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Antiphospholipid syndrome (APS) affects the brain by both hypercoagulation and immunological mechanisms. APS is characterized by several autoantibodies binding to a thrombolytic complex including beta-2-glycoprotein I (β2-GPI) and annexin A2 (ANXA2). Teriflunomide, an oral drug for the treatment of multiple sclerosis (MS), has a cytostatic effect on B cells and is therefore a potential antibody-targeting treatment for APS. In this study, we assessed the effect of teriflunomide in two APS mouse models by inducing autoantibody formation against β2-GPI and ANXA2 in female BALB/c mice. The ANXA2 model displayed a behavioral change suggesting an anti-anxiety effect in open field and forced swim tests, early in the course of the disease. This effect was normalized following teriflunomide treatment. Conversely, behavioral tests done later during the study demonstrated depression-like behavior in the ANXA2 model. No behavioral changes were seen in the β2-GPI model. Total brain IgG levels were significantly elevated in the ANXA2 model but not in the teriflunomide treated group. No such change was noted in the brains of the β2-GPI model. High levels of serum autoantibodies were induced in both models, and their levels were not lowered by teriflunomide treatment. Teriflunomide ameliorated behavioral changes in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with the effect of teriflunomide on neuroinflammation. Teriflunomide ameliorated behavioral and brain IgG levels in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with an effect of teriflunomide on the IgG permeability to the brain and neuroinflammation.

Background: In post hoc analyses of Teriflunomide Multiple Sclerosis Oral study (TEMSO; NCT00134563), teriflunomide 14 mg significantly reduced brain volume loss (BVL) versus placebo in patients with relapsing multiple sclerosis (MS). Objective: In this post hoc analysis of TEMSO and its long-term extension (NCT00803049), we examined the relationship between teriflunomide’s effects on BVL and cognition. Methods: We analyzed data from 709 patients who received teriflunomide 14 mg in TEMSO or its extension. The change in cognitive performance, assessed using the Paced Auditory Serial Addition Test 3 (PASAT-3), was measured in subgroups stratified by BVL over 2 years (least BVL: ⩽ 0.52%; intermediate BVL: >0.52%–2.18%; most BVL: >2.18%). BVL, MRI lesions, and relapses over 2 years were evaluated as potential mediators of the effect of teriflunomide on cognition. Results: Teriflunomide 14 mg significantly improved PASAT-3 Z-scores versus placebo through year 2. In the least- and intermediate-BVL groups, significant improvements in PASAT-3 Z-score were demonstrated versus the most-BVL group over 3 years in the extension. According to the mediation analysis, 44% of the teriflunomide effect on cognition was due to effects on BVL at year 2. Conclusion: Teriflunomide improves cognition largely through its effects on BVL. Accelerated BVL earlier in the disease course may predict cognitive outcomes. ClinicalTrials.gov identifier: NCT00134563, NCT00803049

Teriflunomide is an oral monotherapy used to treat relapsing multiple sclerosis. Although teriflunomide may be associated with gastrointestinal symptoms, these events are mild and self-limiting. We present a 39-year-old female who developed severe diarrhea and lost 20 pounds within 3 weeks of starting teriflunomide. Despite discontinuing teriflunomide and undergoing cholestyramine washout, her symptoms persisted. Celiac disease on genetic testing was positive, but no anti-transglutaminase and anti-endomysial antibodies were detected. She underwent colonoscopy and biopsy was consistent with lymphocytic colitis. Remission was achieved within days of starting budenoside. Our case describes a rare, but serious, gastrointestinal adverse event of teriflunomide.

