Methotrexate is the first line drug treatment for anumber of rheumatic and non-rheumatic diseases. It is effective in controlling disease activity and preventing disease-related damage, and significantly cheaper than ...Methotrexate is the first line drug treatment for anumber of rheumatic and non-rheumatic diseases. It is effective in controlling disease activity and preventing disease-related damage, and significantly cheaper than many alternatives. Use in rheumatoid arthritis infers a significant morbidity and mortality benefit. Methotrexate is generally well tolerated but can cause symptomatic adverse events. Multiple serious adverse events have been attributed to methotrexate, based largely on older reports using high or daily doses, and subsequent case reports and circumstantial evidence. The risk with modern dosing regimens: Lower doses, weekly schedules, and concomitant folic acid is less clear. Clarification and dissemination of the actual risk is crucial so appropriate judgements can be made for patients who may benefit from this treatment. Methotrexate has been associated with a range of liver related adverse events ranging from asymptomatic transaminase elevations to fibrosis and fatal hepatic necrosis. Concern over potential liver toxicity has resulted in treatment avoidance, cessation, or recommendations for investigations which may be costly, invasive and unwarranted. Modern laboratory monitoring of liver blood tests may also influence the risk of more serious complications. The majority of present day studies report an approximate doubling of the relative risk of elevated transaminases in methotrexate treated patients but no increased risk of symptomatic or severe liver related adverse events. In this article we will review the evidence around methotrexate and liver related adverse events.展开更多
AIM:To investigate the efficacy and adverse effects of antioxidant therapy in acute pancreatitis(AP),chronic pancreatitis(CP) and post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP).METHODS:Pub Med,S...AIM:To investigate the efficacy and adverse effects of antioxidant therapy in acute pancreatitis(AP),chronic pancreatitis(CP) and post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP).METHODS:Pub Med,Scopus,Google Scholar,Cochrane library database,and Evidence-based medicine/clinical trials published before August 2014 were searched. Clinical and laboratory outcomes of randomized trials of antioxidant therapy in patients with AP,CP and PEP were included. The methodological quality of the trials was assessed by the Jadad score based on the description of randomization,blinding,and dropouts(withdrawals). The results of the studies were pooled and meta-analyzed to provide estimates of the efficacy of antioxidant therapy.RESULTS:Thirty four trials out of 1069 potentially relevant studies with data for 4898 patients wereeligible for inclusion. Antioxidant therapy significantly reduced the length of hospital stay in AP patients {mean difference-2.59 d(95%CI:-4.25-(-0.93)],P = 0.002}. Although,antioxidant therapy had no significant effect on serum C reactive protein(CRP) after 5-7 d in AP patients [mean difference-9.57(95%CI:-40.61-21.48,P = 0.55],it significantly reduced serum CRP after 10 d {mean difference-45.16 [95%CI:-89.99-(-0.33)],P = 0.048}. In addition,antioxidant therapy had no significant effect on CP-induced pain [mean difference-2.13(95%CI:-5.87-1.6),P = 0.26]. Antioxidant therapy had no significant effects on the incidence of all types of PEP [mean difference 1.05(95%CI:0.74-1.5),P = 0.78],severe PEP [mean difference 0.92(95%CI:0.43-1.97),P = 0.83],moderate PEP [mean difference 0.82(95%CI:0.54-1.23),P = 0.33],and mild PEP [mean difference 1.33(95%CI:0.99-1.78),P = 0.06]. Furthermore,while antioxidant therapy had no significant effect on serum amylase after less than 8 h sampling [mean difference-20.61(95%CI:-143.61-102.39),P = 0.74],it significantly reduced serum amylase close to 24-h sampling {mean difference-16.13 [95%CI:-22.98-(-9.28)],P < 0.0001}.CONCLUSION:While there is some evidence to support antioxidant therapy in AP,its effect on CP and PEP is still controversial.展开更多
AIM To clarify the underlying mechanism of formin-like 3(FMNL3)in the promotion of colorectal carcinoma(CRC)cell invasion.METHODS The in vitro biological function analyses of FMNL3 were performed by gain-and loss-of f...AIM To clarify the underlying mechanism of formin-like 3(FMNL3)in the promotion of colorectal carcinoma(CRC)cell invasion.METHODS The in vitro biological function analyses of FMNL3 were performed by gain-and loss-of function approaches.Changes in the F-actin cytoskeleton were detected by the technologies of phalloidin-TRITC labeling and confocal microscopy.The signaling pathway mediated by FMNL3 was explored by western blot,gelatin zymograph assay,co-immunoprecipitation(co-IP),immunofluorescence colocalization,and glutathione S-transferase(GST)pulldown assay.RESULTS The in vitro experimental results showed that FMNL3 significantly promoted the proliferation,invasion,and migration of CRC cells(P<0.05 and P<0.01).Moreover,FMNL3regulated the remodeling of actin-based protrusions such as filopodia and lamellipodia in a RhoC-dependent manner.The western blot and gelatin zymograph assay results indicated that FMNL3 was involved in the RhoC/focal adhesion kinase(FAK)pathway and acted as an effector of RhoC to activate the downstream signaling of p-FAK as well as p-MAPK and p-AKT.This resulted in the increased expression of matrix metalloproteinase 2(MMP2),matrix metalloproteinase 9(MMP9)and vascular endothelial growth factor(VEGF),and the subsequent promotion of CRC cell invasion.The results of TAE226,U0126 or Ly294002 treatment confirmed an essential role of FMNL3 in activation of the RhoC/FAK pathway and the subsequent promotion of CRC invasion.Co-IP,colocalization and GST pull-down assays showed the direct interaction of FMNL3 with RhoC in vivo and in vitro.CONCLUSION FMNL3 regulates the RhoC/FAK signaling pathway and RhoC-dependent remodeling of actin-based protrusions to promote CRC invasion.展开更多
Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but...Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus(EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.展开更多
Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid...Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins(VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-Ⅱ, very low-density lipoproteins receptor(VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-Ⅲ, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea(BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.展开更多
Diverticular disease(DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK.This high prevalence ranks it as one of the most common bowel disorders in we...Diverticular disease(DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK.This high prevalence ranks it as one of the most common bowel disorders in western nations.The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum.Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality.In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressureinduced damage to the colon wall amongst those with a low intake of dietary fiber.In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development.We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal.We have also identified several gaps in the knowledge base which need to be filled before we can complete a model for the etiology of diverticular disease.展开更多
Asialoglycoprotein receptor(ASGP-R)is a hepatic membrane receptor that uniquely exists on the surface of mammalian hepatocytes,and has been used as target of liver functional imaging agents for many years.We labeled t...Asialoglycoprotein receptor(ASGP-R)is a hepatic membrane receptor that uniquely exists on the surface of mammalian hepatocytes,and has been used as target of liver functional imaging agents for many years.We labeled the Galactosyl-neoglycoalbumin(NGA)with 18F to get a PET molecular probe 18F-FB-NGA and evaluated its ability as a liver functional PET imaging agent.The 18F-FB-NGA was prepared with NGA by conjugation with Nsuccinimidyl-4-18F-fluorobenzoate(18F-SFB)and purified with PD-10 desalting column.The radiolabeling yield and radiochemical purity of 18F-FB-NGA were determined by radio-HPLC.Starting with 18F-F–,the total time for 18F-FB-NGA was about 120±10 min.The decay-corrected radiochemical yield is about 25–30%.The radiochemical purity of purified 18F-FB-NGA was more than 98%.Labeled with 185–1850 MBq 18F-SFB,the specific activity of 18F-FBNGA was estimated to be 7.83–78.3 TBq/mmol.Biodistribution of 18F-FB-NGA in normal mice was investigated after injection through the tail vein.The results showed that the liver accumulated 39.47±3.42 and 12.12±6.11%ID/g at 10 and 30 min after injection,respectively.Dynamic MicroPET images in mice were acquired with and without block after injection of the radiotracer,respectively.High liver activity accumulation was observed at 5 min after injection in normal group.On the contrary,the liver accumulation was significantly lower after block,indicating the specific binding to ASGP-R.18F-FB-NGA is probably a potential PET liver imaging agent.展开更多
The identification of individual factors modulating clinical recovery after a stroke is fundamental to personalize the therapeutic intervention to enhance the final clinical outcome.In this framework,electrophysiologi...The identification of individual factors modulating clinical recovery after a stroke is fundamental to personalize the therapeutic intervention to enhance the final clinical outcome.In this framework,electrophysiological factors are promising since are more directly related to neuroplasticity,which supports recovery in stroke patients,than neurovascular factors.In this retrospective observational study,we investigated brain neuronal activity assessed via spectral features and Higuchi's fractal dimension(HFD) of electroencephalographic signals in acute phase(2–10 days from symptom onset,T0) and sub-acute phase(2.5 months,T1) in 24 patients affected by unilateral middle cerebral artery stroke.Longitudinal assessment of the clinical deficits was performed using the National Institutes of Health Stroke Scale(NIHSS),together with the effective recovery calculated as the ratio between difference of NIHSS at T0 and T1 over the NIHSS value at T0.We observed that delta and alpha band electroencephalographic signal power changed between the two phases in both the hemispheres ipsilateral(ILH) and contralateral(CHL) to the lesion.Moreover,at T0,bilateral higher delta band power correlated with worse clinical conditions(Spearman's rs = 0.460,P = 0.027 for ILH and rs = 0.508,P = 0.013 for CLH),whereas at T1 this occurred only for delta power in ILH(rs = 0.411,P = 0.046) and not for CHL.Inter-hemispheric difference(ILH vs.CLH) of alpha power in patients was lower at T0 than at T1(P = 0.020).HFD at T0 was lower than at T1(P = 0.005),and at both phases,ILH HFD was lower than CLH HFD(P = 0.020).These data suggest that inter-hemispheric low band asymmetry and fractal dimension changes from the acute to the sub-acute phase are sensitive to neuroplasticity processes which subtend clinical recovery.The study protocol was approved by the Bioethical Committee of Ospedale San Giovanni Calibita Fatebenefretelli(No.40/2011) on July 14,2011.展开更多
