Preservation of human heart valves for replacement in children with heart valve disease: past, present and future.

Valvular heart disease affects 30% of the new-borns with congenital heart disease. Valve replacement of semilunar valves by mechanical, bioprosthetic or donor allograft valves is the main treatment approach. However, none of the replacements provides a viable valve that can grow and/or adapt with the growth of the child leading to re-operation throughout life. In this study, we review the impact of donor valve preservation on moving towards a more viable valve alternative for valve replacements in children or young adults.

Formation of myocardium after the initial development of the linear heart tube.

Well after formation of the primary linear heart tube, the mesenchymal cardiac septa become largely myocardial, and myocardial sleeves are formed along the caval and pulmonary veins. This second wave of myocardium formation can be envisioned to be the result of recruitment of cardiomyocytes by differentiation from flanking mesenchyme and/or by migration from existing myocardium (myocardialization). As a first step to elucidate the underlying mechanism, we studied in chicken heart development the formation of myocardial cells within intra- and extracardiac mesenchymal structures. We show that the second wave of myocardium formation proceeds in a caudal-to-cranial gradient in vivo. At the venous pole, loosely arranged networks of cardiomyocytes are observed in the dorsal mesocardium from H/H19 onward, in the atrioventricular cushion region from H/H26 onward, and in the proximal outflow tract (conus) from H/H29 onward. The process is completed at H/H stage 43. Subsequently, we determined the potential of the different cardiac compartments to form myocardial networks in a 3D in vitro culture assay. This analysis showed that the competency to form myocardial networks in vitro is a characteristic of the myocardium that is flanked by intra- or extracardiac mesenchyme, i.e., the inflow tract, atrioventricular canal, and outflow tract. These cardiac compartments can be induced to form myocardial networks by a temporally released or secreted signal that is similar throughout the entire heart. Atrial and ventricular compartments are not competent and do not produce the inducer. Moreover, cardiac cushion mesenchyme was found to be able to (trans-)differentiate into cardiomyocytes in the in vitro culture assay. The combined observations suggest that a common mechanism and molecular regulatory pathway underlies the recruitment of mesodermal cells into the cardiogenic lineage during this second wave of myocardium formation through the entire heart.

[Legislation or market forces? Apothecaries and druggists in the Interwar Period]. / Wetgeving of marktordening? Apothekers en drogisten in het interbellum.

In 1865, Dutch Parliament accepted four laws regulating the national health care system and the organization of the medical profession. Together with the Law on Higher Education, that went into effect in 1876, they led to the raising of pharmacy to academic levels. Many expected this would deal the death blow to the chemist and druggist profession (drogist) and leave the apothecaries with a monopoly. The opposite, however, happened. The number of druggists increased dramatically in the decades following the 1865 legislation; their business was thriving due to the sale of secret remedies, the new synthetic remedies and other remedies that were popular with the public. This article deals with the heated debates between apothecaries and druggists over their position on the pharmaceutical market as well as with their laborious efforts to cooperation, the main question being how to control the sale of medicines: either by state legislation or by market forces. It turns out that the apothecaries expected much of the former but did not, their academic status notwithstanding, reject the latter on fundamental grounds.

UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum.

UDP-galactose:ceramide galactosyltransferase (CGalT) transfers UDP-galactose to ceramide to form the glycosphingolipid galactosylceramide. Galactosylceramide is the major constituent of myelin and is also highly enriched in many epithelial cells, where it is thought to play an important role in lipid and protein sorting. Although the biochemical pathways of glycosphingolipid biosynthesis are relatively well understood, the localization of the enzymes involved in these processes has remained controversial. We here have raised antibodies against CGalT and shown by immunocytochemistry on ultrathin cryosections that the enzyme is localized to the endoplasmic reticulum and nuclear envelope but not to the Golgi apparatus or the plasma membrane. In pulse-chase experiments, we have observed that newly synthesized CGalT remains sensitive to endoglycosidase H, confirming the results of the morphological localization experiments. In protease protection assays, we show that the largest part of the protein, including the amino terminus, is oriented toward the lumen of the endoplasmic reticulum. CGalT enzyme activity required import of UDP-galactose into the lumen of the endoplasmic reticulum by a UDP-galactose translocator that is present in the Golgi apparatus of CHO cells but absent in CHOlec8 cells. Finally, we show that CGalT activity previously observed in Golgi membrane fractions in vitro, in the absence of UDP-glucose, is caused by UDP-glucose:ceramide glucosyltransferase. Therefore all galactosylceramide synthesis occurs by CGalT in vivo in the lumen of the endoplasmic reticulum.

Mice lacking IL-12 develop polarized Th1 cells during viral infection.

Studies in IL-12-deficient mice established the necessity for IL-12 to generate a Th1 cytokine response that is often required for elimination of intracellular pathogens. In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse hepatitis virus (MHV) infection, similar to wild-type animals. In contrast, MHV-infected IFN-gamma receptor-deficient (IFN-gammaR[-/-]) mice showed an increased susceptibility to coronaviral hepatitis. Surprisingly, MHV-infected mice lacking IL-12 produced a polarized Th1-type cytokine response, as evidenced by high IFN-gamma and nondetectable IL-4 production by CD4+ splenocytes and normal virus-specific serum IgG2a/IgG1 ratios. The virus-induced type 1 cytokine secretion pattern was not reversed in IL-12-deficient mice by in vivo neutralization of IFN-gamma nor in IFN-gammaR(-/-) mice receiving IL-12-neutralizing Abs. In IL-12-deficient mice, Th1-type responses were also generated upon immunization with inactivated MHV. In contrast, following immunization with keyhole limpet hemocyanin, mice lacking IL-12 mounted strongly reduced specific IgG2a and increased IgE responses, indicative of a type 2-dominated cytokine pattern. These findings demonstrate that following a virus infection, IL-12 is not essential for the generation of polarized T cell type 1 cytokine expression and associated immune responses, which is in marked contrast to nonviral systems. Our data suggest that viruses may selectively induce IFN-gamma production and Th1-type immune reactions even in the absence of IL-12.