Effects of Sandimmun on T lymphocyte and dendritic cell subpopulations in psoriasis.
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Cyclosporins↗
Biomedical subjects
B S Baker
Publications and source records attributed to B S Baker.
Cytogenetic analysis of chromosome region 73AD of Drosophila melanogaster.
The 73AD salivary chromosome region of Drosophila melanogaster was subjected to mutational analysis in order to (1) generate a collection of chromosome breakpoints that would allow a correlation between the genetic, cytological and molecular maps of the region and (2) define the number and gross organization of complementation groups within this interval. Eighteen complementation groups were defined and mapped to the 73A2-73B7 region, which is comprised of 17 polytene bands. These complementation groups include the previously known scarlet (st), transformer (tra) and Dominant temperature-sensitive lethal-5 (DTS-5) genes, as well as 13 new recessive lethal complementation groups and one male and female sterile locus. One of the newly identified lethal complementation groups corresponds to the molecularly identified abl locus, and another gene is defined by mutant alleles that exhibit an interaction with the abl mutants. We also recovered several mutations in the 73C1-D1.2 interval, representing two lethal complementation groups, one new visible mutant, plucked (plk), and a previously known visible, dark body (db). There is no evidence of a complex of sex determination genes in the region near tra.
Animals↗
Regulation of sex-specific RNA splicing at the Drosophila doublesex gene: cis-acting mutations in exon sequences alter sex-specific RNA splicing patterns.
Sex-specific alternative RNA splicing of the doublesex (dsx) pre-mRNA results in sex-specific polypeptides that regulate both male and female somatic sexual differentiation in Drosophila melanogaster. We have molecularly characterized a class of dsx mutations that act in cis to disrupt the regulation of dsx RNA processing, causing the dsx pre-mRNA to be spliced in the male-specific pattern regardless of the chromosomal sex of the fly. These dsx mutations are associated with rearrangements in the female-specific exon just 3' to the female-specific splice acceptor. The mutations do not affect the female-specific splice sites or intron that are identical to wild-type sequences. These results indicate that sequences in the female-specific exon are important for the regulation of sex-specific RNA splicing, perhaps by acting as sites of interaction with trans-acting regulators. Furthermore, the data suggest that female-specific regulation of dsx RNA processing occurs by promoting the usage of the female splice acceptor site, rather than by repressing the usage of the alternative male-specific splice acceptor.
Amino Acid Sequence↗
Alternative splicing of the sex determination gene transformer-2 is sex-specific in the germ line but not in the soma.
The transformer-2 (tra-2) gene of Drosophila melanogaster plays essential roles in both sexual differentiation in the female soma and spermatogenesis in the male germ line. In the female soma, tra-2 is known to act with other genes in the sex determination regulatory cascade to control the sex-specific alternative splicing of transcripts from the doublesex gene. Here, we determine whether or not any sex-specific tra-2 products are expressed that may account for either of these sex-specific activities. Sequence analysis of the tra-2 gene and 10 tra-2 cDNA clones coupled with nuclease protection analysis reveals a variety of alternatively spliced tra-2 mRNAs that each encode one of four distinct but overlapping polypeptides. Three of the encoded polypeptides contain both a ribonucleoprotein consensus sequence and arginine/serine-rich regions, suggesting a direct role for these products in RNA splicing. We show that although two transcripts are expressed male specifically in the germ line, the tra-2 transcripts expressed in the soma are not sex-specific. The translation of products from a tra-2-lacZ fusion gene in both sexes suggests that the female-specific functioning of tra-2 in somatic tissues is not attributable to a translational mechanism. We suggest that tra-2 activity in somatic tissues is regulated through a post-translational sex-specific interaction with the product of the tra gene rather than through the expression of a female-specific tra-2 polypeptide.
Amino Acid Sequence↗
Four years of experience with cyclosporin A for psoriasis.