Background: Teriflunomide 14 mg significantly reduced brain volume loss (BVL) and confirmed disability worsening (CDW) compared with placebo in the TEMSO core study. Objective: To investigate the relationship between BVL from Baseline to Year 2 in the TEMSO core study and long-term CDW (Year 7) in the TEMSO long-term extension (NCT00803049). Methods: Structural Image Evaluation using Normalization of Atrophy determined BVL. Long-term CDW was assessed by Expanded Disability Status Scale confirmed for 12 and 24 weeks. An additional analysis evaluated the relative contribution of BVL (Year 2) and other outcomes as potential mediators of the effect of teriflunomide 14 mg on 12-week CDW. Results: Patients with the least BVL were significantly less likely to have 12- and 24-week CDW at Year 7 compared with patients with the most BVL. A mediation analysis revealed that BVL (Year 2) explained 51.3% of the treatment effect on CDW; new or enlarging T2w lesions over 2 years explained 30.8%, and relapses in the first 2 years explained 38.5%. Conclusions: These results highlight the potential predictive value of BVL earlier in the disease course on long-term disability outcomes. The mediation analysis suggests that teriflunomide may prevent disability worsening largely through its effects on BVL.

Background: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. Objectives: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. Methods: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). Results: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. Conclusions: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Triple-negative breast cancer (TNBC) is defined as a group of primary breast cancers lacking expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER-2) receptors, characterized by higher relapse rate and lower survival compared with other subtypes. Due to lack of identified targets and molecular heterogeneity, conventional chemotherapy is the only available option for treatment of TNBC, but non-discordant positive therapeutic efficacy could not be achieved. Here, we demonstrated that these TNBC cells were sensitive to teriflunomide, which was a well-known immunomodulatory drug for treatment of relapsing multiple sclerosis (MS). Potent anti-cancer effects in TNBC in vitro, including proliferation inhibition, cell cycle delay, cell apoptosis, and suppression of cell motility and invasiveness, could be achieved with this agent. Of note, we showed that multiple signals involved in TNBC proliferation, survival, migratory, and invasive potential were under regulation by teriflunomide. Among them, we identified down-regulation of growth factor receptors to abolish growth maintenance, suppression of c-Myc, and cyclin D1 to contribute to its anti-proliferative effect, modulation of components of cell cycle to induce S-phase arrest, degradation of Bcl-xL, and up-regulation of BAX via activation of MAPK pathway to induce apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process, matrix metalloproteinase-9 (MMP9) expression, and inactivation of Src/FAK to reduce TNBC migration and invasion. The results identified teriflunomide may be of therapeutic benefit for the more aggressive and difficult-to-treat breast cancer subtype, indicating the use of teriflunomide for clinical trials for treatment of TNBC patients.

N, N-dimethyl-p-toluidine (DMPT; Cas No. 99-97-8), an accelerant for methyl methacrylate monomers in medical devices, is a nasal cavity carcinogen according to a 2-yr cancer study of male and female F344/N rats, with the nasal tumors arising from the transitional cell epithelium. In this study, we exposed male F344/N rats for 5 days to DMPT (0, 1, 6, 20, 60, or 120 mg/kg [oral gavage]) to explore the early changes in the nasal cavity after short-term exposure. Lesions occurred in the nasal cavity including hyperplasia of transitional cell epithelium (60 and 120 mg/kg). Nasal tissue was rapidly removed and preserved for subsequent laser capture microdissection and isolation of the transitional cell epithelium (0 and 120 mg/kg) for transcriptomic studies. DMPT transitional cell epithelium gene transcript patterns were characteristic of an antioxidative damage response (e.g., Akr7a3, Maff, and Mgst3), cell proliferation, and decrease in signals for apoptosis. The transcripts of amino acid transporters were upregulated (e.g., Slc7a11). The DMPT nasal transcript expression pattern was similar to that found in the rat nasal cavity after formaldehyde exposure, with over 1,000 transcripts in common. Molecular changes in the nasal cavity after DMPT exposure suggest that oxidative damage is a mechanism of the DMPT toxic and/or carcinogenic effects.

