Long-Term Outcomes After Stenting in Extracranial vs. Intracranial Stenosis.

Objective: The purpose of this pilot study is to explore the difference in safety and effectiveness after stenting in patients with extracranial or intracranial vertebral artery stenosis. Methods: The study involved 26 patients treated with stents for ≥70% stenosis between January 1, 2017, and September 8, 2020. The patients were divided into intracranial and extracranial groups based on the location of the target vessel stenosis. The incidence of stroke or death within 30 days, long-term recurrence of ischemic symptoms, and restenosis during follow-up were monitored. Results: Within 30 days, no stroke or death was observed in the 26 patients, During the follow-up period, the risk of recurrence of posterior circulation stroke or transient ischemic attack was 23.1% (6/26). Vascular-related complications were 5.6% vs. 12.5% (P = .529) in the intracranial vs. extracranial stenosis group. After 1 year, stroke or transient ischemic attack of posterior circulation was observed in 12.5% (1/8) vs. 16.7% (3/18) in the intracranial and extracranial stenosis group, respectively. The restenosis rate in the intracranial stenosis group was higher than the extracranial stenosis group (37.5% vs. 28.6%, P > .05). This trend was also found in the asymptomatic restenosis rate (25% vs. 7.1%, P = .527). Conclusions: The study results showed that there was no significant difference in the safety and effectiveness after stenting in extracranial and intracranial vertebral artery stenosis, but intracranial vertebral artery stenosis has a low rate of symptomatic restenosis. Symptomatic restenosis may be an important problem that limits the efficacy of extracranial vertebral artery stenting.

A comparative effectiveness study of carotid intervention for long-term stroke prevention in patients with severe asymptomatic stenosis from a large integrated health system.

OBJECTIVE: The results of current prospective trials comparing the effectiveness of carotid endarterectomy (CEA) vs standard medical therapy for long-term stroke prevention in patients with asymptomatic carotid stenosis (ACS) will not be available for several years. In this study, we compared the observed effectiveness of CEA and standard medical therapy vs standard medical therapy alone to prevent ipsilateral stroke in a contemporary cohort of patients with ACS. METHODS: This cohort study was conducted in a large integrated health system in adult subjects with 70% to 99% ACS (no neurologic symptom within 6 months) with no prior ipsilateral carotid artery intervention. Causal inference methods were used to emulate a conceptual randomized trial using data from January 1, 2008, through December 31, 2017, for comparing the event-free survival over 96 months between two treatment strategies: (1) CEA within 12 months from cohort entry vs (2) no CEA (standard medical therapy alone). To account for both baseline and time-dependent confounding, inverse probability weighting estimation was used to derive adjusted hazard ratios, and cumulative risk differences were assessed based on two logistic marginal structural models for counterfactual hazards. Propensity scores were data-adaptively estimated using super learning. The primary outcome was ipsilateral anterior ischemic stroke. RESULTS: The cohort included 3824 eligible patients with ACS (mean age: 73.7 years, 57.9% male, 12.3% active smokers), of whom 1467 underwent CEA in the first year, whereas 2297 never underwent CEA. The median follow-up was 68 months. A total of 1760 participants (46%) died, 445 (12%) were lost to follow-up, and 158 (4%) experienced ipsilateral stroke. The cumulative risk differences for each year of follow-up showed a protective effect of CEA starting in year 2 (risk difference = 1.1%, 95% confidence interval: 0.5%-1.6%) and persisting to year 8 (2.6%, 95% confidence interval: 0.3%-4.8%) compared with patients not receiving CEA. CONCLUSIONS: In this contemporary cohort study of patients with ACS using rigorous analytic methodology, CEA appears to have a small but statistically significant effect on stroke prevention out to 8 years. Further study is needed to appropriately select the subset of patients most likely to benefit from intervention.

A Case of Hypokalemia Caused by Left Native Renal Artery Stenosis in a Kidney Transplant Recipient.

