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Biomedical subjects

A Vahlquist

Publications and source records attributed to A Vahlquist.

At least 19 recordsLinked to original sources
PubMed1999

Positive and negative interaction of 1,25-dihydroxyvitamin D3 and the retinoid CD437 in the induction of human melanoma cell apoptosis.

The natural ligands of the nuclear receptors vitamin D receptor (VDR) and retinoic acid receptor (RAR), i.e., 1alpha,25-dihydroxyvitamin D3 (VD) and all-trans retinoic acid, have important effects on the proliferation, differentiation and apoptosis of a variety of malignant cells, including melanoma. The therapeutic potential of the 2 nuclear hormones can be enhanced by the use of synthetic analogues. In this study, the 2 human melanoma cell lines WM1341 and MeWo were compared for the combined effect of VD and synthetic retinoids. Both cell lines expressed reasonable amounts of VDR, RARgamma and retinoid X receptor alpha and differed only in the relative expression of RARalpha and beta. From 9 functional variants of retinoids, only the RARgamma-selective retinoid CD437 showed, in both cell lines, a significant anti-proliferative effect. In MeWo cells, but not in WM1341 cells, VD induced growth arrest but showed no synergistic interaction with the effects of CD437. In contrast, VD induced apoptosis in WM1341, but not in MeWo, cells. CD437 was a strong inducer of apoptosis in both melanoma cell lines. Parallel treatment with CD437 and VD resulted in synergistic enhancement of apoptosis in WM1341 cells, whereas a clear decrease in induction of apoptosis in MeWo cells occurred. Our results indicate that a combined treatment of melanoma with VD and selected retinoids is promising but should be adapted to individual types of tumor.

Antineoplastic Agents↗
PubMed1999

[New trends in immunodermatology and treatment of skin diseases].

Nowhere in the body are inflammatory reactions more apparent than in the skin. The inflammation may be beneficial, as in defence against tumours or infections, or inimical, as in allergy and psoriasis. The skin is a primary immunological organ which presents antigens to T cells, and produces many types of cytokines. The complex interplay between cells and mediators in immunologically induced skin diseases is beginning to be unveiled. Other new developments include improved immunosuppressive therapy and highly specific anti-inflammatory treatment that induces naturally occurring down-regulatory signals.

Anti-Inflammatory Agents↗
PubMed1999

The vitamin A metabolism and expression of retinoid-binding proteins differ in HaCaT cells and normal human keratinocytes.

HaCaT keratinocytes differ from normal human epidermal keratinocytes (HEK) by constitutive expression of differentiation markers which are normally suppressed by vitamin A. In search of an explanation for this discrepancy we compared the vitamin A content, the expression of retinoid-binding proteins, and the vitamin A metabolism in the two cell types. The concentrations of retinol and 3,4-didehydroretinol in cultured HaCaT cells were less than one-fifth those in HEK, and the content of fatty acyl esters was even lower. Similarly, the concentrations of cellular retinol-binding protein and cellular retinoic acid-binding protein (CRBPI and CRABPII, respectively) were 10-30 times lower in HaCaT cells than in HEK corresponding to a reduced mRNA expression of these proteins. Unexpectedly, HaCaT cells expressed RARbeta in addition to RARalpha, RARgamma and RXRalpha, which are nuclear receptors normally found in HEK. Radioactive retinol added to the culture medium appeared only transiently in HaCaT cells, and pulse labeling confirmed a defective cellular retention of retinyl esters. After 24 h of incubation with [3H]retinol, cell-associated radioactivity corresponding to retinol, 3,4-didehydroretinol, all-trans-retinoic acid and 3,4-didehydroretinoic acid was found in both HaCaT cells and HEK. [3H]Retinoic acid showed a more rapid metabolism to 4-hydroxy/4-keto-retinoic acid in HaCaT cells than in HEK, which could be explained by a higher expression of cytochrome p450RAI in the former cells. In conclusion, the abnormal uptake of vitamin A and low levels of retinoid binding proteins in HaCaT cells, linked with an aberrant metabolism of retinol, may help to explain why these cells differentiate also in the presence of retinoids.

