Intestinal Cckbr-specific knockout mouse as a novel model of salt-sensitive hypertension via sodium over-absorption

OBJECTIVES To investigate the value of CCKBR^(fl/fl)villin-Cre mice as a mouse model of salt-sensitive hypertension(SSH).METHODS In the first part,2-month-old CCKBR^(fl/fl)villin-Cre mice(CKO)and control CCKBR^(fl/fl)mice(WT)were fed with normal diet(0.4%NaCl)or high salt diet(4%NaCl),separately for 6 weeks.In the rescue study,one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet.The blood pressure,biochemical indexes,and the expression of small intestinal sodium transporters(NHE3,NKCC1,eNaC)was detected.The organ injury markers(MMP2/MMP9)and the histopathological changes of kidneys were observed,whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo.RESULTS The CCKBR^(fl/fl)villin-Cre mice with high salt intake exhibited high blood pressure,increased duodenal sodium absorption and urinary sodium excretion,and with renal injury.The protein expression of NHE3,NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice.Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBR^(fl/fl)villin-Cre mice,but no significant histopathological changes were observed.CONCLUSIONS These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBR^(fl/fl)villin-Cre mice.The CCKBR^(fl/fl)villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.

P-selectin glycoprotein ligand 1 deficiency prevents development of acute pancreatitis by attenuating leukocyte infiltration

BACKGROUND Acute pancreatitis(AP) is rapid-onset pancreatic inflammation that causes local and systemic inflammatory response syndrome(SIRS) with high morbidity and mortality, but no approved therapies are currently available. P-selectin glycoprotein ligand 1(PSGL-1) is a transmembrane glycoprotein to initiate inflammatory responses. We hypothesized that PSGL-1 may be involved in the development of AP and would be a new target for the treatment of AP.AIM To investigate the role and mechanism of PSGL-1 in the development of AP.METHODS The PSGL-1 expression on leukocytes was detected in peripheral blood of AP patients and volunteers. Pancreatic injury, inflammatory cytokines expression, and inflammatory cell infiltration was measured in AP mouse models induced with PSGL-1 knockout(PSGL-1-/-) and wild-type(PSGL-1+/+) mice. Leukocyteendothelial cell adhesion was measured in a peripheral blood mononuclear cell(PBMC)-endothelial cell coculture system.RESULTS The expression of PSGL-1 on monocytes and neutrophils was significantly increased in AP patients. Compared with PSGL-1+/+ mice, PSGL-1-/-AP mice induced by caerulein exhibited lower serum amylase, less Interleukin-1 beta(IL-1 beta) and Interleukin-6(IL-6) expression, less neutrophil and macrophage infiltration, and reduced peripheral neutrophil and monocyte accounts. PSGL-1 deficiency alleviated leukocyte-endothelial cell adhesion via IL-6 but not IL-1 beta.CONCLUSION PSGL-1 deficiency effectively inhibits the development of AP by preventing leukocyte-endothelial cell adhesion via IL-6 stimulation and may become a potential therapeutic target for treating AP.

Changes in patients' symptoms and gastric emptying after Helicobacter pylori treatment

AIM: To investigate the changes in clinical symptoms and gastric emptying and their association in functional dyspepsia(FD) patients.METHODS: Seventy FD patients were enrolled and divided into 2 groups Helicobacter pylori(H. pylori)-negative group(28 patients), and H. pylori-positive group(42 patients). Patients in the H. pylori-positive group were further randomly divided into groups: H. pylori-treatment group(21 patients) and conventional treatment group(21 patients). Seventy two healthy subjects were selected as the control group. The proximal and distal stomach area was measured by ultrasound immediately after patients took the test meal, and at 20, 40, 60 and 90 min; then, gastric half-emptying time was calculated. The incidence of symptoms and gastric half-emptying time between the FD and control groups were compared. The H. pylori-negative and conventional treatment groups were givenconventional treatment: domperidone 0.6 mg/(kg/d) for 1 mo. The H. pylori-treatment group was given H. pylori eradication treatment + conventional treatment: lansoprazole 30 mg once daily, clarithromycin 0.5 g twice daily and amoxicillin 1.0 g twice daily for 1 wk, then domperidone 0.6 mg/(kg/d) for 1 mo. The incidence of symptoms and gastric emptying were compared between the FD and control groups. The relationship between dyspeptic symptoms and gastric half-emptying time in the FD and control groups were analyzed. Then total symptom scores before and after treatment and gastric half-emptying time were compared among the 3 groups. RESULTS: The incidence of abdominal pain, epigastric burning sensation, abdominal distension, nausea, belching, and early satiety symptoms in the FD group were significantly higher than in the control group(50.0% vs 20.8%; 37.1% vs 12.5%; 78.6% vs 44.4%; 45.7% vs 22.2%; 52.9% vs 15.3%; 57.1% vs 19.4%; all P < 0.05). The gastric half-emptying times of the proximal end, distal end, and the whole stomach in the FD group were slower than in the control group(93.7 ± 26.2 vs 72.0 ± 14.3; 102.2 ± 26.4 vs 87.5 ± 18.2; 102.1 ± 28.6 vs 78.3 ± 14.1; all P < 0.05). Abdominal distension, belching and early satiety had an effect on distal gastric half-emptying time(P < 0.05). Abdominal distension and abdominal pain had an effect on the gastric half-emptying time of the whole stomach(P < 0.05). All were risk factors(odds ratio > 1). The total symptom score of the 3 groups after treatment was lower than before treatment(P < 0.05). Total symptom scores after treatment in the H. pylori-treatment group and H. pylori-negative group were lower than in the conventional treatment group(5.15 ± 2.27 vs 7.02 ± 3.04, 4.93 ± 3.22 vs 7.02 ± 3.04, All P < 0.05). The gastric half-emptying times of the proximal end, distal end, and the whole stomach in the H. pylori-negative and H. pylori-treatment groups were shorter than in the conventional treatment group(P < 0.05). CONCLUSION: FD patients have delayed gastric emptying. H. pylori infection treatment helps to improve symptoms of dyspepsia and is a reasonable choice for treatment in clinical practice.

