Cinesubstitutie en broomverplaatsing bij inwerking van kaliumamide op 4-gesubstitueerde halogeenpyridinen

A survey is given of investigations on the reactions of halogeno-azahetarenes in strongly basic media, especially towards potassium amide and lithium piperidide, which were found to comprise direct and cine substitutions, ring openings and ring transformations, halogen migrations and several other processes. In this connection we studied reactions of 4-substituted halogenopyridines with potassium amide, involving cine substitutions and halogen migrations (chapter 1).Reaction procedures and methods of analysis applied are described in chapter 2.First we investigated the amination of 3-bromo-4-ethoxypyridine, a substrate previously supposed to be converted at -33° into 2-amino-4-ethoxypyridine, 4-ethoxypyridine and 2-amino-5-bromo-4-ethoxypyridine via a mechanism involving 4-ethoxy-2,3-didehydropyridine as an intermediate and a bromine migration (PIETERSE and DEN HERTOG, 1962). By varying reaction conditions and applying 2H-labelling it was established that 3-bromo-4-ethoxypyridine is transformed into 4-ethoxypyridine and 3,5-dibromo-4-ethoxypyridine by an intermolecular trans-bromination, that 4-ethoxypyridine is formed at the same time by potassium-bromine exchange and that 2(=6)-amino-4-ethoxypyridine does not originate from a didehydropyridine derivative as an intermediate but results from an abnormal-addition-elimination reaction (AE a ) starting with an attack on the nucleus at C-6 by the amide ion. In a base-catalyzed reaction the 3,5-dibromo derivative is converted into 2,5-dibromo-4-ethoxypyridine, which at -33° is aminated to yield 2-amino-5- bromo-4-ethoxypyridine.Action of potassium amide on 3-bromo-2,4-diethoxypyridine results in a bromine shift to C-5 and subsequent formation of 2,4-diethoxypyridine, 6-amino-2,4- diethoxypyridine and 6-amino-3-bromo-2,4-diethoxypyridine (chapter 3).Variation of the substituent at C-4 and the halogen atom at C-3 gave the following results.3-Chloro-4-ethoxypyridine is converted into 4-amino-3-chloropyridine (AE-mechanism). The 3-iodo derivative yields 4-ethoxypyridine and 3-amino-4-ethoxypyridine at -33° whereas at -75° only deiodination takes place.3-Chloro-, 3-bromo- and 3-iodo-4-piperidinopyridine give the 3-amino derivative according to the S N Ar 2 - or AE-mechanism, this strongly temperature dependent process being favoured by the voluminosity of the substituent. Evidence for a nucleophilic substitution via radical anions as a side-reaction is obtained in the conversion of 3-iodo- into 3-amino-4-piperidinopyridine. Only 3-bromo-4-piperidinopyridine yields the 2-amino compound through the AE a -pathway with initial attack of the amide ion at C-2 and C-6. Dehalogenation was found to occur in the aminations of 3-bromo- and 3-iodo-4-piperidino pyridine (potassium-halogen exchange).3-Bromo-4-(4'-pyridyl)pyridine containing a -I, -M substituent is rapidly transformed into 2-amino- and 3-amino-4-(4'-pyridyl)pyridine and into debrominated material. In a mixture of liquid ammonia and ether some 2-bromo-4-(4'- pyridyl)pyridine is formed together with 4-(4'-pyridyl)pyridine; a result indicating that possibly in both media bromine migration takes place, in liquid ammonia followed by a rapid amination.3-Bromo-4-cyanopyridine, the second compound with a -I, -M group studied, yields 4-aminopyridine, 3-bromo-4-aminopyridine, 3,5-dibromo-4-aminopyridine and 2-bromo-4-aminopyridine. Thus in this case bromine migrations occur and subsequently replacements of the cyano by the amino group (chapter 4).In connection with the results described above the reactivities of dibromo- and tribromo-4-ethoxypyridines in liquid ammonia and in a mixture of liquid ammonia and ether were studied.In liquid ammonia 2,3-dibromo-4-ethoxypyridine yields 2,5-dibromo-4-ethoxypyridine and 2-amino-5-bromo-4-ethoxypyridine; 2,5-dibromo-4-ethoxypyridine also gives 2-amino-5-bromo-4-ethoxypyridine, while 3,5-dibromo-4-ethoxypyridine is converted into the 2,5-dibromo- and 2-amino-5-bromo derivative as well, together with substances resulting from side and subsequent reactions. It is supposed that all the reactions start with the abstraction of the most acidic proton. The formed carbanion then abstracts a bromonium ion from a molecule of the starting material yielding 2,3,5-tribromo-4-ethoxypyridine and the anion of the 2- or 5-bromo derivative. From these products by a second migration of a bromonium ion 2,5-dibromo-4-ethoxypyridyl-3-anion and the starting substance are obtained.In the mixture of liquid ammonia and ether the same disproportionation products are formed. In this medium however, they react independently according to different routes. Thus 2,3-dibromo- and 2,5-dibromo-4-ethoxypyridine give mixtures of 2-amino-4-ethoxypyridine, 2,6-dibromo-4-ethoxypyridine and 2,3,6-tribromo-4-ethoxypyridine of the same composition, whereas 3,5-dibromo-4-ethoxypyridine is converted into 3-bromo-4-ethoxypyridine as main product, together with 2,3,6-tribromo-4-ethoxypyridine.2,3,5-Tribromo-4-ethoxypyridine is transformed in both media into 2,3,6-tribromo-4-ethoxypyridine and in liquid ammonia also debrominated to 2,5-dibromo-4-ethoxypyridine.In order to check the validity of the mechanisms proposed several experiments were carried out, viz. the action of potassium amide on mixtures of two substrates. The results are in good agreement with the schemes given and corroborate the introduced reaction mechanisms. Although in nearly all the reactions studied the bromine migration is an intermolecular process, there is an indication of an intramolecular transformation in the isomerization of 3,5-dibromo-6-deutero-4-ethoxypyridine into 2,5-dibromo-6-deutero-4-ethoxypyridine of nearly the same deuterium content.The above was an incentive to investigate the base-catalyzed bromine shift in bromo-chloro-4-ethoxypyridines in both media. The reaction of 3-bromo-2-chloro-4-ethoxypyridine proceeds analogously to that of 2,3-dibromo-4-ethoxypyridine. 2-Bromo-3-chloro-4-ethoxypyridine was found to be the only example of a substrate from which a bromonium ion is abstracted from C-2 in the pyridine nucleus, producing 3-chloro-4-ethoxypyridine and 2,6-dibromo-3-chloro-4-ethoxypyridine. From 3-bromo-5-chloro-4-ethoxypyridine together with the last-mentioned products 2-bromo-5-chloro-4-ethoxypyridine is formed.Finally it is emphasized that several isomerizations described may be used for the synthesis of compounds otherwise not easily accessible (chapter 5).</p