Biomarkers↗
PubMed1999

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.

Calcium-Transporting ATPases↗
PubMed1999

Ultraviolet irradiation depletes cellular retinol and alters the metabolism of retinoic acid in cultured human keratinocytes and melanocytes.

Vitamin A is an intrinsic modulator of proliferation and differentiation in human epidermis, and may be destroyed by ultraviolet radiation (UVR) impinging on the skin. To identify the deleterious effects of a perturbed cellular vitamin A status, we investigated the endogenous retinoid concentrations and the metabolism of [3H]retinol and all-trans [3H]retinoic acid in cultured human keratinocytes and melanocytes exposed to UVR, using high performance liquid chromatography. Before UVR the retinoid content was similar in keratinocytes and melanocytes, but the uptake of [3H]retinol was three-fold higher and the uptake of [3H]retinoic acid was 10-fold higher in the melanocytes. In both cell types, UVR (UVA 360 mJ/cm2 plus UVB 140 mJ/cm2) instantaneously reduced the concentration of retinol by about 50% and that of 3,4-didehydroretinol by about 20%. The retinoid concentrations returned to normal within 1-2 days post-irradiation, despite there being no overt increase in the uptake of [3H]retinol or the biosynthesis of 3,4-didehydroretinol. However, in both types of irradiated cells, the accumulation of the biologically most active metabolite, all-trans [3H]retinoic acid, was about 60% higher than in control cells. Furthermore, the metabolism of authentically supplied [3H]retinoic acid was reduced, especially in irradiated keratinocytes, which probably contributed to the restoration of retinoid levels after UV exposure.

Cells, Cultured↗
PubMed1999

What are natural retinoids?

Vitamin A (retinol) is the prototype of all other natural retinoids. It is composed of a nonaromatic ring structure, a polyprenoid side chain and a carbonyl end group. These features make it liable to metabolic interconversion and protein interactions but also cause detergent-like properties and a sensitivity to UV irradiation and oxidation. Natural retinoids are present in all living organisms, either as preformed vitamin A or as carotenoids, and are required for a vast number of biological processes, e.g. vision, cellular growth and differentiation and reproduction. Although retinol is the most omnipotent compound, natural retinoids like all-trans-, 9-cis- and didehydroretinoic acid (RA) are clearly more potent outside the retina and trigger gene expression via binding to nuclear retinoid receptors. Retinaldehyde takes an intermediate position in this respect, with ability to convert to both retinol and RA. Over the years, many natural retinoids have been tried therapeutically against skin disorders with the best effects achieved with retinol, retinaldehyde, 13-cis-RA and all-trans-RA. The latter compound was the prototype when new, synthetic derivatives of vitamin A were sought, hoping for a better therapeutic index and a higher functional specificity. Inevitably, treatment with such drugs will influence the effects of coexisting natural retinoids. An understanding of the basic principles of these interactions may have major impact on patient outcome.

Carotenoids↗
PubMed1998

The pH gradient over the stratum corneum differs in X-linked recessive and autosomal dominant ichthyosis: a clue to the molecular origin of the "acid skin mantle"?

