Compound Kushen injection induces immediate hypersensitivity reaction through promoting the production of platelet-activating factor via de novo pathway

OBJECTIVE Compound Kushen injection(CKI)is a bis-herbal formulation extracted from Kushen(Radix Sophorae Flavescentis)and Baituling(Rhizoma Heterosmilacis Japonicae).Clinically,it is used as the adjuvant treatment of cancer.However,with the increased application,the cases of immediate hypersensitivity reactions(IHRs)also gradually rise.In this study,we investigated the underlying mechanism(s)and active constituent(s)for CKI-induced IHRs in experimental models.METHODS T helper 2(Th2)immunity-amplified mice were prepared by aluminum adjuvant.Anaphylactic shock was detected by measuring rectal thermometry in propranolol pretreated mice.For evaluating microvascular permeability,Evans blue extravasation assay was used.Platelet-activating factor(PAF),serum total IgE(tIgE)and mouse mast cell protease 1(MMCP1)were measured by ELISA.RESULTS The obtained results showed that CKI did not elevate serum tIgE and MMCP1 after consecutive immunization for five weeks,but could induce Evans blue extravasation(local)and cause obvious hypothermia(systemic)after a single injection.Further study showed that alkaloids in Kushen,especially matrine,were responsible for CKI-induced IHRs.Mechanism study showed that various PAF receptor antagonists could significantly counter CKI-induced IHRs locally or systemically.In cell system,CKI was able to promote PAF production in a non-cell-selective manner.In cell lysate,the effect of CKI on PAF production became stronger and could be abolished by blocking de novo pathway.CONCLUSION In conclusion,our study identifies,for the first time,that CKI is a PAF inducer.It causes non-immunologic IHRs,rather than IgE-dependent IHRs,by promoting PAF production through de novo pathway.Alkaloids in Kushen,especially matrine,are the prime culprits for IHRs.Our findings may provide a potential approach for preventing and treating CKI-induced IHRs.

Investigation of the cell composition and gene expression in the delayed-type hypersensitivity tuberculin skin test

Dear Editor,The tuberculin skin test(TST)reagents have continuously improved,with the ESAT6-CFP10(EC)test having recently been introduced,but are seldom based on the direction of the delayed-type hypersensitivity(DTH)mechanism.Previous studies only partially showed the infiltration and activation of immune cells and the production of cytokines of the skin induration[1,2],and lack the detailed measurements of cell proportions and gene expression in the DTH response.Therefore,in this study,we revealed the comprehensive characteristics of DTH by single-cell RNA sequencing(scRNA-seq)in the guinea pig tuberculosis(TB)model[Experimental Animal Welfare Ethics Committee,Beijing Tuberculosis and Thoracic Tumor Research Institute(2021-064)].

Study on the Impact of Post-Mastectomy Radiotherapy on Immediate Breast Reconstruction and Complications: A Meta-Analysis

Background and objective:Immediate breast reconstruction not only reduces the number of surgeries for patients after mastectomy but also decreases psychological and physical trauma,making it increasingly popular.However,there is currently no consensus on the integration of post-mastectomy radiotherapy(PMRT)with reconstruction techniques.This review evaluates the impact of PMRT on complications following immediate breast reconstruction,providing guidance for clinical treatment decisions.Methods:PubMed,Web of Science,Embase,and other databases were searched for studies published in the past 15 years on outcomes of implant-based breast reconstruction in the context of radiotherapy to identify articles for analysis.RevMan 5.4 software was used to analyze the risks of seroma,infection,wound dehiscence,flap necrosis,implant exposure,capsule contracture,and reconstruction failure.Results:A total of 1l relevant studies were included,comprising 6323 cases of immediate breast reconstruction.It was found that breasts receiving postoperative irradiation had a significantly increased risk of complications,with statistically significant differences in seroma(P=0.004),infection(P<0.00001),wound dehiscence(P=0.04),implant exposure(P<0.00001),capsule contracture(P<0.00001),and reconstruction failure(P<0.00001).There was no statistically significant difference in flap necrosis(P=0.88).Conclusion:The results indicate that postoperative radiotherapy significantly increases the risk of complications for patients undergoing immediate implant-based reconstruction.Preventive measures may be taken in advance with the assistance of healthcare providers if necessary.

