Afamelanotide for Erythropoietic Protoporphyria Langendonk, Janneke G; Balwani, Manisha; Anderson, Karl E ...
New England journal of medicine/The New England journal of medicine,
07/2015, Letnik:
373, Številka:
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Journal Article
Recenzirano
Odprti dostop
In patients with erythropoietic protoporphyria, sensitivity to the sun leads to pain and compromised quality of life. In two clinical trials, one in Europe and one in the United States, a peptide ...analogue of an α-melanocyte–stimulating hormone alleviated symptoms.
Erythropoietic protoporphyria is a rare, autosomal recessive inborn error of metabolism that typically manifests in early childhood as severe painful photosensitivity. The photosensitivity results from accumulated protoporphyrin in erythroid cells and tissues because of the decreased activity of ferrochelatase, the heme biosynthetic enzyme that inserts iron into protoporphyrin to form heme.
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An X-linked form of erythropoietic protoporphyria
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that accounts for 2 to 10% of cases results from a gain of function of erythroid-specific aminolevulinic acid synthase 2.
Pathophysiologically, protoporphyrin is released from erythroid cells into the circulation, gains access to the vascular endothelium and liver, and is excreted . . .
Magnetic resonance imaging (MRI) is a highly versatile imaging modality that can be used to measure features of the tumour microenvironment including cell death, proliferation, metabolism, ...angiogenesis, and hypoxia. Mapping and quantifying these pathophysiological features has the potential to alter the use of adaptive radiotherapy planning. Although these methods are available for use on diagnostic machines, several challenges exist for implementing these functional MRI methods on the MRI-linear accelerators (linacs). This review considers these challenges and potential solutions.
Extreme rainfall is expected to increase under climate change, carrying potential socioeconomic risks. However, the magnitude of increase is uncertain. Over recent decades, extreme storms over the ...West African Sahel have increased in frequency, with increased vertical wind shear shown to be a cause. Drier midlevels, stronger cold pools, and increased storm organization have also been observed. Global models do not capture the potential effects of lower- to midtropospheric wind shear or cold pools on storm organization since they parameterize convection. Here we use the first convection-permitting simulations of African climate change to understand how changes in thermodynamics and storm dynamics affect future extreme Sahelian rainfall. The model, which simulates warming associated with representative concentration pathway 8.5 (RCP8.5) until the end of the twenty-first century, projects a 28% increase of the extreme rain rate of MCSs. The Sahel moisture change on average follows Clausius–Clapeyron scaling, but has regional heterogeneity. Rain rates scale with the product of time-of-storm total column water (TCW) and in-storm vertical velocity. Additionally, prestorm wind shear and convective available potential energy both modulate in-storm vertical velocity. Although wind shear affects cloud-top temperatures within our model, it has no direct correlation with precipitation rates. In our model, projected future increase in TCW is the primary explanation for increased rain rates. Finally, although colder cold pools are modeled in the future climate, we see no significant change in near-surface winds, highlighting avenues for future research on convection-permitting modeling of storm dynamics.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report
the first phase I clinical trial evaluation of CDP791, a ...PEGylated di-Fab′ conjugate that binds VEGFR-2.
Experimental Design: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses.
Results: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving
CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising
28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation
showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of
CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although
no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI),
there was a significant dose level–related reduction in tumor growth. While challenging the recent dogma that active VEGF
inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional
tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no
partial or complete responses were seen.
Conclusion: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered
at 10 mg/kg or more every 3 weeks.
Stenosis is a common complication of Crohn’s disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed ...tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD.
We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system.
We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed.
In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.
The cratered plains of Gusev traversed by Spirit are generally low‐relief rocky plains dominated by impact and eolian processes. Ubiquitous shallow, soil‐filled, circular depressions, called hollows, ...are modified impact craters. Rocks are dark, fine‐grained basalts, and the upper 10 m of the cratered plains appears to be an impact‐generated regolith developed over intact basalt flows. Systematic field observations across the cratered plains identified vesicular clasts and rare scoria similar to original lava flow tops, consistent with an upper inflated surface of lava flows with adjacent collapse depressions. Crater and hollow morphometry are consistent with most being secondaries. The size‐frequency distribution of rocks >0.1 m diameter generally follows exponential functions similar to other landing sites for total rock abundances of 5–35%. Systematic clast counts show that areas with higher rock abundance and more large rocks have higher thermal inertia. Plains with lower thermal inertia have fewer rocks and substantially more pebbles that are well sorted and evenly spaced, similar to a desert pavement or lag. Eolian bed forms (ripples and wind tails) have coarse surface lags, and many are dust covered and thus likely inactive. Deflation of the surface ∼5–25 cm likely exposed two‐toned rocks and elevated ventifacts and transported fines into craters creating the hollows. This observed redistribution yields extremely slow average erosion rates of ∼0.03 nm/yr and argues for very little long‐term net change of the surface and a dry and desiccating environment similar to today's since the Hesperian (or ∼3 Ga).
