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Background: Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants age.Methods: We conducted a case-control study within the Nurses' Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS onset was assessed as 'any' exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders.Results: 'Any' animal exposure was reported by 136 (90.1%) MS cases compared to 200 (85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between 'any' animal exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both 'any' animal and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively).Conclusion: Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding.

Background Benefits of selective serotonin reuptake inhibitors (SSRIs) in modifying the multiple sclerosis (MS) disease course have been suggested, but their ability to delay disability progression remains unknown. We examined the association between SSRI exposure and MS disability progression. Methods A nested case-control study was conducted using the British Columbia (Canada) Multiple Sclerosis clinical data linked to health administrative data. The primary outcome was a sustained score of 6 (requires a cane to walk) on the Expanded Disability Status Scale (EDSS), and the secondary outcome was the onset of secondary progressive MS (SPMS, an advanced stage of MS). The cases were those who reached a study outcome and were matched with up to four randomly selected controls by sex, age, EDSS and calendar year at study entry using incidence density sampling. The associations between disability worsening and SSRI exposure were assessed with conditional logistic regression models, adjusted for confounders. Results A total of 3920 patients were included in the main analyses, of which 272 reached sustained EDSS 6 and 187 reached SPMS. SSRI exposure was significantly different between patients who reached sustained EDSS 6 and controls [adjusted odds ratio (adjOR):1.44; 95% confidence interval (CI):1.03-2.01]. However, SSRI exposure was not significantly different between those who reached SPMS and their controls (adjOR:1.35; 95%CI:0.89-2.04). Conclusion We found no evidence to suggest that SSRI exposure was associated with a delay in MS disability accumulation or progression. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives To examine the association between the use of statins and the risk of systemic lupus erythematosus (SLE) with focus on describing the patterns of risks over time.Setting A population-based cohort study using the UK Clinical Practice Research Datalink.Participants All patients aged 40 years or older who had at least one prescription of statins during the period 1995-2009 were selected and matched by age, sex, practice and date of first prescription to non-users. The follow-up period of statin users was divided into periods of current, recent and past exposure, with patients moving among these three exposure categories over time. Current statin users were also stratified into 1 year of use.Main outcome measures Time-dependent Cox models were used to calculate HRs of SLE, adjusted for disease history and previous drug exposure.Results We included 1 039 694 patients, of whom 519 847 were statin users. Current statin users did not have an increased risk of developing SLE among patients aged >= 40 years (HRadjusted 0.75, 95% CI 0.53 to 1.07). Current statin users who continued the therapy for >1 year had a 38% lower risk of developing SLE (HRadjusted 0.62, 95% CI 0.42 to 0.93). When more specific definitions for SLE were used, this latter finding, however, was not observed.Conclusions Our findings showed no effect of statins on the risk of developing SLE among patients aged >= 40 years. Further research is needed to study the long-term effects of statins on SLE.

Objective:To examine the association between interferon-β (IFN-β) and potential adverse events using population-based health administrative data in British Columbia, Canada.Methods:Patients with relapsing-remitting multiple sclerosis (RRMS) who were registered at a British Columbia Multiple Sclerosis Clinic (1995–2004) were eligible for inclusion and were followed up until death, absence from British Columbia, exposure to a non–IFN-β disease-modifying drug, or December 31, 2008. Incidence rates were estimated for each potential adverse event (selected a priori and defined with ICD-9/10 diagnosis codes from physician and hospital claims). A nested case-control study was conducted to assess the odds of previous IFN-β exposure for each potential adverse event with at least 30 cases. Cases were matched by age (±5 years), sex, and year of cohort entry, with up to 20 randomly selected (by incidence density sampling) controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated with conditional logistic regression adjusted for age at cohort entry.Results:Of the 2,485 eligible patients, 77.9% were women, and 1,031 were treated with IFN-β during follow-up. From the incidence analyses, 27 of the 47 potential adverse events had at least 30 cases. Patients with incident stroke (ORadj 1.83, 95% CI 1.16–2.89), migraine (ORadj 1.55, 95% CI 1.18–2.04), depression (ORadj 1.33, 95% CI 1.13–1.56), and hematologic abnormalities (ORadj 1.32, 95% CI 1.01–1.72) were more likely to have previous exposure to IFN-β than controls.Conclusions:Among patients with RRMS, IFN-β was associated with a 1.8- and 1.6-fold increase in the risk of stroke and migraine and 1.3-fold increases in depression and hematologic abnormalities.

Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have anti-inflammatory and immuno-modulating properties which are effective in the treatment of cardiovascular disease and in suppressing the symptoms of ongoing autoimmunity. On the other hand, these anti-inflammatory and immuno-modulating effects may facilitate the development of autoimmunity potentially resulting in autoimmune diseases such as rheumatic diseases. Objectives: To determine whether ACE inhibitors and ARBs use was associated with an increased risk of incident rheumatoid arthritis (RA). Methods: A matched case-control study was conducted among antihypertensive patients using the Netherlands Information Network of General Practice (LINH) database from 2001 through 2006. Cases were patients over 40 years of age with a first-time diagnosis of RA. Each case was matched to up to five controls for age, sex, and index date which was selected one year before the first diagnosis of RA. ACE inhibitors and ARBs exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). Results: Our study included 211 cases and 667 matched controls. After controlling for potential confounders, users of ACE inhibitors or ARBs had adjusted ORs of 1.10 (95% CI: 0.77–1.57) and 1.06 (0.74–1.53), respectively. The adjusted ORs of incident RA among current and past users of ACE inhibitors were 1.14 (0.73–1.77) and 0.60 (0.27–1.30). Current and past use of ARBs had adjusted ORs of 1.38 (0.79–2.41) and 0.27 (0.05–1.51), respectively. Conclusions: Use of ACE inhibitors or ARBs is not associated with an increased risk of developing RA. (aut. ref.)

ObjectivesStatins offer significant cardiovascular benefits. Their use, however, influences immune regulation, which may potentially facilitate autoimmunity, eventually resulting in autoimmune diseases such as rheumatoid arthritis (RA).The authors studied whether statin use was associated with an increased risk of developing RA by conducting a case–control study using the Netherlands Information Network of General Practice database.MethodsThe authors identified 508 patients aged 40 years or older with a first-time diagnosis of RA in the period 2001–2006. Each RA case was matched to five controls for age, sex and index date, which was selected 1 year before the first diagnosis of RA. Odds ratios for the first-time diagnosis of RA were verified by a referral to a rheumatologist and/or at least one prescription of disease-modifying anti-rheumatic drugs and/or two prescriptions of corticosteroids after the date of first diagnosis.ResultsCases were more often users of statins (15.9%) compared to controls (8.6%). After adjustment for cardiovascular risk factors and use of comedication, statin use was associated with an increased risk of incident RA (adjusted OR, 1.71 (95% CI 1.16 to 2.53); p=0.007). A consistent trend of increasing risk with increased cumulative duration, cumulative defined daily doses and number of prescriptions was not observed. However, a small trend between the potency of statin treatment and the risk of RA was found.ConclusionsStatin use seems to be associated with an increased risk of developing RA. Our findings should be replicated by additional studies.

The nature and the velocities of the reactions occurring in concentrated solutions of urea and formaldehyde may be very similar to what is found in dilute systems. A rapid initial reaction between urea and formaldehyde, as reported in literature, was not observed and is shown to be due to the analytical methods used.

The hydrolysis of methylene diurea giving urea and monomethylolurea was found to be a monomolecular reaction. The rate of the reaction is directly proportional to the hydrogen ion concentration in the pH range measured (3-5) and independent of the buffer concentration. The activation energy appeared to be 19.5 kcal. Generally, the reaction of an amidomethylol group with an amide group leading to the formation of a methylene bridge between urea fragments, will be a reversible reaction. The rates of both the forward and the reverse reactions are proportional to the hydrogen ion concentration.

The reaction of methylene diurea with formaldehyde showed a close resemblance to the previously studied reaction of urea and formaldehyde1), i.e. the reaction appeared to be bimolecular and the rates were found to be directly proportional to the concentration of hydroxyl ions while further an influence of the buffer concentration on the rates was observed. Obviously the reaction is subject to a general acid and/or base catalysis. The activation energy appeared to be about 15 kcal/mol. The values for the rate constants were almost the same as were found for the reaction between urea and formaldehyde.

The reaction of urea and formaldehyde, giving monomethylolurea, is reversible in a neutral, acid or alkaline aqueous solution, the forward reaction being bimolecular and the reverse reaction monomolecular. The forward and reverse reactions are catalyzed to the same extent by hydrogen ions as well as by hydroxyl ions. The specific rates are directly proportional to the hydrogen and hydroxyl ion concentrations. There appears to be an influence of the buffer concentration on the reaction rates probably due to a general acid and general base catalysis. The equilibrium is almost independent of the pH of the solution and of the buffer concentrations. The activation energies of the forward and the reverse reaction have been determined, giving the heat of reaction. Within experimental error these activation energies may be the same for the non-catalyzed and for the catalyzed system. The reaction mechanism is discussed.

