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Papers by Thomas Ling

The Journal of pathology, Apr 12, 2018

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involve... more Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacologic ablation of autophagy in mouse and cell line models of H. pylori infection. Here we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidi...

Journal of the American Geriatrics Society, 1996

To the Editor: Medication use is potentially the most modifiable risk factor for falls in older p... more To the Editor: Medication use is potentially the most modifiable risk factor for falls in older persons, and it is of particular interest clinically, as stated in the excellent review by Drs. King and Tinetti. 1 Surprisingly, among the eight FICSIT Trialsr' the optimizing of medication use was a component of the interventions in one trial only.:' Critical medication reviews were performed focussing on three important issues, (1) postural hypotension, (2) the use of sedative hypnotics benzodiazepines and sleeping medications, and (3) multimedication (;=:4 medications). Medications of special interest, targeted medications, were diuretics, antihypertensives, nitrates, anti~epressa?ts, H 2 blockers, and NSAIDS, apart from hypnotics/sedatives." A recent report indicated that either the use of ~ntide~ressants, any psychotropic medication, centrally act109 antihypertensives, narcotic analgesics, insulin, or the total number of prescribed medications was associated with falls in persons aged 72 years and older living in the comrnuniry.f Postural blood pressure changes (postural hypotension?) were not associated with falling. The data from the intervention trial showed there were no differences in the prevalence of postural hypotension, and of the use of sedative-hypnotic agents, at the time of reassessment. However, as part of the intervention, 55 of 70 persons with postural hypotension, and 19 of 29 persons who used sedative-hypnotic agents, had received medication adjustments. There was a remarkable difference in the prevalence of using four or more medications.:~ The results of this trial, as well as recent data,S,6 bring us to the following questions. For which types of medications were dosages adapted, and which drugs were most often d!scontinued or substituted? Although it is impossible to disentangle the contributions of single components of that multifactorial intervention, information about the kind of medication adjustments would provide at least some hints for further research. With regard to risk constellations, it may be worthwhile to evaluate whether there are associations between falls and combinations of certain, rather than single targeted medicarions.I-" and whether there is also a possible relationship to postural hypotension/postural blood pressure changes.Y'"

The Lancet, 1997

about folic acid. However, 38•8% of women interviewed started to take supplements only after conc... more about folic acid. However, 38•8% of women interviewed started to take supplements only after conception, and most after the fifth week of pregnancy, which may well offer little or no protection 5 since neural-tube closure is 26-27 days after conception. 35•9% of pregnancies in this study were unplanned. Thus, potentially 64•1% of women could have taken preconceptional folate. Although there has been increased awareness of folic acid for prevention of neuraltube defects, there is still a long way to go. 1 Expert Advisory Group. Folic acid and the prevention of neural tube defects. London:

Gastrointestinal Endoscopy, 2001

Background: Bacteria play an important role in the formation of brown pigment stones through adhe... more Background: Bacteria play an important role in the formation of brown pigment stones through adherence and biofilm formation. Scanning electron microscopy of cross sections of these stones reveals a laminated appearance and various bacteria in the different layers. Our postulation was that different bacteria might be involved at different stages of stone formation. Methods: By using standard bacteriologic cultures, the composition, morphology, and antibiotic sensitivity patterns of bacteria isolated from paired stone were compared with bile samples from 70 patients with acute cholangitis. A further comparison was made between bacteria isolated from the periphery and center of 3 randomly selected brown pigment stones. Results: Ninety-one percent of bile and 99% of stone samples yielded positive cultures, with a total of 151 and 149 bacteria isolated from bile and stones, respectively. In 22 patients (33%), the bacteria isolated from the paired bile and stone samples were totally different. The mean percentage similarity of bacteria isolated from bile and stones was 39% (range 0%-100%). Of the 59 pairs of similar bacteria isolated, the antibiotic sensitivity patterns were different in 24 (41%) cases. Of the 3 brown stones studied, either different bacterial species or the same bacteria but different strains with different antibiotic sensitivities were isolated from the center and periphery of the stones. Conclusions: Bacteria present in the different layers of brown pigment stones may represent the bacterial flora in bile at different times. Simple bile culture may not identify bacteria trapped inside the stone. (Gastrointest Endosc 2001;54:340-5.)

