Displaying publications 61 - 80 of 176 in total

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  1. Stear A, Ali AOA, Brujeni GN, Buitkamp J, Donskow-Łysoniewska K, Fairlie-Clarke K, et al.
    Int J Parasitol, 2019 09;49(10):797-804.
    PMID: 31306661 DOI: 10.1016/j.ijpara.2019.05.003
    Lambs with the Major Histocompatibility Complex DRB1*1101 allele have been shown to produce fewer nematode eggs following natural and deliberate infection. These sheep also possess fewer adult Teladorsagia circumcincta than sheep with alternative alleles at the DRB1 locus. However, it is unclear if this allele is responsible for the reduced egg counts or merely acts as a marker for a linked gene. This study defined the MHC haplotypes in a population of naturally infected Scottish Blackface sheep by PCR amplification and sequencing, and examined the associations between MHC haplotypes and faecal egg counts by generalised linear mixed modelling. The DRB1*1101 allele occurred predominately on one haplotype and a comparison of haplotypes indicated that the causal mutation or mutations occurred in or around this locus. Additional comparisons with another resistant haplotype indicated that mutations in or around the DQB2*GU191460 allele were also responsible for resistance to nematode infections. Further analyses identified six amino acid substitutions in the antigen binding site of DRB1*1101 that were significantly associated with reductions in the numbers of adult T. circumcincta.
  2. Heng J, Quan J, Sim LW, Sanmugam S, Broekman B, Bureau JF, et al.
    Attach Hum Dev, 2018 Feb;20(1):24-42.
    PMID: 28840781 DOI: 10.1080/14616734.2017.1365912
    Past research indicates that socioeconomic status (SES) accounts for differences in sensitivity across ethnic groups. However, comparatively little work has been conducted in Asia, with none examining whether ethnicity moderates the relation between SES and sensitivity. We assessed parenting behavior in 293 Singaporean citizen mothers of 6-month olds (153 Chinese, 108 Malay, 32 Indian) via the Maternal Behavioral Q-Sort for video interactions. When entered into the same model, SES (F(1,288) = 17.777, p 
  3. Hanipah ZN, Mulcahy MJ, Sharma G, Punchai S, Steckner K, Dweik R, et al.
    Surg Obes Relat Dis, 2018 Oct;14(10):1581-1586.
    PMID: 30449514 DOI: 10.1016/j.soard.2018.07.015
    BACKGROUND: Data regarding the outcomes of bariatric surgery in patients with pulmonary hypertension (PH) is limited. The aim of this study was to review our experience on bariatric surgery in patients with PH.

    SETTING: An academic medical center.

    METHODS: Patients with PH who underwent either a primary or revisional bariatric surgery between 2005 and 2015 and had a preoperative right ventricle systolic pressure (RVSP) ≥35 mm Hg were included.

    RESULTS: Sixty-one patients met the inclusion criteria. Fifty (82%) were female with the median age of 58 years (interquartile range [IQR] 49-63). The median body mass index was 49 kg/m2 (IQR 43-54). Procedures performed included the following: Roux-en-Y gastric bypass (n = 33, 54%), sleeve gastrectomy (n = 24, 39%), adjustable gastric banding (n = 3, 5%), and banded gastric plication (n = 1, 2%). Four patients (7%) underwent revisional bariatric procedures. Median operative time and length of stay was 130 minutes (IQR 110-186) and 3 days (IQR 2-5), respectively. The 30-day complication rate was 16% (n = 10) with pulmonary complications noted in 4 patients. There was no 30-day mortality. One-year follow-up was available in 93% patients (n = 57). At 1 year, median body mass index and excess weight loss were 36 kg/m2 (IQR 33-41) and 51% (IQR 33-68), respectively. There was significant improvement in the RVSP after bariatric surgery at a median follow-up of 22 months (IQR 10-41). The median RVSP decreased from 44 (IQR 38-53) to 40 mm Hg (IQR 28-54) (P = .03).

    CONCLUSION: Bariatric surgery can be performed without prohibitive complication rates in patients with PH. In our experience, bariatric patients with PH achieved significant weight loss and improvement in RVSP.