The formation and decomposition of dimethylolurea shows a close resemblance to that of monomethylolurea previously studied1 a) The reaction between formaldehyde and monomethylurea giving dimethylolurea leads to an equilibrium which can be reached from both sides. The equilibrium is independent of the pH of the solution. b) The formation of dimethylolurea from formaldehyde and monomethylolurea appeared to be a bimolecular reaction. The decomposition of dimethylolurea is monomolecular. c) Both reactions are catalyzed to the same extent by hydrogen ions and by hydroxyl ions and there is an influence of the buffer concentration on the velocity. The reaction rates are found to be directly proportional to the hydrogen and hydroxyl—ion concentrations. d) The activation energies have been determined. Within experimental error these energies were found to be about the same as the activation energies of the monomethylolurea formation and decomposition, viz. 14 and 19 kcal/mole. The reaction mechanism is briefly discussed. The formation of trimethylolurea could not be observed.

Some condensates of urea and formaldehyde were prepared from solutions of pH 2-7 at temperatures of 20-76° C. These products have been analysed with respect to their content of methylene groups, methylol groups and urea groups. The average molecular weights could be estimated. The analytical data are in harmony with the occurrence of methylene bridges between the urea fragments. The condensates will be formed by a stepwise condensation reaction. “Methylene urea” may be a mixture of condensates with an average molecular weight of 300-500.

The hydroxymethylation of phenols has been investigated in the pH range 1-11 and between 70-130° C in dilute aqueous solution. The reaction appeared to be bimolecular. Below about pH = 4 the rates were found to be proportional to the concentration of the hydrogen ions, while a proportionality to the concentration of the hydroxyl ions was observed in more alcaline solutions. An influence of the concentration of buffers on the rates has not been observed. The presence of small amounts of triethanolamine does not influence the rate of the reaction. The mechanism of the reaction is discussed.

The reaction between monomethylolurea and methylene diurea appeared to be bimolecular and the rate constants were found to be directly proportional to the concentration of the hydrogen ions. An influence of the buffer concentration was not observed. The activation energy was found to be 15 kcal/mol.

Some aspects of the alkylation of phenol with isobutene using small quantities of sulfuric acid as a catalyst are discussed. It is shown that initially ortho and para substitution take place to roughly the same extent. In the course of the reaction the isomer distribution changes in favour of the para isomer, the alkylation being reversible. Equilibrium constants were determined in the temperature range of 50-125°.

It was with great interest that we read the correspondence of Abud-Mendoza1 on our recent paper in which we described a decreased risk of developing systemic lupus erythematosus (SLE) in statin users who continued their therapy for >1 year.2 We agree that prevention of cardiovascular disease in rheumatic diseases is of great importance.3 Whether statins decrease disease activity in SLE is, however, controversial since a recent meta-analysis of five controlled trials did not suggest any significant effect of statin therapy on Systemic Lupus Erythematosus Disease Activity Index.4 Unfortunately, in the UK’s Clinical Practice Research Datalink (CPRD)—an ongoing primary care database of anonymised medical records from general practitioners that was used in our study—no measurements for SLE activity before or after initiating statin therapy are available.2 We, however, do not think that statin …

In concentrated aqueous solution and in the presence of an excess of formaldehyde more than two methylol groups may be attached to one molecule of urea. The equilibrium constant of the formation of trimethylol urea is evaluated.

It has been suggested that statins can both stimulate and suppress the immune system, and thereby, may influence autoimmune diseases. Therefore, we studied effects of statins on innate and adaptive immunity, and self-tolerance by measuring serological levels of C-reactive protein (CRP), neopterin, immunoglobulin E (IgE) antibodies and the presence of autoantibodies (antinuclear antibodies (ANA) and IgM rheumatoid factor (RF)) in the general population. We conducted a nested case-control study within the population-based Doetinchem cohort. Data from health questionnaires, serological measurements and information on medication from linkage to pharmacy-dispensing records were available. We selected 332 statin users (cases) and 331 non-users (controls), matched by age, sex, date of serum collection, history of cardiovascular diseases, diabetes mellitus type II and stroke. Multivariate regression analyses were performed to estimate effect of statins on the immune system. The median level of CRP in statin users (1.28 mg/L, interquartile range (IQR): 0.59-2.79) was lower than in non-users (1.62 mg/L, IQR: 0.79-3.35), which after adjustment was estimated to be a 28% lower level. We observed an inverse association between duration of statin use and CRP levels. Elevated levels of IgE (>100 IU/mL) were more prevalent in statin users compared to non-users. A trend towards increased levels of IgE antibodies in statin users was observed, whereas no associations were found between statin use and levels of neopterin or the presence of autoantibodies. In this general population sub-sample, we observed an anti-inflammatory effect of statin use and a trend towards an increase of IgE levels, an surrogate marker for Th (helper) 2 responses without a decrease in neopterin levels, a surrogate marker for Th1 response and/or self-tolerance. We postulate that the observed decreased inflammatory response during statin therapy may be important but is insufficient to induce loss of self-tolerance.