Since it has been recognized that sarcoidosis(SA) is not an exclusive disorder of the lungs but can also affect other organs such as the liver and spleen, efforts have been made to define specific imaging criteria for...Since it has been recognized that sarcoidosis(SA) is not an exclusive disorder of the lungs but can also affect other organs such as the liver and spleen, efforts have been made to define specific imaging criteria for the diagnosis of the single organ involvement, and the concept has been reinforced that the exclusion of alternative causes is important to achieve the correct diagnosis. Ultrasound(US)is a useful tool to evaluate patients with suspected abdominal SA, such as of the liver, spleen, kidney, pancreas and other organs, showing findings such as organomegaly, focal lesions and lymphadenopathy. While the diagnosis of abdominal SA is more predictable in the case of involvement of other organs(e.g.,lungs), the problem is more complex in the case of isolated abdominal SA. The recent use of contrast-enhanced ultrasound and endoscopic ultrasound elastography has provided additional information about the enhancement patterns and tissue rigidity in abdominal SA. Here we critically review the role of US in abdominal SA, reporting typical findings and limitations of current evidence and by discussing future perspectives of study.展开更多
Waterpipe(WP),a less common method of tobacco smoking than cigarette smoking(CS),has become increasingly popular over the last decade.Contrary to popular belief,WP smoking is far from harmless and has multiple health ...Waterpipe(WP),a less common method of tobacco smoking than cigarette smoking(CS),has become increasingly popular over the last decade.Contrary to popular belief,WP smoking is far from harmless and has multiple health risks similar to,or even exceeding,those seen in CS[1,2].展开更多
BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV p...BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.展开更多
Objective: We describe the abdominal sonographic findings among patients with HIV-tuberculosis (TB) co-infection with advanced immune suppression before initiation of ART and relate these findings to the patients’ ab...Objective: We describe the abdominal sonographic findings among patients with HIV-tuberculosis (TB) co-infection with advanced immune suppression before initiation of ART and relate these findings to the patients’ abdominal symptoms and CD4 T-cell count. Methods: Consecutive HIV-TB co-infected patients, qualifying for ART, were prospectively enrolled in a cohort study at the Mulago National Tuberculosis and Leprosy Programme clinic in Kampala, Uganda. An abdominal ultrasound was performed at enrolment. Results: A total of 209 HIV-TB co-infected patients (76% with pulmonary, 19% with extrapulmonary TB and 5% with extrapulmonary and pulmonary TB) underwent an abdominal ultrasound scan. Only 49 patients (23.4%) had a normal abdominal ultrasound. The following sonographic abnormalities were found: multiple lymphadenopathy (38%), splenomegaly (18%), renal abnormalities (14%), gastro-intestinal tract abnormalities (thickened bowel loops, appendicitis) (13%), splenic abscesses (13%) and ascites (6%). The commonest groups of enlarged lymph nodes were in the porta-hepatis (19%) and peripancreatic (17%) area and 80% of the enlarged lymph nodes were hypoechoic. Conclusion: Most patients with advanced immune suppression and HIV-TB co-infection have sonographic evidence of generalized TB with abdominal involvement, therefore Ultrasound may assist in the early diagnosis of disseminated TB.展开更多
Purpose:To systematically review the risk of permanent disability related to road traffic injuries(RTIs)and to determine the implications for future research regarding permanent impairment following road traffic crash...Purpose:To systematically review the risk of permanent disability related to road traffic injuries(RTIs)and to determine the implications for future research regarding permanent impairment following road traffic crashes.Methods:We conducted this systematic review according to the preferred reporting items for systematic reviews and meta-analysis statement.An extended search of the literature was carried out in 4 major electronic databases for scientific research papers published from January 1980 to February 2020.Two teams include 2 reviewers each,screened independently the titles/abstracts,and after that,reviewed the full text of the included studies.The quality of the studies was assessed using the strengthening the reporting of observational studies in epidemiology(STROBE)checklist.A third reviewer was assessed any discrepancy and all data of included studies were extracted.Finally,the data were systematically analyzed,and the related data were interpreted.Results:Five out of 16 studies