Imaging characterization of myocardial function, fibrosis, and perfusion in a nonhuman primate model with heart failure-like features.

Introduction: The availability of a human-like chronic heart failure (HF) animal model was critical for affiliating development of novel therapeutic drug treatments. With the close physiology relatedness to humans, the non-human primate (NHP) HF model would be valuable to better understand the pathophysiology and pharmacology of HF. The purpose of this work was to present preliminary cardiac image findings using echocardiography and cardiovascular magnetic resonance (CMR) in a HF-like cynomolgus macaque model. Methods: The NHP diet-induced model developed cardiac phenotypes that exhibited diastolic dysfunction with reduced left ventricular ejection fraction (LVEF) or preserved LVEF. Twenty cynomolgus monkeys with cardiac dysfunction were selected by echocardiography and subsequently separated into two groups, LVEF < 65% (termed as HFrEF, n = 10) and LVEF ≥ 65% with diastolic dysfunction (termed as HFpEF, n = 10). Another group of ten healthy monkeys was used as the healthy control. All monkeys underwent a CMR study to measure global longitudinal strain (GLS), myocardial extracellular volume (ECV), and late gadolinium enhancement (LGE). In healthy controls and HFpEF group, quantitative perfusion imaging scans at rest and under dobutamine stress were performed and myocardial perfusion reserve (MPR) was subsequently obtained. Results: No LGE was observed in any monkey. Monkeys with HF-like features were significantly older, compared to the healthy control group. There were significant differences among the three groups in ECV (20.79 ± 3.65% in healthy controls; 27.06 ± 3.37% in HFpEF group, and 31.11 ± 4.50% in HFrEFgroup, p < 0.001), as well as for stress perfusion (2.40 ± 0.34 ml/min/g in healthy controls vs. 1.28 ± 0.24 ml/min/g in HFpEF group, p < 0.01) and corresponding MPR (1.83 ± 0.3 vs. 1.35 ± 0.29, p < 0.01). After adjusting for age, ECV (p = 0.01) and MPR (p = 0.048) still showed significant differences among the three groups. Conclusion: Our preliminary imaging findings demonstrated cardiac dysfunction, elevated ECV, and/or reduced MPR in this HF-like NHP model. This pilot study laid the foundation for further mechanistic research and the development of a drug testing platform for distinct HF pathophysiology.

Attitudes and educational needs of emergency doctors providing palliative and end-of-life care in Hong Kong: a cross-sectional analysis based on a self-report study.

BACKGROUND: Due to the ageing population in Hong Kong, the importance and need of palliative care and end-of-life (EOL) care are coming under the spotlight. The objectives of this study were to evaluate the attitudes of emergency doctors in providing palliative and EOL care in Hong Kong, and to investigate the educational needs of emergency doctors in these areas. METHODS: A questionnaire was used to study the attitudes of ED doctors of six different hospitals in Hong Kong. The questionnaire recorded the attitudes of the doctors towards the role of palliative and EOL care in EDs, the specific obstacles faced, their comfort level and further educational needs in providing such care. The attitudes of emergency doctors of EDs with EOL care services were compared with those of EDs without such services. RESULTS: In total, 145 emergency doctors completed the questionnaire, of which 60 respondents were from EDs with EOL care services. A significant number of participants recognized that the management of the dying process was essential in ED. Providing palliative and EOL care is also accepted as an important competence and responsibility, but the role and priority of palliative and EOL care in ED are uncertain. Lack of time and access to palliative care specialists/ teams were the major barriers. Doctors from EDs with EOL care services are more comfortable in providing such care and discuss it with patients and their relatives. Further educational needs were identified, including the management of physical complaints, communication skills, and EOL care ethics. CONCLUSIONS: The study identified obstacles in promoting palliative and EOL care in the EDs Hong Kong. With the combination of elements of routine ED practice and a basic palliative medicine skill set, it would promote the development of palliative and EOL care in Emergency Medicine in the future.

[Risk Factors for Sepsis Associated-Acute Kidney Injury in Intensive Care Unit Patients].