In a search for pathogenetic mechanisms underlying retention hyperkeratosis, we examined the pH gradient over the stratum corneum in 13 male patients suffering from either x-linked recessive (XRI) or autosomal dominant ichthyosis vulgaris. For recording pH values, a flat glass electrode was repeatedly applied to the skin during tape stripping of mildly involved forearm skin. Before stripping, surface pH was higher in ichthyosis vulgaris (5.3 +/- 0.7; n = 7) than in XRI (4.6 +/- 0.4; n = 6; p < 0.05) and healthy control men (4.5 +/- 0.2; n = 7; p < 0.01). Removal of stratum corneum, which required 100-240 strippings in ichthyotic skin and 80-120 strippings in healthy control skin, disclosed markedly different pH variations in the two types of ichthyosis. The major abnormality in ichthyosis vulgaris skin was that a neutral pH was attained already halfway through the horny layer, possibly reflecting a congenital lack of acidic breakdown products from keratohyaline. By contrast, stripping of XRI skin revealed a shallow pH gradient that plateaued at 6.2-6.6, instead of about 7 as in normal and ichthyosis vulgaris skin. A likely explanation is the XRI-associated accumulation of cholesterol sulfate in lower stratum corneum. Our results suggest that the "acid mantle" of normal skin, which penetrates deep into the stratum corneum, is the combined result of cornification-associated organic acids and back-diffusion of acid material from the surface. Because corneocyte desquamation involves many pH-dependent enzymes, abnormalities in the transcorneal pH gradient might play a role in the pathogenesis of ichthyosis.

Epidermis↗
PubMed1998

Potentiating effect of dietary vitamin A on photocarcinogenesis in hairless mice.

Vitamin A and its derivatives (retinoids) exert modulatory effects on epithelial differentiation and are used therapeutically against skin cancers, but the role of dietary vitamin A in ultraviolet (UV)-induced carcinogenesis is far from clear. To study this process, 220 hairless mice were given diets containing low (0.3-0.6 mg/kg; A-) or high (4-6 mg/kg; A+) amounts of retinol, which resulted after 2 months in an approximately 4-fold difference in liver and skin vitamin A levels as determined by HPLC. Commencing after 1 month of diet, daily irradiations with UVB (280-320 nm) or UVAB (280-380 nm) were given to 176 of the animals for 18 weeks (cumulative doses of UVB and UVA: 26 J/cm2 and 168 J/cm2, respectively). The first skin tumours, known to be squamous cell carcinomas, appeared after 35 weeks in the UVAB-irradiated A+ animals and 5-6 weeks later in the other groups. After one year the frequency of tumour-bearing animals was 49-63% in the A+ groups and 28-39% in the A- groups (P = 0.003). Two months later the corresponding figures were 66-72% and 50-53%, respectively (P = 0.014). Disregarding the effect of dietary vitamin A, there was no difference in the final tumour incidence between UVB- and UVAB-irradiated animals. The epidermal vitamin A content at 72 h post-irradiation was approximately 60% lower in A+ animals and approximately 10% lower in A- animals compared with the non-irradiated controls. Rather than protecting against skin cancer, a diet rich in vitamin A seems to facilitate UV carcinogenesis in hairless mice. A possible explanation is that photodecomposition of excessive vitamin A generates short-lived intermediates that may act as photosensitizers during cutaneous carcinogenesis.

Animals↗
PubMed1997

A controlled trial of acupuncture in psoriasis: no convincing effect.

Several uncontrolled studies have suggested that acupuncture is an effective treatment for psoriasis. To test this hypothesis, 56 patients suffering from long-standing plaque psoriasis were randomized to receive either active treatment (electrostimulation by needles placed intramuscularly, plus ear-acupuncture) or placebo (sham, 'minimal acupuncture') twice weekly for 10 weeks. The severity of the skin lesions was scored (PASI) before, during, and 3 months after therapy. After 10 weeks of treatment the PASI mean value had decreased from 9.6 to 8.3 in the 'active' group and from 9.2 to 6.9 in the placebo group (p < 0.05 for both groups). These effects are less than the usual placebo effect of about 30%. There were no statistically significant differences between the outcomes in the two groups during or 3 months after therapy. The patient's own opinion about the results showed no preference for 'active' therapy. It was also clear from the answers that the blinded nature of the study had not been discovered by the patients. In conclusion, classical acupuncture is not superior to sham (placebo) 'minimal acupuncture' in the treatment of psoriasis.

Acupuncture Therapy↗
PubMed1997

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation?

