[Kindlin-2 regulates endometrium development via mTOR and Hippo signaling pathways in mice].

OBJECTIVE: To investigate the effects and mechanisms of Kindlin-2 on uterus development and reproductive capacity in female mice. METHODS: Cdh16-Cre tool mice and Kindlin-2flox/flox mice were used to construct the mouse model of uterus specific knockout of Kindlin-2, and the effects of Kindlin-2 deletion on uterine development and reproduction capacity of female mice were observed. High expression and knockdown of Kindlin-2 in endometrial cancer cell lines HEC-1 and Ish were used to detect the regulation of mammalian target of rapamycin (mTOR) signaling pathway. In addition, uterine proteins of the female mice with specific knockout of Kindlin-2 and female mice in the control group were extracted to detect the protein levels of key molecules of mTOR signaling pathway and Hippo signaling pathway. RESULTS: The mouse model of uterine specific knockout of Kindlin-2 was successfully constructed. The knockout efficiency of Kindlin-2 in mouse uterus was identified and verified by mouse tail polymerase chain reaction (PCR), Western blot protein identification, immunohistochemical staining (IHC) and other methods. Compared with the control group, the female mice with uterus specific deletion of Kindlin-2 lost weight, seriously impaired reproductive ability, and the number of newborn mice decreased, but the proportion of the female mice and male mice in the newborn mice did not change. Hematoxylin eosin staining (HE) experiment showed that the endometrium of Kindlin-2 knockout group was incomplete and the thickness of uterine wall became thinner. In terms of mechanism, the deletion of Kindlin-2 in endo-metrial cancer cell lines HEC-1 and Ish could downregulate the protein levels of mTOR, phosphorylated mTOR, adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK and phosphorylated ribosomal protein S6 (S6), and the mTOR signal pathway was inhibited. It was found that the specific deletion of Kindlin-2 could upregulate the protein levels of Mps one binding 1 (MOB1) and phosphorylated Yes-associated protein (YAP) in the uterus of the female mice, and the Hippo signal pathway was activated. CONCLUSION: Kindlin-2 inhibits the development of uterus by inhibiting mTOR signal pathway and activating Hippo signal pathway, thereby inhibiting the fertility of female mice.

Relationship between 5-HTTLPR polymorphism and post-stroke depression.

Post-stroke depression (PSD) is a mental illness characterized by subjective feelings of depression, cognitive dysfunction, and decreased interest. The serotoninergic system is involved in the pathogenesis of depressive disorders and is regulated by the serotonin transporter gene. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been examined as a factor associated with depression and other mental disorders. This study was performed to explore the relationship between 5-HTTLPR and PSD in a Han Chinese population. In total, 199 patients with PSD and 202 unrelated non-PSD patients were recruited from psychiatric hospitals. Depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. Blood samples were collected from all patients for 5-HTTLPR genotyping. Genotype and allele frequencies were compared between the two groups. SS genotype frequency was significantly higher in the PSD group than in the non-PSD group. LL genotype frequency was significantly higher in the non-PSD group than in the PSD group (P < 0.01). This study describes a positive association between 5-HTTLPR and PSD in a Han Chinese population and provides genetic evidence to support the genetic susceptibility of PSD.

Expression of APPL1 is correlated with clinicopathologic characteristics and poor prognosis in patients with gastric cancer.

BACKGROUND: Although appl1 is overexpressed in many cancers, its status in gastric cancer (gc) is not known. In the present study, we used relevant pathologic and clinical data to investigate appl1 expression in patients with gc. METHODS: In 47 gc and 27 non-gc surgical specimens, immunohistochemistry was used to detect the expression of appl1, and reverse-transcriptase polymerase chain reaction (rt-pcr) was used to detect messenger rna (mrna). A scatterplot visualized the relationship between survival time and mrna expression in gc patients. The log-rank test and other survival statistics were used to determine the association of appl1 expression with the pathologic features of the cancer and clinical outcomes. RESULTS: In gc, appl1 was expressed in 28 of 47 specimens (59.6%), and in non-gc, it was expressed in 7 of 23 specimens (30.4%, p < 0.05). The expression of mrna in gc was 0.82 [95% confidence interval (ci): 0.78 to 0.86], and in non-gc, it was 0.73 (95% ci: 0.69 to 0.77; p < 0.05). Immunohistochemistry demonstrated that, in gc, appl1 expression was correlated with depth of infiltration (p = 0.005), lymph node metastasis (p = 0.017), and TNM stage (p = 0.022), but not with pathologic type (p = 0.41). Testing by rt-pcr demonstrated that, in gc, appl1 mrna expression was correlated with depth of infiltration (p = 0.042), lymph node metastasis (p = 0.031), and TNM stage (p = 0.04), but again, not with pathologic type (p = 0.98). The correlation coefficient between survival time and mrna expression was -0.83 (p < 0.01). Overexpression of appl1 protein (hazard ratio: 3.88; 95% ci: 1.07 to 14.09) and mrna (hazard ratio: 4.23; 95% ci: 3.09 to 15.11) was a risk factor for death in patients with gc. CONCLUSIONS: Expression of appl1 is increased in gc. Overexpression is prognostic for a lethal outcome.

Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2X4 receptor in spinal microglia in a CCI rat model for neuropathic pain.

BACKGROUND: Although electroacupuncture (EA) is effective in the relief of neuropathic pain, the underlying mechanisms remain unclear. Previous studies have reported immunomodulatory effects of EA in rats. Since excessive release of interferon-γ (IFN-γ) after nerve injury transforms quiescent spinal microglia into an activated state with more neuropathic pain, associated with purinergic receptor P2X4 expression, it is possible that EA may mediate its analgesic effect by attenuating IFN-γ release and subsequent generation of P2X4R(+) microglia. METHODS: Male rats underwent chronic constriction injury (CCI) or IFN-γ intrathecal injection and von Frey tests were performed to evaluate the effect of EA on pain thresholds. Spinal IFN-γ and P2X4R expression levels were measured by immunohistochemistry, real-time PCR, enzyme immunoassay, and/or western blots. In vitro primary cultures of microglia were used to examine IFN-γ activation of P2X4R(+) cells. RESULTS: In CCI rats, EA treatment significantly increased paw withdrawal threshold relative to control. IFN-γ facilitated P2X4R(+) microglia activation both in vitro and in vivo. EA also down-regulated both P2X4R and IFN-γ expression in the spinal cord after CCI. However, EA did not exert the same analgesic effect after intrathecal IFN-γ injection. CONCLUSIONS: EA ameliorated tactile allodynia after peripheral nerve injury by down-regulating excessive expression of IFN-γ in the spinal cord and subsequently reducing expression of P2X4R.

[Under hypoxia condition contactin-1 regulates migration of MKN45 cells through RhoA pathway].

Recent studies have suggested that contactin-1 has a key role in cancer cell proliferation and migration, however the detailed mechanism of this process is still unclear. Here, human gastric cancer cell line MKN45 was employed. It was found that under hypoxia conditions contactin-1 mRNA and protein levels were both up-regulated by HIF-1alpha expression. Furthermore, although hypoxia increased the migration rate of MKN45 cells, contactin-1 (CNTN1) shRNA reversed this process. Meanwhile, RhoA V14 and RhoA V14N19 mutation constructs were employed, and it was found that constitutively active form of RhoA reversed the cell migration suppression induced by contactin-1 knockdown, while dominant-negative form of RhoA blocked hypoxia induced hypermigration. Apart from this, contactin-1 displayed the ability to phosphorylate the RhoA activator p115 RhoGEF. Thus, under hypoxia conditions, elevated HIF-1alpha seems to up-regulate contactin-1 expression and by this activate RhoA and facilitate migration of cancer cells.

Acute kidney injury after infrarenal abdominal aortic aneurysm surgery: a comparison of AKIN and RIFLE criteria for risk prediction.