WOS: 000242341700006, PubMed ID: 17165628, Objective: To present special clinical and laboratory features of 45 cases (44 adult cases) who were intoxicated through oral route. Design: Retrospective study. Setting: Intensive care unit (ICU) of a university hospital. Patients: Forty-five patients admitted to the ICU of Cumhuriyet University Hospital. Results: Forty-five patients between 4 and 97 years of age were evaluated. Intoxication was the result of a suicide attempt in 67% of cases and accidental in 33% of cases. Unconsciousness, nausea and vomiting were the common initial symptoms. The major clinical findings in the ICU were bradycardia, myosis, hypothermia, hyperglycemia, hypotension, coma and respiratory depression. Blood glucose level was increased in 64% of cases. No problem was noted in the patient or the fetus in a pregnant, 27-year-old patient, who was intoxicated with 10 mL of 12.5% amitraz. The length of stay in the ICU was between 2 and 15 days. None of the patients died. All patients were discharged without neurological sequela. Conclusion: The prognosis of amitraz intoxications through oral route is benign and results in complete healing; however, we suggest that these cases should be well monitored and followed-up in ICUs.

Amitraz is used topically in the treatment of demodicosis and other ectoparasitic infestations. Amitraz poisoning in children has been reported in a few cases. We presented 43 cases with amitraz intoxication. Of the patients, 14 had skin exposure. We compared the skin to peroral exposure group considering intoxication findings and outcome. In the peroral exposure group symptoms and recovery were more severe than in the skin exposure group, but mortality was not seen in two groups.

Integral immunohistochemical analysis of immune responses in frozen sections requires that, in addition to constitutively expressed membrane CD markers, less stable determinants can be reliably visualized. Therefore, we compared the commonly used acetone fixation method with pararosaniline fixation for six determinant categories. These categories included selected constitutively expressed markers, inducible co-stimulatory molecules, pro- and anti-inflammatory cytokines (including the novel cytokine IL-18, also known as IGIF and IL-1γ), antigen-specific antibody in plasma cells, bacterial peptidoglycan, and lysosomal acid phosphatase activity. Human spleen and mouse spleen activated by agonistic anti-CD40 antibody or TNP-Ficoll immunization were analyzed in parallel with brain tissue from multiple sclerosis (MS) patients and marmoset monkeys with experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Fixation with pararosaniline resulted in better morphology of all tissues and inhibited endogenous alkaline phosphatase activity in brain tissue. Most determinants could be reliably detected. Staining sensitivity and intensity were markedly increased for selected determinant-tissue combinations, e.g., for IL-4 in human spleen and CD40 in human and mouse spleen. These data show that pararosaniline is a useful alternative to acetone, resulting in superior morphology and specific staining for selected determinant-tissue combinations. This provides additional flexibility for in situ analysis of immune reactivity.

