The isotope effect: Prediction,discussion, and discovery

The precise position of a spectral line emitted by an atomic system depends on the mass of the atomic nucleus and is therefore different for isotopes belonging to the same element. The possible presence of an isotope effect followed from Bohr's atomic theory of 1913, but it took several years before it was confirmed experimentally. Its early history involves the childhood not only of the quantum atom, but also of the concept of isotopy. Bohr's prediction of the isotope effect was apparently at odds with early attempts to distinguish between isotopes by means of their optical spectra. However, in 1920 the effect was discovered in HCl molecules, which gave rise to a fruitful development in molecular spectroscopy. The first detection of an atomic isotope effect was no less important, as it was by this means that the heavy hydrogen isotope deuterium was discovered in 1932. The early development of isotope spectroscopy led to successes as well as problems. At the end of the paper I briefly comment on the relationship between theory, experiment and prediction in this area of spectral physics.     

Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining ‘increased angiogenesis’ as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.Received 24 November 2004; received after revision 21 January 2005; accepted 2 March 2005     

Thioridazine and EKG anomalies

Acute i.v. infusion but not daily oral administration of thioridazine-HCl in the dog produced EKG anomalies similar to those reported in psychiatric patients taking this drug. Lack of EKG effects after thioridazine-5-sulfoxide infusion and presence of anomalies after thioridazine at equivalent doses suggests further evaluation of the relationship between reported plasma levels of thioridazine and its ring-sulfoxide in association with EKG changes.     

Thioridazine and EKG anomalies

Summary Acute i.v. infusion but not daily oral administration of thioridazine-HCl in the dog produced EKG anomalies similar to those reported in psychiatric patients taking this drug. Lack of EKG effects after thioridazine-5-sulfoxide infusion and presence of anomalies after thioridazine at equivalent doses suggests further evaluation of the relationship between reported plasma levels of thioridazine and its ring-sulfoxide in association with EKG changes.This study was supported, in part, by a Grant-in-Aid from Boehringer-Ingelheim, Ltd. Sandoz, Inc. kindly provided thioridazine HCl (Mellaril^®) and thioridazine-5-sulfoxide.     

T helper 17 cells: discovery, function, and physiological trigger

In the few years since their discovery, T helper 17 cells (T_H17) have been shown to play an important role in host defense against infections, and in tissue inflammation during autoimmunity. T_H17 cells produce IL-17, IL-21, IL-10, and IL-22 cytokines, and thus have broad effects on a variety of tissues. Notably, the requirement for the immunosuppressive cytokine TGF-β along with the pro-inflammatory cytokine IL-6 for T_H17 differentiation supports the intimate relationship between the T_H17 subset and FOXP3⁺ regulatory T cells. Here, we discuss current knowledge on effector functions and differentiation of the T_H17 lineage. Furthermore, we now know of a physiological stimulus for T_H17 differentiation: innate immune recognition of cells undergoing apoptosis as a direct result of infection induces unique development of this subset. As our knowledge of T_H17 and T regulatory cells grows, we are building on a new framework for the understanding of effector T cell differentiation and the biology of CD4⁺ T cell adaptive immune responses.     

The ever-growing complexity of the mitochondrial fission machinery

The mitochondrial network constantly changes and remodels its shape to face the cellular energy demand. In human cells, mitochondrial fusion is regulated by the large, evolutionarily conserved GTPases Mfn1 and Mfn2, which are embedded in the mitochondrial outer membrane, and by OPA1, embedded in the mitochondrial inner membrane. In contrast, the soluble dynamin-related GTPase Drp1 is recruited from the cytosol to mitochondria and is key to mitochondrial fission. A number of new players have been recently involved in Drp1-dependent mitochondrial fission, ranging from large cellular structures such as the ER and the cytoskeleton to the surprising involvement of the endocytic dynamin 2 in the terminal abscission step. Here we review the recent findings that have expanded the mechanistic model for the mitochondrial fission process in human cells and highlight open questions.     

