[Rho kinase inhibitor Y27632 promotes survival of human induced pluripotent stem cells during differentiation into functional midbrain dopaminergic progenitor cells in vitro].

OBJECTIVE: To improve the efficiency of induced differentiation of primitive neural epithelial cells derived from human induced pluripotent stem cells (hiPSCs-NECs) into functional midbrain dopaminergic progenitor cells (DAPs). METHODS: HiPSCs were cultured in mTeSRTM medium containing DMH1 (10 µmol/L), SB431542 (10 µmol/L), SHH (200 ng/mL), FGF8 (100 ng/mL), purmorphamine (2 µmol/L), CHIR99021 (3 µmol/L), and N2 (1%) for 12 days to induce their differentiation into primitive neuroepithelial cells (NECs). The hiPSCs-NECs were digested with collagenase Ⅳ and then cultured in neurobasal medium supplemented with 1% N2, 2% B27-A, BDNF (10 ng/mL), GDNF (10 ng/mL), AA, TGF-ß, cAMP, and 1% GlutaMax in the presence of different concentrations of Rho kinase inhibitor Y27632, and the culture medium was changed the next day to remove Y27632. Continuous induction was performed until day 28 to obtain DAPs. RESULTS: Human iPSCs expressed the pluripotency markers OCT4, SOX2, Nanog, and SSEA1 and were positive for alkaline phosphatase staining. The hiPSCs-NECs were obtained on day 13 in the form of neural rosettes expressing neuroepithelial markers SOX2, nestin, and PAX6. In digested hiPSCs-NECs, the addition of 5 µmol/L Y27632 significantly promoted survival of the adherent cells, increased cell viability and the proportion of S-phase cells (P < 0.01), and reduced the rate of apoptotic cells (P < 0.05). On day 28 of induction, the obtained cells highly expressed the specific markers of DAPS (TH, FOXA2, NURR1, and Tuj1). CONCLUSION: Treatment with Y27632 (5 µmol/L) for 24 h significantly promotes the survival of human iPSCs-NECs during their differentiation into DPAs without affecting the cell differentiation, which indirectly enhances the efficiency of cell differentiation.

Mutations in DARS2 result in global dysregulation of mRNA metabolism and splicing.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare neurological disorder caused by the mutations in the DARS2 gene, which encodes the mitochondrial aspartyl-tRNA synthetase. The objective of this study was to understand the impact of DARS2 mutations on cell processes through evaluation of LBSL patient stem cell derived cerebral organoids and neurons. We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) of seven LBSL patients and three healthy controls using an unguided protocol. Single cells from 70-day-old hCOs were subjected to SMART-seq2 sequencing and bioinformatic analysis to acquire high-resolution gene and transcript expression datasets. Global gene expression analysis demonstrated dysregulation of a number of genes involved in mRNA metabolism and splicing processes within LBSL hCOs. Importantly, there were distinct and divergent gene expression profiles based on the nature of the DARS2 mutation. At the transcript level, pervasive differential transcript usage and differential spliced exon events that are involved in protein translation and metabolism were identified in LBSL hCOs. Single-cell analysis of DARS2 (exon 3) showed that some LBSL cells exclusively express transcripts lacking exon 3, indicating that not all LBSL cells can benefit from the "leaky" nature common to splice site mutations. At the gene- and transcript-level, we uncovered that dysregulated RNA splicing, protein translation and metabolism may underlie at least some of the pathophysiological mechanisms in LBSL. To confirm hCO findings, iPSC-derived neurons (iNs) were generated by overexpressing Neurogenin 2 using lentiviral vector to study neuronal growth, splicing of DARS2 exon 3 and DARS2 protein expression. Live cell imaging revealed neuronal growth defects of LBSL iNs, which was consistent with the finding of downregulated expression of genes related to neuronal differentiation in LBSL hCOs. DARS2 protein was downregulated in iNs compared to iPSCs, caused by increased exclusion of exon 3. The scope and complexity of our data imply that DARS2 is potentially involved in transcription regulation beyond its canonical role of aminoacylation. Nevertheless, our work highlights transcript-level dysregulation as a critical, and relatively unexplored, mechanism linking genetic data with neurodegenerative disorders.

