Comprehensive in vitro pro-arrhythmic assays demonstrate that omecamtiv mecarbil has low pro-arrhythmic risk.

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro-arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow-up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half-maximal inhibitory concentration [IC50 ] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC50  > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro-arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro-arrhythmia risk at OM concentration up to 30 µM (100-fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)60 and APD90 significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non-rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro.

Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established. Measuring the expression of surrogate genes for NRF2 activity in silico, in combination with validation in patients' samples, we show that the NRF2 pathway is upregulated in colorectal tumours and that high levels of nuclear NRF2 correlate with a poor patient prognosis. These results highlight the need to overcome the protection provided by NRF2 and present an opportunity to selectively kill cancer cells with hyperactive NRF2. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2 and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 in colorectal cancer cells might present a vulnerability that could potentially be therapeutically exploited by using the Aurora kinase inhibitor AT9283.

Effect of urea-supplemented diets on the ruminal bacterial and archaeal community composition of finishing bulls.

In this study, we evaluated the effects of urea-supplemented diets on the ruminal bacterial and archaeal communities of finishing bulls using sequencing technology. Eighteen bulls were fed a total mixed ration based on maize silage and concentrate (40:60) and randomly allocated to one of three experimental diets: a basal diet with no urea (UC, 0%), a basal diet supplemented with low urea levels (UL, 0.8% dry matter (DM) basis), and a basal diet supplemented with high urea levels (UH, 2% DM basis). All treatments were iso-nitrogenous (14% crude protein, DM basis) and iso-metabolic energetic (ME = 11.3 MJ/kg, DM basis). After a 12-week feeding trial, DNA was isolated from ruminal samples and used for 16S rRNA gene amplicon sequencing. For bacteria, the most abundant phyla were Firmicutes (44.47%) and Bacteroidetes (41.83%), and the dominant genera were Prevotella (13.17%), Succiniclasticum (4.24%), Butyrivibrio (2.36%), and Ruminococcus (1.93%). Urea supplementation had no effect on most phyla (P > 0.05), while there was a decreasing tendency in phylum TM7 with increasing urea levels (P = 0.0914). Compared to UC, UH had lower abundance of genera Butyrivibrio and Coprococcus (P = 0.0092 and P = 0.0222, respectively). For archaea, the most abundant phylum was Euryarchaeota (99.81% of the sequence reads), and the most abundant genus was Methanobrevibacter (90.87% of the sequence reads). UH increased the abundance of genus Methanobrevibacter and Methanobacterium (P = 0.0299 and P = 0.0007, respectively) and decreased the abundance of vadinCA11 (P = 0.0151). These findings suggest that urea-supplemented diets were associated with a shift in archaeal biodiversity and changes in the bacterial community in the rumen.

Atypical antipsychotic therapy in Parkinson's disease psychosis: A retrospective study.

OBJECTIVE: Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs. METHODS: A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs. RESULTS: Forty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs. LIMITATIONS: This study was limited by its retrospective study design and small sample size and with likely selection bias. CONCLUSIONS: The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT 2A inverse agonist, pimavanserin, could be a better alternative in the treatment of PDP.

Pimavanserin: First Global Approval.

Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis.

Performance of lactating crossbred cows on pasture supplemented with conventional urea or slow release urea / Desempenho de vacas mestiças lactantes em pasto suplementadas com ureia convencional ou ureia de liberação lenta

