Summary
Background
Patients with leprosy have a very low risk of Alzheimer disease (AD) and β‐amyloid (Aβ) deposition is significantly lower in the brain tissue of elderly patients with leprosy ...compared with age‐matched controls. Apolipoprotein E (ApoE) plays a critical role in lipid metabolic pathways and in the brain, facilitating the proteolytic clearance of Aβ. We hypothesized that APOE confers risk of leprosy as lipid metabolism is involved in Mycobacterium leprae infection.
Objectives
To investigate the potential genetic associations between APOE and leprosy in two independent Chinese case–control cohorts from the Yuxi and Wenshan prefectures, Yunnan Province of Southwest China.
Methods
Five APOE single‐nucleotide polymorphisms (SNPs) were analysed in 1110 individuals (527 patients and 583 controls) from the Yuxi prefecture using a SNaPshot assay. Genetic variations in the entire APOE exons were screened in 1788 individuals (798 patients and 990 controls) from the Wenshan prefecture using next‐generation sequencing technology.
Results
The AD‐associated SNPs rs405509 and rs439401 increased the risk of leprosy per se and multibacillary leprosy (P < 0·005), but the APOE‐ε4 allele did not. The SNPs rs405509 and rs439401 were cis expression quantitative trait loci (eQTL) for APOE expression in human skin. Differential APOE mRNA expression was observed in skin lesions of patients with type I reaction leprosy and those with multibacillary leprosy. APOE and related lipid genes are involved in an interaction network with leprosy susceptibility genes.
Conclusions
The APOE gene is associated with leprosy, most likely by regulating lipid‐metabolism‐related genes.
What's already known about this topic?
Host genetic factors could influence susceptibility to leprosy, which is a chronic infectious and neurological disease.
Previous studies have reported a significantly lower level of β‐amyloid (Aβ) deposition in the brain tissues of elderly people with leprosy compared with age‐matched controls.
Apolipoprotein E (ApoE) facilitates proteolytic clearance and homeostasis of Aβ peptides in the brain.
What does this study add?
Common variants of APOE were associated with multibacillary leprosy in Han Chinese.
The risk single‐nucleotide polymorphisms rs405509 and rs439401 were cis expression quantitative trait loci for APOE expression in human skin.
ApoE may interact with proteins that are coded as leprosy‐risk genes.
What is the translational message?
Our findings suggested that APOE is associated with leprosy, and this might be mediated by the altered expression of APOE and its potential role in lipid metabolic pathways during Mycobacterium leprae infection.
Future studies that explore the potential function of APOE during leprosy onset may offer a novel therapeutic target in leprosy.
Linked Article: Morgado de Abreu et al. Br J Dermatol 2018; 178:833–834
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Leprosy is a chronic infectious and neurological disease that is caused by infection of Mycobacterium leprae (M. leprae). A recent genome-wide association study indicated a suggestive association of ...LRRK2 genetic variant rs1873613 with leprosy in Chinese population. To validate this association and further identify potential causal variants of LRRK2 with leprosy, we genotyped 13 LRRK2 variants in 548 leprosy patients and 1078 healthy individuals from Yunnan Province and (re-)analyzed 3225 Han Chinese across China. Variants rs1427267, rs3761863, rs1873613, rs732374 and rs7298930 were significantly associated with leprosy per se and/or paucibacillary leprosy (PB). Haplotype A-G-A-C-A was significantly associated with leprosy per se (P=0.018) and PB (P=0.020). Overexpression of the protective allele (Thr2397) of rs3761863 in HEK293 cells led to a significantly increased nuclear factor of activated T-cells' activity compared with allele Met2397 after lipopolysaccharides stimulation. Allele Thr2397 could attenuate 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced autophagic activity in U251 cells. These data suggest that the protective effect of LRRK2 variant p.M2397T on leprosy might be mediated by increasing immune response and decreasing neurotoxicity after M. leprae loading. Our findings confirm that LRRK2 is a susceptible gene to leprosy in Han Chinese population.
The Gorkha earthquake (Magnitude 7.8) on 25 April 2015 and later aftershocks struck South Asia, killing approx.9,000 and damaging a large region. Supported by a large campaign of responsive satellite ...data acquisitions over the earthquake disaster zone, our team undertook a satellite image survey of the earthquakes induced geohazards in Nepal and China and an assessment of the geomorphic, tectonic, and lithologic controls on quake-induced landslides. Timely analysis and communication aided response and recovery and informed decision makers. We mapped 4,312 co-seismic and post-seismic landslides. We also surveyed 491 glacier lakes for earthquake damage, but found only 9 landslide-impacted lakes and no visible satellite evidence of outbursts. Landslide densities correlate with slope, peak ground acceleration, surface downdrop, and specific metamorphic lithologies and large plutonic intrusions.
