Synthesis and Characterization of Segmented Poly(ether ester)s Containing H‐Bonding Units

A series of poly(ether ester)s containing different H‐bonding units (amide, carbamate, urea) was prepared by polycondensation in bulk, using Ti(OBu)₄ as a catalyst. The copolymers were obtained starting from PEG1000, 1,4‐butanediol, and a symmetrical, bis‐ester terminated monomer carrying H‐bonding units. These materials were designed for biomedical applications, in which ultimate biodegradability of the materials is required. The influence of the nature of the H‐bonding unit and of the length of the methylene spacer between H‐bonding groups on the thermal and solubility properties of copolymers was investigated. Amide containing copolymers were more thermally stable than ones containing carbamate, consistent with the observed behavior of the corresponding monomers. In most cases, differential scanning calorimetry (DSC) traces were quite complex because of phase separation and dependent on the applied cooling rate. Copolymers containing urea bonds were less soluble in most organic solvents, but their thermal properties were not significantly different than their amide containing counterparts.

Synthesis of amide‐based diester monomers.     

Copolymerization of ε-caprolactone and morpholine-2,5-dione derivatives

Novel biodegradable poly(ester-amide)s were prepared by ring-opening copolymerization of ε-caprolactone and 3- and/or 6-alkyl-substituted morpholine-2,5-dione derivatives. The copolymerizations were carried out in the bulk using stannous octoate as an initiator. Molecular weights of the copolymers ranged from 1,0 · 10⁴ to 8,3 · 10⁴ and decreased with increasing mole fractions of morpholine-2,5-dione derivatives in the feed. ¹³C NMR sequence analysis indicated that the copolymers had a random distribution of ε-oxycaproyl and depsipeptide units, which resulted from the occurrence of transesterification reactions during copolymerization. The results of the DSC measurements and ¹³C NMR sequence analysis showed a close relationship between the crystallinity and average length of ε-oxycaproyl blocks. Copolymers with a mole fraction of depsipeptide units smaller than 0,20 were semi-crystalline, whereas incorporation of larger amounts of depsipeptide units resulted in amorphous copolymers. The melting point depression as a function of the molar composition of the semi-crystalline copolymers was in good agreement with the melting point depression predicted by the Baur equation, which indicated the rejection of depsipeptide units from crystals consisting of ε-oxycaproyl units.     

Improving medical residents’ self-assessment of their diagnostic accuracy: does feedback help?

Advances in Health Sciences Education - When physicians do not estimate their diagnostic accuracy correctly, i.e. show inaccurate diagnostic calibration, diagnostic errors or overtesting can occur....     

Associations of Dietary Patterns with Incident Depression: The Maastricht Study

Our aim was to assess the association between a priori defined dietary patterns and incident depressive symptoms. We used data from The Maastricht Study, a population-based cohort study (n = 2646, mean (SD) age 59.9 (8.0) years, 49.5% women; 15,188 person-years of follow-up). Level of adherence to the Dutch Healthy Diet (DHD), Mediterranean Diet, and Dietary Approaches To Stop Hypertension (DASH) were derived from a validated Food Frequency Questionnaire. Depressive symptoms were assessed at baseline and annually over seven-year-follow-up (using the 9-item Patient Health Questionnaire). We used Cox proportional hazards regression analyses to assess the association between dietary patterns and depressive symptoms. One standard deviation (SD) higher adherence in the DHD and DASH was associated with a lower hazard ratio (HR) of depressive symptoms with HRs (95%CI) of 0.78 (0.69–0.89) and 0.87 (0.77–0.98), respectively, after adjustment for sociodemographic and cardiovascular risk factors. After further adjustment for lifestyle factors, the HR per one SD higher DHD was 0.83 (0.73–0.96), whereas adherence to Mediterranean and DASH diets was not associated with incident depressive symptoms. Higher adherence to the DHD lowered risk of incident depressive symptoms. Adherence to healthy diet could be an effective non-pharmacological preventive measure to reduce the incidence of depression.     

