Longitudinal, lateral, vertical and temporal thermal heterogeneity in a large impounded river: implications for cold-water refuges.

Dam operations can affect mixing of the water column thereby influencing thermal heterogeneity spatially and temporally. This occurs by restricting or eliminating connectivity in longitudinal, lateral, vertical and temporal dimensions. We examined thermal heterogeneity across space and time and identified potential cold-water refuges for salmonids in a large impounded river in inland northwestern USA. To describe these patterns, we used thermal infrared (TIR) imagery, in situ thermographs, and high-resolution 3-D hydraulic mapping. We explained the median water temperature and probability of occurrence of cool-water areas using generalized additive models (GAMs) at reach and sub-catchment scales, and we evaluated potential cold-water refuge occurrence in relation to these patterns. We demonstrated that (1) lateral contributions from tributaries dominated thermal heterogeneity; (2) thermal variability at confluences was approximately an order of magnitude greater than of the main stem; (3) potential cold-water refuges were mostly found at confluences; and (4) the probability of occurrence of cool areas and median water temperature were associated with channel geomorphology and distance from dam. These findings highlight the importance of using multiple approaches to describe thermal heterogeneity in large impounded rivers and the need to incorporate these types of rivers in the understanding of thermal riverscapes because of their limited representation in the literature.

Elevation and spatial structure explain most surface-water isotopic variation across five Pacific Coast basins.

The stable isotope ratios of stream water can be used to trace water sources within river basins; however, drivers of variation in water isotopic spatial patterns across basins must be understood before ecologically relevant and isotopically distinct water sources can be identified and this tool efficiently applied. We measured the isotope ratios of surface-water samples collected during summer low-flow across five basins in Washington and southeast Alaska (Snoqualmie, Green, Skagit, and Wenatchee Rivers, and Cowee Creek) and compared models (isoscapes) describing the spatial variation in surface-water isotope ratios across a range of hydraulic and climatic conditions. We found strong correlations between mean watershed (MWE) elevation and surface-water isotopic ratios on the windward west side of the Cascades and in Alaska, explaining 48-90% of variation in δ18O values. Conversely, in the Wenatchee basin, located leeward of the Cascade Range, MWE alone had no predicative power. The elevation relationship and predictive isoscapes varied between basins, even those adjacent to each other. Applying spatial stream network models (SSNMs) to the Snoqualmie and Wenatchee Rivers, we found incorporating Euclidean and flow-connected spatial autocovariance improved explanatory power. SSNMs improved the accuracy of river water isoscapes in all cases; however, their utility was greater for the Wenatchee basin, where covariates explained only a small proportion of total variation. Our study provides insights into why basinscale surface-water isoscapes may vary even in adjacent basins and the importance of incorporating spatial autocorrelation in isoscapes. For determining source water contributions to downstream waters, our results indicate that surface water isoscapes should be developed for each basin of interest.

An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine.

PURPOSE: Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. METHODS: The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. RESULTS: 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. CONCLUSIONS: Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics.

BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

Longitudinal thermal heterogeneity in rivers and refugia for coldwater species: effects of scale and climate change.

Climate-change driven increases in water temperature pose challenges for aquatic organisms. Predictions of impacts typically do not account for fine-grained spatiotemporal thermal patterns in rivers. Patches of cooler water could serve as refuges for anadromous species like salmon that migrate during summer. We used high-resolution remotely sensed water temperature data to characterize summer thermal heterogeneity patterns for 11,308 km of 2nd- to 7th-order rivers throughout the Pacific Northwest and northern California (USA). We evaluated (1) water temperature patterns at different spatial resolutions, (2) the frequency, size, and spacing of cool thermal patches suitable for Pacific salmon (i.e., contiguous stretches ≥0.25 km, ≤15°C and ≥2°C cooler than adjacent water), and (3) potential influences of climate change on availability of cool patches. Thermal heterogeneity was nonlinearly related to the spatial resolution of water temperature data, and heterogeneity at fine resolution (<1 km) would have been difficult to quantify without spatially continuous data. Cool patches were generally >2.7 and <13.0 km long, and spacing among patches was generally >5.7 and <49.4 km. Thermal heterogeneity varied among rivers, some of which had long uninterrupted stretches of warm water ≥20°C, and others had many smaller cool patches. Our models predicted little change in future thermal heterogeneity among rivers, but within-river patterns sometimes changed markedly compared to contemporary patterns. These results can inform long-term monitoring programs as well as near-term climate-adaptation strategies.

