Experimental evidence for the co-evolution of hominin tool-making teaching and language.

Hominin reliance on Oldowan stone tools-which appear from 2.5 mya and are believed to have been socially transmitted-has been hypothesized to have led to the evolution of teaching and language. Here we present an experiment investigating the efficacy of transmission of Oldowan tool-making skills along chains of adult human participants (N=184) using five different transmission mechanisms. Across six measures, transmission improves with teaching, and particularly with language, but not with imitation or emulation. Our results support the hypothesis that hominin reliance on stone tool-making generated selection for teaching and language, and imply that (i) low-fidelity social transmission, such as imitation/emulation, may have contributed to the ~700,000 year stasis of the Oldowan technocomplex, and (ii) teaching or proto-language may have been pre-requisites for the appearance of Acheulean technology. This work supports a gradual evolution of language, with simple symbolic communication preceding behavioural modernity by hundreds of thousands of years.

Constraints on adaptation: explaining deviation from optimal sex ratio using artificial neural networks.

Determining processes constraining adaptation is a major challenge facing evolutionary biology, and sex allocation has proved a useful model system for exploring different constraints. We investigate the evolution of suboptimal sex allocation in a solitary parasitoid wasp system by modelling information acquisition and processing using artificial neural networks (ANNs) evolving according to a genetic algorithm. Theory predicts an instantaneous switch from the production of male to female offspring with increasing host size, whereas data show gradual changes. We found that simple ANNs evolved towards producing sharp switches in sex ratio, but additional biologically reasonable assumptions of costs of synapse maintenance, and simplification of the ANNs, led to more gradual adjustment. Switch sharpness was robust to uncertainty in fitness consequences of host size, challenging interpretations of previous empirical findings. Our results also question some intuitive hypotheses concerning the evolution of threshold traits and confirm how neural processing may constrain adaptive behaviour.

Chronic actinic dermatitis treated with mycophenolate mofetil.

Chronic actinic dermatitis (CAD) is a persistent photodermatosis that usually affects elderly men. We report two male patients, aged 55 years (patient A) and 49 years (patient B), who presented with an eczematous eruption on sun-exposed skin. Phototesting revealed a markedly reduced 24-h minimal erythema dose (MED). Both patients had refractory disease and developed significant side-effects to conventional therapies, including topical steroids, prednisolone, psoralen with ultraviolet A, azathioprine and ciclosporin. They had each received at least 6 years of treatment prior to commencing mycophenolate mofetil (MMF). Each noted a significant improvement in symptoms within 6 weeks and subsequent clearing of the eczematous lesions. Patient A still requires continuous treatment with MMF 500 mg twice daily to prevent relapses. Patient B maintains remission by using MMF 1 g twice daily only during the spring and summer months. Both patients have tolerated the treatment well with no abnormalities in blood cell counts or liver biochemistry. Since commencing MMF, their quality of life has significantly improved. These observations suggests that MMF should be considered as an alternative treatment to conventional therapies for refractory CAD.

Treatment of erosive oral lichen planus with topical tacrolimus.

BACKGROUND: Erosive oral lichen planus (LP) is a painful chronic inflammatory condition that is frequently resistant to immunosuppressive agents. Topical tacrolimus has been reported as a safe and effective treatment. OBJECTIVE: To evaluate the efficacy and safety of topical tacrolimus in the treatment of symptomatic erosive oral LP. METHODS: A retrospective review of consecutive patients with oral LP treated with topical tacrolimus between June 1999 and November 2003 was performed. Clinical improvement and adverse events were recorded by the physician. Patients were asked retrospectively to rate their symptoms immediately prior to and after tacrolimus therapy using a visual analogue scale. RESULTS: Physician-observed clinical improvement was found in 21 of 23 patients (91.3%) within 6 weeks. Six patients (26.1%) remained asymptomatic after stopping treatment and 15 patients (65.2%) required maintenance therapy to prevent subsequent flares. Patients' self-reported symptom scores were significantly better (p<0.001) with tacrolimus treatment, which supported physician-observed clinical improvement. There was no evidence of systemic absorption and only minor local side effects were noted. CONCLUSIONS: Topical tacrolimus is an effective treatment for erosive oral LP. The majority of patients require long-term therapy to maintain remission.

Linear IgA disease in a patient with Castleman's disease.