Recent developments in bio-scaffold materials as delivery strategies for therapeutics for endometrium regeneration.

Intrauterine adhesions (IUAs) refer to the repair disorder after endometrial injury and may lead to uterine infertility, recurrent miscarriage, abnormal menstrual bleeding, and other obstetric complications. It is a pressing public health issue among women of childbearing age. Presently, there are limited clinical treatments for IUA, and there is no sufficient evidence that these treatment modalities can effectively promote regeneration after severe endometrial injury or improve pregnancy outcome. The inhibitory pathological micro-environment is the main factor hindering the repair of endometrial damaged tissues. To address this, tissue engineering and regenerative medicine have been achieving promising developments. Particularly, biomaterials have been used to load stem cells or therapeutic factors or construct an in situ delivery system as a treatment strategy for endometrial injury repair. This article comprehensively discusses the characteristics of various bio-scaffold materials and their application as stem cell or therapeutic factor delivery systems constructed for uterine tissue regeneration.

Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans.

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS: Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types.

Persistent Mild Anemia and Hypercalcemia were Ignored as Normal Reaction Secondary to Oral Calcium Supplementation in a Steroid-Dependent Asthma Patient Ultimately Diagnosed as Multiple Myeloma: a Case Report and Literature Review.

BACKGROUND: Anemia can be secondary to many diseases and hypercalcemia can be secondary to oral calcium supplementation. For non-hematologists, anemia and hypercalcemia are usually ignored. Here we report a case of persistent mild anemia and hypercalcemia which were ignored as a normal reaction secondary to oral calcium supplementation in a steroid-dependent asthma patient; it was ultimately diagnosed as multiple myeloma. METHODS: Bone marrow puncture, combined serum, and urine laboratory indexes were performed for diagnosis. RESULTS: A bone marrow puncture specimen comprised 31.5% plasma cells. The serum and urine immunoelectrophoresis showed monoclonal kappa light chains. CONCLUSIONS: When anemia and hypercalcemia occur in an elderly patient, physicians should pay attention to multiple myeloma, especially when accompanied with vertebral and flat bone fractures.

Normal Tumor Markers and Increased Adenosine Deaminase in Pericardial Effusion Misdiagnosed as Tuberculous Pericarditis Ultimately Proven as Lung Adenocarcinoma with Pericardial Metastasis: a Case Report and Literature Review.

BACKGROUND: Elevated adenosine deaminase (ADA) and normal tumor markers in pericardial or pleural effusion are usually considered to be a specific manifestation of benign pericardial or pleural effusion. Here we report a case of lung adenocarcinoma with pericardial metastasis with elevated ADA and normal tumor markers in pericardial effusion. METHODS: Pericardiocentesis and lung puncture combined laboratory indexes and pathology were performed for diagnosis. RESULTS: Analysis of pericardial fluid revealed a white blood cell (WBC) count of 2,000 x 106/L (70% for lymphocytes) with an ADA level of 72.8 U/mL. Pathology of pericardial effusion found no malignant cells. Histopathology of percutaneous lung puncture showed adenocarcinoma. CONCLUSIONS: ADA and tumor markers were not a specific index in differential diagnosis between tuberculosis and metastasis in pericardial effusion.

[Relationship between c-kit mRNA expression and prognosis in patients with rectal carcinoma].