Effects of Immediate Dental Loading Implant Therapy on Electroencephalography (EEG) and Stress

Purpose: Implant therapy restores masticatory function by restoring lost tooth morphology. It has been shown that mastication contributes not only to food intake and digestion, but also to the improvement of overall health. However, there have been no studies on the effects of implant treatment on electroencephalography (EEG). In this study, we investigated the effects of restoration of masticatory function by implant treatment on EEG and stress. Methods: 13 subjects (6 males, 7 females, age 64.1 ± 5.8 years) who had lost masticatory function due to tooth loss and 11 healthy subjects (6 males, 5 females, age 47.6 ± 2.4 years) as a control group. EEG (θ, α, β waves, α/β ratio) and salivary cortisol were measured before immediate dental implant treatment and every month of treatment for 6 months. EEG (θ, α, β waves, α/β ratio) was measured with a simple electroencephalograph miniature DAQ terminal (Intercross-410, Intercross Co., Ltd., Japan) in a resting closed-eye condition, and salivary cortisol was measured using an ELISA kit. Results: Compared to the control group, the appearance of θ and α waves were significantly decreased and β waves were increased, and α/β ratio was significantly decreased. The cortisol level of the subject group was significantly higher compared with the control group. With the course of implant treatment, the appearance of θ and α waves of the subject group increased, while β waves decreased. However, no significant difference was observed. The α/β ratio of the subject group increased from the first month after implant treatment and increased significantly after 5 and 6 months (0 vs. 5 months: p < 0.05, 0 vs. 6 months: p < 0.01). The cortisol levels in the subject group decreased from the first month after implant treatment and significantly decreased after 3 or 4 months (0 vs. 3 months: p < 0.05, 0 vs. 4 months: p < 0.01). These results suggest that tooth loss causes mental stress, which decreases brain stimulation and affects function. Restoration of masticatory function by implants was suggested to alleviate the effects on brain function and stress.

The Beneficial Effect of 3-Month-Induction Therapy with Corticosteroids and Mycophenolate Mofetil Followed by Maintenance Therapy with Yearly Rituximab Infusions as Sole Maintenance Therapy in Cryptogenic Chronic Hypersensitivity Pneumonitis

Background: The available data on cryptogenic chronic hypersensitivity pneumonitis (ccHP) indicate an inherited predisposition to disease with triggering autoimmune phenomena. Hence, we evaluated prospectively the role of a new autoimmune regimen in treatment of its severe and progressive disease. Patients and Methods: A total of 9 patients were included in the study. They had criteria for ccHP viz. 1) clinical features of cryptogenic progressive restrictive lung disease, 2) high-resolution computed tomographic pulmonary abnormalities, and 3) bronchoalveolar lavage lymphocytosis (>30%). The regimen consisted of an initial induction phase of 3-month Solumedrol 1 g IV daily for 3 days followed by 1 month of Prednisone (P) 60 mg/day to tapered down to discontinuation by 3rd month. They also had received Mycophenolate mofetil (MMF) 1 g twice daily for 3 months. This stage was followed by a maintenance phase of yearly Rituximab infusions (1 g followed by 1 g 2 weeks later). Results: compared to their previous 6 months deterioration;all patients showed significant improvement in their forced vital volume, diffusion capacity for carbon monoxide, 6-minutes-walk after the induction phase (at 3 months) which improved further at 15 months with Rituximab therapy. Conclusion: After 3-month induction therapy with P and MMF;yearly R treatment is a safe, practical and effective long-term therapy for ccHP.