Linear IgA disease (LAD) is a well recognized subepidermal blistering disorder characterized by linear deposits of IgA at the basement membrane zone. The aetiology is unknown but there is a recognized association with lymphoproliferative malignancies. We report a case of LAD occurring in a patient with multicentric Castleman's disease (angiofollicular lymph node hyperplasia), an association not previously recorded in the literature.

ADHII in Aspergillus nidulans is induced by carbon starvation stress.

In Aspergillus nidulans there are three NAD(+)-dependent alcohol dehydrogenases (ADHs) that are capable of utilizing ethanol as a substrate. ADHI is the physiological enzyme of ethanol catabolism and ADHIII is induced under conditions of anaerobiosis. The physiological role of ADHII (structural gene alcB) is unknown. We have measured beta-galactosidase in a transformant with an alcB::lacZ fusion and have shown that alcB is maximally expressed under conditions of carbon starvation. The behavior of the alcB::lacZ transformant suggests a hierarchy of repressing carbon sources characteristic of repression by the general carbon catabolite repressor protein, CreA, but in a creA(d)30 background the transformant shows only partial derepression of beta-galactosidase on 1% glucose compared to the creA+ strain. Our results suggest that, in addition to carbon catabolite repression acting via CreA, a CreA-independent mechanism is involved in induction of alcB on carbon starvation.

The Aspergillus niger acuA and acuB genes correspond to the facA and facB genes in Aspergillus nidulans.

Mutants in Aspergillus niger unable to grow on acetate as a sole carbon source were previously isolated by resistance to 1.2% propionate medium containing 0.1% glucose. AcuA mutants lacked acetyl-CoA synthetase (ACS) activity and acuB mutants lacked both ACS and isocitrate lyase activity. An acuA mutant was transformed to the acu+ phenotype with a clone of ACS (facA) from Aspergillus nidulans. The acuB mutant was transformed with the A. niger facB clone which has been identified by cross-hybridisation of an A. nidulans facB clone. These results confirm that acuA in A. niger is the gene for ACS and acuB is analogous to the A. nidulans facB regulatory gene.

ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class.

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

1,25-dihydroxyvitamin D3 regulates estrogen metabolism in cultured keratinocytes.

Local estrogen metabolism may play an important role in modulating cell development in peripheral tissues such as breast, adipose, and bone. C19 androgens are converted to C18 estrogens by the enzyme aromatase, overexpression of which is associated with breast cancer. Interconversion of active estradiol (E2) to inactive estrone is controlled by various isoforms of the enzyme 17beta-hydroxysteroid dehydrogenase (17betaHSD). We have studied the expression of these two enzymes in human keratinocytes and report rapid changes in 17betaHSD activity in response to treatment with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Keratinocytes cultured in serum-free medium showed aromatase activity of 2.5 fmol/h x mg cell protein, which was unaffected by any culture treatment. A much higher level of 17betaHSD activity was observed in the keratinocytes, predominantly conversion of E2 to estrone (approximately 120 pmol/h x mg cell protein). This inactivation of E2 increased in a dose-dependent fashion after treatment of the cells with antiproliferative doses of 1,25-(OH)2D3 (0.1-200 nM). The effect of 1,25-(OH)2D3 on 17betaHSD activity was enhanced by simultaneous treatment with dexamethasone, which also increased the antiproliferative action of 1,25-(OH)2D3. Reverse transcription-PCR and Northern analysis showed that keratinocytes expressed messenger RNA for three 17betaHSD isoenzymes (types I, II, and IV). Treatment with 1,25-(OH)2D3 (10 nM for 20 h) resulted in the up-regulation of messenger RNA levels for type 2 17betaHSD. Further RNA studies combined with E2 binding experiments demonstrated the presence of estrogen receptors in the cultured keratinocytes. These data indicate that keratinocytes are potential targets for systemically or locally produced estrogens, which may, in turn, play a key role in the development of normal skin. In particular, we propose that 17betaHSD isoenzymes are key target genes for 1,25-(OH)2D3 in keratinocytes and may be an important feature of the antipsoriatic effects of vitamin D and its analogs.

Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.

A retrospective study of 487 patients with dermatitis herpetiformis showed that lymphoma developed in eight patients, the expected incidence being 0.21 (standardized registration ratio 3810). All lymphomas occurred in patients whose dermatitis herpetiformis had been controlled without a gluten-free diet (GFD) or in those who had been treated with a GFD for less than 5 years. The results are suggestive of a protective role for a GFD against lymphoma in dermatitis herpetiformis and give further support for advising patients to adhere to a strict GFD for life.

