 with alanine replacements of all five putative Cdk sites (S64, T92, S121, S159, T163) was expressed, it was also phosphorylated and degraded in response to vinblastine. To analyze Mcl-1 phosphorylation in more detail, two-dimensional gel electrophoresis (2D-PAGE) was performed. While untreated cells expressed mainly unphosphorylated Mcl-1 with two minor phosphorylated species, Mcl-1 from vinblastine treated cells migrated during 2D-PAGE as a train of acidic spots representing nine or more phosphorylated species. Immunopurification and mass spectrometry of phosphorylated Mcl-1 derived from mitotically arrested HeLa cells revealed nine distinct sites, including several previously unreported. Mcl-1 bearing substitutions of all nine sites had a longer half-life than wild-type Mcl-1 under basal conditions, but still underwent phosphorylation and degradation in response to vinblastine treatment, and, like wild-type Mcl-1, was unable to protect cells from MTA treatment. These results reveal an unexpected complexity in Mcl-1 phosphorylation in response to MTAs and indicate that previous work has severely underestimated the number of sites, and thus encourage major revisions to the current model.

p53, MDM2, eIF4E and EGFR expression in nasopharyngeal carcinoma and their correlation with clinicopathological characteristics and prognosis: A retrospective study.

In the present study, the expression of p53, mouse double minute 2 homolog (MDM2), eukaryotic translation initiation factor 4E (eIF4E), and epidermal growth factor receptor (EGFR) were investigated in nasopharyngeal carcinoma (NPC), and the correlation between their expression and clinicopathological characteristics and prognosis was analyzed. The medical records of 96 NPC patients who had undergone biopsy prior to radical radiotherapy and chemotherapy between 2005 and 2009 were reviewed, retrospectively. All patients received intensity-modulated radiotherapy with concurrent platinum-based chemotherapy. Patients were followed-up for three years. Streptavidin-peroxidase immunohistochemistry was used to evaluate the expression of p53, MDM2, eIF4E and EGFR in NPC biopsy specimens, and the association between their expression and clinical parameters and survival was analyzed. The p53, MDM2, eIF4E and EGFR expression rates were 65.6% (63/96), 79.16% (76/96), 77.08% (74/96) and 89.5% (86/96), respectively. p53 (χ2,20.322; P=0.001) and EGFR (χ2,8.337; P=0.005) expression were found to correlate with T stage, whereas MDM2 (χ2,16.361; P=0.001) expression was found to correlate with lymph node metastasis. p53 expression was found to inversely correlate with MDM2 expression (r, -3.24; P<0.05). Three-year survival rates were lower in p53-positive (76.2%) patients when compared with p53-negative (93.9%) patients. In addition, three-year survival rates were lower in EGFR-positive (75.8%) patients than in EGFR-negative patients (91.2%). The Cox proportional-hazards regression model revealed that p53 (ß,-0.455; χ2,5.491; P=0.019) and EGFR (ß, 3.93; χ2, 11.95; P=0.001) expression were independent prognostic factors. Thus, it was hypothesized that p53 and EGFR expression present potential unfavorable prognostic markers for patients with NPC.

Accounting for center in the Early External Cephalic Version trials: an empirical comparison of statistical methods to adjust for center in a multicenter trial with binary outcomes.

BACKGROUND: Clustering of outcomes at centers involved in multicenter trials is a type of center effect. The Consolidated Standards of Reporting Trials Statement recommends that multicenter randomized controlled trials (RCTs) should account for center effects in their analysis, however most do not. The Early External Cephalic Version (EECV) trials published in 2003 and 2011 stratified by center at randomization, but did not account for center in the analyses, and due to the nature of the intervention and number of centers, may have been prone to center effects. Using data from the EECV trials, we undertook an empirical study to compare various statistical approaches to account for center effect while estimating the impact of external cephalic version timing (early or delayed) on the outcomes of cesarean section, preterm birth, and non-cephalic presentation at the time of birth. METHODS: The data from the EECV pilot trial and the EECV2 trial were merged into one dataset. Fisher's exact method was used to test the overall effect of external cephalic version timing unadjusted for center effects. Seven statistical models that accounted for center effects were applied to the data. The models included: i) the Mantel-Haenszel test, ii) logistic regression with fixed center effect and fixed treatment effect, iii) center-size weighted and iv) un-weighted logistic regression with fixed center effect and fixed treatment-by-center interaction, iv) logistic regression with random center effect and fixed treatment effect, v) logistic regression with random center effect and random treatment-by-center interaction, and vi) generalized estimating equations. RESULTS: For each of the three outcomes of interest approaches to account for center effect did not alter the overall findings of the trial. The results were similar for the majority of the methods used to adjust for center, illustrating the robustness of the findings. CONCLUSIONS: Despite literature that suggests center effect can change the estimate of effect in multicenter trials, this empirical study does not show a difference in the outcomes of the EECV trials when accounting for center effect. TRIAL REGISTRATION: The EECV2 trial was registered on 30 July 30 2005 with Current Controlled Trials: ISRCTN 56498577.