OBJECTIVE: To explore the risk factors of acute kidney injury (AKI) in patients with sepsis in intensive care unit (ICU). METHODS: The medical records of patients diagnosed with sepsis in ICU of West China Hospital of Sichuan University from March 2009 to June 2016 were retrospectively analyzed. Differences between AKI group and Non-AKI group in general data, background disease, ICU entry and exit dates, complications, laboratory data and other related data were analyzed through univariate and multivariate statistical methods. RESULTS: A total of 2331 patients with sepsis were included in the study, including 626 patients in the AKI group and 1695 patients in the Non-AKI group. The multivariate logistic regression analysis revealed that age >40 yr. (odds ratio (OR) =2.752), diabetes (OR=2.563), hypertension/coronary heart disease (OR=1.851), chronic kidney disease (OR=15.876), heart failure (OR=2.295), acute respiratory distress syndrome (OR=2.067), severe acute pancreatitis (OR=2.725), hypotension (OR=2.140), hypoproteinemia (OR=1.596), lactic acidosis (OR=2.164), organ failure>1 (OR=4.480), WBC>10×10 9L -1 (OR=4.166), serum creatinine (OR=4.401), PCT (OR=1.816), Cys-C (OR=7.046), mild anemia (OR=2.107), moderate anemia (OR=3.817), and severe anemia (OR=6.091) were all independent risk factors of SA-AKI. CONCLUSION: Several risk factors are related to the occurrence of SA-AKI in the ICU. Early identification and monitoring of risk factors for SA-AKI and early prevention of AKI can improve the prognosis of sepsis patients.

Liver extracellular volume fraction values obtained with magnetic resonance imaging can quantitatively stage liver fibrosis: a validation study in monkeys with nonalcoholic steatohepatitis.

OBJECTIVES: This study was to evaluate the diagnostic value of liver extracellular volume (LECV) for the staging of liver fibrosis in a cynomolgus monkey model of nonalcoholic steatohepatitis (NASH). METHODS: Forty-eight cynomolgus monkeys were enrolled in this prospective study. There are 17 healthy monkeys and 31 monkeys with NASH. Ten of these monkeys were used for repeatability assessment. The remaining 38 monkeys were used to compare LECV with other indicators including pathology fibrosis score, native T1, and serum chemical indexes by Spearman, Pearson correlation test, and ROC curves. The inter-reader variability was assessed by interclass correlation. The repeatability measurement of LECV was analyzed using Bland-Altman plots and the coefficient of variation. Partial correlation analysis was performed to assess the effects of fat content and inflammation scores on the correlation between LECV/T1 and liver fibrosis score. RESULTS: This study demonstrated a good intra-reader agreement (intraclass correlation = 0.79) of LECV in all monkeys and an excellent repeatability in 10 monkeys (coefficient of variation = 2.01%). The LECV has a strong correlation with the fibrosis score (r = 0.949; p < 0.0001), low-density lipoprotein (r = 0.72; p < 0.0001), and cholesterol (r = 0.70; p < 0.0001). LECV showed high diagnostic efficacy in the diagnosis of liver fibrosis (area under the curve of ROC, 0.945~1; p < 0.001). CONCLUSIONS: LECV may serve as a noninvasive valuable biomarker for the quantification and differentiating of the non-severe liver fibrosis (stage ≤ F3). However, circulating serum markers low-density lipoprotein and cholesterol (CHO) may not serve for this purpose. KEY POINTS: • This paper demonstrated the excellent repeatability (intraclass correlation coefficient = 0.79) of LECV in monkey animal model. • LECV-MRI has a strong correlation with histopathological fibrosis score stage (r = 0.949; p < 0.0001) and shows high diagnostic efficacy in the staging of non-severe liver fibrosis (the area under ROC curve ≥ 0.945). • The new fibrosis score maps appeared to provide a better imaging tool for the spatial assessment of liver fibrosis. It may eventually facilitate the diagnosis of liver fibrosis distribution.

Anodal Transcranial Direct-Current Stimulation Over the Right Dorsolateral Prefrontal Cortex Influences Emotional Face Perception.

The dorsolateral prefrontal cortex (DLPFC) is considered to play a crucial role in many high-level functions, such as cognitive control and emotional regulation. Many studies have reported that the DLPFC can be activated during the processing of emotional information in tasks requiring working memory. However, it is still not clear whether modulating the activity of the DLPFC influences emotional perception in a detection task. In the present study, using transcranial direct-current stimulation (tDCS), we investigated (1) whether modulating the right DLPFC influences emotional face processing in a detection task, and (2) whether the DLPFC plays equal roles in processing positive and negative emotional faces. The results showed that anodal tDCS over the right DLPFC specifically facilitated the perception of positive faces, but did not influence the processing of negative faces. In addition, anodal tDCS over the right primary visual cortex enhanced performance in the detection task regardless of emotional valence. Our findings suggest, for the first time, that modulating the right DLPFC influences emotional face perception, especially faces showing positive emotion.

[Superior colliculus-pulvinar-amygdala subcortical visual pathway and its biological significance].

