Chemokine inhibition--why, when, where, which and how?

Chemokines are small chemoattractant cytokines that control a wide variety of biological and pathological processes, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Genetic and pharmacological studies have shown that chemokines are responsible for the excessive recruitment of leucocytes to inflammatory sites and damaged tissue. In the present paper, we discuss the rationale behind interfering with the chemokine system and introduce various points for therapeutic intervention using either protein-based or small-molecule inhibitors. Unlike other cytokines, chemokines signal via seven-transmembrane GPCRs (G-protein-coupled receptors), which are favoured targets by the pharmaceutical industry, and, as such, they are the first cytokines for which small-molecule-receptor antagonists have been developed. In addition to the high-affinity receptor interaction, chemokines have an in vivo requirement to bind to GAGs (glycosaminoglycans) in order to mediate directional cell migration. Prevention of the GAG interaction has been shown to be a viable therapeutic strategy. Targeting chemokine intracellular signalling pathways offers an alternative small-molecule approach. One of the key signalling targets downstream of a variety of chemokine receptors identified to date is PI3Kgamma (phosphoinositide 3-kinase gamma), a member of the class I PI3K family. Thus the chemokine system offers many potential entry points for innovative anti-inflammatory therapies for autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and allergic contact dermatitis.

PDK1 regulates growth through Akt and S6K in Drosophila.

The insulin/insulin-like growth factor-1 signaling pathway promotes growth in invertebrates and vertebrates by increasing the levels of phosphatidylinositol 3,4,5-triphosphate through the activation of p110 phosphatidylinositol 3-kinase. Two key effectors of this pathway are the phosphoinositide-dependent protein kinase 1 (PDK1) and Akt/PKB. Although genetic analysis in Caenorhabditis elegans has implicated Akt as the only relevant PDK1 substrate, cell culture studies have suggested that PDK1 has additional targets. Here we show that, in Drosophila, dPDK1 controls cellular and organism growth by activating dAkt and S6 kinase, dS6K. Furthermore, dPDK1 genetically interacts with dRSK but not with dPKN, encoding two substrates of PDK1 in vitro. Thus, the results suggest that dPDK1 is required for dRSK but not dPKN activation and that it regulates insulin-mediated growth through two main effector branches, dAkt and dS6K.

An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.

BACKGROUND: Size regulation is fundamental in developing multicellular organisms and occurs through the control of cell number and cell size. Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K. RESULTS: We demonstrate that varying the activity of the Drosophila insulin receptor homolog (DInr) during development regulates organ size by changing cell size and cell number in a cell-autonomous manner. An amino acid substitution at the corresponding position in the kinase domain of the human and Drosophila insulin receptors causes severe growth retardation. Furthermore, we show that the Drosophila genome contains seven insulin-like genes that are expressed in a highly tissue- and stage-specific pattern. Overexpression of one of these insulin-like genes alters growth control in a DInr-dependent manner. CONCLUSIONS: This study shows that the Drosophila insulin receptor autonomously controls cell and organ size, and that overexpression of a gene encoding an insulin-like peptide is sufficient to increase body size.

[75th annual session of the Swiss Ophthalmological Society; on its founding and its founders]. / 75. Jahresversammlung der Schweizerischen ophthalmologischen Gesellschaft; zu ihrer Gründung und ihren Gründern.

The Swiss Ophthalmological Society (SOS) was founded in Bern on 26 April 1908. An important prelude to the foundation of the Society was the tenth international congress of ophthalmology in Lucerne in 1904, at which Marc Dufour presided. Among the 50 Swiss ophthalmologists who organized and attended this congress were the founders of the Swiss Ophthalmological Society. There are neither any minutes nor a list of participants of the first meeting in April 1908, at which August Siegrist acted as president and Jules Gonin as secretary. Some of the founders of the SOS are described in this paper. The first meetings were mainly concerned with administrative and professional problems. Intense scientific activity only started in 1916, mainly due to the efforts of Alfred Vogt in Aarau. The author concludes this paper by pointing out the importance of the "unknown ophthalmologist, whose quiet, unselfish day-to-day work in practice represents a contribution to culture in the sense of creative human activity.

[On the history of the teaching of squint (author's transl)]. / Zur Geschichte der Lehre vom Strabismus.

After an introduction on the value of history also from modern medicine, the teaching of strabismus from the earliest begin at the time of Hammurapis (1700 BC) up to our times is broadly described. The old greek and latin ideas are analysed linguistically. The work of Johannes Müller and Emil Javel is especially emphasized with regard to advances in the teaching of squint and its treatment. Landolt, Maddox, Sattler and Bielschowsky above all have usefully completed these aspects. The knowledges over squint which were forgotten in many places in the first third of our century were rediscovered and considerably extended, at first by Worth, and later especially by Lyle, Bangerter, Hugonnier, Cüppers, and last but not least Heinrich Harms.

[Centennial of the Basle Eye Hospital and its founder Heinrich Schiess]. / Zum 100jährigen Jubliäum des Basler Augenspitals und zu seinem Gründer Heinrich Schiess.

100 years ago Dr. Heinrich Schiess has founded with private means through his personal initiative the eye clinic of Basle. In the same year this clinic become the University Eye Hospital by subsidising from the State. The development of the clinic since 1864 in the past 100 years in discussed. At the same time the life of Dr. Heinrich Schiess, since 1876 Professor of Ophthalmology at the Medical Faculty of Basle, is described. Especially mentioned are his contacts with Albrecht v. Graefe in Berlin and in Heiden.

[Historical notes on the terms "glaucoma" and "cataract" (author's transl)]. / Sprachgeschichtliches zu dem Begriff "Glaukom" und "Katarakt"

The Greek term "glaucoma" has nothing to do with the disease we call glaucoma today and that we use to translate incorrectly with "grüner Star" throughout the German-speaking countries. The Greek adjective "glaucos" does not mean green but gleaming, sparkling. It signified the discolouring of the pupil in glaucoma. It was later replaced by the pathogenetic term hypochysis, Latin suffusio, denoting the supposed "trübe Feuchte" (opaque humour) that was taught to gather and congeal in front of the crystalline lens. Later on "glaukosis" was reserved for incurable cases, disease of the crystalline lens itself, which was looked at as the "organon visus" up to Felix Plater. The word "cataract"--waterfall--does not exist in Greek medicine. It appears in Salernitan medical science around the year 1000 as a synonym for hypochysis, the disease we call cataract today and which has been identified as opacity of the lens since Brisseau (1705). The nature of "incurable" glaucoma, later considered as a disease of the vitreous body, was clearly recognized as a consequence of intraocular increase of pressure only by v. Graefe.

[Daniel Bernoulli (author's transl)]. / Uber Daniel Bernoulli

History in medicine receives life only from personalities. This is a report on the physician and mathematician Daniel Bernoulli which considers also his relationship to his father Johann Bernoulli and also his ambivalent relationship to his mothertown Basel. Very interesting parallels to the life of Hermann Helmholtz are demonstrated. Daniel Bernoulli, later professor of physics, lectured a mathematically based functional anatomy; in this connection he dealt profoundly with the eye and its function. The author deals with Bernoulli's work on muscle contraction (demonstrated on the abducens muscle) and on the elementary perimetric determination of the blind spot.