A 39-year-old woman with end-stage renal failure of unknown origin was on peritoneal dialysis for 10 years. One year ago, she underwent ABO-incompatible living-donor kidney transplantation from her husband. After the kidney transplantation, her serum creatinine level remained around 0.7 mg/dL, but her serum potassium level remained low at around 3.5 mEq/L despite potassium supplementation and spironolactone. The patient's plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were markedly elevated (20 ng/mL/h and 868 pg/mL, respectively). A CT angiogram of the abdomen performed 1 year previously suggested stenosis of the left native renal artery, which was considered responsible for the hypokalemia. Renal venous sampling was done on both the native kidneys and the transplanted kidney. Since renin secretion from the left native kidney was significantly elevated, a laparoscopic left nephrectomy was performed. Postoperatively, the renin-angiotensin-aldosterone system was markedly improved (PRA: 6.4 ng/mL/h, PAC: 147.3 pg/mL), and the serum potassium levels also improved. Pathological examination of the removed kidney showed many atubular glomeruli and hyperplasia of the juxtaglomerular apparatus (JGA) in residual glomeruli. In addition, renin staining showed strong positivity in the JGA of these glomeruli. Here, we report a case of hypokalemia caused by left native renal artery stenosis in a kidney transplant recipient. This valuable case study provides histological confirmation of maintained renin secretion in an abandoned native kidney after kidney transplantation.

And don't forget your anti in-stent stenosis pill! Commentary on 'Factors associated with in-stent stenosis after cerebral aneurysm embolization using a Pipeline embolization device' by Flores-Milan et al.

In their INR study, Flores-Milan et al. present a retrospective single-centre study that aimed to investigate and determine some of the factors associated with in-stent stenosis (ISS) after intracranial aneurysm (IA) embolization using a commercially available flow diverter stent (FD). The retrospective analyses included ruptured and unruptured intracranial aneurysms treated with standalone flow diverter stent implantation or initial coil obliteration with the FD device placed subsequently two weeks after initial treatment. The article's methodology was carefully tailored to demystify the unknown pathophysiological mechanism behind the entity of interest called in-stent stenosis. Study outcomes also included angiographic evaluation of aneurysm occlusion thrombotic and hemorrhagic events. The authors reported excellent technical and clinical results altogether. The achieved angiographic occlusion rates resonate with the current obliteration results reported in the literature. Mortality and morbidity are congruent with previously published results and were 5.3% and 1.1%, respectively.

Euonymine inhibits in-stent restenosis through enhancing contractile phenotype of vascular smooth muscle cells via modulating the PTEN/AKT/mTOR signaling pathway.

BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for acute myocardial infarction, but the postoperative in-stent re-stenosis (ISR) remains a major risk factor that affects the prognosis of PCI. Clinically, drug-eluting stents (DES) are widely applied to prevent and treat ISR. However, only a few stent coating drugs are currently available for clinical use, including paclitaxel and rapamycin (sirolimus) and their derivatives. These stent-coated drugs have led to a decrease in restenosis rates, but the major adverse outcomes, such as delayed endothelial healing and increased in-stent thrombosis, seriously reduce their therapeutic effects. PURPOSE: Herein, we explored the potential efficacy of Euonymine (Euo), an alkaloid extracted from Tripterygium Hypoglaucum (Levl) Hutch (THH, Lei gong Teng), for the prevention against ISR after PCI. STUDY DESIGN: Our study depicts the potential efficacy of Euo in treating ISR and explores its mechanism with in vitro and in vivo models. METHODS: Primary vascular smooth muscle cells (VSMCs) from the rabbit thoracic aorta were cultured, and the proliferation and migration of VSMCs were monitored. Apoptosis was measured by Transmission Electron Microscopy and TUNEL staining assay. Protein and gene levels were measured to explore the underlying molecular mechanisms. In vivo models of porcine coronary implantation and rabbit carotid balloon injury are used to validate the efficacy of Euo in inhibiting ISR after PCI. RESULTS: With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. We next established a rabbit carotid balloon injury model in which the phosphorylation levels of PI3K and AKT1 (Ser473) as well as mTOR activity were significantly elevated compared to the sham-operated control. These activities were significantly attenuated by the Euo intervention. Additionally, the balloon angioplasty significantly increased the expression of Bcl-2, while decreased the expression of Bax and caspase-3. Euo intervention significantly increased the ratio of Bax/Bcl-2 and the level of caspase-3. Taken together, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model, and the rabbit carotid balloon injury model, we demonstrated that Euo-eluting stents indeed inhibited ISR after PCI. CONCLUSION: For the first time, this study delineates the potential efficacy of Euo, derived from Tripterygium Hypoglaucum (Levl) Hutch, in ameliorating ISR after PCI with two in vivo models. The phytochemical targets PTEN/AKT/mTOR signaling pathway to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby inhibiting the ISR.