Objective: To investigate the correlation between c-kit mRNA expression and prognosis in patients with rectal carcinoma. Methods: The expression of c-kit mRNA in rectal carcinoma tissues(n=66) was detected by multiplex branched-DNA liquid chip method. According to the expression level, the patients were classified into the c-kit mRNA high expression group and the low group. We analyzed the relationship between the c-kit mRNA expression and the clinicopathological characteristics of patients, as well as the factors affecting patients'prognosis. Results: Of the 66 rectal carcinoma patients, 18(27.3%)cases were c-kit mRNA high expression. No significant correlation was found between the c-kit mRNA expression and gender, age, preoperative carcinoembryonic antigen, preoperative hemoglobin, distance to verge, lymph node metastasis, tumor thrombus, T stage, TNM stage and tumor differentiation (P>0.05). In follow-up, 34 patients died, 32 patients and 36 patients were recurrence or metastasis. The 1-, 3-, 5-year overall survival(OS) of c-kit mRNA high expression group were 100.0%, 77.8%, 77.8%, respectively, while those of the low one were 93.8%, 56.3%, 45.8%, respectively. The difference was statistically significant(P=0.025). Lymph node metastasis, T stage and TNM stage were also significant associated with OS(P<0.05). The 1-, 3-, 5-year disease free rate (DFS)of the c-kit mRNA high expression group were 100.0%, 77.8% and 77.8%, respectively, while those of the low one were 77.1%、43.8% and 41.7%, respectively, and the difference between the two groups was significant (P=0.044). As a reslut, c-kit mRNA expression (P=0.038) and TNM stage (P=0.039) were the independent prognostic factors affecting the OS in rectal cancer patients. Conclusions: Low expression of c-kit was associated with poor prognosis of rectal carcinoma. And the mechanism underlying this phenomenon deserves further exploration.

[Factors affecting stability after fixed orthodontic treatment].

Objective: To analyze factors affecting stability after fixed orthodontic treatment. Methods: Five hundred and forty-four patients who had finished fixed orthodontic treatment more than two years in First Department of Orthodontics, China Medical University from January, 2000 to December, 2017 were investigated and the rate of regular revisit was counted. The data of 288 patients were successfully collected by calling or sending text messages and the rate of standard use of retainers as prescribed (patients wore retainers for 24 months or longer) was counted. According to the variation of peer assessment rating (PAR) index at the start of retention and the time the data collected, the patients were divided into relapse group (variation of PAR index >5) and non-relapse group (variation of PAR index ≤5). Difference significance analysis and multiple-factor logistic regression analysis were used. Sixty patients wearing retainers well were collected and the curative effects of Hawley retainer and vacuum formed retainer (VFR) were compared, which included overbite, overjet, maxillary irregularity index, mandibular irregularity index, width betwenn canine and width between first molar. Results: The rate of regular revisit was 41.0% (223/544). Two hundred and one of 288 patients (69.8%) who were visited successfully had regular revisit, and 60.4%(174/288) of the patients wore retainers well; 30.2% (87/288) of the patients who were visited successfully didn't have regular revisit, and 10.4% (30/288) of the patients wore retainers well. Difference significance analysis showed that there was highly significant difference between relapse group and non-relapse group in the type of retainer and duration of retention (P<0.01). One hundred and forty of 224 patients (62.5%) in non-relapse group and 37.5% (24/64) of the patients in relapse group used VFR, and the duration of retention in non-relapse group was significantly longer than that in relapse group (P<0.01). Multiple-factor Logistic regression analysis showed that wearing Hawley retainers (OR=3.067, P<0.05) was the risk factor influencing relapse. The duration of retention (OR=0.832, P<0.01) was the protective factor influencing relapse. Independent-sample t test indicated that the variations of maxillary [(0.82±0.36) mm] and mandibular [(1.05±0.22) mm] irregularity index in Hawley retainer group were larger than maxillary [(0.64±0.29) mm] and mandibular [(0.72±0.35) mm)] irregularity index in VFR group, respectively. The differences between the two groups were significant (P<0.05). Conclusions: Duration of retention was implicated in stability after orthodontic treatment. VFR had better effect in the aspects of irregularity index than Hawley retainer.

Commentary: miR-132/212 Modulates Seasonal Adaptation and Dendritic Morphology of the Central Circadian Clock.

Daily rhythms in behavior and physiology are coordinated by an endogenous clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This central pacemaker also relays day length information to allow for seasonal adaptation, a process for which melatonin signaling is essential. How the SCN encodes day length is not fully understood. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by directing target mRNAs for degradation or translational repression. The miR-132/212 cluster plays a key role in facilitating neuronal plasticity, and miR-132 has been shown previously to modulate resetting of the central clock. A recent study from our group showed that miR-132/212 in mice is required for optimal adaptation to seasons and non-24-hour light/dark cycles through regulation of its target gene, methyl CpG-binding protein (MeCP2), in the SCN and dendritic spine density of SCN neurons. Furthermore, in the seasonal rodent Mesocricetus auratus (Syrian hamster), adaptation to short photoperiods is accompanied by structural plasticity in the SCN independently of melatonin signaling, thus further supporting a key role for SCN structural and, in turn, functional plasticity in the coding of day length. In this commentary, we discuss our recent findings in context of what is known about day length encoding by the SCN, and propose future directions.

