Substance P augments the rate of vasodilation induced by calcitonin gene-related peptide in porcine ophthalmic artery in vitro.

Peptides may function as neurotransmitters liberated antidromically by sensory nerve fibres, provoking vascular responses having potential importance in some neurological disorders. Dose-response relaxation curves induced by substance P (SP) and calcitonin gene related peptide (CGRP) have been studied in porcine ophthalmic arteries in vitro. Both peptides induced vasodilation when tested separately (CGRP much greater than SP). Because of the putative interactions between such peptides in this vascular territory, a computerised system was also used for analysing over time the response to a single addition of either 10(-8) M CGRP, 10(-8) M SP or a combination of 10(-8) M SP + 10(-8) M CGRP. SP did not augment the maximum relaxation induced by CGRP alone, but increased significantly the rate of relaxation during the initial phase of the response. The effect induced by the SP+CGRP combination was stronger than the sum of the individual SP and CGRP-induced relaxations during the first 4 min of the response, which suggests a SP-CGRP synergism in this artery.     

An evaluation of numerical integration algorithms for the estimation of the area under the curve (AUC) in pharmacokinetic studies

Six numerical integration algorithms based on linear and log trapezoidal methods as well as four cubic-spline methods were proposed for estimation of area under the curve (AUC). These six different algorithms were implemented using IMSL/IDL^TM command language and evaluated using data simulated under five different dosing conditions and two different sampling conditions. Comparisons between AUC estimations using these six different algorithms and the theoretical results were made in terms of both overall AUC values and the superimposability of the concentration-time profiles. In well designed studies with ample data points, the algorithm based on IMSL/IDL^TM function CSSHAPE with concavity preservation gave the best performance. In contrast, when the frequency of blood collection was limited, the algorithm based on the log trapezoidal rule proved to be stable with reasonable accuracy, and is recommended as the practical method for numerical interpolation and integration in pharmacokinetic studies. Algorithms based on the combination of the log trapezoidal rule and cubic-spline methods using IMSL/IDL^TM function CSSHAPE can be developed to enhance overall performance.     

Cluster headache: phospholipid metabolism in polymorphonuclear cells

Our group has previously reported significant changes in the incorporation of precursors into glycerophospholipids, particularly phosphatidylserine, in polymorphonuclear cells obtained from the peripheral blood of cluster headache patients, when compared with controls. The potential of these results led to further work using both the previous methodology and a modified isolation technique to obtain polymorphonuclear cells in as pure a state as possible. Neither the new results obtained using the original technique, nor the results with high purity polymorphonuclear cells from controls and cluster headache patients, confirm the marked changes in precursor uptake into glycerophospholipids originally reported.     

Theory and practice of sampling studies: exemplified by the MONICA survey

Résumé Parallèlement à l'enregistrement systématique des cas d'infarctus, le projet MONICA prévoit de mesurer à trois reprises le niveau des facteurs de risque cardio-vasculaires auprès d'un échantillon aléatoire. L'article présente le plan d'échantillonnage de ce premier «examen de santé» MONICA réalisé dans les cantons de Vaud, de Fribourg et du Tessin. Il s'agit d'un plan à deux niveaux, avec tirage stratifié des communes en fonction de leur taille, puis tirage des individus dans les fichiers communaux. Les conditions d'un plan d'échantillonnage efficace dans le cadre plus général de l'inférence statistique sont abordées dans une première partie théorique. Les raisons pratiques (contraintes budgétaires, problèmes de logistique, disponibilité des fichiers administratifs) qui ont motivé le choix de ce plan sont exposées ensuite. Une troisième partie décrit toutes les étapes de sa réalisation, avec les difficultés méthodologiques et concrètes rencontrées. La discussion porte sur une évaluation critique de toute la procédure qui, dans le cadre du projet MONICA, a produit des échantillons dont le degré d'adéquation avec la population est assez élevé.

---

Theoretical and practical aspects of sampling: the MONICA-Project.

