[Predictive factors of poor prognosis in children with acute kidney injury treated with renal replacement therapy].

Objective: To investigate the predictive factors of poor prognosis in children with acute kidney injury (AKI) treated with renal replacement therapy (RRT). Methods: In this retrospective case-control study, the clinical data were collected from 134 pediatric patients (82 male, 52 female) with AKI treated with RRT in six tertiary hospitals from May 2015 to June 2018. According to the serum creatinine level at discharge, the patients were divided into the favorable outcome group and unfavorable outcome group. The data of sex, age, primary diseases, AKI stage, time from diagnosis of AKI to start of RRT (h) and whether to start RRT within 24 hours, urine volume and complications between the two groups were compared. Continuous variables were compared by t test and Mann-Whitney U test, and percentage or proportions were compared by Chi square test. The predictive factors of adverse prognosis were analyzed by using univariate and unconditional binary logistic regression analysis. Results: The average age of the 134 AKI patients was (6±4) years. There were 114 patients (85.0%) in the favorable outcome group and 20 patients (15.0%) in the unfavorable outcome group. No statistically significant differences were found between the two groups in terms of sex (χ(2)=2.596, P=0.107), age (t=0.718, P=0.474), primary disease (χ(2)=2.076, P=0.722), AKI stage (χ(2)=0.004, P=0.998), time from diagnosis of AKI to start RRT (h) (P=0.745), whether to start RRT within 24 hours (χ(2)=0.016, P=0.899), urine volume (χ(2)=3.118, P=0.374), fluid overload (χ(2)=0.014, P=0.905), multiple organ dysfunction syndrome (MODS) (χ(2)=2.972, P=0.085), acidosis (χ(2)=3.204, P=0.073), hyperkalemia (χ(2)=2.829, P=0.093), the level of blood urea nitrogen (t=1.351, P=0.179) and serum creatinine (P=0.901) at the beginning of RRT. In the unfavorable outcome group, the proportion of patients with mechanical ventilation (45.0% (9/20) vs. 12.3% (14/114), χ(2)=12.811, P<0.01) and the incidence of extra organ injury (≥3) (30.0% (6/20) vs. 10.5% (12/114), χ(2)=6.365, P=0.041) were higher than those in the favorable outcome group. Logistic regression analysis showed that mechanical ventilation (OR=12.540, 95%CI: 3.376-46.577, P<0.01) and hyperkalemia (OR=4.611, 95%CI: 1.265-16.805, P=0.021) were the predictive factors of poor prognosis in patients with AKI treated with RRT. Conclusion: Mechanical ventilation and hyperkalemia may predict a poor prognosis in AKI patients treated with RRT.

High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus.

OBJECTIVE: Disease severity in SLE is an important concept related to disease activity, treatment burden and prognosis. We set out to evaluate if high disease activity status (HDAS), based on ever attainment of a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) disease activity score of ≥10, is an indicator for disease severity in SLE. METHODS: Using prospectively collected data, we assessed the association of HDAS with sociodemographic and disease characteristics and adverse clinical outcomes using logistic regression or generalised estimating equations. RESULTS: Of 286 patients with SLE, who were observed for a median (range) of 5.1 years (1-10.8 years), 43.7% experienced HDAS at least once during the observational period. Autoantibody positivity, particularly anti-dsDNA and anti-Sm positivity, were associated with increased likelihood of HDAS. Age ≥45 years at diagnosis was associated with reduced likelihood of HDAS (p=0.002). Patients with HDAS had higher Physician Global Assessment score (>1: OR 8.1, p<0.001) and were more likely to meet criteria for flare (mild/moderate flare: OR 4.4, p<0.001; severe flare: OR 17.2, p<0.001) at the time of experiencing HDAS. They were also more likely to have overall higher disease activity, as defined by time-adjusted mean SLEDAI-2K score in the highest quartile (OR 11.7, 95% CI 5.1 to 26.6; p>0.001), higher corticosteroid exposure (corticosteroid dose in highest quartile: OR 7.7, 95% CI 3.9 to 15.3; p<0.001) and damage accrual (OR 2.3, 95% CI 1.3 to 3.9; p=0.003) when compared with non-HDAS patients. CONCLUSIONS: HDAS is associated with more severe disease, as measured by higher disease activity across time, corticosteroid exposure and damage accrual. The occurrence of HDAS may be a useful prognostic marker in the management of SLE.

Outcomes of treatment for intracapsular fractures of the mandibular condyle: recommendation for a new classification.

