Publisher Correction: Cortical-like mini-columns of neuronal cells on zinc oxide nanowire surfaces.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cortical-like mini-columns of neuronal cells on zinc oxide nanowire surfaces.

A long-standing goal of neuroscience is a theory that explains the formation of the minicolumns in the cerebral cortex. Minicolumns are the elementary computational units of the mature neocortex. Here, we use zinc oxide nanowires with controlled topography as substrates for neural-cell growth. We observe that neuronal cells form networks where the networks characteristics exhibit a high sensitivity to the topography of the nanowires. For certain values of nanowires density and fractal dimension, neuronal networks express small world attributes, with enhanced information flows. We observe that neurons in these networks congregate in superclusters of approximately 200 neurons. We demonstrate that this number is not coincidental: the maximum number of cells in a supercluster is limited by the competition between the binding energy between cells, adhesion to the substrate, and the kinetic energy of the system. Since cortical minicolumns have similar size, similar anatomical and topological characteristics of neuronal superclusters on nanowires surfaces, we conjecture that the formation of cortical minicolumns is likewise guided by the interplay between energy minimization, information optimization and topology. For the first time, we provide a clear account of the mechanisms of formation of the minicolumns in the brain.

Co-localization of IgA and TG3 on healthy skin of coeliac patients.

BACKGROUND: Dermatitis herpetiformis (DH), the skin's expression of coeliac disease (CD), is induced by the presence of IgA antibodies and epidermal transglutaminase (TG3) as the main autoantigen, stored in the papillary dermis and on the vessel walls. AIMS: To evaluate the presence of IgA and TG3 deposits, considered to be the first step in inducing DH, in healthy skin of coeliac patients without cutaneous manifestations. METHODS: Punch biopsies were taken from 11 consecutive coeliac patients, two with DH and nine without cutaneous manifestations, three of whom were adhering to a gluten-free diet (GFD), and evaluated for the presence of deposits in the upper dermis and vessel walls by immunofluorescence and confocal microscopy. RESULTS: In coeliac patients affected by DH we found the presence of IgA and TG3 deposits mainly on the upper dermis, but also in vessel walls. In all coeliac patients without DH and also in those patients who were following a strict GFD, we found widely variable deposits of IgA and TG3 in both the papillary dermis and the vessel walls, although a lower intensity of the fluorescence signal was detected than with coeliac patients affected by DH. Double immunostaining with anti-IgA and anti-TG3 antibodies showed a strong co-localization in the upper dermis in patients with DH and a weaker co-localization in those without DH. CONCLUSIONS: We have demonstrated the presence of IgA and TG3 deposits in the healthy skin of coeliac patients, which are considered to play a central role in the pathogenesis of DH.

Interaction of palladium ions with the skin.

87 subjects sensitive to both nickel sulfate and palladium-chloride pet., were contemporaneously patch retested to nickel sulfate 5% pet., metallic palladium chloride 1% pet. and to palladium chloride 1% aq. Whilst all subjects reacted to nickel sulfate and palladium chloride pet., only 3 reacted to palladium chloride aq. No positive reactions were found to metallic palladium. The negative results to palladium chloride aq. are probably due to the formation of a new palladium ion (PdCl4)2-, achieved on adding an amount of hydrocloric acid to the aqueous solution of PdCl2. The findings seem to demonstrate that the allergic reaction to palladium depends on the arrangement of the metal electrons. The sensitization to palladium does not seem to be dependent on the element itself but on the complexes formed by the different compounds. The concomitant reactions to nickel and palladium ions could be dependent on the generation of similar complexes between the ions and the skin proteins.

Interaction of metals in nickel-sensitive patients.

Nickel (Ni) dermatitis is thought to involve the formation of complexes between Ni ions and suitable proteins. 4 groups of 30 subjects who gave positive patch test responses to NiSO4 2.9% aq. were each retested to 1 of 4 different solutions containing equimolar (0.1 M) amounts of NiSO4 plus MgSO4, NiSO4 plus CuSO4, NiSO4 plus ZnSO4, and NiSO4 plus Li2SO4, respectively. The results, evaluated at 2 days by visual scoring only, demonstrated that the 4 metals exerted a different influence on the nickel reactions, perhaps interfering with one or more factors affecting the formation of Ni+ + complexes.