The complex genetic basis of fibromuscular dysplasia, a systemic arteriopathy associated with multiple forms of cardiovascular disease.

Artery stenosis is a common cause of hypertension and stroke and can be due to atherosclerosis accumulation in the majority of cases and in a small fraction of patients to arterial fibromuscular dysplasia (FMD). Artery stenosis due to atherosclerosis is widely studied with known risk factors (e.g. increasing age, male gender, and dyslipidemia) to influence its etiology, including genetic factors. However, the causes of noninflammatory and nonatherosclerotic stenosis in FMD are less understood. FMD occurs predominantly in early middle-age women, a fraction of the population where cardiovascular risk is different and understudied. FMD arteriopathies are often diagnosed in the context of hypertension and stroke and co-occur mainly with spontaneous coronary artery dissection, an atypical cause of acute myocardial infarction. In this review, we provide a comprehensive overview of the recent advances in the understanding of molecular origins of FMD. Data were obtained from genetic studies using complementary methodological approaches applied to familial, syndromic, and sporadic forms of this intriguing arteriopathy. Rare variation analyses point toward mechanisms related to impaired prostacyclin signaling and defaults in fibrillar collagens. The study of common variation, mainly through a recent genome-wide association study, describes a shared genetic link with blood pressure, in addition to point at potential risk genes involved in actin cytoskeleton and intracellular calcium homeostasis supporting impaired vascular contraction as a key mechanism. We conclude this review with future strategies and approaches needed to fully understand the genetic and molecular mechanisms related to FMD.

Computed tomography enterography predicts surgical-free survival in symptomatic stricturing Crohn's disease.

OBJECTIVES: The study aimed to predict surgical risks for patients with symptomatic stricturing Crohn's disease (CD) using computed tomography enterography (CTE) and to assess the association between CTE findings and pathological changes. METHODS: Crohn's disease patients with symptomatic stricture(s) were included. Exclusion criteria were concomitant penetrating disease, intra-abdominal abscess, previous bowel resection, or asymptomatic. Patients from January 2016 to December 2019 were identified as the primary cohort and those from January 2020 to June 2020 were identified as the validation cohort. Two independent experienced radiologists evaluated CTE variables including mucosal enhancement, mural stratification, wall enhancement, comb sign, lymphadenopathy, thick non-enhancing wall, bowel wall thickness, luminal diameter, and upstream lumen. Receiver operating characteristic, logistic regression, and nomogram were performed to identify the independent predictors of surgical-free survival. Histopathological scores of surgical specimens were also evaluated. RESULTS: 198 patients (primary cohort, 123 with surgery and 75 under non-surgical intervention, and 41 patients (validation cohort) were analyzed. Bowel wall thickness < 5.9 mm, luminal stenosis > 3.35 mm, and upstream lumen < 27.5 mm were predictors of surgical-free survival for symptomatic stricturing CD patients. Logistic analysis showed the three CTE variables were the independent predictors of surgical-free survival (p < 0.001). A nomogram was developed with the concordance indexes of 0.905 and 0.892 in the primary and validation cohorts. Histopathological analysis showed bowel wall muscular hyperplasia/hypertrophy significantly correlated with luminal stenosis (r = - 0.655, p = 0.008) and combined CTE variable (r = - 0.683, p = 0.005). CONCLUSIONS: CTE is highly predictive of disease course and surgical-free survival for patients with symptomatic stricturing CD, suggesting the important role of CTE in decision-making of treatment.

Natural History of Asymptomatic Moderate Carotid Artery Stenosis in a Large Community-Based Cohort.

