The economic and social burden of Alzheimer disease on families in the Lombardy region of Italy

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.     

Effects of sinus surgery on speech

The human 4 hour patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. The protocol is designed to avoid the production of more than mild irritant reactions and meets the highest ethical standards. This paper provides the background to the development of the method and comments on its performance in the light of recent intra- and inter-laboratory investigations. In particular, the value of the method in providing 'gold standard' data for the identification of those substances (or preparations) which should, or should not, be classified as irritant to skin in European legislation is discussed. On the basis of the published data and supplementary investigations, recommendations are made on both the conduct and interpretation of the human 4 hour patch test. Finally, the lack of any necessity for formal validation of this assay is addressed.     

Safety evaluation of perfluoropolyethers, liquid polymers used in barrier creams and other skin-care products

Fomblin HC products are a 'family' of high-purity perfluoropolyethers manufactured for barrier cream and other personal care applications which involve direct application to the skin. To confirm the safety of such use, representative Fomblin HC products were tested in experimental animals for acute toxicity, primary and repeated insult irritancy, sensitization and photosensitization, subacute oral toxicity and comedogenicity; mutagenicity was examined in vitro, and irritancy or sensitization was also investigated on human skin (in patch tests with volunteers). A high molecular weight Fomblin HC only was tested in rats for subacute oral toxicity and in man for dermal effects. Single oral doses of 15 g/kg body weight were without evident toxicity to rats, as were single dermal applications or an ip injection at 5 g/kg. No primary irritant action was seen in rabbits or man, and similarly there was no evidence of skin sensitization or photosensitization in guinea pigs, or sensitization in man. No mutagenic action on Salmonella strains of tester bacteria was seen. In repeat dose irritancy or oral toxicity tests in rabbits or rats, no adverse effects of Fomblin HC products were noted; in particular, daily oral administration (1000 mg/kg/day) to rats over 28 days produced no significant reaction. No comedogenic action was found. From the known chemistry of the perfluoropolyethers, the test programme reported here and the limited published data, it is concluded that the intended use of Fomblin HC products in formulations applied to human skin has a high margin of safety.     

Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site

OBJECTIVE: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. METHODS: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. RESULTS AND CONCLUSIONS: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.     

Compression of the ulnar nerve at the wrist due to an arthro-synovial cyst. Apropos of 2 cases

This study investigates the extent to which sunscreens protect humans from ultraviolet (UV)-radiation-induced immunosuppression. In the presence of solar-simulated UV, three sunscreens with differing UVA transmission were assessed for their ability to protect the contact hypersensitivity (CHS) response to nickel of 16 nickel-allergic subjects. The sunscreens contained 2-ethylhexyl para-methoxycinnamate (cinnamate), cinnamate with oxybenzone, or cinnamate with zinc oxide, respectively. All had sun protection factors of 10 and hence inhibited UV erythema to similar extents. Volunteers were irradiated on their backs with suberythemal UV daily for 5 d after application of the sunscreens and their base lotion to different sites. Nickel-containing patches were then applied to both UV-treated sites and adjacent, unirradiated control sites. Erythema caused by nickel CHS at each site was quantitated 72 h later with a reflectance erythema meter. In comparison of the nickel reactions of irradiated and unirradiated skin, there was 35% mean immunosuppression in unprotected UV-treated skin. Significant immunosuppression also occurred at sites irradiated through the narrow-spectrum cinnamate-only sunscreen but was prevented by the two broad-spectrum sunscreens. To determine whether UV-induced suppression of the nickel response is specific for cell-mediated immunity or reflects suppression of nonspecific inflammation, a further 16 subjects were patch-tested with a skin irritant, sodium lauryl sulfate (SLS), following a sunscreen and irradiation protocol identical to that of the nickel volunteers. UV had no significant effect on SLS responses. We conclude that nickel patch testing is a valid means of assessing UV-induced immunosuppression in humans and that even with suberythemal UV, immune protection was provided only by sunscreens filtering both UVA and UVB.     

Skin sensitization testing: the relevance of rechallenge and pretreatment with sodium lauryl sulfate in the guinea pig maximization test

The guinea pig maximization test is one of the preferred test methods for the identification of skin sensitizers. The OECD/EC test guidelines allow for the conduct of a rechallenge in case doubtful reactions are obtained after challenge. The relevance of rechallenging was investigated by performing multiple challenges (up to four) in the maximization test with four well-known sensitizers of varying strength: nickel sulfate, sulfathiazole, benzocaine, and 1-chloro-2,4-dinitrobenzene. In addition, the effect of sodium lauryl sulfate (SLS)-pretreatment during topical induction with weak sensitizers on rechallenging was investigated. In contrast to what has frequently been hypothesized, rechallenge did not result in an increase of skin reaction as compared with the reactions observed after the first treatment. SLS pretreatment was very effective in increasing the initial challenge response to weak sensitizers. Subsequent rechallenging in these cases however again showed a decrease in sensitivity of the animals.     