We know of no universally accepted classification for intracapsular condylar fractures. We propose here a new classification based on the concept of a "disc-condyle" unit, and validate the classification based on outcomes of treatment. From 1 January 2010 - 31 December 2014, 55 patients with unilateral intracapsular condylar fractures were classified into three types: type A has no reduction in mandibular height or displacement of the disc (n=7); type B has displacement of the disc with no reduction in mandibular height (n=17); and type C has reduced mandibular height with or without displacement of the disc (n=31). We treated types B and C by open reduction and fixation, while type A fractures were managed non-surgically. At six month follow-up, we found no significant differences in the vertical height of the ramus, mandibular deviation, protrusion, or lateral protrusion between the fractured and healthy sides. All patients had normal occlusion postoperatively and only one patient (type C) reported pain. Magnetic resonance imaging and computed tomography showed good osseous healing and disc-condylar relations in all cases. Our results show that this new classification of intracapsular condylar fractures is a safe and easy way to obtain satisfactory outcomes of treatment. However, it needs further independent validation.

Serum angiopoietin-like 4 is over-expressed in COPD patients: association with pulmonary function and inflammation.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is both a pulmonary and systematic disease, which will cause abnormal expression of some circulating factors. Angiopoietin-like protein 4 (ANGPTL4) has been reported to play important role in inflammatory responses and several diseases. However, whether it contributes to COPD is an open question. The aim of this study is to explore the potential relationship between ANGPTL4 and COPD. PATIENTS AND METHODS: In this study, circulating levels of ANGPTL4, C-reactive protein (CRP), adiponectin, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 and monocyte chemotactic protein (MCP)-1 in 73 COPD patients and 40 healthy volunteers were investigated using multiplex enzyme-linked immunosorbent assay Kits. Then, we analyzed the correlations between ANGPTL4 with other inflammatory mediators and pulmonary function. RESULTS: Serum ANGPTL4 levels were significantly elevated in COPD patients compared with healthy controls (122.86 ± 38.59 ng/mL versus 99.03 ± 31.84 ng/mL, p = 0.001). Besides, serum ANGTPL4 levels were much higher in ever-smokers with COPD than in never-smokers with COPD (131.71 ± 32.92 ng/mL versus 113.25 ± 42.34 ng/mL, p = 0.03). More importantly, the concentrations of circulating ANGPLT4 correlated inversely with forced expiratory volume in 1 second (FEV1) % predicted, an index of lung function in COPD (r = -0.450, p < 0.001) and in all participants (r = -0.369, p < 0.001), while correlated positively with CRP (r = 0.312, p = 0.007 for COPD; r = 0.404, p < 0.001 for total subjects), adiponectin (r = 0.266, p = 0.004 for total subjects), and MMP-9 (r = 0.254, p = 0.03 for COPD). CONCLUSIONS: Our results suggest that circulating ANGPTL4 levels are up-regulated in COPD patients, and have correlations with pulmonary function and systematic inflammation in COPD, which provides a novel idea to further dig the pathogenic mechanisms of COPD, and justifies more studies to determine how ANGPTL4 contributes to COPD.

Correction of facial asymmetry associated with vertical maxillary excess and mandibular prognathism by combined orthognathic surgery and guiding templates and splints fabricated by rapid prototyping technique.

The facial asymmetry associated with vertical maxillary excess and mandibular prognathism is one of the more complicated types in the field of oral and maxillofacial surgery. The purpose of this study was to investigate the efficacy of combined orthognathic surgeries, together with guiding templates and splints fabricated by rapid prototyping technique, for the correction of facial asymmetry. Fourteen patients with facial asymmetry associated with vertical maxillary excess and mandibular prognathism were included. A maxillary Le Fort I osteotomy, a sagittal split ramus osteotomy on the shorter side of the face, and an intraoral vertical ramus osteotomy on the longer side of the face were performed with the aid of guiding templates and splints fabricated by rapid prototyping technique. Parameters reflecting maxillary canting, ramal inclination, mandibular deviation, and chin inclination were measured before surgery, 7 days after surgery, and 1 year after surgery, and compared. Significant differences in these parameters were found between the two sides preoperatively, whereas no differences were observed postoperatively. Facial asymmetry was corrected in all patients with satisfactory outcomes. In conclusion, combined orthognathic surgery and guiding templates and splints can offer improvements in accuracy, complexity, and duration over traditional procedures for the correction of facial asymmetry associated with vertical maxillary excess and mandibular prognathism.

