A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin ( 1) and variecolactone ( 2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues ( 5- 7). Analysis of the compounds' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

Introduction: Bullous pemphigoid (BP) is a chronic, autoimmune blistering disease occurring primarily in the elderly population. The pathogenesis of this condition has been strongly linked to the presence of circulating and tissue-bound autoantibodies against the basement membrane antigens BP180 and BP230. In most cases, the causative agent remains unidentified, but in a selected few, certain medications have been implicated in the pathogenesis of the disease. Dipeptidyl peptidase-4 inhibitors (-gliptins), in particular, which are used primarily in the treatment of diabetes mellitus, have been increasingly suspected to be a prime aggravating drug in the incidence of BP. Case summary: Bullous pemphigoid (BP) is a chronic autoimmune blistering disease mainly affecting the elderly population. While the pathogenesis has not yet been fully elucidated, it has been suggested that there is a correlation observed with certain groups of medications. Among drugs correlated with bullous pemphigoid, the group of dipeptidyl peptidase-4 inhibitors (-gliptins) used in the treatment of diabetes mellitus has been one of the most strongly associated. This is a case of a 64-year-old female on regular maintenance medications including linagliptin who developed generalized pruritus followed a week after by appearance of localized fluid-filled vesicles and bullae on the right lower leg. BP associated with dipeptidyl peptidase-4 inhibitors is characterized as “non-inflammatory” – lesions are localized and associated with less erythema compared to the classic presentation. Serum eosinophilia was absent, and serum autoantibody against BP180 was positive. Histopathologic and immunohistologic results revealed characteristics similar to classic bullous pemphigoid. The association of dipeptidyl peptidase-4 inhibitors to the development of BP was observed to have a long latency period between initiation of drug to onset of lesions. There was significant improvement after both withdrawal of the drug and standard steroids and doxycycline. Unlike other drug-induced BP, dipeptidyl peptidase-4 inhibitor-associated BP was found to have similar prognosis with the classic manifestation as the patient noted recurrence one month after remission despite withdrawal of inciting drug. Conclusion: There has been increasing incidence in DPP-4 inhibitor-associated BP. Though its clinical course is similar to classic BP, a non-inflammatory and more localized presentation would prompt suspicion of association with drug. The long latency in DPP-4 inhibitor and lesion onset suggests that rather than being simply an adverse reaction to treatment, DPP-4 inhibitor-associated BP should be viewed as a drug-associated or drug-aggravated disease. Determining the association of BP to DPP4-inhibitors is significant as the management for these patients not only entails standard management of BP but also withdrawal of the suspect drug, which in this case was found to significantly improve the patient’s lesions after one month. Unlike other drug-induced BP, however, DPP-4 inhibitor associated BP was found to have the same prognosis with classic BP as the patient noted recurrence one month after remission.
Dipeptidyl-Peptidase IV Inhibitors ; Pemphigoid, Bullous ; Pharmaceutical Preparations ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents

Background/Aims: Data on treatment efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) for chronic hepatitis C virus (HCV) infection in Asian patients with severe renal impairment are limited. This study aimed to study the treatment and side effects of GLE/PIB in these patients infected with non-1 genotype (GT) HCV. Methods: We prospectively recruited patients with Child’s A cirrhosis and eGFR <30 mL/min/1.73 m2 in Hong Kong and Taiwan during 2017–2018 to receive GLE/PIB treatment. Results: Twenty-one patients (GT2, n=7; GT3, n=6; and GT6, n=8) received GLE/PIB for 11.2±1.8 weeks. All except one were treatment-naïve. GLE/PIB was initiated in 16 patients while on dialysis (seven on peritoneal dialysis [PD] and nine on hemodialysis) and in five patients before dialysis. One patient died of PD-related peritonitis during treatment and two were lost to follow up. The SVR12 rate in the remaining 18 patients was 100%. All patients achieved undetectable levels at 4-, 12-, 24- and 48-week after treatment. Patients with deranged alanine aminotransferase showed normalization after 4 weeks and the response was sustained for 48 weeks. No significant adverse event was observed. Conclusions GLE/PIB treatment was associated with high efficacy and tolerability in HCV-infected patients with severe renal impairment.