BACKGROUND: Moderate carotid artery stenosis is a poorly defined risk factor for ischemic stroke. As such, practice recommendations are lacking. In this study, we describe the long-term risk of stroke in patients with moderate asymptomatic stenosis in an integrated health care system. METHODS: All adult patients with asymptomatic moderate (50%-69%) internal carotid artery stenosis between 2008 and 2012 were identified, with follow-up through 2017. The primary outcome was acute ischemic stroke attributed to the ipsilateral carotid artery. Stroke rates were calculated using competing risk analysis. Secondary outcomes included disease progression, ipsilateral intervention, and long-term survival. RESULTS: Overall, 11 614 arteries with moderate stenosis in 9803 patients were identified. Mean age was 74.2±9.9 years with 51.4% women. Mean follow-up was 5.1±2.9 years. There were 180 ipsilateral ischemic strokes (1.6%) identified (crude annual risk, 0.31% [95% CI, 0.21%-0.41%]), of which thirty-one (17.2%) underwent subsequent intervention. Controlling for death and intervention as competing risks, the cumulative incidence of stroke was 1.2% (95% CI, 1.0%-1.4%) at 5 years and 2.0% (95% CI, 1.7%-2.4%) at 10 years. Of identified strokes, 50 (27.8%) arteries had progressed to severe stenosis or occlusion. During follow-up, there were 17 029 carotid studies performed in 5951 patients, revealing stenosis progression in 1674 (14.4%) arteries, including 1614 (13.9%) progressing to severe stenosis and 60 (0.5%) to occlusion. The mean time to stenosis progression was 2.6±2.1 years. Carotid intervention occurred in 708 arteries (6.1%). Of these, 66.1% (468/708) had progressed to severe stenosis. The overall mortality rate was 44.5%, with 10.5% of patients lost to follow-up. CONCLUSIONS: In this community-based sample of patients with asymptomatic moderate internal carotid artery stenosis followed for an average of 5 years, the cumulative incidence of stroke is low out to 10 years. Future research is needed to optimize management strategies for this population.

Cervical arterial dissection and traumatic myelopathy following yoga: surgical case report.

INTRODUCTION: Cervical spondylosis can predispose patients to central canal stenosis. In this setting, myelopathy through further flattening of the cord from extrinsic compression can be precipitated by relatively minor traumas. Arterial dissection is similarly considered a result of high velocity or momentum during trauma, commonly associated with fractures, cervical hyperflexion, or direct blunt force to the neck. Overall, precautions for both arterial dissection and myelopathy are rarely considered in low-velocity, static activities such as yoga. CASE PRESENTATION: The authors report the case of a 63-year-old man who suffered concurrent cervical myelopathy from multilevel spondylopathy, right vertebral artery dissection, and left cervical carotid artery dissection following a yoga session. Symptomatology consisted of acute onset neck pain, upper extremity sensory paresthesia, worsening gait and balance, and impaired dexterity for several weeks. Cervical MRI was obtained given myelopathic symptoms and revealed spondylosis with compression and T2 signal change at C3-C4. CT angiography of the neck revealed aforementioned dissections without flow limiting stenosis or occlusion. A therapeutic heparin infusion was started preoperatively until the patient underwent C3-C4 anterior cervical discectomy and fusion. Aspirin and Plavix were then started without incidence and the patient had significant but gradual improvement in myelopathic symptoms at 6-week follow-up. DISCUSSION: The static yet intensive poses associated with yoga present a rare etiology for arterial dissection and myelopathy, but patients with persistent and progressive symptoms should be screened with the appropriate imaging modality. Cervical decompression should be expedited before initiating an antiplatelet medication.

Hirsutella sinensis fungus improves cardiac function in mouse model of heart failure.

Cordyceps sinensis, including Hirsutella sinensis, is a highly valuable traditional Chinese medicine and is used to treat patients with pulmonary heart disease in clinical practice. However, the underlying mechanisms of its effects remain unclear. In this study, a mouse model of heart failure established by non-thoracic, transverse aortic constriction (TAC) was developed to determine the underlying mechanisms of therapeutic effects of Hirsutella sinensis fungus (HSF) powder. The results showed that HSF treatment remarkably ameliorated myocardial hypertrophy, collagen fiber hyperplasia, and cardiac function in mice with heart failure. Using transcriptional and epigenetic analyses, we found that the mechanism of HSF mainly involved a variety of signaling pathways related to myocardial fibrosis and determined that HSF could reduce the levels of TGF-ß1 proteins in heart tissue, as well as type I and III collagen levels. These data suggest that HSF alleviates heart failure, inhibits irreversible ventricular remodeling, and improves cardiac function through the regulation of myocardial fibrosis-related signaling pathways, which can provide novel opportunities to improve heart failure therapy.

