One of the public health issues faced worldwide is antibiotic resistance (AR). During the novel coronavirus (COVID-19) pandemic, AR has increased. Since some studies have stated AR has increased during the COVID-19 pandemic, and others have stated otherwise, this study aimed to explore this impact. Seven databases-PubMed, MEDLINE, EMBASE, Scopus, Cochrane, Web of Science, and CINAHL-were searched using related keywords to identify studies relevant to AR during COVID-19 published from December 2019 to May 2022, according to PRISMA guidelines. Twenty-three studies were included in this review, and the evidence showed that AR has increased during the COVID-19 pandemic. The most commonly reported resistant Gram-negative bacteria was Acinetobacterbaumannii, followed by Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa. A. baumannii and K. pneumonia were highly resistant to tested antibiotics compared with E. coli and P. aeruginosa. Moreover, K. pneumonia showed high resistance to colistin. Commonly reported Gram-positive bacteria were Staphylococcus aureus and Enterococcus faecium. The resistance of E. faecium to ampicillin, erythromycin, and Ciprofloxacin was high. Self-antibiotic medication, empirical antibiotic administration, and antibiotics prescribed by general practitioners were the risk factors of high levels of AR during COVID-19. Antibiotics' prescription should be strictly implemented, relying on the Antimicrobial Stewardship Program (ASP) and guidelines from the World Health Organization (WHO) or Ministry of Health (MOH).
1. The effect of flavonoids on coumarin 7-hydroxylation, an activity marker of an important human liver cytochrome P450 isoform, cytochrome P450 2A6 (CYP2A6), was investigated in this study. 2. Coumarin 7-hydroxylase activity was measured fluorometrically in reaction mixtures containing cDNA-expressed CYP2A6, nicotinamide adenine dinucleotide phosphate generating system and 10 uM coumarin, at various concentrations of flavonoids. 3. Among the 23 compounds tested, most of the active members were from flavonol group of hydroxylated flavonoids, with myricetin being the most potent inhibitor followed by quercetin, galangin, and kaempferol. 4. Further exploration of the inhibition mechanism of these compounds revealed that myricetin, galangin, and kaempferol exhibited mixed-type of inhibition pattern while quercetin was observed to exhibit competitive mode of inhibition. 5. Structure-function analyses revealed that degree of inhibition was closely related to the number and location of hydroxyl groups, glycosylation of the free hydroxyl groups, degree of saturation of the flavane nucleus as well as the presence of the alkoxylated function.
The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.
OBJECTIVES: Leprosy remains a public health concern in Malaysia and globally. We aim to review the characteristics of leprosy patients in a tertiary institution in urban Malaysia.
DESIGN: This is a case series of 27 leprosy patients who presented between 2008 and 2013.
RESULTS: The majority of our patients consisted of male (74.1%), Malaysian (63.0%), blue collar workers (51.9%) and married (59.3%) patients; 48.1% had lepromatous leprosy. All except one of the patients presented with skin lesions, 25.9% had nerve involvement and 33.3% developed lepra reactions. Forty-four point four percent (44.4%) of the cases seen initially in the primary care setup were misdiagnosed.
CONCLUSIONS: Doctors need to have a high index of suspicion for leprosy when patients present with suggestive skin, nerve or musculoskeletal lesions. Immigrants accounted for 37% of cases and these patients may become a reservoir of infection, thus accounting for the rise in incidence. An increasing trend in multibacillary cases may be attributed to the spread from migrants from countries with a high burden of leprosy.
This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 μM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 μM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 μM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations.
A total of 51 novel benzimidazoles were synthesized by a 4-step reaction starting from basic compound 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The structure of the novel benzimidazoles was confirmed by mass spectra as well as (1)H NMR spectroscopic data. Out of the 51 novel synthesized compounds, 42 of them were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain using BacTiter-Glo™ Microbial Cell Viability (BTG) method. Results of activity screened using Alamar Blue method was also provided for comparison purposes. Two of the novel benzimidazoles synthesized showed moderately good activity with IC50 of less than 15 μM. Compound 5g, ethyl 2-(4-(trifluoromethyl)phenyl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole-5-carboxylate, was found to be the most active with IC50 of 11.52 μM.
