Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS.

Human cancers typically express a high level of tumor-promoting mutant p53 protein (Mutp53) with a minimal level of tumor-suppressing wild-type p53 protein (WTp53). In this regard, inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy. Herein, a new carrier-free nanoprodrug (i.e., Mn-ZnO2 nanoparticles) was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species (ROS) within tumor to regulate the p53 protein for high anti-tumor efficacy. In response to the mild tumor acidic environment, the released Zn2+ and H2O2 from Mn-ZnO2 NPs induced ubiquitination-mediated proteasomal degradation of Mutp53, while the liberative Mn2+ and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level. Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical (•OH) through the Fenton-like reaction. With the integration of multiple functions (i.e., carrier-free ion and ROS delivery, tumor accumulation, p53 protein modulation, toxic •OH generation, and pH-activated MRI contrast) in a single nanosystem, Mn-ZnO2 NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.

Zafirlukast inhibits the growth of lung adenocarcinoma via inhibiting TMEM16A channel activity.

Lung cancer has the highest mortality among cancers worldwide due to its high incidence and lack of the effective cures. We have previously demonstrated that the membrane ion channel TMEM16A is a potential drug target for the treatment of lung adenocarcinoma and have identified a pocket of inhibitor binding that provides the basis for screening promising new inhibitors. However, conventional drug discovery strategies are lengthy and costly, and the unpredictable side effects lead to a high failure rate in drug development. Therefore, finding new therapeutic directions for already marketed drugs may be a feasible strategy to obtain safe and effective therapeutic drugs. Here, we screened a library of over 1400 Food and Drug Administration-approved drugs through virtual screening and activity testing. We identified a drug candidate, Zafirlukast (ZAF), clinically approved for the treatment of asthma, that could inhibit the TMEM16A channel in a concentration-dependent manner. Molecular dynamics simulations and site-directed mutagenesis experiments showed that ZAF can bind to S387/N533/R535 in the nonselective inhibitor binding pocket, thereby blocking the channel pore. Furthermore, we demonstrate ZAF can target TMEM16A channel to inhibit the proliferation and migration of lung adenocarcinoma LA795 cells. In vivo experiments showed that ZAF can significantly inhibit lung adenocarcinoma tumor growth in mice. Taken together, we identified ZAF as a novel TMEM16A channel inhibitor with excellent anticancer activity, and as such, it represents a promising candidate for future preclinical and clinical studies.

TMEM16A Protein: Calcium-Binding Site and its Activation Mechanism.

TMEM16A mediates the calcium-activated transmembrane flow of chloride ions and a variety of physiological functions. The binding of cytoplasmic calcium ions of TMEM16A and the consequent conformational changes of it are the key issues to explore the structure-function relationship. In recent years, researchers have explored this issue through electrophysiological experiments, structure resolving, molecular dynamic simulation, and other methods. The structures of TMEM16 family members determined by cryo-Electron microscopy (cryo-EM) and X-ray crystallization provide the primary basis for the investigation of the molecular mechanism of TMEM16A. However, the binding and activation mechanism of calcium ions in TMEM16A are still unclear and controversial. This mini-review discusses four Ca2+ sensing sites of TMEM16A and analyzes activation properties of TMEM16A by them, which will help understand the structure-function relationship of TMEM16A and throw light on the molecular design targeting the TMEM16A channel.

Utility of Diffusion-Weighted Imaging for Guiding Clinical Management of Patients With Kidney Transplant: A Prospective Study.