were evaluated as high-quality according to the STROBE checklist.Fifteen studies ranked the initial injuries according to the abbreviated injury scale 2005.Five studies reported the total risk of permanent medical impairment following RTIs which varied from 2%to 23%for car occupants and 2.8%to 46%for cyclists.Seven studies reported the risk of permanent medical impairment of the different body regions.Eleven studies stated the most common body region to develop permanent impairment,of which 6 studies demonstrated that injuries of the cervical spine and neck were at the highest risk of becoming permanent injured.Conclusion:The finding of this review revealed the necessity of providing a globally validated method to evaluate permanent medical impairment following RTIs across the world.This would facilitate decisionmaking about traffic injuries and efficient management to reduce the financial and psychological burdens for individuals and communities.展开更多
Background: The use of traditional and complementary medicine (T&CM) is increasing in both developed and developing countries. The school of Persian medicine (PM) in Iran is a comprehensive medical school that is ...Background: The use of traditional and complementary medicine (T&CM) is increasing in both developed and developing countries. The school of Persian medicine (PM) in Iran is a comprehensive medical school that is rich in history and has its own special principles, elements, philosophy, and diagnostic and treatment options. Many complementary therapy modalities are also popular and in demand among patients and physicians. The aim of this paper is to provide logic for the policymakers in Iranian medical education to make changes in medical education curricula, particularly on integrating T&CM. Methods: We reviewed the global experience in teaching T&CM to medical students, and highlighting the strengths of PM, described why it is necessary to integrate T&CM into general medicine curricula in Iran. Results: PM is a traditional system of medicine that dates back about 7000 years. Although there are few studies about the safety and effectiveness of PM, research into it has recently been accelerated. There is a suitable opportunity for integrating T&CM with conventional medicine. Physicians should be familiar with T&CM to avoid any contraindications, interactions, and unwanted effects. Conclusion: Traditional medicine is part of Iran's heritage and. thus, needs special attention. Familiarization of physicians with T&CM can help them choose the best treatment options for their patients. To integrate T&CM into the medical education curricula of Iran, a two-credit course has been proposed for implementation across the country.展开更多
Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelialcells, activation of immune responses, and progression of tissue fibrosis in the skin and various inter...Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelialcells, activation of immune responses, and progression of tissue fibrosis in the skin and various internal organs.According to epidemiological data, women’s populations are more susceptible to systemic sclerosis than men. Untilnow, various therapeutic options are employed to manage the symptoms of the disease. Since stem cell-basedtreatments have developed as a novel approach to rescue from several autoimmune diseases, it seems that stemcells, especially mesenchymal stem cells as a powerful regenerative tool can also be advantageous for systemicsclerosis treatment via their remarkable properties including immunomodulatory and anti-fibrotic effects.Accordingly, we discuss the contemporary status and future perspectives of mesenchymal stem cell transplantationfor systemic sclerosis.展开更多
Injectable thermal gels are a useful tool for drug delivery and tissue engineering.However,most thermal gels do not solidify rapidly at body temperature(37C).We addressed this by synthesizing a thermo-sensitive,rapid...Injectable thermal gels are a useful tool for drug delivery and tissue engineering.However,most thermal gels do not solidify rapidly at body temperature(37C).We addressed this by synthesizing a thermo-sensitive,rapidly biodegrading hydrogel.Our hydrogel,poly(ethylene glycol)-co-poly(propanol serinate hexamethylene urethane)(EPSHU),is an ABA block copolymer comprising A,methoxy poly ethylene glycol group and B,poly(propanol L-serinate hexamethylene urethane).EPSHU was characterized by gel permeation chromatography for molecular weight and 1H NMR and Fourier transformed infrared for structure.Rheological studies measured the phase transition temperature.In vitro degradation in cholesterol esterase and in Dulbecco’s phosphate buffered saline(DPBS)was tracked using the average molecular weight measured by gel permeation chromatography.LIVE/DEAD and resazurin reduction assays performed on NIH 3T3 fibroblasts exposed to EPSHU extracts demonstrated no cytotoxicity.Subcutaneous implantation into BALB/cJ mice indicated good biocompatibility in vivo.The biodegradability and biocompatibility of EPSHU together make it a promising candidate for drug delivery applications that demand carrier gel degradation withinmonths.展开更多
