We have addressed the need for improved measurements of cloud condensation nuclei (CCN) by developing a continuous-flow instrument that provides in situ measurements of CCN. The design presented in ...this article can operate between 0.1 and 3% supersaturation, at sampling rates sufficient for airborne operation. The design constitutes a cylindrical continuous-flow thermal-gradient diffusion chamber employing a novel technique of generating a supersaturation: by establishing a constant streamwise temperature gradient so that the difference in water vapor and thermal diffusivity yield a quasi-uniform centerline supersaturation. Our design maximizes the growth rate of activated droplets, thereby enhancing the performance of the instrument. The temperature gradient and the flow through the column control the supersaturation and may be modified to retrieve CCN spectra.
The principle of the CCN instrument was validated in controlled laboratory experiments at different operating conditions using a monodisperse aerosols with known composition and size. These experiments yield sharp activation curves, even for those kinetically limited particles that have not exceeded their critical diameter. The performance of the CCN instrument was also assessed using polydisperse laboratory-generated aerosol of known composition and size distributions similar to ambient particulate matter. In all tests, the measured CCN concentrations compared well with predicted values and highlight the instrument's ability to measure CCN at various size distributions.
The full potential of the new design has yet to be explored; however, model simulations suggest that direct measurements in the climatically important range of supersaturations of less than 0.1% (certainly down to 0.07%) are possible. The new instrument clearly offers a unique level of design simplicity, robustness, and flexilibity (temperature control, large range of supersaturations without flow reversal, and multiple configurations for same supersaturation) necessary for atmospheric studies.
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary ...substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high‐quality AIT products are inherently linked to each other. While allergen products are available in many ...countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.
Molecular self-assembly of peptides into ordered nanotubes is highly important for various technological applications. Very short peptide building blocks, as short as dipeptides, can form assemblies ...with unique mechanical, optical, piezoelectric, and semiconductive properties. Yet, the control over nanotube length in solution has remained challenging, due to the inherent sequential self-assembly mechanism. Here, in line with polymer chemistry paradigms, we applied a supramolecular polymer coassembly methodology to modulate peptide nanotube elongation. Utilizing this approach, we achieved a narrow, controllable nanotube length distribution by adjusting the molecular ratio of the diphenylalanine assembly unit and its end-capped analogue. Kinetic analysis suggested a slower coassembly organization process as compared to the self-assembly dynamics of each of the building blocks separately. This is consistent with a hierarchal arrangement of the peptide moieties within the coassemblies. Mass spectrometry analysis demonstrated the bimolecular composition of the coassembled nanostructures. Moreover, the peptide nanotubes’ length distribution, as determined by electron microscopy, was shown to fit a fragmentation kinetics model. Our results reveal a simple and efficient mechanism for the control of nanotube sizes through the coassembly of peptide entities at various ratios, allowing for the desired end-product formation. This dynamic size control offers tools for molecular engineering at the nanoscale exploiting the advantages of molecular coassembly.
Lithium Poisoning Baird-Gunning, Jonathan; Lea-Henry, Tom; Hoegberg, Lotte C. G. ...
Journal of intensive care medicine,
05/2017, Letnik:
32, Številka:
4
Journal Article
Recenzirano
Lithium is a commonly prescribed treatment for bipolar affective disorder. However, treatment is complicated by lithium’s narrow therapeutic index and the influence of kidney function, both of which ...increase the risk of toxicity. Therefore, careful attention to dosing, monitoring, and titration is required. The cause of lithium poisoning influences treatment and 3 patterns are described: acute, acute-on-chronic, and chronic. Chronic poisoning is the most common etiology, is usually unintentional, and results from lithium intake exceeding elimination. This is most commonly due to impaired kidney function caused by volume depletion from lithium-induced nephrogenic diabetes insipidus or intercurrent illnesses and is also drug-induced. Lithium poisoning can affect multiple organs; however, the primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Lithium poisoning has a low mortality rate; however, chronic lithium poisoning can require a prolonged hospital length of stay from impaired mobility and cognition and associated nosocomial complications. Persistent neurological deficits, in particular cerebellar, are described and the incidence and risk factors for its development are poorly understood, but it appears to be uncommon in uncomplicated acute poisoning. Lithium is readily dialyzable, and rationale support extracorporeal treatments to reduce the risk or the duration of toxicity in high-risk exposures. There is disagreement in the literature regarding factors that define patients most likely to benefit from treatments that enhance lithium elimination, including specific plasma lithium concentration thresholds. In the case of extracorporeal treatments, there are observational data in its favor, without evidence from randomized controlled trials (none have been performed), which may lead to conservative practices and potentially unnecessary interventions in some circumstances. More data are required to define the risk–benefit of extracorporeal treatments and their use (modality, duration) in the management of lithium poisoning.