BACKGROUND: Although both Acute Kidney Injury Network (AKIN) and risk, injury, failure, loss, and end-stage (RIFLE) kidney disease criteria are frequently used to diagnose acute kidney injury (AKI), they have rarely been compared in the diagnosis of AKI in patients undergoing surgery for infrarenal abdominal aortic aneurysm (AAA). This study investigated the incidence of, and risk factors for, AKI, defined by AKIN and RIFLE criteria, and compared their ability to predict mortality after infrarenal AAA surgery. METHODS: This study examined 444 patients who underwent infrarenal AAA surgery between January 1999 and December 2011. Risk factors for AKI were assessed by multivariable analyses, and the impact of AKI on overall mortality was assessed by a Cox's proportional hazard model with inverse probability of treatment weighting (IPTW). Net reclassification improvement (NRI) was used to assess the performance of AKIN and RIFLE criteria in predicting overall mortality. RESULTS: AKI based on AKIN and RIFLE criteria occurred in 82 (18.5%) and 55 (12.4%) patients, respectively. The independent risk factors for AKI were intraoperative red blood cell (RBC) transfusion and chronic kidney disease (CKD) by AKIN criteria, and age, intraoperative RBC transfusion, preoperative atrial fibrillation, and CKD by RIFLE criteria. After IPTW adjustment, AKI was related to 30 day mortality and overall mortality. NRI was 15.2% greater (P=0.04) for AKIN than for RIFLE criteria in assessing the risk of overall mortality. CONCLUSIONS: Although AKI defined by either AKIN or RIFLE criteria was associated with overall mortality, AKIN criteria showed better prediction of mortality in patients undergoing infrarenal AAA surgery.

Five-minute parameter of thromboelastometry is sufficient to detect thrombocytopenia and hypofibrinogenaemia in patients undergoing liver transplantation.

BACKGROUND: Early detection of coagulopathy is important to prevent bleeding during liver transplantation (LT). Rotation thromboelastometry (ROTEM(®)) provides the earliest parameter of clot amplitudes at 5 min (A5). We evaluated whether A5 correlates with platelet count (PLT) and fibrinogen concentration (Fib) and can predict thrombocytopenia and hypofibrinogenaemia in hypocoagulable patients undergoing living-donor LT (LDLT). METHODS: A total of 3446 retrospective ROTEM(®) measurements, including 1139 EXTEM, 1182 INTEM, and 1125 FIBTEM, with simultaneously measured PLT and Fib, were analysed during LDLT in 239 patients. The correlations between A5 and maximum clot firmness (MCF) index, PLT, and Fib were calculated. Receiver operating characteristic analysis with area under the curve (AUC) was used to assess A5 thresholds predictive of PLT and Fib. RESULTS: The median PLT was 47 000 mm(-3) and the median Fib was 100 mg dl(-1) during LDLT. The A5 parameters of EXTEM (A5EXTEM) and INTEM (A5INTEM) were highly correlated with MCF (r=0.96 and r=0.95, respectively), PLT (r=0.76 and r=0.77, respectively), and Fib (r=0.63 and r=0.64, respectively). A5 of FIBTEM (A5FIBTEM) was also correlated with MCF (r=0.91) and Fib (r=0.75). A5EXTEM thresholds of 15 and 19 mm predicted PLT<30 000 mm(-3) (AUC=0.90) and <50 000 mm(-3) (AUC=0.87), respectively, whereas A5FIBTEM 4 mm predicted Fib<100 mg dl(-1) (AUC=0.86). Biases from A5EXTEM and A5FIBTEM to their MCFs were 16.4 and 1.3 mm, respectively. CONCLUSIONS: A5 as an early variable of clot firmness is effective in detecting critically low PLT and Fib. A5 can therefore be a reliable fast index guiding transfusion therapy in hypocoagulable patients undergoing LDLT.

Case series of tracheal extubation in prone position after endoscopic retrograde cholangiopancreatography general anesthesia.

OBJECTIVE: The study aims to present a 15-patient case series of tracheal extubation in the prone position after endoscopic retrograde cholangiopancreatography (ERCP) general anesthesia. PATIENTS AND METHODS: Fifteen inpatients who underwent elective ERCP in our hospital were prospectively enrolled, and a series of case studies were conducted with the prone extubation technique after general anesthesia. All patients underwent routine operation of tracheal intubation under general anesthesia. After the surgery, when the train-of-four ratio (TOFr) ≥0.9, bispectral index (BIS) ≥80, tidal volume ≥6 ml/kg and the required actions could be performed, the endotracheal catheter was removed after sufficient negative pressure suction of oral secretions. After the endotracheal catheter was removed, the patient autonomously turned to the transport bed with the assistance of medical staff and was then admitted to the post-anesthesia care unit (PACU) for further observation. When the patient awoke, he had regained orientation, and presented stable vital signs, no nausea and vomiting, and no other discomfort symptoms, he/she was able to leave PACU and returned to the ward with a Steward score of ≥5. RESULTS: All 15 patients who underwent ERCP elective surgery were successfully extubated in the prone position after surgery. Transient hypoxemia with SpO2 below 90% occurred in 2 of the 15 patients and returned to normal with oxygen mask administration. 7 patients had coughs and were without special treatment. Another 1 patient showed transient abnormal hemodynamic fluctuations after extubation, mean airway pressure (MAP) was higher than 20% of the baseline value, and hemodynamics was stable after drug treatment. CONCLUSIONS: The prone extubation technique is feasible for ERCP general anesthesia patients. However, a larger sample size is needed to validate its safety and to verify whether there exist advantages of the extubation technique in a prone position over a supine position.