Quantification of nuclear pleomorphism using an asymptotic fractal model

Validated in vitro alternatives are being utilized extensively for mutagenicity and ocular irritancy testing. However, validation of alternative assays for dermal irritancy is progressing more slowly. As the irritant response in human skin is mediated, at least in part, by eicosanoids derived from arachidonic acid, the effect of relatively pure anionic surfactants (AS, n=8) and surfactant-containing finished products (FP, n=25) on the release of [3H]arachidonic acid from a prelabelled murine fibroblast cell line (C3H-10T1/2 cells) in vitro was examined. Test substances were administered at various non-lethal concentrations, in triplicate, to 12- and 24-well plates containing preconfluent monolayers (80-90% confluence) of C3H-10T1/2 cells. Because it is impossible to test all concentrations of each test substance in a single assay, statistical techniques were developed to 'standardize' in vitro assay results. In each assay, radiolabel release due to a positive control was also measured, using 0.04, 0.05 and 0.06 mM concentrations of sodium dodecyl sulfate (SDS). Test substance releases were then transformed into 'SDS equivalent' responses, significantly reducing both inter- and intra-assay variability. A straight line was fitted to the test substance responses and compared with that for SDS to calculate the relative potency in vitro for individual AS and FP. Relative potencies correlated with in vivo responses, that is primary dermal irritation indices obtained in rabbits, with Spearman p=0.408 (P<0.03) for 32 tested agents, and p=0.976 (P<0.001) for the eight AS. Exclusion of extremely alkaline or acidic FP (pH>11 or <2, n=4) and those which were insoluble in the aqueous cell culture media at the 1% stock dilution (n=5), improved the overall in vivo-in vitro correlation significantly (p=0.683, P<0.001, n=23) and produced a significant correlation for FP alone (p=0.539, P<0.05, n=15). These results suggest that release of [3H]arachidonic acid from cultured skin cells represents a novel, mechanistically based in vitro screen for dermal irritancy testing.     

Influence of alkalinization of glutaraldehyde biocidal solutions on acute toxicity, primary irritancy, and skin sensitization

Aqueous glutaraldehyde (GA) is used at a concentration around 2% for the cold sterilization of endoscopy and dental instruments. Stock GA solution (pH 3.1-4.5) is alkalinized (pH 7.8-8.0) before use to optimize biocidal activity. The possible differential handling hazards between acidic unbuffered GA (UGA) and alkaline buffered GA (BGA) were compared for acute toxicity, primary irritancy and skin sensitizing potential using a 2.2% GA solution. Peroral LD5.0 values (with 95% confidence limits) in rats (combined sexes) were 3.45 (3.13-3.80) g/kg for UGA and 4.16 (3.13-5.52) g/kg for BGA; signs and gross pathology were similar. A 24-h occluded cutaneous application of 16.0 g/kg in the rabbit did not produce mortality; moderate skin irritancy was observed. No systemic effects occurred with UGA and only a few with BGA (unsteady gait, sluggishness, rapid breathing). Local skin irritation from a 4-h occluded contact with 0.5 ml was relatively minor and slightly more marked with BGA than UGA. Rats exposed to a statistically generated saturated vapor atmosphere for 6 h did not show any signs or gross pathology, and only slight weight loss occurred (UGA females). Rabbit eye irritation studies (0.1 ml) showed slightly more marked conjunctival reactions with BGA, but corneal injury was marked and persistent with BGA and only slight and transient with UGA. With 0.01 ml, no corneal injury occurred, but conjunctival reaction was more marked with UGA. A guinea pig maximization study showed UGA to produce a higher sensitizing index (68% at challenge, 32% at rechallenge) than BGA (30% at challenge, 5% at rechallenge). Severity indices at challenge was also higher for UGA [0.84 (24 h), 0.47 (48 h)] than BGA [0.45 (24 h), 0.18 (48 h)]. Both UGA and BGA have generally similar acute toxicity and skin irritancy; BGA has greater corneal injuring potential, and UGA has a greater skin sensitizing potential.     

Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells

Exposure to irritants may cause chronic irritant contact dermatitis (ICD), characterized by irregular epidermal thickening and a predominantly dermal mononuclear cell infiltrate. The mechanisms involved, and why only certain individuals are affected, are not clearly understood. Different irritants may trigger different cellular and molecular interactions between resident skin cells and recruited inflammatory cells. In some individuals these interactions may become self-perpetuating resulting in persistent inflammation in the absence of continued exposure. This study examined Langerhans cell (LC) density in clinically normal skin of 46 patients with chronic ICD and 10 healthy individuals, and compared the action of the two irritants nonanoic acid (NA) and sodium lauryl sulphate (SLS) on the LCs and keratinocytes of clinically normal skin in patients with chronic ICD. There was a higher number of LCs/mm basement membrane in patients compared with controls, although there was no difference in the number of dendrites/LC nor in dendrite length. SLS induced keratinocyte proliferation after 48 h exposure, had no effect on LC number or distribution, and induced keratinocyte apoptosis after 24 and 48 h exposure. In contrast, NA decreased keratinocyte proliferation after 24 h exposure but this returned to basal levels after 48 h, and induced epidermal cell apoptosis after only 6 h exposure. NA dramatically decreased LC number after 24 and 48 h exposure, which was accompanied by basal redistribution and decreased dendrite length. Most significantly, NA induced apoptosis in over half of the LCs present after 24 and 48 h exposure.     

Lipoarabinomannan induced cytotoxic effects in human mononuclear cells

The percutaneous absorption studies were performed using a flow-through diffusion cell system with skin specimens from 24 healthy women to assess the penetration of glycolic acid (GA). Percentages of GA, based on 14C-labelled activity, found in the skin after application of 4% GA at pH 2.0 or pH 3.8, after 24 h were as follows: stratum corneum (SC)= 2.65+/-1.80 versus 1.13+/-1.14 (P<0.05); viable skin (VS)= 13.46+/-7.44 versus 2.23+/-1.51 (P< 0.05) and effluent fraction (EF) = 12.22+/-9.03 versus 1.42+/-0.77 (P < 0.05), respectively. The applications of 4-60%, GA at their native pH resulted in an increased penetration of GA through the skin. For example, application of 20% GA, pH 1.9, resulted in the following values: SC = 2.69+/-2.26 (P > 0.05); VS = 4.88+/-4.05 (P > 0.05) and EF = 30.69+/-13.25 (P < 0.05). Duration of application also affected the extent of penetration of drug. For example, application of 20% GA, pH 1.9, for 6 h resulted in the following levels: SC = 1.16+/-0.80 (P < 0.05); VS = 4.07+/-1.78 (P > 0.05) and EF = 6.12+/-4.95 (P < 0.05). In conclusion: (i) absorption of GA in human skin are pH-, strength- and time-dependent; and (ii) the in vitro method appears to provide an appropriate model to reflect in vivo absorption of GA through human skin.     

Antianxiety and behavioral suppressant actions of the novel 5-HT1A receptor agonist, flesinoxan

Flesinoxan is a potent and selective 5-HT1A receptor agonist. In this study, the effects of this compound on behavior in the murine elevated plus-maze have been assessed using a recently developed ethological scoring method. Results show that, at low doses (0.1-0.5 mg/kg), flesinoxan inhibited risk assessment behaviors (stretched attend postures and closed arm returns) indicative of a reduction in anxiety. These effects were maintained at a higher dose of 1.0 mg/kg, which also increased percent open entries and time spent on the central platform and open arms. However, this more convincing anxiolytic profile was associated with significant reductions in total arm entries and rearing, suggesting a combination of anxiolysis and behavioral suppression at high doses. The plus-maze profile observed with flesinoxan is very similar to that previously reported for 8-OH-DPAT in the same test but, despite superficial similarities, can be distinguished from that seen with buspirone. Data are discussed in relation to behavioral similarities and differences between 5-HT1A receptor agonists, and the advantages of a more detailed approach to the analysis of plus-maze behavior.     