Superior colliculus-pulvinar-amygdala pathway is one of the subcortical visual pathways in mammalian brain. Some recent studies suggest that this pathway is involved in processing emotion-related visual information. This review discusses the possibility that this pathway is more related to visual alert rather than simply the early visual information processing. The biological significance of this pathway is also discussed. Instead of detecting "where" or "what" the visual target is, the task of this early visual stage is to send out a warning signal, i.e., "something appears", so that the brain can be set up in a state of alert, which is important for the survival of animals. Thus, in the early visual information process, detection of new object "emerging" or "disappearing" takes priority over the acquisition of its feature information of "texture" and "shape", etc. The subcortical pathway may provide the neural basis of early visual warning in topological perception, a biological significance critical for animal survival.

In Vivo Confocal Microscopic Study of Hard Contact Lens-Induced Lipid Keratopathy Secondary to Corneal Neovascularization in a Rabbit Hypercholesterolemic Model.

OBJECTIVES: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV. METHODS: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma-associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages. RESULTS: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high-cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma. CONCLUSIONS: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition.

Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network.

Efficacy and safety of alcohol sclerotherapy involving single-session multiple injections to treat simple renal cysts: a multicenter, prospective, randomized, controlled trial.

BACKGROUND: Alcohol has been used for treating simple renal cysts since 1981. Since then, various observational studies have examined the technique, but they differ significantly in the details of the procedures and efficacy measures used. This has made it difficult to assess the safety and efficacy of this technique. We carried out a randomized controlled trial to evaluate the efficacy and safety of ultrasound-guided alcohol sclerotherapy involving single-session multiple injections to treat simple renal cysts. METHODS: A total of 144 patients with simple renal cysts were randomly allocated to either the treatment group (ultrasound-guided percutaneous drainage and alcohol sclerotherapy with single-session multiple injections) or control group (ultrasound-guided simple percutaneous drainage). Follow-up CT scans of ablated cysts were collected 3 and 6 months after the procedure. The outcome was considered successful if cyst volume between baseline and 6 months decreased by at least 87.5%. RESULTS: Intention-to-treat analysis revealed an average volume reduction of 94.2% in the treatment group and 50.8% in the control group (P < 0.0001). The percentage of patients achieving successful outcomes was 88.9% (95%CI 77.0% - 100.0%) in the treatment group and 22.2% (95%CI 6.54% - 37.9%) in the control group (P < 0.0001). The corresponding results in the per-protocol analysis were an average volume reduction of 96.4% in the treatment group and 50.8% in the control group (P < 0.0001). The percentage of patients achieving a successful outcome was 94.3% (95%CI 85.6% - 100.0%) in the treatment group and 22.2% (95%CI 6.54% - 37.9%) in the control group (P < 0.0001). CONCLUSION: Alcohol sclerotherapy involving single-session multiple injections is safe and efficacious in the treatment of renal cysts.

[Antibacterial activity determination of six kinds of natural herbs in yunnan on normal oral predominant].

OBJECTIVE: To determine the antibacterial activity of six kinds of natural herbs in Yunnan on normal oral predominant bacteria in vitro. METHODS: Agar dilution method, the antimicrobial susceptibility testing of anaerobes which was recommended by National Committee for Clinical Laboratory Standard (NCCLs), was used to determine the antimicrobial susceptibility of herbs to 21 kinds of oral model strains and clinical isolates. The results were expressed by minimum inhibitory concentration (MIC). RESULTS: All six kinds of herbs were effective to the oral predominant bacteria. For the ten kinds of cariogenic bacteria, the MIC of caesalpinia sappan lignum was between 5-10 mg x mL(-1), and the MIC of other herbs was above 20 mg x mL(-1). For the eleven kinds of predominant bacteria which normally involved in pulp periapical disease and periodontitis, the MIC of caesalpinia sappan lignum was below 0.062 5 mg x mL(-1), and the MIC of the terminalia chebula retz was between 10-20 mg x mL(-1), and the others were above 20 mg x mL(-1). CONCLUSION: The six kinds of herbs in Yunnan could be used in treatment or prevention of oral bacterial diseases.

[Expression of adhension molecule CD146 in renal tubular epithelial cells and its clinical significance in IgA nephropathy].