Dexras1 is a homeostatic regulator of exercise-dependent proliferation and cell survival in the hippocampal neurogenic niche.

Adult hippocampal neurogenesis is highly responsive to exercise, which promotes the proliferation of neural progenitor cells and the integration of newborn granule neurons in the dentate gyrus. Here we show that genetic ablation of the small GTPase, Dexras1, suppresses exercise-induced proliferation of neural progenitors, alters survival of mitotic and post-mitotic cells in a stage-specific manner, and increases the number of mature newborn granule neurons. Dexras1 is required for exercise-triggered recruitment of quiescent neural progenitors into the cell cycle. Pharmacological inhibition of NMDA receptors enhances SGZ cell proliferation in wild-type but not dexras1-deficient mice, suggesting that NMDA receptor-mediated signaling is dependent on Dexras1. At the molecular level, the absence of Dexras1 abolishes exercise-dependent activation of ERK/MAPK and CREB, and inhibits the upregulation of NMDA receptor subunit NR2A, bdnf, trkB and vegf-a expression in the dentate gyrus. Our study reveals Dexras1 as an important stage-specific regulator of exercise-induced neurogenesis in the adult hippocampus by enhancing pro-mitogenic signaling to neural progenitor cells and modulating cell survival.

Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus.

Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young versus aged mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age.

Expression and prognostic roles of magnesium-dependent phosphatase-1 in gastric cancer.

OBJECTIVE: Gastric cancer is a leading cause of cancer deaths and has a poor prognosis after diagnosis. Previous studies showed that Magnesium-Dependent Phosphatase-1 (MDP-1) might be a key component for glycosylation in human protein repair, and an alteration of its function has been involved in some aspects of cellular metabolic networks linked to either normal or pathological processe. In this study, we investigate the MDP-1 status in patients with gastric carcinoma, and determine the potential relationship between MDP-1 and clinical outcome. PATIENTS AND METHODS: One hundred and seventy-one consecutive patients with stage I-III gastric carcinoma who had received a D2 gastrectomy were recruited. The MDP-1 expression was determined by immunohistochemistry (IHC). Disease-free survival (DFS) and overall survival (OS) were evaluated. RESULTS: We generate an IHC score on a continuous scale of 0-7. The IHC cutoff point generated by ROC analysis and the threshold IHC score was 2. Low MDP-1 expression was scored for 61 (35.7%) and high MDP-1 expression for 110 (64.3%) patients. We saw a significant down-regulation of MDP-1 expression in G3-4 and stage III tumor tissue compared with G1-2 and stage I-II tumors, p=0.023 and p=0.047. In univariate survival analysis, high expression of MDP-1 predicted a significantly better DFS (56.0 months vs. 25.0 months, p=0.029) and OS (59.0 months vs. 41.0 months, p=0.043) compared with low expression. In a multivariate analysis, the tumor stage was a significant predictor for DFS and OS even after adjustment for all other covariates. The MDP-1 status was a joint predictor for DFS and OS with a multivariate HR 0.728, 95% CI 0.530-0.999, p=0.049 and a multivariate HR 0.745, 95% CI 0.543-1.022, p=0.068, respectively. CONCLUSIONS: We showed that down-regulation of MDP-1 expression was correlated with poorly differentiated carcinoma and later tumor stage, and it predicted a significantly poorer DFS and OS. Down-regulation of MDP-1 expression was a predictor of a poor prognosis for gastric cancer patients, and it may refer to tumor cells that have lost a protective enzymatic system.

Sonographic evaluation of diaphragmatic function during breathing control.

