抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Basics of qualitative research: Grounded theory procedures and techniques

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

As we enter the twenty-first century, research at the interface of polymer chemistry and the biomedical sciences has given rise to the first nano-sized (5-100 nm) polymer-based pharmaceuticals, the 'polymer therapeutics'. Polymer therapeutics include rationally designed macromolecular drugs, polymer-drug and polymer-protein conjugates, polymeric micelles containing covalently bound drug, and polyplexes for DNA delivery. The successful clinical application of polymer-protein conjugates, and promising clinical results arising from trials with polymer-anticancer-drug conjugates, bode well for the future design and development of the ever more sophisticated bio-nanotechnologies that are needed to realize the full potential of the post-genomic age.

The dawning era of polymer therapeutics

The relative in-vivo intracellular concentration of various macrolides in phagocytes cannot be directly extrapolated from in-vitro experiments that use a fixed and constant extracellular concentration for all compounds, since this fails to consider different rates of intracellular penetration, dosage regimens and pharmacokinetic data. In the proposed model, which takes into account the free plasma concentrations and accumulation characteristics of three antibiotics, roxithromycin, azithromycin and erythromycin, we show that roxithromycin and azithromycin may reach similar concentrations in human polymorphonuclear leucocytes when conditions mimic clinical administration of these drugs, while erythromycin concentrations are lower. This approach may be useful to predict the behaviour of other drugs or other cells, and to assist in the design of rational treatment schemes.

http://www.facm.ucl.ac.be/Full-texts-FACM/Bouvierdyvoire-1998.pdf

Computer-aided prediction of macrolide antibiotic concentrations in human circulating polymorphonuclear leucocytes.

Endocytosis is one of the mechanisms trough which foreign material is taken up by living cells and transferred to their lysosornes (de Duve et alf 1974) The succession of events involves an invagination of the plasma membrane, the formation of a closed vesicle, called a phagosome, and the subsequent fusion of this vesicle with lysosornes, leading to the formation of a digestive vacuole (Jacques, 1969)

Studies on the mechanism of endocytosis in fibroblasts with the use of specific antibodies

The cellular uptake and intracellular localization of indomethacin and ketoprofen were studied on rat embryo fibroblasts in vitro. The two drugs are taken up by the cells, but to a lesser extent for ketoprofen than for indomethacin. Inside fibroblasts ketoprofen is rapidly metabolized whereas indomethacin seems accumulated as such inside the cells. After different incubation times, ketoprofen is partly associated to the cytosol and partly to another cellular component, probably the endoplasmic reticulum. Indomethacin on the other hand is almost exclusively distributed inside the cytosol. No clear association of the two drugs can be found with the lysosomes.

Cellular uptake and subcellular distribution of two non-steroidal anti-inflammatory drugs: indomethacin and ketoprofen.

Summary Clinical Pharmacy, also called Pharmaceutical care, aims to maximise therapeutic effect, to minimise risk, to minimise cost, and to respect patient choice. North American countries and the United Kingdom have a large experience of pharmaceutical care, and this service is complementary to the activities performed by physicians, nurses, and other healthcare professionals. Experimental studies have shown that clinical pharmacy brings a definite added value in terms of the quality of use of medicines in various settings (hospitals, retail pharmacies, and outpatient clinics. These studies also demonstrate the economical benefits of pharmaceutical care. Clinical pharmacy is now under development in Belgium, and the pilot projects launched since 2000 have been well accepted. This has triggered the University Hospitals and the Faculties to launch actions oriented towards both education and research. Changes introduced in the educational curriculum of pharmacy students make them more alert to their future pharmaceutical care activities. A specific post-graduate program is now developed and implemented in two universities. The professional organizations also organize postgraduate training in pharmaceutical care. In the near future, an official recognition at the National level will be important to create the necessary framework in which Clinical Pharmacy can develop in Belgium. The combination of our local experience with the demonstrated advantages of Clinical Pharmacy (as seen from foreign studies) makes this project more and more realistic in our country. La pharmacie clinique, encore appelee “soins pharmaceutiques”, vise a assurer une therapie medicamenteuse sure, efficace, et d’un bon rapport cout/benefice, tout en respectant les choix du patient. L’Angleterre, les Etats-Unis et le Canada ont une grande experience des soins pharmaceutiques. La pharmacie clinique y est un element complementaire et souvent juge essentiel aux soins prodigues par les medecins et le personnel infirmier. Les etudes montrent que la mise en place de services de pharma cie clinique apporte une valeur ajoutee reelle tant en milieu hospitalier que dans le cadre des officines ouvertes au public et des consultations pharmaceutiques pour patients ambu

/pdf/la-pharmacie-clinique-un-developpement-recent-de-l-activite-20nbr5rfbq.pdf

La pharmacie clinique : un développement récent de l'activité des pharmaciens pour une prise en charge optimisée des patients du point de vue médicamenteux

Paul M. Tulkens

Papers

Computer-aided prediction of macrolide antibiotic concentrations in human circulating polymorphonuclear leucocytes.

Studies on the mechanism of endocytosis in fibroblasts with the use of specific antibodies

Cellular uptake and subcellular distribution of two non-steroidal anti-inflammatory drugs: indomethacin and ketoprofen.

La pharmacie clinique : un développement récent de l'activité des pharmaciens pour une prise en charge optimisée des patients du point de vue médicamenteux

Presenec of extended-spectrum beta-lactamase-producing Enterobacteriaceae in the fecal flora of patients from general practice