Spatholobi Caulis dispensing granule reduces deep vein thrombus burden through antiinflammation via SIRT1 and Nrf2.

BACKGROUND: Deep vein thrombosis (DVT) is a kind of blood stasis syndrome. Spatholobi Caulis (SC) has been widely used for the treatment of blood stasis syndrome in China, but the underlying mechanism remains poorly understood. PURPOSE: The aim of present study was to investigate the anti-DVT mechanism of Spatholobi Caulis dispensing granule (SCDG). STUDY DESIGN/METHODS: A rat model of inferior vena cava (IVC) stenosis-induced DVT and a cell model of oxygen-glucose deprivation (OGD) were performed. Rats were orally administered with SCDG solution once daily for seven consecutive days. IVC stenosis-induced DVT was operated on the sixth day. Thrombi were harvested and weighed on the seventh day. Pathological changes were observed by hematoxylin-eosin (HE) staining. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß of serum were analyzed by enzyme-linked immunosorbent assay. C-reactive protein (CRP) was measured with turbidimetric immunoassay. Protein expressions in thrombosed IVCs and/or OGD-stimulated EA. hy926 cells were evaluated by western blot and/or immunofluorescence analyses. RESULTS: SCDG dramatically decreased thrombus weight. SCDG decreased tissue factor (TF) protein expression, inflammatory cells influxes in thrombosed vein wall and serum levels of inflammatory cytokines and CRP. Further, SCDG up-regulated Sirtuin 1 (SIRT1) protein expression and down-regulated acetylated-NF-κB p65 (Ace-p65) protein expression. Moreover, SCDG up-regulated nuclear factor-erythroid 2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions, and down-regulated phosphorylated-NF-κB p65 (p-p65) protein expression. In the OGD cell model, SCDG medicated serum decreased the protein expression of TF. SCDG medicated serum enhanced SIRT1 protein expression and reduced Ace-p65 nuclear protein expression. SCDG medicated serum promoted protein expressions of nuclear Nrf2 and total HO-1, and inhibited translocation of p65. Furthermore, inhibiting SIRT1 and Nrf2 reversed the protective effect of SCDG medicated serum on OGD-induced EA. hy926 cells. CONCLUSION: SCDG may prevent DVT through antiinflammation via SIRT1 and Nrf2.

Extra-Anatomic Stents in Ureteric Obstruction: Our Experience.

OBJECTIVES: To present our experience of the Detour extra-anatomic stent (EAS; Porges-Coloplast, Denmark) to bypass ureteric obstruction. Use of the EAS is indicated in patients with complex ureteric strictures or malignant disease, where long-term nephrostomy drainage is undesirable. MATERIALS AND METHODS: Between December 2001 and October 2017, 20 Detour EAS were implanted into 13 patients. The primary indication was ureteric obstruction or injury secondary to metastatic malignancy, or from treatment for malignancy. Five patients required bilateral EAS, with two patients having bilateral EAS following initial unilateral insertion. In 11 patients, the stent was inserted into their bladder, with 2 diverted into a double-barreled stoma. The mean age at the time of implantation was 64 years (range: 50-83 years), and the median follow-up was 12 months (range: 1.5-42 months). RESULTS: Four patients required stent revision for urinary leaks, and two developed recurrent urinary tract infections in their stent requiring intravenous antibiotics. All EAS continued to drain successfully following treatment or revision. One patient died due to complications from dislodgement of the stent, leading to laparotomy and intra-abdominal sepsis. Seven patients died due to progression of metastatic malignant disease, and the Detour EAS was functioning in all seven at time of death. The remaining five patients are well with functioning Detour EAS. CONCLUSIONS: The Detour EAS system provides a suitable alternative option for urinary diversion, affording a good quality of life to carefully selected patients with multiple comorbidities and malignant disease.

Ischemic or toxic injury: A challenging diagnosis and treatment of drug-induced stenosis of the sigmoid colon.