  4. Hayyan BN, Sharma RSK, Raimy N, Nisha M, Hussain K, Busin VM, et al.
    Parasite Immunol., 2020 06;42(6):e12707.
    PMID: 32118305 DOI: 10.1111/pim.12707
    AIMS: Most breeds of goat are more susceptible to nematode infection than sheep, and this appears to be a consequence of less effective immune responses. Several papers have considered the effectiveness of eosinophils and immunoglobulin A (IgA) in goats but differences in the induction of responses have not been studied in the same detail. The aim of this study was to look at the induction of eosinophil and IgA responses in Boer goats reared indoors under intensive conditions.

    METHODS AND RESULTS: The goats were experimentally infected with a low dose of 2400 Haemonchus contortus, Trichostrongylus spp. and Oesophagostomum spp. at a 6:1:1 ratio. Faecal egg counts (FEC), packed cell volume (PCV), IgA activity against third-stage larvae and peripheral eosinophilia were measured twice a week for eight weeks. The infection generated an IgA response but did not significantly increase peripheral eosinophilia in the 25 infected kids compared with the 4 control animals. FEC was not associated with IgA activity or eosinophilia.

    CONCLUSION: A detailed analysis of IgA and eosinophil responses to deliberate nematode infection in Boer goats showed that there was an increase in nematode-specific IgA activity but no detectable eosinophil response. In addition, there was no association between increased IgA activity or eosinophilia with egg counts and worm burdens. These suggest that IgA and eosinophils do not act to control nematode infection in goats.

  5. Rathore C, Rathbone MJ, Chellappan DK, Tambuwala MM, Pinto TJA, Dureja H, et al.
    Expert Opin Drug Deliv, 2020 04;17(4):479-494.
    PMID: 32077770 DOI: 10.1080/17425247.2020.1730808
    Introduction: Thymoquinone (TQ), 2-isopropyl-5-methylbenzo-1, 4-quinone, the main active constituent of Nigella sativa (NS) plant, has been proven to be of great therapeutic aid in various in vitro and in vivo conditions. Despite the promising therapeutic activities of TQ, this molecule is not yet in the clinical trials, restricted by its poor biopharmaceutical properties including photo-instability.Area covered: This review compiles the different types of polymeric and lipidic nanocarriers (NCs), encapsulating TQ for their improved oral bioavailability, and augmented in vitro and in vivo efficacy, evidenced on various pathologies. Furthermore, we provide a comprehensive overview of TQ in relation to its encapsulation approaches advancing the delivery and improving the efficacy of TQ.Expert opinion: TQ was first identified in the essential oil of Nigella sativa L. black seed. TQ has not been used in formulations because it is a highly hydrophobic drug having poor aqueous solubility. To deal with the poor physicochemical problems associated with TQ, various NCs encapsulating TQ have been tried in the past. Nevertheless, these NCs could be impending in bringing forth this potential molecule to clinical reality. This will also be beneficial for a large research community including pharmaceutical & biological sciences and translational researchers.
  6. Asaduzzaman M, Igarashi Y, Wahab MA, Nahiduzzaman M, Rahman MJ, Phillips MJ, et al.
    Genes (Basel), 2019 12 30;11(1).
    PMID: 31905942 DOI: 10.3390/genes11010046
    The migration of anadromous fish in heterogenic environments unceasingly imposes a selective pressure that results in genetic variation for local adaptation. However, discrimination of anadromous fish populations by fine-scale local adaptation is challenging because of their high rate of gene flow, highly connected divergent population, and large population size. Recent advances in next-generation sequencing (NGS) have expanded the prospects of defining the weakly structured population of anadromous fish. Therefore, we used NGS-based restriction site-associated DNA (NextRAD) techniques on 300 individuals of an anadromous Hilsa shad (Tenualosa ilisha) species, collected from nine strategic habitats, across their diverse migratory habitats, which include sea, estuary, and different freshwater rivers. The NextRAD technique successfully identified 15,453 single nucleotide polymorphism (SNP) loci. Outlier tests using the FST OutFLANK and pcadapt approaches identified 74 and 449 SNPs (49 SNPs being common), respectively, as putative adaptive loci under a divergent selection process. Our results, based on the different cluster analyses of these putatively adaptive loci, suggested that local adaptation has divided the Hilsa shad population into two genetically structured clusters, in which marine and estuarine collection sites were dominated by individuals of one genetic cluster and different riverine collection sites were dominated by individuals of another genetic cluster. The phylogenetic analysis revealed that all the riverine populations of Hilsa shad were further subdivided into the north-western riverine (turbid freshwater) and the north-eastern riverine (clear freshwater) ecotypes. Among all of the putatively adaptive loci, only 36 loci were observed to be in the coding region, and the encoded genes might be associated with important biological functions related to the local adaptation of Hilsa shad. In summary, our study provides both neutral and adaptive contexts for the observed genetic divergence of Hilsa shad and, consequently, resolves the previous inconclusive findings on their population genetic structure across their diverse migratory habitats. Moreover, the study has clearly demonstrated that NextRAD sequencing is an innovative approach to explore how dispersal and local adaptation can shape genetic divergence of non-model anadromous fish that intersect diverse migratory habitats during their life-history stages.
  7. Griffiths MJ, Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, et al.
    J Infect Dis, 2012 Sep 15;206(6):881-92.
    PMID: 22829643 DOI: 10.1093/infdis/jis446
    BACKGROUND: Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood.