OBJECTIVE: To detect the expression of adhension molecule CD146 in renal tubular epithelial cells and its clinical significance in IgA nephropathy. METHODS: The expression level of CD146 was measured by immunochemistry method in serial sections of 44 specimens from the patients with biopsy-proven IgA nephropathy. The relationship between CD146 expression and clinicopathological changes was analyzed. RESULTS: CD146 was mainly expressed in renal tubular epithelial cells, also slightly in the endothelial cells of peritubular capillary and smooth muscle cells. The expression of CD146 had no relationship with Lee's grade of IgA nephropathy, but positively correlated with 24-hour urine protein(r = 0.381, P = 0.011), hypertention, serum creatinine, triglyceride (Z = -2.738, -2.166, - 2.313, P = 0.006, 0.030, 0.021), index of glomerular sclerosis (r = 0 410, P = 0.006), degree of interstitial fibrosi s (r = 0.311, P = 0.040). CONCLUSION: CD146 might play an important role in the progression of renal interstitial fibrosis.

Neuroaxonal ion dyshomeostasis of the normal-appearing corpus callosum in experimental autoimmune encephalomyelitis.

Atrophy of the corpus callosum (CC) is a well-documented observation in clinically definite multiple sclerosis (MS) patients. One recent hypothesis for the neurodegeneration that occurs in MS is that ion dyshomeostasis leads to neuroaxonal damage. To examine whether ion dyshomeostasis occurs in the CC during MS onset, experimental autoimmune encephalomyelitis (EAE) was utilized as an animal MS model to induce autoimmunity-mediated responses. To date, in vivo investigations of neuronal ion homeostasis has not been feasible using traditional neuroscience techniques. Therefore, the current study employed an emerging MRI method, called Mn2+-enhanced MRI (MEMRI). Mn2+ dynamics is closely associated with important neuronal activity events, and is also considered to be a Ca2+ surrogate. Furthermore, when injected intracranially, Mn2+ can be used as a multisynaptic tracer. These features enable MEMRI to detect neuronal ion homeostasis within a multisynaptic circuit that is connected to the injection site. Mn2+ was injected into the visual cortex to trace the CC, and T1-weighted imaging was utilized to observe temporal changes in Mn2+-induced signals in the traced pathways. The results showed that neuroaxonal functional changes associated with ion dyshomeostasis occurred in the CC during an acute EAE attack. In addition, the pathway appeared normal, although EAE-induced immune-cell infiltration was visible around the CC. The findings suggest that ion dyshomeostasis is a major neuronal aberration underlying the deterioration of normal-appearing brain tissues in MS, supporting its involvement in neuroaxonal functioning in MS.

Neuronal dysfunction of a long projecting multisynaptic pathway in response to methamphetamine using manganese-enhanced MRI.

RATIONALE: Manganese (Mn2+)-enhanced magnetic resonance imaging (MEMRI) is an emerging in vivo MR approach for pharmacological research. One new application of MEMRI in this area is to characterize functional changes of a specific neural circuit that is essential to the central effects of a drug challenge. OBJECTIVES: To develop and validate such use of MEMRI in neuropharmacology, the current study applied MEMRI to visualize functional changes within a multisynaptic pathway originating from fasciculus retroflexus (FR) that is central to a commonly abused psychostimulant, methamphetamine (MA). METHODS: Twelve rats were injected intraperitoneally with MA (10 mg/kg) or saline every 2 h for a total of four injections. After 6 days, Mn2+ was injected into the habenular nucleus (FR origin) of all animals, and MEMRI was repeatedly performed at certain points in time over 48 h. The evolution of Mn2+-induced signal enhancement was assessed across the FR tract, the ventral tegmental area (VTA), the striatum, the nucleus accumbens, and the prefrontal cortex (PFC), in both MA-injected animals and controls. RESULTS: MA treatment was found to affect the complexity and efficiency of Mn2+ uptake in the VTA, via the FR tract, with significantly increased Mn2+ accumulation in the VTA, the dorsomedial part of the striatum, and the PFC. CONCLUSIONS: MEMRI successfully visualizes disruptions in the multisynaptic pathway as the consequences of repeated MA exposure. MEMRI is potentially an important method in the future to investigate functional changes within a specific pathway under the influences of pharmacological agents, given its excellent functional, in vivo, spatial, and temporal properties.

[The characterization of scaffold made of N,O-carboxymethyl chitosan and tricalcium phosphate].