Forty-four patients with severe psoriasis have been treated with cyclosporin A (CyA) for 2-50 months (mean 17 months). During the study, 31 (70%) of these patients achieved a greater than 70% reduction in PASI score, 39 (88%) achieved a greater than 60% reduction and 42 (95%) a greater than 50% reduction. The mean initial dose of CyA was 3 mg/kg/day and the mean dose was 3.3 mg/kg/day throughout the study. Twenty-five (57%) patients were maintained on less than or equal to 3 mg and six (14%) required greater than 5 mg/kg/day for limited periods to obtain significant improvement. In three of these patients, this was achieved with 6 mg/kg/day but, of the remainder, one required 7 mg and two required 10 mg/kg/day. Of the 44 patients, 32 (73%) are still taking CyA. Patients were discontinued because of: side-effects directly attributable to treatment (n = 4); remission of psoriasis (n = 4); death (n = I); defaulting (n = I); infrequent attendance (n = I); high doses of NSAID were necessary for arthritis (n = I). Before starting CyA, 39 patients were normotensive; 21 (54%) developed mild hypertension. In 28 patients where the GFRs were estimated before and during treatment, there was a 16% reduction (P less than 0.0001) during a mean period of 8 months. Two patients developed malignancies. The incidence of hypertension and percentage decrease in GFR were strongly correlated with the dose required to control the psoriasis.
Adult↗
Intradermal antigen tests in psoriasis.
To assess whether elicitation of delayed hypersensitivity may be superior to trauma in inducing the Koebner reaction in psoriasis, 12 affected patients and 9 control subjects were tested with 0.1 ml intradermal injections of streptokinase/streptodornase (20 mu/5 mu per 0.1 ml), PPD (1 in 1000) and saline control solutions in a double-blind study; Koebner status was also established in the psoriatic patients. Injected sites were examined at 48 h and 7, 14, 21 and 28 days for local development of psoriasis, erythema and induration (diameter). One patient was Koebner-positive and developed psoriasis at all three injection sites. The other, Koebner-negative psoriatic subjects did not develop psoriasis locally. However, compared with non-psoriatic controls they showed a marked delay in resolution of the delayed hypersensitivity reaction to the PPD antigen and a similar but less marked phenomenon was observed for streptokinase/streptodornase. These findings indicate that intradermal antigen, of the nature and amount used in this study, is no more effective in inducing the Koebner phenomenon than injury alone. However, the ability of psoriasis patients to switch off cell-mediated immune reaction appears to be impaired.
Adult↗
Epidermal rupture is the initiating factor for the Koebner response in psoriasis.
The Koebner phenomenon was studied using low pressure suction and/or sellotape stripping. Each of 10 patients with psoriasis had 5 suction blisters induced and sellotape stripping. In each patient the roof of 4 of the 5 blisters was removed. In 6 of the 10 patients, psoriasis developed where the blister roof was removed, but not where the blister was left intact. However, only 3 of these 10 patients were also Koebner-positive at the tape-stripped site. Similarly, in a group of 37 psoriasis patients who were sellotape-stripped alone, only 8 (21.6%) were Koebner-positive at the tape-stripped site. In another experiment, 5 suction blisters were produced in each of 4 patients. The roof of 4 blisters was removed, one of which was occluded. Psoriasis developed in 3 of the 4 patients, but only where the blister roof had been removed and left unoccluded. These findings suggest that rupture of the epidermis can initiate the Koebner response, but that secondary dermal events are necessary for a psoriatic lesion to form.
Adult↗
Sex in flies: the splice of life.
The discovery that the primary transcripts of many genes are processed to produce more than one kind of messenger RNA focuses attention on the control of RNA processing as a developmental regulatory mechanism. In the fruit-fly Drosophila melanogaster, differential splicing of a hierarchy of regulatory genes determines sex, and thus the molecular biology of sex determination in the fruit-fly may lead to insights into the mechanisms by which alternative splicing is regulated.
Animals↗
Drosophila doublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides.
