An investigation of the general, reproductive and postnatal developmental toxicity of Betapol, a human milk fat equivalent.

Betapol consists of triglyceride fatty acids commonly found in vegetable and animal fats. A similarity to human milk fat indicated a potential use in infant formulae as well as for food use in general. To test the potential for substantial equivalence with a related food grade oil, palm oil, Betapol was fed to rats at 15% content in the diet using an augmented two-generation study, in order to obtain information on general (6 months), reproductive and postnatal developmental toxicity in a single study rather than separate studies. For comparison there were two control groups, namely a comparative control fed a diet containing 15% of food grade oil and a negative, or laboratory standard control fed a commercial rodent breeding diet (LAD), containing 2.3-4.7% fat. It was reasoned that if Betapol fed groups showed differences from the comparative control in the direction of the negative control these would reflect differences in the nutritional value of the high fat diets. Presence of a toxicant might be indicated by differences from the comparative control group opposite to the negative control group. The group fed 15% Betapol showed occasional, statistically significant differences from the comparative control group but the direction of difference was towards the negative control group and did not indicate the presence of an unexpected toxicant.     

Inadequate oral intake in surgical patients: a rational indication for nutritional support

Seven days or more of inadequate oral intake (IOI) inevitably results in a deterioration in nutritional status. Despite this well-known fact, little information is available as to the frequency with which such periods of IOI occur in clinical practice. This study results from an audit of IOI in a gastroenterological unit over a 6-month period. The results demonstrate that 17% of patients sustained significant periods of IOI of 7 days or longer. This has important implications with regard to the provision of adjuvant nutritional support.     

Vaccine efficacy and control measures in pertussis.

An outbreak of pertussis in primary school-children in the St David''s area of Pembrokeshire provided the opportunity to estimate pertussis vaccine efficacy. The estimate of efficacy was 88% when notified cases were used, but this fell to 68% when all children with bouts of coughing for two or more weeks were included. Notified cases were significantly less likely to have been vaccinated than other cases with similar symptoms. Therefore vaccine efficacy estimates based upon notified cases are likely to be biased. However, even the lower estimates suggest that pertussis immunisation is highly desirable and efforts to improve coverage should be increased.     

Effects of Pravastatin on Plasma Lipid Concentrations in Poloxamer 407-Induced Hyperlipidemic Rats

A new animal model of hyperlipidemia is being developed using the nonionic surfactant poloxamer 407 (P-407). We investigated the impact of pravastatin on P-407-induced hyperlipidemia. Twenty rats received P-407 300 mg intraperitoneally to induce hyperlipidemia, and 20 control rats received saline injection. Pravastatin was administered orally to an equal number of rats in both groups using three different regimens. A fourth group did not receive pravastatin. At 24 hours after injection, total cholesterol levels in two of the pravastatin groups were 28% and 34% lower than those in animals that did not receive pravastatin (p≤0.01). At 48 hours, triglyceride levels were significantly lower in all pravastatin groups (21–44%) versus animals not receiving pravastatin. Pravastatin diminished the effects of P-407 on lipoproteins. This new animal model may be useful in screening for investigational antihyperlipidemic agents.     

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.