Ethics and statistical methodology in clinical trials.

Statisticians in medicine can disagree on appropriate methodology applicable to the design and analysis of clinical trials. So called Bayesians and frequentists both claim ethical superiority. This paper, by defining and then linking together various dichotomies, argues there is a place for both statistical camps. The choice between them depends on the phase of clinical trial, disease prevalence and severity, but supremely on the ethics underlying the particular trial. There is always a tension present between physicians primarily obligated to their own patients (the weight of 'individual ethics') and ethical committees responsible for the scientific merit of the trial and its long-term implications ('collective ethics'). Individual ethics, it is proposed, favour the Bayesian approach; collective ethics, the frequentist. Though in some situations the choice appears clear-cut, there remain other where both methodologies can be appropriate.     

Water-borne stimuli released by predatory crabs and damaged prey induce more predator-resistant shells in a marine gastropod

Individuals of the morphologically variable, rocky intertidal gastropod Thais (or Nucella) lamellosa developed larger apertural teeth when held in the presence of the predatory crab Cancer productus than when held in its absence, regardless of whether snails were fed or not. In addition, among fed snails larger apertural teeth were produced in the presence of crabs fed conspecific snails than in the presence of crabs fed frozen fish. Because all snails were held in containers through which water flowed from physically separated aquaria holding the crabs, these results indicate that water-soluble chemical cues released by this predatory crab and by damaged conspecifics induced T. lamellosa to improve the defense effectiveness of their shells. Finally, when allowed access to food, snails exposed to these stimuli ate fewer barnacles and grew less than those in the controls.     

Posttraumatic skeletal muscle proteolysis: The role of the hormonal environment

To investigate the role of hormones as mediators of net skeletal muscle proteolysis following injury, healthy normal male volunteers received a continuous 76-hour infusion of the 3 stress hormones: hydrocortisone, glucagon, and epinephrine. As a control, each subject received a saline infusion during another 4-day period. Ten paired studies were conducted. Diets were constant and matched on both occasions. Triple hormone infusion achieved hormone concentrations similar to those seen following mild-moderate injury. After 72 hours of infusion, skeletal muscle intracellular glutamine concentrations were lower in the hormone studies than in the control group (N=4). Free amino acid concentrations in arterial whole blood and forearm amino acid efflux were little affected by hormonal infusion. Thus, alteration of the hormonal environment by the triple hormone infusion was not a sufficient stimulus to induce all of the changes in skeletal muscle proteolysis observed in critical illness. Since studies utilizing neurohormonal blockade have shown diminished net muscle proteolysis, the stress hormones appear to be necessary but not sufficient for the protein catabolic response to injury.

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Resumen Con el propósito de investigar el papel de las hormonas como agentes mediadores de la proteolisis muscular neta que se presenta en el trauma y en otros estados críticos, se administró una infusión de las 3 hormonas del estrés, hidrocortisona, glucagón, y epinefrina, a voluntarios sanos por períodos continuos de 76 horas. Como control, cada individuo recibió una infusión de solución salina durante otro período de 4 días. Se condujeron 10 estudios apareados, con dietas constantes y similares en ambas ocasiones. La infusión triple de hormonas produjo concentraciones sanguíneas hormonales similares a las observadas en pacientes con trauma leve-moderado. A las 72 horas de la infusión las concentraciones intracelulares de glutamina en el mÚsculo esquelético aparecieron menores que en los estudios de control (N=4). Las concentraciones de aminoácidos libres en la sangre arterial y el flujo de salida de aminoácidos en el antebrazo resultaron mínimamente afectados por la infusión hormonal. Por lo tanto, la alteración del medio hormonal producida por infusión triple de hormonas no representa un estímulo suficiente para inducir la totalidad de las alteraciones en la proteolisis del mÚsculo esquelético que se observa en la enfermedad crítica. Puesto que los estudios con bloqueo neurohumoral han demostrado una disminución en la proteolisis muscular neta, las hormonas del estrés parecen ser necesarias, pero no suficientes de por sí, para la respuesta catabólica a la injuria biológica.

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Résumé Pour étudier le rôle des hormones dans la protéolyse posttraumatique de muscle squelettique, des volontaires de sexe mâle en bonne santé ont été perfusés pendant 76 heures avec les 3 hormones de stress: hydrocortisone, glucagon, et adrénaline. En contrôle, chaque patient a reÇu une perfusion de sérum physiologique pendant quatre jours. Dix études appariées ont été faites. Pendant les deux études, l'alimentation était la mÊme et constante. La perfusion des 3 hormones a provoqué une concentration semblable à celle qu'on observe après un traumatisme moyen. Après 72 heures, le taux de glutamine dans les muscles squelettiques était plus bas dans l'étude hormonale que dans l'étude contrôle (N=4). La concentration en acides aminés libres dans le sang artériel et notamment l'arrivée de sang dans l'avant-bras n'étaient que peu influencées par la perfusion hormonale. Ainsi, la perfusion avec augmentation de la concentration des 3 hormones de stress ne suffisait pas pour provoquer la protéolyse musculaire squelettique que l'on observe lors des maladies graves. Puisque d'autres études ont montré que le blocage neurohormonal diminue nettement la protéolyse musculaire, les hormones de stress semblent donc nécessaires mais non suffisantes dans la réponse catabolique protéinique au traumatisme.

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Supported by the National Institutes of Health Trauma Center Grant P50-GM 29327-03 and Clinical Research Center Grant no. 290-9299.     

Characterization of an immunoprotective protein complex of Anaplasma marginale by cloning and expression of the gene coding for polypeptide Am105L.

Immunization with an Anaplasma marginale surface protein complex containing two polypeptides (Am105U and Am105L), each having a molecular weight of 105,000, protected cattle against challenge with virulent organisms. These polypeptides were immunoprecipitated together from detergent extracts of A. marginale by a neutralizing monoclonal antibody. After surface radioiodination of intact parasites, both Am105U and Am105L contained the radiolabel. To define the structural and antigenic relationships between Am105U and Am105L and to determine individual efficacies as protective immunogens, we cloned and expressed A. marginale DNA in Escherichia coli. We identified recombinant bacteria which expressed a novel protein of 105,000 molecular weight as a major cellular component. The recombinant protein was structurally and antigenically homologous to Am105L. There were multiple, partially homologous copies of the cloned DNA sequence in the rickettsial genome.     

The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites

Summary: Exposure to irradiated Plasmodium sporozoites (g‐spz) results in protection against malaria. Like infectious spz, g‐spz colonize hepatocytes to undergo maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (IHMC). We demonstrated that P. berghei g‐spz‐immune murine IHMC adoptively transfer protection to naive recipients. Characterization of intrahepatic CD4+ T cells revealed an immediate, albeit transient, response to g‐spz, while the response of CD8+ T cells is delayed until acquisition of protection. It is presumed that activated CD8+ T cells home to the liver to die; g‐spz‐induced CD8+CD45RBloCD44hi T cells, however, persist in the liver, but not the spleen, during protracted protection. The association between CD8+CD45RBloCD44hi T cells and protection has been verified using MHC class I and CD1 knockout mice and mice with disrupted liver stage parasites. Based on kinetic studies, we propose that interferon‐g, presumably released by intrahepatic effector CD8+ T cells, mediates protection; the persistence of CD8+ T cells is, in turn, linked to Plasmodium antigen depots and cytokines released by CD4+ T cells and/or NK T cells.