BACKGROUND: Although biopsy is essential for the diagnosis and management of kidney transplant recipients, it is invasive. Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is a noninvasive technique that can assess both capillary perfusion and tissue diffusion. PURPOSE: To evaluate the capability of IVIM-DWI as a differentiation of kidney transplant patients who need clinical intervention from those who need not. STUDY TYPE: Prospective. SUBJECTS: In all, 33 kidney transplant patients who needed clinical intervention and 19 who need not. FIELD STRENGTH/SEQUENCE: 3.0T; IVIM-DWI with a single-shot echo planar imaging sequence. ASSESSMENT: All patients underwent kidney transplant biopsy and IVIM-DWI scans. Patients were dichotomized into those who needed clinical intervention (CHANGE group) and those who need not (Non-CHANGE group) based on biopsy results. The values of total apparent diffusion coefficient (ADCT ), diffusion coefficient (D), and perfusion fraction (f) were acquired from renal cortex and medulla, respectively. The area under the curve (AUC) was calculated and compared. STATISTICAL TESTS: Independent Student's t-test, receiver-operating characteristic curve, and Spearman correlation analysis. RESULTS: All the cortical and medullary DWI parameters in the CHANGE group were significantly lower than those in the Non-CHANGE group (all P ≤ 0.012). Except for medullary fp, all DWI parameters in both the cortex and the medulla were inversely correlated with both the chronic (ρ ranging from -0.33 to -0.54, all P ≤ 0.02) and acute (ρ ranging from -0.35 to -0.60, all P ≤ 0.01) composite scores. Cortical ADCT and D had the largest AUC and specificity of 0.84 and 75.8%, respectively. Combined use of cortical D and medullary fp at each optimal cutoff point yielded a specificity of 90.9%. DATA CONCLUSION: DWI demonstrated potential as a noninvasive biomarker to allow the stratification of patients into categories in which kidney allograft biopsy results are or are not likely to change clinical management. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5 J. Magn. Reson. Imaging 2020;52:565-574.

Assessment of transplant renal artery stenosis with diffusion-weighted imaging: A preliminary study.

OBJECTIVE: To characterize capillary perfusion and tissue diffusion changes in transplant renal artery stenosis (TRAS) with diffusion-weighted imaging (DWI). MATERIALS & METHODS: We retrospectively identified 30 patients with non-contrast enhanced magnetic resonance angiography-proven TRAS. Another 20 kidney transplant recipients without TRAS were prospectively recruited to serve as control group. DWI parameters were compared among various groups with one-way analysis of variance and post hoc Tukey test. Additionally, DWI parameters were compared in 7 severe TRAS patients before and after successful angioplasty using paired Student t-test. Receiver-operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of various DWI parameters. RESULTS: All DWI parameters of renal cortex and medulla were not statistically different between normal allografts and allografts with mild TRAS. Nonetheless, cortical total apparent diffusion coefficient (ADCT) of allografts with moderate TRAS was significantly decreased compared with normal allografts. All cortical and medullary DWI parameters were significantly reduced in severe TRAS compared with normal allografts. ROC curve analysis indicated ADCT could identify severe TRAS with 93.8% sensitivity, 82.4% specificity and an area under the curve of 0.930. ADCT increased significantly after successful angioplasty while it showed no significant change in a patient with unsuccessful angioplasty. CONCLUSION: DWI is a robust technique that revealed no tissue diffusion and perfusion impairment in mild TRAS. ADCT has good sensitivity and specificity for identifying patients with severe TRAS. DWI is potentially an alternative radiologic biomarker for assessing microstructural and perfusion alterations in TRAS. DWI is useful in detecting renal functional recovery following successful angioplasty.

ß-Catenin Expression Correlates With Prognosis in Hepatocellular Carcinoma Patients Treated With Transcatheter Arterial Chemoembolization.

BACKGROUND/AIM: Transcatheter arterial chemoembolization (TACE) is one of the most widely used palliative therapies for the unresectable hepatocellular carcinoma (HCC). However, a large difference is found in prognosis among patients treated with TACE. The aim of the present study was to investigate the prognostic value of ß-catenin in HCC patients treated with TACE. MATERIALS AND METHODS: Seventy patients with HCC were included in this study. Expression of ß-catenin was determined by immunohistochemistry in biopsy samples taken before TACE. The patients were treated with TACE and followed-up. Clinicopathological parameters, progression-free survival (PFS) and overall survival (OS) were evaluated to analyze the association of ß-catenin expression with prognosis for HCC patients after TACE. RESULTS: HCC patient biopsies exhibited a significantly higher positive rate of ß-catenin expression (72.86%) compared to paracancer normal tissues (19.44%) (p<0.01). ß-Catenin expression was closely correlated with tumor differentiation, tumor size, serum α-fetoprotein (AFP) level and TACE treatment frequency (all p<0.05). Patients with negative ß-catenin expression had longer PFS and OS after TACE compared to those with positive ß-catenin expression (PFS: 44.2 vs. 14.1 months, p=0.004; OS: 56.4 vs. 35.9 months, p<0.001). Multivariate Cox regression analysis indicated that ß-catenin expression in HCC patients treated with TACE was an independent prognostic factor for higher PFS and OS. CONCLUSION: The HCC patients with increased ß-catenin expression have a poor prognosis with lower survival rate.