Vasectomy and vasectomy reversal : development of newly designed nonabsorbable polymeric stent for reconstructing the vas deferens

UBL - phd migration 201

A paraplegic patient with fever and leucocytosis: not always what it seems

A 54-year-old obese woman with a history of spina bifida was admitted to the hospital with malaise and fever accompanied by leucocytosis, thrombocytosis, and hypercalcaemia. As treatment for neurogenic bladder dysfunction she had a suprapubic catheter. Diagnostic workup for osteomyelitis revealed an unknown mass originating from the urinary bladder on MRI of the pelvis. Further diagnostic analyses showed that the mass was a squamous-cell carcinoma (SCC) with laboratory abnormalities as paraneoplastic phenomena mediated by PTH-related peptide and cytokines released by the SCC. Despite radiotherapy the patient died within two months after initial diagnosis. Squamous-cell carcinoma of the bladder is rare in western countries. In unresectable or metastatic disease survival rates are low due to low responsiveness to standard chemotherapy. Concurrent chemoradiotherapy might be an alternative in unresectable or locally advanced disease; however, evidence to support this is lacking. The poor survival in these patients raises the question of whether high-risk groups for SCC of the bladder, like paraplegic patients or patient with neurogenic bladder dysfunction, should receive screening even though the ideal starting point and frequency are still unknown.