The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.

We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augmented the VRX-007-mediated inhibition of tumor growth, in both CP-treated and non-CP-treated hamsters, even though radiation did not lead to increased viral replication in tumors when compared with those treated with VRX-007 alone. Moreover, tumor growth inhibition was similar in tumors irradiated either 1 week before or after injection with VRX-007, which suggests that radiation exerts its antitumor effect independently from vector therapy. Thus, our results demonstrate that these two therapies do not have to be provided simultaneously to enhance their combined effectiveness against subcutaneous hamster tumors.

The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors.

We have previously reported that intratumoral injection of VRX-007--an Ad5 (a species C adenovirus)-based vector overexpressing adenovirus death protein--can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here, we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007, to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either 1 week before or 1 week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome.

Tongue musculomucosal flap for soft palate reconstruction in patients with OSAHS - clinical experience in technical strategy.

BACKGROUND: With the idea of "replacing lost tissure with similar tissure in kind", vessel-pedicled palate mucosal flap, pedicled buccal musculomucosal flap and adjacent tongue musculomucosal flap could be the ideal approaches to soft palate reconstruction. AIM: To assess the adjacent tongue musculomucosal flap for soft palate reconstruction. PATIENTS AND METHODS: From August 2010 to July 2011, we applied tongue musculomucosal flap for soft palate reconstruction in three patients with Obstructive Sleep Apnoea/Hypopnoes Syndrome (OSAHS) in order to release OSAHS symptom by glossal volume reduction. RESULTS: All patients recovered from intraoral operations with good objective as subjective speech and swallowing. Suffice it to say that OSAHS symptom was released for these patients. CONCLUSIONS: Here we provide a case to deal with problems related to OSAHS symptom when one works on oral surgery or reconstructing oral structure.

Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population.

Interleukin-18 (IL-18) has been implicated in a wide variety of cellular functions that affect the biological response to tumors. However, there is insufficient evidence to prove that IL-18 gene variants are associated with risk of prostate cancer. We examined a possible association between two promoter polymorphisms, -137G/C (rs187238) and -607C/A (rs1946518), in the IL-18 gene and prostate cancer occurrence and prognosis in Han Chinese. We used a high-resolution melting method to genotype these two polymorphisms in 375 Chinese Han patients with prostate cancer and in 400 age-matched healthy controls. A hundred and eighty-one prostate cancer patients who had been receiving androgen deprivation therapy, including operational and medical castration, were enrolled to follow-up in this study. Carriers of the GG genotype of the -137G/ C polymorphism had a 2.165-times higher risk of prostate cancer progression than carriers of GC [95% confidence interval (CI) = 1.270-3.687]. Patients with the GG genotype at clinical stages III and IV also had significantly lower rates of progression-free survival (relative risk = 2.174, 95%CI = 1.211-3.906). However, we found no significant association of genotype or allele distributions of these two polymorphisms with occurrence of prostate cancer. We conclude that there is evidence that the IL-18 gene promoter polymorphism -137G/ C influences the prognosis of prostate cancer patients in androgen deprivation therapy, although neither of the two SNPs contributes to prostate cancer development.

Association of polymorphisms in interleukin-18 and interleukin-28B with hepatitis B recurrence after liver transplantation in Chinese Han population.

Interleukin-18 (IL-18) is a potent proinflammatory cytokine, which can promote hepatitis B virus clearance. The latest studies find that genetic polymorphisms near the IL-28B gene are strongly associated with sustained viral response and spontaneous viral clearance in patients with chronically infected hepatitis C and hepatitis B. We investigated the effect of rs187238 and rs1946518 in IL-18 gene and rs8099917 in IL-28B gene on HBV recurrence in liver transplant patients. A total of 200 liver transplant recipients and relevant donors were enrolled in this study. The patients' mean follow-up was 39 month (range 10-65 month). All liver transplant recipients were in a stable stage. The total recipients (n = 200) were divided into end-stage liver disease secondary to hepatitis B (n = 140) and end-stage liver disease secondary to other diseases (n = 60) before transplantation. Recipients (n = 140) with hepatitis B before transplantation were defined to nonHBV recurrence group (n = 119) or HBV recurrence group (n = 21), which was positive for HBsAg or elevatory in HBV DNA (>2.0 × 10(2) IU mL(-1)) after transplantation. For the recipients (n = 140) had hepatitis B before transplantation, we studied the single-nucleotide polymorphisms (SNPs) of IL-18 gene (rs187238 and rs1946518) and IL-28B gene (rs8099917) by high-resolution melting (HRM) curve analysis. The serum levels of IL-18 and IFN-γ were tested by ELISA. The serums levels of IFN-γ were lower in HBV recurrence group than that in nonHBV recurrence group (P < 0.01). The genotype of IL-28B gene rs8099917 was associated with alanine aminotransferase (ALT) levels and aspartate aminotransferase (AST) levels in HBV-related liver transplant recipients (n = 140). The recipients with allele G (GG+GT) had higher ALT and AST levels (P < 0.05). No association was found between IL-18 gene and IL-28B gene polymorphisms with HBV recurrence in the liver transplant recipients or the donors. We identified that the IFN-γ was a protective factor of HBV recurrence after liver transplantation. The allele G of rs8099917 was associated with hepatitis B-related hepatocytes injury. The rs8099917 G allele subgroup should reinforce antiviral therapy.