Contact dermatitis to fragrances.

2 groups of patients (1200 and 1500 respectively) were patch tested with different concentrations of perfume mix and fragrance raw materials. The study was to evaluate the incidence of contact dermatitis to fragrances in Roma, Italy, and the influence of limited variations in fragrance and perfume mix concentrations on patch test responses. The results showed that a decrease in the perfume mix concentration from 16% to 8% correlated with a decrease in the % of positive patients (from 5.2% to 3.6%). Variations in the concentration of fragrance raw materials did not influence the % of positive reactions in the 2 groups. The perfume mixture at 16% or 8% gave some positive results, without a corresponding reaction to any of the constituents, that were not related to an excited skin syndrome.

Nickel sensitivity: effects of prolonged oral intake of the element.

25 nickel-sensitive females were given 10 mg NiSO4 in water in a single dose. 18 experienced generalized or localized flare-ups. 15 days later, 17 of the 25 patients were given gradually increasing daily doses of NiSO4 in water for 3 months. 14 ended the trial without flare-up, 3 had to stop because of intense worsening of cutaneous manifestations. A relationship does exist between the daily oral intake of nickel and its clinical manifestations, but it is not uniform and depends on the changing quantities and, above all, on the manner of intake. It would seem that a 10 mg NiSO4 oral challenge represents a sudden and large intake of the element to which the majority of sensitized subjects are not able to adapt. On the other hand, a gradual intake permits a majority of subjects to adapt to the element. We hypothesize that this behaviour is more likely due to intestinal adaptivity than to immunological tolerance.

Nickel chloride/chlorides of divalent metal interactions in nickel-sensitive subjects.

To verify if the counter-ion Cl- permits the same interactions between nickel and divalent metals with physicochemical similarities as the counter-ion SO4- does, 50 sensitive subjects to nickel sulfate 5% pet. who previously gave positive patch test reactions either to 8 mu 1 of aq. nickel sulfate 0.1 M or to 8 mu 1 of aq. nickel chloride 0.1 M, or to both, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M and aq. nickel chloride 0.1 M, and to 8 mu 1 of aq. mixed solutions containing, respectively, nickel chloride 0.1 M+magnesium chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.5 M, nickel chloride 0.1 M+manganese chloride 0.3 M, and nickel chloride 0.1 M+manganese chloride O.5 M. Whilst 4 subjects gave a positive patch test response to only nickel sulphate, 8 gave a positive response to nickel chloride alone and the remaining 38 gave a concomitant positive response to both. In all subjects who gave positive responses to nickel chloride, the chlorides of divalent metals were not able to inhibit or reduce the positive reaction. 25 healthy subjects patch tested to both single salts and mixed solutions, and all gave negative responses. 9 of the 50 subjects, 4 who previously gave positive reactions to only nickel chloride 0.1 M, and 5 with concomitant reactions of equal intensity to both nickel chloride and nickel sulfate 0.1 M, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M, aq. nickel chloride 0.1 M and aq. mixed solutions containing nickel sulfate (0.1 M) mixed with sulfates (0.3 M) and nickel chloride (0.1 M) mixed with chlorides of Mg, Zn, Mn (0.3 M). Whilst the mixed sulfate solutions were able to reduce nickel sulfate, 0.1 M patch test positive reactions, those containing chlorides, at all concentrations tested, did not inhibit the nickel chloride reactions in any of the subjects. The results of the tests to chlorides, compared to those reached on testing to sulfates of the same metals, lead us to hypothesize that the anion probably affects the uptake and local tissue distribution of the metal, modulating in this way, together with the individual cutaneous ligands, its effects.

Interactions of sulfates of divalent metals in nickel-sulfate-sensitive patients.

