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21.
22.
Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis
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Kevin J. Mills Michael K. Robinson Joseph D. Sherrill Daniel J. Schnell Jun Xu 《Experimental dermatology》2018,27(9):1000-1008
Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (eg psoriasis, atopic dermatitis, seborrhoeic dermatitis and acne) and a novel statistical algorithm were used to define a unifying molecular signature referred to as the “unhealthy skin signature” (USS). Using a pattern‐matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions. 相似文献
23.
Damien Contou Romain Sonneville Florence Canoui-Poitrine Gwenhaël Colin Rémi Coudroy Frédéric Pène Jean-Marc Tadié Martin Cour Gaëtan Béduneau Antoine Marchalot Laurent Guérin Sébastien Jochmans Stephan Ehrmann Nicolas Terzi Sébastien Préau François Barbier Guillaume Schnell Damien Roux Olivier Leroy Claire Pichereau Elodie Gélisse Lara Zafrani Richard Layese Christian Brun-Buisson Armand Mekontso Dessap Nicolas de Prost For the Hopeful Study Group 《Intensive care medicine》2018,44(9):1502-1511
Purpose
Data on purpura fulminans (PF) in adult patients are scarce and mainly limited to meningococcal infections. Our aim has been to report the clinical features and outcomes of adult patients admitted in the intensive care unit (ICU) for an infectious PF, as well as the predictive factors for limb amputation and mortality.Methods
A 17-year national multicenter retrospective cohort study in 55 ICUs in France from 2000 to 2016, including adult patients admitted for an infectious PF defined by a sudden and extensive purpura, together with the need for vasopressor support. Primary outcome variables included hospital mortality and amputation during the follow-up period (time between ICU admission and amputation, death or end of follow-up).Results
Among the 306 included patients, 126 (41.2%; 95% CI 35.6–46.9) died and 180 (58.8%; 95% CI 53.3–64.3) survived during the follow-up period [13 (3–24) days], including 51/180 patients (28.3%, 95% CI 21.9–35.5) who eventually required limb amputations, with a median number of 3 (1–4) limbs amputated. The two predominantly identified microorganisms were Neisseria meningitidis (63.7%) and Streptococcus pneumoniae (21.9%). By multivariable Cox model, SAPS II [hazard-ratio (HR)?=?1.03 (1.02–1.04); p?<?0.001], lower leucocytes [HR 0.83 (0.69–0.99); p?=?0.034] and platelet counts [HR 0.77 (0.60–0.91); p?=?0.007], and arterial blood lactate levels [HR 2.71 (1.68–4.38); p?<?0.001] were independently associated with hospital death, while a neck stiffness [HR?0.51 (0.28–0.92); p?=?0.026] was a protective factor. Infection with Streptococcus pneumoniae [sub-hazard ratio 1.89 (1.06–3.38); p?=?0.032], together with arterial lactate levels and ICU admission temperature, was independently associated with amputation by a competing risks analysis.Conclusion
Purpura fulminans carries a high mortality and morbidity. Pneumococcal PF leads to a higher risk of amputation.Trials registration
NCT03216577.24.
This paper reviews the 19 published studies that have utilized psychological assessments in determining the outcome of children
with phenylketonuria who have discontinued a phenylalanine-restricted diet. About half the studies showed that, after diet
termination, the intellectual performance of children decreased, while the other studies indicated that the intellectual performance
of the children did not change. Difficulties in the use of intelligence tests to answer questions about diet termination are
outlined. Due to the methodological difficulties and the varying results reported, the issue concerning the safety of diet
discontinuation remains unresolved. The conclusion is that the task now is to differentiate those children who should remain
on the diet from those who may safely terminate.
Supported in part by Project 928, Maternal and Child Health Service, DHEW, and by the Department of Public Health, Commonwealth
of Massachusetts. 相似文献
25.
Koser ML McGettigan JP Tan GS Smith ME Koprowski H Dietzschold B Schnell MJ 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(25):9405-9410
Rabies virus (RV) nucleoprotein (N) tightly encapsidates the genomic and antigenomic RNA of RV to form the viral ribonucleoprotein (RNP) complex. Antigens, such as N, presented in a highly organized structure are sufficient and even desirable to activate B cells to proliferate and produce antibodies. In addition to activating B cells to proliferate, it has been shown that RV N in the RNP complex induces potent T helper cell responses resulting in long-lasting and strong humoral immune responses against RV. The possibility to systematically incorporate foreign genes into the genome of RV and produce a recombinant virus allows us to examine whether the immunogenicity of foreign antigens can be enhanced by incorporation into the RV RNP structure. To test this hypothesis we constructed a recombinant RV expressing a RV N-GFP fusion protein. The chimeric N-GFP fusion protein was efficiently expressed and incorporated into RV RNP and virions. Moreover, the recombinant RNP induces a strong humoral immune response against GFP in mice. In contrast, mice inoculated with GFP alone or a combination of wild-type RV RNPs and GFP did not trigger any GFP-specific humoral responses using the same immunization schedule. These data indicate the usefulness of RV-based vectors as killed vaccines against other infectious diseases. 相似文献
26.
