σFactor SigW/Anti-σFactor RsiW参与东湖假单胞菌HYS对秀丽隐杆线虫毒性作用

东湖假单胞菌HYS对秀丽隐杆线虫具有较强毒性,但机制尚不完全了解。本研究旨在探究东湖假单胞菌HYS中σ因子SigW与反σ因子RsiW在其对秀丽隐杆线虫毒性中的作用。通过对东湖假单胞菌HYS减毒突变株突变位点序列进行生物信息分析,构建目的基因敲除突变株,借助酵母双杂交、荧光定量PCR以及假单胞菌-秀丽隐杆线虫互作等研究方法进行相关基因蛋白功能验证。结果发现:(1)基因rsiW与东湖假单胞菌HYS菌株对秀丽隐杆线虫毒性相关;(2)RsiW与基因组上邻近的SigW(σ24)是一对σ因子与反σ因子,在蛋白水平存在互作;(3)RsiW与SigW互作参与东湖假单胞菌HYS对秀丽隐杆线虫毒性作用且存在一定的剂量效应,即SigW表达相对较强时,存在减毒效应。该研究发现一对σ因子与反σ因子(SigW/RsiW)参与东湖假单胞菌HYS对秀丽隐杆线虫的毒性作用,为深入探讨假单胞菌毒力因子调控机制提供了新线索和思路。

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

Predictive Factors of Renal Failure in COVID-19 Patients at the Anti-COVID Center in Lome, Togo

Background: Angiotensin-converting enzyme 2 has been identified as the receptor that allows the entry of SarsCov2 into the human cell. Its expression in the kidney is 100 times higher than in the lung;thus, making the kidney an excellent target for SarsCov2 infection manifesting as renal failure (RF). The objective of this study was to determine the predictive factors of RF during COVID-19 in the Togolese context. Patients and Methods: This was a retrospective descriptive and analytical study conducted at the Lomé Anti-COVID Center including the records of patients hospitalized for COVID-19, of age ≥ 18 years and having performed a creatinemia. RF was defined by a GFR 2 calculated according to the MDRD formula. Patients were randomized into 2 groups according to GFRResults: 482 patients were selected for this study with a mean age of 58.02 years. Sixty-five percent of the patients were men, i.e., a sex ratio of 1.88. Fifty-two patients had RF, i.e., a frequency of 10.8%.There were 65% men (315 cases), for a sex ratio (M/F) of 1.88. Risk factors for renal failure in COVID-19 were age ≥ 65 years (ORa 2.42;CIa95% [1.17 - 4.95];p = 0.016), anemia (ORa 2.49;CIa95% [1.21 - 5.26];p = 0.015), moderate (ORa 13;CIa95% [2.30 - 2.44];p = 0.017), severe (ORa 26.2;CIa95% [4.85 - 4.93];p = 0.002) and critical (ORa 108;CIa95% [16.5 - 21.76];p Conclusion: Renal failure would therefore be related to the severity of COVID-19 and is the most formidable factor, conditioning the course of the disease and the patient’s vital prognosis.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Functions of nuclear factor Y in nervous system development,function and health

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

Nomogram for predicting short-term response to anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration:An observational study

BACKGROUND Anti-vascular endothelial growth factor(anti-VEGF)therapy is critical for managing neovascular age-related macular degeneration(nAMD),but understanding factors influencing treatment efficacy is essential for optimizing patient outcomes.AIM To identify the risk factors affecting anti-VEGF treatment efficacy in nAMD and develop a predictive model for short-term response.METHODS In this study,65 eyes of exudative AMD patients after anti-VEGF treatment for≥1 mo were observed using optical coherence tomography angiography.Patients were classified into non-responders(n=22)and responders(n=43).Logistic regression was used to determine independent risk factors for treatment response.A predictive model was created using the Akaike Information Criterion,and its performance was assessed with the area under the receiver operating characteristic curve,calibration curves,and decision curve analysis(DCA)with 500 bootstrap re-samples.RESULTS Multivariable logistic regression analysis identified the number of junction voxels[odds ratio=0.997,95%confidence interval(CI):0.993-0.999,P=0.010]as an independent predictor of positive anti-VEGF treatment outcomes.The predictive model incorporating the fractal dimension,number of junction voxels,and longest shortest path,achieved an area under the curve of 0.753(95%CI:0.622-0.873).Calibration curves confirmed a high agreement between predicted and actual outcomes,and DCA validated the model's clinical utility.CONCLUSION The predictive model effectively forecasts 1-mo therapeutic outcomes for nAMD patients undergoing anti-VEGF therapy,enhancing personalized treatment planning.

The effects of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents:a meta-analysis

Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

Influence of granulocyte-macrophage colonystimulating factor and tumor necrosis factor on anti-hepatoma activities of human dendritic cells

INTRODUCTIONDendritic cells (DCs) play a key regulatory role inantitumor immunity,especially in its immuneaccessory role via MHC-Ⅰ molecules.We haverecently reported that DCs were able to enhance thekilling activity of Lymphokine and PHA activatedkiller (LPAK) cells in vitro.In the presentstudy,we evaluated the effects of GM-CSF andTNF upon antitumor activities of freshly

Near-infrared photoimmunotherapy of pancreatic cancer using an indocyanine green-labeled anti-tissue factor antibody

AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor(TF) antibody conjugated to indocyanine green(ICG) in a pancreatic cancer model.METHODS Near-infrared photoimmunotherapy(NIR-PIT) is a highly selective tumor treatment that utilizes an antibody-photosensitizer conjugate administration, followed by NIR light exposure. Anti-TF antibody 1849-ICG conjugate was synthesized by labeling of rat IgG2 b anti-TF monoclonal antibody 1849(anti-TF 1849) to a NIR photosensitizer,ICG. The expression levels of TF in two human pancreatic cancer cell lines were examined by western blotting. Specific binding of the 1849-ICG to TF-expressing BxPC-3 cells was examined by fluorescence microscopy. NIR-PITinduced cell death was determined by cell viability imaging assay. In vivo longitudinal fluorescence imaging was used to explore the accumulation of 1849-ICG conjugate in xenograft tumors. To examine the effect of NIRPIT, tumor-bearing mice were separated into 5 groups:(1) 100 μg of 1849-ICG i.v. administration followed by NIR light exposure(50 J/cm2) on two consecutive days(Days 1 and 2);(2) NIR light exposure(50 J/cm2) only on two consecutive days(Days 1 and 2);(3) 100 μg of 1849-ICG i.v. administration;(4) 100 μg of unlabeled antiTF 1849 i.v. administration; and(5) the untreated control. Semiweekly tumor volume measurements, accompanied with histological and immunohistochemical(IHC) analyses of tumors, were performed 3 d after the 2nd irradiation with NIR light to monitor the effect of treatments. RESULTS High TF expression in BxPC-3 cells was observed via western blot analysis, concordant with the observed preferential binding with intracellular localization of 1849-ICG via fluorescence microscopy. NIR-PIT-induced cell death was observed by performing cell viability imaging assay. In contrast to the other test groups, tumor growth was significantly inhibited by NIR-PIT with a statistically significant difference in relative tumor volumes for 27 d after the treatment start date [2.83 ± 0.38(NIR-PIT) vs 5.42 ± 1.61(Untreated), vs 4.90 ± 0.87(NIR), vs 4.28 ±1.87(1849-ICG), vs 4.35 ± 1.42(anti-TF 1849), at Day 27, P < 0.05]. Tumors that received NIR-PIT showed evidence of necrotic cell death-associated features upon hematoxylin-eosin staining accompanied by a decrease in Ki-67-positive cells(a cell proliferation marker) by IHC examination.CONCLUSION The TF-targeted NIR-PIT with the 1849-ICG conjugate can potentially open a new platform for treatment of TF-expressing pancreatic cancer.

Anti-tumour necrosis factor agent and liver injury:literature review,recommendations for management

Abnormalities in liver function tests,including transient and self-limiting hypertransaminasemia,cholestatic disease and hepatitis,can develop during treatment with anti-tumour-necrosis-factor(TNF)therapy.The optimal management of liver injury related to antiTNF therapy is still a matter of debate.Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than5 times the upper limit of normal,or the occurrence of jaundice,there are no standard guidelines for the management of anti-TNF-related liver injury.Bibliographical searches were performed in Pub Med,using the following key words:inflammatory bowel disease(IBD);TNF inhibitors;hypertransaminasemia;drugrelated liver injury;infliximab.According to published data,elevation of transaminases in patients with IBD treated with anti-TNF is a common finding,but resolution appears to be the usual outcome.Anti-TNF agents seem to be safe with a low risk of causing severe drugrelated liver injury.According to our centre experience,we found that hypertransaminasemia was a common,mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses.An algorithm for the management of liver impairment occurring during antiTNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases.However,hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy:A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.

Two-year delay in ulcerative colitis diagnosis is associated with anti-tumor necrosis factor alpha use

BACKGROUND Ulcerative colitis(UC)is an uncommon inflammatory bowel disease(IBD).However,its incidence has recently increased in South Korea.Moreover,UC diagnoses are frequently delayed,and the relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.AIM To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.METHODS Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed;167 cases were excluded because the first symptom date was unknown.We evaluated the relationship between the prognosis and a diagnostic delay of 3,6,12,18,and 24 mo by comparing the prognostic factors[anti-tumor necrosis factor(TNF)-αuse,admission history due to acute flare-ups,frequent admission due to flare-ups,surgery associated with UC,and the clinical remission state at the latest followup]at each diagnostic interval.RESULTS The mean diagnostic interval was 223.3±483.2 d(median,69 d;75th percentile,195 d).Among the prognostic factors,anti-TNFαuse was significantly increased after a diagnostic delay of 24 mo.Clinical risk factors predictive of a 24-mo diagnostic delay were age<60 years at diagnosis[odd ratio(OR)=14.778,95%confidence interval(CI):1.731-126.121],smoking history(OR=2.688,95%CI:1.239-5.747,P=0.012),and misdiagnosis of hemorrhoids(OR=11.066,95%CI:3.596-34.053).Anti-TNFαuse was associated with extensive UC at diagnosis(OR=3.768,95%CI:1.860-7.632)and 24-mo diagnostic delay(OR=2.599,95%CI:1.006-4.916).CONCLUSION A diagnostic delay>24 mo was associated with increased anti-TNFαuse.Age<60 years at diagnosis,smoking history,and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis

AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs(DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.RESULTS Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events(-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events(+5.85 mg/d L, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events(-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β =-0.58, P = 0.01) and hydroxychloroquine(β =-5.78, P = 0.01) use as predictors of lower post-medicationinitiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure(β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.CONCLUSION No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease

Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy.

Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.