First Report of Powdery Mildew Caused by Leveillula taurica on Cynanchum kashgaricum in China.

Cynanchum kashgaricum Liou f., belonging to the family Apocynaceae, is an endemic herbaceous perennial and extremely endangered plant species, only found in the wild in desert regions of Xinjiang, China (3), and is valuable for sand stabilization. In August 2010, a previously unknown and widespread powdery mildew disease was observed on C. kashgaricum growing in the Taklimakan Desert in Xinjiang, China. Disease symptoms included the appearance of a white mycelial coating on the upper surfaces of leaves, while the corresponding abaxial surfaces of infected leaves became chlorotic. As the disease progressed, the infected leaves turned yellow and necrotic. In this survey, the incidence of affected C. kashgaricum plants was 60%. On the basis of microscopic examination, the morphology of the fungus can be described as follows: the primary conidia of the fungus were lanceolate or clavate, with a pointed apex and rounded base, measuring 40.4 to 82.5 × 11.1 to 24.6 µm, with an irregular surface covered by warts; the secondary conidia varied in shape from subcylindrical to cylindrical, with rounded ends, and had lateral borders that were parallel to each other with rounded or truncate bases, measuring 40.5 to 73.5 × 11.2 to 23.9 µm. The ascomata were nearly gregarious and globe-shaped, of dust-colored appearance, and 113 to 267 µm in diameter; they were immersed in dense mycelial tomentum with numerous asci (usually 10 to 18 per ascoma). Numerous, well-developed appendages were present on the lower half of the ascomata; these appendages were irregularly branched and their length was 0.15 to 0.3 times the diameter of the ascomata. The asci were stalked, long or wide ellipsoidal in shape, and 93 to 140 × 27.6 to 52.9 µm. The asci usually contained two ellipsoidal ascospores 24.5 to 49.5 × 18.3 to 29.5 µm. On the basis of morphologic characteristics, the fungus was identified as Leveillula taurica (2). A voucher specimen of the fungus under the identifier HMTU09021 was deposited in the Mycological Herbarium of Tarim University (HMTU). To verify the identity of the fungus, the internal transcribed spacer (ITS) rDNA was amplified and sequenced, and the sequences were deposited as GenBank Accession No. JN861731. Comparison with sequences in the GenBank database revealed that the ITS sequence showed 100% homology with the sequence of L. taurica on Capsicum annuum (Accession No. GQ167201) and Lepidium latifolium (Accession No. AB044349). Thus, the pathogen was identified as L. taurica on the basis of the anamorphic and teleomorphic morphological characters and the ITS sequence. To our knowledge, while L. taurica infection in plants of the family Apocynaceae has been reported around the world (1), in east Asia only a single report of C. glaucum infection in this genus has occurred, in Afghanistan (1). This is the first report of L. taurica infection of C. kashgaricum. Outbreaks of this powdery mildew could not only threaten growth of the endangered plant but also accelerate local ecological deterioration. References: (1) K. Amano. Host Range and Geographical Distribution of the Powdery Mildew Fungi, 2nd ed. Japan Scientific Societies Press, Tokyo, Japan, 1986. (2) U. Braun. A Monograph of the Erysiphales (Powdery Mildews). Nova Hedwigia Beiheft 89:1, 1987. (3) F. Ying et al. Acta Bot. Boreali-Occidentalia Sin. 23:263, 2003.

First Report of Powdery Mildew of Hexinia polydichotoma Caused by Leveillula lactucae-serriolae in China.