Setting spatial conservation priorities despite incomplete data for characterizing metapopulations.

Management of spatially structured species poses unique challenges. Despite a strong theoretical foundation, practitioners rarely have sufficient empirical data to evaluate how populations interact. Rather, assumptions about connectivity and source-sink dynamics are often based on incomplete, extrapolated, or modeled data, if such interactions are even considered at all. Therefore, it has been difficult to evaluate whether spatially structured species are meeting conservation goals. We evaluated how estimated metapopulation structure responded to estimates of population sizes and dispersal probabilities and to the set of populations included. We then compared outcomes of alternative management strategies that target conservation of metapopulation processes. We illustrated these concepts for Chinook salmon (Oncorhynchus tshawytscha) in the Snake River, USA. Our description of spatial structure for this metapopulation was consistent with previous characterizations. We found substantial differences in estimated metapopulation structure when we had incomplete information about all populations and when we used different sources of data (three empirical, two modeled) to estimate dispersal, whereas responses to population size estimates were more consistent. Together, these findings suggest that monitoring efforts should target all populations occasionally and populations that play key roles frequently and that multiple types of data should be collected when feasible. When empirical data are incomplete or of uneven quality, analyses using estimates produced from an ensemble of available datasets can help conservation planners and managers weigh near-term options. Doing so, we found trade-offs in connectivity and source dominance in metapopulation-level responses to alternative management strategies that suggest which types of approaches may be inherently less risky.

Putting watershed restoration in context: alternative future scenarios influence management outcomes.

Predicting effects of habitat restoration is an important step for recovery of imperiled anadromous salmonid populations. Habitat above three major hydropower dams in the Lewis River watershed, southwestern Washington, USA, will soon become accessible to anadromous fish. We used multiple models to estimate habitat conditions above dams and fish population responses. Additionally, we used scenario planning to predict how habitat and fish will respond to potential future trends in land use due to human population growth and riparian conservation policies. Finally, we developed a hypothetical management strategy (i.e., a set of prioritized restoration projects in specific locations within the watershed) as an example of how a fixed amount of restoration funds might be spent to enhance the success of reintroducing fish above dams. We then compared predicted outcomes from this new strategy to those of six previously modeled strategies. We estimated how the choice of the best management strategy might differ among alternative future scenarios. Results suggest that dam passage will provide access to large amounts of high-quality habitat that will benefit fish populations. Moreover, conservation of existing riparian areas, if implemented, has the potential to improve conditions to a much greater extent than restoration strategies examined, despite expected urban growth. We found that the relative performance of management strategies shifted when fish were allowed to migrate above dams, but less so among alternative futures examined. We discuss how predicted outcomes from these seven hypothetical management strategies could be used for developing an on-the-ground strategy to address a real management situation.

Development of an in vitro skin permeation model simulating atopic dermatitis skin for the evaluation of dermatological products.

Atopic dermatitis (AD) skin has a defective barrier function as indicated by increased transepidermal water loss (TEWL). In order to test potential new formulations for AD, it was our aim to develop a skin permeation model simulating AD skin by inducing barrier impairment to otherwise healthy skin simulating the barrier properties of AD skin as evaluated by TEWL measurements. Pig ear skin was mounted to Franz-type diffusion cells. Skin barrier impairment was induced by tape strippings. As the number of strips increased, higher TEWL values were obtained. By performing 25 tape strippings, the TEWL value within the range reported for involved skin of AD patients was reached. The in vitro skin permeation of fusidic acid and betamethasone-17-valerate was found to correlate with the number of tape strippings used to remove stratum corneum cell layers. A comparison of the permeability of fusidic acid and betamethasone-17-valerate from Fucicort cream to a new Fucicort Lipid formulation was studied with intact (0 strippings) and barrier-impaired skin simulating involved AD skin (25 strippings). As opposed to intact skin, no statistically significant difference through barrier-impaired skin was found for fusidic acid and betamethasone-17-valerate for the two formulations. This is in accordance with the clinical results of an international multicentre study and thus confirms the predictability of the model.

The hairless guinea-pig as a model for treatment of acute irritation in humans.

BACKGROUND: The effect of six skin care formulations on experimentally induced acute irritation was studied in hairless guinea-pigs (HLGP) and in human volunteers (HV). The formulations were a basic cream, a carbomer cream and four modifications of the carbomer cream, containing either 10% isopropyl palmitate (IPP cream), 10% glycerol (glycerol cream), 19.5% canola oil (canola oil cream) or 0.5% (-)-alpha-bisabolol (bisabolol cream). METHODS: Acute irritation was induced by occlusive tests with 1% sodium lauryl sulfate aq. in both HLGP and HV, and in HV also by using nonanoic acid in n-propanol (NON) 20%. The irritant reactions were treated twice daily with the formulations from the time of removal of the patches. Evaluation of skin irritation and efficacy of treatments was performed daily for 4 days using clinical scoring, evaporimetry (transepidermal water loss), hydration measurement and colorimetry. RESULTS: The glycerol cream was the only product showing effects potentially better than no treatment in HV. CONCLUSION: The HLGP was too sensitive an animal model as a predictor for effect in humans. There was no difference in efficacy of the formulations against the two different irritants in HV.

The hairless guinea-pig as a model for treatment of cumulative irritation in humans.

BACKGROUND: The effect of six skin-care formulations (SCFs) on experimentally induced cumulative irritation was studied in hairless guinea-pigs (HLGPs) and in human volunteers (HVs). The formulations were a basic cream, a carbomer cream and four modifications of the carbomer cream, containing either 10% isopropyl palmitate (IPP cream), 10% glycerol (glycerol cream), 19.5% canola oil (canola oil cream) or 0.5% (-)-alpha-bisabolol (bisabolol cream). METHODS: In HLGP, irritant dermatitis was induced with 30 min daily exposure for 4 days to 0.5% sodium lauryl sulfate aq. (SLS). In HVs, irritant dermatitis was induced with 10 min daily exposure for 5+4 days (no irritation on weekends) to 3% SLS aq. on the right and 30% nonanoic acid (NON) in n-propanol on the left volar forearm. Clinical scoring was performed daily; evaporimetry (total epidermal water loss (TEWL)), hydration and colorimetry were measured at baseline (day 0) in the middle and at the end of treatment. Treatments were applied twice daily. The basic cream and the IPP cream were excluded from testing in HLGP because they were known from previous studies to be irritant in HLGP, while all formulations were known to be equally and well tolerated locally in humans. RESULTS: All formulations worsened the skin irritation in HLGP: the glycerol cream the least, the canola oil cream the most, while the bisabolol cream and the carbomer cream were indistinguishable. In humans, the glycerol cream was better than 'No Treatment' after cumulative irritation with both SLS and NON. The basic cream was better tolerated in humans than was expected from previous testing in HLGPs. CONCLUSION: In conclusion, the results from the studies in HLGPs and HVs are in agreement with regard to ranking of the SCFs. Further, the glycerol cream showed a positive treatment effect on both SLS- and NON-irritated skin in HVs.

Guidelines for visualization of cutaneous blood flow by laser Doppler perfusion imaging. A report from the Standardization Group of the European Society of Contact Dermatitis based upon the HIRELADO European community project.

This report reviews how to set up a laser Doppler perfusion imaging system intended for visualization of skin blood perfusion, capture images and evaluate the results obtained. A brief summary of related papers published in the literature within the areas of skin irritant and allergy patch testing, microdialysis and skin tumour circulation is presented, as well as early applications within other fields such as diabetology, wound healing and microvascular research.

Evidence of endogenous mono-ADP-ribosylation of cardiac proteins via anti-ADP-ribosylarginine immunoreactivity.