Treatment guidelines recommend combination antifungal therapy with amphotericin B (AmB) as an induction therapy for cryptococcal meningitis. The objective of this study was to compare the survival ...benefit between 5-FC (flucytosine) and fluconazole as second-line drugs given in combination with AmB. We carried out a systematic review and meta-analysis of prospective controlled studies reporting early combination treatment for human immunodeficiency virus (HIV)-associated cryptococcal meningitis. We searched MEDLINE, EMBASE and the Cochrane Library up to October 2013. Randomised trials and prospective cohort studies were selected. The primary outcome was mortality in the first 14 and 70 days. The secondary outcome was early fungicidal activity (EFA) in the first 2 weeks. Four trials were included in our study. All included studies could be considered to be of fair quality in their methodology. The meta-analysis suggested that mortality was lower in patients who were given AmB and 5-FC at the 2 weeks point (Fig.
2
); the overall reduction in mortality with the 5-FC combination group was 44 % risk ratio (RR) 0.56, 95 % confidence interval (CI) 0.33–0.95,
p
= 0.03. EFA was significantly shorter in patients receiving AmB plus 5-FC mean difference (MD) −0.10 log
10
colony-forming units (CFU) per day, 95 % CI −0.11–0.09,
p
< 0.00001. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (
p
= 0.15) (Fig.
4
). Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.
Summary Background Handwashing to prevent transmission of respiratory tract infections (RTIs) has been widely advocated, especially during the H1N1 pandemic. However, the role of handwashing is ...debated, and no good randomised evidence exists among adults in non-deprived settings. We aimed to assess whether an internet-delivered intervention to modify handwashing would reduce the number of RTIs among adults and their household members. Methods We recruited individuals sharing a household by mailed invitation through general practices in England. After consent, participants were randomised online by an automated computer-generated random number programme to receive either no access or access to a bespoke automated web-based intervention that maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs. We enrolled participants into an additional cohort (randomised to receive intervention or no intervention) to assess whether the baseline questionnaire on handwashing would affect handwashing behaviour. Participants were not masked to intervention allocation, but statistical analysis commands were constructed masked to group. The primary outcome was number of episodes of RTIs in index participants in a modified intention-to-treat population of randomly assigned participants who completed follow-up at 16 weeks. This trial is registered with the ISRCTN registry, number ISRCTN75058295. Findings Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20 066 participants and randomly assigned them to receive intervention (n=10 040) or no intervention (n=10 026). 16 908 (84%) participants were followed up with the 16 week questionnaire (8241 index participants in intervention group and 8667 in control group). After 16 weeks, 4242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0·86, 95% CI 0·83–0·89; p<0·0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 4% of 5429 in intervention group vs 79 1% of 6087 in control group) and no reported serious adverse events. Interpretation In non-pandemic years, an effective internet intervention designed to increase handwashing could have an important effect in reduction of infection transmission. In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic. Funding Medical Research Council.
To analyze and evaluate the expressions and clinical value of tuftelin (TUFT1) and Krüppel-like factor 5 (KLF5) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues.
KLF5 mRNA ...and TUFT1 mRNA transcriptional status in cancer and non-cancer groups were compared according to the Cancer Genome Atlas (TCGA) database. The differences and prognostic value between the groups were analyzed. Postoperative liver cancer and its paired pericancerous tissues, with the approval of the ethics committee, were collected to build tissue chips. The expression of KLF5 and TUFT1 and their intracellular localization were verified by immunohistochemistry. Tissue expression and clinicopathological characteristics were analyzed by immunoblotting. SPSS software was used to analyze the relationship between SPSS and patient prognosis.
The transcription level of TUFT1 or KLF5 mRNA was significantly higher in the HCC group than the non-cancer group (
< 0.001), according to TCGA data. Immunohistochemistry and Western b
The recent rapid development in the field of extracellular vesicles (EVs) based nanotechnology has provided unprecedented opportunities for nanomedicine platforms. As natural nanocarriers, EVs such ...as exosomes, exosome-like nanoparticles and outer membrane vesicles (OMVs), have unique structure/composition/morphology characteristics, and show excellent physical and chemical/biochemical properties, making them a new generation of theranostic nanomedicine. Here, we reviewed the characteristics of EVs from the perspective of their formation and biological function in inflammatory bowel disease (IBD). Moreover, EVs can crucially participate in the interaction and communication of intestinal epithelial cells (IECs)-immune cells-gut microbiota to regulate immune response, intestinal inflammation and intestinal homeostasis. Interestingly, based on current representative examples in the field of exosomes and exosome-like nanoparticles for IBD treatment, it is shown that plant, milk, and cells-derived exosomes and exosome-like nanoparticles can exert a therapeutic effect through their components, such as proteins, nucleic acid, and lipids. Moreover, several drug loading methods and target modification of exosomes are used to improve their therapeutic capability. We also discussed the application of exosomes and exosome-like nanoparticles in the treatment of IBD. In this review, we aim to better and more clearly clarify the underlying mechanisms of the EVs in the pathogenesis of IBD, and provide directions of exosomes and exosome-like nanoparticles mediated for IBD treatment.
