Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined. OBJECTIVES: To examine the treatment utilization patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR). METHODS: The study cohort included adults with chronic plaque psoriasis who were followed up for ≥ 12 months. Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received with the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined. RESULTS: In total, 2980 patients (adalimumab: 1675; etanercept: 996; ustekinumab: 309) were included; 79·2% were biologic-naïve. Over 12 months, 77·4% of patients continued the biologic, 2·6% restarted therapy after a break of ≥ 90 days, 2·5% discontinued, and 17·5% switched biologic therapy. Most patients (85·7%) received the RCD of the biologic, although 8·1% were exposed to a higher CD. In total, 749 (25·1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458; 61·2%). Of those using combination therapy, 454 (60·6%) continued the use of the conventional systemic therapy for > 120 days after the start of the biologic. CONCLUSIONS: More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently, which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies.

Identification of aster yellows phytoplasma in garlic and green onion by PCR-based methods.

In the summer of 1999, typical yellows-type symptoms were observed on garlic and green onion plants in a number of gardens and plots around Edmonton, Alberta, Canada. DNA was extracted from leaf tissues of evidently healthy and infected plants. DNA amplifications were conducted on these samples, using two primer pairs, R16F2n/R2 and R16(1)F1/R1, derived from phytoplasma rDNA sequences. DNA samples of aster yellows (AY), lime witches'-broom (LWB) and potato witches'-broom (PWB) phytoplasmas served as controls and were used to determine group relatedness. In a direct polymerase chain reaction (PCR) assay, DNA amplification with universal primer pair R16F2n/R2 gave the expected amplified products of 1.2 kb. Dilution (1/40) of each of the latter products were used as template and nested with specific primer pair R16(1)F1/R1. An expected PCR product of 1.1 kb was obtained from each phytoplasma-infected garlic and green onion samples, LWB and AY phytoplasmas but not from PWB phytoplasma. An aliquot from each amplification product (1.2 kb) with universal primers was subjected to PCR-based restriction fragment length polymorphism (RFLP) to identify phytoplasma isolates, using four restriction endonucleases (AluI, KpnI, MseI and RsaI). DNA amplification with specific primer pair R16(1)F1/R1 and RFLP analysis indicated the presence of AY phytoplasma in the infected garlic and green onion samples. These results suggest that AY phytoplasma in garlic and green onion samples belong to the subgroup 16Sr1-A.

A novel family of small cysteine-rich antimicrobial peptides from seed of Impatiens balsamina is derived from a single precursor protein.

Four closely related peptides were isolated from seed of Impatiens balsamina and were shown to be inhibitory to the growth of a range of fungi and bacteria, while not being cytotoxic to cultured human cells. The peptides, designated Ib-AMP1, Ib-AMP2, Ib-AMP3, and Ib-AMP4, are 20 amino acids long and are the smallest plant-derived antimicrobial peptides isolated to date. The Ib-AMPs (I. balsamina antimicrobial peptides) are highly basic and contain four cysteine residues which form two intramolecular disulfide bonds. Searches of protein data bases have failed to identify any proteins with significant homology to the peptides described here. Characterization of isolated cDNAs reveals that all four peptides are encoded within a single transcript. The predicted Ib-AMP precursor protein consists of a prepeptide followed by 6 mature peptide domains, each flanked by propeptide domains ranging from 16 to 35 amino acids in length. Such a primary structure with repeated alternating basic mature peptide domains and acidic propeptide domains has, to date, not been reported in plants.

Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase.

Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.

A homologue of the 65 kDa regulatory subunit of protein phosphatase 2A in early pea (Pisum sativum L.) embryos.

A partial cDNA, isolated from an early developing pea (Pisum sativum L.) embryo library, was found to encode a plant homologue of the regulatory subunit (PR65) of protein phosphatase 2A (PP2A). Comparison of the deduced amino acid sequence with a human PR65 sequence showed that the regulatory subunit of PP2A has been highly conserved during evolution. Southern analysis demonstrated that in pea and rape the catalytic and regulatory subunits of PP2A are encoded by multigene families. The levels of the transcripts encoding each subunit are developmentally regulated during pea embryogenesis and expression of the regulatory subunit is not solely restricted to the embryo.

A gene from pea (Pisum sativum L.) with homology to metallothionein genes.

While searching for 'organ-specific' genes in pea (Pisum sativum L.) we have isolated a gene (designated PsMTA) which has an ORF encoding a predicted protein with some similarity to metallothioneins (MTs). The PsMTA transcript is abundant in roots which have not been exposed to elevated concentrations of trace metals.

Identification of nodX, a gene that allows Rhizobium leguminosarum biovar viciae strain TOM to nodulate Afghanistan peas.

