Skin penetration and lag times of neat and aqueous diethyl phthalate, 1,2-dichloroethane and naphthalene

Cutaneous exposures to occupational chemicals may cause toxic effects. For any chemical, the potential for systemic toxicity from dermal exposure depends on its ability to penetrate the skin. Most laboratory studies measure chemical penetration from an aqueous solution through isolated human or laboratory animal skin, although most exposures are not from pure aqueous solutions. The US EPA Interagency Testing Committee (ITC) mandated by the Toxic Substances Control Act, has required industry to measure the in vitro penetration of 34 chemicals in their pure or neat form (if liquid). The goal of the present study was to measure skin permeability and lag time for three neat chemicals of industrial importance, representing the general types of chemicals to be studied by the ITC (non-volatile liquids, volatile liquids, and solids), and to examine interlaboratory variation from these studies. Steady state fluxes and lag times of diethyl phthalate (DEP, slightly volatile), 1,2-dichloroethane (DCE, highly volatile), and naphthalene (NAP, solid) were studied in two different laboratories using different analytical methods. One lab also measured fluxes and lag times from saturated aqueous vehicle. Static diffusion cells, dermatomed hairless guinea pig skin, and gas chromatography were used to measure skin penetration. In the two laboratories, the steady state fluxes (mean+/-SD; microg cm(-2)hour(-1)) of DEP applied neat were: 11.8+/-4.1 and 23.9+/-7.0; fluxes of DCE (neat) were 6280+/-1380 and 3842+/-712; fluxes of NAP from powder were 30.4+/-2.0 and 7.5+/-4.7. Compared with neat fluxes measured in the same laboratory, flux from saturated aqueous solution was higher with DEP (1.9 x) but lower with DCE (0.17 x) and NAP (0.45 x). The three chemicals studied including a dry powder, demonstrate the potential for significant dermal penetration.     

Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease

Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA–gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA–gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD.Celiac disease (CD) is an inflammatory enteropathy induced by gluten-derived prolamines in genetically susceptible individuals. CD affects about 1 in 100 individuals in Europe and the United States (1, 2). The associated intestinal inflammation results from synergism between innate and adaptive immune responses to gliadin peptides. The adaptive immune response is orchestrated by CD4⁺ T cells recognizing various deamidated gliadin peptides (3), including a 33-mer (peptide 56-88 [p56-88]) (4), bound to HLA-DQ2/8 molecules (5). p56-88 is a powerful immunodominant gliadin peptide extremely resistant to gastrointestinal digestion and has far higher T cell stimulatory potency than its 12-mer counterparts (6). The innate immune response in CD is triggered by a distinct set of gliadin peptides: one prototype innate peptide is p31-49, common to the N terminus of A-gliadins and shown to be toxic for CD patients both in vitro and in vivo (7–9). This peptide was recently shown to stimulate the synthesis of IL-15 (10, 11), a proinflammatory cytokine that can promote the CD4⁺ adaptive immune response (11) and activate cytotoxic activity and IFN-γ production in intraepithelial lymphocytes (12–14).This activation of the local immune system implies that undigested gliadin fragments present in the intestinal lumen somehow cross the intestinal epithelium. Indeed, apical to basal transport and processing of gliadin peptides, particularly of p31-49 and 33-mer, are severely altered in active CD, leading to the release of intact peptides on the basal side, whereas the same peptides are almost entirely degraded during their intestinal transport in control individuals and treated CD patients (15, 16). Several lines of evidence argue against simple nonspecific paracellular leakage of gliadin peptides across the celiac mucosa. In particular, a 12-mer gliadin peptide, p57-68, is completely degraded during intestinal transport in patients with active CD, suggesting no paracellular leakage of molecules of this size or larger. In addition, only 0.3% of the apical peptide crosses the epithelium during a 3-h incubation period, arguing against free diffusion across a damaged mucosa. The “protected” transport of p31-49 thus involves a transcellular pathway (15, 16), which enables the peptide to escape lysosomal degradation. As active CD is associated with high concentrations of antigliadin IgA antibodies in the intestinal lumen (17, 18), we postulated that the transport of intact gliadin peptides might result from abnormal retrotranscytosis of IgA–gliadin complexes. Indeed, although antigliadin IgA antibodies are a hallmark of CD, they have no known pathogenic role. We obtained evidence that polymeric/secretory IgA (pIgA/SIgA) can mediate protected transport of p31-49 and 33-mer gliadin peptides through their binding to CD71, the transferrin (Tf) receptor. Importantly, we found that this receptor was abnormally expressed at the apical pole of enterocytes in patients with active CD. Although initially implicated in endocytosis of iron-loaded Tf, CD71 was recently recognized as an IgA receptor mediating mesangial deposition of IgA1 complexes in IgA nephropathy (19).     