The effect of using conventional urea (CU) or slow release urea (SRU) was evaluated by replacing soybean meal (SBM) in concentrated supplements in levels of 2, 4 or 6% (dry matter basis) on productive performance of crossbred Holstein x Zebu lactating dairy cows (499±61kg body weight and 167 days of lactation) grazing on elephant grass (11.5% CP and 60% NDF) under rotational grazing during the rainy season. A supplement control (no urea) was used containing SBM as a protein source. A total of 21 cows were distributed an incomplete randomized block design with three periods of 21 days each (14 days of adaptation and seven days of collection). The animals entered the paddocks with a pasture height of 110-120cm and left when the grass reached the height of 40-50cm. The concentrated isonitrogenous supplements (24% crude protein, dry matter basis) were provided in the amount of 3.2kg/cow/day (fed basis). There was no effect (P>0.05) on source of crude protein (SBM vs source NPN), source NPN, level of NPN, interaction between source NPN and level of NPN on milk production (10.0kg/day), fat milk production corrected to 3.5% (10.7kg/day), levels of fat (4.01%), protein (3.66%), lactose (4.16%), total solids (12.86%) and non-fat solids (8.60%) in milk. The replacement of CU by SRU does not promote improvement in the productive performance of crossbred dairy cows grazing on elephant grass during the rainy season. Urea (CU or SRU) can be included in up to 6% of the DM concentrated supplements, replacing SBM, without affecting the productive performance of crossbred cows (Holstein x Zebu) in pasture during the rainy season...

Avaliou-se o efeito da utilização de ureia convencional (UC) ou de ureia de liberação lenta (ULL) em suplementos concentrados, nos níveis de 2, 4 ou 6% (base da matéria seca), em substituição ao farelo de soja, sobre o desempenho produtivo de vacas mestiças Holandês x Zebu (499±61kg de peso corporal e 167 dias de lactação) mantidas em pastos de capim-elefante (11,5% de proteína bruta e 60% de FDNcp), sob lotação intermitente, no período das chuvas. Um suplemento controle (sem ureia) foi utilizado contendo farelo de soja como fonte proteica. Foram utilizadas 21 vacas, distribuídas em delineamento em blocos incompletos balanceados, com três períodos de 21 dias cada (14 dias de adaptação e sete dias de coleta). Os animais entraram nos piquetes com altura do pasto de 110-120cm e saíram quando atingiram altura de 40-50cm. Os suplementos concentrados isonitrogenados (24% de proteína bruta, base da matéria seca) foram fornecidos na quantidade de 3,2kg/vaca/dia (base da matéria natural). Não houve efeito (P>0,05) de fonte de proteína bruta (farelo de soja vs. fonte de NNP), de interação entre fonte de NNP (UC vs. ULL) e nível de NNP (2, 4 e 6% na MS do suplemento), de fonte de NNP e de nível de NNP e sobre a produção de leite (10,0kg/dia), produção de leite corrigida para 3,5% de gordura (10,7kg/dia), teores de gordura (4,01%), proteína (3,66%), lactose (4,16%), extrato seco total (12,86%) e extrato seco desengordurado (8,60%) no leite. A substituição da ureia convencional pela ULL não promove melhoria no desempenho produtivo de vacas leiteiras mestiças em pastagem de capim-elefante, no período das chuvas. A ureia (convencional ou de liberação lenta) pode ser incluída em até 6% na MS de suplementos concentrados, em substituição ao farelo de soja, sem afetar o desempenho produtivo de vacas mestiças (Holandês x Zebu) em pastagem, no período das chuvas...

Can green tea be used to reverse compromised bond strength after bleaching?

The objective of this study was to evaluate the antioxidant effect of green tea on microtensile bond strength (µTBS) to bleached enamel. Forty-two human third molars were randomly divided into six experimental groups (n = 7 each group): group 1, no treatment; group 2, bleaching (10% carbamide peroxide); group 3, bleaching + 10% sodium ascorbate gel (SA); group 4, bleaching + 10% green tea gel (GT); group 5, SA; and group 6, GT. In groups 2, 3, and 4, bleach was applied onto the enamel surface for 6 h, every day for 14 d. In groups 3 and 5, SA was applied for 1 h; and in groups 4 and 6, GT was applied for 1 h. Immediately after treatment, the specimens were bonded with Adper Single Bond 2 and Filtek Z350 XT. The µTBS of the specimens was tested using a universal testing machine. Fracture mode analysis of the bonded enamel surface was performed using scanning electron microscopy. The mean µTBS values for each group were: group 1, 33.2 ± 5.8 MPa; group 2, 22.6 ± 5.5 MPa; group 3, 30.0 ± 5.2 MPa; group 4, 31.6 ± 3.8 MPa; group 5, 29.1 ± 4.2 MPa; and group 6, 32.2 ± 4.5 MPa. All groups had a higher percentage of mixed failures. In conclusion, green tea can be used as an alternative antioxidant on bleached enamel before bonding procedures.

Effect of salivary factors on the susceptibility of hydroxyapatite to early erosion.

OBJECTIVE: Salivary pellicle is known to reduce the erosion of enamel and differences in the level of protection exist between individual saliva sources, but which parameters or components are important is not known. The focus of this study was to investigate the relationship between saliva parameters and early erosion of hydroxyapatite (HAp) with an in situ grown saliva film. METHODS: Twenty-eight volunteers carried two HAp and one porcelain discs in their buccal sulcus for 1.5 h. Next, the discs covered with pellicle and the attached saliva film were exposed extraorally to 50 mM (pH = 3) citric acid for 2 min and unstimulated and stimulated saliva was collected. Calcium loss from HAp after erosive challenge was measured, corrected for calcium loss from pellicle on porcelain discs and averaged. Several salivary parameters were analysed. Pearson's linear correlation and multiple regression analysis were used to study the relation between saliva parameters and HAp erosion. RESULTS: Significant correlations were found between HAp erosion and the concentration of phosphorus in unstimulated saliva (r = 0.40, p = 0.03) and between HAp erosion and the concentration of sodium (r = -0.40, p = 0.03), chloride (r = -0.47, p = 0.01), phosphorus (r = 0.45, p = 0.01) and flow (r = -0.39, p = 0.04) of stimulated saliva. Multivariate analysis revealed a significant role in the HAp erosion for sodium, urea, total protein, albumin, pH and flow of unstimulated saliva and for sodium, potassium, urea, and phosphorus of stimulated saliva. CONCLUSIONS: Several salivary parameters are associated with the susceptibility of HAp to erosion.

Non-fragrance allergens in specific cosmetic products.

OBJECTIVES: Reports about the nature of the ingredients responsible for allergic contact dermatitis caused by specific cosmetic products are scarce. METHODS: Between January 2000 and December 2010, the specific cosmetic products having caused allergic contact dermatitis, as well as the individual allergenic cosmetic ingredients present in them, were recorded by use of a standardized form. RESULTS: Among 11 different categories of cosmetic product, skin care products, followed by hair care and body-cleansing products, were most often involved. The presence of the allergenic ingredient(s) in a specific cosmetic product was confirmed according to the ingredient label in 959 of 1448 records. Six hundred and twenty-one of 959 concerned non-fragrance components, preservatives being responsible for 58% of them. Reactions to formaldehyde and formaldehyde-releasers were most often correlated with body-cleansing products, particularly 2-bromo-2-nitropropane-1,3-diol and skin care products. They were followed by the methylchloroisothiazolinone/methylisothiazolinone mixture, most frequently found as allergens in hair care and intimate hygiene products, and facial cleansers (in the last category together with diazolidinyl urea). Octocrylene was by far the most frequent (photo)allergen in sun care products. CONCLUSIONS: This study provides information on the presence and frequency of allergens in specific causal cosmetic products.

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer.

AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. The in vivo antitumor activity of AT-9283 has also been demonstrated in human tumor xenograft models. Based on these preclinical studies, several clinical trials have been conducted in patients with hematological malignancies, such as leukemias, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, lymphomas and multiple myeloma, and also in patients with solid tumors. Although phase II clinical trials have not been completed, AT-9283 demonstrated good safety and efficacy in phase I clinical trials. Thus, AT-9283 has potential as a therapeutic agent in several patient populations through its different inhibitory activities.

Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.

RATIONALE: Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders. OBJECTIVES: The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop co-morbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice. RESULTS: Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity. CONCLUSIONS: These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders.

The effect of 16 percent carbamide peroxide on enamel staining susceptibility.

STATEMENT OF PROBLEM: Recently, vital bleaching by carbamide peroxide has become more popular; therefore, it is necessary to study the effect of this agent on enamel and dentin. PURPOSE: The purpose of this study was to evaluate the effect of a 16 percent carbamide peroxide bleaching gel, Vivastyle, on enamel staining susceptibility. MATERIALS AND METHODS: Thirty bovine specimens were selected and randomly divided into two groups of 15. The experimental group was subjected to Vivastyle gel and then was immersed in coffee for half an hour daily for three weeks. The control group was only immersed in coffee. The teeth were evaluated using a colorimeter to measure L*, a*, b* of each tooth. Value (black to white) is denoted as L*, wheres chroma (a* b*) is denoted as red (+a*), green (_a*), yellow (+b*), and blue (_b*). Total color differences between two colors (deltaE) were calculated using the following formula: deltaE = [(deltaL*)2 + (deltaa*)2+(deltab*)2]: deltaE1.Bleached, AE2: bleached and immersed in coffee, deltaE3: immersed in coffee. RESULTS: Mean differences were: deltaE1 = 9.478, deltaE2 = 13.808 and deltaE3 = 7.230. Paired comparison by use of Duncan test showed there was a significant difference between deltaE1 and deltaE2 (P0.000); and t test showed there was no significant difference between deltaE3 and deltaE1. (P0.08 > 0.05), but deltaE3 showed a significant difference with deltaE2(P0.000). CONCLUSION: After vital bleaching, the enamel staining susceptibility significantly increased.

Daily and alternate day supplementation of urea or biuret to ruminants consuming low-quality forage: I. Effects on cow performance and the efficiency of nitrogen use in wethers.

Two experiments were conducted to determine the influence of supplemental nonprotein N (NPN) provided daily (D) or every other day (2D) on ruminant performance and N efficiency. Treatments included an unsupplemented control (CON) and a urea (28.7% CP) or biuret (28.6% CP) supplement provided D or 2D at 0700. In Exp. 1, five wethers (39 +/- 1 kg BW) were used in an incomplete 5 x 4 Latin square with four 24-d periods to determine the influence of supplemental NPN source and supplementation frequency (SF) on the efficiency of N use in lambs consuming low-quality grass straw (4% CP). The amount of CP supplied by each supplement was approximately 0.10% of BW/d (averaged over a 2-d period). In Exp. 2, 80 Angus x Hereford cows (540 +/- 8 kg BW) in the last third of gestation were used to determine the effect of NPN source and SF on cow performance. The NPN treatments were formulated to provide 90% of the estimated degradable intake protein requirement. The supplemented treatments received the same amount of supplemental N over a 2-d period; therefore, the 2D treatments received double the quantity of supplemental N on their respective supplementation day than the D treatments. In Exp. 1, total DM, OM, and N intake; DM, OM, and N digestibility; N balance; and digested N retained were greater (P < 0.03) for supplemented than for CON wethers, with no difference (P > 0.05) between NPN sources or SF. Plasma urea-N (PUN) was increased with N supplementation compared with CON (P < 0.01), and urea treatments had greater PUN than biuret (P < 0.01). In addition, PUN was greater (P = 0.02) for D than for 2D treatments. In Exp. 2, pre- and postcalving (within 14 d and 24 h after calving, respectively) cow weight and body condition score change were more positive (P < 0.05) for supplemented groups than for CON. These results suggest that supplements containing urea or biuret as the primary source of supplemental N can be effectively used by lambs and cows consuming low-quality forage, even when provided every other day.

Daily and alternate-day supplementation of urea or biuret to ruminants consuming low-quality forage: III. Effects on ruminal fermentation characteristics in steers.

