Abstract
Background
Artemisinin resistance in falciparum malaria is associated with kelch13 propeller mutations, reduced ring stage parasite killing, and, consequently, slow parasite clearance. We ...assessed how parasite age affects parasite clearance in artemisinin resistance.
Methods
Developmental stages of Plasmodium falciparum parasites on blood films performed at hospital admission and their kelch13 genotypes were assessed for 816 patients enrolled in a multinational clinical trial of artemisinin combination therapy.
Results
Early changes in parasitemia level (ie, 0–6 hours after admission) were determined mainly by modal stage of asexual parasite development, whereas the subsequent log-linear decline was determined mainly by kelch13 propeller mutations. Older circulating parasites on admission were associated with more-rapid parasite clearance, particularly in kelch13 mutant infections. The geometric mean parasite clearance half-life decreased by 11.6% (95% CI 3.4%–19.1%) in kelch13 wild-type infections and by 30% (95% CI 17.8%–40.4%) in kelch13 mutant infections as the mean age of circulating parasites rose from 3 to 21 hours.
Conclusion
Following the start of antimalarial treatment, ongoing parasite sequestration and schizogony both affect initial changes in parasitemia. The greater dependency of parasite clearance half-life on parasite age in artemisinin resistant infections is consistent with ring stage resistance and consequent parasite clearance by sequestration. The stage of parasite development should be incorporated in individual assessments of artemisinin resistance.
The effect of parasite stage of development on the parasite clearance curve was investigated in areas affected by artemisinin resistance. Parasite stage shapes the early part of the clearance curve and also influences the subsequent log-linear decline.
Miscarriage Among Flight Attendants Grajewski, Barbara; Whelan, Elizabeth A.; Lawson, Christina C. ...
Epidemiology (Cambridge, Mass.),
2015-March, Volume:
26, Issue:
2
Journal Article
Peer reviewed
Open access
BACKGROUND:Cosmic radiation and circadian disruption are potential reproductive hazards for flight attendants.
METHODS:Flight attendants from 3 US airlines in 3 cities were interviewed for pregnancy ...histories and lifestyle, medical, and occupational covariates. We assessed cosmic radiation and circadian disruption from company records of 2 million individual flights. Using Cox regression models, we compared respondents (1) by levels of flight exposures and (2) to teachers from the same cities, to evaluate whether these exposures were associated with miscarriage.
RESULTS:Of 2654 women interviewed (2273 flight attendants and 381 teachers), 958 pregnancies among 764 women met study criteria. A hypothetical pregnant flight attendant with median first-trimester exposures flew 130 hours in 53 flight segments, crossed 34 time zones, and flew 15 hours during her home-base sleep hours (10 pm–8 am), incurring 0.13 mGy absorbed dose (0.36 mSv effective dose) of cosmic radiation. About 2% of flight attendant pregnancies were likely exposed to a solar particle event, but doses varied widely. Analyses suggested that cosmic radiation exposure of 0.1 mGy or more may be associated with increased risk of miscarriage in weeks 9–13 (odds ratio = 1.7 95% confidence interval = 0.95–3.2). Risk of a first-trimester miscarriage with 15 hours or more of flying during home-base sleep hours was increased (1.5 1.1–2.2), as was risk with high physical job demands (2.5 1.5–4.2). Miscarriage risk was not increased among flight attendants compared with teachers.
CONCLUSIONS:Miscarriage was associated with flight attendant work during sleep hours and high physical job demands and may be associated with cosmic radiation exposure.
Recent epidemiological and experimental animal data, as well as reanalyses of data previously accumulated, indicate that the lens of the eye is more radiosensitive than was previously thought. This ...has resulted in a reduction of the occupational lens dose limit within the European Union countries, Japan and elsewhere. This Commentary introduces the work done by the LDLensRad Consortium contained within this Focus Issue, towards advancement of understanding of the mechanisms of low dose radiation cataract.
Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated ...by antithrombin III or anti-Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE.
To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients.
This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States.
The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency.
Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median range days, 1.0 0.0-2.0 vs 1.0 1.0-2.0; P = .39), and the number of patients who missed at least 1 dose was also similar (43 48.3% vs 54 56.3%; P = .30). Rates of VTE (6 6.7% vs 6 6.3%; P > .99) were similar, but the difference in bleeding complications (5 5.6% vs 13 13.5%; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05).
The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported.
clinicaltrials.gov Identifier: NCT00990236.
•A novel and highly sensitive IP–HILIC–MS/MS method was reported for the quantitation of nucleotides.•The lower limit of quantitation (LLOQ) of 2.00ng/mL obtained for ATP.•This novel chromatographic ...mechanism is first reported and named as IP–HILIC–MS/MS.
We present here a novel and highly sensitive ion-pair hydrophilic interaction chromatography–tandem mass spectrometry (IP–HILIC–MS/MS) method for quantitation of highly polar acid metabolites like adenine nucleotides. A mobile phase based on diethylamine (DEA) and hexafluoro-2-isopropanol (HFIP) and an aminopropyl (NH2) column were applied for a novel chromatographic separation for the determination of AMP, ADP and ATP in biological matrices. This novel IP–HILIC mechanism could be hypothesized by the ion-pairing reagent (DEA) in the mobile phase forming neutral and hydrophilic complexes with the analytes of polar organic acids. The IP–HILIC–MS/MS assay for adenine nucleotides was successfully validated with satisfactory linearity, sensitivity, accuracy, reproducibility and matrix effects. The lower limit of quantitation (LLOQ) at 2.00ng/mL obtained for ATP showed a least 10-fold higher sensitivity than previous LC–MS/MS assays except nano-LC–MS/MS assay. In summary, this novel IP–HILIC–MS/MS assay provides a sensitive method for nucleotides bioanalysis and shows great potential to determine a number of organic acids in biological matrices.
