Granulomatosis with polyangiitis presenting as high fever with diffuse alveolar hemorrhage and otitis media: A case report

BACKGROUND Granulomatosis with polyangiitis is a necrotizing inflammation of small andmedium-sized vessels accompanied by formation of granuloma, involvement ofprimary granulomatous upper and lower respiratory tracts, glomerulonephritis,and vasculitis of small vessels.CASE SUMMARY Herein, we described a case of a 52-year-old man admitted with pulmonarynodules and high fever. Autoantibody workup revealed that the patient waspositive for c-anti-neutrophil cytoplasmic antibodies and proteinase-3 antineutrophilcytoplasmic antibodies. Pulmonary biopsies revealed a localgranulomatous structure. The patient received therapy with methylprednisoloneand intravenous immunoglobulin, and his clinical symptoms improved.CONCLUSION Intravenous immunoglobulin may act on granulomatosis with polyangiitis similarto immunosuppressants.

Stable chlorine isotopic signatures and fractionation mechanism of groundwater in Anyang,China

The present work provides an online Bench II-IRMS technique for the measurement of stable chlorine isotope ratio,which is used to measure the δ^(37)Cl of 38 groundwater samples from the Karst and Quaternary aquifers in Anyang area.The regional distribution and signature of δ^(37)Cl value are characterized on the base of isotopic data.The results suggest that the δ^(37)Cl value of Quaternary groundwater decreases with increasing Cl^(−) concentration,and has no correlation with δ^(18)O andδD values,but closely correlates with the depth to water table.The fractionation mechanism of the chlorine isotope is expounded according to the type of groundwater.The δ^(37)Cl value of karst water is generally positive,which is relevant to the dissolution of evaporite(gypsum mine),and may be caused by the mixing of groundwater and precipitation.The groundwater of Quaternary unconfined aquifer is mainly recharged by precipitation,and the δ^(37)Cl value of groundwater is generally negative.The δ^(37)Cl value of groundwater in Quaternary confined aquifer is more negative with increasing the depth to water level and elevated Cl^(−) concentration,which is possible to result from the isotope fractionation of ion filtration.The groundwater with inorganic pollutants in Quaternary unconfined aquifer has generally a positive δ^(37)Cl value.

Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.

Drug utilization of clarithromycin for gastrointestinal disease treatment

AIM: To evaluate the patterns of use of clarithromycin for gastrointestinal disease treatment and promote its rational use. METHODS: Using a structured pro forma,we conducted a two-month survey of the electronic prescriptions containing immediate-release (IR) or sustained-release (SR) product of clarithromycin for outpatients with gastrointestinal diseases in a 2200-bed general hospital. Suitability of the prescription was audited retrospectively. RESULTS: One hundred and sixty-four prescriptions of SR product and 110 prescriptions of IR product were prescribed for gastrointestinal disease treatment. Among prescriptions for anti-Helicobacter pylori (H pylori) therapy,triple therapy take the dominant position (91.8%),followed by quadruple therapy (4.3%) and dual therapy (3.9%). Amoxicillin was the most frequently co-prescribed antibiotic.Furazolidone and levofloxacin are used more widely than metronidazole or tinidazole. Clarithromycin SR was administered at inappropriate time points in all prescriptions. Fifty percent of all prescriptions of clarithromycin SR,and 6.4% of prescriptions of clarithromycin IR,were prescribed at inappropriate dosing intervals. Surprisingly,disconcordance between diagnoses and indications was observed in all prescriptions of clarithromycin SR which has not been approved for treating H pylori infection although off-label use for this purpose was reported in literature. On the contrary,only one prescription (0.9%) of clarithromycin IR was prescribed for unapproved indication (i.e. gastro-oesophageal reflux disease). 1.4% of prescriptions for chronic gastritis or peptic ulcer treatment were irrational in that clarithromycin was not co-prescribed with gastric acid inhibitors. Clinical significant CYP3A based drug interactions with clarithromycin were identified. CONCLUSION: There is a great scope to improve the quality of clarithromycin prescribing in patients with gastrointestinal disease,especially with regard to administration schedule,concordance between indications and diagnoses and management of drug interactions.

Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006.RESULTS:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole antifungals.They showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues.CONCLUSION:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy.The relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

Effect of Yiguanjian decoction on cell differentiation and proliferation in CCl_4-treated mice

AIM:To investigate the cellular mechanisms of action of Yiguanjian(YGJ) decoction in treatment of chronic hepatic injury.METHODS:One group of mice was irradiated,and received enhanced green fluorescent protein(EGFP)positive bone marrow transplants followed by 13 wk of CCl4 injection and 6 wk of oral YGJ administration.A second group of Institute for Cancer Research mice was treated with 13 wk of CCl4 injection and 6 wk of oral YGJadministration.Liver function,histological changes in the liver,and Hyp content were analyzed.The expression of-smooth muscle actin(-SMA),F4/80,albumin(Alb),EGFP,mitogen-activated protein kinase-2(PKM2),Ki-67,fetoprotein(AFP),monocyte chemotaxis protein-1 and CC chemokine receptor 2 were assayed.RESULTS:As hepatic damage progressed,EGFP-positive marrow cells migrated into the liver and were mainly distributed along the fibrous septa.They showed a conspicuous coexpression of EGFP with-SMA and F4/80 but no coexpression with Alb.Moreover,the expression of PKM2,AFP and Ki-67 was enhanced dynamically and steadily over the course of liver injury.YGJ abrogated the increases in the number of bone marrow-derived fibrogenic cells in the liver,inhibited expression of both progenitor and mature hepatocyte markers,and reduced fibrogenesis.CONCLUSION:YGJ decoction improves liver fibrosis by inhibiting the migration of bone marrow cells into the liver as well as inhibiting their differentiation and suppressing the proliferation of both progenitors and hepatocytes in the injured liver.

Salvianolic acid B protects hepatocytes from H2O2 injury by stabilizing the lysosomal membrane

AIM To investigate the capability of salvianolic acid B(Sal B) to protect hepatocytes from hydrogen peroxide(H_2O_2)/carbon tetrachloride(CCl_4)-induced lysosomal membrane permeabilization. METHODS Cell Counting Kit-8 assay was used to measure cell viability. Apoptosis and death were assayed through flow cytometry. Brd U incorporation was used to detect cell proliferation. Serum alanine aminotransferase activity and liver malondialdehyde(MDA) content were measured. Liver histopathological changes were evaluated using hematoxylin-eosin staining. Lysosomal membrane permeability was detected with Lyso Tracker Green-labeled probes and acridine orange staining. The levels of protein carbonyl content(PCC), cathepsins(Cat)B/D, and lysosome-associated membrane protein 1(LAMP1) were evaluated through western blotting. Cytosol Cat B activity analysis was performed with chemiluminescence detection. The m RNA level ofLAMP1 was evaluated through quantitative real-time polymerase chain reaction. RESULTS Results indicated that H_2O_2 induced cell injury/death. Sal B attenuated H_2O_2-induced cell apoptosis and death, restored the inhibition of proliferation, decreased the amount of PCC, and stabilized the lysosome membrane by increasing the LAMP1 protein level and antagonizing Cat B/D leakage into the cytosol. CCl_4 also triggered hepatocyte death. Furthermore, Sal B effectively rescued hepatocytes by increasing LAMP1 expression and by reducing lysosomal enzyme translocation to the cytosol.CONCLUSION Sal B protected mouse embryonic hepatocytes from H_2O_2/CCl_4-induced injury/death by stabilizing the lysosomal membrane.

High mobility group box-1 release from H2O2-injured hepatocytes due to sirt1 functional inhibition

BACKGROUND High mobility group box-1 (HMGB1), recognized as a representative of damageassociated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited. AIM To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress. METHODS C57BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H2O2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H2O2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2- deoxyguanosine content, nicotinamide adenine dinucleotide (NAD+) levels, and Sirtuin 1 (Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot. Relative mRNA levels were assayed by qPCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1 (Parp1) were analyzed by Immunoprecipitation. RESULTS When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-siRNA or Sirt1 inhibitor (EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2O2 could be reversed by Parp1 inhibitor (DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress . We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deacetylation. CONCLUSION The functional inhibition between Parp1 and Sirt1 leads to HMGB1 hyperacetylation, which leads to its translocation from the nucleus to the cytoplasm and finally outside the cell.

