Fourier transform infrared spectroscopy studies of alginate-PLL capsules with varying compositions

Microencapsulation of cells is a promising approach to prevention of rejection in the absence of immunosuppression. Clinical application, however, is hampered by insufficient insight into the factors that influence the biocompatibility of the capsules. Capsules prepared of alginates with a high guluronic (G) acid content proved to be more adequate for clinical application since they are more stable, but, unfortunately, they are less biocompatible than capsules prepared of intermediate-G alginate. In order to get some insight into the physicochemical factors that influence the biocompatibility of capsules for the encapsulation of living cells, the chemical compositions of alginate[bond]Ca beads and alginate[bond]PLL capsules were studied by Fourier transform infrared spectroscopy. We found that during the transition of the alginate[bond]Ca beads to alginate[bond]PLL capsules, Ca connecting the alginate molecules, disappeared at the surface of both high-G and intermediate-G alginate[bond]PLL capsules. At the same time, it turned out that high-G alginate[bond]PLL capsules contained more hydrogen bonding than did intermediate[bond]G alginate capsules. Thus the well-known higher stability of high-G alginate[bond]PLL compared to intermediate-G alginate[bond]PLL capsules is not caused by a higher degree of binding to Ca of the alginate molecules but rather by the presence of more hydrogen bonds. Another observation was that after the transition from bead to capsule, high-G alginate[bond]PLL capsules contained 20% more PLL than the intermediate-G alginate[bond]PLL capsules. Finally, we show that in both high-G and intermediate-G alginate[bond]PLL capsules, the PLL exists in the alpha-helix, in the antiparallel beta-sheet, and in the random coil conformation. This study shows that FT-IR allows for successful analyses of the chemical factors essential for understanding differences in the biocompatibility of alginate[bond]PLL capsules.     

Effects of a nationwide programme: interventions to reduce perceived barriers to collaboration and to increase structural one-on-one contact

OBJECTIVE: To describe the implementation of a nationwide programme and to determine the effects of specific quality improvement (QI) interventions within this programme on perceived barriers to collaboration between general practitioner (GPs) and mental health professionals and frequency of structural one-on-one contact regarding individual patients. METHODS: The implementation of regional QI-interventions, perceived barriers to collaboration, and frequency of structural one-on-one contact, were assessed in a cohort study involving two surveys (2001 and 2003) among a random sample of 2757 GPs. RESULTS: 1336 and 1358 GPs returned baseline and follow-up questionnaires respectively. Most of the interventions were only offered to a minority of GPs. Less than 25% of GPs that had been offered interventions actually participated. The frequency of structural one-on-one contact with mental health professionals did not change, but barriers to collaboration decreased between 2001 and 2003. For GPs who actually participated in interactive small group meetings or in intervention in which mental health professionals were integrated in general practice, a reduction of perceived barriers could be observed as well as an increase in the frequency of structural one-on-one contact. CONCLUSION: Interventions that could be characterized as interactive small group meetings as well as interventions that involved the integration of mental health professionals in general practice led to a reduction of perceived barriers as well as an increase in the frequency of structural one-on-one contact. These findings add to the knowledge of which interventions have an effect on the collaboration between different health care providers.     

Pregnant women with inflammatory bowel disease: the effects of biologicals on pregnancy,outcome of infants,and the developing immune system

Introduction: Relapse of inflammatory bowel disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review.

Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, antitumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti-interleukin (IL)-12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search.

The occurrence of unfavorable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFα, but the effects on the developing immune system are largely unknown. For anti-integrins and anti IL-12/23, the numbers of exposed pregnancies are too small to draw any conclusions.

Expert commentary: Follow-up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design.     

Early parenting intervention aimed at maternal sensitivity and discipline: a process evaluation

This study investigated the influence of the intervention process on the effectiveness of a program aimed at promoting positive parenting. The study involved a homogeneous intervention sample (N=120) of mothers and their 1-, 2-, or 3-year-old children screened for high levels of externalizing problems. The alliance between mother and intervener, mothers' active skills implementation, and father involvement were examined in relation to changes in maternal sensitivity and positive discipline strategies. Results revealed that only alliance predicted change in positive parenting. Implications for future process evaluations and intervention programs are discussed. © 2008 Wiley Periodicals, Inc.     