A 48-year-old woman was admitted with 15-mo history of abdominal pain, diarrhea and hematochezia, and 5-mo history of defecation difficulty. She had been successively admitted to nine hospitals, with an initial diagnosis of inflammatory bowel disease with stenotic sigmoid colon. Findings from computed tomography virtual colonoscopy, radiography with meglumine diatrizoate, endoscopic balloon dilatation, metallic stent implantation and later overall colonoscopy, coupled with the newfound knowledge of compound Qingdai pill-taking, led to a subsequent diagnosis of ischemic or toxic bowel disease with sigmoid colon stenosis. The patient was successfully treated by laparoscopic sigmoid colectomy, and postoperative pathological examination revealed ischemic or toxic injury of the sigmoid colon, providing a final diagnosis of drug-induced sigmoid colon stenosis. This case highlights that adequate awareness of drug-induced colon stenosis has a decisive role in avoiding misdiagnosis and mistreatment. The diagnostic and therapeutic experiences learnt from this case suggest that endoscopic balloon expansion and colonic metallic stent implantation as bridge treatments were demonstrated as crucial for the differential diagnosis of benign colonic stenosis. Skillful surgical technique and appropriate perioperative management helped to ensure the safety of our patient in subsequent surgery after long-term use of glucocorticoids.

Peritonitis espontánea por Streptococcus equi subsp. zooepidemicus / Spontaneous peritonitis by Streptococcus equi subsp. zooepidemicus

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Pneumosinus dilatans of the spheno-ethmoidal complex associated with hypovitaminosis D causing bilateral optic canal stenosis.

INTRODUCTION: Pneumosinus dilatans (PSD) is a rare disorder of undetermined etiology characterized by expansion of the paranasal sinuses without bony erosion. Of the few cases of PSD described in indexed pediatric literature, there has been no reported case of this disorder presenting with optic canal stenosis in the setting of a vitamin deficiency. CASE MATERIAL: A 12-year-old girl presented with a 3-month history of progressive, painless, and asymmetric visual deterioration in her eyes. MRI showed prominent perioptic CSF spaces bilaterally and mild atrophy of both the optic nerves. CT head showed hyperpneumatization of the sphenoethmoidal air cells and both anterior clinoid processes with the optic nerves contained within narrowed intact bony canals. Blood investigations showed reduced vitamin D levels, and a subsequent skeletal survey showed diffuse osteopenia. She underwent endoscopic sphenoidotomy and bilateral decompression of the optic nerves. Following surgery, she reported improvement of vision in her left eye. She was started on vitamin D supplements for the endocrine abnormality. At a follow-up visit 6 months later, her visual acuity in both her eyes had improved. CONCLUSION: Pneumosinus dilatans is an unusual cause of progressive optic nerve dysfunction in the pediatric population. In the absence of any associated intracranial pathologies, conditions like hypovitamosis D should be ruled out.

Complementary Indicators for Diagnosis of Hepatic Vein Stenosis After Pediatric Living-donor Liver Transplantation.

INTRODUCTION: Although hepatic vein stenosis after liver transplantation is a rare complication, the complication rate of 1% to 6% is higher in pediatric living-donor liver transplantation than that in other liver transplantation cases. Diagnosis is very important because this complication can cause hepatic congestion that develops to liver cirrhosis, graft loss, and patient loss. However, this is unlikely in cases where there are no ascites or hypoalbuminemia. OBJECTIVES: Eleven of 167 patients who had undergone pediatric living-donor liver transplantation were identified in the outpatient clinic at Jichi Medical University as having suffered from hepatic vein stenosis, and were enrolled in the study. METHODS: We conducted a retrospective study in which we reviewed historical patient records to investigate the parameters for diagnosis and examine treatment methods and outcomes. RESULTS: The 11 patients were treated with 16 episodes of balloon dilatation. Three among these received retransplantation and another 2 cases required the placement of a metallic stent at the stenosis. Histological examination revealed severe fibrosis in four of nine patients who had a liver biopsy, with mild fibrosis revealed in the other five grafts. Furthermore, hepatomegaly and splenomegaly diagnosed by computed tomography, elevated levels of hyarulonic acid, and/or a decrease in calcineurin inhibitor clearance were found to be pathognomonic at diagnosis, and tended to improve after treatment. CONCLUSIONS: Diagnosis of hepatic vein stenosis after liver transplantation can be difficult, so careful observation is crucial to avoid the risk of acute liver dysfunction. Comprehensive assessment using volumetry of the liver and spleen and monitoring of hyarulonic acid levels and/or calcineurin inhibitor clearance, in addition to some form of imaging examination, is important for diagnosis and evaluation of the effectiveness of therapy.