The effect of tight glycaemic control, during and after cardiac surgery, on patient mortality and morbidity: A systematic review and meta-analysis.

BACKGROUND: Hyperglycaemia is a common occurrence during cardiac surgery, however, there remains some uncertainty surrounding the role of tight glycaemic control (blood glucose <180 mg/dL) during and/or after surgery. The aim of this study was to systematically review the literature to determine the effects of tight versus normal glycaemic control, during and after cardiac surgery, on measures of morbidity and mortality. METHOD: The literature was systematically reviewed, based on pre-determined search criteria, for clinical trials evaluating the effect of tight versus normal glycaemic control during and/or after cardiac surgery. Each paper was reviewed by two, independent reviewers and data extracted for statistical analysis. Data from identified studies was combined using meta-analysis (RevMan5®). The results are presented either as odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: A total of seven randomised controlled trials (RCTs) were identified in the literature, although not all trials could be used in each analysis. Tight glycaemic control reduced the incidence of early mortality (death in ICU) (OR 0.52 [95% CI 0.30, 0.91]); of post-surgical atrial fibrillation (odds ratio (OR 0.76 [95%CI 0.58, 0.99]); the use of epicardial pacing (OR 0.28 [95%CI 0.15, 0.54]); the duration of mechanical ventilation (mean difference (MD) -3.69 [95% CI -3.85, -3.54]) and length of stay in the intensive care unit (ICU) (MD -0.57 [95%CI -0.60, -0.55]) days. Measures of the time spent on mechanical ventilation (I2 94%) and time spent in ICU (I2 99%) both had high degrees of heterogeneity in the data. CONCLUSION: The results from this study suggest that there may be some benefit to tight glycaemic control during and after cardiac surgery. However, due to the limited number of studies available and the significant variability in glucose levels; period of control; and the reporting of outcome measures, further research needs to be done to provide a definitive answer on the benefits of tight glycaemic control for cardiac surgery patients.

Prevalence of hepatitis B virus genotypes and their relationship to clinical laboratory outcomes in Tibetan and Han Chinese.

This study was designed to investigate the prevalence of hepatitis B virus (HBV) genotypes in Tibetan and Han nationalities in Sichuan Province, China, and their clinical significance. Sera from 376 patients (286 Han nationals, 90 Tibetan nationals) were genotyped by polymerase chain reaction. Of the 286 Han nationals, 127 were HBV asymptomatic carriers, 90 were symptomatic patients and 69 had hepatocellular carcinoma. The distribution of HBV genotypes was related to geography as well as ethnicity. The HBV genotype frequencies were: B, 57.9%; C, 16.0%; and BC, 26.1%. Association studies between genotypes and clinical laboratory outcomes showed HBV genotype C to be more virulent. There was a higher prevalence of mixed genotype BC in Tibetan nationals compared with Han nationals. There was no synergistic effect in terms of virulence in patients coinfected with genotypes B and C.

INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies.

