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To explore the genetic basis of a Chinese patient with Bardet-Biedl syndrome (BBS).Clinical data of the patient was analyzed. Next-generation sequencing was carry out to screen pathogenic variants, and candidate variants were verified by Sanger sequencing and subjected to bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics.Next-generation sequencing revealed that the proband has harbored two pathogenic variants of the MKKS gene (c.635CT and c.1664CG) and one likely pathogenic variant of the TMEM67 gene (c.2498TC). Sanger sequencing of the proband and her mother confirmed that the proband has harbored two compound heterozygous MKKS variants and a heterozygous TMEM67 variant. Both of the MKKS variants were previously unreported and located in a highly conserved domain and predicted to be disease-causing by bioinformatic analysis.The two novel MKKS/BBS6 variants probably underlay the BBS in the proband. The TMEM67 variant may have an epistatic effect on mutations of BBS-associated loci.

Erdheim–Chester disease is a rare form of non-Langerhans histiocytosis. A 40-year-old woman was diagnosed as Erdheim-Chester disease based on typical bone scintigraphy, symmetric osteosclerosis and findings of foamy, non-Langerhans histiocytes in bone marrow. BRAFV600E mutation was detected in a bone biopsy. Treatment with IFN-α showed significant improvement. The BRAFV600E mutant was detected in plasma cell-free DNA (cfDNA) by a droplet-digital PCR assay. Longitudinal analysis of BRAFV600E in plasma cfDNA showed a decreasing trend during treatment. We could not detect the mutant in urinary cfDNA. While, similar studies have detected the BRAFV600E mutant in urine, but not in plasma. A combination of allele burden assessments in plasma and urine may be helpful for detecting the residual mutant burden and monitoring therapeutic response.

Background C3 glomerulopathy (C3G) is a recent disease classification that is characterized by the presence of glomerular deposits (composed of C3) in the absence of significant amounts of immunoglobulin and comprises dense deposit disease and C3 glomerulonephritis (C3GN). Most C3GN manifests as membranoproliferative, mesangial proliferative glomerulonephritis patterns via light microscopy. Pure membranous nephropathy (MN)-like glomerular lesions are rare manifestations of C3GN. Anti-neutrophil cytoplasmic antibodies (ANCAs) are also seldomly reported to be positive in C3GN. Herein, we report the case of a C3GN patient presenting with an MN-like glomerular pattern with ANCA positivity. Case presentation A 68-year-old woman was admitted to a local hospital with elevated serum creatinine for two weeks. Laboratory tests showed a hemoglobin level of 85 g/L. Urinalysis was positive for 2 + protein and 360 RBCs/HPF. Blood biochemistry analysis revealed the following concentrations: albumin, 30.3 g/L; globulin, 46.2 g/L; blood urea nitrogen, 19.9 mmol/L; and serum creatinine, 234 µmol/L. The serum C3 level was 0.4950 g/L, and the serum C4 level was 0.1050 g/L. The direct Coombs test was positive. Serologic testing for ANCA revealed the presence of p-ANCA (1:10) by indirect immunofluorescence microscopy assay, as well as the presence of PR3 1.2 (normal range Conclusions We present the rare case of a patient with MN-like C3GN with ANCA positivity. C3GN with ANCA positivity may be represented by more crescents, severe renal dysfunction and more extrarenal manifestations. More cases are needed to elucidate the clinicopathologic features and optimal treatments of these patients.

Aims Lipoprotein glomerulopathy (LPG) is a rare inherited renal disease. Several apolipoprotein E (apoE) mutations have been reported to be related to LPG. Herein, we report a case of a LPG patient with a novel apoE mutation. Methods A 45-year-old Chinese female was diagnosed as LPG by renal biopsy. APOE gene was sequenced. Clinical and genetic studies were conducted. Results The patient presented with nephrotic syndrome and hypertension. A fasting lipid panel showed mild hyperlipidemia and elevated serum apoE (5.6 mg/dL). Renal biopsy revealed typical LPG lesions with whorled, mesh-like material in dilated glomerular capillary lumens that stained positive for Sudan Ⅲ and apoE. apoE gene analysis revealed a T-to-C point mutation at amino acid 173 that caused a substitution of a proline residue for a leucine residue, which has not been reported previously. We named this mutation apoE Chengdu (c.518T＞C, p.L173P). Two of five of the family members carried this mutation, including the patient's brother who was receiving hemodialysis, and her sister, whose urine protein levels were normal. All mutation carriers were heterozygotes with the apoE genotype e3/e3. This mutation was not found among 200 of the local people. Fenofibrate treatment for one year induced clinical improvement. Conclusions ApoE Chengdu (p.L173P) is a novel mutation causing LPG. This case supports the hypothesis that the substitution of proline in or near the LDL receptor-binding area contributes to the development of LPG. The detailed mechanism of action of this variant remains to be elucidated.

AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy (ADCK4-GN) is an inherited mitochondrial nephropathy caused by mutations in the ADCK4 gene. Herein, we report a case of ADCK4-GN. The patient, a 14-year-old Chinese male, presented with asymptomatic proteinuria and steroid resistance. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and dysmorphic mitochondria in podocytes. Coenzyme Q10 treatment was partially effective. No adverse events were observed. Next generation and Sanger sequencing analyses revealed compound heterozygous mutations (c.625C > G, p.D209H and c.918G > T, p.C306X). Both inherited mutations are located in the highly conserved ABC1 domain. The unreported nonsense mutation causes a loss of 197 amino acids from the C-terminal portion of ADCK4, suggesting a deleterious effect of the truncating mutation by abolishing ADCK4 function. In conclusion, we identified a novel ABC1 domain-localized pathogenic mutation responsible for ADCK4-GN, further supporting the importance of the C-terminal portion of ADCK4. Next generation sequencing facilitated the early diagnosis. CoQ10 treatment may reduce proteinuria and postpone ADCK4-GN progression.

To analyze the clinicopathologic features and genetic mutation in a patient diagnosed with focal segmental glomerulosclerosis (FSGS).Clinicopathologic data of the patient, who was diagnosed with primary FSGS by renal biopsy, was collected. Mutations of FSGS-related genes were screened with next-generation sequencing. Suspected pathogenic mutation was verified with Sanger sequencing.Next-generation sequencing detected a missense mutation (c.2215C to G, p.P739A) in exon 28 of the COL4A5 gene in the patient. The same mutation was also detected in his mother who was asymptomatic. Another missense mutation (c.2215C to T, p.P739S) in the same codon has been related with Alport syndrome.The c.2215C to G (p.P739A) mutation may be one of pathogenic mutations underlying FSGS. This has provided further evidence for the phenotypic heterogeneity of COL4A5 gene mutations.

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

Lipoprotein glomerulopathy is a rare inherited renal disease, caused by mutation of the APOE gene, characterized by proteinuria and nephrotic syndrome with elevated serum apoE. Since its treatment and outcome are unknown, we retrospectively studied 35 patients within 31 unrelated Han families with biopsy-proven lipoprotein glomerulopathy residing in the same county in southwest China. DNA sequencing detected the APOE Kyoto mutation (p. Arg25Cys) in all patients and 28 asymptomatic relatives. All shared the same e3 allele. The patients presented with proteinuria, higher total triglyceride, and serum apoE levels relative to non-carriers. The serum apoE and triglyceride levels of asymptomatic carriers were between those of the patients and non-carriers. Sixteen patients received fenofibrate treatment for over 12 months. Six reached complete remission (proteinuria under 0.3g/day with stable serum creatinine) with intensive control of their lipid profile (normalized serum apoE and triglycerides under 100mg/dl). Eight reached partial remission. At 3 years of follow-up, patients treated with fenofibrate had superior survival and stable renal function. Thus, fenofibrate can induce lipoprotein glomerulopathy remission and the fibrate effects depend on the degree of lipid control and baseline proteinuria. Moreover, normalization of serum apoE and triglycerides can be used to judge the efficacy of lipid-lowering treatment.