Comprehensive toxicological studies of the herbicide acetochlor are presented and discussed. Although it gave a negative profile of responses in the many toxicity tests conducted there were some findings that prompted further investigation. First, although non-mutagenic in the Sal monella assay, acetochlor was clastogenic to mammalian cells treated in vitro. This clastogenic potential was not expressed in vivo in four rodent cytogenetic assays (bone marrow and germ cells). Second, although acetochlor gave a negative response in rat liver UDS assays when tested at the acute MTD, gavage administration of a single, supra- MTD dose (2000 mg/kg) gave a weak positive assay response. This dose-level (2000 mg/kg) was necrotic to the liver, depressed hepatic glutathione levels by up to ∼80%, altered the metabolism of acetochlor, and was associated with up to 33% lethality. In contrast, reference liver genotoxins such as DMN, DMH and 2AAF were shown to elicit UDS in the absence of such effects, and at ∼400 x lower dose-levels. Finally, microscopic nasal polypoid adenomas were induced in the rat when acetochlor was administered for two years at the maximum tolerated dose (MTD). The tumours were not life-threatening, they did not metastasize, and no DNA damage was induced in the nasal cells of rats maintained on a diet containing the MTD of acetochlor for either 1 or 18 weeks (comet assay). In order to probe the mechanism of action of these high dose toxicities a series of chemical and genetic toxicity studies was conducted on acetochlor and a range of structural analogues. These revealed the chloroacetyl sub structure to be the clastogenic species in vitro. Although relatively inert, this substituent is preferentially reactive to sulphydryl groupings, most evidently, to glutathione (GSH). Similar chemical reactivity and clastogenicity in vitro was observed for two related chemicals bearing a chloroacetyl group, both of which have been defined as non-carcinogens in studies reported by the US NTP. These collective observations indicate that the source of the clastogenicity of acetochlor in vitro is also the source of its rapid detoxification in the rat in vivo, via reaction with GSH. Metabolic studies of acetochlor are described which reveal the formation of a series of GSH-associated biliary metabolites in the rat that were not produced in the mouse. The metabolism of acetochlor in the rat changes with increasing dose-levels, probably because of depletion of hepatic GSH. It is most likely that a rat-specific metabolite is responsible for the rat nasal tumours observed uniquely at elevated dose-levels. The absence of genetic toxicity to the nasal epithelium of rats exposed acutely or sub- chronically to acetochlor favours a non-genotoxic me chanism for the induction of these adenomas. The observation of a time- and dose-related increase in S- phase cells in the nasal epithelium is consistent with this conclusion. Despite some confusion caused by the early use of peri- lethal gavage administrations of acetochlor to rodents, and supra-MTD dietary concentrations in some of the chronic studies, the available MTD data are consistent with acetochlor not posing a genetic or carcinogenic hazard to humans.

Reliable adherence of resin-based cements is of prime importance for the longevity of cemented restorations. The present study investigated whether a relationship exists between adherence energy to a metal substrate and the degree of cross-linking and wetting characteristics of resin-based luting agents. The adherence energies between a sand-blasted metal surface and a series of experimental resin cements were measured by means of the wedge test. The degree of cross-linking was calculated from the monomer composition of the resin cements. The measured wetting characteristics were work of adhesion and surface tension, and their dispersive and polar components. Adherence energy varied between 22 and 81 J/m2 and was influenced by the nature of the resin cements: Those with a low degree of cross-linking resulted in high adherence values. Furthermore, resin cements whose monomers were relatively polar gave rise to high adherence values. Although other metals may not behave in exactly the same way, these results may help in the formulation of new, more retentive resin cements.

WOS: 000175702000010 PubMed: 12046725 Amitraz, a formamidine insecticide and acaricide used in veterinary practice, presents side effects in humans related to its pharmacological activity on alpha 2-adrenergic receptors. There is little information available in the literature about the toxicology of the product in man and the treatment of this poisoning. In this report, the clinical and laboratory features of amitraz poisoning in two patients by a veterinary formulation also containing xylene are presented. The major clinical findings were unconsciousness, drowsiness, respiratory failure requiring mechanical ventilation, miosis, hypothermia and bradycardia. The laboratory findings were hyperglycemia, hypertransaminasemia and increased urinary output. Supportive management of this poisoning in humans is suggested in only a few articles and there is no specific antidote for the subsequent possible pharmacological effects of amitraz. In our two cases, we performed supportive treatment such as mechanical ventilation, atropine, gastric lavage, active carbon, oxygen and fluid administration. We concluded that the basic approach to the patient with amitraz poisoning, including initial stabilization to correct immediate life-threatening problems, treatment to reduce absorption and measures to improve elimination of the toxin, is effective.

Amitraz is an acaricide and insecticide indicated for the treatment of generalized demodicosis in dogs and for the control of ticks and mites in cattle and sheep. There is little information available in the human literature about the toxicology of the product. In this study, the clinical and laboratory features of amitraz poisoning in 11 children are presented. The age range ofthe patients was 2-1/2 to 6 years. Accidental ingestion of an improperly stored liquid pesticide was determined in all patients. Unconsciousness (100%), drowsiness (100%), and myosis (84%) were the most common abnormal signs; 45%, 27%, and 18%o of patients had bradycardia, respiratory insufficiency, and hypotension, respectively. All of the patients were treated with atropine, gastric lavage, activated charcoal, and supportive care. Although the patients had a prompt response to therapy, three patients required multiple doses of atropine during a 24-h period. This study revealed that clinical poisoning by oral route emerged within 30-90 min and that central nervous system (CNS) depression, which is the most important sign, resolved within 8-1/2-14 h. All cases were discharged.