[Result of prenatal diagnosis for 151 high-risk women by noninvasive prenatal screening based on high-throughput sequencing].

OBJECTIVE: To assess the value of combined fetal karyotyping and chromosomal microarray analysis (CMA) for the verification of high-risk pregnancy signaled by noninvasive prenatal screening (NIPS) based on high-throughput sequencing. METHODS: One hundred and fifty-one pregnant women with high risks for aneuploidies of chromosomes 13, 18, 21, X and Y or pathological copy number variations (CNVs) by NIPS were subjected to amniocytic karyotyping and CMA analysis. RESULTS: One hundred and forty-two women were found to have a high risk for fetal chromosomal aneuploidies, which included 83 cases of trisomy 21, 17 cases of trisomy 18, 2 cases of trisomy 13, and 40 cases of sex chromosome aneuploidies. Amniocytic karyotyping and CMA analysis has confirmed 81 cases of trisomy 21, 15 cases of trisomy 18, 10 cases of 47,XXY, 4 cases of 47,XXX, 2 cases of 47,XYY and 1 case of 46,X,del(X)(q26.1). Two trisomy 21, two trisomy 18, 2 trisomy 13, and 23 cases of sex chromosomal aneuploidies were verified as false positives. For 9 women with pathological fetal CNVs detected by NIPS, combined fetal karyotyping and CMA has confirmed 1 case of chromosome 13 microdeletion, 1 case of chromosome 18 microduplication, and 1 case of chromosome 18 deletion. For a case with 30 Mb duplication of chromosome 2 and 25 Mb duplication of chromosome 8, CMA analysis had no positive finding, while fetal umbilical cord blood karyotyping has yielded a 46,XX,dup(2)(p23.1p25.3)[13]/46,XX[87] karyotype. The remaining 5 cases were confirmed as false positive results. CONCLUSION: Combined fetal karyotyping and CMA has provided a powerful tool for verifying high-risk fetuses signaled by NIPS.

Combination of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio is a useful prognostic factor in advanced non-small cell lung cancer patients.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) was recently shown to be a remarkable prognostic factor in tumors. Moreover, some studies have indicated that the combination of NLR and platelet to lymphocyte ratio (PLR) could be a better prognostic factor. As the combined prognostic value of NLR and PLR in non-small cell lung cancer (NSCLC) is not clear, we conducted this study to explore this further. METHODS: A total of 366 primary NSCLC patients with stage III or IV were finally included. The neutrophil, platelet, and lymphocyte counts were recorded before treatment was initiated. NLR and PLR were calculated and NLR > 2.68 or PLR > 119.50 was defined as elevated. Univariate and multivariate survival analyses were conducted to test their prognostic value. RESULTS: The median of NLR and PLR were 3.14 and 152.63, respectively, in all patients. It was indicated that PLR is linearly associated with NLR. PLR is associated with survival, but is not an independent prognostic factor. Removing NLR, PLR is an independent prognostic factor (overall survival [OS]: hazard ratio [HR] = 1.918, P = 0.003; progression-free survival [PFS]: HR = 1.822, P = 0.007 in condition of NLR ≤ 2.68). It was also indicated that elevated NLR is an independent prognostic factor (OS: HR = 1.778, P = 0.009; PFS: HR = 1.535, P = 0.022) in all patients. CONCLUSIONS: PLR is a useful complement of NLR, thus, advanced NSCLC patients could be divided into three prognostic groups prior to treatment: poor: NLR > 2.68; moderate: NLR ≤ 2.68 and PLR > 119.50; and good: NLR ≤ 2.68 and PLR ≤ 119.50.

Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway.

