Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome; screening for genes under selection may suggest ...potential drug or immune targets. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of ∼1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Previous efforts to eradicate malaria parasites, particularly Plasmodium falciparum, have failed in part due to the emergence of drug resistant parasites and mosquitoes resistant to insecticides. ...Using an artemisinin-based combination therapy (ACT) that kills parasites quickly, a strategy was designed to eliminate the source of transmission by mass treatment of human populations in malaria-endemic areas Cambodia.
A combination drug of artemisinin and piperaquine given with low doses of primaquine was used to eliminate all stages of parasites from human carriers.
In a pilot study, mass administration of artemisinin-piperaquine (two tablets of 62.5 mg artemisinin and 375 mg piperaquine for adults aged > or =16 years at 0 and 24 hrs; 1.5 tablet for children aged 11-15 years; and one tablet for children aged 6-10 years) and primaquine (9 mg for adults, at 10 day intervals for 6 months) was carried out in 17 villages (3,653 individuals). Parasite rates were dramatically reduced from 52.3% to 2.6% after three years. The P. falciparum rate in children decreased from 37.0% to 1.4%, reaching 0% in eight of 17 villages. In a second field study, that included one additional mass treatment of artemisinin-piperaquine, the P. falciparum rate in children was reduced from 20.8% to 0% within six months. No major adverse effects were observed.
Mass administration of artemisinin-piperaquine and low doses of primaquine can be an effective, safe, and affordable strategy for efficiently eliminating malaria parasites in human carriers and interrupting parasite transmission. This study provides important information for future strategies for the eradication of malaria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed ...in 1980s-1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria.
Artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine phosphate (DHP) and artemether-lumefantrine (AL) were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours) of AP, 2,880 mg (eight tablets, four times over two days) of DHP, and 3,360 mg (24 tablets, six times over three days) of AL. The 28-day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines.
The mean parasite clearance time was similar in all three groups (66.7 ± 21.9 hrs, 65.6 ± 27.3 hrs, 65.3 ± 22.5 hrs in AP, DHP and AL groups, respectively), and there was no remarkable difference between them; the fever clearance time was also similar (31.6 ± 17.7 hrs, 34.6 ± 21.8 hrs and 36.9 ± 15.4 hrs, respectively). After following up for 28-days, the cure rate was 95.1%(97/102), 98.2%(54/55) and 82.4%(42/51); and the recrudescence cases was 4.9%(5/102), 1.8%(1/55) and 17.6%(9/51), respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously.The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness) could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups.
AP, DHP and AL all remained efficacious treatments for the treatment of falciparum malaria in Cambodia-Thailand border area. However, in this particular setting, the AP regimen turned out to be favourable in terms of efficacy and effectiveness, simplicity of administration, cost and compliance.
The trial was registered at Chinese Clinical Trial Register under identifier 2005L01041.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The purpose of this study was to elucidate the expression of the long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) in rats with Alzheimer's disease (AD) and to explore its ...potential mechanisms.
Methods
An AD rat model was induced by microinjection of Aβ25‐35. On the first day after successful modeling, pcDNA3.1 plasmid and pcDNA3.1‐MEG3 plasmid were continuously infused into the third ventricle through a micro‐osmotic pump to interfere with the expression level of MEG3. The spatial learning ability and memory ability, the histopathological changes of hippocampus tissues, the ultrastructure of hippocampal neurons, astrocyte activation as well as the survival and apoptosis of hippocampal neurons in each group was observed. The expression of apoptosis, PI3/Akt signaling pathway‐related proteins, glial fibrillary acidic protein, inflammatory factors, malondialdehyde, glutathione‐peroxidase, and superoxide dismutase levels were determined. The deposition of amyloid beta (Aβ) in the hippocampus of rats by was observed by Aβ immunohistochemical staining.
Results
Downregulated MEG3 was detected in the tissues of AD rats. In addition, upregulation of MEG3 contributed to an improvement of spatial learning ability and memory ability, inhibited the pathological injury and its apoptosis of hippocampal neurons, decreased Aβ positive expression, inhibited oxidative stress injury and inflammatory injury as well as the activated astrocytes in AD rats via inactivation of the PI3/Akt pathway.
Conclusion
Our study highlights that upregulation of the lncRNA MEG3 improves cognitive impairment, alleviates neuronal damage, and inhibits activation of astrocytes in hippocampus tissues in AD through inhibiting the PI3K/Akt signaling pathway.