Ethnic Harassment and the Protective Effect of Positive Parenting on Immigrant Youths’ Antisocial Behavior

Background

The existing literature suggests that positive parenting might serve as a protective factor against immigrant adolescents’ engagement in externalizing difficulties when they are exposed to negative experiences of ethnic derogation. To date, little is known, however, about whether different dimensions of positive parenting may moderate the detrimental impact of ethnic harassment at school on immigrant youth’s antisocial behavior.

Objective

This study aimed to investigate which specific dimensions of positive parenting may act as a buffer against the detrimental impact of ethnic harassment at school on immigrant adolescents’ antisocial behavior (i.e., delinquency and violence).

Method

Using longitudinal data, we followed first- and second-generation immigrant adolescents (N?=?365; Mage?=?13.93, SD?=?.80; 46% girls; 37% first-generation) in Sweden over a period of one year. Data collection at Time 1 (T1) was completed in the spring semester of the school year, and Time 2 (T2) assessments took place a year after the first data collection. We ran a series of regressions analyses via the SPSS PROCESS macro for each dimension of positive parenting behavior and each type of antisocial behavior.

Results

We found that ethnically harassed immigrant adolescents who received parental warmth, perceived their influence on family decisions and whose parents were aware of their children’s daily activities were less likely to engage in delinquency and violence one year later. In addition, we saw that immigrant youth whose parents actively sought information about their offsprings’ lives were less prone to display violence in the face of ethnic harassment.

Conclusions

The results suggest that parents are important in overriding the noxious effects of negative peer interactions targeting their children’s ethnic background, even during an adolescence marked by significant changes in child–parent and child–peer relationships. These findings might inform the development of intervention components for testing in interventions studies aimed at preventing immigrant youths’ antisocial behavior and future involvement in violent criminal offences.

     

Transport,Uptake, and Metabolism of the Bis(pivaloyloxymethyl)-Ester Prodrug of 9-(2- Phosphonylmethoxyethyl)Adenine in an In Vitro Cell Culture System of the Intestinal Mucosa (Caco-2)

Purpose. To evaluate intestinal transport, uptake and metabolism characteristics of the bis(pivaloyloxymethyl)-ester [bis(POM)-ester] of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA]. Methods. Intestinal transport, uptake and metabolism of bis(POM)-PMEA were studied using an in vitro cell culture system of the intestinal mucosa (Caco-2 monolayers). Concentrations of bis(POM)-PMEA and its metabolites mono(POM)-PMEA and PMEA were determined using a reversed-phase HPLC method. Enzymatic stability of bis(POM)-PMEA was evaluated by incubation with purified liver carboxylesterase, homogenates of Caco-2 cells and scraped pig small intestinal mucosa. Results. The use of bis(POM)-PMEA as a prodrug of PMEA resulted in a significant increase in transport of total PMEA [bis(POM)-PMEA, mono(POM)-PMEA and PMEA] across Caco-2 monolayers. While transepithelial transport of PMEA (500 M) was lower than 0.1% during a 3 hr incubation period, transport of total PMEA after addition of bis(POM)-PMEA (100 M) amounted to 8.8% over the same incubation period. Only 23% of the amount transported appeared as intact bis-ester at the basolateral side, while 33% of this amount was free PMEA and 44% was mono(POM)-PMEA, suggesting susceptibility of the prodrug to chemical and enzymatic degradation. Uptake studies revealed that only negligible amounts of bis(POM)-PMEA (< 0.2%) were present inside the cells. Very high intracellular concentrations of PMEA were found 1.2 mM, after a 3 hr incubation with 50 M bis(POM)-PMEA), which suggests that PMEA was trapped inside the cells probably due to its negative charge. This explains that efflux of PMEA was relatively slow (25% of the intracellular amount in 3 hr). Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (K_m = 87 M and V_max = 9.5 M/min). Incubation of bis(POM)-PMEA (10 M) with cell homogenate of Caco-2 monolayers and pig small intestinal mucosa produced similar degradation profiles. Conclusions. The use of the bis(POM)-prodrug significantly enhances the intestinal permeability of PMEA. Intracellular trapping of PMEA in the intestinal mucosa may result in slow release of PMEA to the circulation after oral administration of bis(POM)-PMEA.     