We report a 32-year-old man with an unusual combination of congenital ichthyosis, sclerosing palmoplantar keratoderma with pseudoainhum, and bizarre striate hyperkeratosis in the fixtures, but no systemic involvement. The condition, which improved on oral etretinate therapy, had not appeared previously in the family. On light microscopy the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis. Electron microscopy disclosed numerous large keratohyaline granules in superficial keratinocytes. The clinical picture and histology are virtually identical to those of a Spanish family suffering from an autosomally recessive skin disease of unknown etiology. We hypothesize that the condition is due to a genetic defect in the formation of keratohyaline granules.

Adult↗
PubMed1997

Topical application of a platelet-activating factor (PAF) antagonist in atopic dermatitis.

Platelet-activating factor (PAF acether) is a lipid mediator with a potent proinflammatory activity. Results derived both from in vitro and in vivo studies suggest a possible role of this substance in the pathophysiology of atopic dermatitis. A double-blind, randomized, multi-center, within-patient study was performed to evaluate the efficacy of a topically applied PAF antagonist (RO-24-0238) in 36 patients with atopic dermatitis. Over a period of 28 days, 0.25 ml of the PAF antagonist and the vehicle (placebo) were applied twice daily on opposite sites of symmetrical lesions (measuring 10 to 20 cm2 each). The overall assessment of the therapeutic efficacy did not demonstrate a superior effect of the PAF antagonist in comparison to placebo, and this was the same with the individual study parameters erythema, scaling, induration and exudation. For reducing pruritus, as assessed by the patient using a visual analogue scale, a statistically significant action was documented during the first 2 weeks of the study (p < 0.04; Wilcoxon rank sum test), with a continued, yet not statistically significant efficacy after weeks 3 and 4. The exact role of the pathological events of atopic dermatitis that might be influenced by a PAF antagonist remains to be determined, but the anti-pruritic component of this substance especially deserves further scientific interest.

Administration, Topical↗
PubMed1996

Allelotypes of primary cutaneous melanoma and benign melanocytic nevi.

A multistep genetic model of tumorigenesis, based on genetic alterations in benign and primary malignant lesions, has been proposed for neoplasms such as colonic carcinoma. However, evidence for a similar genetic progression in melanoma has relied heavily on findings in cultured lesions or metastases. We have investigated every autosomal arm for loss of heterozygosity in 41 primary cutaneous melanomas and 32 benign melanocytic nevi, and have investigated several chromosome arms that show loss in melanoma in 27 Spitz nevi (a nevus with histological similarities to melanoma). Loss of heterozygosity in primary melanoma was identified most frequently on chromosomes 9p (46%) at loci near the p16INK4 gene, 10q (31%), 6q (31%), and 18q (22%); loss of these chromosome arms were related to the progression of the melanoma. Only two benign melanocytic nevi (both of which showed atypical features on histology) demonstrated genetic alterations, including p9 loss in one case. In addition, two Spitz nevi contained interstitial deletions on chromosome 9p. Our findings show that loss of heterozygosity of 9p is not confined to melanoma, but that other uncultured melanocytic lesions can also display loss of this chromosome arm, and that other genetic changes (e.g., loss of 10q, 6q, and 18q) may be important in conveying the malignant phenotype to melanoma.

Alleles↗
PubMed1996

Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralen-ultraviolet A irradiation.

OBJECTIVE: To study the use of combined photopheresis and psoralen-ultraviolet A irradiation (PUVA) in the treatment of psoriatic arthritis. METHODS: Eight patients with psoriasis and sero-negative arthritis received photopheresis for 12 weeks, followed by photopheresis plus PUVA for another 12 weeks. Clinical and laboratory examinations were performed every 3 months for up to 1 year after therapy. RESULTS: Four patients experienced a marked improvement of joint symptoms that lasted for > or = 12 months post-therapy (74% decrease in the Ritchie articular index; P < 0.01). Prior to therapy, these patients had a higher CD4:CD8 ratio than the poor responders. Only minor laboratory changes occurred. CONCLUSION: A more extensive trial of photopheresis plus PUVA in psoriatic arthritis is warranted.