OBJECTIVE: To investigate the effect of "breathing control" on sonographic diaphragmatic excursion. METHOD: A prospective, randomized, assessor-blinded study design involving 20 physiotherapy students; ten with knowledge of the breathing control technique (Group BC) and ten without (Group CON). All participants were asked to perform a Chester step test. Group BC performed BC, while Group CON adopted their own breathing pattern during recovery after the step test. Respiratory rate and sonographic parameters of the diaphragm including diaphragmatic excursion, speed of diaphragmatic contraction (slope of contraction), and inspiratory time were recorded before and after the step test. RESULTS: All baseline data were similar for both groups except age. Respiratory rate at 1 min post-step test was higher in Group CON (24.6±4.9 bpm) compared to Group BC (15.6 ± 3.8 bpm) (p < 0.001). Post-step test sonographic evaluation demonstrated an increase in diaphragmatic excursion with a significant time and group interaction (F(4,72) = 5.499, p = 0.005). Post hoc analysis revealed that the diaphragmatic excursion was significantly higher in Group BC compared to Group CON at first, second and third minute post-step test. Time and group interactions were not significant in inspiration time (F(4,72) = 2.459, p = 0.082) nor the slope of contraction (F(4,72) = 0.655, p = 0.582)]. CONCLUSION: Post-exercise diaphragmatic excursion was higher in participants applying BC. Non-invasive ultrasonography is able to promote objective evaluation of the relationship between breathing techniques and diaphragmatic function.

miR-132/212 Modulates Seasonal Adaptation and Dendritic Morphology of the Central Circadian Clock.

The central circadian pacemaker, the suprachiasmatic nucleus (SCN), encodes day length information by mechanisms that are not well understood. Here, we report that genetic ablation of miR-132/212 alters entrainment to different day lengths and non-24 hr day-night cycles, as well as photoperiodic regulation of Period2 expression in the SCN. SCN neurons from miR-132/212-deficient mice have significantly reduced dendritic spine density, along with altered methyl CpG-binding protein (MeCP2) rhythms. In Syrian hamsters, a model seasonal rodent, day length regulates spine density on SCN neurons in a melatonin-independent manner, as well as expression of miR-132, miR-212, and their direct target, MeCP2. Genetic disruption of Mecp2 fully restores the level of dendritic spines of miR-132/212-deficient SCN neurons. Our results reveal that, by regulating the dendritic structure of SCN neurons through a MeCP2-dependent mechanism, miR-132/212 affects the capacity of the SCN to encode seasonal time.

Clostridium difficile infection in inflammatory bowel disease: challenges in diagnosis and treatment.

The problem of Clostridium difficile infection (CDI) has reached epidemic proportions, particularly in industrialized nations. The pathophysiology, disease course and the potential complications are well appreciated in the general hospitalized patient. However, when CDI occurs in the setting of inflammatory bowel disease (IBD), a number of distinct differences in the diagnosis and clinical management of the infection in this population should be appreciated by gastroenterologists, hospitalists and other care providers. This review highlights the unique aspects of CDI when it occurs in IBD patients with an emphasis on the challenge of distinguishing persistent infection from exacerbation of underlying chronic colitis. An understanding of how CDI may differ in presentation and how management should be altered can prevent serious and life-threatening complications.

RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal.

Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty.

Significant publications on infectious diseases pharmacotherapy in 2015.

PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2015, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in prominent peer-reviewed journals in 2015 that were thought to have a major impact in the field of ID pharmacotherapy. A list of 55 nominated articles on general ID-related topics and 10 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 361 SIDP members surveyed, 153 (42%) and 76 (21%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked publications (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the growing number of significant ID-related publications each year, it can be challenging to stay current with the literature. This review of important ID pharmacotherapy publications in 2015 may be helpful in identifying key articles and lessening this burden.

[Value of intravoxel incoherent motion diffusion-weighted imaging in differential diagnosis of benign and malignant hepatic lesions and blood perfusion evaluation].