文摘Methotrexate is the first line drug treatment for anumber of rheumatic and non-rheumatic diseases. It is effective in controlling disease activity and preventing disease-related damage, and significantly cheaper than many alternatives. Use in rheumatoid arthritis infers a significant morbidity and mortality benefit. Methotrexate is generally well tolerated but can cause symptomatic adverse events. Multiple serious adverse events have been attributed to methotrexate, based largely on older reports using high or daily doses, and subsequent case reports and circumstantial evidence. The risk with modern dosing regimens: Lower doses, weekly schedules, and concomitant folic acid is less clear. Clarification and dissemination of the actual risk is crucial so appropriate judgements can be made for patients who may benefit from this treatment. Methotrexate has been associated with a range of liver related adverse events ranging from asymptomatic transaminase elevations to fibrosis and fatal hepatic necrosis. Concern over potential liver toxicity has resulted in treatment avoidance, cessation, or recommendations for investigations which may be costly, invasive and unwarranted. Modern laboratory monitoring of liver blood tests may also influence the risk of more serious complications. The majority of present day studies report an approximate doubling of the relative risk of elevated transaminases in methotrexate treated patients but no increased risk of symptomatic or severe liver related adverse events. In this article we will review the evidence around methotrexate and liver related adverse events.
文摘AIM:To investigate the efficacy and adverse effects of antioxidant therapy in acute pancreatitis(AP),chronic pancreatitis(CP) and post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP).METHODS:Pub Med,Scopus,Google Scholar,Cochrane library database,and Evidence-based medicine/clinical trials published before August 2014 were searched. Clinical and laboratory outcomes of randomized trials of antioxidant therapy in patients with AP,CP and PEP were included. The methodological quality of the trials was assessed by the Jadad score based on the description of randomization,blinding,and dropouts(withdrawals). The results of the studies were pooled and meta-analyzed to provide estimates of the efficacy of antioxidant therapy.RESULTS:Thirty four trials out of 1069 potentially relevant studies with data for 4898 patients wereeligible for inclusion. Antioxidant therapy significantly reduced the length of hospital stay in AP patients {mean difference-2.59 d(95%CI:-4.25-(-0.93)],P = 0.002}. Although,antioxidant therapy had no significant effect on serum C reactive protein(CRP) after 5-7 d in AP patients [mean difference-9.57(95%CI:-40.61-21.48,P = 0.55],it significantly reduced serum CRP after 10 d {mean difference-45.16 [95%CI:-89.99-(-0.33)],P = 0.048}. In addition,antioxidant therapy had no significant effect on CP-induced pain [mean difference-2.13(95%CI:-5.87-1.6),P = 0.26]. Antioxidant therapy had no significant effects on the incidence of all types of PEP [mean difference 1.05(95%CI:0.74-1.5),P = 0.78],severe PEP [mean difference 0.92(95%CI:0.43-1.97),P = 0.83],moderate PEP [mean difference 0.82(95%CI:0.54-1.23),P = 0.33],and mild PEP [mean difference 1.33(95%CI:0.99-1.78),P = 0.06]. Furthermore,while antioxidant therapy had no significant effect on serum amylase after less than 8 h sampling [mean difference-20.61(95%CI:-143.61-102.39),P = 0.74],it significantly reduced serum amylase close to 24-h sampling {mean difference-16.13 [95%CI:-22.98-(-9.28)],P < 0.0001}.CONCLUSION:While there is some evidence to support antioxidant therapy in AP,its effect on CP and PEP is still controversial.
基金Supported by the National Natural Science Foundation of China,No.81201972the China Postdoctoral Science Foundation,No.2013M531555the Postdoctoral Science Foundation of Jiangxi province,No.2013KY44
文摘AIM To clarify the underlying mechanism of formin-like 3(FMNL3)in the promotion of colorectal carcinoma(CRC)cell invasion.METHODS The in vitro biological function analyses of FMNL3 were performed by gain-and loss-of function approaches.Changes in the F-actin cytoskeleton were detected by the technologies of phalloidin-TRITC labeling and confocal microscopy.The signaling pathway mediated by FMNL3 was explored by western blot,gelatin zymograph assay,co-immunoprecipitation(co-IP),immunofluorescence colocalization,and glutathione S-transferase(GST)pulldown assay.RESULTS The in vitro experimental results showed that FMNL3 significantly promoted the proliferation,invasion,and migration of CRC cells(P<0.05 and P<0.01).Moreover,FMNL3regulated the remodeling of actin-based protrusions such as filopodia and lamellipodia in a RhoC-dependent manner.The western blot and gelatin zymograph assay results indicated that FMNL3 was involved in the RhoC/focal adhesion kinase(FAK)pathway and acted as an effector of RhoC to activate the downstream signaling of p-FAK as well as p-MAPK and p-AKT.This resulted in the increased expression of matrix metalloproteinase 2(MMP2),matrix metalloproteinase 9(MMP9)and vascular endothelial growth factor(VEGF),and the subsequent promotion of CRC cell invasion.The results of TAE226,U0126 or Ly294002 treatment confirmed an essential role of FMNL3 in activation of the RhoC/FAK pathway and the subsequent promotion of CRC invasion.Co-IP,colocalization and GST pull-down assays showed the direct interaction of FMNL3 with RhoC in vivo and in vitro.CONCLUSION FMNL3 regulates the RhoC/FAK signaling pathway and RhoC-dependent remodeling of actin-based protrusions to promote CRC invasion.