Diagnostic Microbiology and Infectious Disease, 2005

The BD Phoenix Automated Microbiology System SMIC/ID panel was evaluated for identification and a... more The BD Phoenix Automated Microbiology System SMIC/ID panel was evaluated for identification and antimicrobial susceptibility testing (AST) of various streptococci. A group of 97 consecutive clinical isolates of Streptococcus pneumoniae, 23 Streptococcus pyogenes, 24 Streptococcus agalactiae, and 34 viridans streptococci were collected and comparisons made with routine manual methods used in the clinical microbiology laboratory. Overall, in 162 (91%) of 178 isolates, Phoenix identification results demonstrated agreement. For AST results for the 162 isolates that demonstrated identification concordance, the overall essential agreement rate was 98.5%; the category agreement was 94.9%; and the very major error, major error, and minor error rates were 0%, 0.15%, and 5.8%, respectively. Although relatively high minor error rates were observed with S. pneumoniae and beta-lactams, 79.2% of the 77 minor errors were the result of a single log(2) dilution difference. The Phoenix SMIC/ID panel performed favorably and demonstrated the advantages of automation and simple methodology.

Chemotherapy, 1999

The susceptibility of 492 Enterobacteriaceae, 227 other gram-negative bacteria, 448 gram-positive... more The susceptibility of 492 Enterobacteriaceae, 227 other gram-negative bacteria, 448 gram-positive bacteria and 108 anaerobic organisms was determined by the agar dilution method against trovafloxacin and other antibiotics. Trovafloxacin was highly active against most of the Enterobacteriaceae including Enterobacter spp. and Citrobacter spp. [minimum inhibitory concentration (MIC)90 <1 mg/l], Acinetobacter spp. and Pseudomonas aeruginosa (MIC90 = 0.25 and 2 mg/l, respectively). The antimicrobial activity was extended to the gram-positive bacteria including streptococci, Streptococcus pneumoniae, coagulase-negative staphylococci and methicillin-sensitive Staphylococcus aureus with MIC90 <1 mg/l. Enterococci and methicillin-resistant S. aureus were inhibited (MIC90 = 2 mg/l; sparfloxacin and ciprofloxacin were 16 and 64 mg/l, respectively). Almost all anaerobic organisms were inhibited by trovafloxacin (MIC90 = 1 mg/l).

Chemotherapy, 2005

This study was done to evaluate the in vitro activity of a new ketolide telithromycin in comparis... more This study was done to evaluate the in vitro activity of a new ketolide telithromycin in comparison with clarithromycin, erythromycin, moxifloxacin and levofloxacin against Streptococcus pneumoniae (n = 67), Haemophilus influenzae (n = 139), and Moraxella catarrhalis (n = 46)collected between January and June 2003 in Hong Kong. Among the H. influenzae isolates, 25.2% produced β-lactamase, while 97.8% of M. catarrhalis isolates produced β-lactamase. Half of the S. pneumoniae isolates were nonsusceptible to penicillin, and 90.9% of these strains were resistant to clarithromycin and erythromycin. One (1.5%) S. pneumoniae strain was resistant to levofloxacin (MIC = 8 mg/l) and all isolates were sensitive to moxifloxacin and telithromycin with MIC <1 mg/l. H. influenzae isolates were sensitive to all fluoroquinolones tested and 2.2% of H. influenzae were resistant to clarithromycin. M. catarrhalis isolates were sensitive except 1 strain which was resistant to levofloxacin (MIC = 4 mg/...

Chemotherapy, 2001

The in vitro activities of quinupristin/dalfopristin (Synercid), ampicillin, erythromycin, clarit... more The in vitro activities of quinupristin/dalfopristin (Synercid), ampicillin, erythromycin, clarithromycin, vancomycin, teicoplanin, ciprofloxacin and tetracycline were examined and compared against 526 gram-positive bacteria. The minimal inhibitory concentrations (MICs) for quinupristin/dalfopristin against Staphylococcus aureus, including methicillin-resistant strains, were low (MIC90 = 0.5 mg/l), and were comparable with those of vancomycin and teicoplanin. This compound was superior to the macrolides and highly active against Streptococcus pneumoniae (both penicillin-sensitive and penicillin-resistant strains), with MIC90 = 2 mg/l. It was also active against other streptococci, with MIC90 = 4 mg/l. However, this agent is less active against enterococci (MIC90 = 32 mg/l). Quinupristin/dalfopristin showed high activity against gram-positive anaerobes, including Clostridium spp., Peptococcus spp. and Peptostreptococcus spp., with MIC90 ≤2 mg/l. Quinupristin/dalfopristin was also inv...