An increasing number of studies have focused on the phenomenon that mitochondrial DNA (mtDNA) activates innate immunity responses. However, the specific role of mtDNA in inflammatory lung disease remains elusive. This study was designed to examine the proinflammatory effects of mtDNA in lungs and to investigate the putative mechanisms. C57BL/6 mice were challenged intratracheally with mtDNA with or without pretreatment with chloroquine. Changes in pulmonary histopathology, cytokine concentrations, and phosphorylation levels of p38 MAPK were assayed at four time points. In in vitro experiments, THP-1 macrophages were pretreated or not pretreated with chloroquine, TLR9 siRNA, p38 MAPK siRNA, or SB203580 and then incubated with mtDNA. The levels of cytokines and p-p38 MAPK were detected by ELISA and Western blot, respectively. The intratracheal administration of mtDNA induced infiltration of inflammatory cells, production of proinflammatory cytokines (including IL-1ß, IL-6, and TNF-α), and activation of p38 MAPK. The chloroquine pretreatment resulted in an abatement of mtDNA-induced local lung inflammation. In vitro experiments showed that the exposure of THP-1 macrophages to mtDNA also led to a significant upregulation of IL-1ß, IL-6, and TNF-α and the activation of p38 MAPK. And these responses were inhibited either by chloroquine and TLR9 siRNA or by SB203580 and p38 MAPK siRNA pretreatment. The intratracheal administration of mtDNA induced a local inflammatory response in the mouse lung that depended on the interactions of mtDNA with TLR9 and may be correlated with infiltrating macrophages that could be activated by mtDNA exposure via the TLR9-p38 MAPK signal transduction pathway.

Genetic effects of a 13q31.1 microdeletion detected by noninvasive prenatal testing (NIPT).

Microdeletions of chromosome 13q31.1 are relatively rare. These types of deletions may cause different genetic effects on genotypes and/or phenotypes. There are several ways to detect microdeletions; noninvasive prenatal testing (NIPT) is the newest detection method. In this study, we aimed to investigate the genetic effects of a 13q31.1 microdeletion detected by NIPT and to reconfirm the feasibility of this procedure in predicting sub-chromosomal copy number variations (CNVs). The 13q31.1 microdeletion, which has previously been described as a disease-associated fragment, was detected by NIPT in a pregnant woman. To validate the finding and to explain the origin of this sub-chromosomal CNV, we collected fetal amniotic fluid and parental blood samples and tested the samples using array-based comparative genomic hybridization (aCGH). Karyotype analysis was performed on all of the samples to rule out balanced or mosaic anomalies. The aCGH results confirmed the NIPT findings. We detected the same type of microdeletion in the fetus and the mother via aCGH. The mother had a normal phenotype; therefore, in a post-test genetic counseling session, we predicted a normal phenotype for the fetus. After delivery, the normal phenotype of the newborn confirmed our prediction. Based on the present study, this 13q31.1 microdeletion may be considered as a chromosomal polymorphism. This study also reconfirmed the feasibility of obtaining a molecular karyotype of a fetus via NIPT.

Altered modular organization of functional connectivity networks in cirrhotic patients without overt hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with changes in functional connectivity. To investigate the patterns of modular changes of the functional connectivity in the progression of MHE, resting-state functional magnetic resonance imaging was acquired in 24 MHE patients, 31 cirrhotic patients without minimal hepatic encephalopathy (non-HE), and 38 healthy controls. Newman's metric, the modularity Q value, was maximized and compared in three groups. Topological roles with the progression of MHE were illustrated by intra- and intermodular connectivity changes. Results showed that the Q value of MHE patients was significantly lower than that of controls (P < 0.01) rather than that of non-HE patients (P > 0.05), which was correlated with neuropsychological test scores rather than the ammonia level and Child-Pugh score. Less intrasubcortical connections and more isolated subcortical modules were found with the progression of MHE. The non-HE patients had the same numbers of connect nodes as controls and had more hubs compared with MHE patients and healthy controls. Our findings supported that both intra- and intermodular connectivity, especially those related to subcortical regions, were continuously impaired in cirrhotic patients. The adjustments of hubs and connector nodes in non-HE patients could be a compensation for the decreased modularity in their functional connectivity networks.

Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials.

