that GPs find it difficult to recognize skin cancer and prioritize referrals. Limited urgent capacity is filled with routine referrals at the expense of delaying detection of skin cancer from nonurgent referrals. Dermatologists must therefore pay particular attention to nonurgent referrals to ensure that these referrals are assigned equal priority.In summary, skin cancers are referred urgently and nonurgently by GPs. The urgency assigned to the referral influences the waiting time. Administrative streamlining helps to meet the 2-week target for urgent referrals but further resources are needed so that nonurgent referrals can be seen more quickly. SIR, Granuloma faciale (eosinophilicum) is a rare granulomatous inflammation of the skin usually presenting as infiltrated multiloculated reddish nodes of the face, although there have been several reports of similar lesions in extrafacial localizations. 1-3 The aetiopathogenesis of this condition is not clear, and several hypotheses including cutaneous vasculitis have been proposed. 4 A histological hallmark of the disease is the infiltration of numerous eosinophilic granulocytes together with macrophages and lymphocytes in a typical granulomatous pattern. 5 We have analysed the cellular infiltrate and cytokine production in two patients presenting with granuloma faciale (eosinophilicum).Patient 1 was a 44-year-old white man who described slowly progressive dark red papules and plaques arising at the cheeks and ear lobes for at least 10 years (Fig. 1A). He had undergone several treatments including local steroid injections, cryosurgery and dapsone before being transferred to our department. After informed consent was obtained, a biopsy was taken from an untreated newly developing lesion at his left ear lobe.Patient 2 was a 67-year-old white woman who presented with a 5-year history of continuously growing firm red plaques at both cheeks and the forehead. The skin lesions were painless and had inconstantly increased in size. At initial presentation we saw multiple painless red nodules of 1-2 cm diameter with a tender consistency located at the forehead and both cheeks (Fig. 1E). After informed consent was obtained, two biopsies were taken from different skin lesions and were split for (immuno)histology and molecular biology.Routine haematoxylin and eosin staining in both patients showed subcutaneous granuloma formation with multinucleated giant cells surrounded by lymphocytes and a prominent infiltration of granulocytes among which eosinophils clearly dominated (Fig. 1B,F). The histological picture and the clinical appearance were consistent with facial granuloma.Immunohistochemistry showed a dominant recruitment of CD4+ T cells among the infiltrating lymphocytes (Fig. 1C,G) and only a weak staining for CD8 (data not shown), a result which confirmed previous investigations 6 (all antibodies from Dako, Hamburg, Germany).We next searched for an explanation for the parallel infiltration of CD4+ T cells and the infiltration of numerous eosinophils into the skin. A major cyto...
Enzymes group naturally into families according to similarity of sequence, structure, and underlying mechanism. Enzymes belonging to the same family are considered to be homologs-the products of evolutionary divergence, whereby the first family member provided a starting point for conversions to new but related functions. In fact, despite their similarities, these families can include remarkable functional diversity. Here we focus not on minor functional variations within families, but rather on innovations-transitions to genuinely new catalytic functions. Prior experimental attempts to reproduce such transitions have typically found that many mutational changes are needed to achieve even weak functional conversion, which raises the question of their evolutionary feasibility. To further investigate this, we examined the members of a large enzyme superfamily, the PLP-dependent transferases, to find a pair with distinct reaction chemistries and high structural similarity. We then set out to convert one of these enzymes, 2-amino-3-ketobutyrate CoA ligase (Kbl2), to perform the metabolic function of the other, 8-amino-7-oxononanoate synthase (BioF2). After identifying and testing 29 amino-acid changes, we found three groups of active-site positions and one single position where Kbl2 side chains are incompatible with BioF2 function. Converting these side chains in Kbl2 makes the residues in the active-site cavity identical to those of BioF2, but nonetheless fails to produce detectable BioF2-like function in vivo. We infer from the mutants examined that successful functional conversion would in this case require seven or more nucleotide substitutions. But evolutionary innovations requiring that many changes would be extraordinarily rare, becoming probable only on timescales much longer than the age of life on earth. Considering that Kbl2 and BioF2 are judged to be close homologs by the usual similarity measures, this result and others like it challenge the conventional practice of inferring from similarity alone that transitions to new functions occurred by Darwinian evolution.
New functions requiring multiple mutations are thought to be evolutionarily feasible if they can be achieved by means of adaptive paths-successions of simple adaptations each involving a single mutation. The presence or absence of these adaptive paths to new function therefore constrains what can evolve. But since emerging functions may require costly over-expression to improve fitness, it is also possible for reductive (i.e., cost-cutting) mutations that eliminate over-expression to be adaptive. Consequently, the relative abundance of these kinds of adaptive pathsconstructive paths leading to new function versus reductive paths that increase metabolic efficiency-is an important evolutionary constraint. To study the impact of this constraint, we observed the paths actually taken during longterm laboratory evolution of an Escherichia coli strain carrying a doubly mutated trpA gene. The presence of these two mutations prevents tryptophan biosynthesis. One of the mutations is partially inactivating, while the other is fully inactivating, thus permitting a two-step adaptive path to full tryptophan biosynthesis. Despite the theoretical existence of this short adaptive path to high fitness, multiple independent lines grown in tryptophan-limiting liquid culture failed to take it. Instead, cells consistently acquired mutations that reduced expression of the double-mutant trpA gene. Our results show that competition between reductive and constructive paths may significantly decrease the likelihood that a particular constructive path will be taken. This finding has particular significance for models of gene recruitment, since weak new functions are likely to require costly over-expression in order to improve fitness. If reductive, cost-cutting mutations are more abundant than mutations that convert or improve function, recruitment may be unlikely even in cases where a short adaptive path to a new function exists.
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