The doublesex (dsx) gene regulates somatic sexual differentiation in both sexes in D. melanogaster. Two functional products are encoded by dsx: one product is expressed in females and represses male differentiation, and the other is expressed in males and represses female differentiation. We have determined that the dsx gene is transcribed to produce a common primary transcript that is alternatively spliced and polyadenylated to yield male- and female-specific mRNAs. These sex-specific mRNAs share a common 5' end and three common exons, but possess alternative sex-specific 3' exons, thus encoding polypeptides with a common amino-terminal sequence but sex-specific carboxyl termini. Genetic and molecular data suggest that sequences including and adjacent to the female-specific splice acceptor site play an important role in the regulation of dsx expression by the transformer and transformer-2 loci.
Actins↗
The sex determination locus transformer-2 of Drosophila encodes a polypeptide with similarity to RNA binding proteins.
The D. melanogaster transformer-2 (tra-2) gene regulates somatic sexual differentiation in females and is necessary for spermatogenesis in males. Wild-type tra-2 function is required for the female-specific splicing of the pre-mRNA of the next known gene (doublesex) downstream of tra-2 in the sex determination regulatory hierarchy. The tra-2 gene was cloned, and P element-mediated transformation was used to demonstrate that a 3.9 kb genomic fragment contains all sequences necessary for tra-2 function. A 1.7 kb transcript was shown to be the product of the tra-2 locus based on its reduced level in flies containing a tra-2 mutant allele. The sequence of a cDNA corresponding to this transcript indicates that it encodes a polypeptide with strong similarity to a family of RNA binding proteins that includes proteins found associated with hnRNPs and snRNPs, suggesting that the tra-2 product may directly regulate the processing of the double-sex pre-mRNA in females.
Amino Acid Sequence↗
Cloning and characterization of the scarlet gene of Drosophila melanogaster.
DNA from the scarlet (st) region of Drosophila melanogaster has been cloned by chromosome walking, using the breakpoints of a new X-ray-induced third chromosome inversion (In(3LR)st-a27) which breaks in the scarlet (73A3.4) and rosy (87D13-14) regions. Two spontaneous mutants of st(st1 and stsp) contain insertions of non-st DNA located within 3.0 kb of the site of the inversion breakpoint used to isolate the gene, and a second scarlet inversion breaks within 6.5 kb of this site. However no changes detectable by Southern blotting were found in 5 X-ray-induced st mutants with cytologically normal third chromosomes. A 2.3-kb transcript arising from the st gene region (as defined by mutant analysis and DNA transformation) has been detected. This transcript is present throughout development at low levels, with a peak level during the early to mid-pupal stage. The size and amount of this transcript is altered in st1, and its amount is drastically reduced in stsp. Flies carrying the white1 mutation show normal levels of expression of the st transcript, suggesting that the w+ gene does not regulate transcription of the st+ gene. Nucleotide homology between sequences from the st transcription unit and a fragment carrying coding information from the white gene has been detected. This suggests that the st and w proteins are related; they appear to belong to a family of membrane-spanning, ATP-binding proteins involved in the transport of pigment precursors into cells.
Amino Acid Sequence↗
Genes controlling essential cell-cycle functions in Drosophila melanogaster.
On the basis of the hypothesis that mutants in genes controlling essential cell cycle functions in Drosophila should survive up to the larval-pupal transition, 59 such 'late lethals' were screened for those mutants affecting cell division. Examination of mitosis in brain neuroblasts revealed that 30 of these lethals cause disruptions in mitotic chromosome behavior. These mutants identify genes whose wild-type functions are important for: (1) progression through different steps of interphase, (2) the maintenance of mitotic chromosome integrity, (3) chromosome condensation, (4) spindle formation and/or function, and (5) completion of cytokinesis or completion of chromosome segregation. The presence of mitotic defects in late lethal mutants is correlated tightly with the presence of defective imaginal discs. Thus, the phenotypes of late lethality and poorly developed imaginal discs are together almost diagnostic of mutations in essential cell-cycle functions. The terminal phenotypes exhibited by these Drosophila mitotic mutants are remarkably similar to those observed in mammalian cell-cycle mutants, suggesting that these diverse organisms use a common genetic logic to regulate and integrate the events of the cell cycle.
