New therapeutic strategies for systemic sclerosis--a critical analysis of the literature

Abstract Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted. Methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, and IVIg may be beneficial in improving the skin tightness in SSc. Calcium channel blockers, the angiotensin II receptor type 1 antagonist losartan, prazocin, the prostacyclin analogue iloprost, N-acetylcysteine and the dual endothelin-receptor antagonist bosentan may be beneficial for Raynaud's phenomenon. Epoprostenol and bosentan are approved for therapy of pulmonary hypertension (PAH). Other options under investigation include intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy is effective in suppressing active alveolitis. Stem cell and lung transplantation is a viable option for carefully selected patients. Renal crisis can be effectively managed when hypertension is aggressively controlled with angiotensin converting enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hope of discontinuing dialysis. Antithymocyte globulin and mycophenolate mofetil appear safe in SSc. The improvement in skin score and the apparent stability of systemic disease during the treatment period suggest that controlled studies of these agents are justified. Stem cell transplantation is under investigation for severe disease. Novel therapies are currently being tested in the treatment of SSc and have the potential of modifying the disease process and overall clinical outcome. The evaluation of these studies is still a difficult process

Construction of an ~700-kb transcript map around the Familial Mediterranean Fever locus on human chromosome 16p13.3

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the ∼700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron–exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (betweenD16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.Michael Centola, Xiaoguang Chen, Raman Sood, Zuoming Deng, Ivona Aksentijevich, Trevor Blake, Darrell O. Ricke, Xiang Chen, Geryl Wood, Nurit Zaks, Neil Richards, David Krizman, Elizabeth Mansfield, Sinoula Apostolou, Jingmei Liu, Neta Shafran, Anil Vedula, Melanie Hamon, Andrea Cercek, Tanaz Kahan, Deborah Gumucio, David F. Callen, Robert I. Richards, Robert K. Moyzis, Norman A. Doggett, Francis S. Collins, P. Paul Liu, Nathan Fischel-Ghodsian and Daniel L. Kastne

New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature

Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted

Branched-chain and aromatic amino acid catabolism into aroma volatiles in Cucumis melo L. fruit

The unique aroma of melons (Cucumis melo L., Cucurbitaceae) is composed of many volatile compounds biosynthetically derived from fatty acids, carotenoids, amino acids, and terpenes. Although amino acids are known precursors of aroma compounds in the plant kingdom, the initial steps in the catabolism of amino acids into aroma volatiles have received little attention. Incubation of melon fruit cubes with amino acids and α-keto acids led to the enhanced formation of aroma compounds bearing the side chain of the exogenous amino or keto acid supplied. Moreover, L-[13C6]phenylalanine was also incorporated into aromatic volatile compounds. Amino acid transaminase activities extracted from the flesh of mature melon fruits converted L-isoleucine, L-leucine, L-valine, L-methionine, or L-phenylalanine into their respective α-keto acids, utilizing α-ketoglutarate as the amine acceptor. Two novel genes were isolated and characterized (CmArAT1 and CmBCAT1) encoding 45.6 kDa and 42.7 kDa proteins, respectively, that displayed aromatic and branched-chain amino acid transaminase activities, respectively, when expressed in Escherichia coli. The expression of CmBCAT1 and CmArAT1 was low in vegetative tissues, but increased in flesh and rind tissues during fruit ripening. In addition, ripe fruits of climacteric aromatic cultivars generally showed high expression of CmBCAT1 and CmArAT1 in contrast to non-climacteric non-aromatic fruits. The results presented here indicate that in melon fruit tissues, the catabolism of amino acids into aroma volatiles can initiate through a transamination mechanism, rather than decarboxylation or direct aldehyde synthesis, as has been demonstrated in other plants

Effects of Chronic, Low-Dose Cannabinoids, Cannabidiol, Delta-9-Tetrahydrocannabinol and a Combination of Both, on Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease

There is an urgent need for novel therapies to treat Alzheimer’s disease (AD). Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg), or a combination of both (CBD:THC; 0.273:0.205mg/kg) in the 5xFAD mouse model of AD. Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of amyloid beta 1–42. These effects were not accompanied by changes in molecular parameters of inflammation at the messenger RNA (mRNA) or protein level. These data reveal differential effects of chronic low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in brains of 5xFAD mice.peer-reviewed871 K

A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups

Familial Mediterranean fever (FMF) is a recessive disorder of inflammation caused by mutations in a gene (designated MEFV) on chromosome 16p13.3. We have recently constructed a 1-Mb cosmid contig that includes the FMF critical region. Here we show genotype data for 12 markers from our physical map, including 5 newly identified microsatellites, in FMF families. Intrafamilial recombinations placed MEFV in the approximately 285 kb between D16S468/D16S3070 and D16S3376. We observed significant linkage disequilibrium in the North African Jewish population, and historical recombinants in the founder haplotype placed MEFV between D16S3082 and D16S3373 (approximately 200 kb). In smaller panels of Iraqi Jewish, Arab, and Armenian families, there were significant allelic associations only for D16S3370 and D16S2617 among the Armenians. A sizable minority of Iraqi Jewish and Armenian carrier chromosomes appeared to be derived from the North African Jewish ancestral haplotype. We observed a unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians and two other haplotypes restricted to either the Iraqi Jewish or the Armenian population. These data support the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another.James E. Balow Jr. David A. Shelton, Annette Orsborn, Marie Mangelsdorf, Ivona Aksentijevich, Trevor Blake, Raman Sood, Dawn Gardner, Raymond Liu, Elon Pras, Ernesto N. Levy, Michael Centola, Zuoming Deng, Nurit Zaks, Geryl Wood, Xiaoguang Cheng, Neil Richards, Mordechai Shohat, Avi Livneh, Mordechai Pras, Norman A. Doggett, Francis S. Collins, P.Paul Liu, Jerome I. Rotter, Nathan Fischel-Ghodsian, Deborah Gumucio, Robert I. Richards, Daniel L. Kastne