Amitraz poisoning is a rare disorder characterised by central nervous system and respiratory depression, bradycardia, hypotension, hypothermia, hyperglycemia, vomiting, convulsion and glycosuria. In this study, eight pediatric patients with amitraz poisoning were presented. This study revealed that clinical manifestations of poisoning by oral and dermal route emerged within 30- 120 min and that central nervous system depression which is the most important sign resolved with 8-18 h and others 36-48 h. All cases were discharged as recovered after 48 h. To our knowledge only six cases have been reported in the literature. Because of the limited information in the literature, the cases were reported.

Amitraz, 1,5 di-(2,4-dimethylphenyl)-3-methyl-1,3,5-tria za-penta-1,4-diene, a formamidine pesticide, is used worldwide. It causes side-effects in animals that resemble those caused by pure α2-adrenergic agonist drugs such as clonidine. Data on poisonings in humans are scanty. We report on a case of human poisoning with amitraz with typical signs of α2-adrenoreceptor stimulation.

Fifty hospitalized infants and small children in the age-group of 3 months to 2 years admitted with scabies were treated with 5 applications of either 10% crotamiton cream or lotion on consecutive days. In this trial, the second to be performed exclusively in infants and young children, an improvement in itching was observed in all patients within 3 days of starting the treatment and the examination on Day 7 showed absence of skin lesions in all patients. Crotamiton cream as well as lotion rendered a 100% cure rate. All patients, including those having secondary pyoderma and/or eczematization tolerated the treatment with crotamiton cream and lotion well and no adverse reactions, either due to the topical application or to the transcutaneous systemic absorption of crotamiton, were reported. Post-treatment laboratory investigations did not reveal any unwanted effect due to transcutaneous systemic absorption of crotamiton on the blood, kidneys or liver.Crotamiton is the only scabicide available today which displays not only antipruritic but also marked antibacterial properties. It is especially indicated in the treatment of scabies in children as they are very prone to secondary bacterial infection following scratching. In view of its good efficacy and excellent tolerability the 5-application treatment schedule, with crotamiton cream applied to the whole body from the chin downward, can therefore be recommended as an optimum form of treatment for scabies in infants and young children.

1 In Charles River CD rats the pesticide MITAC 20 EC (containing amitraz and 75% xylene) given orally at an LD80 dose caused toxicity featuring hypothermia, reduced spontaneous activity, episodes of increased activity and minor signs of general debilitation. Recovery in survivors was complete within about 8 days. 2 Therapies including absorption retardants, diuretics, reduction of urine pH, thermal support and treatment with phentolamine or nikethamide were given to groups showing these signs of poisoning. 3 None of the therapies gave consistent evidence of benefit during acute poisoning in terms of reduced intensity or duration of symptoms or reduced mortality. 4 Comparison with animals given amitraz alone suggested that the hypothermia and the later phase of reduced spontaneous activity were attributable to the pharmacological effects of amitraz. While the product was apparently more acutely toxic by the oral route than xylene alone, the evidence was that xylene caused the early signs of poisoning. 5 This work indicates that any case of poisoning by ingestion of MITAC 20 EC should initially be treated for the xylene exposure. There is no specific therapy or antidote for the subsequent possible pharmacological effects of amitraz. Many other pesticides also contain high proportions of aromatic solvents and the importance of the solvent in cases of ingestion is seen to be applicable to a variety of pesticides as well as MITAC 20 EC.