The Prosocial Cyberball Game: Compensating for social exclusion and its associations with empathic concern and bullying in adolescents

In this study we examined prosocial compensating behavior towards socially excluded ingroup and outgroup members by using a ‘Prosocial Cyberball Game’ in 9–17 year old Dutch adolescents (N = 133). Results showed that adolescents compensated for the social exclusion of an unknown peer in a virtual ball tossing game, by tossing the ball more often to that player in compensation conditions compared to the fair play condition. The proportion of tosses towards the excluded player did not significantly differ as a function of the group status of that player. Although compensating behavior towards ingroup versus outgroup members did not differ, the underlying motivation for this behavior may vary. More empathic concern was associated with more prosocial tosses towards an ingroup member, while more self-reported bullying behavior was associated with less compensating behavior in the outgroup condition. These findings may have practical implications for programs intending to change bystander behavior in bullying situations

Wij willen smaaklessen : voorstel voor de implementatie van het programma Smaaklessen in het basisonderwijs

Smaaklessen© is zinnenprikkelend, speels en praktisch onderwijs over voeding en voedsel voor jongeren. Door het proeven, ruiken, voelen, zien en horen – ofwel het ervaren van eten –leren jongeren dat eten leuk en interessant is

Stressful Family Environments and Children's Behavioral Control: A Multimethod Test and Replication Study With Twins.

Young children's behavioral control predicts a broad range of developmental outcomes in child- and adulthood. It is therefore important to study how individual differences in behavioral control arise. Previous studies suggest that there are both genetic and environmental influences, which were estimated in the current study using a sample of mono- and dizygotic same-sex twins. Furthermore, we examined the associations between indicators of a stressful family environment like household chaos, parenting daily hassles, and parental depressive symptoms and children's behavioral control in 2 samples. Children of the same twin pair were randomly divided over 2 samples; a test (N = 201, 48.3% boys, M age 46.53 months) and replication sample (N = 201, 49.8% boys, M age 46.06 months). Both parents reported on their children's effortful control via the Child Behavior Questionnaire and children's cheating behavior was observed during a throwing game. We found that AE models fitted the data for effortful control (A = 31%, E = 69%) and cheating (A = 16%, E = 84%) best. Path analyses revealed that children of parents experiencing more parenting daily hassles and depressive symptoms had lower levels of effortful control in the test sample. Furthermore, we found that children growing up in more chaotic households (parent report) had an increased risk of being in the cheating group versus the possible intention to cheat group in the test sample. These results were partially replicated. We suggest that the role of stressful family environments in the development of behavioral control should be considered when setting up prevention and intervention programs targeting children's behavioral control. (PsycINFO Database RecordDevelopment Psychopathology in context: famil

Child care in times of COVID-19:Predictors of distress in Dutch children and parents when re-entering center-based child care After a 2-month lockdown

As a consequence of the outbreak of the Coronavirus Disease 2019 (COVID-19) child care facilities all over the world were temporarily closed to minimize the spread of the virus. In Netherlands, the first closure lasted for almost 2 months. The return to the child care center after this significant interruption was expected to be challenging, because earlier studies demonstrated that transitions into child care can be stressful for both children and their parents. The current paper retrospectively examined the distress of Dutch children (aged 0–4) and their parents during the first 2 weeks after the reopening of child care centers, and what factors accounted for individual differences in distress. In total, 694 parents filled out an online questionnaire about stress during closure and distress after the reopening of child care centers. Furthermore, questions regarding several demographic variables and child care characteristics were included, as well as questionnaires measuring child temperament, parental separation anxiety, and parental perception of the child care quality. Results showed that younger children and children with parents scoring higher on separation anxiety experienced more distress after the reopening, as reported by parents. Furthermore, children were more distressed upon return when they attended the child care center for less hours per week after the reopening, experienced less stress during closure, and grew up in a one-parent family. With regard to parental distress after the reopening, we found that parents scoring higher on separation anxiety and fear of COVID-19 experienced more distress. Moreover, parents experiencing less stress during closure and mothers were more distressed when the child returned to the child care center. Finally, concurrent child and parental distress after reopening were positively related. The results of the current study may help professional caregivers to identify which children and parents benefit from extra support when children return to the child care center after an interruption. Especially the role that parental separation anxiety played in predicting both child and parental distress deserves attention. More research is required in order to study the underlying mechanisms of these associations and to design appropriate interventions

