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Background Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females are mosaics who, because of X-chromosome inactivation (Lyonisation), may have low G6PD activity in the majority of their erythrocytes, yet they usually are reported as G6PD “normal” by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. Methods and Findings \in a cohort study nested within a randomised clinical trial which compared different treatment regimens of Plasmodium vivax malaria, patients with a normal standard NADPH fluorescent spot test result (~>30-40% of normal G6PD activity) were randomised to receive 3 days of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5mg base/kg/day for 14 days or a higher dose of 1mg base/kg/day for 7 days. Patterns of haemolysis were compared between G6PD wild type and G6PD heterozygous females. Between 21 February 2012 and 04 July 2014, 241 female patients were enrolled of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis 24 was substantially greater and a larger proportion of patients reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 day) primaquine dose, 9/17 (53%) compared with G6PD heterozygotes taking the standard high (14 day) dose, 2/16 (13%); p=0.022. In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7 day regimen): -20.4% (95% CI -26.0 to -14.8) (nadir on day 5) compared with the standard high (14 day) dose: -13.1% (95% CI -17.6 to -8.6) (nadir day 6). Two heterozygotes taking the higher (7 day) primaquine dose required blood transfusion. In wild type patients mean haematocrit reductions were clinically insignificant and similar with both doses; -5.8 (95% CI -7.2 to -4.4) (nadir day 3) compared with -5.5% (95% CI - 7.4 to -3.7) (nadir day 4) respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype, and that the heterozygote groups were small. Conclusion Higher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests.

Kidney development and physiology require polarization of epithelia that line renal tubules. Genetic studies show that polarization of invertebrate epithelia requires the crumbs, partition-defective-3, and discs large complexes. These evolutionarily conserved protein complexes occur in mammalian kidney; however, their role in renal development remains poorly defined. Here, we find that mice lacking the small PDZ protein mammalian LIN-7c (MALS-3) have hypomorphic, cystic, and fibrotic kidneys. Proteomic analysis defines MALS-3 as the only known core component of both the crumbs and discs large cell polarity complexes. MALS-3 mediates stable assembly of the crumbs tight junction complex and the discs large basolateral complex, and these complexes are disrupted in renal epithelia from MALS-3 knockout mice. Interestingly, MALS-3 controls apico-basal polarity preferentially in epithelia derived from metanephric mesenchyme, and defects in kidney architecture owe solely to MALS expression in these epithelia. These studies demonstrate that defects in epithelial cell polarization can cause cystic and fibrotic renal disease. © The Rockefeller University Press.

The ∼74 ka Toba eruption was one of the largest volcanic events of the Quaternary. There is much interest in determining the impact of such a large event, particularly on the climate and hominid populations at the time. Although the Toba eruption has been identified in both land and marine archives as the Youngest Toba Tuff, its precise place in the ice core record is ambiguous. Several volcanic sulfate signals have been identified in both Antarctic and Greenland ice cores and span the Toba eruption 40Ar/39Ar age uncertainty. Here, we measure sulfur isotope compositions in Antarctic ice samples from the Dome C (EDC) and Dronning Maud Land (EDML) ice cores at high temporal resolution across 11 of these potential Toba sulfate peaks to identify candidates with sulfur mass-independent fractionation (S-MIF), indicative of an eruption whose plume reached altitudes at or above the stratospheric ozone layer. Using this method, we identify several candidate sulfate peaks that contain stratospheric sulfur. We further narrow down potential candidates based on the isotope signatures by identifying sulfate peaks that are due to a volcanic event at tropical latitudes. In one of these sulfate peaks at 73.67 ka, we find the largest ever reported magnitude of S-MIF in volcanic sulfate in polar ice, with a Δ33S value of −4.75 ‰. As there is a positive correlation between the magnitude of the S-MIF signal recorded in ice cores and eruptive plume height, this could be a likely candidate for the Toba super-eruption, with a plume top height in excess of 45 km. These results support the 73.7±0.3 ka (1σ) 40Ar/39Ar age estimate for the eruption, with ice core ages of our candidates with the largest magnitude S-MIF at 73.67 and 73.74 ka. Finally, since these candidate eruptions occurred on the transition into Greenland Stadial 20, the relative timing suggests that Toba was not the trigger for the large Northern Hemisphere cooling at this time although we cannot rule out an amplifying effect.

© 2015 American Chemical Society. With the oceans covering 71% of the Earth, sea spray aerosol (SSA) particles profoundly impact climate through their ability to scatter solar radiation and serve as seeds for cloud formation. The climate properties can change when sea salt particles become mixed with insoluble organic material formed in ocean regions with phytoplankton blooms. Currently, the extent to which SSA chemical composition and climate properties are altered by biological processes in the ocean is uncertain. To better understand the factors controlling SSA composition, we carried out a mesocosm study in an isolated ocean-atmosphere facility containing 3,400 gallons of natural seawater. Over the course of the study, two successive phytoplankton blooms resulted in SSA with vastly different composition and properties. During the first bloom, aliphatic-rich organics were enhanced in submicron SSA and tracked the abundance of phytoplankton as indicated by chlorophyll-a concentrations. In contrast, the second bloom showed no enhancement of organic species in submicron particles. A concurrent increase in ice nucleating SSA particles was also observed only during the first bloom. Analysis of the temporal variability in the concentration of aliphatic-rich organic species, using a kinetic model, suggests that the observed enhancement in SSA organic content is set by a delicate balance between the rate of phytoplankton primary production of labile lipids and enzymatic induced degradation. This study establishes a mechanistic framework indicating that biological processes in the ocean and SSA chemical composition are coupled not simply by ocean chlorophyll-a concentrations, but are modulated by microbial degradation processes. This work provides unique insight into the biological, chemical, and physical processes that control SSA chemical composition, that when properly accounted for may explain the observed differences in SSA composition between field studies.