Hexinia polydichotoma (Ostenf) H.L. Yang (synonym Chondrilla polydichotoma Ostenf.) is an indigenous sand-binding plant that is widely distributed only in the desert regions of Northwest China. During the summer of 2007, severe outbreaks of a previously unknown powdery mildew were observed in the Taklimakan Desert in Xinjiang, China. Almost 95% of the plants surveyed were affected in this area. The upper surfaces of the stem were covered with white mycelia and the corresponding abaxial surfaces of infected leaves were chlorotic. Affected young, green stems also showed extended chlorosis. As the disease progressed, the infected stems turned yellow and necrotic. Heavy infection resulted in death of the plants. The primary conidia of the fungus were lanceolate with apical pointed, rarely cylindrical or subcylindrical with attenuated apex. They measured 53 to 73 × 15 to 21 µm and had a surface with a net of irregular rides and warts. Subcylindrical or subclavate secondary conidia with rounded ends measuring 50 to 77 × 13 to 20 µm were observed. The ascomata are subgregarious to scattered, globose, and 165 to 200 µm in diameter that are immersed in the dense mycelial tomentum. Numerous and well-developed appendages on the lower half of the ascomata are irregularly branched and can be as long as up to the ascomata diameter. The appendages measure 79 to 106 × 5 to 10 µm and are aseptate, thin walled, and smooth. Asci are numerous (usually more than 20 per ascoma), stalked, clavate-ovoid to nearly cylindrical, and contain two spores (rarely one or three). Ascospores are ellipsoid, hyaline, and measure 25 to 35 × 14 to 20 µm. On the basis of these characteristics, the fungus was identified as Leveillula lactucae-serriolae (2). A voucher specimen was deposited in the Herbarium of Martin Luther University, Halle, Germany (Accession No. HAL 2439F). To confirm the identification, the internal transcribed spacer (ITS) rDNA was amplified and sequenced, and deposited in GenBank (Accession No. HQ821500). Comparison with sequences available in the GenBank database revealed that the ITS sequence shares 99% similarity with that of L. lactucaeserriolae on Lactuca serriola from Iran (Accession No. AB044375.1) (1). Thus, the pathogen was identified as L. lactucae-serriolae based on the host plant species, anamorph morphology, and ITS sequence. Pathogenicity was confirmed through inoculation by gently pressing a diseased stem onto the stem of healthy H. polydichotoma plants. Five inoculated plants were kept under a plastic humid chamber, whereas the same number of noninoculated plants served as the control. The plants were placed under natural conditions (25 to 28°C) with 80 to 90% humidity. At 15 days after inoculation, typical symptoms of powdery mildew developed on the inoculated plants. No symptoms were seen on the control plants. To our knowledge, this is the first report of L. lactucaeserriolae in China and the first record of L. lactucae-serriolae on H. polydichotoma in the world ( http://nt.ars-grin.gov/fungaldatabases/index.cfm ). Because the plant is becoming widely cultivated in the Taklimakan Desert for use in sand-binding, the powdery mildew poses a serious threat to desertification control. References: (1) S. A. Khodaparast et al. Mycol Res. 105:909. 2001. (2) S. A. Khodaparast et al. Mycoscience 43:459, 2002.

A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundice.

BACKGROUND: To compare isoflurane anesthesia in patients with or without hyperbilirubinemia undergoing hepatobiliary surgery. METHODS: Forty-two patients with obstructive jaundice and 40 control patients with normal liver function scheduled for hepatobiliary surgery under isoflurane anesthesia were studied. Anesthesia was induced with propofol (1.5-2 mg/kg) and remifentanil (2 microg/kg). After tracheal intubation, anesthesia was titrated using isoflurane in oxygen-enriched air, adjusted to maintain a bispectral index (BIS) value of 46-54. Ephedrine, atropine and remifentanil were used to maintain hemodynamic parameters within 30% of the baseline. The mean arterial blood pressure (MAP), heart rate (HR), drug doses and the time taken to recover from anesthesia were recorded. RESULTS: Demographic data, duration and BIS values were similar in both groups. Anesthesia induction and maintenance were associated with more hemodynamic instability in the patients with jaundice and they received more ephedrine and atropine and less remifentanil and isoflurane (51.1+/-24.2 vs. 84.6+/-20.3 mg/min; P for all <0.05) than control patients. Despite less anesthetic use, the time to recovery and extubation was significantly longer than that in control. CONCLUSION: Patients with obstructive jaundice have an increased sensitivity to isoflurane, more hypotension and bradycardia during anesthesia induction and maintenance and a prolonged recovery time compared with controls.

Different bispectral index values from both sides of the forehead in unilateral carotid artery stenosis.