Arginine-specific mono-ADP-ribosylation of proteins and arginine-specific mono-ADP-ribosyltransferase occur in heart. We developed a polyclonal antiserum, R-28, against ADP-ribosylpolyarginine that recognized mono-ADP-ribosylated proteins and identified the major mono-ADP-ribosylation products of quail heart. Treatment of Immobilon-bound ADP-ribosylated Gs protein with hydroxylamine under conditions that remove ADP-ribose from its arginines eliminated R-28 immunoreactivity to Gs. Also, R-28 immunoreactivity to quail heart proteins was removed by NaOH and phosphodiesterase I treatments. Similar treatment with mercuric chloride did not remove the immunoreactivity but did remove exogenously (via in vitro pertussis toxin treatment) added ADP-ribose from cysteine of cardiac Gi/Go proteins. The antiserum did not appear to react with ADP-ribosylasparagine of Rho (formed by C3 toxin), ADP-ribosyldiphthamide of elongation factor 2 (formed by diphtheria toxin) in quail heart preparations, or polyADP-ribosylated proteins of a neonate rat cardiac nuclear preparation. Thus, the R-28 antiserum appears to contain predominantly antibodies directed against ADP-ribosylarginine. To test the usefulness of R-28, immunoblotting of subcellular fractions of quail heart was performed. R-28 showed the greatest immunoreactivity in the sarcolemma with significant immunoreactivity in denser membrane fractions. The cytosol also contained an immunoreactive band distinct from those found in the membranes. Hydroxylamine treatment eliminated immunoreactivity in the sarcolemma and denser membrane fractions but not the cytosol, suggesting the membranous immunoreactive bands contain ADP-ribosylarginine. In conclusion, a polyclonal antiserum that recognizes ADP-ribosylarginine proteins has been raised. The usefulness of the antiserum is demonstrated by the characterization of endogenous arginine mono-ADP-ribosylation products in quail heart. The quail heart has several sarcolemmal and denser membrane fraction proteins that appear to be mono-ADP-ribosylated on arginines.

A reliability study of measures assessing the impact of deinstitutionalization.

This study examined the reliability of several scales and indices used to measure outcome variables (independence, integration, productivity, and satisfaction) among people with developmental disabilities. A stratified random sample of 112 people was interviewed twice in a two-week period and included equal numbers of verbal and nonverbal consumers, of parent versus other caregivers, and consumers with diagnosed level of retardation being dichotomized into high and low. In addition, half of the interviews were test-retest and half were interrater. After stratifying on these four variables, the sample was chosen randomly within subgroups from the total database of 3,700 individuals who receive services through the Developmental Disabilities Services Division of the Oklahoma Department of Human Services. Correlation and proportion agreement analyses were performed on the pre- and post-tests and comparisons made on each scale for each stratification to examine variations in reliability. Acceptable correlations and matched agreements of at least 0.70 for all measures were found, with the Adaptive Development Scale having particularly strong correlations. In addition, responses from people with developmental disabilities on items of the Consumer Satisfaction scale were acceptably reliable.

In vitro reconstitution of microtubule plus end-directed, GTPgammaS-sensitive motility of Golgi membranes.

Purified Golgi membranes were mixed with cytosol and microtubules (MTs) and observed by video enhanced light microscopy. Initially, the membranes appeared as vesicles that moved along MTs. As time progressed, vesicles formed aggregates from which membrane tubules emerged, traveled along MTs, and eventually generated extensive reticular networks. Membrane motility required ATP, occurred mainly toward MT plus ends, and was inhibited almost completely by the H1 monoclonal antibody to kinesin heavy chain, 5'-adenylylimidodiphosphate, and 100 microM but not 20 microM vanadate. Motility was also blocked by GTPgammaS or A1F4- but was insensitive to A1C13, NaF, staurosporin, or okadaic acid. The targets for GTPgammaS and A1F4- were evidently of cytosolic origin, did not include kinesin or MTs, and were insensitive to several probes for trimeric G proteins. Transport of Golgi membranes along MTs mediated by a kinesin has thus been reconstituted in vitro. The motility is regulated by one or more cytosolic GTPases but not by protein kinases or phosphatases that are inhibited by staurosporin or okadaic acid, respectively. The pertinent GTPases are likely to be small G proteins or possibly dynamin. The in vitro motility may correspond to Golgi-to-ER or Golgi-to-cell surface transport in vivo.