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.     

Unusual presentation of benign cystic brenner tumor with exuberant psammomatous calcifications

Transitional cell tumors of the ovary comprise about 1% to 2% of all ovarian neoplasms. Most of these tumors are benign Brenner tumors and account for about 5% of benign surface epithelial-stromal tumors. Spicules of calcifications are found in the stroma of about 50% of benign Brenner tumors. Although diagnostic challenges might occur more frequently with either of the borderline or malignant Brenner tumors, this problem is not that common when diagnosing a benign Brenner tumor. This study reports a case of benign Brenner tumor with exuberant dystrophic calcifications that obscured most of the epithelium and posed a diagnostic challenge in differentiating it from the more common malignant counterparts such as serous carcinoma and specifically psammocarcinoma.     

Cerebral vasculitis in a patient with rheumatoid arthritis

Inflammatory vasculitis of the central nervous system is exceedingly rare in patients with rheumatoid arthritis (RA). The symptoms may be misleading. Most of the reported cases occurred in males with long-standing, nodular, destructive, rheumatoid factor-positive disease. Severe constitutional symptoms and prominent extraarticular manifestations of vasculitis were usually present. We report a case of cerebral vasculitis in a 59-year-old woman with a 20-year history of destructive rheumatoid factor-positive RA that was well controlled by methotrexate. Headache that was unresponsive to symptomatic treatment developed abruptly, together with gait disorders. Magnetic resonance imaging of the brain showed dot-like areas of high-signal in a periventricular subcortical distribution on both sides. Magnetic resonance angiography visualized a long tight stenosis of the right internal carotid artery and a string-of-beads stenosis of the left internal carotid artery suggesting vasculitis. Pulse therapy with methylprednisolone (1 g/d for 3 days) and cyclophosphamide (1 g) once a month ensured resolution of the neurological symptoms and laboratory evidence of inflammation. There was no evidence of a relapse at last follow-up after 5 months. Cerebral vasculitis is usually treated with monthly glucocorticoid and cyclophosphamide boluses separated by continuous glucocorticoid therapy. TNFalpha antagonists may be effective in patients who fail to respond to conventional treatment. However, other vasculitides such as giant cell arteritis and Wegener's granulomatosis must be ruled out, as they are refractory to TNFalpha antagonist therapy.     

An outbreak of nosocomial cholera in a rural Bangladesh hospital

At a time of year when Vibrio cholerae infection accounted for over 50% of admissions to a rural Bangladeshi diarrhoea treatment centre, 29% of 48 patients hospitalized with non-cholera diarrhoea developed nosocomial V. cholerae infection. During an investigation of the 8-week outbreak, only the severity of the non-cholera diarrhoea which prompted hospital admission emerged as an important risk factor for nosocomial infection; food, intravenous solutions, oral rehydration fluid, patient attendants and hospital personnel could not be implicated as transmission sources. Patients receiving antibiotics while hospitalized did not develop nosocomial infection. Antecedent non-cholera diarrhoea may represent an important risk factor in some cases of V. cholerae infection occurring in persons who reside in cholera-endemic areas where rates of non-cholera diarrhoea are also high.     