Analysis of the action of idazoxan calls into question the reliability of the rat isolated small mesenteric artery assay as a predictor for α1-adrenoceptor-mediated pressor activity

We have studied the effects of idazoxan in rat aorta and small mesenteric artery. In the aorta, idazoxan behaved as a partial agonist (pK_A=6.30). Prazosin produced rightward shift (pA₂=9.88) and steepening of the idazoxan curve. In contrast, idazoxan had no effect of basal tension in the mesenteric artery, but shifted the noradrenaline curve to the right in a parallel manner (pA₂=6.12). The selective al-adrenoceptor agonist, indanidine, also behaved as a partial agonist in the aorta and produced no significant contractions of the small mesenteric artery. Since idazoxan and indanidine have been reported to raise blood pressure in the pithed rat via an action at vascular ₁-adrenoceptors, these results call into question the reliability of the small mesenteric artery assay as a predictor for ₁-adrenoceptor-mediated pressor activity in vivo.     

5-Hydroxytryptamine-induced increase in left ventricular dP/dtmax does not suggest the presence of ventricular 5-HT4 receptors in the pig

Summary Although 5-hydroxytryptamine (5-HT) increases porcine atrial force and rate via 5-HT₄ receptors, its effect on left ventricular contractility is not known. Therefore, using the maximum rate of rise of left ventricular pressure (LVdP/dt_max) as an index of cardiac contractility, we have attempted to analyze the possible role of ventricular 5-HT₄ receptors in the anaesthetized pig. The full agonists at 5-HT₄ receptors, 5-HT and 5-methoxytryptamine (each 3, 10 and 30 g · kg^–1), and the -adrenoceptor agonist, isoprenaline (0.01, 0.03 and 0.1 g · kg^–1), increased heart rate, LVdP/dt_max and cardiac output. For a given degree of tachycardia, the increase in LVdP/dt_max by isoprenaline was substantially more than that observed with either 5-HT or 5-methoxytryptamine. The 5-HT₄ receptor partial agonist, renzapride (3, 10, 30, 100 and 300 g · kg^–1), also increased heart rate and LVdP/dt_max dose-dependently. When the heart was paced at 150 beats · min^–1, increases in LVdP/dt_max as well as cardiac output (except with the highest doses) by 5-HT, 5-methoxytryptamine and isoprenaline were clearly attenuated. However, the magnitude of attenuation of LVdP/dt_max responses by cardiac pacing was more marked in the case of 5-HT and 5-methoxytryptamine than with isoprenaline.The effects of renzapride (300 g · kg^–1) and tropisetron (0.3 and 3 mg · kg^–1) on increases in heart rate and LVdP/dt_max by 5-HT, 5-methoxytryptamine and isoprenaline were also studied. In the absence of atrial pacing, both renzapride and tropisetron (3 mg · kg^–1) effectively antagonized the responses to 5-HT and 5-methoxytryptamine; except for some decrease in the LVdP/dt_max response by tropisetron, the effect of isoprenaline remained essentially unchanged after the antagonists. During atrial pacing, renzapride significantly antagonized the responses to the first two doses of 5-HT, but the responses to the highest 5-HT dose and to 5-methoxytryptamine remained unaffected. Though, particularly after its higher dose, tropisetron reduced the responses to 5-HT and 5-methoxytryptamine, isoprenaline responses were also affected.The above results show that a significant part of the increase in LVdP/dt_max by 5-HT receptor agonists in the anaesthetized pig is a consequence of tachycardia elicited by these compounds via 5-HT₄ receptors. Since the increase in LVdP/dt_max, compared to tachycardia, was much less with 5-HT and 5-methoxytryptamine than with isoprenaline, and since the antagonism by renzapride and tropisetron against 5-HT and 5-methoxytryptamine during atrial pacing was relatively weaker and/or unspecific, it appears unlikely that the increase in LVdP/dt_max, during atria] pacing is mediated by ventricular 5-HT₄ receptors. This view is substantiated by our recent in vitro experiments where 5-HT (0.01 to 100 mol/l) failed to significantly increase contractions of porcine left ventricular trabeculae.Correspondence to P. R. Saxena at the above address     

Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data

Summary Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 g/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide.