Avascular Necrosis of the Foot and Ankle in a Patient with Systemic Sclerosis: A Case Based Review

This review describes a case of atraumatic avascular necrosis in the foot and ankle in a patient with systemic sclerosis who did not receive corticosteroid therapy. Both avascular necrosis and systemic sclerosis are uncommon disease entities. This case demonstrates that vasculitis and secondary vasoconstriction in the pathogenesis of systemic sclerosis are important risk factors for the development of avascular necrosis of the foot and ankle. Therefore, if these patients develop chronic foot and ankle pain, avascular necrosis should be included in the differential diagnosis, even if they do not receive corticosteroids. For the diagnosis and follow-up of avascular necrosis MRI remains the gold standard. Thus, MRI should be used to diagnose avascular necrosis in an early stage. Level of Clinical Evidence: 4.This review describes a case of atraumatic avascular necrosis in the foot and ankle in a patient with systemic sclerosis who did not receive corticosteroid therapy. Both avascular necrosis and systemic sclerosis are uncommon disease entities. This case demonstrates that vasculitis and secondary vasoconstriction in the pathogenesis of systemic sclerosis are important risk factors for the development of avascular necrosis of the foot and ankle. Therefore, if these patients develop chronic foot and ankle pain, avascular necrosis should be included in the differential diagnosis, even if they do not receive corticosteroids. For the diagnosis and follow-up of avascular necrosis MRI remains the gold standard. Thus, MRI should be used to diagnose avascular necrosis in an early stage. Level of Clinical Evidence: 4

Processing Induced Changes in Food Proteins: Amyloid Formation during Boiling of Hen Egg White

Amyloid fibrils (AFs) are highly ordered protein nanofibers composed of cross β-structure that occur in nature, but that also accumulate in age-related diseases. Amyloid propensity is a generic property of proteins revealed by conditions that destabilize the native state, suggesting that food processing conditions may promote AF formation. This had only been shown for foie gras, but not in common foodstuffs. We here extracted a dense network of fibrillar proteins from commonly consumed boiled hen egg white (EW) using chemical and/or enzymatic treatments. Conversion of EW proteins into AFs during boiling was demonstrated by thioflavin T fluorescence, Congo red staining, and X-ray fiber diffraction measurements. Our data show that cooking converts approximately 1–3% of the protein in EW into AFs, suggesting that they are a common component of the human diet

Genome-wide BAC-end sequencing of Cucumis melo using two BAC libraries

<p>Abstract</p> <p>Background</p> <p>Although melon (<it>Cucumis melo </it>L.) is an economically important fruit crop, no genome-wide sequence information is openly available at the current time. We therefore sequenced BAC-ends representing a total of 33,024 clones, half of them from a previously described melon BAC library generated with restriction endonucleases and the remainder from a new random-shear BAC library.</p> <p>Results</p> <p>We generated a total of 47,140 high-quality BAC-end sequences (BES), 91.7% of which were paired-BES. Both libraries were assembled independently and then cross-assembled to obtain a final set of 33,372 non-redundant, high-quality sequences. These were grouped into 6,411 contigs (4.5 Mb) and 26,961 non-assembled BES (14.4 Mb), representing ~4.2% of the melon genome. The sequences were used to screen genomic databases, identifying 7,198 simple sequence repeats (corresponding to one microsatellite every 2.6 kb) and 2,484 additional repeats of which 95.9% represented transposable elements. The sequences were also used to screen expressed sequence tag (EST) databases, revealing 11,372 BES that were homologous to ESTs. This suggests that ~30% of the melon genome consists of coding DNA. We observed regions of microsynteny between melon paired-BES and six other dicotyledonous plant genomes.</p> <p>Conclusion</p> <p>The analysis of nearly 50,000 BES from two complementary genomic libraries covered ~4.2% of the melon genome, providing insight into properties such as microsatellite and transposable element distribution, and the percentage of coding DNA. The observed synteny between melon paired-BES and six other plant genomes showed that useful comparative genomic data can be derived through large scale BAC-end sequencing by anchoring a small proportion of the melon genome to other sequenced genomes.</p

Mechanosensing and Sphingolipid-Docking Mediate Lipopeptide-Induced Immunity in Arabidopsis

Bacteria-derived lipopeptides are immunogenic triggers of host defenses in metazoans and plants. Root-associated rhizobacteria produce cyclic lipopeptides that activate systemically induced resistance (IR) against microbial infection in various plants. How these molecules are perceived by plant cells remains elusive. Here, we reveal that immunity activation inArabidopsis thalianaby the lipopeptide elicitor surfactin is mediated by docking into specific sphingolipid-enriched domains and relies on host membrane deformation and subsequent activation of mechanosensitive ion channels. This mechanism leads to host defense potentiation and resistance to the necrotrophB. cinereabut is distinct from host pattern recognition receptor-mediated immune activation and reminiscent of damage-induced plant immunity

