In patients with thrombotic thrombocytopenic purpura (TTP), excessive intravascular platelet aggregation has been associated with appearance in plasma of unusually large von Willebrand factor (vWF) ...multimers. These extremely adhesive vWF multimers may arise due to deficiency of a "depolymerase" cleaving vWF to smaller molecular forms, either by reducing the interdimeric disulfide bridges or by proteolytic degradation. We studied the activity of a recently described vWF-cleaving protease in four patients with chronic relapsing TTP. Diluted plasma samples of TTP patients were incubated with purified normal human vWF in the presence of a serine protease inhibitor, at low ionic strength, and in the presence of urea and barium ions. The extent of vWF degradation was assayed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. Four patients, that included two brothers, with chronic relapsing TTP displayed either substantially reduced levels or a complete absence of vWF-cleaving protease activity. In none of these patient plasmas was an inhibitor of or an antibody against the vWF-cleaving protease established. Our data suggest that the unusually large vWF multimers found in TTP patients may be caused by deficient vWF-cleaving protease activity. Deficiency of this protease may be inherited in an autosomal recessive manner and seems to predispose to chronic relapsing TTP. The assay of the vWF-cleaving protease activity may be used as a sensitive diagnostic tool for identification of subjects with a latent TTP tendency.
Summary Background Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early ...death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. Methods In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80–320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. Findings Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. Interpretation cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. Funding German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.
Beginning with the first event in Washington, DC in 2002, the Department of Energy's Solar Decathlon has brought attention to the promise of PV-powered, zero-energy homes through the format of a ...riveting collegiate competition. As an internationally recognized event, it demonstrates innovative solutions-using energy efficiently and generating the needs of modern domestic life with solar energy. At the 2007 event (the third Solar Decathlon), a new era of the competition was conceived, in which the U.S. Department of Energy's event (produced and managed by the National Renewable Energy Laboratory) would be complemented by a European Solar Decathlon in Madrid, with each competition to be held in alternating years. Each of these upcoming events is described.
The Solar Decathlon is a college-level student competition to design, construct, and operate approximately 800-ft/sup 2/ homes that are highly energy efficient and use solar thermal and photovoltaic ...technologies to meet all household energy needs. In fall 2005, 19 teams compete for about one week in ten contests, six of which test energy usage and production. The competition takes place on the National Mall in Washington, D.C., and is open to the public. A comprehensive building-energy simulation and monitoring project developed for Solar Decathlon homes is outlined in this paper. Simulation, monitoring, and analysis activities are conducted before, during, and after the competition in five phases. The level of detail of monitoring activities progressively increases in each phase. The level of detail of the simulations remains consistent throughout, but the simulation accuracy is expected to improve as more detailed monitoring data become available for model calibration. The results of the various phases of the project are expected to be of interest to five diverse groups: visitors to the Solar Decathlon, competition organizers, current Solar Decathlon teams, future Solar Decathlon teams, and building scientists.
. A retrospective analysis of 395 51Chromium‐ethylenediaminotetraacetate single injection clearances performed in infants and children is presented. In 61% of infants and 30% of the children the ...clearance values were calculated on the basis of a plasma disappearance half time of the reference substance, which was longer than the standard study, i.e. on the basis of extrapolated data. Plasma creatinine and urea levels were found to be appropriate indicators for predicting the plasma disappearance half time of the marker substance. 14 additional patients were studied prospectively with a duration of the study predicted by means of the plasma creatinine and urea levels. In these patients, separate determinations of the clearances using either the data obtained during the standard time of procedure only, or the data of the entire study, clearly demonstrated that the clearances obtained by means of the standard procedure overestimated glomerular filtration rate. The analysis of the data in infants show that the plasma urea level is a reasonably good indicator for predicting the time schedule of the study whereas plasma creatinine should not be used. Additionally the retrospective data indicate that a prolongation of the study should be recommended in all infants. This study demonstrates the necessity and offers means of adapting the time schedule of isotope single injection clearances to physiological and pathophysiological facts.
Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of ...Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.
Summary Background Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been ...undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. Methods Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture–recapture analysis was used to estimate completeness of ascertainment. Findings We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30–1·96). Capture–recapture analysis suggested that case ascertainment was 89% (95% CI 77–97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36–6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year 95% CI 1·18–2·12 for boys and 1·61 per 100 000 per year 1·18–2·14 for girls). Asian (relative risk 2·14, 95% CI 1·11–3·85; p=0·017) and black (2·28, 1·00–4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. Interpretation Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. Funding The Stroke Association, UK.
Polar ice core records attest to a colossal volcanic eruption that took place ca. A.D. 1257 or 1258, most probably in the tropics. Estimates based on sulfate deposition in these records suggest that ...it yielded the largest volcanic sulfur release to the stratosphere of the past 7,000 y. Tree rings, medieval chronicles, and computational models corroborate the expected worldwide atmospheric and climatic effects of this eruption. However, until now there has been no convincing candidate for the mid-13th century “mystery eruption.” Drawing upon compelling evidence from stratigraphic and geomorphic data, physical volcanology, radiocarbon dating, tephra geochemistry, and chronicles, we argue the source of this long-sought eruption is the Samalas volcano, adjacent to Mount Rinjani on Lombok Island, Indonesia. At least 40 km ³ (dense-rock equivalent) of tephra were deposited and the eruption column reached an altitude of up to 43 km. Three principal pumice fallout deposits mantle the region and thick pyroclastic flow deposits are found at the coast, 25 km from source. With an estimated magnitude of 7, this event ranks among the largest Holocene explosive eruptions. Radiocarbon dates on charcoal are consistent with a mid-13th century eruption. In addition, glass geochemistry of the associated pumice deposits matches that of shards found in both Arctic and Antarctic ice cores, providing compelling evidence to link the prominent A.D. 1258/1259 ice core sulfate spike to Samalas. We further constrain the timing of the mystery eruption based on tephra dispersal and historical records, suggesting it occurred between May and October A.D. 1257.
We analyse business‐NGO (B2N) alliances through the lenses of multiple agency and behavioural agency theories to identify the sources of agency problems and the most effective choice of mitigation ...mechanisms. We contend that three types of agency relationships constitute B2N alliances: the relationship between the firm's managers and B2N alliance employees; the relationship between the NGO's managers and the B2N alliance employees; and the novel ‘claimed principal‐agent relationship’ involving the external beneficiary, the NGO's managers and the alliance employees. We argue that B2N alliances’ three types of agency problems stem from (1) the relative emphasis on public vs. private goods, both at the employee and at the partner levels, and (2) the level of the external beneficiary's voice. We then predict the mechanisms to mitigate these problems: hiring altruistic over self‐interested individuals; narrowly specifying the employees’ activities; emphasizing input‐based and intrinsic incentive mechanisms; and investing significantly into non‐intrusive monitoring mechanisms.
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