70 nickel-sensitive subjects who previously gave positive patch test response to 10 microliters of nickel sulfate 0.1 M, were patch tested to 10 microliters of mixed aqueous solutions containing nickel sulfate 0.1 M+magnesium sulfate 0.3 M, nickel sulfate 0.1 M+zinc sulfate, 0.3 and 0.5 M, respectively, nickel sulfate 0.1 M+ manganese sulphate 0.3 and 0.5 M, respectively nickel sulphate 0.1 M+ cadmium sulfate 0.1 and 0.3 M, respectively, nickel sulfate 0.1 M+iron sulfate (III) 0.1 and 0.3 M, respectively, and to 10 microliters of aq. cadmium sulfate 0.1 M, aq. cadmium sulfate 0.3 M, aq. iron sulfate 0.1 M, aq. iron sulfate 0.3 M. The results showed that, whilst sulfates of divalent metals with similar size and redox properties (Mg, Zn and Mn) were able to reduce or to suppress, in a dose-dependent way, the majority (75%) of nickel reactions, those with large radius and different oxidation state(Fe III), generally gave an increase in the reactions. In about 15% of the tested subjects, an increase in all the positive reactions to the mixed solutions was found. The findings seem to demonstrate that in only a majority but not all of nickel sulfate allergic reactions, is Ni(II) able to substitute for divalent ions with similar properties at the ion sites of some proteins. This tendency reproduces the results of experimental systems, in which nickel toxicity and cancerogenity are considered responsible. In contrast, in about 15% of the tested subjects, there was a general enhancement of the reactions. In these cases, either the occurrence of a "hyper-irritable" skin caused by the adopted test system or, more likely, the formation of Ni complexes with different geometries, is hypothesized.

Nickel/magnesium interactions in nickel-sensitive patients.

Experimentally demonstrated interactions between Ni2+ and Mg2+ were examined in human beings. 110 subjects patch-test-positive to 10 microliters aq. NiSO4 0.1 M were subdivided into groups of 30, 50 and 30 people. Each subgroup was tested to 10 microliters NiSO4 0.1 M solution as a control and to mixed solutions containing NiSO4 0.1 M together with, respectively MgSO4 0.1 and 0.3, 0.3 and 0.5 and 0.5 and 1 M. On increasing the applied concentrations of MgSO4, the % of patients with reduced or suppressed nickel reactions, with 1 exception, proportionally increased. The exception concerned testing with 0.5 M, where a paradoxically exacerbating increase in nickel reactions was seen in a majority of nickel-sensitive subjects. MgCl2 aq. at 0.3, 0.5 and 1 M concentrations was not able to reduce the cutaneous patch test positive reactions to NiCl2 0.1 M in 25 sensitive patients. On increasing the applied concentrations of MgCl2, both the number and intensity of patch test reactions to NiCl2 proportionally increased. A supposed rôle of the sulfate and chloride counterions in the penetration of nickel was examined in 30 NiSO4 5% patch-test-positive patients, testing to 10 microliters of aq. NiSO4 0.1 M, NiCl2 0.1 M, NiSO4 0.1 M + MgCl2 0.3 M, NiCl2 0.1 M + MgSO4 0.3 M, Na2SO4 0.3 M, NaCl 0.3 M, NiSO4 0.1 M + Na2SO4 0.3 M, NiCl2 0.1 M + NaCl 0.3 M. The findings suggest that the addition of sulfate or chloride to nickel could determine the formation of different Ni complexes directed toward different targets, one Mg(2+)-dependent, the other Mg(2+)-independent.

Multiple sensitivities to transition metals: the nickel palladium reactions.

Patch test data of 1000 consecutive patients sensitive to at least 1 substance of our standard series showed that transition metals gave associated reactions amongst themselves more frequently than they did with the remaining substances. The responses to transition metals were largely variable and seemed dependent not only upon the associated exposure to different metals or the concomitant responses of the T cell clones, as reported by others, but also upon the chemical properties of the metals and the consequent interactions inside the skin. Concomitant reactions to nickel sulfate and palladium chloride were the most frequently found associated positivities and occurred in a minority of nickel-sulfate-sensitive subjects. In 43 out of 45 of these subjects, patch tests to mixed solutions containing nickel sulfate, plus sulfates of magnesium, zinc, and manganese at higher doses, were not able to reduce the nickel sulfate reactions. This behaviour contrasted with that found in the majority of subjects sensitive only to nickel sulfate. These findings seem to demonstrate that, whilst in subjects with positive reactions to nickel sulfate alone antigen formation involves biomolecules containing ions, in those with concomitant reactions to palladium chloride, other structures are involved.