Reduction of periodontal pathogens adhesion by antagonistic strains

INTRODUCTION: Periodontitis results from a shift in the subgingival microflora into a more pathogenic direction with Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans considered as periodontopathogens. In many cases, treatment procures only a temporary shift towards a less pathogenic microflora. An alternative treatment could be the deliberate colonization of pockets with antagonistic microorganisms to control the adhesion of periodontopathogens. The aim of this study was to identify bacterial strains that reduce adhesion of periodontopathogens to surfaces. METHODS: Streptococcus sanguinis, Streptococcus crista, Streptococcus salivarius, Streptococcus mitis, Actinomyces naeslundii, and Haemophilus parainfluenzae were evaluated as potential antagonists against P. gingivalis ATCC 33277, P. intermedia ATCC 49046, and A. actinomycetemcomitans ATCC 43718 as periodontopathogens. Adhesion of periodontopathogens to the bottom plate of a parallel plate flow chamber was studied in the absence (control) and the presence of pre-adhering antagonistic strains up to a surface coverage of 5%. RESULTS: The largest reduction caused by antagonistic strains was observed for P. gingivalis. All antagonistic strains except S. crista ATCC 49999 inhibited the adhesion of P. gingivalis by at least 1.6 cells per adhering antagonist, with the largest significant reduction observed for A. naeslundii ATCC 51655 (3.8 cells per adhering antagonist). Adhering antagonists had a minimal effect on the adhesion of A. actinomycetemcomitans ATCC 43718. Intermediate but significant reductions were perceived for P. intermedia, most notably caused by S. mitis BMS. CONCLUSION: The adhesion of P. gingivalis was inhibited best by antagonistic strains, while S. mitis BMS appeared to be the most successful antagonist.     

Dimethyl sulfoxide: Inhibition of acetylcholinesterase in the mammalian heart

The heart rate of the isolated, perfused, working rat heart was significantly and equally depressed by 1 × 10^?6 M acetylcholine (ACh) and by 6 × 10^?5 M 4-ketoamyltrimethylammonium (4K), a cholinomimetic agonist. Dimethyl sulfoxide (DMSO) (10 μl/ml, 140 mM) strongly potentiated the effect of ACh but did not alter the effect of 4K. DMSO (10 μl/ml, 140 mM final concentration) alone had no significant effect upon heart rate when added to the perfusate in incremental additions of 1 μl · (ml perfusate)^?1 · min^?1 over a 10-min period. The specific activity of atrial homogenate cholinesterase was $\text{48.8 ± 3.46}\text{nmoles}\text{·}\text{min}{}^{\mathrm{?1}}\text{· (}\text{mg protein}\text{)}{}^{\mathrm{?1}}\text{(}\text{mean}\text{±}\text{S.E.M.}\text{), 38.2 ± 1.60}$ for butyrylcholinesterase, and 11.2 ± 0.86 for acetylcholinesterase (AChE). True AChE activity (measured in the presence of a maximally effective concentration of tetraisopropylpyrophosphoramide) had a V_max of 13.4 ± 0.17 nmoles · min^?1 · (mg protein)^?1 and an apparent K_m value of 1 × 10^?4 M acetylthiocholine. At this K_m substrate concentration, DMSO inhibited atrial AChE activity (I₅₀ = 9 μl/ml). At the concentration tested, DMSO inhibited atrial AChE and potentiated ACh effects.     

Availability of polycyclic aromatic hydrocarbons to earthworms (Eisenia andrei,Oligochaeta) in field-polluted soils and soil-sediment mixtures

The bioavailability of polycyclic aromatic hydrocarbons (PAHs) for earthworms (Eisenia andrei) was experimentally determined in seven field-polluted soils and 15 soil-sediment mixtures. The pore-water concentration of most PAHs was higher than predicted. However, most of the compound was associated with dissolved organic carbon (DOC) and not directly available for uptake by earthworms. The apparent sorption could be reasonably predicted on the basis of interactions with DOC; however, the biota-soil accumulation factors (BSAFs) for earthworms were up to two orders of magnitude lower than predicted by equilibrium partitioning. The large variability between sites was not fully explained by differences in sorption. Experimental results indicate that the pool of freely dissolved PAHs in the pore water became partially depleted because of uptake by the earthworms and that bioaccumulation is thus also influenced by the kinetics of PAH desorption and mass transport. A pilot study with Lumbricus rubellus showed that steady-state body residues were well correlated to E. andrei. Current results show that depositing dredge spoil on land may lead to increased bioavailability of the lower-molecular-weight PAHs. However, risk assessment can conservatively rely on equilibrium partitioning, but accurate prediction requires quantification of the kinetics of bioavailability.     

Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors.

PURPOSE: TZT-1027 [N(2)-(N,N-dimethyl-l-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide] is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m(2). For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. RESULTS: Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m(2), with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027. CONCLUSIONS: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m(2) given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.