Pharmaco-metabonomic phenotyping and personalized drug treatment

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.     

Nerve growth factor is a mitogen for cultured chromaffin cells

Nerve growth factor (NGF) is essential for the survival and differentiation of a number of neural crest derivatives, including sympathetic and sensory neurones. While early studies suggested that NGF might also have a mitogenic effect on these neurones, subsequent work has favoured the interpretation that NGF promotes cell survival or differentiation rather than proliferation. We have addressed the issue of a mitogenic effect of NGF using adrenal chromaffin cells, which are endocrine cells derived from the neural crest, and are closely related to sympathetic neurones. Adrenal chromaffin cells respond to NGF in vitro by expressing neuronal traits. We now report that NGF elicits a mitotic response in cultured chromaffin cells from young rats, and that this response is blocked by an antiserum to 2.5S NGF. The chromaffin cells that divided in response to NGF can subsequently become neuronal in the continued presence of NGF.     

A recombinant dromedary antibody fragment (VHH or nanobody) directed against human Duffy antigen receptor for chemokines

Fy blood group antigens are carried by the Duffy antigen receptor for chemokines (DARC), a red cells receptor for Plasmodium vivax broadly implicated in human health and diseases. Recombinant VHHs, or nanobodies, the smallest intact antigen binding fragment derivative from the heavy chain-only antibodies present in camelids, were prepared from a dromedary immunized against DARC N-terminal extracellular domain and selected for DARC binding. A described VHH, CA52, does recognize native DARC on cells. It inhibits P. vivax invasion of erythrocytes and displaces interleukin-8 bound to DARC. The targeted epitope overlaps the well-defined DARC Fy6 epitope. K _D of CA52?CDARC equilibrium is sub-nanomolar, hence ideal to develop diagnostic or therapeutic compounds. Immunocapture by immobilized CA52 yielded highly purified DARC from engineered K562 cells. This first report on a VHH with specificity for a red blood cell protein exemplifies VHHs?? potentialities to target, to purify, and to modulate the function of cellular markers.     

德米特里·帕帕哈乔泡洛斯(1934～1998)--脂质体研究的先驱者

德米特里·帕帕哈乔泡洛斯（D．Papah-adjopoulos），开发脂质体研究及其应用的先驱者，已于1998年9月21日在旧金山去世。脂质体的用途之一是作为一种有效且有针对性地释放药物和疫苗的手段，可使给药取得最佳效果。帕帕哈乔泡洛斯1934年8月24日生于帕特拉，该市在长达2500多年的时间里一直是希腊的西大门之一。他在雅典大学获得化学理学士学位，后又在美国西雅图的华盛顿大学，在D·J·哈那汉姆指导下获博士学位。1966年，由于对磷脂及其在凝血中的作用发生兴趣，他到剑桥郡巴勃拉哈姆动物生理研究所的A·D·班哈姆实验室工作，当时脂质…     

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.     

Hereditary pancreatitis caused by triplication of the trypsinogen locus

Hereditary pancreatitis has been reported to be caused by 'gain-of-function' missense mutations in the cationic trypsinogen gene (PRSS1). Here we report the triplication of a approximately 605-kb segment containing the PRSS1 gene on chromosome 7 in five families with hereditary pancreatitis. This triplication, which seems to result in a gain of trypsin through a gene dosage effect, represents a previously unknown molecular mechanism causing hereditary pancreatitis.     

La pseudohémoglobine et le catabolisme des composés hémiques

Summary (1) Coupled oxidation by atmospheric oxygen of systems containing hæmoglobin and various reducing agents results in the successive formation of oxyhæm, oxohæm, and pseudohæm from the prosthetic group of hæmoglobin.(2) Of the verdoglobins, sulfhæmoglobin is analogous to oxohæm whereas choleglobin and pseudohæmoglobin are pseudohæms and apparently identical.(3) It is at present impossible to decide whether the green intermediate in the physiological formation of bilirubin is sulfhæmoglobin or pseudohæmoglobin.(4) Part of the bilirubin formed in the body is probably derived from catalase, hæmatin, myoglobin and the cytochromes.

---

---

Conférence principale, présentée à la Société suisse de biologie médicale lors de la 127me Assemblée générale de la Société helvétique des sciences naturelles à Genève, le 31 août 1947.     

Another continental pool in the terrestrial silicon cycle

Silicon is the second most abundant element on Earth. It is an important nutrient for phytoplankton and is readily absorbed by terrestrial vegetation; it also assists the removal of carbon dioxide from the atmosphere through the weathering of silicates. But the continental cycle of silicon is not well known, and only a few studies have attempted to use silicon stable isotopes (28Si, 29Si and 30Si) to quantify the continental silicon reservoirs. Dissolved silicon in sea and river waters forms a reservoir of mean isotopic value +1.1 per thousand (refs 7, 10). It is enriched in 30Si with respect to the igneous rocks reservoir, which has a mean isotopic value of -0.3 per thousand (refs 4, 9). This enrichment can only be produced by a major fractionation during weathering, and should result in the formation of a continental 30Si-depleted reservoir. Such a reservoir, however, has not been identified to date. Here we analyse silicon isotopes of in situ quartz from a sandstone series in France, using a new-generation secondary ion mass spectrometry apparatus. We show that quartz that precipitates as siliceous cements forms a strongly 30Si-depleted reservoir with isotopic values down to -5.7 per thousand, a more negative value than any previously published for terrestrial samples. Our findings suggest that quartz re-precipitation plays an important role in the biogeochemical cycle of silicon.     

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.