Bispectral index (BIS) values derived from the left and right forehead are usually the same. We report on two patients with unilateral carotid artery stenosis in whom we observed differences between the BIS values obtained from sensors placed on each side of the forehead. During surgery, the BIS values of the diseased side decreased more than those of the opposite side when the mean arterial pressure decreased below 70 mmHg. BIS monitors should be used with caution in patients with unilateral carotid artery and cerebrovascular disease.

Association between central venous pressure and blood loss during hepatic resection in 984 living donors.

BACKGROUND: Although low central venous pressure (CVP) anesthesia has been used to minimize blood loss during hepatectomy, the efficacy of this technique remains controversial. We therefore assessed the association between blood loss and CVP during hepatic resection, and examined significant determinants associated with intraoperative hemorrhage during hepatectomy in living donors. METHODS: Between April 2004 and April 2008, 984 living donors who underwent a hepatic resection were assessed retrospectively. Univariate and multivariate analyses were performed to explore the relationships between intraoperative blood loss and several variables including CVP. RESULTS: The mean intraoperative blood loss was 691.3 +/- 365.5 ml. Only four donors required packed red blood cell transfusions (mean, 1.5 U). The mean duration of hepatic resection was 92.1 +/- 26.3 min. The mean, maximum, and minimum values of CVP measured during hepatectomy were 4.6 +/- 1.7, 5.3 +/- 1.8, and 4.0 +/- 1.8 mmHg, respectively, and were not significantly correlated with intraoperative blood loss. On multivariate analysis, predictors of hemorrhage were liver fatty change, gender, and body weight, but none of the mean CVP, surgeons, anesthesiologists, anesthesia duration, resected liver volume, hepatectomy type, systolic blood pressure, heart rate, or body temperature were significant. CONCLUSIONS: CVP during hepatic resection was not associated with intraoperative blood loss in living liver donors, suggesting that CVP may not be an important factor in predicting blood loss during hepatectomy in healthy subjects.

The effects of obstructive jaundice on the pharmacodynamics of propofol: does the sensitivity of intravenous anesthetics change among icteric patients?

BACKGROUND: Some studies suggest that certain clinical symptoms of cholestasis, such as fatigue and pruritus, result from altered neurotransmission. Patients with obstructive jaundice also have labile blood pressure and heart rate. In the present study, the authors investigated whether obstructive jaundice affects a patient's sensitivity to hypnotics and the haemodynamic profile of propofol. METHODS: Thirty-six ASA physical status I/II/III patients with serum total bilirubin (TBL) from 7.8 to 362.7 micromol/l scheduled for bile duct surgery were recruited. A computer-controlled propofol infusion programmed for effect site target was used to rapidly attain and maintain sequential increase of the compartment concentration (from 1 to 3 microg/ml). Each target-controlled concentration was maintained for about 12 min, and arterial blood samples were drawn for propofol concentration determination. The bispectral index (BIS) and mean arterial pressures (MAP) were used as indices of the propofol effect. The relation between the concentration and the effects was described by the Hill equation. The pharmacodynamic parameters were optimized using a nonlinear mixed-effect model. RESULTS: TBL was not a significant covariate of EC(50) for the pharmacodynamic model. For BIS and MAP, the parameters of the pharmacodynamic model were E(max)=75.77%, EC(50)=2.34 microg/ml, and gamma=1.82, and E(max)=47.83%, EC(50)=1.49 microg/ml, and gamma=1.88, respectively. CONCLUSIONS: We demonstrated that obstructive jaundice with serum TBL from 7.8 to 362.7 micromol/l had no effect on propofol pharmacodynamics observed by BIS and MAP.

Propofol pharmacokinetics in patients with obstructive jaundice.

The effect of obstructive jaundice on the distribution and elimination of propofol was studied in 15 patients with obstructive jaundice (total serum bilirubin, TBL >/= 17.1micromol.l(-1)) and in 15 control patients (TBL < 17.1micromol.l(-1)). Following an i.v. bolus dose of propofol (2-2.5 mg.kg(-1)) multiple arterial samples were obtained at timed intervals for 4 h and blood concentrations of propofol were measured by high pressure liquid chromatography. Compartmental analysis of propofol concentrations revealed a three-compartment model with elimination from a central compartment in all patients. Pharmacokinelic parameters: volumes of distribution at steady state (V(SS)), volumes of distribution at equilibrium (V(r)), volumes of the central compartment (V) and total body clearance (Cl) were similar in patients with obstructive jaundice (mean 12.3 (SD 6.0) litre.kg(-1), 32.99(21.42) litre.kg(-1), 0.241(0.131) litre.kg(-1), and 28.8(8.2) ml.min(-1).kg(-1) respectively) compared with contro1 group (11.9 (5.4) litre.kg(-1), 28.30(13.70) litre.kg(-1), 0.297(0.112) litre.kg(-1), and 33.9(7.6) ml.min(-1).kg(-1) respectively) (P>0.05). Half-times of the three phases (T(1/2)(alpha),T(1/2)(beta),T(1/2)(gamma)) were also similar between both groups.We conclude that in patients with obstructive jaundice the pharmacokinetics of propofol are similar to those of patients without obstructive jaundice.

