Biomimetic coating of organic polymers with a protein-functionalized layer of calcium phosphate: the surface properties of the carrier influence neither the coating characteristics nor the incorporation mechanism or release kinetics of the protein

Polymers that are used in clinical practice as bone-defect-filling materials possess many essential qualities, such as moldability, mechanical strength and biodegradability, but they are neither osteoconductive nor osteoinductive. Osteoconductivity can be conferred by coating the material with a layer of calcium phosphate, which can be rendered osteoinductive by functionalizing it with an osteogenic agent. We wished to ascertain whether the morphological and physicochemical characteristics of unfunctionalized and bovine-serum-albumin (BSA)-functionalized calcium-phosphate coatings were influenced by the surface properties of polymeric carriers. The release kinetics of the protein were also investigated. Two sponge-like materials (Helistat® and Polyactive®) and two fibrous ones (Ethisorb and poly[lactic-co-glycolic acid]) were tested. The coating characteristics were evaluated using state-of-the-art methodologies. The release kinetics of BSA were monitored spectrophotometrically. The characteristics of the amorphous and the crystalline phases of the coatings were not influenced by either the surface chemistry or the surface geometry of the underlying polymer. The mechanism whereby BSA was incorporated into the crystalline layer and the rate of release of the truly incorporated depot were likewise unaffected by the nature of the polymeric carrier. Our biomimetic coating technique could be applied to either spongy or fibrous bone-defect-filling organic polymers, with a view to rendering them osteoconductive and osteoinductive.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia

Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem.

Acceptance of two liquid vitamin D₃ formulations among mothers with newborn infants: a randomized, single-blind trial

In Switzerland, children are prescribed 7.5-12.5 μg per day of vitamin D(3) dissolved in alcohol, but many families do not adhere to the recommendation. The aim of the trial was to compare the acceptance of vitamin D(3) dissolved in alcohol or in medium-chain triglycerides among mothers of Swiss newborn infants. The acceptance was tested in 42 healthy newborn infants (20 girls and 22 boys) aged between 2 and 7 days. Their neonatal body weight ranged between 2.225 and 4.150 kg, and the gestational age between 36 1/7 and 41 3/7 weeks. The blinded mothers rated the facial reaction of their children by pointing on a facial hedonic scale. Thirty eight of the 41 mothers, who brought the comparison to completion, assigned a better score to the oily preparation with no difference in the remaining three cases (P < 0.0001). The acceptance for the oily preparation was significantly better both among mothers whose babies were initially presented the alcoholic preparation and among mothers whose babies were initially presented the oily preparation. Furthermore, the acceptance for the oily preparation was better irrespective of gender of the infant or parity of the mother. In conclusion, from the perspective of mothers, Swiss newborn infants prefer the taste of the oily vitamin D(3) preparation over the alcoholic preparation.

Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers

Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria

The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.

High-resolution computer simulation of the dynamics of isoelectric focusing using carrier ampholytes: focusing with concurrent electrophoretic mobilization is an isotachophoretic process

Focusing of four hemoglobins with concurrent electrophoretic mobilization was studied by computer simulation. A dynamic electrophoresis simulator was first used to provide a detailed description of focusing in a 100-carrier component, pH 6-8 gradient using phosphoric acid as anolyte and NaOH as catholyte. These results are compared to an identical simulation except that the catholyte contained both NaOH and NaCl. A stationary, steady-state distribution of carrier components and hemoglobins is produced in the first configuration. In the second, the chloride ion migrates into and through the separation space. It is shown that even under these conditions of chloride ion flux a pH gradient forms. All amphoteric species acquire a slight positive charge upon focusing and the whole pattern is mobilized towards the cathode. The cathodic gradient end is stable whereas the anodic end is gradually degrading due to the continuous accumulation of chloride. The data illustrate that the mobilization is a cationic isotachophoretic process with the sodium ion being the leading cation. The peak height of the hemoglobin zones decreases somewhat upon mobilization, but the zones retain a relatively sharp profile, thus facilitating detection. The electropherograms that would be produced by whole column imaging and by a single detector placed at different locations along the focusing column are presented and show that focusing can be commenced with NaCl present in the catholyte at the beginning of the experiment. However, this may require detector placement on the cathodic side of the catholyte/sample mixture interface.

Precolostral serology in calves born from Neospora-seropositive mothers

The present study was designed to exploratively determine (a) how many healthy calves, born from seropositive mothers, were also precolostrally seropositive; (b) how many precolostrally negative calves became postcolostrally positive; and (c) in these calves, how the IgG1/IgG2 situation developed pre- and postcolostrally. All calves were born from mothers that were determined to be seropositive in a conventional Neospora caninum-ELISA and by immunoblotting. When the diagnostic performance of the conventional ELISA was compared with that of immunoblotting and an IgG1/IgG2-ELISA in the calves, the latter two exhibited a higher sensitivity: From a total of 15 precolostral calf sera, 7 were positive in the conventional ELISA (diagnostic sensitivity 47%) compared to 15 that were positive by immunoblotting (diagnostic sensitivity 100%) and 12 that were positive by the IgG1/IgG2-ELISA (diagnostic sensitivity 80%). With regard to IgG1/IgG2 findings in the dams, IgG2 appeared as the dominant subclass in the humoral immune response of adult cattle, while in calves, IgG1 appeared as the main prenatally/precolostrally reactive antibody isotype. Provided that precolostral seropositivity reflects postnatal persistent infection with N. caninum, we then postulate that, basically, all of our study calves born form N. caninum-seropositive mothers were prenatally infected with the parasite, and may, thus, all become members of the next transmitting generation.

Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms

RATIONALE: Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in asthma. Its role in the disease process before the onset of respiratory symptoms remains unclear. Objectives: To examine whether elevated NO in newborns with clinically naive airways is associated with subsequent respiratory symptoms in infancy. METHODS: We measured exhaled NO concentration and output after birth and prospectively assessed respiratory symptoms during infancy in a birth cohort of 164 unselected healthy neonates. We examined a possible association between NO and respiratory symptoms using Poisson regression analysis. RESULTS: In infants of atopic mothers, elevated NO levels after birth were associated with increased risk of subsequent respiratory symptoms (risk ratio [RR], 7.5; 95% confidence interval [CI], 1.7-32.4 for each nl/s increase in NO output; p = 0.007). Similarly, a positive association between NO and symptoms was seen in infants of smoking mothers (RR, 6.6; 95% CI, 2.3-19.3; p = 0.001), with the strongest association in infants whose mothers had both risk factors (RR, 21.8; 95% CI, 5.8-81.3; p < 0.001). CONCLUSIONS: The interaction of NO with maternal atopy and smoking on subsequent respiratory symptoms is present early in life. Clinically, noninvasive NO measurements in newborns may prove useful as a new means to identify high-risk infants. Future confirmation of a role for NO metabolism in the evolution of respiratory disease may provide an avenue for preventative strategies.