    METHODS: We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died.

    RESULTS: Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%).

    CONCLUSIONS: Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

  8. Sukumaran SD, Nasir SB, Tee JT, Buckle MJC, Othman R, Rahman NA, et al.
    J Enzyme Inhib Med Chem, 2021 Dec;36(1):130-137.
    PMID: 33243025 DOI: 10.1080/14756366.2020.1847100
    A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).
  9. O'Brien MJ, Hector A, Kellenberger RT, Maycock CR, Ong R, Philipson CD, et al.
    Proc Biol Sci, 2022 Jun 08;289(1976):20220739.
    PMID: 35703055 DOI: 10.1098/rspb.2022.0739
    The role of conspecific density dependence (CDD) in the maintenance of species richness is a central focus of tropical forest ecology. However, tests of CDD often ignore the integrated effects of CDD over multiple life stages and their long-term impacts on population demography. We combined a 10-year time series of seed production, seedling recruitment and sapling and tree demography of three dominant Southeast Asian tree species that adopt a mast-fruiting phenology. We used these data to construct individual-based models that examine the effects of CDD on population growth rates (λ) across life-history stages. Recruitment was driven by positive CDD for all species, supporting the predator satiation hypothesis, while negative CDD affected seedling and sapling growth of two species, significantly reducing λ. This negative CDD on juvenile growth overshadowed the positive CDD of recruitment, suggesting the cumulative effects of CDD during seedling and sapling development has greater importance than the positive CDD during infrequent masting events. Overall, CDD varied among positive, neutral and negative effects across life-history stages for all species, suggesting that assessments of CDD on transitions between just two stages (e.g. seeds seedlings or juveniles mature trees) probably misrepresent the importance of CDD on population growth and stability.
  10. Jr VMB, Luo J, Li Z, Gidley MJ, Bird AR, Tetlow IJ, et al.
    Front Genet, 2020;11:289.
    PMID: 32300357 DOI: 10.3389/fgene.2020.00289
    The enzyme starch synthase IIa (SSIIa) in cereals has catalytic and regulatory roles during the synthesis of amylopectin that influences the functional properties of the grain. Rice endosperm SSIIa is more active in indica accessions compared to japonica lines due to functional SNP variations in the coding region of the structural gene. In this study, downregulating the expression of japonica-type SSIIa in Nipponbare endosperm resulted in either shrunken or opaque grains with an elevated proportion of A-type starch granules. Shrunken seeds had severely reduced starch content and could not be maintained in succeeding generations. In comparison, the opaque grain morphology was the result of weaker down-regulation of SSIIa which led to an elevated proportion of short-chain amylopectin (DP 6-12) and a concomitant reduction in the proportion of medium-chain amylopectin (DP 13-36). The peak gelatinization temperature of starch and the estimated glycemic score of cooked grain as measured by the starch hydrolysis index were significantly reduced. These results highlight the important role of medium-chain amylopectin in influencing the functional properties of rice grains, including its digestibility. The structural, regulatory and nutritional implications of down-regulated japonica-type SSIIa in rice endosperm are discussed.
  11. Philipson CD, Dent DH, O'Brien MJ, Chamagne J, Dzulkifli D, Nilus R, et al.
    Ecol Evol, 2014 Sep;4(18):3675-88.
    PMID: 25478157 DOI: 10.1002/ece3.1186