Hypertrophic allergic contact dermatitis from hair dye.

We report a case of hypertrophic allergic contact dermatitis probably due to p-phenylenediamine (PPDA) in a 26-year-old female, which developed at the sites of application of a black hair dye to the skin. Histological examination revealed an eczematous process. The lesions subsided completely except for leukoderma that remained on the leg. Patch tests showed positive reactions to PPDA, p-aminophenol and Disperse Orange 3. PPDA, which was one of the components of the dye, was considered to be the primary sensitizer because it was the only substance able to reproduce at the patch test site both the hypertrophic pattern and the permanent leukoderma found in the patient's lesions. To explain the difference in reaction between PPDA and the other 2 para-group substances, we speculate that they are due to different quantities of reactive intermediates, oxidation products and free radicals, produced by these substances.

Nickel dermatitis from cheap earrings.

In 1988, 64% of our patients patch test positive to at least 1 allergen of the ICDRG standard series were nickel sensitive. In 70% of 300 patients evaluated, dermatitis started on the earlobes and was related to the regular wearing of cheap earrings. At the same time, 62% of 735 young schoolgirls were found to have dermatitis of their earlobes and all regularly wore cheap earrings. 9 clasps and clips commonly used in earrings released high quantities of nickel ions (between 49 and 103 micrograms/12 h), having been stored in synthetic sweat. A round piece cut from a clasp was taped to the skin of 30 nickel-sensitive patients, previously tested with 20 microliters of NiSO4 5%, 2.5%, 1% aq. solutions, giving a response similar to that caused by the 5% solution. High daily absorption of Ni ions through the skin follows its repetitive exposure to cheap earrings, causing, firstly, a direct inflammatory reaction, then followed, in our opinion, by sensitization.

Scavenging effects of terbinafine on free radicals in vitro.

One of the goals of antifungal therapy is to combine an anti-inflammatory activity with antimycotic properties, and therefore it is interesting to evaluate the capacity of active antifungal drugs to interfere with different phases of the inflammatory reaction. In order to identify a possible scavenger property of free radical species of the antifungal agent terbinafine, we studied its activity on the reduction of nitrotetrazolium blue chloride (NTB), induced by superoxide anions with the ultraviolet (UV)- and chemical-induced peroxidation of unsaturated lipid targets. NTB reduction was followed by spectrophotometer and the decomposition of squalene or methyl arachidonate by gas chromatography-mass spectrometry. Terbinafine (20 microgram and over) was capable of significantly inhibiting NTB reduction, indicating that the drug scavenges superoxide anion radicals. In these conditions no modifications of the concentration of the drug, as evaluated by high performance liquid chromatography, were observed. The UV- or chemically induced peroxidation of squalene and arachidonic acid was significantly reduced in the presence of 50 microgram of terbinafine, suggesting that the substance interferes with the chemical properties of peroxyl radicals. In all the tests used the degree of inhibition was proportional to the amount of free radicals generated. In conclusion our results indicate that terbinafine, at therapeutic concentrations, can be considered to be a free radical interceptor in vitro and could exert a mild anti-inflammatory activity in vivo.

Thimerosal positivities: patch testing to methylmercury chloride in subjects sensitive to ethylmercury chloride.