Adult↗
PubMed1996

Increased concentrations of 3,4-didehydroretinol and retinoic acid-binding protein (CRABPII) in human squamous cell carcinoma and keratoacanthoma but not in basal cell carcinoma of the skin.

Retinoids are biologic response modifiers that are present in normal skin and may possibly be perturbed in carcinogenesis. To examine this possibility in human skin, we analyzed vitamin A and cytosolic retinoid binding proteins (cellular retinol binding protein and cellular retinoic acid binding protein [CRABP]) in a total of 38 non-melanoma skin tumors and 25 healthy skin samples using high performance liquid chromatography, radioligand electrophoresis, and reverse transcriptase-polymerase chain reaction. The mean +/- SEM retinol concentration was normal in basal cell carcinoma (0.60 +/- 0.10 microM) and seborrheic keratosis (0.47 +/- 0.07 microM), but increased in keratoacanthoma (1.60 +/- 0.41 microM) and squamous cell carcinoma (1.17 +/- 0.28 microM) (p < 0.05 for both). Also, the concentrations of 3,4-didehydroretinol, a major vitamin A metabolite produced in human skin, were markedly elevated (6-7 times normal) in keratoacanthoma and squamous cell cancer. All types of tumors showed moderately increased levels of cellular retinol binding protein. In addition, keratoacanthoma and squamous cell cancer showed markedly increased levels (6-7 times normal) of CRABPII protein. Transcriptional activity of the CRABPII gene was demonstrated in both normal and neoplastic epidermis, but clear CRABPI mRNA expression was found only in basal cell carcinoma. The data indicate that characteristic perturbations of the vitamin A and retinoid binding protein levels occur in squamous cell-derived skin tumors, but whether these reflect intrinsic errors in retinoid metabolism or are secondary to abnormal cellular differentiation is unknown.

Aged↗
PubMed1996

Retinoids can be classified according to their effects on vitamin A metabolism in HeLa cells.

Although retinoids may exert their action via binding to nuclear retinoic acid receptors (RARs), other mechanisms of action are not excluded. For example, the anti-acne drug, isotretinoin, lacks affinity for the receptors, but is a very potent inhibitor of endogenous vitamin A metabolism in human epidermal cells. To further extend this observation, we studied the effect of 12 different retinoids on the metabolism of [3H]retinol ([3H]ROH) in HeLa cells, previously shown to produce constant levels of 3,4-didehydroretinol (ddROH). The cells were cultured in the presence of the unlabeled retiniods for 20 h, followed by 4 h incubation with [3H]ROH. The accumulation of [3H]ROH and [3H]ddROH in cellular extracts was analysed by HPLC. Addition of 10(-10) to 10(-5) M of four naturally occurring isomers of retinoic acid caused a 4- to 6-fold increase in [3H]ROH accumulation and an 80% decrease in [3H]ddROH. Addition of synthetic retinoids with a terminal carboxyl (CD270, CD271, CD367 and Ro 13-7410) decreased the [3H]ddROH accumulation with about 70%, but hardly at all affected the accumulation of [3H]ROH. We conclude that cultured HeLa cells appear to be useful for screening retinoids for their effects on vitamin A metabolism showing that a terminal carboxylic acid is a prerequisite for any major effects on metabolism to occur. Whether this effect is due to interaction with RARs or to competitive inhibition of vitamin-A-metabolizing enzymes demands to be studied.

Cell Survival↗
PubMed1996

Macular posterior pigmentary incontinence: its relation to macular amyloidosis and notalgia paresthetica.

Patients with clinical features of dorsal macular amyloidosis but without subepidermal amyloid deposits were followed for 2-11 years. The clinical appearance was fairly stable during this period of time, with little tendency of healing. Only 2 of the patients developed typical macular amyloidosis during the follow-up. It is concluded that a condition strongly resembling macular amyloidosis but without amyloid is an entity, and the designation "macular posterior pigmentary incontinence" is proposed. The relationship between macular posterior pigmentary incontinence and the two conditions macular amyloidosis and notalgia paresthetica is discussed.

Adult↗