Five ruminally and duodenally cannulated steers (491 +/- 21 kg BW) were used in an incomplete 5 x 4 Latin square with four 24-d periods to determine the influence of supplemental nonprotein N (NPN) source and supplementation frequency (SF) on the dynamics of ruminal fermentation in steers consuming low-quality grass straw (4% CP). Treatments (TRT) included an unsupplemented control (CON) and a urea or biuret supplement that were placed directly into the rumen at 0700 daily (D) or every other day (2D). The NPN treatments were formulated to provide 90% of the estimated degradable intake protein requirement; therefore, the urea and biuret treatments received the same amount of supplemental N over a 2-d period. Daily TRT were supplemented with CP at 0.04% of BW/d, whereas the 2D TRT were supplemented at 0.08% of BW every other day. Forage was provided at 120% of the previous 5-d average intake in two equal portions at 0715 and 1900. Ruminal fluid was collected 0, 3, 6, 9, 12, and 24 h after supplementation on a day of and a day before supplementation for all TRT. Ruminal NH3-N increased (P < 0.04) with CP supplementation on the day all supplements were provided and on the day on which only daily supplements were provided compared with the CON. However, an NPN source x SF interaction (P = 0.03) on the day all supplements were provided indicated that NH3-N increased at a greater rate for urea as SF decreased compared with biuret. Ruminal NH3-N on the day only daily supplements were provided was greater (P = 0.02) for D compared with 2D. On the day all supplements were provided, D increased (P = 0.05) ruminal indigestible acid detergent fiber passage rate and ruminal fluid volume compared with 2D. These results suggest that urea or biuret can be used effectively as a supplemental N source by steers consuming low-quality forage without adversely affecting ruminal fermentation, even when provided every other day.

Efficacy of the novel phosphodiesterase-4 inhibitor BAY 19-8004 on lung function and airway inflammation in asthma and chronic obstructive pulmonary disease (COPD).

Selective inhibitors of phosphodiesterase-4 (PDE4) inhibit the hydrolysis of intracellular cAMP, which may result in bronchodilation and suppression of inflammation. We examined the effect of 1 week treatment with BAY 19-8004 (5 mg once daily), a novel orally administered PDE4 inhibitor, on trough FEV1 and markers of inflammation in induced sputum in patients with asthma or chronic obstructive pulmonary disease (COPD). Seven patients with asthma (mean [SD] FEV1 69.5 [9.3]% predicted; reversibility in FEV1 26.2 [10.1]%; all non-smokers) and 11 patients with COPD (FEV1 58.6 [8.3]% predicted; reversibility in FEV1 6.5 [4.7]%; median [range] 44 [21-90] pack years of smoking) were included in this randomized, double-blind, placebo-controlled trial. FEV1 was measured before and after 1 week of treatment; sputum was induced by 4.5% saline inhalation on the last day of treatment. FEV1 did not improve during either treatment in both patient groups (p>0.2). Sputum cell counts were not different following placebo and BAY 19-8004 treatment in asthma and COPD patients (p>0.2). However, only in patients with COPD, small but significant reductions in sputum levels of albumin and eosinophil cationic protein were observed (p<0.05). In conclusion, 1 week of treatment with the selective PDE4 inhibitor BAY 19-8004 does not affect FEV1 and sputum cell numbers in patients with asthma or COPD. However, such treatment does seem to reduce levels of albumin and eosinophil cationic protein in sputum samples obtained from patients with COPD.

Occupational rhinitis and bronchial asthma due to TBTU and HBTU sensitization.