Fourteen research flights were conducted in the Pacific Dust Experiment (PACDEX) during April and May 2007 to sample pollution and dust outbreaks from east Asia as they traveled across the northern ...Pacific Ocean into North America and interacted with maritime storms. Significant concentrations of black carbon (BC, consisting of soot and other light‐absorbing particles measured with a soot photometer 2 instrument) and dust were observed both in the west and east Pacific Ocean from Asian plumes of dust and pollution. BC particles were observed through much of the troposphere, but the major finding is that the percentage of these particles compared with the total number of accumulation mode particles increased significantly (by a factor of 2–4) with increasing altitude, with peak values occurring between 5 and 10 km. Dust plumes had only a small impact on total cloud condensation nuclei at the sampling supersaturations but did exhibit high concentrations of ice nuclei (IN). IN concentrations in dust plumes exceeded typical tropospheric values by 4–20 times and were similar to previous studies in the Saharan aerosol layer when differences in the number concentrations of dust are accounted for. Enhanced IN concentrations were found in the upper troposphere off the coast of North America, providing a first direct validation of the transport of high‐IN‐containing dust layers near the tropopause entering the North American continent from distant sources. A source‐specific chemical transport model was used to predict dust and other aerosols during PACDEX. The model was able to predict several features of the in situ observations, including the general altitudes where BC was found and a peak in the ratio of BC to sulfate between 5 and 10 km.
Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between ...anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.
Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.
Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.
Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.
ANCA-associated vasculitis (AAV) is characterized by a chronic relapsing course. Rituximab (RTX) is an effective maintenance treatment; however, the long-term outcomes after its discontinuation are ...unclear. The aim of this study was to explore the long-term outcomes of AAV patients treated with repeat-dose RTX maintenance therapy.
AAV patients receiving a RTX treatment protocol consisting of an induction and maintenance phase were included. For initial remission induction, RTX was dosed at 1 g every 2 weeks or 375 mg/m(2) weekly for 4 consecutive weeks and for remission maintenance at 1 g every 6 months for 24 months. At the first RTX administration, ongoing immunosuppressives were withdrawn.
Sixty-nine patients were identified, 67 of whom were failing other therapies. Nine relapsed during the RTX treatment protocol; however, all 69 were in remission at the end of the maintenance phase on a median prednisolone dose of 2.5 mg/day and 9% were receiving additional immunosuppression. During subsequent observation, 28 patients relapsed a median of 34.4 months after the last RTX infusion. Risk factors for relapse were PR3-associated disease (P = 0.039), B cell return within 12 months of the last RTX infusion (P = 0.0038) and switch from ANCA negativity to positivity (P = 0.0046). Two patients died and two developed severe hypogammaglobulinaemia.
This study supports the efficacy and safety of a fixed-interval RTX maintenance regimen in relapsing/refractory AAV. Relapses after discontinuation of maintenance therapy did occur, but at a lower rate than after a single RTX induction course. PR3-associated disease, the switch from ANCA negative to positive and the return of B cells within 12 months of the last RTX administration were risk factors for further relapse.
Highlights • Macaques were implanted with intrathecal catheters for repeated, awake CSF sampling. • Macaques were treated with intranasal and intravenous oxytocin. • Concurrent plasma and CSF samples ...were taken at five time points after treatment. • Our results extend and partially replicate the findings of similar studies. • We highlight the importance of methodological consistency across oxytocin studies.
The observational network around the North Atlantic has improved significantly over the last few decades with subsurface profiling floats and satellite observations and the recent efforts to monitor ...the Atlantic Meridional Overturning Circulation (AMOC). These have shown decadal time scale changes across the North Atlantic including in heat content, heat transport, and the circulation. However, there are still significant gaps in the observational coverage. Ocean reanalyses integrate the observations with a dynamically consistent ocean model and can be used to understand the observed changes. However, the ability of the reanalyses to represent the dynamics must also be assessed. We use an ensemble of global ocean reanalyses to examine the time mean state and interannual‐decadal variability of the North Atlantic ocean since 1993. We assess how well the reanalyses are able to capture processes and whether any understanding can be gained. In particular, we examine aspects of the circulation including convection, AMOC and gyre strengths, and transports. We find that reanalyses show some consistency, in particular showing a weakening of the subpolar gyre and AMOC at 50°N from the mid‐1990s until at least 2009 (related to decadal variability in previous studies), a strengthening and then weakening of the AMOC at 26.5°N since 2000, and impacts of circulation changes on transports. These results agree with model studies and the AMOC observations at 26.5°N since 2005. We also see less spread across the ensemble in AMOC strength and mixed layer depth, suggesting improvements as the observational coverage has improved.
Plain Language Summary
The observational network around the North Atlantic has improved significantly over the last few decades revealing changes over decadal time scales in the North Atlantic, including in heat content, heat transport, and the circulation. However, there are still significant gaps in the observational coverage. Ocean reanalyses fill in these gaps by combining the observations with a computer model of the ocean to give consistent estimates of the ocean state. These reanalyses are potentially useful tools that can be used to understand the observed changes; however, their skill must also be assessed. We use an ensemble of global ocean reanalyses in order to examine the mean state and variability of the North Atlantic ocean since 1993. In particular, we examine the convection, circulation, transports of heat and fresh water, and temperature and salinity changes. We find that reanalyses show some consistency in their results, suggesting that they may be useful for understanding circulation changes in regions and times where there are no observations. We also show improvements in some aspects of the ocean circulation as the observational coverage has improved. This highlights the importance of continuing observational campaigns.
Key Points
Ocean reanalyses are potentially useful tools for understanding ocean circulation
There is some consistency in interannual and decadal variability of the circulation among reanalyses
There have been improvements in aspects of ocean circulation as observational coverage has improved
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