Prenatal exposure to toxic trace elements, including heavy metals, is an important public health concern. Few studies have assessed if individual and multiple trace elements simultaneously affect ...cardiac development. The current study evaluated the association between maternal blood lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and selenium (Se) levels and congenital heart defects (CHDs) in offspring. This hospital-based case-control study included 112 case and 107 control infants. Maternal peripheral blood draw was made during gestational weeks 17–40 and used to determine trace element levels by inductively coupled plasma mass spectrometry. Multivariable logistic regression was used to assess associations and interactions between individual and multiple trace elements and fetal CHDs, adjusted for maternal age, parity, education, newborn gender, migrant, folic acid or multivitamin intake, cigarette smoking, maternal prepregnancy body mass index, and time of sample collection. Control participants had medians of 2.61μg/dL Pb, 1.76μg/L Cd, 3.57μg/L Cr, 896.56μg/L Cu, 4.17μg/L Hg, and 186.47μg/L Se in blood. In a model including all measured trace elements and adjusted for confounders, high levels of maternal Pb (OR=12.09, 95% CI: 2.81, 51.97) and Se (OR=0.25, 95% CI: 0.08, 0.77) were harmful and protective predictors of CHDs, respectively, with positive and negative interactions suggested for Cd with Pb and Se with Pb, respectively. Similar associations were detected for subgroups of CHDs, including conotruncal defects, septal defects, and right ventricle outflow tract obstruction. Our results suggest that even under the current standard for protecting human health (10μg/dL), Pb exposure poses an important health threat. These data can be used for developing interventions and identifying high-risk pregnancies.
•Few studies assessed trace elements' effects on congenital heart defects (CHDs).•We measured six trace elements in maternal blood as predictors of CHDs in offspring.•Higher blood lead and lower blood selenium significantly predicted CHDs.•Maternal blood cadmium levels modified the effects of lead and selenium on CHDs.•Current lead exposure levels in Guangdong Province, China may threaten fetal health.
•First study of congenital heart defects (CHDs) association with PFAS in maternal and cord blood.•Higher levels of maternal PFAS exposure were associated with higher odds of CHDs.•The association is ...specifically significant in septal and conotuncal defects.
Accumulating evidence suggests that environmental pollutants may contribute to the occurrence of congenital heart defects (CHDs). However, no previous studies have evaluated the impact of perfluoroalkyl substances (PFAS), persistent environmental pollutants, on CHDs. This exploratory study aimed to generate testable hypotheses of the association between gestational PFAS and the risk of CHDs.
A nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios were compared between 158 CHD cases and 158 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 27 PFAS, including linear and branched isomers, were determined in maternal peripheral blood and cord blood plasma collected before and during delivery using a ultra-performance liquid chromatography coupled to mass spectrometry. Conditional logistic regression was utilized to evaluate associations between individual PFAS and the risk of CHDs, adjusted for confounding variables.
Maternal gestational exposure to the highly branched perfluorooctanesulfonate (PFOS) isomer potassium 6-trifluoromethyperfluoroheptanesulfonate 6 m-PFOS, adjusted odds ratio (aOR) (95% CI) = 2.47(1.05,5.83) and perfluorodecanoic acid PFDA, aOR (95% CI) = 2.33(1.00,5.45) were associated with increased odds of septal defects with statistical significance, while linear PFOS aOR (95% CI) = 3.65(1.09,12.16) and perfluoro-n-dodecanoic acid PFDoA, aOR (95% CI) = 6.82(1.75, 26.61) were associated with conotruncal defects. Effect estimates also suggested associations for higher maternal 6 m-PFOS and PFDA concentrations with ventricular septal defect. However, we did not observe these associations in cord blood.
These exploratory findings suggested that gestational exposure to most PFAS, especially linear PFOS, 6 m-PFOS, PFDA, and PFDoA, was associated with greater risks for septal and conotruncal defects. However, a larger, adequately powered study is needed to confirm our findings, and to more comprehensively investigate the potential teratogenic effects of other more recently introduced PFAS, and on associations with individual CHD subtypes.
Left atrial myxoma during pregnancy is rare. We present three cases in order to aid in the management.
Three cases of left atrial myxoma during pregnancy were presented in this article. Three ...patients all received multidisciplinary team work and acquired good outcomes. The case 1 had no symptoms and delivered before traditional cardiac surgery. The case 2 and case 3 undergone totally endoscopic minimally invasive cardiac surgery during pregnancy. The case 3 maintained pregnancy to term and gave birth to a healthy baby via vaginal delivery. No relapse of the tumor was observed.
The management of left atrial myxoma during pregnancy ought to be individualized and combined with the gestational age. If the diagnosis was made in the first two trimesters of pregnancy, totally endoscopic minimally invasive cardiac surgery during pregnancy would be an optimal choice. The patients can benefit from the multidisciplinary team work.