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China:focus on the safety

Background:World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis(DR-TB)should develop and implement a system for active pharmacovigilance that allows for detection,reporting and management of adverse events.The aim of the study is to evaluate the frequency and severity of adverse events(AEs)of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant(MDR)/extensively drug-resistant(XDR)-TB based on active drug safety monitoring(aDSM)system of New Drug Introduction and Protection Program(NDIP).

Improvement cues of lesion absorption using the adjuvant therapy of traditional Chinese medicine Qinbudan tablet for retreatment pulmonary tuberculosis with standard anti-tuberculosis regimen

Background:China is the second highest pulmonary tuberculosis(PTB)burden country worldwide.However,retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs.The cure rate(approximately 50.0–73.3%)and management of retreatment of PTB in China needs to be improved.Qinbudan decoction has been widely used to treat PTB in China since the 1960s.Previously clinical studies have shown that the Qinbudan tablet(QBDT)promoted sputum-culture negative conversion and lesion absorption.However,powerful evidence from a randomized controlled clinical trial is lacking.Therefore,the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB.Methods:We conducted a multicenter,randomized,double-blind,placebo-controlled clinical trial in China.People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013.The treatment group received an anti-TB regimen and QBDT,and the control group was administered an anti-TB regimen plus placebo.Anti-TB treatment options included isoniazid,rifampicin,pyrazinamide,ethambutol,streptomycin for 2 months(2HRZES),followed by isoniazid,rifampicin,ethambutol for 6 months(6HRE),daily for 8 months.Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method.Secondary outcomes included lung lesion absorption and cavity closure.Adverse events and reactions were observed after treatment.A structured questionnaire was used to record demographic information and clinical symptoms of all subjects.Data analysis was performed by SPSS 25.0 software in the full analysis set(FAS)population.Results:One hundred eighty-one cases of retreatment PTB were randomly divided into two groups:the placebo group(88 cases)and the QBDT group(93 cases).A total of 166 patients completed the trial and 15 patients lost to follow-up.The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences(79.6%vs 69.3%;rate difference=0.10,95%confidence interval(CI):-0.02–0.23;F=2.48,P=0.12)after treatment.A significant 16.6%increase in lesion absorption was observed in the QBDT group when compared with the placebo group(67.7%vs 51.1%;rate difference=0.17,95%CI:0.02–0.31;χ2=5.56,P=0.02).The intervention and placebo group did not differ in terms of cavity closure(25.5%vs 21.1%;rate difference=0.04,95%CI:-0.21–0.12;χ2=0.27,P=0.60).Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting.Conclusions:No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen.However,QBDT as an adjunct therapy significantly promoted lesion absorption,thereby reducing lung injury due to Mycobacterium tuberculosis infection.Trial registration:This trial is registered at ClinicalTrials.gov,NCT02313610.

Hot deformation behavior of GH4945 superalloy using constitutive equation and processing map

The hot deformation behavior of GH4945 superalloy was investigated by isothermal compression test in the temperature range of 1000--1200 ℃with strain rates of 0.001 10.000 s 1 toa total strain of 0.7. Dynamic recrystallization is the primary softening mechanism for GH4945 superalloy during hot deformation. The constitutive equation is established, and the calculated apparent activation energy is 458. 446 kJ/moh The processing maps at true strains of 0.2, 0.4 and 0.6 are generally similar, dem- onstrating that strain has little influence on processing map. The power dissipation efficiency and in- stability factors are remarkably influenced by deformation temperature and strain rate. The optimal hot working conditions are determined in temperature range of 1082 -1131 ℃ with strain rates of 0.004--0.018 s-1. Another domain of1134--1150 ℃ and 0. 018 0.213s ^- can also be selected as the optimal hot working conditions. The initial grains are replaced by dynamically reerystallized ones in optimal domains. The unsafe domains locate in the zone with strain rates above 0, 274 s^- 1, mainly characterized by uneven microstructure. Hot working is not recommended in the unsafe domains.