Clinical suppression of experimental allergic encephalomyelitis by muramyl dipeptide “adjuvant”

Experimental allergic encephalomyelitis (EAE) is a model for several human diseases including multiple sclerosis and post-vaccinal encephalopathies. EAE is generally thought to be an autoimmune response to the antigen myelin basic protein (MBP). Oddly, MBP can also suppress EAE, and many observations suggest that an independent immune response to so-called "adjuvant" material is also necessary to EAE induction. Thus, EAE may be a result of a pair of interactive immune responses, one against MBP, and one against adjuvant. If so, the adjuvant should, like MBP, suppress EAE. We present data from experiments on strain 13 guinea pigs demonstrating EAE suppression by muramyl dipeptide, an active component of complete Freund's adjuvant. These results are striking because classically adjuvants are defined as immunopotentiators, not immunosuppressants. Our results, therefore, suggest that a revaluation of the role of adjuvants in inducing autoimmune diseases may be necessary.     

The importance of the margin of resection and external radiation in non-lipomatous retroperitoneal sarcoma

BackgroundPrior studies evaluating the impact of adjuvant or neoadjuvant radiation on clinical outcomes of patients with non-lipomatous retroperitoneal sarcoma have been underpowered.MethodsWe queried the National Cancer Database to identify patients undergoing surgical resection of retroperitoneal sarcoma with non-lipomatous histology from 2004 to 2016. Multivariable logistic regression and Cox proportional hazards modelling with patients stratified by tumor size were used to identify factors associated with overall survival.Results3,394 patients met inclusion criteria. 592 had small (<5 cm), 1,186 had intermediate (5–10 cm), and 1,616 had large (>10 cm) tumors. Use of either neoadjuvant or adjuvant radiotherapy was associated with improved survival for patients with intermediate (neoadjuvant HR 0.67, CI [0.46, 0.98]; adjuvant HR 0.61, CI [0.50, 0.76]) and large (neoadjuvant HR 0.50, CI [0.37, 0.68]; adjuvant HR 0.56, CI [0.47, 0.69]) tumors, while adjuvant radiation therapy was associated with a survival benefit for small-sized tumors (HR 0.67, CI [0.46, 0.99]).ConclusionsRadiation therapy is associated with an overall survival benefit in patients presenting undergoing resection of non-lipomatous retroperitoneal sarcoma.     

Mammographic screening for breast cancer: Background of a pilot program in the Canton of Vaud

Summary For several years now, substantial efforts have been devoted to the development and the implementation of a screening program for breast cancer in the Canton of Vaud. A four-year pilot phase is now starting, involving two regional hospitals with their catchment areas; women over 50 and under 70 years old will be invited to participate in the program. A double view mammography will be made, with a double reading made by the hospital radiologists; a third reading will be made in case of discrepancy between the two first radiologists. Patients classified as positive for screening (e.g., with a suspect radiological image) will be referred to their practitioner for further diagnosis and treatment. The medical and public health background of this program is discussed, more specifically the reasons for developing a screening program, the choice of mammography rather than other tools, and the need to implement screening as an organized program.

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Zusammenfassung Vertreter verschiedener medizinischer Fachgebiete bemühen sich seit einigen Jahren darum, für den Kanton Waadt ein Früherfassungsprogramm für den Brustkrebs auf die Beine zu stellen. In zwei Regionen des Kantons wird nun ein Pilotprojekt gestartet, das sich an die 50 bis 70jährigen Frauen richtet und vier Jahre dauern soll. Angeboten wird eine Mammographie in zwei Ebenen, die von zwei Röntgenologen unabhängig voneinander beurteilt werden wird (kommen die beiden Experten zu unterschiedlichen Beurteilungen, wird eine dritte Meinung eingeholt). Bei einem positiven Befund wird die betroffene Frau dem Hausarzt überwiesen, der die diagnostischen Abklärungen und nötigenfalls die Behandlung einleiten wird. Die medizinischen Grundlagen und der epidemiologische Hintergrund werden dargestellt; speziell erwähnt werden die Gründe für die Entwicklung eines Früherfassungsprogrammes und für die Wahl der Mammographie als Screeningmethode.

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Résumé Depuis plusieurs années, un groupe réunissant les compétences de plusieurs disciplines médicales examine les possibilités d'implanter le dépistage du cancer du sein dans le Canton de Vaud. Un projet-pilote d'une durée de 4 ans va démarrer dans deux zones sanitaires du canton, adressé aux femmes âgées entre 50 et 70 ans: il s'agira d'une mammographie à double incidence et double lecture (avec une troisième lecture en cas de discordance entre les radiologues hospitaliers). Les femmes classées positives après l'examen de dépistage seront transférées à leur médecin traitant pour le diagnostic et, le cas échéant, le traitement. Le contexte médical et sanitaire de ce programme est discuté, en particulier les raisons spécifiques qui ont poussé les promoteurs à développer un programme organisé de dépistage par mammographie.

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Paper presented at a symposium on The Public Health Perspective of Social and Preventive Medicine, in celebration of the 20th anniversary of the Department of Social and Preventive Medicine, University of Berne, 25 June 1992 in Berne.     

Deletions in the ligand for CD40 in X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1)

Patients with X-linked Ig deficiency with normal or elevatedIgM (HIGMX-1) fail to switch from IgM/IgD to other Ig isotypes.Interaction between the B cell antigen CD40 and the CD40 ligandexpressed on activated T cells is critical for T cell drivenisotype switching. We have reported that T lymphocytes fromthree unrelated male patients with HIGMX-1 failed to expressCD40 ligand on their surface, but the mRNA for CD40 ligand wasof an apparently normal size and level. Analysis of CD40 ligandcDNA from two of the patients revealed deletions that alterthe reading frame. Patient 1 displayed two mutations: a C Atransversion at nucleotide 590 and the deletion of an adjacentC nucleotide. The second patient had a 58 bp deletion from nucleotides289–346. Furthermore, neither patient expressed a proteinproduct detectable by the CD40L mAb, 5c8.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.