Objective: To investigate the value of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in the differential diagnosis and blood perfusion evaluation of benign and malignant hepatic lesions. Methods: A retrospective analysis was performed for 86 patients (96 lesions) with pathologically or clinically confirmed hepatic lesions or hepatic lesions diagnosed based on follow-up results, among whom 48 had malignant lesions (53 lesions) and 38 had benign lesions (43 lesions). The patients underwent conventional magnetic resonance (MR) plain scan, contrast-enhanced scan, and diffusion-weighted imaging (DWI) with different b values (b = 0, 50, 100, 150, 200, 400, 600, 800, 1 000, and 1 200 s/mm2) to determine the parameters of the double exponential model for intravoxel incoherent motion (IVIM): fast diffusion coefficient Dfast, slow diffusion coefficient Dslow, and percentage of fast-diffusion constituent F value. The patients were divided into groups according to the blood supply to lesions on conventional MR plain scan and contrast-enhanced scan, and there were 47 lesions in abundant blood supply group and 49 in poor blood supply group. The data for analysis were Dfast, Dslow, and F values of benign/malignant lesion groups and abundant/poor blood supply groups. The independent samples t-test was used for statistical analysis; the independent samples non-parametric test Mann-Whitney U test was used for the comparison of F value; the receiver operating characteristic (ROC) curve was used to evaluate the value of above parameters in the differentiation of benign and malignant lesions and blood supply evaluation. Results: Compared with the malignant lesion group, the benign lesion group had significantly higher Dslow, and F values (P< 0.001 orP= 0.001) and a higher Dfast value (P= 0.053). Compared with the poor blood supply group, the abundant blood supply group had significantly higher Dfast and F values (P< 0.001 orP= 0.001) and a higher Dslow value (P= 0.185). According to the ROC curve, the cut-off values of Dslow, Dfast, and F values in the diagnosis of benign/malignant hepatic lesions and evaluation of abundant/poor blood supply were 1.18×10-3mm2/s, 27.20×10-3mm2/s, 20.25%, 1.17×10-3mm2/s, 20.30×10-3mm2/s, and 17.80%, respectively, with sensitivities, specificities, accuracy, and areas under the ROC curve of 90.69%/92.45%/91.66%/0.938, 46.51%/73.58%/61.45%/0.589, 74.41%/50.94%/62.50%/0.653, 59.57%/57.14%/58.33%/0.559, 55.32%/63.26%/59.37%/0.618, and 93.61%/89.79%/90.62%/0.961, respectively. Conclusion: The parameter of the double exponential model for IVIM, Dslow value, has a certain value in the differential diagnosis of benign and malignant hepatic lesions, and F value can show blood perfusion in benign and malignant hepatic lesions without the need for contrast-enhanced scan, which provides a reference for the qualitative diagnosis of liver tumor.

Predicting the risk of nephrotoxicity in patients receiving colistimethate sodium: a multicentre, retrospective, cohort study.

OBJECTIVES: With increasing rates of infections caused by MDR Gram-negative organisms, clinicians resort to older agents such as colistimethate sodium (CMS) despite a significant risk of nephrotoxicity. Several risk factors for CMS-associated nephrotoxicity have been reported, but they have yet to be validated. We compared the performance of published mathematical models in predicting the risk of CMS-associated nephrotoxicity. METHODS: In a multicentre, retrospective, cohort study, adult patients (≥18 years of age) were evaluated from five large academic medical centres in the USA. Patients with normal renal function (baseline serum creatinine ≤1.5 mg/dL) who received intravenous CMS for ≥72 h were followed for up to 30 days. The development of nephrotoxicity was as defined by the RIFLE criteria. Each published model was conditioned using patient-specific variables to predict the risk of nephrotoxicity. The predictive performance of the models was evaluated using the observed-to-expected (O/E) ratio. The most significant cut-off threshold for stratifying patients into high and low risk of nephrotoxicity was identified using classification and regression tree analysis. RESULTS: A total of 106 patients were examined (mean age 53.3 ±â€Š14.9 years, 66% male); the overall observed nephrotoxicity rate was 52.8%. We identified a simple model demonstrating reasonable overall nephrotoxicity risk assessment [O/E ratio of 1.07 (95% CI = 0.81-1.39)] and high sensitivity (92.9%) in predicting nephrotoxicity development in patients on CMS therapy. CONCLUSIONS: We identified a model that could be incorporated into patient management strategies to reduce the risk of nephrotoxicity in patients requiring CMS therapy.