Chemotherapy, 2007

Background: Fluoroquinolone-resistant Helicobacter pylori emerged in 1995 and the resistance was ... more Background: Fluoroquinolone-resistant Helicobacter pylori emerged in 1995 and the resistance was due to point mutation in the gyrA gene. In this study we investigate the resistance mechanism and the antimicrobial susceptibilities of clarithromycin, metronidazole, amoxicillin, tetracycline and telithromycin against levofloxacin-resistant H. pylori in Hong Kong. Methods: One hundred and ninety-one nonduplicate H. pylori isolates were collected during 2004 and 2005, and 25 isolates with levofloxacin zone sizes less than 30 mm were selected for minimal inhibitory concentration determination by agar dilution, gyrA gene amplication and sequencing the amplified gyrA gene. Results: The prevalence of levofloxacin-resistant H. pylori was 11.5% (22/191). Among these levofloxacin-resistant strains, 7 (31.8%) and 10 (45.5%) were resistant to clarithromycin and metronidazole, respectively, 17 (77.3%) had point mutations in gyrA gene at amino acids 87, 91 and 130 and the most frequent mutation poi...

Clinical Infectious Diseases, 2009

Background. The molecular epidemiology of endemic and outbreak Clostridium difficile strains acro... more Background. The molecular epidemiology of endemic and outbreak Clostridium difficile strains across time is not well known. Methods. HindIII restriction endonuclease analysis (REA) typing was performed on available clinical C. difficile isolates from 1982 to 1991. Results. The annual incidence of C. difficile infection (CDI) ranged from 3.2 to 9.9 cases per 1000 discharges and was significantly higher in 1982, 1983, 1985, and 1991 (high-incidence years) than in other years (mean ‫ע‬ standard deviation number of cases for the high-vs the low-incidence years, and ; 121.8 ‫ע‬ 20.4 70.0 ‫ע‬ 15.0 P p). A total of 696 (76.6%) of 908 C. difficile isolates were available for REA typing over the 10-year period. .002 Large clusters (у10 CDI cases in consecutive months) were caused by REA types B1 and B2 in 1982 and 1983, F2 and B1 in 1985, and K1 in 1991 (high-incidence years). Small clusters of 4-9 CDI cases in consecutive months were caused by REA types G1 (1984), Y4 and Y6 (1987), Y2 (1988), L1 (1989), Y1 (1990), and K1 (1991). Current epidemic REA group BI (unrelated to type B1) was isolated 6 times, twice in 1984, 1988, and 1990. Conclusions. Years with a high incidence of CDI were associated with large clusters of specific REA types that changed yearly. The molecular epidemiology of CDI in this hospital was characterized by a wide diversity of C. difficile types and an ever-changing dominance of specific C. difficile types over time. The current epidemic BI group was found sporadically on 6 occasions. A changing CDI molecular epidemiology should be expected in the future. Clostridium difficile infection (CDI) is the most commonly diagnosed cause of hospital-acquired infectious diarrhea [1]. Current hospital costs associated with the disease are estimated at US $3.2 billion [2]. At large medical centers, CDI is typically an endemic infection, with outbreaks or periodic increases in CDI rates occurring sporadically [3]. Although certain CDI outbreaks have been associated with the emergence of new and possibly clinically distinct strains [4, 5], little is known about the longitudinal epidemiology of endemic