Pretransplantation Cystatin C, but not Creatinine, Predicts 30-day Cardiovascular Events and Mortality in Liver Transplant Recipients With Normal Serum Creatinine Levels.

BACKGROUND: The connection between renal dysfunction and cardiovascular dysfunction has been consistently shown. In patients with liver cirrhosis, renal dysfunction shows a tight correlation with prognosis after liver transplantation (LT); therefore, precise renal assessment is mandatory. Cystatin C, a sensitive biomarker for assessing renal function, has shown superiority in detecting mild renal dysfunction compared to classical biomarker creatinine. In this study, we aimed to compare cystatin C and creatinine in predicting 30-day major cardiovascular events (MACE) and all-cause mortality in LT recipients with normal serum creatinine levels. PATIENTS AND METHODS: Between May 2010 and October 2015, 1181 LT recipients (mean Model for End-stage Liver Disease score 12.1) with pretransplantation creatinine level ≤1.4 mg/dL were divided into tertiles according to each renal biomarker. The 30-day MACE was a composite of troponin I >0.2 ng/mL, arrhythmia, congestive heart failure, death, and cerebrovascular events. RESULTS: The highest tertile of cystatin C (≥0.95 mg/L) was associated with a higher risk for a 30-day MACE event (odds ratio: 1.62; 95% confidence interval: 1.07 to 2.48) and higher risk of death (hazard ratio: 1.96; 95% confidence interval: 1.04 to 3.67) than the lowest tertile (<0.74 mg/L) after multivariate adjustments. However, the highest tertile of creatinine level showed neither increasing MACE event rate nor worse survival rate compared with the lowest tertile (both insignificant after multivariate adjustment). CONCLUSIONS: Pretransplantation cystatin C is superior in risk prediction of MACE and all-cause mortality in LT recipients with normal creatinine, compared to creatinine. It would assist further risk stratification which may not be detected with creatinine.

Application of the Revised Cardiac Risk Index to the Model for End-Stage Liver Disease Score Improves the Prediction of Cardiac Events in Patients Undergoing Liver Transplantation.

INTRODUCTION: Although the revised cardiac risk index (RCRI) is a useful tool for estimating the risk of postoperative cardiac events, whether it improves the prediction of cardiac events in patients undergoing liver transplantation (LT) has not been sufficiently demonstrated. METHODS: We retrospectively analyzed 1429 patients who underwent LT. Cardiac events were defined as myocardial infarction, death, or combined events within 30 days after surgery. The RCRI was defined as the number of independent predictors including high-risk surgery, ischemic heart disease, congestive heart failure, cerebrovascular disease, insulin treatment, and creatinine level >2 mg/dL. Multivariate logistic regression analysis was performed to identify factors independently associated with cardiac events. The additive predictability of RCRI for the Model for End-Stage Liver Disease (MELD) score was assessed using receiver operating characteristic curve analysis. RESULTS: Forty-four (3.1%) cardiac events occurred within 30 days after surgery. Both the MELD score (adjusted odds ratio [aOR], 1.05; P = .005) and RCRI (aOR, 4.35; P < .001 for RCRI score 2; aOR, 6.27; P = .009 for RCRI score 3 compared with RCRI score 1) independently predicted postoperative 30-day cardiac events. The model with MELD score plus RCRI was significantly more predictive for postoperative 30-day cardiac events than the model with MELD score alone (C-statistics 0.800 vs 0.757; P = .030). CONCLUSIONS: For preoperative risk stratification, RCRI showed additive value to MELD score in predicting postoperative 30-day cardiac events after LT.

Prevalence of Antiphospholipid Antibody Positivity and Association of Pretransplant Lupus Anticoagulant Positivity With Early Allograft Dysfunction in Liver Transplantation.