We thank Mathieu and colleagues for their interest in our recent publication [1] and for reporting their very interesting experiments showing that intraperitoneal but not subcutaneous simvastatin inhibits arthritis progression in the mouse collagen-induced arthritis (CIA) model [2]. These results are in line with those of Palmer and colleagues, who showed that intraperitoneal but not oral simvastatin administration inhibited pre-existing CIA [3]. According to Mathieu and colleagues, in our study we found that 'oral atorvastatin and pravastatin had no effect on the arthritis score after CIA induction' [2]. This statement is not correct, however. In our study, the number of arthritic animals increased from seven out of 12 in the nonstatin-treated controls to 12 out of 12 animals given oral atorvastatin and pravastatin, both after CIA induction (Figure 3A in [1]). Moreover, the summed arthritis score increased from 21 in the nonstatin-treated controls to 37 for oral pravastatin and 49 for oral atorvastatin, both after CIA induction (Figure 3B in [1]). Since our aim was to investigate the possible effects of statin intake upon arthritis development and severity, we chose to administer statins orally-the common route of administration for patients receiving statins. The findings from Mathieu and colleagues [2] underscore that statins have an immunomodulatory activity. Altogether, one may conclude that the outcome of statins on immune responses may depend on the type of statin, the dose, and the route of administration. Whereas we acknowledge that statins may have beneficial immunological effects, statins may also play a role in the induction of autoimmunity, as we have also shown in a general population-based study [4].

Objective: To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO). Methods: We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI). Results: We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89-20.85). Conclusion: The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism.

Introduction: Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding. Methods: The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured. Results: Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFN gamma production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine. Conclusion: These data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective in the treatment of cardiovascular disease. Next to effects on hypertension and cardiac function, these drugs have anti-inflammatory and immunomodulating properties which may either facilitate or protect against the development of autoimmunity, potentially resulting in autoimmune diseases. Therefore, we determined in the current study the association between ACE inhibitor and ARB use and incident rheumatoid arthritis (RA).A matched case-control study was conducted among patients treated with antihypertensive drugs using the Netherlands Information Network of General Practice (LINH) database in 2001-2006. Cases were patients with a first-time diagnosis of RA. Each case was matched to five controls for age, sex, and index date, which was selected 1 year before the first diagnosis of RA. ACE inhibitor and ARB exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI).Our study included 211 cases and 667 matched controls. After controlling for potential confounders, ever use of ACE inhibitors or ARBs was not associated with incident RA (adjusted ORs [95%CI], 0.99 [0.55-1.79] and 1.02 [0.67-1.56], respectively). The adjusted ORs (95%CI) for current and past use of ACE inhibitors were 1.18 (0.75-1.85) and 0.61 (0.28-1.35). For current and past use of ARBs, these adjusted ORs (95%CI) were 1.40 (0.80-2.45) and 0.29 (0.05-1.67), respectively. No duration and dose-effect relationship was observed.ACE inhibitor or ARB use is not associated with incident RA.

Objectives Several case reports of lupus-like syndrome suggest that statins could have triggered the development of this rare autoimmune disease. However, data on the association between statin use and lupus-like syndrome are scarce. We assessed whether there was an association between statin use and the occurrence of lupus-like syndrome. Methods A case/noncase study based on individual case safety reports listed in the World Health Organization global individual case safety reports database (VigiBase) was conducted. According to World Health Organization adverse reaction terminology, cases were defined as reports of lupus-like syndrome. Each case was matched with 5 noncases by age, gender, and time of reporting. Use of statins was classified according to the Anatomical Therapeutic Chemical classification code system. Covariates, ie, use of corticosteroids, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, proton pump inhibitors, and cardiovascular drugs, were determined. Multivariate logistic regression was used to calculate the reporting odds ratios with 95% confidence intervals. Results We identified 3362 reports of lupus-like syndrome as cases and 27,092 reports of other adverse drug reactions as noncases. Statins were more frequently reported as suspected drug in cases (3.2%) than in noncases (1.5%). After adjustment for several covariates, statins were associated with the reporting of lupus-like syndrome (reporting odds ratios 2.01; 95% confidence intervals 1.61-2.51). Conclusions We found an association between reporting of statins and lupus-like syndrome. Further studies are needed to confirm this finding in more detail and establish causality.