Digestive Diseases and Sciences, 2012

Background: The effects of Helicobacter pylori (H. pylori) infection on metabolic syndrome (MetS)... more Background: The effects of Helicobacter pylori (H. pylori) infection on metabolic syndrome (MetS) in pregnant women are unclear to date. This study was designed to explore the relationship between H. pylori infection and MetS during pregnancy. Methods: Pregnant women were enrolled in the prospective cohort study, and their demographic data and metabolic parameters were collected. H. pylori infection was measured using the C13 urea breath test. All enrolled patients were followed up until the last baby was born. Metabolic disorders, including elevated levels of serum triglycerides (TG), high-density lipoprotein (HDL) cholesterol and blood glucose (BG), and adverse pregnancy outcomes, including gestational diabetes mellitus (GDM), preeclampsia, spontaneous preterm birth (SPB), fetal growth restriction (FGR), and uncomplicated pregnancy, were recorded during follow up. Results: There were 320 pregnant women enrolled in this study. They were divided into two groups according to H. pylori infection, and each group was then divided into two subgroups on whether their BMI was more than 24 or not. The results showed that H. pylori infection significantly increased the incidence of MetS as well as other metabolic disorders, especially in pregnant women with high BMI. Multivariable logistic regression analysis showed that risk factors of MetS were high BMI and H. pylori infection. Besides, H. pylori infection increased the incidence of GDM and preeclampsia and potentially reduced the incidence of uncomplicated pregnancy. Conclusions: H. pylori infection in pregnant women acts as a crucial risk factor of Mets and affects the incidence of several adverse pregnancy outcomes.

This article cites 40 articles, 27 of which can be accessed free

Journal of Clinical Microbiology, 1998

Since the means of culturing Helicobacter pylori may not be available in some laboratories, prolo... more Since the means of culturing Helicobacter pylori may not be available in some laboratories, prolonging the survival of this organism during transportation is a major concern in terms of improving detection rates. A selective transport medium was evaluated for the preservation of H. pylori from 254 gastric biopsy specimens collected from a rural area in China where culturing is not feasible. Gastric biopsy specimens were inoculated in sterile broth consisting of brain heart infusion (BHI) broth, horse serum, and yeast extract supplemented with vancomycin, amphotericin B, and nalidixic acid (VAN). Of the 254 biopsy specimens, 238 were identified by histology to haveH. pylori infection. Total rates of recovery ofH. pylori from the H. pylori-positive gastric biopsy specimens stored in the BHI-VAN broth ranged from 76 to 46% after storage of specimens for 5 to 9 days. In conclusion, the selective medium is useful for prolonging the survival of H. pylori in gastric biopsy specimens for wh...

Journal of Antimicrobial Chemotherapy, 2016

†Other investigators from the SMART Asia-Pacific Group are listed in the Acknowledgements section.

International journal of antimicrobial agents, Jan 20, 2017

This study was conducted to investigate the epidemiology and antimicrobial susceptibility pattern... more This study was conducted to investigate the epidemiology and antimicrobial susceptibility patterns of Gram-negative bacilli (GNB) isolated from intra-abdominal infections (IAIs) in the Asia-Pacific region (APR) from 2010-2013. A total of 17 350 isolates were collected from 54 centres in 13 countries in the APR. The three most commonly isolated GNB were Escherichia coli (46.1%), Klebsiella pneumoniae (19.3%) and Pseudomonas aeruginosa (9.8%). Overall, the rates of extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae were 38.2% and 24.3%, respectively, and they were highest in China (66.6% and 38.7%, respectively), Thailand (49.8% and 36.5%, respectively) and Vietnam (47.9% and 30.4%, respectively). During 2010-2013, the rates of ESBL-producing E. coli and K. pneumoniae isolates causing community-associated (CA) IAIs (collected <48 h after admission) were 26.0% and 13.5%, respectively, and those causing hospital-associated (HA) IAIs were 48.0% and 30.6%, respect...