Three-dimensional computed topography analysis of a patient with an unusual anatomy of the maxillary second and third molars

We present a case of a patient with rare anatomy of a maxillary second molar with three mesiobuccal root canals and a maxillary third molar with four separate roots, identified using multi-slice computed topography （CT） and three-dimensional reconstruction techniques. The described case enriched/might enrich our knowledge about possible anatomical aberrations of maxillary molars. In addition, we demonstrate the role of multi-slice CT as an objective tool for confirmatory diagnosis and successful endodontic management.

Rapid Structure-Based Screening Informs Potential Agents for Coronavirus Disease(COVID-19)Outbreak

Coronavirus Disease 2019(COVID-19),caused by the novel coronavirus,has spread rapidly across China.Consequently,there is an urgent need to sort and develop novel agents for the prevention and treatment of viral infections.A rapid structure-based virtual screening is used for the evaluation of current commercial drugs,with structures of human angiotensin converting enzymeⅡ(ACE2),and viral main protease,spike,envelope,membrane and nucleocapsid proteins.Our results reveal that the reported drugs Arbidol,Chloroquine and Remdesivir may hinder the entry and release of virions through the bindings with ACE2,spike and envelope proteins.Due to the similar binding patterns,NHC(β-d-N4-hydroxycytidine)and Triazavirin are also in prospects for clinical use.Main protease(3 CLpro)is likely to be a feasible target of drug design.The screening results to target 3 CLpro reveal that Mitoguazone,Metformin,Biguanide Hydrochloride,Gallic acid,Caffeic acid,Sulfaguanidine and Acetylcysteine seem be possible inhibitors and have potential application in the clinical therapy of COVID-19.

An Open-label, Self-control, Prospective Study on Cognitive Function, Academic Performance, and Tolerability of Osmotic-release Oral System Methylphenidate in Children with Attention-deficit Hyperactivity Disorder

Background： Attention-deficit hyperactivity disorder （ADHD） is the most common mental and behavioral disorder in school-aged children. This study evaluated the effect of osmotic-release oral system （OROS） methylphenidate （MPH） on cognitive function and academic performance of Chinese school-aged children with ADHD. Methods： This 12-week, prospective, multicenter, open-label, self-controlled study enrolled 153 Chinese school-aged children with ADHD and 41 non-ADHD children. Children with ADHD were treated with once-daily OROS-MPH （18 mg, 36 mg, or 54 mg）. The primary endpoints were Inattention/Overactivity （I/O） with Aggression Conners Behavior Rating Scale （IOWA） and Digit Span Test at week 12 compared with baseline. Secondary endpoints included opposition/defiant （O/D） subscale of IOWA, Clinical Global Impression （CGI）, Coding Test, Stroop Color-word Test, Wisconsin Card Sorting Test （WCST）, academic performance on teacher-rated school examinations, and safety at week 12 compared with baseline. Both non-ADHD and ADHD children received the same frequency of cognitive operational test to avoid the possible bias caused by training. Results： A total of 128 patients were evaluated with cognitive assessments. The OROS-MPH treatment significantly improved IOWA Conners I/O subscale scores at week 12 （3.8 ± 2.3） versus baseline （10.0 ± 2.4; P 〈 0.0001）. Digit Span Test scores improved significantly （P 〈 0.0001 ） with a high remission rate （81.1%） at week 12 versus baseline. A significant （P 〈 0.0001 ） improvement was observed in O/D subscale of IOWA, CGI, Coding Test, Stroop Color-word Test, WCST, and academic performance at week 12 versus baseline. Very few practice-related improvements were noticed in the non-ADHD group at week 12 compared with baseline. No serious adverse events and deaths were reported during the study. Conclusions： The OROS-MPH treatment effectively controlled symptoms of ADHD and significantly improved academic performance and cognitive fimction of Chinese school-aged children with ADHD. The treatment was found to be sate and generally well-tolerated over 12 weeks.