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•This is the first study of congenital heart defect (CHD) association with greenness.•A total of 8042 cases and 6887 controls were included.•Higher levels of maternal greenness ...exposure were associated with lower odds of CHD.•We identified a protective threshold of over 0.21 satellite-derived normalized difference vegetation index on CHD.
Proximity to greenness has shown protective effects on coronary heart diseases by limiting exposure to environmental hazards, encouraging physical activity, and reducing mental stress. However, no studies have previously evaluated the impacts of greenness on congenital heart defects (CHDs). We examined the association between maternal residential greenness and the risks of CHDs.
We conducted a case-control study (8042 children with major CHDs and 6887 controls without malformations) in 21 cities in Southern China, 2004 – 2016. CHDs cases were diagnosed and verified by obstetrician, pediatrician, or pediatric cardiologists, within one year. We estimated maternal residential greenness using satellite-derived normalized difference vegetation index (NDVI) in zones of 500 meters (m) and 1000 m surrounding participants’ residences. Logistic regression models were used to assess NDVI-CHD relationships adjusting for confounders.
Interquartile range NDVI increases within 500 m or 1000 m were associated with odds ratios (OR) of 0.95 (95% confidence interval (CI): 0.92, 0.98) and 0.94 (95%CI: 0.91, 0.97) for total CHDs respectively. Air pollutants mediated 52.1% of the association. We also identified a protective threshold at 0.21 NDVI on CHD. Similar protective effects from greenness were found in most CHDs subtypes. The protective associations were stronger for fall, urban or permanent residents, higher household income maternal age ≤35 years of age, and high maternal education (ORs: ranged from 0.85 to 0.96).
Our findings suggest a beneficial effect of maternal residential greenness on CHDs. Further studies are needed to confirm our findings, which will help to refine preventive health and urban design strategies.
•A new type Al-Zn alloy as metal fuel is prepared by high-speed centrifugal atomization method.•Al and Zn are uniformly distribution on the surface and inside of the particles.•The vaporization of Zn ...could destroy the barrier of Al2O3 shell and accelerate the heat release of Al combustion.
In this work, a heterogeneous Al-Zn alloy was developed as a metallic fuel to overcome the ignition time delay and low combustion rate of Al energetic materials. Al-Zn alloy powders were prepared by a high-speed centrifugal atomization method, which distributed Al and Zn uniformly on the surfaces and insides of the resulting spherical particles. The temperature at which the particles’ oxide shells cracked was lower and the laser ignition delay was 35 ms shorter for the Al-Zn alloy than for Al, based on TG-DSC results. The reason is that the low-temperature vaporization of Zn exacerbated the breakage of Al2O3 shells, and the heat accumulated during the vapour-phase combustion of Zn heated the particle to the reaction temperature of Al. Therefore, the addition of Zn enhances the combustion behaviour of Al by accelerating the rate of heat release.
Congenital heart diseases (CHDs) are associated with an extremely heavy global disease burden as the most common category of birth defects. Genetic and environmental factors have been identified as ...risk factors of CHDs previously. However, high volume clinical indicators have never been considered when predicting CHDs. This study aimed to predict the occurrence of CHDs by considering thousands of variables from self-reported questionnaires and routinely collected clinical laboratory data using machine learning algorithms.
We conducted a birth cohort study at one of the largest cardiac centers in China from 2011 to 2017. All fetuses were screened for CHDs using ultrasound and cases were confirmed by at least two pediatric cardiologists using echocardiogram. A total of 1,127 potential predictors were included to predict CHDs. We used the Explainable Boosting Machine (EBM) for prediction and evaluated the model performance using area under the Receive Operating Characteristics (ROC) curves (AUC). The top predictors were selected according to their contributions and predictive values. Thresholds were calculated for the most significant predictors.
Overall, 5,390 mother-child pairs were recruited. Our prediction model achieved an AUC of 76% (69-83%) from out-of-sample predictions. Among the top 35 predictors of CHDs we identified, 34 were from clinical laboratory tests and only one was from the questionnaire (abortion history). Total accuracy, sensitivity, and specificity were 0.65, 0.74, and 0.65, respectively. Maternal serum uric acid (UA), glucose, and coagulation levels were the most consistent and significant predictors of CHDs. According to the thresholds of the predictors identified in our study, which did not reach the current clinical diagnosis criteria, elevated UA (>4.38 mg/dl), shortened activated partial thromboplastin time (<33.33 s), and elevated glucose levels were the most important predictors and were associated with ranges of 1.17-1.54 relative risks of CHDs. We have developed an online predictive tool for CHDs based on our findings that may help screening and prevention of CHDs.
Maternal UA, glucose, and coagulation levels were the most consistent and significant predictors of CHDs. Thresholds below the current clinical definition of "abnormal" for these predictors could be used to help develop CHD screening and prevention strategies.
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