文摘Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus(EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.
基金the BRET (Bardhan Research Education Trust) charity, which has supported funding for materials and equipment costs
文摘Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins(VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-Ⅱ, very low-density lipoproteins receptor(VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-Ⅲ, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea(BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.
基金Supported by Food Standards Agency, N12105Northumbria Colorectal Research Funds
文摘Diverticular disease(DD) is an age-related disorder of the large bowel which may affect half of the population over the age of 65 in the UK.This high prevalence ranks it as one of the most common bowel disorders in western nations.The majority of patients remain asymptomatic but there are associated life-threatening co-morbidities, which, given the large numbers of people with DD, translates into a considerable number of deaths per annum.Despite this public health burden, relatively little seems to be known about either the mechanisms of development or causality.In the 1970s, a model of DD formulated the concept that diverticula occur as a consequence of pressureinduced damage to the colon wall amongst those with a low intake of dietary fiber.In this review, we have examined the evidence regarding the influence of ageing, diet, inflammation and genetics on DD development.We argue that the evidence supporting the barotrauma hypothesis is largely anecdotal.We have also identified several gaps in the knowledge base which need to be filled before we can complete a model for the etiology of diverticular disease.
基金Supported by Jiangsu Province’s Key Medical Talents Program(No.RC2007097)Natural Science Foundation of Jiangsu Province,China(No.BK2010154)Science Foundation of Health Department of Jiangsu Province(No.H201226)
文摘Asialoglycoprotein receptor(ASGP-R)is a hepatic membrane receptor that uniquely exists on the surface of mammalian hepatocytes,and has been used as target of liver functional imaging agents for many years.We labeled the Galactosyl-neoglycoalbumin(NGA)with 18F to get a PET molecular probe 18F-FB-NGA and evaluated its ability as a liver functional PET imaging agent.The 18F-FB-NGA was prepared with NGA by conjugation with Nsuccinimidyl-4-18F-fluorobenzoate(18F-SFB)and purified with PD-10 desalting column.The radiolabeling yield and radiochemical purity of 18F-FB-NGA were determined by radio-HPLC.Starting with 18F-F–,the total time for 18F-FB-NGA was about 120±10 min.The decay-corrected radiochemical yield is about 25–30%.The radiochemical purity of purified 18F-FB-NGA was more than 98%.Labeled with 185–1850 MBq 18F-SFB,the specific activity of 18F-FBNGA was estimated to be 7.83–78.3 TBq/mmol.Biodistribution of 18F-FB-NGA in normal mice was investigated after injection through the tail vein.The results showed that the liver accumulated 39.47±3.42 and 12.12±6.11%ID/g at 10 and 30 min after injection,respectively.Dynamic MicroPET images in mice were acquired with and without block after injection of the radiotracer,respectively.High liver activity accumulation was observed at 5 min after injection in normal group.On the contrary,the liver accumulation was significantly lower after block,indicating the specific binding to ASGP-R.18F-FB-NGA is probably a potential PET liver imaging agent.