The aim of this paper was to evaluate whether methylmercury chloride (MeHgCl) aq., when patch tested in a group of thimerosal-positive subjects reacting to ethylmercury chloride (EtHgCl), might be a reliable model for the better understanding of interactions between alkylmercury compounds and the skin. 19 out of 21 consecutive patients who previously had given positive patch-test reactions to both ethylmercury chloride 0.0165% eth.(EtHgCl, 0.615 mM) and MeHgCl 0.031% aq.(1.23 mM), and negative reactions to thiosalicylic acid 0.05% (3.24 mM) aq./eth. 50/50, were repatch tested to 8 microl of MeHgCl 0.031% aq. and to 8 microl of aq. solutions containing MeHgCl mixed with cysteine, glutathione, ZnSO4, MgSO4, MnSO4, ZnCl2, MgCl2 and MnCl2, respectively. The results showed that cysteine, glutathione and Zn(II) salts were able to abolish the positive reactions, demonstrating the rôle played by both thiol groups and Zn(II) itself. Patch tests concomitantly carried out in 16 out of 19 patients to 8 microl of aqueous MeHgCl and to 8 microl of aqueous solutions containing MeHgCl and MeHgCl mixed to fragment 56-61 of metallothionein I (MT I), MT I and MT II-Zn, respectively, revealed that all the MTs tested were able to reduce or to inhibit the reactions, demonstrating the effect of the thiol groups. Due to the close chemical similarities to EtHgCl and to its water solubility, MeHgCl seems to be a suitable model for evaluating the reactivity of alkylmercury compounds in the skin. We speculate that both EtHg- and MeHg-derivatives are xenobiotics with similar reactivity. However, the lack of clinical relevance of the reactions to both alkyl compounds lead us to conclude that, since environmental exposure does not seem to play a pivotal rôle, they probably have mostly to do with compounds included in in the standard series, and are elicited by reduced function of physiological SH chelators.

Thimerosal positivities: the rôle of SH groups and divalent ions.

For a better understanding of the mechanistic details of the interactions of organomercury compounds inside the skin, 32 subjects who previously had given positive patch-test reactions to thimerosal (TH) and negative reactions to thiosalicylic acid, were divided into 2 groups. 16 subjects were repatch tested to ethylmercury chloride (EtHgCl) and to solutions containing EtHgCl mixed with L-cysteine and glutathione, respectively. The remaining 16 were repatch tested to EtHgCl and to solutions containing EtHgCl mixed with chlorides of Zn, Mg, and Mn, respectively. The results showed that whilst L-cysteine, glutathione and ZnCl2 were able to abolish or to reduce the positive reactions to EtHgCl, chlorides of Mg and Mn were unable to do so. Patch tests revealed that in causing positive reactions to TH, EtHg probably interacted with thiol groups and with Zn ions, as in biological systems when causing toxic effects. The limited number of TH reactions in the general population, the constant presence of concomitant positive reactions to EtHgCl and MeHgCl, and the lack of cross-reactivity with other organic or inorganic mercury compounds, lead us to speculate that reactions to TH are due to organomercury alkyl compounds, and that positive subjects have a constitutively reduced capability to metabolize organomercury compounds, rather than to reveal previous exposure.

Thimerosal positivities: the role of organomercury alkyl compounds.

Contact allergy to thimerosal (TH) has not been considered a marker for mercury allergy, since there is a low degree of cross-sensitivity to inorganic as well as to organic mercury salts. 40 subjects, who previously gave a positive patch test reaction only to thimerosal 0.1% pet. (Hermal), when simultaneously repatch-tested to solutions containing TH, mersalyl acid, p-amino-phenylmercuric acid, mercuric acetate and thiosalicylic acid, respectively, gave positive reactions only to TH. 36 out of 40 subjects were divided into 2 groups of 18 subjects and simultaneously repatch-tested to solutions containing TH, methylmercury chloride (MeHgCl), thiosalicylic acid, and, ethylmercury chloride (EtHgCl), respectively. EtHgCl was tested in the 1st group at 0.031% and in the 2nd group at 0.015%. The results showed that all subjects gave concomitant positive reactions to TH, EtHgCl and MeHgCl. EtHgCl 0.031% gave a higher number of reactions than EtHgCl 0.015%, underlining the rôle of the solvent in these reactions. Patch test results in 300 consecutive patients to a standard series, to which MeHgCl was added, showed that MeHgCl and TH were never able to give isolated positive reactions, and that the concomitant positive reactions occurred in only 3.6% of subjects. In conclusion, our data seem to suggest that the positive reactions to TH found in our patients were due to EtHgCl, and that the structural similarities with MeHgCl were so close that the skin reacted against each as if they were identical.