INTRODUCTION: Comprehensively evaluating the efficacy and safety of high-frequency oscillatory ventilation (HFOV) is important to allow clinicians who are using or considering this intervention to make appropriate decisions. METHODS: To find randomized controlled trials (RCTs) comparing HFOV with conventional mechanical ventilation (CMV) as an initial treatment for adult ARDS patients, we searched electronic databases (including PubMed, MedLine, Springer Link, Elsevier Science Direct, ISI web of knowledge, and EMBASE) with the following terms: "acute respiratory distress syndrome", "acute lung injury", and "high frequency oscillation ventilation". Additional sources included reference lists from the identified primary studies and relevant meta-analyses. Two investigators independently screened articles and extracted data. Meta-analysis was conducted using random-effects models. RESULTS: We included 6 RCTs with a total of 1,608 patients in this meta-analysis. Compared with CMV, HFOV did not significantly reduce the mortality at 30 or 28 days. The pooled relative risk (RR) was 1.051 (95% confidence interval (CI) 0.813 to 1.358). ICU mortality was also not significantly reduced in HFOV group, with a pooled RR of 1.218 (95% CI 0.925 to 1.604). The pooled effect sizes of HFOV for oxygenation failure, ventilation failure and duration of mechanical ventilation were 0.557 (95% CI 0.351 to 0.884), 0.892 (95% CI 0.435 to 1.829) and 0.079 (95% CI -0.045 to 0.203), respectively. The risk of barotrauma and hypotension were similar between the CMV group and HFOV group, with a RR of 1.205 (95% CI 0.834 to 1.742) and a RR of 1.326 (95% CI 0.271 to 6.476), respectively. CONCLUSIONS: Although HFOV seems not to increase the risk of barotrauma or hypotension, and reduces the risk of oxygenation failure, it does not improve survival in adult acute respiratory distress syndrome patients.

The common single-nucleotide polymorphism rs2681472 is associated with early-onset preeclampsia in Northern Han Chinese women.

Preeclampsia, characterized by hypertension and proteinuria, remains a leading cause of maternal morbidity and mortality. Recently, a genome-wide association study (GWAS) identified the single-nucleotide polymorphism, rs2681472, as a new hypertension susceptibility genetic variant. The purpose of this study was to evaluate the association between preeclampsia and rs268172 in a Northern Han Chinese population. We genotyped 1218 unrelated Northern Han Chinese women, including 515 patients with preeclampsia and 703 healthy controls. No significant differences were detected in the allele frequencies between patients and controls (P = .23). When patients were divided into early-onset and late-onset preeclampsia according to gestational age of disease onset, the allele frequencies significantly differed between controls and patients with early-onset preeclampsia (P = .02). Genotype frequencies also were significantly different between controls and patients early-onset preeclampsia when data were analyzed under additive (P = .03) and dominant (P = .009) models. We replicated this association in an independent Northern Han Chinese population and observed a significant difference in the allele frequencies between patients with early-onset preeclampsia and controls (P = .011). We report that rs2681472 is associated with early-onset preeclampsia in Northern Han Chinese women.

Cerebral blood flow measured by arterial-spin labeling MRI: a useful biomarker for characterization of minimal hepatic encephalopathy in patients with cirrhosis.

PURPOSE: To investigate the role of arterial-spin labeling (ASL) MRI to non-invasively characterize the patterns of cerebral blood flow (CBF) changes in cirrhotic patients and to assess the potential of ASL MRI to characterize minimal hepatic encephalopathy (MHE). MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Thirty six cirrhosis patients without overt hepatic encephalopathy (16 MHE patients and 20 non hepatic encephalopathy (non-HE) patients) and 25 controls underwent ASL MRI, and CBF was measured for each subject. One-way ANOCOVA test with age and gender as covariences was used to compare CBF difference among three groups, and post hoc analysis was performed between each two groups. Region-based correlation analysis was applied between Child-Pugh score, venous blood ammonia level, neuropsychological tests and CBF values in cirrhosis patients. Receiver operator characteristic (ROC) analysis was used for assessing CBF measurements in ASL MRI to differentiate MHE from non-HE patients. RESULTS: The gray matter CBF of MHE patients (71.09 ± 11.88 mL min(-1)100g(-1)) was significantly higher than that of non-HE patients (55.28 ± 12.30 mL min(-1)100g(-1), P<0.01) and controls (52.09 ± 9.27 mL min(-1)100g(-1), P<0.001). Voxel-wise ANOCOVA results showed that CBFs were significantly different among three groups in multiple gray matter areas (P<0.05, Bonferroni corrected). Post hoc comparisons showed that CBF of these brain regions was increased in MHE patients compared with controls and non-HE patients (P<0.05, Bonferroni corrected). CBF of the right putamen was of the highest sensitivity (93.8%) and moderate specificity (75.0%) for characterization of MHE when using the cutoff value of 50.57 mL min(-1)100g(-1). CBFs in the bilateral median cingulate gyri, left supramarginal gyrus, right angular gyrus, right heschl gyrus and right superior temporal gyrus have both sensitivity and specificity of approximately 80% for the diagnosis of MHE. CONCLUSION: Higher CBF was found in many brain regions in cirrhotic patients than controls and gradually increased with the progress of disease. CBF measured with ASL MRI can be a useful marker for differentiating MHE from non-HE patients.