Effect of Training Nurses in ICU in Immediate Care Post Cardiac Surgery

The specialty of cardiovascular surgical nursing has advanced patient care significantly both before and after surgery, and it is now a well-established field. The primary goal of cardiovascular surgical nursing is to optimize the patient's recovery and prevent complications. Immediate nursing care for post-operative cardiac patients in a state of controlled shock due to fluid shift and varying vascular tone. Aim of the Study: Assessment of nurse’s knowledge and performance after the training program of nursing care immediately after a patient arrives from cardiac surgery. Methods: This pre and post-intervention study was conducted at cardiac centers in Sudan Alshaab and Ahmed Gasim Cardiac Center. The aim of the study was to evaluate the impact on nurses’ performance after training program post open-heart surgery. In the initial phase of the study, all 98 nurses working in the intensive care units at Alshaab and Ahmed Gasim cardiac centers were designated as the study group and evaluated before the intervention. Subsequently, the same group was reassessed after the intervention (phase 2), allowing for a comparison of the pre- and post-intervention results. The assessment involved the use of a specifically designed questionnaire and an observation checklist developed in accordance with the standards recommended by the American Nurses Association (phase 3). Result: Descriptive analysis was performed using the Chi-square test, the difference in the performance between the study group before intervention and after the intervention was assessed by the mean of chi-square significantly was taken as p < 0.05.

Practices of Maternity’s Care Providers in the Municipality of Kozah 1 Regarding the Administration of Vitamin K1, Eye Care, and Umbilical Cord Care in Immediate Postpartum Newborns

Background: Neonatal mortality is a real public health problem in the world and particularly in countries with limited resources. Essential care remains an effective means of reducing this mortality. Objective: To evaluate the practice of administering of vitamin K1, ocular and cord care in maternity wards in the Kozah 1 municipality. Method: This is a cross-sectional study conducted from March 1st to June 30th, 2022 in all maternity wards in the Kozah 1 municipality. Socioprofessional aspects of providers and those related to the administration of vitamin K1, ocular and cord care were studied. Results: Eighty-five (85) maternity providers were included in this study. The average age of the providers was 36.2 years with extremes of 21 and 55 years. Providers were midwives (51.8%), childbirth attendants (35.3%), and matrons (12.9%). The average length of practice was 9.5 years with extremes of 1 and 28 years. For three out of four providers (75.3%), the postpartum period was defined as a period of 02 hours following delivery. The importance of cord, ocular care, and administration of vitamin K1 in postpartum was known respectively by 84.7%, 98.8%, and 92.9% of the providers. Chlorhexidine gel was used by 81.2% of providers for umbilical cord care. For ocular disinfection, more than half of the providers (52.9%) reported using half-diluted povidone iodine. No center had displayed care protocol. Conclusion: This study highlighted the level of knowledge and practice of three essential postpartum care practices. The products used for the different care practices are consistent with recommendations but vary according to the care providers.

Management of Immediate Postpartum Hemorrhage at the University Hospital Center of the Sino-Central African Friendship

Introduction: Immediate postpartum hemorrhages constitute a frequent maternal complication and remain at the forefront of maternal death in our countries. Objective: Contribute to improving the management of immediate postpartum hemorrhage in our context with a view to reducing maternal mortality. Patients and Methods: We conducted a retrospective descriptive and analytical study over a period of 12 months from January 1st to December 31st 2020. Results: We collected a total of 109 files on a total of 4360 deliveries. The frequency of postpartum haemorrhages was of the order of 2.5%. The most represented age group was between 20 and 24 years old. Pauciparas represented the majority of our study population. 64.5% of patients were uneducated. These hemorrhages occurred in patients who often gave birth outside the department with 63.8%. The main causes of postpartum hemorrhage were cervical tears (51.2%) and partial placental retention (30.7%). The majority of these deliveries (48.8%) were carried out by midwives followed by assistant midwives (33.2%). Active management of the third period of delivery was systematic and immediate followed by the valve examination completed by the infusion of oxytocin in case of uterine atony, tranexamic acid ans misoprostol intrarectally. In the event of persistent hemorrhage, suture of the cervical lesions, ligation of the cervical vessels or even laparotomy either for the selective ligation of the blood vessels or for the hysterectomy for hemostasis were practiced. We do not have a Nalador, nor a Bakry balloon, nor an Interventional Radiology service for embolization of the uterine arteries. We deplore 1.3% of deaths from afibrinogenemia. Conclusion: The frequency of immediate postpartum hemorrhages is lower in our health facility. This is due to the rapid handling of cases. Improving the quality of services offered to women during childbirth can further help reduce the frequency of these hemorrhages.