Histochemical localization of sialomucins and sulfated polysaccharides have been demonstrated in the mucous membrane of the middle ear in different middle ear effusions. Inasmuch as a more neutral stain with alcian blue-PAS is still present after treatment with neuraminidase, it is strongly suggested that neutral polysaccharides coexist with neuraminic acid in the middle ear glycoproteins. Sulfated polysaccharides are present only in the mucoid effusions. The use of precise nomenclature for mucosubstances is strongly recommended and is outlined. The nature of the specificity of the histochemical stains is discussed.

Seven commercial visible-light-cured (VL) dental composite resins were analytically studied for identification of the photo-initiator consisting of photo-sensitizer and reducing agent. Gas-liquid chromatography (GC) was used for the determination of the dilute components extracted from the composite resin. Mass spectroscopy (GC-MS) was used for confirmation of the qualitative data obtained by GC. The results showed that all composite resins examined included camphorquinone (CQ) as a photo-sensitizer. The concentration of CQ in the resin phase, however, ranged from 0.17 to 1.03% w/w. The composite resin with hybrid-sized filler tended to have a higher concentration of CQ than did the micro-filled composite resin. As for the reducing agent, two out of seven brands contained dimethylaminoethyl methacrylate (DMAEMA), and one included dimethyl-p-toluidine (DMPTI). The mixing ratio between CQ and the amine in these three composite resins also varied. Another four brands did not contain either DMAEMA or DMPTI, and would utilize different reducing agents.

The basic ingredients in composite restorative materials include: monomers, polymerization stabilizers, color stabilizers, polymerization initiators, polymerization accelerators, inorganic reinforcing fillers, and coupling agents. Typical members of each category are discussed.

The Feulgen reaction is used for cytophotometric quantitation of nuclear DNA. Schiff's reagents used in the Feulgen reaction usually are prepared from basic fuchsin, a variable mixture of four triaminotriphenylmethane analogs. The effect of the several fuchsin analogs on the quality of Schiff's staining of hydrolyzed DNA is not known. In this investigation Schiff's reagents prepared from relatively pure fuchsin analogs were used to determine whether different fuchsin analogs affect the absorbance of the Schiff's reagent-DNA complexes formed in solution. It has been determined that the complex formed by pararosaniline-Schiff's reagent and hydrolyzed DNA exhibits lower absorption than do corresponding complexes formed by Schiff's reagents prepared from magenta II or from new fuchsin.

In this paper the nature and some of the properties of bis-GMA and other related products were characterized using infrared spectroscopy, viscometry, and refractive index studies. Then, using the determined constituents of these products, simulated formulations were prepared.

Yellow mixtures form on adding essentially colorless N,N-dimethyl-p-toluidine (DMPT) to colorless methacrylate monomers containing phthalate, isophthalate, or terephthalate diester groups. The color-causing interactions between the amines and monomers were investigated using ultraviolet spectroscopy. Equations were derived for predicting interactions between formulation ingredients and DMPT that would lead to undesired color.

The accelerating activity of N,N-substituted aminoethyl methacrylates on the curing of methyl methacrylate and composite resins with benzoyl peroxide is somewhat smaller than that of dimethyl-p -toluidine. Resins cured with aminoethyl methacrylates containing a p-tolyl and 3,5-xylyl substituent on the nitrogen atom turned approximately the same color in ultraviolet light as resins cured with dimethyl-p-toluidine. The incorporation of the predominant part of an unsaturated tertiary amine into polymer chains reduces to a minimum the possibility of its diffusion from the resin into the surrounding tissue.

The interaction between phospholipids and stabilizing lysosome agents such as acetylsalicylic acid (ASA), colchicine (CC), prednisolone (PD), etc., was studied using NMR spectroscopy. The peak intensity of protons arising from these compounds was reduced in liposomes containing lecithin and various agents with a molar ratio of 1:1 in D2O. The reduced percentage of protons in the agents differed due to their molecular structures: ASA was about 20%, CC about 30%, and PD about 100%.