    A life-history trade-off between low mortality in the dark and rapid growth in the light is one of the most widely accepted mechanisms underlying plant ecological strategies in tropical forests. Differences in plant functional traits are thought to underlie these distinct ecological strategies; however, very few studies have shown relationships between functional traits and demographic rates within a functional group. We present 8 years of growth and mortality data from saplings of 15 species of Dipterocarpaceae planted into logged-over forest in Malaysian Borneo, and the relationships between these demographic rates and four key functional traits: wood density, specific leaf area (SLA), seed mass, and leaf C:N ratio. Species-specific differences in growth rates were separated from seedling size effects by fitting nonlinear mixed-effects models, to repeated measurements taken on individuals at multiple time points. Mortality data were analyzed using binary logistic regressions in a mixed-effects models framework. Growth increased and mortality decreased with increasing light availability. Species differed in both their growth and mortality rates, yet there was little evidence for a statistical interaction between species and light for either response. There was a positive relationship between growth rate and the predicted probability of mortality regardless of light environment, suggesting that this relationship may be driven by a general trade-off between traits that maximize growth and traits that minimize mortality, rather than through differential species responses to light. Our results indicate that wood density is an important trait that indicates both the ability of species to grow and resistance to mortality, but no other trait was correlated with either growth or mortality. Therefore, the growth mortality trade-off among species of dipterocarp appears to be general in being independent of species crossovers in performance in different light environments.
  12. Aravind SR, Ismail SB, Balamurugan R, Gupta JB, Wadhwa T, Loh SM, et al.
    Curr Med Res Opin, 2012 Aug;28(8):1289-96.
    PMID: 22738801 DOI: 10.1185/03007995.2012.707119
    To compare the incidence of symptomatic hypoglycemia between sitagliptin and sulfonylurea in Muslim patients with type 2 diabetes who fasted during Ramadan.
  13. Amrun SN, Tan JJL, Rickett NY, Cox JA, Lee B, Griffiths MJ, et al.
    Sci Rep, 2020 03 02;10(1):3810.
    PMID: 32123257 DOI: 10.1038/s41598-020-60761-5
    Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets.
  14. Chua EG, Wise MJ, Khosravi Y, Seow SW, Amoyo AA, Pettersson S, et al.
    DNA Res, 2017 Feb 01;24(1):37-49.
    PMID: 27803027 DOI: 10.1093/dnares/dsw046
    Helicobacter pylori is a highly successful gastric pathogen. High genomic plasticity allows its adaptation to changing host environments. Complete genomes of H. pylori clinical isolate UM032 and its mice-adapted serial derivatives 298 and 299, generated using both PacBio RS and Illumina MiSeq sequencing technologies, were compared to identify novel elements responsible for host-adaptation. The acquisition of a jhp0562-like allele, which encodes for a galactosyltransferase, was identified in the mice-adapted strains. Our analysis implies a new β-1,4-galactosyltransferase role for this enzyme, essential for Ley antigen expression. Intragenomic recombination between babA and babB genes was also observed. Further, we expanded on the list of candidate genes whose expression patterns have been mediated by upstream homopolymer-length alterations to facilitate host adaption. Importantly, greater than four-fold reduction of mRNA levels was demonstrated in five genes. Among the down-regulated genes, three encode for outer membrane proteins, including BabA, BabB and HopD. As expected, a substantial reduction in BabA protein abundance was detected in mice-adapted strains 298 and 299 via Western analysis. Our results suggest that the expression of Ley antigen and reduced outer membrane protein expressions may facilitate H. pylori colonisation of mouse gastric epithelium.
  15. Post LA, Lin JS, Moss CB, Murphy RL, Ison MG, Achenbach CJ, et al.
    J Med Internet Res, 2021 02 01;23(2):e25454.
    PMID: 33464207 DOI: 10.2196/25454
    BACKGROUND: The COVID-19 pandemic has had a profound global impact on governments, health care systems, economies, and populations around the world. Within the East Asia and Pacific region, some countries have mitigated the spread of the novel coronavirus effectively and largely avoided severe negative consequences, while others still struggle with containment. As the second wave reaches East Asia and the Pacific, it becomes more evident that additional SARS-CoV-2 surveillance is needed to track recent shifts, rates of increase, and persistence associated with the pandemic.