Hypersensitivity Reaction Caused by Intravenous Gadolinium-based MRI Contrast Agents

Objective To present a rare case of skin allergic reaction to gadobutrol,a magnetic resonance imaging(MRI)contrast agent,in a 37-year-old man.Methods The adverse reactions of gadobutrol were analyzed combined with the instructions and related literatures.Results and Conclusion The presence of this patient is consistent with the adverse reactions in the instructions of gadobutrol.The incidence of ADR in gadobutrol is considered to be low,although sometimes patients report a hypersensitivity reaction when undergoing MRI.There are only a few cases of immediate adverse reactions to gadobutrol.However,we should improve the ability of medical staff to use drugs safely and take preventive measures.

Improved Behavioural Engagement of Students through Low-stakes Online Tests and Immediate Dialogic Feedback

The engagement of students is a recognised challenge for teachers.Technology offers some practical student engagement tools,and this paper examines the use of low-stakes online tests and immediate dialogic feedback to improve behavioural engagement.The academic exploration of low-stakes tests and dialogic feedback has been extensive,and they are credible teaching tools.In this study,we explore the learning benefit of their combination.Postgraduate engineering students’self-reported and learning analytics data shows conclusive evidence of improved behavioural engagement.We measured a 500%increase in the Learning Management System(LMS)page views on the days when we ran the low-stakes tests(each worth 2%of the marks for the subject)and engaged in immediate dialogic feedback.To interpret these results,we draw on theories of behavioural engagement,low-stakes tests,and feedback.We conclude that the combination of low-stakes tests and immediate feedback improves student behavioural engagement.

Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry

BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.

A randomized trail comparing primary percutaneous coronary intervention with a strategy of short-acting thrombolysis and immediate planned primary percutaneous coronary intervention in acute myocardial infarction

Objective This study was to evaluate the efficacy and safety of a short acting reduced dose fibrinolytic regimen to promote early infarct related artery (IRA) patency for acyute myocardial infarction (AMI) patients referred for percutaneous coronary intervention (PCI).Methods Following aspirin and heparin, 166 patients were randomized to a 50 mg bolus of recombinant tissue type plasminogen activator(rt PA) or to a same volume sodium chloride injection followed by immediate primary PCI. The end points included patency rates on catheterization laboratory (cath lab) arrival, revascularization results when PCI was performed, complication rates, left ventricular function and restored patency rate following PCI. Results Patency on cath lab arrival was 64% with rt PA (34% TIMI 3,30% TIMI 2), while 31% of placebo (13% TIMI 3, 18% TIMI 2). There was no difference in the restored TIMI 3 rates of IRA between the two groups (85% vs 87%). No difference were observed in stroke or major bleeding. Left ventricular function was similar in both groups (52±9% vs 50±8%), but left ventricular ejection fraction fraction (LVEF) was higher with patent IRA (TIMI 3) on cath lab arrival than that of others (56±12% vs 48±10%).Conclusions Strategy thrombolytic regimens were compatible with subsequent PCI lead to more frequenc early recanalization (before cath lab arrival), which facilitates greater left ventricular function preservation with no augmentation of adverse events.

Comparison of the analgesic effects between electro-acupuncture and moxibustion with visceral hypersensitivity rats in irritable bowel syndrome

AIM To observe whether there are differences in the effects of electro-acupuncture(EA) and moxibustion(Mox) in rats with visceral hypersensitivity. METHODS EA at 1 m A and 3 m A and Mox at 43?℃ and 46?℃ were applied to the Shangjuxu(ST37, bilateral) acupoints in model rats with visceral hypersensitivity. Responses of wide dynamic range neurons in dorsal horns of the spinal cord were observed through the extracellular recordings. Mast cells(MC) activity in the colons of rats were assessed, and 5-hydroxytryptamine(5-HT), 5-hydroxytryptamine 3 receptor(5-HT3R) and 5-HT4Rexpressions in the colons were measured.RESULTS Compared with normal control group, responses of wide dynamic range neurons in the dorsal horn of the spinal cord were increased in the EA at 1 m A and 3 m A groups(1 m A: 0.84 ± 0.74 vs 2.73 ± 0.65, P < 0.001; 3 m A: 1.91 ± 1.48 vs 6.44 ± 1.26, P < 0.001) and Mox at 43?℃ and 46?℃ groups(43?℃: 1.76 ± 0.81 vs 4.14 ± 1.83, P = 0.001; 46?℃: 5.19 ± 2.03 vs 7.91 ± 2.27, P = 0.01). MC degranulation rates and the expression of 5-HT, 5-HT3 R and 5-HT4 R in the colon of Mox 46?℃ group were decreased compared with model group(MC degranulation rates: 0.47 ± 0.56 vs 0.28 ± 0.78, P < 0.001; 5-HT: 1.42 ± 0.65 vs 7.38 ± 1.12, P < 0.001; 5-HT3R: 6.62 ± 0.77 vs 2.86 ± 0.88, P < 0.001; 5-HT4R: 4.62 ± 0.65 vs 2.22 ± 0.97, P < 0.001). CONCLUSION The analgesic effects of Mox at 46?℃ are greater than those of Mox at 43?℃, EA 1 m A and EA 3 m A.