PURPOSE: To study the mechanical and chemical characterization of scaffold made of N,O-carboxymethyl chitosan (N,O-CMCS) and tricalcium phosphate(TCP) with various weight ratios. METHODS: Three composites of N,O-CMCS/TCP with weight ratios of 2:1,1:1 and 1:2 were mixed using the same volume of distilled water. The characteristic bands, morphologic structure, compressive strength and Young modulus of the composites were analyzed by infrared spectroscopy (IR),scanning electron microscopy(SEM) and universal testing machine respectively. RESULTS: The shift of IR characteristic bands of -COO(-)and -NH(2) to lower wave number was observed in three composites gradually, which resulted from the complexation of -COO(-) and -NH(2) with calcium ions. The pores of the three-dimensional porous structure and compressive strength of the composite increased when there were more N,O-CMCS in the composite. When there were more TCP in the composite, its porosity became less and Young modulus increased, so that the composite demonstrated more rigidity. CONCLUSIONS: N,O-CMCS had the capability of complexing with calcium ions. The scaffold made of N,O-CMCS and TCP had the properties of three-dimensional porous structure, flexible remolding and mechanical strength, so it will be a promising biomaterial for bone substitute.

[Effects of hepatocyte growth factor on TGF-beta1 triggered tubular epithelial-myofibroblast transdifferentiation by CTGF in vitro].

OBJECTIVE: To observe the effects of hepatocyte growth factor (HGF) on TGF-beta1 triggered tubular epithelial-myofibroblast transdifferentiation (TEMT) and on the expression of connective tissue growth factor (CTGF). METHODS: The morphology of transdifferentiate tubular cells was observed using phase-contrast microscopy and scanning electron microscopy. alpha-SMA was assessed by immunohistochemistry and semiquantified by mean intergrated opitical density (IOD). The level of fibronectin (FN) in the culture supernatant was measured by ELISA. CTGF mRNA expression was examined by RT-PCR. RESULTS: The TGF-beta1-induced TEMT characterized by expression of alpha-SMA was shown by immunohistochemistry. TGF-beta1 was also shown to stimulate the secretion of FN in cultured supernatant and the CTGF mRNA expression of NRK52E cells. There was no statistically significant difference between HGF-treated groups and control group in the result of alpha-SMA immunostaining and the level of FN, except that CTGF mRNA expression was slightly increased in the HGF-treated groups. The addition of HGF inhibited the TGF-beta1-induced TEMT, the secretion of FN, and the CTGF expression of NRK52E cells, there was a significant correlation between the expression of CTGF and the expression of alpha-SMA. CONCLUSION: HGF could block TEMT and FN secretion triggered by TGF-beta1, which implies that HGF could participate in renal interstitial fibrosis as a negative regulator. The negative regulation of transdifferentiation of HGF may be partially achieved by attenuation of CTGF expression.

[Effect of high glucose on the expression of fibronectin and plasminogen activator inhibitor-1 in human peritoneal mesothelial cells].

OBJECTIVE: To evaluate the effect of high glucose on the expression of fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) in human peritoneal mesothelial cells (HPMC). METHODS: The cultured HPMC were exposed to the culture medium containing different concentrations of glucose (1.5%, 2.5%, 4.25%) for 6, 12, 24, 48 hours, and normal culture medium was used as control. FN and PAI-1 in supernatant were detected by enzyme-linked immunoassay(ELISA). RESULTS: The glucose at 1. 5%, 2.5%, 4.25% resulted in a time- and concentration-dependent increase in FN expression in HPMC(P < 0.05). The glucose at 2.5%, 4.25% increased PAI-1 expression in HPMC (P < 0.05), and the effect was time- and concentration-dependent. PAI-1 expression was not affected by 1.5% glucose (P > 0.05). CONCLUSION: High glucose increases the expression of FN and PAI-1 in HPMC, thus playing a part in the progression of peritoneal fibrosis.

[Clinical and pathological analyses of lipoprotein glomerulopathy].

OBJECTIVE: To investigate the clinical and pathological characteristics of lipoprotein glomerulopathy. METHODS: We retrospectively analyzed 3 cases of lipoprotein glomerulopathy. RESULTS: The 3 patients, 1 male and 2 females, were young Hans. They were admitted to our hospital because of edema. Patient 1 had a positive family history. Her proteinuria ranged between 0.8-1.5 g/d, her serum albumin levels were below the normal lower limit, and she was afflicted with anemia. Patient 2 was found having slightly increased serum creatinine, hypertension, and increased total cholesterol and triglyceride level. The kidneys of patient 3 were enlarged. Increments of glomerular size and capillary lumen space were observed under microscope. Bioptic specimens of the patients' kidneys displayed extensive prominent lucent casts in the capillary lumen, which were stained as pale mesh-like substance and were not stained by silver impregnation. Immunofluorescence microscopy revealed faint immunoglobulin deposit. These casts were stained positive for apoE. CONCLUSION: Lipoprotein glomerulopathy is pathologically characterized by extensive glomerular capillary casts which are stained positive for apoE, and clinically it is characterized by edema, proteinuria, hypoalbuminaemia and anemia.