The obesity epidemic has major public health consequences. Expert dietetic and behavioural counselling with intensive follow-up is effective, but resource requirements severely restrict widespread ...implementation in primary care, where most patients are managed. We aimed to estimate the effectiveness and cost-effectiveness of an internet-based behavioural intervention (POWeR+) combined with brief practice nurse support in primary care.
We did this pragmatic, parallel-group, randomised controlled trial at 56 primary care practices in central and south England. Eligible adults aged 18 years or older with a BMI of 30 kg/m2 or more (or ≥28 kg/m2 with hypertension, hypercholesterolaemia, or diabetes) registered online with POWeR+—a 24 session, web-based, weight management intervention lasting 6 months. After registration, the website automatically randomly assigned patients (1:1:1), via computer-generated random numbers, to receive evidence-based dietetic advice to swap foods for similar, but healthier, choices and increase fruit and vegetable intake, in addition to 6 monthly nurse follow-up (control group); web-based intervention and face-to-face nurse support (POWeR+Face-to-face POWeR+F; up to seven nurse contacts over 6 months); or web-based intervention and remote nurse support (POWeR+Remote POWeR+R; up to five emails or brief phone calls over 6 months). Participants and investigators were masked to group allocation at the point of randomisation; masking of participants was not possible after randomisation. The primary outcome was weight loss averaged over 12 months. We did a secondary analysis of weight to measure maintenance of 5% weight loss at months 6 and 12. We modelled the cost-effectiveness of each intervention. We did analysis by intention to treat, with multiple imputation for missing data. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN21244703.
Between Jan 30, 2013, and March 20, 2014, 818 participants were randomly assigned to the control group (n=279), the POWeR+F group (n=269), or the POWeR+R group (n=270). Weight loss averaged over 12 months was recorded in 666 (81%) participants. The control group lost almost 3 kg over 12 months (crude mean weight: baseline 104·38 kg SD 21·11; n=279, 6 months 101·91 kg 19·35; n=136, 12 months 101·74 kg 19·57; n=227). The primary imputed analysis showed that compared with the control group, patients in the POWeR+F group achieved an additional weight reduction of 1·5 kg (95% CI 0·6–2·4; p=0·001) averaged over 12 months, and patients in the POWeR+R group achieved an additional 1·3 kg (0·34–2·2; p=0·007). 21% of patients in the control group had maintained a clinically important 5% weight reduction at month 12, compared with 29% of patients in the POWeR+F group (risk ratio 1·56, 0·96–2·51; p=0·070) and 32% of patients in the POWeR+R group (1·82, 1·31–2·74; p=0·004). The incremental overall cost to the health service per kg weight lost with the POWeR+ interventions versus the control strategy was £18 (95% CI −129 to 195) for POWeR+F and –£25 (−268 to 157) for POWeR+R; the probability of being cost-effective at a threshold of £100 per kg lost was 88% and 98%, respectively. No adverse events were reported.
Weight loss can be maintained in some individuals by use of novel written material with occasional brief nurse follow-up. However, more people can maintain clinically important weight reductions with a web-based behavioural program and brief remote follow-up, with no increase in health service costs. Future research should assess the extent to which clinically important weight loss can be maintained beyond 1 year.
Health Technology Assessment Programme of the National Institute for Health Research.
Hypoxia-inducible factor (HIF)-1α is over-expressed in hepatocellular carcinoma (HCC) and degraded by ubiquitin-proteasome pathways under normoxic conditions. Hepatocyte hypoxia enhances ...proliferation, angiogenesis, metastasis, chemoresistance, and radioresistance of HCC. The importance role of HIF-1α expression in HCC may improve the prognostic and therapeutic technique. This article reviews the HIF-1α expression and its gene during the rat HCC development, the level of HIF-1α expression in HCC patients, and the effect of silencing HIF-1α gene by miRNA on inhibition of HepG2 cell proliferation.
Complement factor H (CFH) is an essential regulator in the homeostasis of the complement system that plays multiple roles in leprosy. We previously reported a preliminary association of CFH with ...leprosy, but potentially causal variants remain to be identified. In this study, we performed a fine-mapping association analysis in 1110 individuals (527 leprosy patients and 583 controls) followed by bioinformatic analyses. We identified no association of typical missense CFH variants with leprosy and factor H-binding protein was not detected in Mycobacterium leprae. However, robust associations (PBonferroni<0.003) of several CFH intronic tag single-nucleotide polymorphisms with leprosy were observed. Expression quantitative trait locus analysis showed that these leprosy-protective alleles were associated with higher CFH level and lower CFHR3 (complement factor H-related 3) level. Our results indicated that CFH variants may contribute to leprosy pathogenesis through altering CFH expression, leading to regulation of complement activity rather than mediating immune evasion by bacteria binding.
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