Repetitive mild or "concussive" traumatic brain injury (TBI) can cause substantial neurologic impairment, but the pathological features of this type of injury are not fully understood. We report an ...experimental model of TBI in which the closed skulls of anesthetized male C57BL/6J mice are struck with an electromagnetically controlled rubber impactor twice with an interval of 24 hours between impacts. The mice had deficits in Morris water maze performance in the first week after injury that only partially resolved 7 weeks later. By routine histology, there was no apparent bleeding, neuronal cell loss, or tissue disruption, and amyloid precursor protein immunohistochemistry demonstrated very few immunoreactive axonal varicosities. In contrast, silver stainingrevealed extensive abnormalities in the corpus callosum and bilateral external capsule, the ipsilateral cortex and thalamus, and the contralateral hippocampal CA1 stratum radiatum and stratum oriens. Electron microscopy of white matter regions demonstrated axonal cytoskeletal disruption, intra-axonal organelle compaction, and irregularities in axon caliber. Reactive microglia were observed in the same areas as the injured axons by both electron microscopy and Iba1 immunohistochemistry. Quantitative analyses of silver staining and Iba1 immunohistochemistry at multipletime points demonstrated transient cortical and thalamic abnormalities but persistent white matter pathology as late as 7 weeks after injury.Thus, prominent and long-lasting abnormalities in this TBI model were underestimated using conventional approaches. The model may be useful for mechanistic investigations and preclinical assessmentof candidate therapeutics.
Dengue is a major public health problem in tropical and subtropical countries. Rapid and easy diagnosis of dengue can assist patient triage and care-management. The detection of DENV NS1 on rapid ...lateral flow tests offers a fast route to a presumptive dengue diagnosis but careful evaluations are urgently needed as more and more people use them.
The sensitivity and specificity of the Bio-Rad NS1 Ag Strip and SD Dengue Duo (NS1/IgM/IgG) lateral flow rapid tests were evaluated in a panel of plasma samples from 245 Vietnamese patients with RT-PCR confirmed dengue and 47 with other febrile illnesses.
The NS1 rapid tests had similar diagnostic sensitivities (respectively 61.6% and 62.4%) in confirmed dengue cases but were 100% specific. When IgM/IgG results from the SD Dengue Duo were included in the test interpretation, the sensitivity improved significantly from 62.4% with NS1 alone to 75.5% when NS1 and/or IgM was positive and 83.7% when NS1 and/or IgM and/or IgG was positive. Both NS1 assays were significantly more sensitive for primary than secondary dengue. NS1 positivity was associated with the underlying viraemia as NS1-positive samples had a significantly higher viraemia than NS1-negative samples.
These data suggest that the NS1 test component of these assays are highly specific and have similar levels of sensitivity. The IgM parameter in the SD Duo test improved overall test sensitivity without compromising specificity. The SD Dengue Duo lateral flow rapid test deserves further prospective evaluation in dengue endemic settings.
Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-β and tau proteins have been observed within hours following severe ...TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-β and tau abnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-β accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer's disease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic Tau(P301L) mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in this setting.
Adsorption in the continuous mode plays a significant role in wastewater treatment. In this study, Mimosa pigra-derived biochar modified with 2 M AlCl3 salt was used to pack a lab-scale column to ...eliminate PO43− from aqueous solutions. The influence of the operational factors, such as inlet PO43− concentration (25–100 mg/L), flow rate (6–18 mL/min), and biochar bed height (1.5–4.5 cm), on the breakthrough curve was evaluated. The kinetic models of Adam–Bohart and Yoon–Nelson were utilized to analyze the experimental results. The best conditions were determined to be the influent PO43− strength of 50 mg/L, injection speed of 6 mL/min, and column height of 4.5 cm. These results can be applied in the design of large-scale columns for the sequestration of PO43− from wastewater.
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•Phosphate was successfully removed using fixed-bed modified biochar column.•The inlet PO43−, flow rate, and bed height affected the breakthrough curve.•The optimal conditions were 50 mg/L of PO43−, 6 mL/min flow rate, and 4.5 cm height.•Adam–Bohart and Yoon–Nelson models were utilized to describe experimental results.
Most cases of cryptococcal meningitis occur in patients with HIV infection: the course and outcome of disease in the apparently immunocompetent is much more poorly understood. We describe a cohort of ...HIV uninfected Vietnamese patients with cryptococcal meningitis in whom underlying disease is uncommon, and relate presenting features of patients and the characteristics of the infecting species to outcome.
A prospective descriptive study of HIV negative patients with cryptococcal meningitis based at the Hospital for Tropical Diseases, Ho Chi Minh City. All patients had comprehensive clinical assessment at baseline, were cared for by a dedicated study team, and were followed up for 2 years. Clinical presentation was compared by infecting isolate and outcome.
57 patients were studied. Cryptococcus neoformans var grubii molecular type VN1 caused 70% of infections; C. gattii accounted for the rest. Most patients did not have underlying disease (81%), and the rate of underlying disease did not differ by infecting species. 11 patients died while in-patients (19.3%). Independent predictors of death were age > or = 60 years and a history of convulsions (odds ratios and 95% confidence intervals 8.7 (1 - 76), and 16.1 (1.6 - 161) respectively). Residual visual impairment was common, affecting 25 of 46 survivors (54.3%). Infecting species did not influence clinical phenotype or outcome. The minimum inhibitory concentrations of flucytosine and amphotericin B were significantly higher for C. neoformans var grubii compared with C. gattii (p < 0.001 and p = 0.01 respectively).
In HIV uninfected individuals in Vietnam, cryptococcal meningitis occurs predominantly in people with no clear predisposing factor and is most commonly due to C. neoformans var grubii. The rates of mortality and visual loss are high and independent of infecting species. There are detectable differences in susceptibility to commonly used antifungal drugs between species, but the clinical significance of this is not clear.
Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite ...considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions.
We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio OR 2.10 for a 7-mEq/L increase in base deficit 95% CI 1.93-2.28), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen 95% CI 1.58, 1.86), coma (OR 3.59 95% CI 3.07-4.21), seizures (OR 1.40 95% CI 1.16-1.68), shock (OR 1.51 95% CI 1.14-1.99), and presumed pulmonary oedema (OR 1.58 95% CI 1.04-2.39). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit 95% CI 0.80-0.95). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase 95% CI 0.94-1.11), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 95% CI 0.56-0.74). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 95% CI 0.97-1.02). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness.
These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.
A Brief History of Qinghaosu White, Nicholas J; Hien, Tran T; Nosten, François H
Trends in parasitology,
12/2015, Volume:
31, Issue:
12
Journal Article
Peer reviewed
Open access
The 2015 Nobel Prize for Medicine or Physiology was awarded to William C. Campbell and Satoshi Ōmura for their discovery of avermectins, and to Tu You You for her contribution to the discovery of ...artemisinin. The discovery and development of qinghaosu (artemisinin) as an antimalarial drug is a remarkable and convoluted tale.
Background Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We ...aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy. Methods A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality. Results We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio aOR, 7.18, 95% CI 2.01-25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27-98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13-22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan-Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria. Conclusions Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia. Keywords: Severe malaria, Plasmodium falciparum, Pregnancy, Maternal mortality, Foetal loss, Small-for-gestational-age, Preterm birth
Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment ...paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure (PODs) for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.
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