Characterization of the Interactions between Fluoroquinolone Antibiotics and Lipids: a Multitechnique Approach

Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and intracellular activity between two fluoroquinolones, ciprofloxacin and moxifloxacin, that may actually result from their differential susceptibility to efflux by the ciprofloxacin transporter. In view of the critical role of lipids for the drug cellular uptake and differences observed for the two closely related fluoroquinolones, we investigated the interactions of these two antibiotics with lipids, using an array of complementary techniques. Moxifloxacin induced, to a greater extent than ciprofloxacin, an erosion of the DPPC domains in the DOPC fluid phase (atomic force microscopy) and a shift of the surface pressure-area isotherms of DOPC/DPPC/fluoroquinolone monolayer toward lower area per molecule (Langmuir studies). These effects are related to a lower propensity of moxifloxacin to be released from lipid to aqueous phase (determined by phase transfer studies and conformational analysis) and a marked decrease of all-trans conformation of acyl-lipid chains of DPPC (determined by ATR-FTIR) without increase of lipid disorder and change in the tilt between the normal and the germanium surface (also determined by ATR-FTIR). All together, differences of ciprofloxacin as compared to moxifloxacin in their interactions with lipids could explain differences in their cellular accumulation and susceptibility to efflux transporters

Towards a TILLING platform for functional genomics in Piel de Sapo melons

Background The availability of genetic and genomic resources for melon has increased significantly, but functional genomics resources are still limited for this crop. TILLING is a powerful reverse genetics approach that can be utilized to generate novel mutations in candidate genes. A TILLING resource is available for cantalupensis melons, but not for inodorus melons, the other main commercial group. Results A new ethyl methanesulfonate-mutagenized (EMS) melon population was generated for the first time in an andromonoecious non-climacteric inodorus Piel de Sapo genetic background. Diverse mutant phenotypes in seedlings, vines and fruits were observed, some of which were of possible commercial interest. The population was first screened for mutations in three target genes involved in disease resistance and fruit quality (Cm-PDS, Cm-eIF4E and Cm-eIFI(iso)4E). The same genes were also tilled in the available monoecious and climacteric cantalupensis EMS melon population. The overall mutation density in this first Piel de Sapo TILLING platform was estimated to be 1 mutation/1.5 Mb by screening four additional genes (Cm-ACO1, Cm-NOR, Cm-DET1 and Cm-DHS). Thirty-three point mutations were found for the seven gene targets, six of which were predicted to have an impact on the function of the protein. The genotype/phenotype correlation was demonstrated for a loss-of-function mutation in the Phytoene desaturase gene, which is involved in carotenoid biosynthesis. Conclusions The TILLING approach was successful at providing new mutations in the genetic background of Piel de Sapo in most of the analyzed genes, even in genes for which natural variation is extremely low. This new resource will facilitate reverse genetics studies in non-climacteric melons, contributing materially to future genomic and breeding studies.González, M.; Xu, M.; Esteras Gómez, C.; Roig Montaner, MC.; Monforte Gilabert, AJ.; Troadec, C.; Pujol, M.... (2011). 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Theor Appl Genet. 2008, 118: 139-150. 10.1007/s00122-008-0883-3.Deleu W, Esteras C, Roig C, González-To M, Fernández-Silva I, Blanca J, Aranda MA, Arús P, Nuez F, Monforte AJ, Picó MB, Garcia-Mas J: A set of EST-SNPs for map saturation and cultivar identification in melon. BMC Plant Biol. 2009, 9: 90-10.1186/1471-2229-9-90.Mascarell-Creus A, Cañizares J, Vilarrasa J, Mora-García S, Blanca J, González-Ibeas D, Saladié M, Roig C, Deleu W, Picó B, López-Bigas N, Aranda MA, Garcia-Mas J, Nuez F, Puigdomènech P, Caño-Delgado A: An oligo-based microarray offers novel transcriptomic approaches for the analysis of pathogen resistance and fruit quality traits in melon (Cucumis melo L.). BMC Genomics. 2009, 10: 467-10.1186/1471-2164-10-467.Blanca JM, Cañizares J, Ziarsolo P, Esteras C, Mir G, Nuez F, Garcia-Mas J, Pico B: Melon transcriptome characterization. SSRs and SNPs discovery for high throughput genotyping across the species. 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Plant J. 2006, 45: 684-94. 