Methylol groups in condensates of urea and formaldehyde may be determined using an alkaline solution of potassium cyanide. Excess cyanide is back titrated with mercuric nitrate.

A method described by Pfeil and Schroth1) for the quantitative determination of formaldehyde appeared to be applicable in the presence of phenols and phenol alcohols.

Objective Determine the adherence to recommendations of concomitant proton-pump inhibitor (PPI) treatment in regular low-dose of aspirin (LDASA) users, taking factors associated with the probability of receiving a PPI into account. Design Cohort study. Setting Data were obtained from 120 Dutch primary care centres participating in the Netherlands Information Network of Primary Care (LINH). Participants Patients 18 years and older who were regularly prescribed LDASA (30–325 mg) in 2008–2010 were included. Main outcome measures Regular medication use was defined as receiving each consecutive prescription within 6 months after the previous one. Based on national guidelines, we categorised LDASA users into low and high gastrointestinal (GI) risk. A multilevel multivariable logistic regression analysis was applied to identify patient characteristics that influenced on the probability of regular PPI prescriptions. Results We identified 12 343 patients who started LDASA treatment, of whom 3213 (26%) were at increased risk of GI complications. In this group, concomitant regular use of PPI was 46%, 36% did not receive PPI prescriptions and 18% obtained prescriptions irregularly (p

A kinetic investigation is made of the reactions between monomethylol urea, dimethylol urea and urea in acid aqueous solution. Strong indications are obtained that these reactions are all of one type viz. bimolecular hydrogen ion catalyzed reactions between an amidomethylol group and an amide group, leading to the formation of methylene linkages between urea fragments: The rate constant of this reaction appeared to depend on the type of amide group or amidomethylol group that are reacting. The activation energy is about 15 kcal/mole. The reaction between two molecules of dimethylol urea was found to be very slow if occurring at all. The formation of cyclic structures by trimerisation of monomeric methylene urea and the formation of dimethylene ether linkages between urea fragments may be excluded.

When 2 mol. of phenyllithium are allowed to react with 1 mol. of lutidine and the mixture is then treated with an excess of benzyl chloride, α-methyl-α′-(dibenzyl-methyl) pyridine (I) is produced along with α-methyl-α′-phenylethylpyridine (VI). The statement of Bergmann and Rosenthal, that α,α′-bis-(phenylethyl)pyridine (II) should be produced in this reaction, is incorrect. When 2 mols. of phenyllithium are allowed to react with 1 mol, of lutidine and the product is treated with an exces of benzoic anhydride, a derivative of lutidine is produced, which, contrary to the opinion of Kloppenburg and Wibaut, is to be considered as the benzoate of the enol form of 2-phenacyl-6-methylpyridine (VIIb). (VIII). By the interaction of 2 mols. of phenyllithium and 2 mols. of The action of 1 mol. of phenyllithium and 1 mol. of benzonitrile on 1 mol. of α,α′-lutidine leads to the formation of 6-methyl-2-phenacylpyridine (VIII). By the interaction of 2 mols of phenyllithium and 2 mols of benzonitrile on 1 mol. of α,α′-lutidine, a complicated reaction takes place with the formation of a compound C21H19N3, to which a tricyclic structure (XI) is ascribed.

It was found that only unsubstituted amide groups in derivatives of urea are rapidly attacked by bromine in neutral solution while the reaction with alkylated amide groups is very slow. Dimethylol urea has a symmetrical structure.

The addition of phenol to acetone appeared to be the rate-determining step in the formation of bisphenol-A in the presence of sulfuric acid. The kinetic picture was further supplemented by the synthesis of two possible intermediates and by measuring their equilibrium.

The action of α-picolyl-lithium on benzonitrile, acetontrile and α-cyanopyridine is described. The ketimides of α-picolyl phenyl ketone, α-picolyl-methyl ketone and α-picolyl α-pyridyl ketone are the primary products from which the corresponding ketones are eventually obtained. A method of preparation for α-pyridyl α-picolyl ketone, which is a new compound, is described.