T-type calcium channels are responsible for generating low-threshold spikes that facilitate burst firing and neurotransmitter release in neurons. Gonadotropin-releasing hormone (GnRH) neurons exhibit ...burst firing, but the underlying conductances are not known. Previously, we found that 17beta-estradiol (E2) increases T-type channel expression and excitability of hypothalamic arcuate nucleus neurons. Therefore, we used ovariectomized oil- or E2-treated EGFP (enhanced green fluorescent protein)-GnRH mice to explore the expression and E2 regulation of T-type channels in GnRH neurons. Based on single-cell reverse transcriptase-PCR and real-time PCR quantification of the T-type channel alpha(1) subunits, we found that all three subunits were expressed in GnRH neurons, with expression levels as follows: Cav3.3 > or = Cav3.2 > Cav3.1. The mRNA expression of the three subunits was increased with surge-inducing levels of E2 during the morning. During the afternoon, Cav3.3 mRNA expression remained elevated, whereas Cav3.1 and Cav3.2 were decreased. The membrane estrogen receptor agonist STX increased the expression of Cav3.3 but not Cav3.2 in GnRH neurons. Whole-cell patch recordings in GnRH neurons revealed that E2 treatment significantly augmented T-type current density at both time points and increased the rebound excitation during the afternoon. Although E2 regulated the mRNA expression of all three subunits in GnRH neurons, the increased expression combined with the slower inactivation kinetics of the T-type current indicates that Cav3.3 may be the most important for bursting activity associated with the GnRH/LH (luteinizing hormone) surge. The E2-induced increase in mRNA expression, which depends in part on membrane-initiated signaling, leads to increased channel function and neuronal excitability and could be a mechanism by which E2 facilitates burst firing and cyclic GnRH neurosecretion.
Myocardial damage as a consequence of cardiotropic viruses leads to a broad variety of clinical presentations and is still a complicated condition to diagnose and treat. Whereas the extracellular ...matrix protein Secreted Protein Acidic and Rich in Cysteine or SPARC has been implicated in hypertensive and ischemic heart disease by modulating collagen production and cross-linking, its role in cardiac inflammation and endothelial function is yet unknown.
Absence of SPARC in mice resulted in increased cardiac inflammation and mortality, and reduced cardiac systolic function upon coxsackievirus-B3 induced myocarditis. Intra-vital microscopic imaging of the microvasculature of the cremaster muscle combined with electron microscopic imaging of the microvasculature of the cardiac muscle uncovered the significance of SPARC in maintaining endothelial glycocalyx integrity and subsequent barrier properties to stop inflammation. Moreover, systemic administration of recombinant SPARC restored the endothelial glycocalyx and consequently reversed the increase in inflammation and mortality observed in SPARC KO mice in response to viral exposure. Reducing the glycocalyx in vivo by systemic administration of hyaluronidase, an enzyme that degrades the endothelial glycocalyx, mimicked the barrier defects found in SPARC KO mice, which could be restored by subsequent administration of recombinant SPARC.
In conclusion, the secreted glycoprotein SPARC protects against adverse cardiac inflammation and mortality by improving the glycocalyx function and resulting endothelial barrier function during viral myocarditis.
•The vascular glycocalyx is an extracellular matrix that regulates inflammation in the heart.•Absence of glycoprotein SPARC compromises the integrity of the endothelial glycocalyx.•Compromised glycocalyx is shown using intra-vital microscopy and electron microscopy.•Restoring the glycocalyx with exogenous SPARC improves the outcome in viral myocarditis.
The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In ...this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta), in 17beta-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ERalpha and ERbeta gene-deficient mice. Our study shows that whereas ERalpha mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that preferentially occurs in T cell receptor beta chain(-/low) double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor-kappa B in CD25(-)CD4(-)CD8(-) double-negative thymocytes through an ERalpha-dependent yet ERbeta- and GPR30-independent pathway. Differential inhibition of nuclear factor-kappaB by ERalpha and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development.
Abstract
Background
Understanding the effect of immunity on Plasmodium falciparum clearance is essential for interpreting therapeutic efficacy studies designed to monitor emergence of artemisinin ...drug resistance. In low-transmission areas of Southeast Asia, where resistance has emerged, P. falciparum antibodies confound parasite clearance measures. However, variation in naturally acquired antibodies across Asian and sub-Saharan African epidemiological contexts and their impact on parasite clearance re yet to be quantified.
Methods
In an artemisinin therapeutic efficacy study, antibodies to 12 pre-erythrocytic and erythrocytic P. falciparum antigens were measured in 118 children with uncomplicated P. falciparum malaria in the Democratic Republic of Congo (DRC) and compared with responses in patients from Asian sites, described elsewhere.
Results
Parasite clearance half-life was shorter in DRC patients (median, 2 hours) compared with most Asian sites (median, 2–7 hours), but P. falciparum antibody levels and seroprevalences were similar. There was no evidence for an association between antibody seropositivity and parasite clearance half-life (mean difference between seronegative and seropositive, −0.14 to +0.40 hour) in DRC patients.
Conclusions
In DRC, where artemisinin remains highly effective, the substantially shorter parasite clearance time compared with Asia was not explained by differences in the P. falciparum antibody responses studied.
The substantially shorter Plasmodium falciparum parasite clearance time after artemisinin treatment observed in an African site, where artemisinin remains highly effective, compared with Asian sites, cannot be explained by differences in naturally acquired P. falciparum antibody responses.
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