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

The pharmacokinetics of morphine sulphate was studied in 10 Chinese healthy volunteers after a single oral dose. Blood samples were collected before and after administration of controlled release tablets (CRMS, 30 mg) and immediate release tablets (IRMS, 20 mg). The plasma concentration of morphine was determined by GC MS. The pharmacokinetic parameters of controlled release tablets and immediate release tablets were calculated∶ C max was 19.38±3.80 and 21.27±6.21 ng/ml, t max was 2.36 ±0.37 h and 0.56±0.16 h, t 1/2β was 3.53±0.87 and 3.03±0.74 h, AUC was 145.15±17.65 and 93.08±16.65 ng/ml, respectively. The steady state plasma concentration of morphine sulphate in cancer patients after multiple doses was achieved, C max of CRMS and IRMS was 27.43±0.33 ng/ml and 22.68±0.16 ng/ml, C min of CRMS and IRMS was 19.45±1.44 ng/ml and 18.14±0.49 ng/ml, respectively.

Antinociceptive effect of berberine on visceral hypersensitivity in rats

AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 ℃) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement. RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000). CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.

Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrheapredominant irritable bowel syndrome

BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.

Visceral hypersensitivity and electromechanical dysfunction as therapeutic targets in pediatric functional dyspepsia

Functional gastrointestinal disorders(FGID) are common clinical syndromes diagnosed in the absence of biochemical,structural,or metabolic abnormalities. They account for significant morbidity and health care expenditures and are identifiable across variable age,geography,and culture. Etiology of abdominal pain associated FGIDs,including functional dyspepsia(FD),remains incompletely understood,but growing evidence implicates the importance of visceral hypersensitivity and electromechanical dysfunction. This manuscript explores data supporting the role of visceral hypersensitivity and electromechanical dysfunction in FD,with focus on pediatric data when available,and provides a summary of potential therapeutic targets.

Role of nesfatin-1 in a rat model of visceral hypersensitivity

AIM: To explore the role of nesfatin-1 on irritable bowel syndrome (IBS)-like visceral hypersensitivity. METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8-21. Experiments were performed when rats became adults. The visceral sensitivity of rats was evaluated by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activity of the external oblique muscle to graded colorectal distension. The content of nesfatin-1 in serum was determined using enzyme-linked immunosorbent assay. After implantation of an intracerebroventricular (ICV) cannula and two electrodes into the external oblique muscle, model rats were randomly divided into four groups. Animals then received ICV injection of 8 μg of anti-nesfatin-1/ nucleobindin-2 (NUCB2), 50 μg of α-helical cortico-tropin releasing factor (CRF) 9-41 (non-selective CRF receptor antagonist), 50 μg of NBI-27914 (selective CRF1 receptor antagonist) or 5 μL of vehicle. After 1 h of ICV administration, visceral sensitivity of each group was measured again, and comparisons between groups were made. RESULTS: Rats treated with AA showed higher mean AWR scores and EMG activity at all distension pressures compared with controls (P < 0.05). On histopathologic examination, no evidence of inflammation or abnormalities in structure were noted in the colon of either control or AA-treated groups. Myeloperoxidase values were not significantly different between the two groups. The level of nesfatin-1 in serum was significantly higher in the AA-treated group than in the control group (5.34 ± 0.37 ng/mL vs 4.81 ± 0.42 ng/mL, P < 0.01). Compared with rats injected with vehicle, rats which received ICV anti-nesfatin-1/NUCB2, α-helical CRF9-41 or NBI-27914 showed decreased mean AWR scores and EMG activity at all distension pressures (P < 0.05). CONCLUSION: Nesfatin-1 may be associated with IBS-like visceral hypersensitivity, which may be implicated in brain CRF/CRF1 signaling pathways.

Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B

Several clinical trials have demonstrated the potent antiviral efficacy of entecavir (ETV), and this relatively new nucleoside analogue drug has rapidly become a frequently prescribed therapy for chronic hepatitis B (CHB) worldwide. While the studies have also shown a good overall safety profile for ETV, adverse drug reactions (ADRs) in patients with advanced cirrhosis have been reported and represent a broad spectrum of drug-induced injuries, including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses (i.e., allergic reactions). Cutaneous ADRs associated with ETV are very rare, with only two case reports in the publicly available literature; both of these cases were classified as unspecified hypersensitivity allergic (type I) ADR, but neither were reported as pathologically proven or as evaluated by cytokine release analysis. Here, we report the case of a 45-year-old woman who presented with a generalized maculopapular rash after one week of ETV treatment for lamivudine-resistant CHB. The patient reported having experienced a similar skin eruption during a previous three-month regimen of ETV, for which she had self-discontinued the medication. Histopathological analysis of a skin biopsy showed acanthotic epidermis with focal parakeratosis and a perivascular lymphocytic infiltrate admixed with interstitial eosinophils in the papillary and reticular dermis, consistent with a diagnosis of drug sensitivity. A lymphocyte stimulation test showed significantly enhanced IL-4, indicating a classification of type IVb delayed hypersensitivity. The patient was switched to an adefovir-lamivudine combination regimen and the skin eruption resolved two weeks after the ETV withdrawal. This case represents the first pathologically and immunologically evidenced ETV-induced delayed type hypersensitivity skin reaction reported to date. Physicians should be aware of the potential, although rare, for cutaneous ADRs associated with ETV treatment.

TLR4 upregulates CBS expression through NF-κB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity

AIM:To investigate the roles of toll-like receptor 4(TLR4) and nuclear factor(NF)-κB on cystathionine βsynthetase(CBS) expression and visceral hypersensitivity in rats.METHODS:This study used 1-7-wk-old male SpragueDawley rats.Western blot analysis was employed to measure the expression of TLR4,NF-kB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia(DRG) from control and "irritable bowel syndrome" rats induced by neonatal colonic inflammation(NCI).Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques.Immunofluorescence was employed to determine the co-expression of TLR4,NF-kB and CBS in Dil-labeled DRG neurons.RESULTS:NCI significantly upregulated the expression of TLR4 in colon-related DRGs(0.34 ± 0.12 vs 0.72 ±0.02 for the control and NCI groups,respectively,P <0.05).Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats.CLI-095 treatment also markedly reversed the hyperexcitability of colonspecific DRG neurons and reduced the expression of CBS(1.7 ± 0.1 vs 1.1 ± 0.04,p < 0.05) and of the NF-kB subunit p65(0.8 ± 0.1 vs 0.5 ± 0.1,P< 0.05).Furthermore,the NF-KB-selective inhibitor pyrrolidine dithiocarbamate(PDTC) significantly reduced the upregulation of CBS(1.0 ± 0.1 vs 0.6 ± 0.1,P< 0.05)and attenuated visceral hypersensitivity in the NCI rats.In vitro,incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65(control vs 8 h:0.9 ± 0.1 vs1.3 ± 0.1;control vs 12 h:0.9 ± 0.1 vs 1.3 ± 0.1,P< 0.05;control vs 24 h:0.9 ± 0.1 vs 1.6 ± 0.1,P <0.01) and CBS(control vs 12 h:1.0 ± 0.1 vs 2.2 ±0.4;control vs 24 h:1.0 ± 0.1 vs 2.6 ± 0.1,P< 0.05),whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression(1.2 ± 0.1 vs 0.6 ± 0.0,P< 0.01).CONCLUSION:Our results suggest that the activation of TLR4 by NCI upregulates CBS expression,which is mediated by the NF-kB signaling pathway,thus contributing to visceral hypersensitivity.