Little is known about the frequency features of spontaneous neural activity in the brains of moderate and late preterm (MLPT) newborns. We used resting-state functional magnetic resonance imaging (rs-fMRI) and the amplitude of low-frequency fluctuation (ALFF) method to investigate the frequency properties of spontaneous blood oxygen level-dependent (BOLD) signals in 26 MLPT and 35 term newborns. Two frequency bands, slow-4 (0.027–0.073 Hz) and slow-5 (0.01–0.027 Hz), were analyzed. Our results showed widespread differences in ALFF between the two bands; differences occurred mainly in the primary sensory and motor cortices and to a lesser extent in association cortices and subcortical areas. Compared with term newborns, MLPT newborns showed significantly altered neural activity predominantly in the primary sensory and motor cortices and in the posterior cingulate gyrus/precuneus. In addition, a significant interaction between frequency bands and groups was observed in the primary somatosensory cortex. Intriguingly, these primary sensory and motor regions have been proven to be the major cortical hubs during the neonatal period. Our results revealed the frequency of spontaneous BOLD signal differences between MLPT and term newborns, which contribute to the understanding of regional development of spontaneous brain rhythms of MLPT newborns.

INTRODUCTION: The Sichuan earthquake caused a large number of crush injuries and many of them developed acute renal failure (ARF). A retrospective study was performed on victims with crush injuries of West China Hospital to investigate the predictive factors for acute renal failure (ARF) in crush injuries. PATIENTS AND METHODS: Medical records of injured victims treated in West China Hospital within the first week after the Sichuan earthquake were retrospectively reviewed and 101 patients with crush injury were enrolled in the study. We divided them into an ARF group and a non-ARF group. The clinical data of included patients were extracted and analysed. RESULTS: Patients with ARF accounted for 42% of the included population. Patients younger than 20 made up the biggest age category (45%), and the entrapped time under the debris (22 [IQR 3.5-38]h) was longer than previous reports. In univariate analysis, male gender, multiple crush injuries, medical comorbidities, surgical interventions and infections were more frequent in patients with ARF than in those without ARF. Mean arterial pressure was higher in the ARF group. Besides, the risk of ARF was increased by creatine kinase >14,494.5IU/L most significantly, followed by time under the rubble >4h, aspartate transaminase >453.5IU/L, albumin 11.8×10(9)/L. In multivariate analysis, male gender, time under the rubble, multiple crush injuries, surgical interventions, infections and creatine kinase level were independently associated with ARF in crush injuries. CONCLUSIONS: The entrapped time under the debris, multiple crush injuries, male gender, infections, and creatine kinase level are predictive factors for ARF in crush injuries. Language: en

Cerebral glucose metabolism was measured by (18)F-fluorodeoxyglucose position emission tomography in infants at different gestational ages and with neonatal hypoxic-ischemic encephalopathy. Thirty-six preterm and term infants at different gestational ages without brain injury were divided into four subgroups: ≤32 weeks (n = 4), 33-34 weeks (n = 5), 35-36 weeks (n = 12), and ≥37 weeks (n = 15). Twenty-four newborn infants with hypoxic-ischemic encephalopathy were divided into three subgroups: mild (n = 13), moderate (n = 7), and severe (n = 4). Cerebral glucose metabolism manifested a trend toward increase, and the structure of cranial (18)F-fluorodeoxyglucose positron emission tomography images became clear with increased gestational age, especially at ≥37 weeks. Uptakes of (18)F-fluorodeoxyglucose in the ≥37-week group were significantly higher than in the ≤32-week group (P < 0.01). Cerebral glucose metabolism changed significantly in neonatal hypoxic-ischemic encephalopathy, and was either unbalanced bilaterally or relatively low at all sites. Moreover, uptakes of (18)F-fluorodeoxyglucose were significantly lower in severe than in mild and medium hypoxic-ischemic encephalopathy (P < 0.05). Cerebral glucose metabolism, as measured by (18)F-fluorodeoxyglucose positron emission tomography, may prove useful for estimating brain development and injury in newborn infants, and its clinical values need further investigation.

Objective: An 8.0-magnitude earthquake struck Sichuan province of China on May 12, 2008. Over the next 10 days, the firstly arrived uniformed pediatricians in the epicenter zone took part in emergency relief care for children. The investigations of major injuries and diseases in children were taken. Methods: Demographic data collected included (if possible) age, date of presentation, injury, disease, and surgery performed. Results: Total casualties were estimated to be more than 80,000, and much more were injured. Eight hundred eighty-two inpatients were treated by the relief team during the first 10 days. Of 882 inpatients, 192 (21.8%) were younger than 18 years. Children's ages were not evenly distributed. Twenty-seven patients were neonates, infants, and toddlers (14%), 105 were school-aged (55%), and were 60 adolescents (31%). The admitted children had 256 injuries. Limb (106 cases, 55.2%) and body surface (67 cases, 34.9%) were the majorly injured locations. One hundred twenty-seven cases (66.2%) had simple open injuries, and 106 (55.2% had fractures. The children's conditions were evaluated as mild (121 cases, 63.0%), moderate (56 cases, 29.7%), severe (8 cases, 4.2%), and fatal (7 cases, 3.7%). Conclusions: More than 20% of patients requiring hospitalization were children. School-aged children were heavily injured. The increase in infectious diseases followed on. The data show that there is an immediate need for orthopedic and general surgery skills, and pediatricians should play an important role in early rescue and subsequent control of infectious diseases in a huge earthquake hazard.