Gene(s) conferring the ability of Rhizobium leguminosarum biovar viciae strain TOM to nodulate primitive peas (cultivar Afghanistan) had been located in a 2.0 kb region of its sym plasmid, pRL5JI. In this DNA, a single open reading frame of 1101 bp, corresponding to a gene, nodX was found. nodX is downstream of nodJ which is present in strain TOM and also in the sym plasmid of a typical strain of this biovar. nodX specifies a hydrophobic protein (of Mr 41,036) with no clear similarity to other proteins in data bases. Mutations in nodX abolished nodulation of Afghanistan peas but not nodulation of commercial peas. nodX-lacZ fusions were used to show that transcription of nodX was activated by root exudates from both commercial and Afghanistan peas and by defined flavonoids. Exudate from Afghanistan peas activated nod genes of typical strains of R. leguminosarum biovar viciae which fail to nodulate these peas; thus, their failure to nodulate these primitive peas is not due to a lack of activation of their nod genes by exudate from Afghanistan peas. A homologue of nodX exists in R. leguminosarum biovar trifolii (which nodulates clover) but not in typical strains of R. leguminosarum biovar viciae.

Regulation of storage-protein synthesis in pea (Pisum sativum L.) cotyledons under conditions of sulphur deficiency.

The effects of sulphur deficiency on the expression of storage-protein genes in developing pea (Pisum sativum) cotyledons were studied. Legumin-gene transcription was decreased by S-deficiency, but not to the same extent as the decrease in the level of legumin mRNA. Vicilin-gene transcription was not significantly affected. Control of gene expression may thus occur during transcription and/or post-transcriptional events.

Phenylthioalkylamines in experimental tumor treatment in mice.

Two phenylthioalkylamines, phenylthioethylamine (PTEA) and phenylthiopropylamine (PTPA), were prepared and tested for cytotoxicity in vitro and as antitumor agents in (C57BL X DBA/2)F1 (BDF1) mice. Low concentrations of PTEA (median effective concentrations of 8.0, 12.0, and 1.3 micrograms PTEA/ml) inhibited the growth of P388 murine lymphoma, L1210 leukemia, and B16 melanoma cells in culture. PTPA was more effective; concentrations of 0.80, 0.56, and 0.35 micrograms PTPA/ml inhibited the growth of P388, L1210, and B16 in vitro by 50%. PTEA and PTPA treatment increased survival times in BDF1 mice bearing the P388 lymphoma, L1210 leukemia, B16 melanoma, and Lewis lung tumors. Multiple daily administrations of the test compounds were more effective than single daily injections in increasing the life-span in mice bearing the P388 lymphoma and B16 melanoma. Both PTEA and PTPA inhibited the enzyme copper-zinc superoxide dismutase.

Control of storage-protein synthesis during seed development in pea (Pisum sativum L.).

The tissue-specific syntheses of seed storage proteins in the cotyledons of developing pea (Pisum sativum L.) seeds have been demonstrated by estimates of their qualitative and quantitative accumulation by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and rocket immunoelectrophoresis respectively. Vicilin-fraction proteins initially accumulated faster than legumin, but whereas legumin was accumulated throughout development, different components of the vicilin fraction had their predominant periods of synthesis at different stages of development. The translation products in vitro of polysomes isolated from cotyledons at different stages of development reflected the synthesis in vivo of storage-protein polypeptides at corresponding times. The levels of storage-protein mRNA species during development were estimated by 'Northern' hybridization using cloned complementary-DNA probes. This technique showed that the levels of legumin and vicilin (47000-Mr precursors) mRNA species increased and decreased in agreement with estimated rates of synthesis of the respective polypeptides. The relative amounts of these messages, estimated by kinetic hybridization were also consistent. Legumin mRNA was present in leaf poly(A)+ RNA at less than one-thousandth of the level in cotyledon poly(A)+ (polyadenylated) RNA, demonstrating tissue-specific expression. Evidence is presented that storage-protein mRNA species are relatively long-lived, and it is suggested that storage-protein synthesis is regulated primarily at the transcriptional level.

Bracken carcinogenicity.

The study of bracken carcinogenicity affords an interesting example of the close alliance, with mutual benefit, between the work of veterinarians in the field and experimental research. On the one hand was the condition found in many parts of the world of bovine enzootic haematuria with uncertain aetiology and, on the other, the investigations conducted on the acute radiomimetic cattle bracken poisoning under laboratory conditions. The two have led to the recognition of the long term cancer dangers of bracken consumption and the vulnerability of a wide variety of species of animals. In these the types of tumour vary to include many organs other than the bladder, such as the gastrointestinal tract and blood forming tissues. Work on the search for the chemical compounds involved is described, together with the possible hazards, both mutagenic and carcinogenic, on an environmental basis.