10.1111/j.1365-313X.2006.02670.x.Cooper JL, Till BJ, Laport RG, Darlow MC, Kleffner JM, Jamai A, El-Mellouki T, Liu S, Ritchie R, Nielsen N, et al: TILLING to detect induced mutations in soybean. BMC Plant Biol. 2008, 8 (1): 9-10.1186/1471-2229-8-9.Dalmais M, Schmidt J, Le Signor C, Moussy F, Burstin J, Savois V, Aubert G, de Oliveira Y, Guichard C, Thompson R, Bendahmane A: UTILLdb, a Pisum sativum in silico forward and reverse genetics tool. Genome Biol. 2008, 9: R43-10.1186/gb-2008-9-2-r43.Dierking EC, Bilyeu KD: New sources of soybean meal and oil composition traits identified through TILLING. BMC Plant Biol. 2009, 9: 89-10.1186/1471-2229-9-89.Perry J, Brachmann A, Welham T, Binder A, Charpentier M, Groth M, Haage K, Markmann K, Wang TL, Parniske M: TILLING in Lotus japonicus identified large allelic series for symbiosis genes and revealed a bias in functionally defective ethyl methanesulfonate alleles toward glycine replacements. 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Nat Biotechnol. 2005, 23: 75-81. 10.1038/nbt1043.Till BJ, Cooper J, Tai TH, Colowit P, Greene EA, Henikoff S, Comai L: Discovery of chemically induced mutations in rice by TILLING. BMC Plant Biol. 2007, 7: 19-10.1186/1471-2229-7-19.Xin Z, Wang ML, Barkley NA, Burow G, Franks C, Pederson G, Burke J: Applying genotyping (TILLING) and phenotyping analyses to elucidate gene function in a chemically induced sorghum mutant population. BMC Plant Biol. 2008, 8: 103-10.1186/1471-2229-8-103.Dong C, Dalton-Morgan J, Vincent K, Sharp P: A modified TILLING method for wheat breeding. Plant Genome. 2009, 2: 39-47. 10.3835/plantgenome2008.10.0012.Sestili F, Botticella E, Bedo Z, Phillips A, Lafiandra D: Production of novel allelic variation for genes involved in starch biosynthesis through mutagenesis. Mol Breeding. 2010, 25: 145-154. 10.1007/s11032-009-9314-7.Watanabe S, Mizoguchi T, Aoki K, Kubo Y, Mori H, Imanishi S, Yamazaki Y, Shibata D, Ezura H: Ethylmethanesulfonate (EMS) mutagenesis of Solanum lycopersicum cv. Micro-Tom for large-scale mutant screens. Plant Biotech. 2007, 24: 33-38. 10.5511/plantbiotechnology.24.33.Elias R, Till BJ, Mba Ch, Al-Safadi B: Optimizing TILLING and Ecotilling techniques for potato (Solanum tuberosum L). BMC Res Notes. 2009, 2: 141-10.1186/1756-0500-2-141.Piron F, Nicolaı M, Minoıa S, Piednoir E, Moretti A, Salgues A, Zamir D, Caranta C, Bendahmane A: An induced mutation in tomato eIF4E leads to immunity to two Potyviruses. PLoS ONE. 2010, 5 (6): e11313-10.1371/journal.pone.0011313.Himelblau E, Gilchrist EJ, Buono K, Bizell C, Mentzer L, Vogelzang R, Osborn T, Amasino RM, Parkin IAP, Haughn : Forward and reverse genetics of papid cycling Brassica oleracea. Theor Appl Genet. 2009, 118: 953-961. 10.1007/s00122-008-0952-7.Stephenson P, Baker D, Girin T, Perez A, Amoah S, King GJ, Østergaard L: A rich TILLING resource for studying gene function in Brassica rapa. BMC Plant Biol. 2010, 10: 62-10.1186/1471-2229-10-62.Pitrat M: Melon (Cucumis melo L.). Handbook of Crop Breeding Vol I. Vegetables. Edited by: Prohens J, Nuez F. 2008, New York:Springer, 283-315.Dahmani-Mardas F, Troadec Ch, Boualem A, Leveque S, Alsadon AA, Aldoss AA, Dogimont C, Bendahman A: Engineering Melon Plants with Improved Fruit Shelf Life Using the TILLING Approach. PLoS ONE. 2010, 5: e15776-10.1371/journal.pone.0015776.Nieto C, Piron F, Dalmais M, Marco CF, Moriones E, Gómez-Guillamón ML, Truniger V, Gómez P, Garcia-Mas J, Aranda MA, Bendahmane A: EcoTILLING for the identification of allelic variants of melon eIF4E, a factor that controls virus susceptibility. 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Curr Opin Plant Biol. 2007, 10: 1-7. 10.1016/j.pbi.2006.11.012.Davuluri GR, van Tuinen A, Mustilli AC, Manfredonia A, Newman R, Burgess D, Brummell DA, King SR, Palys J, Uhlig J, Pennings HMJ, Bowler C: Manipulation of DET1 expression in tomato results in photomorphogenic phenotypes caused by post-transcriptional gene silencing. Plant J. 2004, 40: 344-354. 10.1111/j.1365-313X.2004.02218.x.Wei S, Li X, Gruber MI, Li R, Zhou R, Zebarjadi A, Hannoufa A: RNAi-mediated suppression of DET1 alters the levels of carotenoids and sinapate esters in seeds of Brassica napus. J Agric Food Chem. 2009, 57 (12): 5326-5333. 10.1021/jf803983w.Wang TW, Zhang CG, Wu W, Nowack LM, Madey E, Thompson JE: Antisense suppression of deoxyhypusine synthase in tomato delays fruit softening and alters growth and development DHS mediates the first of two sequential enzymatic reactions that activate eukaryotic translation initiation factor-5A. Plant Physiol. 2005, 138: 1372-1382. 10.1104/pp.105.060194.Ng PC, Henikoff S: SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003, 31 (13): 3812-3814. 10.1093/nar/gkg509.Guzman P, Ecker JR: Exploiting the triple response of Arabidopsis to identify ethylene-related mutants. The Plant Cell. 1990, 2: 513-523.Henikoff S, Comai L: Single-nucleotide mutations for plant functional genomics. Ann Rev Plant Biol. 2003, 54: 375-401. 10.1146/annurev.arplant.54.031902.135009.Greene EA, Codomo CA, Taylor NE, Henikoff JG, Till BJ, Reynolds SH, Enns LC, Burtner C, Johnson JE, Odden AR, et al: Spectrum of chemically induced mutations from a large-scale reverse genetic screen in Arabidopsis. Genetics. 2003, 164 (2): 731-740.Britt AB: DNA damage and repair in plants. 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Health Policy and Systems Research in Twelve Eastern Mediterranean Countries: a stocktaking of production and gaps (2000-2008)