基金FZ and FT obtained financial support from the Italian Ministry of Health Cod.GR-2008-1138642 "Promoting recovery from Stroke:individually enriched therapeutic intervention in Acute phase"PNR-CNR Aging Program
文摘The identification of individual factors modulating clinical recovery after a stroke is fundamental to personalize the therapeutic intervention to enhance the final clinical outcome.In this framework,electrophysiological factors are promising since are more directly related to neuroplasticity,which supports recovery in stroke patients,than neurovascular factors.In this retrospective observational study,we investigated brain neuronal activity assessed via spectral features and Higuchi's fractal dimension(HFD) of electroencephalographic signals in acute phase(2–10 days from symptom onset,T0) and sub-acute phase(2.5 months,T1) in 24 patients affected by unilateral middle cerebral artery stroke.Longitudinal assessment of the clinical deficits was performed using the National Institutes of Health Stroke Scale(NIHSS),together with the effective recovery calculated as the ratio between difference of NIHSS at T0 and T1 over the NIHSS value at T0.We observed that delta and alpha band electroencephalographic signal power changed between the two phases in both the hemispheres ipsilateral(ILH) and contralateral(CHL) to the lesion.Moreover,at T0,bilateral higher delta band power correlated with worse clinical conditions(Spearman's rs = 0.460,P = 0.027 for ILH and rs = 0.508,P = 0.013 for CLH),whereas at T1 this occurred only for delta power in ILH(rs = 0.411,P = 0.046) and not for CHL.Inter-hemispheric difference(ILH vs.CLH) of alpha power in patients was lower at T0 than at T1(P = 0.020).HFD at T0 was lower than at T1(P = 0.005),and at both phases,ILH HFD was lower than CLH HFD(P = 0.020).These data suggest that inter-hemispheric low band asymmetry and fractal dimension changes from the acute to the sub-acute phase are sensitive to neuroplasticity processes which subtend clinical recovery.The study protocol was approved by the Bioethical Committee of Ospedale San Giovanni Calibita Fatebenefretelli(No.40/2011) on July 14,2011.
文摘Since it has been recognized that sarcoidosis(SA) is not an exclusive disorder of the lungs but can also affect other organs such as the liver and spleen, efforts have been made to define specific imaging criteria for the diagnosis of the single organ involvement, and the concept has been reinforced that the exclusion of alternative causes is important to achieve the correct diagnosis. Ultrasound(US)is a useful tool to evaluate patients with suspected abdominal SA, such as of the liver, spleen, kidney, pancreas and other organs, showing findings such as organomegaly, focal lesions and lymphadenopathy. While the diagnosis of abdominal SA is more predictable in the case of involvement of other organs(e.g.,lungs), the problem is more complex in the case of isolated abdominal SA. The recent use of contrast-enhanced ultrasound and endoscopic ultrasound elastography has provided additional information about the enhancement patterns and tissue rigidity in abdominal SA. Here we critically review the role of US in abdominal SA, reporting typical findings and limitations of current evidence and by discussing future perspectives of study.
基金supported by the National Natural Science Foundation of China[82003401&81972981]the Key Projects of Colleges and Universities of Henan Education Department[21A330006]the Opening Foundation of National Health Commission Key Laboratory of Birth Defects Prevention and Henan Key Laboratory of Population Defects Prevention[ZD202001]。
文摘Waterpipe(WP),a less common method of tobacco smoking than cigarette smoking(CS),has become increasingly popular over the last decade.Contrary to popular belief,WP smoking is far from harmless and has multiple health risks similar to,or even exceeding,those seen in CS[1,2].
文摘BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.
文摘Objective: We describe the abdominal sonographic findings among patients with HIV-tuberculosis (TB) co-infection with advanced immune suppression before initiation of ART and relate these findings to the patients’ abdominal symptoms and CD4 T-cell count. Methods: Consecutive HIV-TB co-infected patients, qualifying for ART, were prospectively enrolled in a cohort study at the Mulago National Tuberculosis and Leprosy Programme clinic in Kampala, Uganda. An abdominal ultrasound was performed at enrolment. Results: A total of 209 HIV-TB co-infected patients (76% with pulmonary, 19% with extrapulmonary TB and 5% with extrapulmonary and pulmonary TB) underwent an abdominal ultrasound scan. Only 49 patients (23.4%) had a normal abdominal ultrasound. The following sonographic abnormalities were found: multiple lymphadenopathy (38%), splenomegaly (18%), renal abnormalities (14%), gastro-intestinal tract abnormalities (thickened bowel loops, appendicitis) (13%), splenic abscesses (13%) and ascites (6%). The commonest groups of enlarged lymph nodes were in the porta-hepatis (19%) and peripancreatic (17%) area and 80% of the enlarged lymph nodes were hypoechoic. Conclusion: Most patients with advanced immune suppression and HIV-TB co-infection have sonographic evidence of generalized TB with abdominal involvement, therefore Ultrasound may assist in the early diagnosis of disseminated TB.
基金funded by Sina Trauma and Surgery Research Center,Tehran University of Medical Sciences(grant number is 98-01-38-41758).