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-ß1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure.

UNLABELLED: Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. METHODS: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-ß1 and Smad3 were measured by western blot analysis. RESULTS: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-ß1 and Smad3 were down regulated. CONCLUSION: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-ß1/Smad3 signaling pathway in CHF rabbits.

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model.

Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (Δ(9)-tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required µ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

High frequency transcutaneous electrical nerve stimulation with diphenidol administration results in an additive antiallodynic effect in rats following chronic constriction injury.

The impact of coadministration of transcutaneous electrical nerve stimulation (TENS) and diphenidol is not well established. Here we estimated the effects of diphenidol in combination with TENS on mechanical allodynia and tumor necrosis factor-α (TNF-α) expression. Using an animal chronic constriction injury (CCI) model, the rat was estimated for evidence of mechanical sensitivity via von Frey hair stimulation and TNF-α expression in the sciatic nerve using the ELISA assay. High frequency (100Hz) TENS or intraperitoneal injection of diphenidol (2.0µmol/kg) was applied daily, starting on postoperative day 1 (POD1) and lasting for the next 13 days. We demonstrated that both high frequency TENS and diphenidol groups had an increase in mechanical withdrawal thresholds of 60%. Coadministration of high frequency TENS and diphenidol gives better results of paw withdrawal thresholds in comparison with high frequency TENS alone or diphenidol alone. Both diphenidol and coadministration of high frequency TENS with diphenidol groups showed a significant reduction of the TNF-α level compared with the CCI or HFS group (P<0.05) in the sciatic nerve on POD7, whereas the CCI or high frequency TENS group exhibited a higher TNF-α level than the sham group (P<0.05). Our resulting data revealed that diphenidol alone, high frequency TENS alone, and the combination produced a reduction of neuropathic allodynia. Both diphenidol and the combination of diphenidol with high frequency TENS inhibited TNF-α expression. A moderately effective dose of diphenidol appeared to have an additive effect with high frequency TENS. Therefore, multidisciplinary treatments could be considered for this kind of mechanical allodynia.

Hyperbaric oxygenation treatment alleviates CCI-induced neuropathic pain and decreases spinal apoptosis.

BACKGROUND: Increased apoptotic changes in the spinal cord may be responsible for the development of chronic constriction injury (CCI)-induced neuropathic pain. We previously reported the beneficial effect of hyperbaric oxygen (HBO) in the treatment of CCI-induced neuropathic pain. In this study, we tested our hypotheses that HBO may achieve its beneficial effect by inhibiting CCI-induced proapoptosis gene expression and apoptosis in the spinal cord. METHODS: Male rats were randomized into: SHAM, CCI and CCI + HBO groups. Mechanical hyperalgesia was tested daily following surgery. CCI + HBO rats were treated with HBO for 1 h daily. At 3 days post-CCI, the expression of tumour necrosis factor (TNF)-α and caspase-3 genes was detected. At 7 days post-CCI, apoptotic cells in the spinal cord were detected. RESULTS: Three days post-CCI, mechanical allodynia had developed in the ipsilateral paw compared with SHAM animals. HBO significantly alleviated CCI-induced mechanical allodynia. In comparison with SHAM, CCI-induced neuropathic pain was associated with higher mRNA levels of TNF-α and caspase-3. HBO significantly decreased CCI-induced mRNA levels of TNF-α and caspase-3. CCI-induced neuropathic pain was also associated with more apoptotic cells in the spinal cord 7 days post-CCI. HBO significantly reduced CCI-induced apoptosis to the level of SHAM animals. CONCLUSIONS: Overly expressed proapoptosis genes, and subsequent increase in spinal apoptotic cells, seem to contribute to the development of CCI-induced neuropathic pain. The inhibitory role of HBO on spinal proapoptosis genes and apoptotic changes may contribute to its beneficial effect on CCI-induced neuropathic pain.