Young children's cortisol levels at out-of-home child care: a meta-analysis

Education and Child StudiesEducation and Child Studie

Behavioral genetics of temperament and frontal asymmetry in early childhood

Temperament has been suggested to be influenced by genetic and environmental factors. The current study examined genetic shared environmental and unique environmental factors accounting for variation in Fear, Effortful Control (EC), and Frontal Asymmetry (FA) in 4- to 6-year-old children using bivariate behavioral genetic modeling. We included a total of 214 same-sex twin pairs: 127 monozygotic (MZ) and 87 dizygotic (DZ) pairs. FA was measured during a rest electroencephalogram (EEG) recording, and Fear and EC were measured using parent report. Results show that differences between twins were best explained by genetic factors (about a quarter of the variance) and unique environmental factors (about three quarters of the variance). However, the cross-trait, within-twin correlations were not significant, implying no overlapping genetic or environmental factors on Fear and EC or on Fear and FA. Future research should try to elucidate the large role of unique environmental factors in explaining variance in these temperament-related traits

Chora z niedowładem kończyn dolnych, gorączką i leukocytozą: infekcja to nie wszystko

Pięćdziesięcioczteroletnia chora z otyłością i wywiadem rozszczepu kręgosłupa została przyjęta do szpitala z powodu złego samopoczucia oraz gorączki, którym towarzyszyły leukocytoza, trombocytoza oraz hiperkalcemia. Ze względu na neurogenną dysfunkcję pęcherza moczowego chora miała założony stały cewnik nadłonowy. W ramach diagnostyki, z powodu podejrzenia zapalenia kości i szpiku, wykonano badanie rezonansu magnetycznego (MRI) miednicy, w którym uwidoczniono obecność guza pęcherza moczowego, zajmującego kanał przetoki nadpęcherzowej. W toku dalszej diagnostyki potwierdzono rozpoznanie raka płaskonabłonkowego pęcherza moczowego, z wtórnym zespołem paranowotworowym spowodowanym nadmierną sekrecją peptydu PTH-podobnego oraz cytokin. Mimo zastosowanej radioterapii chora zmarła po 2 miesiącach od ustalenia rozpoznania. Rak płaskonabłonkowy pęcherza moczowego występuje rzadko w krajach uprzemysłowionych. Rokowanie w przypadku niekwalifikującego się do resekcji lub przerzutowego raka płaskonabłonkowego pęcherza moczowego jest niekorzystne, głównie ze względu na wysoką oporność tego nowotworu na chemioterapię. Jednoczesna radiochemioterapia jest alternatywną opcją postępowania dla chorych z miejscowo zaawansowanym rakiem płaskonabłonkowym pęcherza moczowego niekwalifikującym się do resekcji, choć brakuje dowodów naukowych oceniających skuteczność takiego leczenia. Niekorzystne rokowanie zmusza do refleksji nad wartością badań przesiewowych w przypadkach wysokiego ryzyka, takich jak chorzy z niedowładem kończyn dolnych lub neurogenną dysfunkcją pęcherza. Niemniej brakuje danych pozwalających określić optymalny czas rozpoczęcia obserwacji oraz częstotliwość dalszych badań kontrolnych