Preclinical biodistribution studies with INGN 007, an oncolytic adenovirus (Ad) vector, supporting an early stage clinical trial were conducted in Syrian hamsters, which are permissive for Ad replication, and mice, which are a standard model for assessing toxicity and biodistribution of replication-defective (RD) Ad vectors. Vector dissemination and pharmacokinetics following intravenous administration were examined by real-time PCR in nine tissues and blood at five time points spanning 1 year. Select organs were also examined for the presence of infectious vector/virus. INGN 007 (VRX-007), wild-type Ad5 and AdCMVpA (an RD vector) were compared in the hamster model, whereas only INGN 007 was examined in mice. DNA of all vectors was widely disseminated early after injection, but decayed rapidly in most organs. In the hamster model, DNA of INGN 007 and Ad5 was more abundant than that of the RD vector AdCMVpA at early times after injection, but similar levels were seen later. An increased level of INGN 007 and Ad5 DNA but not AdCMVpA DNA in certain organs early after injection, and the presence of infectious INGN 007 and Ad5 in lung and liver samples at early times after injection, strongly suggests that replication of INGN 007 and Ad5 occurred in several Syrian hamster organs. There was no evidence of INGN 007 replication in mice. In addition to providing important information about INGN 007, the results underscore the utility of the Syrian hamster as a permissive immunocompetent model for Ad5 pathogenesis and oncolytic Ad vectors.

Plasma ghrelin levels and weight loss in Chinese Uygur patients with chronic obstructive pulmonary disease.

Ghrelin is an important orexigenic hormone that reduces fat oxidation and increases adiposity. This study investigated plasma ghrelin levels in Chinese Uygur patients with chronic obstructive pulmonary disease (COPD). Plasma ghrelin and anabolic and catabolic factors were measured in 38 patients and 24 control subjects. COPD patients were divided into two groups based on body mass index (BMI): underweight (BMI < 20 kg/m(2), n = 18) or normoweight (BMI > or = 20 kg/m(2), n = 20). Plasma ghrelin levels were found to be significantly higher in underweight than in normoweight patients or healthy controls. Circulating tumour necrosis factor-alpha and interleukin-6 concentrations were significantly higher in underweight than in normoweight patients, whereas insulin concentrations were significantly lower. Plasma ghrelin levels correlated negatively with forced expiratory volume in 1 s (FEV(1); r = 0.35), but did not significantly correlate with FEV(1)/forced vital capacity. Plasma ghrelin levels were elevated in underweight COPD patients and were associated with cachexia and abnormal pulmonary function.

Vintage year determination of bottled Chinese rice wine by VIS-NIR spectroscopy.

The feasibility of noninvasive visible and near infrared (VIS-NIR) spectroscopy for determining vintage year of Chinese rice wine was investigated. VIS-NIR spectra of 100 samples were collected in transmission mode in 600-mL square brown glass bottles by a fiber spectrometer system. Discriminant models were developed based on discriminant analysis (DA) together with raw, 1st, and 2nd derivative spectra. The concentration of alcohol content, total acid, and degrees Brix was determined to validate the VIS-NIR results. The calibration result for raw spectra was better than that for 1st and 2nd derivative spectra. The percentage of samples correctly classified for raw spectra was 97.1%. For the sample groups in the vintage years of 2002, 2003, and 2004, the samples were all correctly classified. And for the 2000 and 2001 sample groups, the percentage of samples correctly classified was 92.9%. In validation analysis, the samples were all correctly classified. The results demonstrated that the VIS-NIR spectroscopic technique could be used as a noninvasive and rapid method for predicting vintage year of bottled Chinese rice wine.

Reconstruction of mandibular symphyseal defects by trifocal distraction osteogenesis: an experimental study in Rhesus.

Mandibular symphyseal defects caused by tumor surgery, trauma, or congenital misshape can produce maxillofacial deformity and functional handicap. Recently, the technique of distraction osteogenesis has become a valuable reconstructive method for craniofacial bone defects. Four adult rhesus monkeys were used in this study. The anterior mandibulectomy (ranged from canine to canine) was performed, and bilateral transport segments (ranged from first premolar to first molar) were created. Custom-made multiplanar distractors were applied for the reconstruction of the monkeys' artificial mandibular symphyseal defects by trifocal distraction osteogenesis. After a delay period of 7 days, the bilateral transport discs were distracted forward and inward simultaneously. Serial X-ray and three-dimensional CT films were taken within the experimental period. Two monkeys were sacrificed at 8 and 16 weeks, respectively, after the completion of distraction. The distracted calluses and united areas between bilateral transport discs were harvested and processed for histological examination. The mandibular symphyseal defects in all animals were repaired successfully and the anterior mandibular contours were similar to the normal ones. Perfect bone regeneration in the distraction gaps was found, and fibro-bony union between the bilateral transport segments was observed in the midline region at 16 weeks after the end of distraction. The success of distraction osteogenesis for repair of mandibular symphseal defects in monkeys by this distractor may provide an alternative method to reconstruct the anterior part of mandible.

Identification of a high-affinity binding site involved in the transport of endocannabinoids.

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.