BACKGROUND: Overweight, obesity, and cardiovascular disease risk factors are prevalent among firefighters in some developed countries. It is unclear whether physical activity and cardiopulmonary fitness reduce cardiovascular disease risk and the cardiovascular workload at work in firefighters. The present study investigated the relationship between leisure-time physical activity, cardiopulmonary fitness, cardiovascular disease risk factors, and cardiovascular workload at work in firefighters in Hong Kong. METHODS: Male firefighters (n = 387) were randomly selected from serving firefighters in Hong Kong (n = 5,370) for the assessment of cardiovascular disease risk factors (obesity, hypertension, diabetes mellitus, dyslipidemia, smoking, known cardiovascular diseases). One-third (Target Group) were randomly selected for the assessment of off-duty leisure-time physical activity using the short version of the International Physical Activity Questionnaire. Maximal oxygen uptake was assessed, as well as cardiovascular workload using heart rate monitoring for each firefighter for four "normal" 24-hour working shifts and during real-situation simulated scenarios. RESULTS: Overall, 33.9% of the firefighters had at least two cardiovascular disease risk factors. In the Target Group, firefighters who had higher leisure-time physical activity had a lower resting heart rate and a lower average working heart rate, and spent a smaller proportion of time working at a moderateintensity cardiovascular workload. Firefighters who had moderate aerobic fitness and high leisuretime physical activity had a lower peak working heart rate during the mountain rescue scenario compared with firefighters who had low leisure-time physical activities. CONCLUSION: Leisure-time physical activity conferred significant benefits during job tasks of moderate cardiovascular workload in firefighters in Hong Kong.
Cardiovascular Diseases ; Developed Countries ; Diabetes Mellitus ; Dyslipidemias ; Firefighters* ; Heart Rate ; Hong Kong ; Humans ; Hypertension ; Leisure Activities* ; Male ; Motor Activity* ; Obesity ; Overweight ; Oxygen ; Risk Factors* ; Smoke ; Smoking

INTRODUCTIONIntensive care unit (ICU) prognostic models are predominantly used in more developed nations such as the United States, Europe and Australia. These are not that popular in Southeast Asian countries due to costs and technology considerations. The purpose of this study is to evaluate the suitability of the acute physiology and chronic health evaluation (APACHE) IV model in a single centre Malaysian ICU.

MATERIALS AND METHODSA prospective study was conducted at the single centre ICU in Hospital Sultanah Aminah (HSA) Malaysia. External validation of APACHE IV involved a cohort of 916 patients who were admitted in 2009. Model performance was assessed through its calibration and discrimination abilities. A first-level customisation using logistic regression approach was also applied to improve model calibration.

RESULTSAPACHE IV exhibited good discrimination, with an area under receiver operating characteristic (ROC) curve of 0.78. However, the model's overall fit was observed to be poor, as indicated by the Hosmer-Lemeshow goodness-of-fit test (Ĉ = 113, P <0.001). Predicted in-ICU mortality rate (28.1%) was significantly higher than the actual in-ICU mortality rate (18.8%). Model calibration was improved after applying first-level customisation (Ĉ = 6.39, P = 0.78) although discrimination was not affected.

CONCLUSIONAPACHE IV is not suitable for application in HSA ICU, without further customisation. The model's lack of fit in the Malaysian study is attributed to differences in the baseline characteristics between HSA ICU and APACHE IV datasets. Other possible factors could be due to differences in clinical practice, quality and services of health care systems between Malaysia and the United States.

APACHE ; Adult ; Female ; Hospital Mortality ; Humans ; Intensive Care Units ; Malaysia ; Male ; Middle Aged ; Models, Theoretical ; Prognosis ; Prospective Studies ; ROC Curve ; Severity of Illness Index ; Tertiary Care Centers

PURPOSE: Because the shock wave passes through various body tissues before reaching the stone, stone composition may affect the treatment efficacy of shock wave lithotripsy (SWL). We investigated the effect of various tissue components along the shock wave path on the success of SWL. MATERIALS AND METHODS: From October 2008 to August 2010, a total of 206 patients with kidney stones sized 5 to 20 mm were prospectively recruited for a study of the factors that affect the outcome of treatment with a Sonolith Vision lithotripter. Successful SWL was defined as either stone-free status or residual fragments <4 mm at 12 weeks. Logistic regression analysis was performed to assess the factors that predicted treatment outcomes. Potential predictors included the patient's age, shock wave delivery rate, stone volume (SV), mean stone density (MSD), skin-to-stone distance (SSD), and the mean thickness of the three main components along the shock wave path: renal cortical thickness (KT), muscle thickness (MT), and soft-tissue thickness (ST). RESULTS: The mean age of the patients was 53.8 years (range, 25-82 years). The overall treatment success rate after one session of SWL was 43.2%. The mean KT, MT, and ST were 26.9, 16.6, and 40.8 mm, respectively. The logistic regression results showed that a slower shock wave delivery rate, smaller SV, a lower MSD, and a thicker KT were found to be significant predictors for successful SWL. SSD, MT, and ST were not predictors of successful treatment. CONCLUSIONS: Among the main tissue components along the shock wave path, a thicker KT was a favorable factor for successful SWL after adjustment for SV, MSD, and the shock wave delivery rate.
Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Kidney Calculi/*therapy ; Kidney Cortex/*radiography ; *Lithotripsy ; Logistic Models ; Male ; Middle Aged ; Prospective Studies ; Tomography, X-Ray Computed ; Treatment Outcome

INTRODUCTIONIn Singapore, the age-standardised event rates of myocardial infarction (MI) are 2- and 3-fold higher for Malays and Indians respectively compared to the Chinese. The objectives of this study were to determine the prevalence and quantity of coronary artery calcification (CAC) and non-calcified plaques across these 3 ethnic groups.