Immediate and delayed nerve repair using freeze-thawed muscle autografts in complex nerve injuries. Associated arterial injury.

Five sheep underwent repair of the median nerve along with the establishment and repair of a brachial artery defect adjacent to the site of nerve injury. The defect in the brachial artery was of similar length to the nerve defect and lay in parallel with it. It was repaired using a reversed vein autograft harvested from one of the superficial veins of the arm. A further five sheep underwent similar treatment with the repair of the nerve delayed for 30 days after the establishment of the complicating vascular injury. Six months after the nerve repair, each group of sheep was assessed using electrophysiological and morphometric methods in order to establish objective indices of nerve recovery and regeneration. These results were compared with those from other sheep which had undergone nerve repair both immediate and delayed with no complicating injury and groups in which the complicating injury consisted of a cavity, fibrosis and haematoma. It was found that delay in the nerve repair and the presence of a complicating arterial injury, both separately and additively, contributed to a poorer outcome in recovery of nerve function and maturation. The effect of an arterial injury, in both of these respects, was to produce a worse outcome than the presence of a cavity with fibrosis and haematoma.

The calcipotriol dose-irritation relationship: 48 hour occlusive testing in healthy volunteers using Finn Chambers.

Calcipotriol is widely used in the treatment of psoriasis. Adverse lesional and perilesional irritation may occur. Allergy may occasionally be suspected. Allergy patch testing with calcipotriol may be difficult or impossible because calcipotriol is a local irritant. The aim of the present study was to assess the calcipotriol dose-irritation relationship, and establish a non-irritant patch test concentration for calcipotriol allergy patch testing. The study was a prospective, double-blind, randomized, dose titration evaluation in 180 healthy volunteers never previously exposed to calcipotriol. All individuals were patch tested with a calcipotriol dilution series (range 0.016-250 micrograms/mL). Clinical reading of test sites and measurement of erythema using a Minolta ChromaMeter were performed on days 2 and 3. Laser Doppler perfusion imaging of cutaneous blood flow was performed on day 3. Doubtful reactions (score 1/2) and weak reactions (score 1) were frequent and observed even at low dose exposure. Reactions declined in strength between the readings on day 2 and day 3. Only score 2 reactions with moderate erythema and some infiltration showed a threshold of no irritation. This threshold was confirmed by colorimetry and flowmetry. Cases of suspected allergy to calcipotriol may to avoid irritant reaction and false positive readings, be patch tested with calcipotriol 2 micrograms/mL citrate-buffered isopropanol solution applied under occlusion for 48 h using small Finn Chambers. Score 1/2 and 1 reactions are likely to reflect irritation. A positive test should be repeated after a minimum period of 3 months to ensure its consistency over time. A repeated open application test may be indicated.

Characterization of irritant patch test reactions to topical D vitamins and all-trans retinoic acid in comparison with sodium lauryl sulphate. Evaluation by clinical scoring and multiparametric non-invasive measuring techniques.

The study was a single-centre, double-blind randomized, placebo-controlled within-subject comparison of 42 healthy volunteers. Occlusive patch test for 48 h was performed with solutions of 1 alpha,25(OH)2D3 (calcitriol), two vitamin D analogues (calcipotriol and KH 1060 (lexacalcitol)), all-trans retinoic acid and sodium lauryl sulphate (SLS) as reference irritant. Solution vehicles and an empty chamber was also included. Test evaluation was performed at day 2, day 3 and again on day 7. Test evaluation was based both on clinical scoring and on various non-invasive measuring methods. 1 alpha,25(OH)2D3, calcipotriol and KH 1060 all showed mild irritation in the concentrations tested. The number and severity of test reactions was found to be dose dependent based both on clinical scoring and on non-invasive measurements. Irritation of the vitamin D analogues mainly affected the vasculature with vasodilation and increased cutaneous blood flow. All-trans retinoic acid showed irritant reactions with some similarity to the tested vitamin D analogues; however, the reactions were more prolonged. Transepidermal water loss (TEWL) was affected neither after application of vitamin D analogues nor after application of all-trans retinoic acid and it was thus concluded that these substances are non-corrosive. SLS showed the known irritant mechanism with corrosion and increase in TEWL as the primary event.

IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments.

Activated forms of the GTPases, Rac and Cdc42, are known to stimulate formation of microfilament-rich lamellipodia and filopodia, respectively, but the underlying mechanisms have remained obscure. We now report the purification and characterization of a protein, IQGAP1, which is likely to mediate effects of these GTPases on microfilaments. Native IQGAP1 purified from bovine adrenal comprises two approximately 190-kD subunits per molecule plus substoichiometric calmodulin. Purified IQGAP1 bound directly to F-actin and cross-linked the actin filaments into irregular, interconnected bundles that exhibited gel-like properties. Exogenous calmodulin partially inhibited binding of IQGAP1 to F-actin, and was more effective in the absence, than in the presence of calcium. Immunofluorescence microscopy demonstrated cytochalasin D-sensitive colocalization of IQGAP1 with cortical microfilaments. These results, in conjunction with prior evidence that IQGAP1 binds directly to activated Rac and Cdc42, suggest that IQGAP1 serves as a direct molecular link between these GTPases and the actin cytoskeleton, and that the actin-binding activity of IQGAP1 is regulated by calmodulin.

Topical D-vitamins: multiparametric comparison of the irritant potential of calcipotriol, tacalcitol and calcitriol in a hairless guinea pig model.

The irritant potential of calcipotriol, 1 alpha,24-dihydroxyvitamin D3 (tacalcitol) and 1 alpha,25-dihydroxy-vitamin D3 (calcitriol) was compared in a hairless guinea pig model, Randomized, occlusive patch testing for 2 days was used. Each group of 8 animals was tested simultaneously with the 3 substances and a placebo vehicle. 3 dose levels i.e. 500 micrograms/ml, 50 micrograms/ml and 5 micrograms/ml were used. Test sites were evaluated at day 2 (2 h after removal of the patches) and again at day 3. Evaluation was blinded and based on a multiple parameter assessment of skin irritancy, comparing clinical scoring, skin perfusion using high resolution laser Doppler image scanning, skin colour (a*, Minolta ChromaMeter) and skin thickening (20 MHz ultrasound) indicating oedema. Skin biopsies were taken for histological preparation and assessment of epidermal hyperplasia. No difference was observed between the irritant potential for calcipotriol, tacalcitol and calcitriol based on clinical scoring as well as objective non-invasive measuring techniques. All 3 substances showed a dose-dependent and equal increase in clinical irritation score, cutaneous blood flow, skin colour and epidermal hyperplasia. The cutaneous inflammatory reaction was dominated by vasodilation and increased cutaneous perfusion. Oedema formation was only seen at the highest dosages tested. Skin barrier damage was not induced as TEWL remained unaffected. The hairless guinea pig appears a valid model to test irritancy of topical D-vitamins since the same profile of irritancy was previously established in humans for 2 of the compounds tested, calcitriol and calcipotriol.

Site, gender and age variation in normal skin colour on the back and the forearm: tristimulus colorimeter measurements.

BACKGROUND/AIMS: To study whether anatomical location and age and gender of subjects had any influence on the objective skin colour measurements. METHODS: Baseline colour in prone position was measured with the Minolta ChromaMeter® in the upper, middle and lower level of the upper back and on the forearm of 168 volunteers. These two sites are commonly used in skin testing. RESULTS AND CONCLUSIONS: Higher basal a* and lower basal L* levels were found on the upper scapular region compared to the lower scapular region and the subscapular region. The basal b* level showed no variation relative to site. The basal a* and the basal b* levels were lower on the forearm compared to the upper back while the basal L* level was higher. Females above 65 years showed a less coloured skin with lower values as compared to those of younger age. Females were found to have a generally lower basal a* level than males both on the upper back and forearm skin. These relatively major differences and sources of variation have to be considered when planning irritancy studies where colour differences between erythema and normal skin is used.