World Journal of Gastroenterology, 2003

AIM: Helicobacter pylori can be diagnosed by invasive or non-invasive tests but to obtain bacteri... more AIM: Helicobacter pylori can be diagnosed by invasive or non-invasive tests but to obtain bacteria for culture and antibiotic susceptibility testing, an upper GI endoscopy is often required. The string test may be a minimally-invasive alternative method of obtaining H. pylori samples. This study evaluates the sensitivity and specificity of the string test in the diagnosis of H. pylori in comparison with endoscopic means of diagnosis. METHODS: This was a prospective open comparative study of patients with dyspepsia with endoscopy-based tests as gold standard (defined as a positive CLO test and antral histology). Fasting patients swallowed the encapsulated-string (Entero-test Hp), which was withdrawn after 1 hour. The gastric juice from the string was plated onto H. pylori-selective media for culture. Helicobacter pylori was identified by typical colony morphology, gram stain and biochemical test results. RESULTS: Thirty dyspeptic patients were recruited of whom 21 (70 %) were positive for H. pylori according to the gold standard. The sensitivity, specificity, positive predictive value, and negative predictive value for the string test were 38 %, 100 %, 100 % and 41 % respectively, and for endoscopic biopsies 81 %, 100 %, 100 %, 69 % respectively (P=0.004). Logistic regression showed that only abundant growth density from endoscopic biopsy cultures to be a predictor of a positive string test (P=0.018). CONCLUSION: The string test is an alternative method to endoscopy in obtaining H. pylori but has a low sensitivity compared to endoscopic biopsies.

Structure, 2012

Bacterial flagellar switching between counterclockwise and clockwise directions is mediated by th... more Bacterial flagellar switching between counterclockwise and clockwise directions is mediated by the coupling of the chemotactic system and the motor switch complex. The conformational changes of FliG are closely associated with this switching mechanism. We present two crystal structures of FliG MC from Helicobacter pylori, each showing distinct domain orientations from previously solved structures. A 180 rotation of the charged ridge-containing C-terminal subdomain FliG Ca1-6 that is prompted by the rotational freedom of Met245 psi and Phe246 phi at the MFXF motif was revealed. Studies on the swarming and swimming behavior of Escherichia coli mutants further identified the importance of the 245 MFXF 248 motif and a highly conserved residue, Asn216, in motor switching. Additionally, multiple conformations of FliG Ca1-6 were demonstrated by intramolecular cysteine crosslinking. The conformational flexibility of FliGc leads us to propose a model that accounts for the symmetrical torque generation process and for the dynamics of the motor.

Journal of Medical Microbiology, 2008

TUBEX (IDL Biotech) is a 5 min semiquantitative colorimetric test for typhoid fever, a widely end... more TUBEX (IDL Biotech) is a 5 min semiquantitative colorimetric test for typhoid fever, a widely endemic disease. TUBEX detects anti-Salmonella O9 antibodies from a patient's serum by the ability of these antibodies to inhibit the binding between an indicator antibody-bound particle and a magnetic antigen-bound particle. Herein, we report that TUBEX could also be used to specifically detect soluble O9 lipopolysaccharide in antigen-spiked buffer by the ability of the antigen to inhibit the same binding between the particles. Sensitivity of antigen detection was improved (8–31 μg ml−1) by using a modified protocol in which the test sample was mixed with the indicator particles first, rather than with the magnetic particles as for antibody detection. The antigen was also detectable in spiked serum and urine samples, albeit less well (2–4-fold) than in buffer generally. However, no antigen was detected from six typhoid sera examined, all of which had anti-O9 antibodies. In addition, wh...

Journal of Clinical Microbiology, 2003

This study explores the possibility of combining the BacT/Alert Microbial Detection System with t... more This study explores the possibility of combining the BacT/Alert Microbial Detection System with the VITEK 2 system to achieve rapid bacterial identification and susceptibility testing. Direct inoculation of bacterial suspension to the VITEK 2 ID-GNB card and AST-NO09 card was made by differential centrifugation of blood cultures of organisms with gram-negative enteric bacillus-like morphology. A total of 118 strains were investigated; of these, 97 (82.2%) strains were correctly identified to the species level and 21 (17.8%) strains were not identified; by comparing the results with those of the reference method of API identification systems using a pure culture, it was found that no strain had been misidentified. Among the 21 strains with no identification, 13 (61.9%) strains were nonfermenters. The direct-identification reporting time of VITEK 2 was 3.3 h. Direct testing of susceptibility to 11 antibiotics, i.e., amikacin, cefepime, ceftazidime, ciprofloxacin, gentamicin, imipenem,...