Urinary soluble urokinase receptor levels are elevated and pathogenic in patients with primary focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. Recent studies have proposed that plasma soluble urokinase receptor (suPAR) might be a causative circulating factor but this proposal has caused controversy. This study aimed to measure urinary suPAR levels in patients with primary FSGS and its significance in the pathogenesis of FSGS. METHODS: Sixty-two patients with primary FSGS, diagnosed between January 2006 and January 2012, with complete clinical and pathologic data were enrolled, together with disease and normal controls. Urinary suPAR levels were measured using commercial ELISA kits and were corrected by urinary creatinine (Cr). The associations between urinary suPAR levels and clinical data at presentation and during follow up were analyzed. Conditionally immortalized human podocytes were used to study the effect of urinary suPAR on activating ß3 integrin detected by AP5 staining. RESULTS: The urinary suPAR level of patients with primary FSGS (500.56, IQR 262.78 to 1,059.44 pg/µmol Cr) was significantly higher than that of patients with minimal change disease (307.86, IQR 216.54 to 480.18 pg/µmol Cr, P = 0.033), membranous nephropathy (250.23, IQR 170.37 to 357.59 pg/µmol Cr, P <0.001), secondary FSGS (220.45, IQR 149.38 to 335.54 pg/µmol Cr, P <0.001) and normal subjects (183.59, IQR 103.92 to 228.78 pg/µmol Cr, P <0.001). The urinary suPAR level of patients with cellular variant was significantly higher than that of patients with tip variant. The urinary suPAR level in the patients with primary FSGS was positively correlated with 24-hour urine protein (r = 0.287, P = 0.024). During follow up, the urinary suPAR level of patients with complete remission decreased significantly (661.19, IQR 224.32 to 1,115.29 pg/µmol Cr versus 217.68, IQR 121.77 to 415.55 pg/µmol Cr, P = 0.017). The AP5 signal was strongly induced along the cell membrane when human differentiated podocytes were incubated with the urine of patients with FSGS at presentation, and the signal could be reduced by a blocking antibody specific to uPAR. CONCLUSIONS: Urinary suPAR was specifically elevated in patients with primary FSGS and was associated with disease severity. The elevated urinary suPAR could activate ß3 integrin on human podocytes.

Assessment of KDIGO definitions in patients with histopathologic evidence of acute renal disease.

BACKGROUND AND OBJECTIVES: AKI is a clinical syndrome with various causes involving glomerular, interstitial, tubular, and vascular compartments of the kidney. Acute kidney disease (AKD) is a new concept that includes both AKI and the conditions associated with subacute decreases in GFR (AKD/non-AKI). This study aimed to investigate the correlation between AKI/AKD defined by clinical presentation and diffuse histologic criteria for acute abnormalities based on renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All 303 patients who were histologically diagnosed as having acute tubular necrosis (ATN), acute tubulointerstitial nephritis, cellular crescentic GN, acute thrombotic microangiopathy, or complex lesions on renal biopsy from January 2009 to December 2011 were enrolled in the study. The 2012 Kidney Disease Improving Global Outcomes AKD/AKI definitions were applied to classify patients as follows: AKI, AKD/non-AKI, non-AKD, or unclassified. RESULTS: A total of 273 patients (90.1%) met the AKD criteria; 198 patients (65.3%) were classified as having AKI according to serum creatinine (SCr) and urine output criteria. The urine output criteria added 4.3% to the SCr criteria and reclassified 6.7% of the AKI cases into higher stages. Of patients with ATN on pathology, 79.2% met AKI criteria; this was a higher percentage than for those who had other individual pathologic lesions (50%-64%). The major cause of not being defined as having AKI was a slower SCr increase than that required by the definition of AKI (98, 93.3%). Patients with AKI had more severe clinical conditions and worse short-term renal outcome than those in the non-AKI group. CONCLUSIONS: Diffuse, acute abnormality defined by renal biopsy and AKI defined by clinical presentation are two different entities. Most patients who have diffuse acute histologic findings met the criteria for AKD, whereas only two thirds met the definition of AKI.