BACKGROUND: Antiphospholipid antibodies (aPL), including anticardiolipin (aCL), anti-ß2-glycoprotein I (anti-ß2GPI), and lupus anticoagulant (LA) antibodies, are frequently found in liver cirrhosis and associated with splanchnic vein thrombosis. Although the risk factors of early allograft dysfunction (EAD) are known, the association between EAD and aPL has been poorly investigated. We hypothesized that LA, potent aPL with thrombotic potential, may be associated with EAD development after living donor liver transplantation (LDLT). METHODS: Data of 719 patients who underwent LDLT from February 2014 to June 2016 at our center were retrospectively collected and analyzed. Patients were divided into 2 groups according to the positivity of LA screening test (LA group [n = 148] vs no-LA group [n = 571]). Risk factors for EAD were investigated using multivariable regression analysis and inverse probability of treatment weighting (IPTW) of propensity scores. RESULTS: The prevalence of LA screening positivity, confirmatory test positivity, and EAD was 20.6%, 1.1%, and 11.3%, respectively. aCL positivity rate was 7.5% and anti-ß2GPI positivity rate was 7.0%. The EAD prevalence in LA and no-LA group was 25.7% and 7.5%, respectively. However, multivariable and IPTW analyses showed no association between EAD and LA screening positivity (P = .263 and P = .825, respectively), although a significant association was found in univariate analysis (odds ratio, 4.242; P < .001). Model for End-stage Liver Disease score, operation time, and C-reactive protein level remained significant after multivariable analysis. CONCLUSION: A positive LA screening test result was associated with EAD only in the univariate analysis. Inflammation, based on C-reactive protein level, was more important for EAD development.

v-Src increases diacylglycerol levels via a type D phospholipase-mediated hydrolysis of phosphatidylcholine.

Activating the protein-tyrosine kinase of v-Src in BALB/c 3T3 cells results in rapid increases in the intracellular second messenger, diacylglycerol (DAG). v-Src-induced increases in radiolabeled DAG were most readily detected when phospholipids were prelabeled with myristic acid, which is incorporated predominantly into phosphatidylcholine. Consistent with this observation, v-Src increased the level of intracellular choline. No increase in DAG was observed when cells were prelabeled with arachidonic acid, which is incorporated predominantly into phosphatidylinositol. Inhibiting phosphatidic acid (PA) phosphatase, which hydrolyzes PA to DAG, blocked v-Src-induced DAG production and enhanced PA production, implicating a type D phospholipase. Consistent with the involvement of a type D phospholipase, v-Src increased transphosphatidylation activity, which is characteristic of type D phospholipases. Thus, v-Src-induced increases in DAG most likely result from the activation of a type D phospholipase/PA phosphatase-mediated signaling pathway.

Prediction of Fluid Responsiveness by a Non-invasive Respiratory Systolic Time Interval Variation Using Heart Sound Signals in Recipients Undergoing Liver Transplantation.

BACKGROUND: The fluid management of cirrhotic patients undergoing liver transplantation (LT) is challenging. Phonocardiography, a graphic recording of heart sounds, provides valuable information concerning heart function and hemodynamic condition. We assessed whether the systolic time interval (STI) and its respiratory variation could predict fluid responsiveness in cirrhotic patients undergoing LT. METHODS: Thirty LT recipients who needed volume expansion were included. The fluid challenge consisted of 500 mL 5% albumin administered over a period of 10 minutes. STI was measured as the time interval between the maximal amplitude of each heart sound corrected with the corresponding RR interval (cSTI). The respiratory variation in STI (STV) induced by mechanical ventilation was calculated. Responders were defined as those showing a ≥10% increase in stroke volume index after volume expansion. RESULTS: In all, 14 of the 30 patients were responders. Significant increases in cSTI were observed after volume expansion in both responders (P < .001) and non-responders (P = .008). Responders showed significant decreases in STV (11.1% ± 4.3% vs 6.1% ± 2.6%, P < .001) after fluid loading, whereas STV in non-responders remained unchanged (6.4% ± 2.6% vs 6.4% ± 4.2%, P = .86). A cut-off value of ≥7.5% STV from baseline could predict fluid responsiveness with an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.618-0.925). CONCLUSIONS: Intra-operative STV can predict fluid responsiveness in patients undergoing LT. Beat-to-beat monitoring of STI and STV may be useful as a non-invasive hemodynamic index and for fluid management.