In a patient with refractory temporal lobe epilepsy, EEG-fMRI showed activation in association with left anterior temporal interictal discharges, in the left temporal, parietal and occipital lobes. ...Dynamic causal modelling suggested propagation of neural activity from the temporal focus to the area of occipital activation. Tractography showed connections from the site of temporal lobe activation to the site of occipital activation. This demonstrates the principle of combining EEG-fMRI and tractography to delineate the pathways of propagation of epileptic activity.
To quantitatively investigate water diffusion changes in normal-appearing white matter (NAWM) and gray matter in patients with MS, and to evaluate whether these changes are correlated with clinical ...disability and disease duration.
Diffusion tensor imaging provides quantitative information about the magnitude and directionality (anisotropy) of water diffusion in vivo and detects pathologic changes in MS brain tissue.
Diffusion tensor imaging was performed in 39 patients with MS and in 21 age-matched control subjects. Quantitative indices, including fractional anisotropy, volume ratio, and mean diffusivity, were obtained in 30 regions of interest located in normal-appearing basal ganglia, cerebellar gray matter, and supratentorial and infratentorial NAWM.
Patients with MS showed significantly reduced anisotropy and a trend toward increased diffusivity in the infratentorial and supratentorial NAWM, and significantly increased anisotropy in the basal ganglia. In all patients with MS, both fractional anisotropy and mean diffusivity in the cerebral peduncles were inversely correlated with the Expanded Disability Status Scale and pyramidal functional scores. In patients with relapsing-remitting MS, there was a strong correlation between Expanded Disability Status Scale score and fractional anisotropy in both supratentorial and infratentorial NAWM. In primary and secondary progressive MS, disease duration correlated strongly with mean diffusivity in infratentorial NAWM and fractional anisotropy in the cerebral peduncles, respectively.
The most striking finding of decreased fractional anisotropy in supratentorial and infratentorial NAWM and increased fractional anisotropy in basal ganglia may result from axonal degeneration due to fiber transection in remote focal lesions. Diffusion tensor imaging indices, in particular fractional anisotropy, appear sensitive to structural damage in NAWM that is associated with disability and progression in MS.
OBJECTIVE To review and update consensus-based recommendations for medical and
public health professionals following a Bacillus anthracis attack against a civilian population. PARTICIPANTS The ...working group included 23 experts from academic medical centers,
research organizations, and governmental, military, public health, and emergency
management institutions and agencies. EVIDENCE MEDLINE databases were searched from January 1966 to January 2002, using
the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified
work published before 1966. Participants identified unpublished sources. CONSENSUS PROCESS The first draft synthesized the gathered information. Written comments
were incorporated into subsequent drafts. The final statement incorporated
all relevant evidence from the search along with consensus recommendations. CONCLUSIONS Specific recommendations include diagnosis of anthrax infection, indications
for vaccination, therapy, postexposure prophylaxis, decontamination of the
environment, and suggested research. This revised consensus statement presents
new information based on the analysis of the anthrax attacks of 2001, including
developments in the investigation of the anthrax attacks of 2001; important
symptoms, signs, and laboratory studies; new diagnostic clues that may help
future recognition of this disease; current anthrax vaccine information; updated
antibiotic therapeutic considerations; and judgments about environmental surveillance
and decontamination.
Naming difficulties are a well recognised, but difficult to predict, complication of anterior temporal lobe resection (ATLR) for refractory epilepsy. We used MR tractography preoperatively to ...demonstrate the structural connectivity of language areas in patients undergoing dominant hemisphere ATLR. Greater lateralisation of tracts to the dominant hemisphere was associated with greater decline in naming function. We suggest that this method has the potential to predict language deficits in patients undergoing ATLR.
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