MATERIALS AND METHODSThis was a retrospective descriptive study. We identified 1041 patients (810 Chinese, 139 Malays, 92 Indians) without previous history of cardiovascular disease who underwent cardiac computed tomography for atypical chest pain evaluation. A cardiologist, who was blinded to the patients' clinical demographics, reviewed all scans. We retrospectively analysed all their case records.

RESULTSOverall, Malays were most likely to be active smokers (P = 0.02), Indians had the highest prevalence of diabetes mellitus (P = 0.01) and Chinese had the highest mean age (P <0.0001). The overall prevalence of patients with non-calcified plaques as the only manifestation of sub-clinical coronary artery disease was 2.1%. There was no significant difference in the prevalence of CAC, mean CAC score or prevalence of non-calcified plaques among the 3 ethnic groups. Active smoking, age and hypertension were independent predictors of CAC. Non-calcified plaques were positively associated with male gender, age, dyslipidaemia and diabetes mellitus.

CONCLUSIONThe higher MI rates in Malays and Indians in Singapore cannot be explained by any difference in CAC or non-calcified plaque. More research with prospective follow-up of larger patient populations is necessary to establish if ethnic-specific calibration of CAC measures is needed to adjust for differences among ethnic groups.

Adult ; Age Distribution ; Aged ; Analysis of Variance ; Asian Continental Ancestry Group ; statistics & numerical data ; Case-Control Studies ; China ; ethnology ; Coronary Artery Disease ; diagnostic imaging ; ethnology ; Coronary Vessels ; diagnostic imaging ; Diabetes Mellitus ; ethnology ; Dyslipidemias ; ethnology ; European Continental Ancestry Group ; statistics & numerical data ; Female ; Humans ; Hypertension ; ethnology ; India ; ethnology ; Malaysia ; ethnology ; Male ; Middle Aged ; Plaque, Atherosclerotic ; diagnostic imaging ; ethnology ; Prevalence ; Retrospective Studies ; Sex Distribution ; Singapore ; epidemiology ; ethnology ; Smoking ; ethnology ; Tomography, X-Ray Computed ; Vascular Calcification ; diagnostic imaging ; ethnology

Edible bird's nest (EBN) is derived from the saliva of certain types of swiftlets. It is consumed in many parts of the world for its nutritional and medicinal values. Although many claims have been made on the therapeutic and health-promoting effects of EBN, scientific documentations regarding these effects are very limited in published literature. It is not until recently that the biological effects of EBN are being investigated and evidence-based studies are being conducted. Several studies have found that EBN may enhance cell proliferation and differentiation and various beneficial effects have been reported in vitro as well as in vivo. While these studies point towards the potential use of EBN in the treatment or even prevention of several diseases, the mechanisms of action of EBN remain largely unknown and more explorations are needed. This review is one of the very few scientific reviews on EBN which focuses on recent evidence-based discoveries.
Animals ; Birds ; Food ; Humans ; Medicine, Chinese Traditional ; Saliva ; chemistry

OBJECTIVETo examine the Eastern-Western difference in the interpretation of Integrative Medicine Attitude Questionnaire (IMAQ) by assessing the psychometric properties of a revised Chinese medicine (CM)-specific version of IMAQ (CM-IMAQ).

METHODSFactor and Rasch analysis were performed with data collected from a mail survey of 165 Hong Kong Western medical doctors (WMD) randomly sampled from the official registry. The structural validity, unidimensionality, item fit, and differential item functioning (DIF) of the Hong Kong CM-IMAQ were evaluated.

RESULTSConfirmatory factor analysis (CFA) demonstrated that the original IMAQ factor structure was not concordant with our data on Chinese WMD, and subsequent explanatory factor analysis (EFA) validated a new three-factor model for CM-IMAQ: (1) attitude towards "tonification", (2) attitude towards the effectiveness of CM, and (3) attitude towards CM knowledge. The original IMAQ factor on holism and doctor-patient relationship disappeared. Rasch analysis confirmed the unidimensionality of "tonification" and the effectiveness domains, but further refinement of the knowledge domain is needed.

CONCLUSIONSCultural adaptation of the IMAQ has demonstrated differences between Eastern and Western doctors trained in allopathic medicine in their interpretations of holism in healthcare. For Chinese WMD, the emphasis of holistic care is placed on "tonifying" the body rather than on nurturing the mind and spirit. Confucian and Taoist conceptualizations of mental health as well as the persistent stigma towards mental illness within modern Chinese culture may explain why Chinese WMD do not regard mental health promotion as part of routine healthcare.

Aged ; Attitude of Health Personnel ; Emotions ; Factor Analysis, Statistical ; Female ; Holistic Health ; statistics & numerical data ; Hong Kong ; epidemiology ; Humans ; Integrative Medicine ; statistics & numerical data ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Surveys and Questionnaires