Animals↗
Intralesional cyclosporin in psoriasis: effects on T lymphocyte and dendritic cell subpopulations.
On each of 10 patients with untreated plaque psoriasis, two symmetrical plaques were injected with cyclosporin A or placebo on six occasions over 12 days, in a double-blind manner. Biopsies taken from these lesions at 14 days were examined for differences in cellular composition using a double-labelling immunofluorescent technique. The cyclosporin-injected plaques cleared significantly better than those injected with placebo (P less than 0.001). In the epidermis of the cyclosporin-injected plaques, total and HLA-DR+ CD4+ and CD8+ T cell numbers were significantly decreased compared to corresponding plaques treated with placebo (total CD4+, total CD8+, DR+ CD4+, P less than 0.01; DR+ CD8+, P less than 0.02). Similarly, T lymphocyte numbers in the dermis were decreased in the cyclosporin compared to placebo-treated plaques; the reduction in total CD4+ and DR+ CD8+ T cell numbers was statistically significant (P less than 0.05). Although total numbers of epidermal dendritic cells were not significantly altered, the DR+CD1- dendritic cell subpopulation was markedly decreased (P less than 0.01) and DR-CD1+ dendritic cells increased (P less than 0.05) in the plaques injected with cyclosporin compared to corresponding placebo-treated plaques. These findings show that cyclosporin injected in situ is effective in clearing psoriasis and probably exerts this beneficial effect by its action on T lymphocytes. A suitable topical preparation that allows penetration of the drug should prove helpful in the treatment of psoriasis.
Adult↗
Long-term cyclosporin for psoriasis.
Thirteen patients with severe persistent psoriasis, intolerant of, or unresponsive to, other current treatments have been treated with cyclosporin (Cys) for periods varying from 12-25 (mean 18) months. The dose ranged from 1-4 mg/kg/day (mean 2.8 mg). There was a 72% reduction in the mean PASI score at 4 weeks, and at the end of the study, an 81% reduction. Adjuvant therapy with topical steroids was used in 11 of the 13 patients after the first 3 months of Cys treatment to persistent patches on an intermittent basis with beneficial effect. Six patients developed mild to moderate hypertension, in three this was controlled by a reduction in the dose of Cys, and in the other three by hypotensive agents. The mean serum creatinine rose from 72 to 90 microM/l during the study. Hypertrichosis occurred in seven of the 13 patients. Low dosage Cys is an effective treatment for clearing psoriasis and maintaining improvement on a long-term basis.
Adult↗
Molecular genetic aspects of sex determination in Drosophila melanogaster.
The molecular analyses of three of the regulatory genes (transformer (tra), doublesex (dsx), and transformer-2 (tra-2)) controlling sexual differentiation in Drosophila have demonstrated that the control of RNA processing has a major role in regulating somatic sexual differentiation. The activities of both the tra and dsx genes are controlled at the level of RNA processing. In the case of tra the use of different splice acceptor sites results in a functional transcript being produced only in females, whereas at dsx the use of different splice acceptor sites in the two sexes results in the production of transcripts that encode different proteins in males and females. The tra-2 gene has been shown to be necessary for the processing of the dsx pre-mRNA in females and the conceptual translation of a tra-2 cDNA shows that it encodes a protein with similarity to a family of RNA-binding proteins which includes known splicesome components. We previously suggested that the pattern of sexual differentiation and dosage compensation characteristic of a male was a default regulatory state. The findings reviewed here provide a molecular basis for this default expression in males as well as an insight into how females differ from males in control of the expression of these genes. For both the tra and dsx genes the molecular basis of their male (default) state of expression appears to be the processing of their transcripts by the housekeeping RNA splicing machinery.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Long-term cyclosporin for psoriasis.
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Adult↗
Intralesional cyclosporin in psoriasis.
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Adult↗
Psoriasis and cyclosporin withdrawal.
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Cyclosporins↗