Microtubules,interkinetic nuclear migration and neurulation

Summary The hypotheses dealing with mechanisms of neurulation are reviewed briefly. The phenomenon of interkinetic nuclear migration is thought to be an important factor to be considered in the invagination of the neuroepithelium in the chick embryo. Evidence is presented that implicates cytoplasmic microtubules in this phenomenon. It is suggested that microtubules not only participate in cell elongation but also that they are involved, through interkinetic nuclear migration, in the broadening of the basal region of the cells; this widening progressively creates the strain that ensures the invagination of the neuroepithelium.Acknowledgments. This work is supported by the MRC of Canada. We are grateful to C. Auclair for his invaluable collaboration and to Miss H. Stephens for her help in improving the English composition of this text.     

The impact of W. K. Röntgen's discovery on the use of internalizable sources of ionizing energy in diagnostic and therapeutic nuclear medicine

The early history of cathode rays, X-rays and a third kind of natural radiation from several minerals and atomic fission is described. In this way the fundamental concept of radioactivity, laws of decay and atomic models were developed. With artificial radioactive isotopes, new tailored radiopharmaceuticals could be introduced into metabolic research, medical diagnostics and therapy. Von Hevesy's concept of the dynamic state of body constituents led to examination of the locations and movements of labelled atoms and molecules as a function of time. That was the birth of nucler medicine. The principles and value at the molecular level of several specific tracer studies in research and diagnostic or therapeutic use are explained. Typically, diagnostic tests with tracer agents are non-invasive and have low radiation exposure. Competing with other diagnostic and therapeutic modalities, nuclear medicine is a speciality in its own right. But there are moves to classify it as a subspecialization of other organ-oriented clinical disciplines. That is a misunderstanding of the radiologist's role and does not answer the question: What is the best way of woking for the patient? New horizons in diagnostic modalities, biochemistry, immunology, imaging and the use of immunogenic therapeutic agents demand a continuous cooperation within interdisciplinary teams. That is as necessary with radiologic departments, participating in changed organizational structures, as with other clinical departments.     

Molecular aspects of membrane fission in the secretory pathway

Membrane fission is essential in various intracellular dissociative transport steps. The molecular mechanisms by which endocytic vesicles detach from the plasma membrane are being rapidly elucidated. Much less is known about the fission mechanisms operating at Golgi tubular networks; these include the Golgi transport and sorting stations, the trans-Golgi and cis-Golgi networks, where the geometry and physical properties of the membranes differ from those at the cell surface. Here we discuss the lipid and protein machineries that have so far been related to the fission process, with emphasis on those acting in the Golgi complex. Received 10 May 2002; received after revision 20 June 2002; accepted 26 June 2002 RID="*" ID="*"Corresponding author.     

Microtubules, interkinetic nuclear migration and neurulation.

The hypotheses dealing with mechanisms of neurulation are reviewed briefly. The phenomenon of interkinetic nuclear migration is thought to be an important factor to be considered in the invagination of the neuroepithelium in the chick embryo. Evidence is presented that implicates cytoplasmic microtubules in this phenomenon. It is suggested that microtubules not only participate in cell elongation but also that they are involved, through interkinetic nuclear migration, in the broadening of the basal region of the cells; this widening progressively creates the strain that ensures the invagination of the neuroepithelium.     

Concepts, anomalies and reality: a response to Bloor and Fehér

In this article I respond to the defences of the Strong Programme put forward by David Bloor and Márta Fehér in this issue. I dispute the claim that it is attention to only limited parts of the Strong Programme framework that allows me to argue that this approach: (i) leads to weak idealism, (ii) undermines the idea that theories have varying levels of instrumental success, and (iii) challenges the theoretical claims of scientific actors. Rather, I argue that these problematic positions are entailed by the constructionist tenets at the core of the Strong Programme.