Assessment of topical corticosteroid activity on experimentally induced contact dermatitis: echographic evaluation with binary transformation and image analysis

A new echographic evaluation method employing a B scanner and a dedicated software (Dermavision 2D, Cortex Technology, Hadsund, Denmark) was used in assessing the potency of three different corticosteroids. Experimental lesions were induced by patch tests with nickel sulfate 5% in petrolatum in 10 sensitized subjects and treated with two medications of different steroids (clobetasol propionate, fluocinolone acetonide or clobetasone butyrate) performed 16 and 40 h after the application of the nickel patch tests. Clinical and echographic evaluations were carried out at the beginning of the experiment and 64 h after the induction of the reactions. After obtaining echographic images, these were processed by software, enabling the selection of amplitudes of interest, the highlighting of parts of images and their assessment by a value corresponding to the number of pixels (picture elements). For evaluations a low reflecting band was chosen, marking edema and inflammatory infiltration. At positive patch test sites we observed a progressive increase in the number of low reflecting pixels, in accordance with the intensity of the reaction. Therapeutic response was assessed as the difference between values of treated and untreated test sites. The rank order of the efficacy of test substances as determined echographically was identical to the rank order generally accepted for these steroids. This evaluation method of topical corticosteroid activity could be usefully employed besides traditional evaluation methods.     

A case of eosinophilic pustular folliculitis (Ofuji's disease) induced by patch and challenge tests with indeloxazine hydrochloride

A 73-year-old male developed disseminated erythema over his entire body after exposure to indeloxazine hydrochloride, a cerebral activator. Patch testing with indeloxazine hydrochloride showed a positive reaction, and plaques, vesicles and pustules developed on the face after the patch test. These had the pathologic feature of eosinophilic pustular folliculitis (EPF, Ofuji's disease). A challenge test also provoked eruptions on the face, trunk, arms and legs, which were compatible with EPF. Moreover, both the patch and challenge tests with indeloxazine hydrochloride induced eosinophilia. This is the first report of drug allergy-induced EPF, where drug sensitivity induced an abnormal eosinophilic response mimicking EPF.     

Improved detection of differential information-processing speed deficits between two disease-course types of multiple sclerosis.

Patients with multiple sclerosis (MS) frequently demonstrate impairments of information-processing speed (IPS) on measures such as the Paced Auditory Serial Addition Test (PASAT; D. M. A. Gronwall, 1977). The authors have previously shown that their new PASAT scoring method (mean dyad score) is better correlated in comparison with more traditional PASAT scoring method(s), with magnetic resonance imaging measurement of the total area (mm2) of white-matter sclerotic lesions (P. J. Snyder & I. C. Cappelleri, 2001). The present study reports that the mean dyad score discriminated 20 relapsing-remitting MS (RRMS) patients from 15 secondary-progressive MS (SPMS) patients noticeably better than did the standard scoring method(s). Mean dyad scores     

Effect of acute dietary fibre supplementation on colonic pH in healthy volunteers

Two patients presented with a tumor involving mainly the supplementary motor area or the premotor cortex. Shortly after tumor resection, each developed transient impairment of voluntary movements. An electromyogram, with the skin electrodes placed over the muscles of the upper arms and forearms, demonstrated aberrant ipsilateral, contralateral or bilateral muscle activation during unilateral motor tasks in both patients. The bilateral activation was more prominent in the patient who had an intact dominant hemisphere. The present study suggests for the first time the importance of non-primary motor areas of the human brain in activating the proper set of muscles on the proper side of the body.     

Down-regulation of protein kinase C isoforms in irritant contact dermatitis

Protein kinase C (PKC) isoforms are important in cell signal transduction associated with regulation of cell proliferation and differentiation. In this study, alterations of PKC isoform levels in irritant patch test reactions were detected by Western immunoblots. 4 chemically and structurally different irritants, 4% and 8% hydrochloric acid (HCl); 1% and 2% sodium hydroxide (NaOH); 20% and 40% nonanoic acid (NON) in 1-propanol; and 5% and 10% sodium dodecyl sulfate (SDS) were applied on the backs of mice in Finn Chambers and fixed with surgical dressings. The patches were kept on the skin for 24 h and removed. 24 h after removal, mild erythema with thickening of skin without vesicles was observed in all irritated skin, except that 4% HCl and 1% NaOH treated skin showed unremarkable skin reaction. No visible skin reaction was detected in vehicle-treated skin. PKC isoform alpha, beta, gamma, and delta levels in irritated skin revealed a 10% to 65% decrease compared to vehicle treated skin. These results indicate that in HCl, NaOH, NON and SDS-induced irritation, activation of the PKC related cell signal transduction cascade may be involved, and that PKC mediated events may be a common phenomenon in irritant contact dermatitis.     