Graphene, which as a new carbon material shows great potential for a range of applications because of its exceptional electronic and mechanical properties, becomes a matter of attention in these years. The use of graphene in nanoscale devices plays an important role in achieving more accurate and faster devices. Although there are lots of experimental studies in this area, there is a lack of analytical models. Quantum capacitance as one of the important properties of field effect transistors (FETs) is in our focus. The quantum capacitance of electrolyte-gated transistors (EGFETs) along with a relevant equivalent circuit is suggested in terms of Fermi velocity, carrier density, and fundamental physical quantities. The analytical model is compared with the experimental data and the mean absolute percentage error (MAPE) is calculated to be 11.82. In order to decrease the error, a new function of E composed of α and β parameters is suggested. In another attempt, the ant colony optimization (ACO) algorithm is implemented for optimization and development of an analytical model to obtain a more accurate capacitance model. To further confirm this viewpoint, based on the given results, the accuracy of the optimized model is more than 97% which is in an acceptable range of accuracy.
In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.
Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6 16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6 16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.
Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/ml. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.
Psoriasis is a chronic dermatological disorder that has a negative impact on quality of life (QoL). This hospital-based cross-sectional study determined factors associated with health-related QoL (HRQoL) impairment in adult psoriasis patients. HRQoL was assessed using the Dermatology Life Quality Index (DLQI). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI). A total of 223 patients, aged 18 to 83 years, were recruited. For 67 (30%) patients, psoriasis had very large to extremely large effect on their life (DLQI score = 11-30). The median DLQI score was 7 (interquartile range = 7). Factors significantly associated with severe impact on HRQoL (DLQI ≥ 10) were disease severity, single status, working status, sports activities, nail dystrophy, exposed area involvement, itch, disturbed sleep, stress, and infection. The factor predictive of severe impact of psoriasis on HRQoL was disease severity. A holistic approach in the management, including psychosocial issues, is absolutely crucial for the optimal care of psoriasis patients.
Study site: Universiti Malaya Medical Centre (UMMC)
Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug-herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.
In this study, a series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis (MTB) H(37)Rv and isoniazid resistant M. tuberculosis (INHR-MTB). All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 6,7-dimethoxy-3-(4-chloro phenyl)-4H-indeno[1,2-c]isoxazole (4b) was found to be the most promising compound, active against MTB H(37)Rv and INHR-MTB with minimum inhibitory concentrations of 0.22 and 0.34 μM.
Heat-sensitive bioactive compounds such as β-carotene and tocols, are widely used in the pharmaceutical and cosmetic fields. Their chemical stability in delivery systems is one of the major concerns in the production of nanostructured lipid carriers (NLCs). A previously established high-temperature high-pressure homogenisation technique involved in the preparation of NLCs can cause degradation of heat-sensitive compounds. Therefore, a novel preparation process needs to be developed to minimise the degradation of heat-sensitive active compounds during the preparation of NLCs. In this work, modified methods A and B were designed to minimise the degradation of β-carotene and tocols during the production of NLCs. These methods improved the chemical stability of heat-sensitive bioactive compounds (β-carotene and tocols) significantly compared to the previously established method. The physical stability of the formulation was maintained throughout study duration.
Eurycoma longifolia (E. longifolia), a herb commonly consumed for its aphrodisiac properties, is widely used by Asian males. This may include hypertensive patients receiving propranolol which may cause sexual dysfunction as one of its side-effects. There is no published study of the potential pharmacokinetic interaction between propranolol and the herb.
Variation in CYP2A6 levels and activity can be attributed to genetic polymorphism and, thus, functional characterization of allelic variants is necessary to define the importance of CYP2A6 polymorphism in humans. The aim of the present study was to investigate the reported alleles CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22, in terms of the functional consequences of their mutations on the enzyme catalytic activity. With use of the wild-type CYP2A6 cDNA as template, site-directed mutagenesis was performed to introduce nucleotide changes encoding K194E substitution in CYP2A6*15, R203S substitution in CYP2A6*16, K476R substitution in CYP2A6*21, and concurrent D158E and L160I substitutions in CYP2A6*22. Upon sequence verification, the CYP2A6 wild-type and mutant constructs were individually coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. A kinetic study using a coumarin 7-hydroxylase assay indicated that CYP2A6*15 exhibited higher V(max) than the wild type, whereas all mutant constructs, except for variant CYP2A6*16, exhibited higher K(m) values. Analysis of the V(max)/K(m) ratio revealed that all mutants demonstrated 0.85- to 1.05-fold differences from the wild type, with the exception of variant CYP2A6*22, which only portrayed 39% of the wild-type intrinsic clearance. These data suggested that individuals carrying the CYP2A6*22 allele are likely to have lower metabolism of CYP2A6 substrate than individuals expressing CYP2A6*15, CYP2A6*16, CYP2A6*21, and the wild type.