Recent evidence suggested that angiogenesis played a pivotal role in the development of hepatocellular carcinoma cells (HCC), thus the therapy strategy targeting antiangiogenesis has been regarded as promising method for HCC therapy. Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. However, the antiangiogenesis therapy of HCC based on TEM8 has not been reported. In this study, the recombinant adenovirus encoding TEM8 was constructed, and the DCs were transduced with the Ad-TEM8. In addition, the modified DCs were transferred into the BALB/c mice to determine whether DCs transduced with TEM8 could elicit a potent antitumor immunogenic response in vivo. The results demonstrated that DCs transduced with Ad-TEM8 induced specific CTLs effectively, which could secrete IFN-γ and lyse HCC. Furthermore, the modified DCs could effectively protect BALB/c mice from lethal challenges against HCC, reduce tumor growth and increase the mice life span by decreasing tumor vasculature density. These data suggest that the Ad-TEM8 modified DCs may induce antitumor immunity by disrupting tumor vasculature and may thus be used as an efficient therapy strategy to influence tumor development in clinical applications.

The Oxford classification of immunoglobulin A (IgA) nephropathy (IgAN) provides a histopathologic grading system that is associated with kidney disease outcomes independent of clinical features. We evaluated the Oxford IgAN classification in a large cohort of patients from China.Retrospective study.1,026 adults with IgAN from 18 referral centers in China. Inclusion criteria and statistical analysis were similar to the Oxford study.Histologic findings of mesangial hypercellularity score, endocapillary proliferation, segmental sclerosis or adhesion, crescents, necrosis, and tubular atrophy/interstitial fibrosis. Clinical features, blood pressure, estimated glomerular filtration rate (eGFR), proteinuria, and treatment modalities.Time to a 50% reduction in eGFR or end-stage renal disease (the combined event); the rate of eGFR decline (slope of eGFR); proteinuria during follow-up.Compared with the Oxford cohort, the Chinese cohort had a lower proportion of patients with mesangial hypercellularity (43%) and endocapillary proliferation (11%), higher proportion with segmental sclerosis or adhesion (83%) and necrosis (15%), and similar proportion with crescents (48%) and tubular atrophy/interstitial fibrosis (moderate, 24%; severe, 3.3%). During a median follow-up of 53 (25th-75th percentile, 36-67) months, 159 (15.5%) patients reached the combined event. Our study showed that patients with a mesangial hypercellularity score higher than 0.5 were associated with a 2.0-fold (95% CI, 1.5-2.8; P0.001) higher risk of the combined event than patients with a score of 0.5 or lower. Patients with tubular atrophy/interstitial fibrosis of 25%-50% and50% versus25% were associated with a 3.7-fold (95% CI, 2.6-5.1; P0.001) and 15.1-fold (95% CI, 9.5-24.2; P0.001) higher risk of the combined event, respectively. Endocapillary proliferation, glomerular crescents, and necrosis were not significant.Retrospective study; the therapeutic interventions were miscellaneous.We confirmed the associations of mesangial hypercellularity and tubular atrophy/interstitial fibrosis with kidney disease outcomes.

Seventeen cases of Acinetobacter baumannii infection in a neonatal intensive care unit (NICU) were evaluated. The strains were characterized as resistant to carbapenems. The aim of the present study was therefore to investigate the clinical and molecular epidemiological characteristics of the 17 carbapenem-resistant A. baumannii strains.Samples were isolated from blood or sputum from the patients in the NICU, cultured using conventional techniques and an automated system. Multiplex polymerase chain reaction (PCR) was used to detect blaOXA-51-like, blaOXA-23-like, OXA-24, OXA-58 and Ambler class B carbapenemases. The genotype of the strains was identified on pulsed-field gel electrophoresis (PFGE).BlaOXA-23 was detected in all of the isolates. PFGE genotype analysis suggested three clones among the 17 strains. Two clones were isolated from other wards of the hospital including the adult ICU and Department of Pulmonology. The other clone was proved to be the first appearance in the hospital as genotype analysis.BlaOXA-23 was the drug-resistant gene that made A. baumannii resistant to carbepenem. The source of blaOXA-23 in the 17 isolates was different.