Investigation of structural,morphological, and transport properties of a multifunctional Li-ferrite compound

The development of multifunctional materials is an exceptional research area, which is aimed at enhancing the versatility of materials in various applications. In this context, the exceptional properties of ferrite materials have attracted the attention of researchers. For this reason, we synthesized LiMn_0.5Fe₂O₄ sintered at a temperature of 1100 °C. The X-ray powder diffraction analysis reveals the presence of one cubic phase with the Fd$\bar{3}$m space group and confirms the spinel structure formation. Moreover, the elemental analysis by EDX reveals the homogeneous distribution of iron and manganese cations. Scanning electron microscopy shows that the grain size is of the order of 2.48 μm. Impedance spectroscopy was performed in the temperature and frequency ranges from 200 K to 380 K and 40 Hz to 10⁶ Hz, respectively. The Nyquist plots revealed the presence of grains and grain boundary contributions. The semiconductor nature, obtained by the conductivity study, indicates that LiMn_0.5Fe₂O₄ is promising in optoelectronic applications. Dc conductivity is found to be thermally activated with an activation energy of 370 meV, 255 meV, and 199 meV for 200–270 K, 280–330 K, and 340–380 K regions, respectively. From the Jonscher power law, the correlated barrier hopping model (CBH) and non-overlapping small polaron tunneling (NSPT) prevailed in the conduction process. Besides, the temperature coefficient of resistivity (TCR) affirmed that LiMn_0.5Fe₂O₄ is a good candidate for detecting infrared radiations and infrared bolometric applications.

Oxide lithium-manganese ferrite spinel representation, with stoichiometry LiMn_0.5Fe₂O₄, in the (110) plane.     

Mice chronically fed a westernized experimental diet as a model of obesity, metabolic syndrome and osteoporosis

Background Most studies in animals use diets with several features (for example low-fat, rich in micronutriments), likely to be strongly protective against chronic diseases. Aim of the study The present study, performed in wild type outbred mice, was designed to evaluate the validity of a model of ‘westernized’ (W) diet reproducing, as closely as possible, the overall composition of an average human regime in western countries Results In contrast to the standard (S) diet, the W diet triggered a marked increase in adiposity with some characteristics of metabolic syndrome (hypercholesterolemia, hyperinsulinemia...). There was an heterogeneity in the propensity to become obese upon exposure to the W diet in female mice. Overweight mice also presented some disturbances of renal function, such as hyperalbuminuria and hypocitraturia. Mice adapted to the W diet showed a reduction of bone mineral density, especially the non-obese ones. Conclusion These data suggest that a model of westernized diet could be appropriate for exploring the effects of mutations, drugs, or specific nutritional factors in animals and could be more relevant for human situations.     

MiR-181a-5p inhibits uveal melanoma development by targeting GNAQ and AKT3

Uveal melanoma (UM) is the most common primary intraocular malignant tumor type in adults. Even after the treatment of the ocular tumor, the prognosis of patients with metastasis remains poor. Hence, an urgent unmet need exists to identify novel approaches to treat advanced UM. Previous studies have revealed G subunit alpha Q and alpha 11 (GNAQ/11) mutations in more than 85% of patients with UM, thus indicating the importance of GNAQ and downstream signaling pathways in UM occurrence. Here, we demonstrate that microRNA (miR)-181a-5p, a small non-coding RNA, effectively inhibited the viability, proliferation, and colony formation but induced apoptosis of UM cells. Furthermore, silencing GNAQ or AKT3 mimicked the anti-UM effects of miR-181a-5p, whereas overexpression of GNAQ or AKT3 rescued the anti-UM effects induced by miR-181a-5p. In addition, miR-181a-5p had a stronger effect in decreasing the viability of GNAQ mutant than GNAQ wild-type cells. Moreover, miR-181a-5p suppressed the total expression and phosphorylation of members of the ERK and PI3K/AKT/mTOR signaling pathways. Importantly, miR-181a-5p potently inhibited the growth of UM xenografts in nude mice. MiR-181a-5p also decreased the expression of Ki67, GNAQ, and AKT3, and induced the expression of cleaved-caspase3 in UM tumors. These results suggest that miR-181a-5p inhibits UM development by targeting GNAQ and AKT3.