Adhesion molecules in atopic dermatitis: patch tests elicited by house dust mite

Different T-helper subsets, which are characterized by the secretion of distinct cytokines (Th1, Th2), have been found in house dust mite-exposed skin of sensitized individuals and in nickel-specific T lymphocytes from nickel contact allergic and non-allergic individuals. In order to evaluate the role which adhesion molecules may play in the homing of different T-cell subsets into allergen-exposed skin of atopic and normal individuals, we compared the expression pattern of adhesion molecules in patch test reactions to house dust mite antigen (D.pt.), nickel sulfate (Ni) and the irritant anthralin. Biopsies were taken at various time points after application of these agents and studied by immuncytochemistry. To exclude an endogenous difference in adhesion molecule expression in atopic and non-atopic skin, sequential biopsies from Ni patch tests of 2 normal individuals were also included in this study. The expression of E-selectin, P-selectin, CD31, VCAM-1 and ICAM-1 on endothelial cells and other cells in the skin was quantified by microscopic evaluation. Skin homing T cells were also quantified using antibodies to CD3, CD4, CD8, UCHL-1, L-selectin and the cutaneous lymphocyte antigen (CLA). Independent of the eliciting substance, all lesions showed an upregulation of all adhesion molecules tested, with the exception of CD62. The appearance of E-selectin and an increase in ICAM-1 and VCAM-1 expression were first observed at 12 h after application of the various agents. In parallel, the number of CLA+ and L-selectin+ lymphocytes increased steadily. No principle differences could be established between the various types of skin reactions in atopic individuals, nor did the skin of patients with AD differ from normal controls. Our results provide evidence that differential expression of adhesion molecules does not play a major part in observed differential homing of Th1 and Th2-cell subsets into patch test sites provoked by house dust mite and nickel sulfate in atopic and non-atopic individuals.     

Allergy testing in serious cutaneous drug reactions--harmful or beneficial?

We report on 3 cases of adverse cutaneous drug reactions of erythema multiforme type. Despite the serious previous clinical conditions, patch tests with the possible causative drugs have been performed in all our patients, because of multiple candidate drugs and the need of the patients for further treatment with at least some of the agents. We demonstrate that patch tests are a good and safe approach to initial evaluation of the nature of a cutaneous drug reaction. In the case of a positive patch test reaction to one of the substances, re-exposure to the non-reactants in a clinical setting is recommended. If a one-side-blinded placebo-controlled challenge test is well tolerated, then the clinician should be able to reintroduce drugs previously suspected as causing the allergy.     

Cellular interactions in the thymus regulate the protein kinase C signaling pathway

Lung cancers occur more commonly in the upper lobes than in the lower lobes, but its pathophysiologic basis is not well understood. Because numerous studies have reported a consistent inverse relationship between lung cancer risk and intake of certain vegetables and fruits, we hypothesized that the balance between diet-derived protective substances delivered via the circulation and cigarette-derived carcinogenic substances delivered via the airways would be less favorable in the upper lobes compared with the lower lobes, hence accounting for the upper lobe predominance of tumors among smokers. Thus, we examined the association between diet and tumor location in 328 patients with lung cancer. The ratio of upper to lower lobe tumors was 2.5:1.0. In univariate analysis, age, height, weight, sex, race, family history of cancer, education level, tumor histology, calories consumed per day, and intake of animal fat did not differ significantly between patients with upper versus lower lobe tumors. Predictors of tumor location in univariate analysis were family history of lung cancer; smoking history; history of asbestos exposure; and intakes of yellow-orange vegetables, alpha-carotene, beta-carotene, and vitamins A, C, and E. In multivariable logistic regression analysis, the independent predictors of upper lobe tumor location were family history of lung cancer (p = 0.03), history of asbestos exposure (p = 0.02), less intake of yellow-orange vegetables (p < 0.04), and less intake of vitamin E (p = 0.05). Our results show a strong inverse association between upper lobe location of lung cancer and intake of yellow-orange vegetables and vitamin E.     

Prenatal diagnosis of choroid plexus papillomas of the lateral ventricle. A report of two cases

The aim of the present study was to investigate whether a difference in susceptibility to chemically induced irritation of the oral mucosa in 14 pre- and 14 post-menopausal women exists, following local exposure to sodium lauryl sulphate (SLS) in toothpastes. 4 different pastes differing only in detergent concentration present, or not, were used. The participants applied 1 cm of the different test toothpastes to a cap splint covering the teeth and the oral mucosa of the upper jaw 2 x daily for 2 min during a period of 4 days. 42 desquamative reactions of the oral mucosa (in 20 subjects) were observed, 29 and 13 in the pre- and the post-menopausal group, respectively. Desquamation was only experienced following exposure to SLS-containing toothpastes, not succeeding SLS-free paste. The results demonstrated that oral mucosa of pre-menopausal women was significantly more sensitive to SLS than oral mucosa of post-menopausal women. The difference in mucosal irritation between the 2 groups increased with increasing concentration of SLS.