文摘Purpose:To systematically review the risk of permanent disability related to road traffic injuries(RTIs)and to determine the implications for future research regarding permanent impairment following road traffic crashes.Methods:We conducted this systematic review according to the preferred reporting items for systematic reviews and meta-analysis statement.An extended search of the literature was carried out in 4 major electronic databases for scientific research papers published from January 1980 to February 2020.Two teams include 2 reviewers each,screened independently the titles/abstracts,and after that,reviewed the full text of the included studies.The quality of the studies was assessed using the strengthening the reporting of observational studies in epidemiology(STROBE)checklist.A third reviewer was assessed any discrepancy and all data of included studies were extracted.Finally,the data were systematically analyzed,and the related data were interpreted.Results:Five out of 16 studies were evaluated as high-quality according to the STROBE checklist.Fifteen studies ranked the initial injuries according to the abbreviated injury scale 2005.Five studies reported the total risk of permanent medical impairment following RTIs which varied from 2%to 23%for car occupants and 2.8%to 46%for cyclists.Seven studies reported the risk of permanent medical impairment of the different body regions.Eleven studies stated the most common body region to develop permanent impairment,of which 6 studies demonstrated that injuries of the cervical spine and neck were at the highest risk of becoming permanent injured.Conclusion:The finding of this review revealed the necessity of providing a globally validated method to evaluate permanent medical impairment following RTIs across the world.This would facilitate decisionmaking about traffic injuries and efficient management to reduce the financial and psychological burdens for individuals and communities.
文摘Background: The use of traditional and complementary medicine (T&CM) is increasing in both developed and developing countries. The school of Persian medicine (PM) in Iran is a comprehensive medical school that is rich in history and has its own special principles, elements, philosophy, and diagnostic and treatment options. Many complementary therapy modalities are also popular and in demand among patients and physicians. The aim of this paper is to provide logic for the policymakers in Iranian medical education to make changes in medical education curricula, particularly on integrating T&CM. Methods: We reviewed the global experience in teaching T&CM to medical students, and highlighting the strengths of PM, described why it is necessary to integrate T&CM into general medicine curricula in Iran. Results: PM is a traditional system of medicine that dates back about 7000 years. Although there are few studies about the safety and effectiveness of PM, research into it has recently been accelerated. There is a suitable opportunity for integrating T&CM with conventional medicine. Physicians should be familiar with T&CM to avoid any contraindications, interactions, and unwanted effects. Conclusion: Traditional medicine is part of Iran's heritage and. thus, needs special attention. Familiarization of physicians with T&CM can help them choose the best treatment options for their patients. To integrate T&CM into the medical education curricula of Iran, a two-credit course has been proposed for implementation across the country.
文摘Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelialcells, activation of immune responses, and progression of tissue fibrosis in the skin and various internal organs.According to epidemiological data, women’s populations are more susceptible to systemic sclerosis than men. Untilnow, various therapeutic options are employed to manage the symptoms of the disease. Since stem cell-basedtreatments have developed as a novel approach to rescue from several autoimmune diseases, it seems that stemcells, especially mesenchymal stem cells as a powerful regenerative tool can also be advantageous for systemicsclerosis treatment via their remarkable properties including immunomodulatory and anti-fibrotic effects.Accordingly, we discuss the contemporary status and future perspectives of mesenchymal stem cell transplantationfor systemic sclerosis.
基金This work was supported by the National Institutes of Health and Clinical and Translational Science Institute(NIH UL1TR000005)the National Science Foundation under grant no.1247842.The authors thank Dr Keewon Lee for helpful discussions on cell culture and fluorescence microscopy.
文摘Injectable thermal gels are a useful tool for drug delivery and tissue engineering.However,most thermal gels do not solidify rapidly at body temperature(37C).We addressed this by synthesizing a thermo-sensitive,rapidly biodegrading hydrogel.Our hydrogel,poly(ethylene glycol)-co-poly(propanol serinate hexamethylene urethane)(EPSHU),is an ABA block copolymer comprising A,methoxy poly ethylene glycol group and B,poly(propanol L-serinate hexamethylene urethane).EPSHU was characterized by gel permeation chromatography for molecular weight and 1H NMR and Fourier transformed infrared for structure.Rheological studies measured the phase transition temperature.In vitro degradation in cholesterol esterase and in Dulbecco’s phosphate buffered saline(DPBS)was tracked using the average molecular weight measured by gel permeation chromatography.LIVE/DEAD and resazurin reduction assays performed on NIH 3T3 fibroblasts exposed to EPSHU extracts demonstrated no cytotoxicity.Subcutaneous implantation into BALB/cJ mice indicated good biocompatibility in vivo.The biodegradability and biocompatibility of EPSHU together make it a promising candidate for drug delivery applications that demand carrier gel degradation withinmonths.