Vitamin D analogues and psoriasis.

Over recent years there has been increasing interest in the effects of vitamin D3 and its analogues upon the skin, with particular relevance to the treatment of psoriasis. As well as offering an alternative therapeutic option, research into the mode of action of vitamin D3 upon the psoriatic lesion has provided insight into the pathogenesis of psoriasis. This article reviews the effects of vitamin D3 and its analogues upon normal skin and on psoriasis.

The cloning and sequencing of the alcB gene, coding for alcohol dehydrogenase II, in Aspergillus nidulans.

Alcohol dehydrogenase II (ADH II, structural gene alcB) was purified from a strain H1035, biA1; alcE1; alc500 alcD1, which produces 100-times more ADH II activity than the alcAalcR deletion strain (alc500). Antibodies were raised against this ADH, and were used to screen a cDNA library in lambda gt11. We have isolated the gene for an ADH which is over-expressed in H1035, and which we believe to be the alcB gene: cDNA and genomic clones were sequenced. The sequence contains three introns and encodes a protein of 367 amino acids. This protein shows a clear level of identity to a range of alcohol dehydrogenases, but is no more closely related to the ADH I and ADH III previously described in A. nidulans than to the ADHs of S. pombe and S. cerevisiae. The significance of consensus sequences found in the 5' region of the gene is discussed in relation to the regulation of the gene.

Urticaria pigmentosa and acute lymphoblastic leukaemia.

Childhood urticaria pigmentosa is generally considered to have a good prognosis with the majority of cases undergoing spontaneous resolution. However, there have been a number of reports of haematological malignancies occurring in association with urticaria pigmentosa. We describe a child with extensive urticaria pigmentosa and a congenital cardiac anomaly who developed acute lymphoblastic leukaemia and suggest a possible common aetiology.

Substrate specificity of nine NAD(+)-dependent alcohol dehydrogenases in Aspergillus nidulans.

In Aspergillus nidulans three alcohol dehydrogenases (ADHs) have been described. ADHI is induced by ethanol and is the physiological enzyme of ethanol utilization, ADHII has not been attributed a function but is repressed by ethanol. The ALCR regulatory protein acts positively to induce ADHI, and negatively in its control of ADHII. ADHIII is specifically induced by anaerobic stress. We have characterized the substrate specificity of these three enzymes by looking at their staining profile on polyacrylamide gels with a range of alcohols. In addition to these enzymes we have observed six other NAD(+)-dependent ADHs, two of which, propan-2-ol dehydrogenase and pentan-2-ol dehydrogenase, share similar control with ADHII. The inducibility of these enzymes with some alcohols has also been investigated. The profile of ADHs with NADP+ as an electron acceptor is also reported.

25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis.

Gluten-free diets have been used in the treatment of patients with dermatitis herpetiformis in our department since 1967. Of the 212 patients with dermatitis herpetiformis attending between 1967 and 1992, 133 managed to take the diet, and 78 of these achieved complete control of their rash by diet alone. Of the remaining 55 patients taking a gluten-free diet, all but three were taking partial diets; over half of these patients managed to substantially reduce the dose of medication required. Of the 77 patients taking a normal diet, eight entered spontaneous remission, giving a remission rate of 10%; a further two patients who had been taking gluten-free diets were found to have remitted when they resumed normal diets. Loss of IgA from the skin was observed in 10 of 41 (24%) patients taking strict gluten-free diets. These patients had been taking their diets for an average of 13 years (range 5-24 years), and their rash had been controlled by diet alone for an average of 10 years (range 3-16 years). The advantages of a gluten-free diet in the management of patients with dermatitis herpetiformis are: (i) the need for medication is reduced or abolished; (ii) there is resolution of the enteropathy, and (iii) patients experience a feeling of well-being after commencing the diet. Thus, we propose that a gluten-free diet is the most appropriate treatment for patients with dermatitis herpetiformis.

Therapeutic progress. II: Treatment of psoriasis.

Treatment of psoriasis is rapidly changing with improved understanding of the pathogenesis of the disease. Newer topical preparations such as calcipotriol and immunosuppressive agents such as cyclosporin A and FK506 are having a major impact on the therapy of psoriasis. This article reviews the conventional therapies and newer agents used in the treatment of this common dermatosis.