Identification of viral genomic elements responsible for rabies virus neuroinvasiveness 总被引:10,自引:0,他引:10
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Faber M Pulmanausahakul R Nagao K Prosniak M Rice AB Koprowski H Schnell MJ Dietzschold B 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(46):16328-16332
Attenuated tissue culture-adapted and natural street rabies virus (RV) strains differ greatly in their neuroinvasiveness. To identify the elements responsible for the ability of an RV to enter the CNS from a peripheral site and to cause lethal neurological disease, we constructed a full-length cDNA clone of silver-haired bat-associated RV (SHBRV) strain 18 and exchanged the genes encoding RV proteins and genomic sequences of this highly neuroinvasive RV strain with those of a highly attenuated nonneuroinvasive RV vaccine strain (SN0). Analysis of the recombinant RV (SB0), which was recovered from SHBRV-18 cDNA, indicated that this RV is phenotypically indistinguishable from WT SHBRV-18. Characterization of the chimeric viruses revealed that in addition to the RV glycoprotein, which plays a predominant role in the ability of an RV to invade the CNS from a peripheral site, viral elements such as the trailer sequence, the RV polymerase, and the pseudogene contribute to RV neuroinvasiveness. Analyses also revealed that neuroinvasiveness of an RV correlates inversely with the time necessary for internalization of RV virions and with the capacity of the virus to grow in neuroblastoma cells. 相似文献
27.
Summary Kwashiorkor, the human disease of protein-energy malnutrition, has been implicated in the aetiology of malnutrition-related diabetes mellitus, a form of diabetes not uncommon in developing countries. We have previously demonstrated that temporary protein-energy malnutrition in young rats causes a persisting impairment of insulin secretion. The present study investigates whether this secretory deficiency is accompanied by structural alterations of the endocrine pancreas. Three-week-old rats were weaned onto semi-synthetic diets containing either 15% or 5% protein and these diets were maintained for 3 weeks. From 6 weeks of age all rats were fed a commercial chow containing 18% protein. The endocrine pancreas was investigated by light and electron microscopic morphometry at 3, 6 and 12 weeks of age. In rats not subjected to protein-energy malnutrition there was a progressive increase, with age, of total pancreatic Beta-cell weight and individual Beta-cell size. In 6-week-old rats fed the low protein diet total pancreatic Beta-cell weight and individual Beta-cell size were diminished. In 12-week-old rats previously fed the low protein diet total Beta-cell weight remained lower compared to control rats. It is concluded that protein-energy malnutrition early in life may result in a diminished reserve for insulin production. This may predispose to glucose intolerance or even diabetes in situations with an increased insulin demand.This work was presented in part at the 26th Annual Meeting of the European Association for the Study of Diabetes in Copenhagen, Denmark 10–13 September 1990 相似文献
28.
J W Schnell R A Anderson J E Stegner S P Schindler R B Weinberg 《Atherosclerosis》2001,159(2):459-466
Oxidative modification of high-density lipoproteins (HDL) impairs several biologic functions critical to its role in reverse cholesterol transport. We therefore investigated the effect of dietary polyunsaturated fat and vitamin E on the kinetics of HDL oxidation. Ten subjects were fed sequentially: a baseline diet in which the major fat source was olive oil; a high polyunsaturated fat diet in which the major fat source was safflower oil; and the safflower oil diet plus 800 I.U. vitamin E per day. Plasma lipoprotein levels, vitamin E content, fatty acid composition, and oxidation lag time and rate were determined after 3 weeks on each diet. The polyunsaturated fat diet increased the mean HDL(2) lag time from 45.8+/-12.5 to 83.3+/-11.6 min with no change in oxidation rate. Addition of vitamin E further increased the HDL(2) lag time to 115.6+/-4.4 min and decreased the HDL(2) oxidation rate 10-fold. Neither the polyunsaturated diet alone nor the diet with vitamin E supplementation had any effect on HDL(3) oxidation. We conclude that under conditions of controlled dietary fat intake, a high polyunsaturated fat intake does not increase the oxidation susceptibility of HDL subfractions, and that in this setting, vitamin E supplementation reduces the oxidation susceptibility of HDL(2). These data suggest that antioxidants could influence HDL function in vivo. 相似文献
29.
Oliver Schnell 《Diabetes/metabolism research and reviews》2001,17(4):243-245
A key problem in ischemia‐induced impairment of the vascular performance of the diabetic heart is the often‐unrecognized cardiac sympathetic dysfunction. Advanced single‐photon emission computed tomography (SPECT) and positron emission tomography (PET) using the radiopharmaceuticals, 123I‐metaiodobenzylguanidine (123I‐MIBG) and 11C‐hydroxyephedrine (11C‐HED), have shown that dysfunction of cardiac sympathetic nerves is present to a large extent in both type 1 and type 2 diabetes. The pattern of sympathetic disturbances is heterogeneous with a predominant effect in the posterior myocardial region. Furthermore, myocardial blood flow assessment with PET has shown that endothelial‐dependent vasodilatation is reduced in proportion to the magnitude of cardiac sympathetic dysfunction. These mechanisms are currently proposed to lead from early changes to advanced impairment of cardiac function in diabetes. Copyright © 2001 John Wiley & Sons, Ltd. 相似文献
30.
Hübel K Hegener K Schnell R Mansmann G Oberhäuser F Staib P Diehl V Engert A 《Annals of hematology》1999,78(2):73-77
Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative
chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms
existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated
whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with
the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years
(range 20–70 years). According to the development of infectious complications the patients were assigned retrospectively to
group 1 (no or only mild infections, n=29) or to group 2 (severe infection or death due to infection, n=15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7±13.7 (SEM) vs 170.0±19.2,
mean channel fluorescence;p=0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in
group 2 (24.8±6.1 vs 14.5±3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy
might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters
could help to estimate the individual risk of infection for a patient with ANLL.
Received: July 3, 1998 / Accepted: September 9, 1998 相似文献