    OBJECTIVE: The goal of this study is to provide advanced surveillance metrics for COVID-19 transmission that account for speed, acceleration, jerk, persistence, and weekly shifts, to better understand country risk for explosive growth and those countries who are managing the pandemic successfully. Existing surveillance coupled with our dynamic metrics of transmission will inform health policy to control the COVID-19 pandemic until an effective vaccine is developed. We provide novel indicators to measure disease transmission.

    METHODS: Using a longitudinal trend analysis study design, we extracted 330 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in East Asia and the Pacific as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R.

    RESULTS: The standard surveillance metrics for Indonesia, the Philippines, and Myanmar were concerning as they had the largest new caseloads at 4301, 2588, and 1387, respectively. When looking at the acceleration of new COVID-19 infections, we found that French Polynesia, Malaysia, and the Philippines had rates at 3.17, 0.22, and 0.06 per 100,000. These three countries also ranked highest in terms of jerk at 15.45, 0.10, and 0.04, respectively.

    CONCLUSIONS: Two of the most populous countries in East Asia and the Pacific, Indonesia and the Philippines, have alarming surveillance metrics. These two countries rank highest in new infections in the region. The highest rates of speed, acceleration, and positive upwards jerk belong to French Polynesia, Malaysia, and the Philippines, and may result in explosive growth. While all countries in East Asia and the Pacific need to be cautious about reopening their countries since outbreaks are likely to occur in the second wave of COVID-19, the country of greatest concern is the Philippines. Based on standard and enhanced surveillance, the Philippines has not gained control of the COVID-19 epidemic, which is particularly troubling because the country ranks 4th in population in the region. Without extreme and rigid social distancing, quarantines, hygiene, and masking to reverse trends, the Philippines will remain on the global top 5 list of worst COVID-19 outbreaks resulting in high morbidity and mortality. The second wave will only exacerbate existing conditions and increase COVID-19 transmissions.

  16. Benavente ED, de Sessions PF, Moon RW, Grainger M, Holder AA, Blackman MJ, et al.
    Int J Parasitol, 2018 03;48(3-4):191-196.
    PMID: 29258833 DOI: 10.1016/j.ijpara.2017.09.008
    Plasmodium knowlesi, a common parasite of macaques, is recognised as a significant cause of human malaria in Malaysia. The P. knowlesi A1H1 line has been adapted to continuous culture in human erythrocytes, successfully providing an in vitro model to study the parasite. We have assembled a reference genome for the PkA1-H.1 line using PacBio long read combined with Illumina short read sequence data. Compared with the H-strain reference, the new reference has improved genome coverage and a novel description of methylation sites. The PkA1-H.1 reference will enhance the capabilities of the in vitro model to improve the understanding of P. knowlesi infection in humans.
  17. Ali AO, Stear A, Fairlie-Clarke K, Brujeni GN, Isa NM, Salisi MS, et al.
    Immunogenetics, 2017 03;69(3):157-163.
    PMID: 27921144 DOI: 10.1007/s00251-016-0962-6
    Understanding the structure of the major histocompatibility complex, especially the number and frequency of alleles, loci and haplotypes, is crucial for efficient investigation of the way in which the MHC influences susceptibility to disease. Nematode infection is one of the most important diseases suffered by sheep, and the class II region has been repeatedly associated with differences in susceptibility and resistance to infection. Texel sheep are widely used in many different countries and are relatively resistant to infection. This study determined the number and frequency of MHC class II genes in a small flock of Texel sheep. There were 18 alleles at DRB1, 9 alleles at DQA1, 13 alleles at DQB1, 8 alleles at DQA2 and 16 alleles at DQB2. Several haplotypes had no detectable gene products at DQA1, DQB1 or DQB2, and these were defined as null alleles. Despite the large numbers of alleles, there were only 21 distinct haplotypes in the population. The relatively small number of observed haplotypes will simplify finding disease associations because common haplotypes provide more statistical power but complicate the discrimination of causative mutations from linked marker loci.
  18. Heng HL, Chee CF, Thy CK, Tee JT, Chin SP, Herr DR, et al.
    Chem Biol Drug Des, 2019 02;93(2):132-138.
    PMID: 30216681 DOI: 10.1111/cbdd.13390
    Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb  = 8.14 at the 5-HT2C receptor). Both (R)- and (S)-glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5-HT2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT2A receptor.
  19. Chua EG, Debowski AW, Webberley KM, Peters F, Lamichhane B, Loke MF, et al.
    Gastroenterol Rep (Oxf), 2019 Feb;7(1):42-49.
    PMID: 30792865 DOI: 10.1093/gastro/goy048
    Background: Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection. Hence, the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals. Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H. pylori. However, metronidazole resistance can also arise in H. pylori strains expressing functional RdxA protein, suggesting that there are other mechanisms that may confer resistance to this drug.