<p>Abstract</p> <p>Background</p> <p>The objectives of this study are to: (1) profile the production of Health Policy and Systems Research (HPSR) published between 2000 and 2008 in 12 countries in the Eastern Mediterranean Region (EMR): Bahrain, Egypt, Jordan, Lebanon, Libya, Morocco, Oman, Palestine, Sudan, Syria, Tunisia, and Yemen; (2) identify gaps; and (3) assess the extent to which existing HPSR produced in the region addresses regional priorities pertaining to Health Financing, Human Resources for Health and the Role of the Non-State Sector. This is the first stocktaking paper of HPSR production and gaps in the EMR.</p> <p>Methods</p> <p>Articles indexed on Medline between years 2000 and 2008 for the 12 study countries were selected. A MeSH term based search was conducted using country names. Articles were assessed using a coding sheet adapted for the region which included themes on: Governance Arrangements, Financial Arrangements, Delivery Arrangements, and Implementation Strategies. Identified articles were matched against regional research priorities to assess the extent to which research production aligns with priorities.</p> <p>Results</p> <p>A total of 1,487 articles (11.94%) fit the criteria in the coding sheet. Results showed an increase in HPSR production which peaked after 2005. Most identified articles focused on Delivery Arrangements (68.1%), and Implementation Strategies (24.4%). Most HPSR addressed priorities in Human Resources for Health (39%<b>)</b>, and some articles focused on Health Financing (12%) and Role of the Non-State Sector (6.1%).</p> <p>Conclusions</p> <p>Despite global calls for producing and translating HPSR into policy, there are still significant gaps in the EMR. More efforts are needed to produce HPSR and align production and translation with the demand for evidence by policymakers. Findings can help inform and direct future plans and activities for the Evidence Informed Policy Network- EMR, World Health Organization- EMR, and the Middle East and North Africa Health Policy Forum, in addition to being useful for countries that host or are planning to host KT platforms in the region.</p

The DAC system and associations with multiple myeloma

Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in monotherapy of these drugs in relapsed/refractory MM patients has been very modest. This has prompted the development of combinations such as the one with bortezomib or lenalidomide and dexamethasone, which have already been taken into the clinics with positive preliminary results