The work described in this study aimed to express CYP2C8 wild-type and mutant proteins in bacterial expression system and to use the expressed proteins to investigate the structural and functional consequences of a reported allele CYP2C8(*)4 (carrying Ile264Met substitution) on protein activity. Ile264 was replaced by three different amino acids resulting in three mutant constructs, 2C8I264M, 2C8I264R and 2C8I264D. The presence of isoleucine at position 264 in CYP2C8 was found to be important for proper haem insertion and protein folding; whereas bulkier or charged residues were highly disruptive resulting in inactive proteins with minimum spectral and catalytic activities. This was evidenced from the low levels of Soret peak at 450 nm and negligible levels of tolbutamide methylhydroxylase activity. Kinetic study using paclitaxel indicated that all three mutants exhibited only 9.7 to 35.4% of the activity level observed in the wild-type. In addition, the mutants were more sensitive to proteinase K digestion, indicating a possible alteration of conformation. The combined effects of protein instability and compromised catalytic activity resulted in defective CYP2C8 protein which may have clinical implications in carriers of CYP2C8*4, particularly in terms of their capacity to clear potent drugs and their susceptibility to adverse drug reactions.
Seventeen single nucleotide polymorphisms (SNPs) have been identified so far, within the beta-2 receptor (beta(2) AR) gene. The presence of so many SNPs within the beta(2) AR gene causes a problem, for those studying beta(2) AR pharmacogenetics, in relation to which SNPs to choose. Most of the work has focused on the three common SNPs within the coding block (alleles 16, 27 and 164) and the techniques developed have been for these three functionally important alleles.
This study was designed to evaluate the health and economic benefits of a workplace vaccination programme against influenza funded by the employer. Employees of a Malaysian petrochemical plant volunteered to take part in this prospective, non-randomised, non-placebo-controlled study. Demographic and health information, including influenza-like symptoms, sick leave and post-vaccination adverse events were collected via questionnaires. Cost-benefit analyses were performed from the employer's perspective.
RESULTS: A total of 1,022 employees took part in the study, with 504 choosing to be vaccinated against influenza, and 518 remaining unvaccinated. The rate of influenza-like illness (ILI) was lower among vaccinated (8.13%) than non-vaccinated subjects (30.31%). Fever and respiratory symptoms were associated with all ILI cases. ILI-related sick leave was taken by 58.54% of vaccinated employees with ILI and 71.34% of non-vaccinated employees with ILI. Vaccination was financially beneficial, with the employer saving up to US dollar 53.00 per vaccinated employee when labour costs only were considered. Savings rose to up to US dollar 899.70 when the operating income of each employee was also considered. Workplace vaccination of healthy adults against influenza had a clear impact on ILI rates, absenteeism and reduced productivity in this Malaysian company. The health benefits translated into financial benefits for the employer, with cost savings significantly outweighting the costs of the vaccination programme.
Recent development of trilayer graphene nanoribbon Schottky-barrier field-effect transistors (FETs) will be governed by transistor electrostatics and quantum effects that impose scaling limits like those of Si metal-oxide-semiconductor field-effect transistors. The current-voltage characteristic of a Schottky-barrier FET has been studied as a function of physical parameters such as effective mass, graphene nanoribbon length, gate insulator thickness, and electrical parameters such as Schottky barrier height and applied bias voltage. In this paper, the scaling behaviors of a Schottky-barrier FET using trilayer graphene nanoribbon are studied and analytically modeled. A novel analytical method is also presented for describing a switch in a Schottky-contact double-gate trilayer graphene nanoribbon FET. In the proposed model, different stacking arrangements of trilayer graphene nanoribbon are assumed as metal and semiconductor contacts to form a Schottky transistor. Based on this assumption, an analytical model and numerical solution of the junction current-voltage are presented in which the applied bias voltage and channel length dependence characteristics are highlighted. The model is then compared with other types of transistors. The developed model can assist in comprehending experiments involving graphene nanoribbon Schottky-barrier FETs. It is demonstrated that the proposed structure exhibits negligible short-channel effects, an improved on-current, realistic threshold voltage, and opposite subthreshold slope and meets the International Technology Roadmap for Semiconductors near-term guidelines. Finally, the results showed that there is a fast transient between on-off states. In other words, the suggested model can be used as a high-speed switch where the value of subthreshold slope is small and thus leads to less power consumption.