    Methods: We performed whole-genome sequencing on 121 H. pylori clinical strains, among which 73 were metronidazole-resistant. Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed. Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H. pylori.

    Results: Resistance due to RdxA truncation was identified in 34% of metronidazole-resistant strains. Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance. These sites included R16H/C in RdxA, D85N in the inner-membrane protein RclC (HP0565), V265I in a biotin carboxylase protein (HP0370) and A51V/T in a putative threonylcarbamoyl-AMP synthase (HP0918).

    Conclusions: Our approach identified new potential mechanisms for metronidazole resistance in H. pylori that merit further investigation.

  20. Hii KC, Robie ER, Saihidi I, Berita A, Alarja NA, Xiu L, et al.
    Trop Dis Travel Med Vaccines, 2021 Nov 01;7(1):32.
    PMID: 34719397 DOI: 10.1186/s40794-021-00154-2
    BACKGROUND: Leptospirosis diagnoses have increased in Sarawak, Malaysia in recent years.

    METHODS: To better understand the burden of disease and associated risk factors, we evaluated 147 patients presenting with clinical leptospirosis to local hospitals in Sarawak, Malaysia for the presence of Leptospira and associated antibodies. Sera and urine specimens collected during the acute illness phase were assessed via a commercially available rapid diagnostic test (Leptorapide, Linnodee Ltd., Antrim, Northern Ireland), an ELISA IgM assay (Leptospira IgM ELISA, PanBio, Queensland, Australia) and a pan-Leptospira real-time PCR (qPCR) assay to estimate disease prevalence and diagnostic accuracy of each method. Microagglutination testing was performed on a subset of samples.

    RESULTS: Overall, 45 out of 147 patients (30.6%) showed evidence of leptospires through qPCR in either one or both sera (20 patients) or urine (33 patients), and an additional ten (6.8%) were considered positive through serological testing, for an overall prevalence of 37.4% within the study population. However, each diagnostic method individually yielded disparate prevalence estimates: rapid test 42.2% for sera and 30.5% for urine, ELISA 15.0% for sera, qPCR 13.8% for sera and 23.4% for urine. Molecular characterization of a subset of positive samples by conventional PCR identified the bacterial species as Leptospira interrogans in 4 specimens. A multivariate risk factor analysis for the outcome of leptospirosis identified having completed primary school (OR = 2.5; 95 CI% 1.0-6.4) and weekly clothes-washing in local rivers (OR = 10.6; 95 CI% 1.4-214.8) with increased likelihood of leptospirosis when compared with those who had not.

    CONCLUSION: Overall, the data suggest a relatively high prevalence of leptospirosis in the study population. The low sensitivities of the rapid diagnostic test and ELISA assay against qPCR highlight a need for better screening tools.

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