Transjugular intrahepatic portosystemic shunt induced short- and long-term cerebral blood flow variations in cirrhotic patients: an arterial spin labeling MRI study.

Short- and long-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on cerebral blood flow (CBF) in patients with cirrhosis are still unclear. The purpose of this longitudinal study was to explore CBF alteration patterns in cirrhotic patients after TIPS. Thirteen cirrhotic patients (7 male, 6 female, mean age 50.0 ± 9.3 years) underwent arterial-spin labeling (ASL) MRI 1-9 days (median 1 days) before TIPS. Follow-up MR examinations were performed about 1 week (median 6 days), 3 months (n = 6), 6-9 months (n = 5) and 12-18 months (n = 5) after TIPS. CBF, ammonia level, Child-Pugh score, number connection test type A (NCT-A) and digit symbol test (DST) scores were converted into relative values by dividing by his/her pre-TIPS values, and then, compared via one-way analysis of variance (ANOVA). Correlations between the pre- and post-TIPS changes of relative CBF (rCBF) and the changes of relative ammonia (rAmmonia), Child-Pugh (rChild-Pugh), and NCT-A/DST (rNCT-A/rDST) scores were calculated by crossing subjects. Compared with the pre-TIPS level, the global rCBF slightly increased by 10.9 % about 1 week later, then rapidly decreased by 14.2 % 3 months later, and flatly decreased by 17.2 % in 6-9 months and 18.0 % in 12-18 months following TIPS. The changes of 3-month rDST score were slightly correlated with 3-month rCBF rather than 1-week rCBF, (P < 0.1, FDR-corrected) No difference was found between the pre- and post-TIPS rAmmonia levels, rChild-Pugh and rNCT-A/rDST scores (Post-hoc P > 0.05). CBF measured at different time points after TIPS insertion showed different patterns, indicating varying longitudinal effects of TIPS on CBF. A sharp decline of rCBF was found in the 1 week to 3 months period after insertion, indicating that high event rate of hepatic encephalopathy might relate with the unadaptable CBF in patients undergoing TIPS insertion.

Changes in cerebral blood flow after transjugular intrahepatic portosystemic shunt can help predict the development of hepatic encephalopathy: an arterial spin labeling MR study.

BACKGROUND AND PURPOSE: Cerebral blood flow (CBF) changes after transjugular intrahepatic portosystemic shunt (TIPS) are still unclear. Our aim is to assess the TIPS-induced CBF changes and their potential clinical significance using the arterial spin labeling (ASL) perfusion magnetic resonance imaging. MATERIALS AND METHODS: Nine cirrhotic patients underwent ASL 1-8 days before and 4-7 days after TIPS. CBF was calculated at each voxel and mean CBF values were computed in the whole brain, gray matter and white matter. Changes of CBFs before and after TIPS were compared by paired t-test. RESULTS: Voxel-wise results showed CBF diffusely increased in patients after TIPS, but no region with significant decrease in CBF was found, nor was any significant mean CBF difference detected in the whole brain, gray matter and white matter. Six patients out of nine showed a global CBF increase of 9-39%; one patient presented a global CBF decrease of 6%; another two showed a global CBF decrease of 16% and 31% respectively. Follow-up studies showed that the two patients with greatly decreased global CBF suffered from multiple episodes of overt hepatic encephalopathy (OHE) after TIPS and one died of OHE. CONCLUSIONS: CBF derived from noninvasive ASL MRI could be used as a useful biomarker to predict the development of OHE through consecutively tracking CBF changes in patients with inserted TIPS. Increased CBFs in many cortical regions could be common effects of the TIPS procedure, while decreased global CBF following TIPS might indicate the development of OHE.

A novel mutation in TPRS1 gene caused tricho-rhino-phalangeal syndrome in a Chinese patient with severe osteoporosis.

Tricho-rhino-phalangeal syndrome (TRPS) was first reported in 1966. Although mutation of TRPS1 gene is considered to be responsible for the syndromes in 2000, investigation of bone metabolism and changes of serum insulin-like growth factor (IGF)-1 level in this kind of patients is rare. Here, we report a patient with TRPS I (MIM 190350) presenting a novel mutation (1096insA) and abnormal changes of severe osteoporosis as well as low serum IGF-I level.