Exposure to an increasing amount of products in the work environment is leading to new cases of occupational asthma among workers. We report the case of a worker at a pharmaceutical plant who developed occupational rhinitis and bronchial asthma due to HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate sensitization, two chemical products widely used in peptide synthesis and coupling. Skin tests (prick test) with HBTU and TBTU solutions in PBS were positive at a concentration of 1 mg/ml. Skin tests with the same solutions in 10 atopic controls yielded a negative result. Nasal challenge tests with these products were positive with HBTU at a concentration of 0.01 mg/ml and TBTU at a concentration of 1 mg/ml. In both cases PNIF (peak nasal inspiratory flow) decreased by more than 60% and severe sneezing and rhinorrhea were induced. Nasal challenge tests performed on 10 atopic controls with TBTU and HBTU at a concentration of 1 mg/ml were negative. We conclude that the patient presents occupational rhinitis and bronchial asthma due to TBTU and HBTU; the operational mechanism is probably immunological IgE-mediated given the positive prick tests and nasal challenge with these products.

In vitro evaluation of human dental enamel surface roughness bleached with 35% carbamide peroxide and submitted to abrasive dentifrice brushing.

The aim of this in vitro study was to evaluate the surface roughness of human enamel bleached with 35% carbamide peroxide at different times and submitted to different superficial cleaning treatments: G1 - not brushed; G2 - brushed with fluoride abrasive dentifrice; G3 - brushed with a non-fluoride abrasive dentifrice; G4 - brushed without dentifrice. Sixty fragments of human molar teeth with 4 x 4 mm were obtained using a diamond disc. The specimens were polished with sandpaper and abrasive pastes. A perfilometer was used to measure roughness average (Ra) values of the initial surface roughness and at each 7-day-interval after the beginning of treatment. The bleaching was performed on the surface of the fragments for 1 hour a week, and the surface cleaning treatment for 3 minutes daily. The samples were stored in individual receptacles with artificial saliva. Analysis of variance and the Tukey test revealed significant differences in surface roughness values for G2 and G3, which showed an increase in roughness over time; G1 and G4 showed no significant roughness differences. The bleaching with 35% carbamide peroxide did not alter the enamel surface roughness, but when the bleaching treatment was performed combined with brushing with abrasive dentifrices, there was a significant increase in roughness values.

Latent coeliac disease in a child with epilepsy, cerebral calcifications, drug-induced systemic lupus erythematosus and intestinal folic acid malabsorption associated with impairment of folic acid transport across the blood-brain barrier.

UNLABELLED: A 15-year-old boy with epilepsy and cerebral calcifications, treated with valproic acid, ethyl phenylbarbiturate and ethosuximide, was referred for drug induced systemic lupus erythematosus. Anti-gliadin (AGA) and anti-endomysium (EMA) antibody tests were both positive (EMA titre 1:50). Endoscopic duodenal biopsy showed intense chronic inflammation without villous atrophy or crypt hyperplasia. The child was discharged with a gluten-containing diet. The follow-up showed an increase in EMA titre (1:200) and the persistence of AGA. After 15 months, a second endoscopic intestinal biopsy showed flat mucosa and villous atrophy. Three serum folic acid determinations showed 1.8, 2.4, 2.0 ng/ml (reference range 2.5-16.9 ng/ml) prior to the two intestinal biopsies, but returned to normal levels (11.8 ng/ml) after a gluten-free diet and oral supplementation together. Two years later, the frequency of epileptic seizures was unchanged despite ongoing anti-epileptic treatment and a gluten-free diet. As cerebral calcification and epilepsy are reminiscent of the findings in congenital folate malabsorption, oral loading tests with 5 mg folic acid were carried out and showed impaired intestinal absorption and a defect in the transport across the blood-brain barrier. Low CSF folate levels (13.9 and 12.6 ng/ml, reference range 15-40 ng/ml) and an alteration in the CSF/serum folate ratio (1.43 and 1.16, normal ratio 3:1) were also found as well as increased levels of cystathionine both in CSF (40 micromol/l, reference range 18-28 micromol/l) and in serum (32 micromol/l, reference value <0.10 micromol/l). CONCLUSION: Impairment of intestinal folic acid absorption with a defect in folic acid transport across the blood-brain barrier has been demonstrated in a case of epilepsy and cerebral calcifications associated with coeliac disease.