Autosomal dominant polycystic kidney disease (ADPKD) is a common and severe renal disease. Mutations of PKD1 and PKD2 genes are responsible for approximately 85% and 15% of ADPKD cases, respectively. In the present study, PKD1 and PKD2 genes were analyzed in a large Chinese family with ADPKD using denaturing high-performance liquid chromatography and DNA sequencing. A novel mutation, c.3623-3624insGTGT in exon 15 of the PKD1 gene, was identified in all nine affected family members, but not in any unaffected consanguineous relatives or 100 unrelated controls. These findings suggest that the unique 4 bp insertion, c.3623-3624insGTGT, in the PKD1 gene might be the pathogenic mutation responsible for the disease in this family.

Background Lipoprotein glomerulopathy (LPG) is a rare inherited renal disease characterized by intraglomerular lipoprotein within the lumina of severely dilated glomerular capillaries. The common clinical presentation of LPG includes proteinuria or nephrotic syndrome. Hypertension and anemia were thought to be mild in LPG. Thrombotic microangiopathy (TMA) in LPG has not been previously reported. In this report, we present a patient with LPG that developed TMA. To the best of our knowledge, this is the first report of TMA in LPG. Case presentation Four years ago (2005), a 19-year-old Chinese woman was diagnosed with nephrotic syndrome and provided prednisone treatment. A combination of prednisone and cyclophosphamide did not have any effect and was discontinued after six months. Although she was steroid-resistant, over the next subsequent three years, she maintained normal renal function without anemia and thrombocytopenia. In February 2009, she had a severe headache and blurry vision and presented at a local hospital with severe hypertension. Blood pressure was 220/160 mmHg. Laboratory data showed hemoglobin 3.8 g/dL; platelet counts 29×109/L; urinary protein 7.90 g/d; total bilirubin 29.9 umol/L; indirect bilirubin 28.2 umol/L; LDH 1172 U/L; ALB 2.66 g/dL; urea nitrogen 52 mg/dL; serum creatinine 3.2 mg/dL; triglyceride 253 mg/dL; total cholesterol 273 mg/dL. ANA, ds-DNA, ANCA, anti-GBM antibody and anticardiolipin were all negative. A renal biopsy revealed LPG with TMA. Genetic evaluation showed the patient carried the APOE Kyoto mutation. Adequate control of blood pressure improved microangiopathic anemia and thrombocytopenia, however, renal function did not improve and she eventually developed uremia and became hemodialysis dependent. Conclusion We report on a rare case of TMA probably due to malignant hypertension in LPG. Early lipid-lowering and antihypertensive treatment may improve outcome. The pathophysiologic relationship between LPG and TMA should be investigated further.

Background Anti-glomerular basement membrane (GBM) glomerulonephritis and systemic lupus erythematosus (SLE) are both disorders of the immune system; however, they are known as distinct diseases. Till now no clinical evidence suggests the genetic relationship between these two diseases. Herein, we present two identical twins; one was diagnosed as anti-GBM glomerulonephritis, the other SLE. This is the first clinical report on the genetic relationship between these two diseases. Case presentation A 25-year-old female was admitted complaining of intermittent gross hematuria for 6 months and elevated serum creatinine for 1 month. She denied hemoptysis. Laboratory examinations showed hemoglobin 7.4 g/dL, serum creatinine 7.15 mg/dL and albumin 2.8 g/dL. Urinalysis showed hematuria (484 RBCs per high-power field) and proteinuria 4+. Antinuclear antibody, complement levels and ANCAs were all normal. Renal ultrasound showed normal-sized kidneys without obstruction or masses. Serum anti-GBM antibody assay showed 119.70 RU/mL (normal range, Conclusion The presence of identical twins having anti-GBM nephritis and SLE respectively provides clinical evidence to support that anti-GBM nephritis and lupus may share a common genetic background to some extent, while environment may contribute to disease evolution in part.