Summary In parallel with the systematic registration of myocardial infarction, the MONICA-Project attempts to investigate at three different times the prevalence of risk factors for cardiovascular disease in the population. This article presents the sampling plan of the first MONICA survey in the cantons of Vaud, Fribourg and Tessin. The sampling procedure was at two levels: first, a sample of communes stratified according to community size was chosen, and secondly, within these communities, individuals were selected from the population registries. The prerequisites for an efficient sampling plan are discussed on a theoretical level. In addition, the practical constraints (budget, organizational problems, population registry files) are presented. Finally, all steps of the sampling procedure are described including the difficulties encountered. The discussion attempts a critical evaluation of the whole MONICA sampling procedure whose results are largely satisfactory.

---

Theorie und Praxis der Stichprobenbildung: das Beispiel des MONICA-Projektes

Zusammenfassung Neben einer systematischen Erfassung der Infarktfälle sieht das MONICA-Projekt eine dreimalige Erfassung der Risikofaktorenprävalenz vermittels einer Zufallsauswahl vor. Der vorliegende Artikel schildert den Stichprobenplan der ersten in den Kantonen Waadt, Freiburg und Tessin durchgeführten Untersuchung. Es handelt sich um einen zweistufigen Stichprobenplan: zuerst wurde eine Ziehung der Gemeinden — stratifiziert nach Gemeindegrösse — vorgenommen, danach wurden die Individuen auf Grund der Einwohnerregister gezogen. Die Grundbedingungen für einen effizienten Stichprobenplan werden in einem ersten theoretischen Abschnitt diskutiert. Im weiteren werden die konkreten Bedingungen der MONICA-Stichprobenziehung dargestellt (Budget-Limiten, organisatorische Probleme, Aufbau der Einwohnerregister). Ein dritter Teil beschreibt sämtliche Schritte der eigentlichen Stichprobenbildung einschliesslich der aufgetretenen Schwierigkeiten. Die Diskussion nimmt eine Gesamtbeurteilung der Stichprobenziehung im MONICA-Projekt vor, deren Ergebnis recht befriedigend ausfällt.

     

Possible role of alpha-2-noradrenergic receptors in modulation of sexual behavior in female guinea pigs

These studies examine whether alpha 1-noradrenergic receptor stimulation alone is sufficient to facilitate lordosis behavior in ovariectomized, estrogen-primed female guinea pigs and to what extent alpha 2-noradrenergic receptors are involved in this steroid-dependent behavior. Neither of the alpha 1-agonists, phenylephrine or methoxamine, significantly facilitated lordosis in ovariectomized females primed with 10 micrograms of estradiol benzoate for 1 or 3 days. Animals exhibiting estrogen plus clonidine-facilitated lordosis showed a decrease in the behavior when given one of two alpha 2-antagonists (yohimbine or idazoxan). Idazoxan also attenuated lordosis in animals given estrogen plus progesterone. These findings, in combination with previous findings (that specific alpha 1-antagonists block lordosis), suggest that alpha 2-receptors, in addition to alpha 1-receptors play a role in modulation of lordosis behavior.     

Disease Management and the Medical Home Model

For the past decade, US physicians have failed to embrace disease management (DM) approaches offered by private DM companies and health plans. Until recently, physicians have not offered an alternative, systematic approach to caring for patients with chronic illnesses and conditions.The medical home model has become the centerpiece of reforms proposed by associations that represent family medicine physicians (the American Academy of Family Physicians [AAFP]) and general internal medicine physicians (the American College of Physicians [ACP]). In February 2007, the AAFP and the ACP were joined by the American Academy of Pediatrics and the American Osteopathic Association in issuing joint principles for the patient-centered medical home. While the medical home model is promoted primarily as a comprehensive approach to primary care reform, there is one aspect where the medical home and DM overlap: care coordination.Medicare has been exploring alternative mechanisms to manage and reimburse chronic care and care-coordination activities. In 2003, the US Congress passed legislation to require pilot projects for chronic care improvement programs; the program implementing this legislation is Medicare Health Support (MHS). To date, very little information has been available about the progress of MHS projects. The three early announcements about MHS progress have not been encouraging: the expected financial results are not being achieved.In December 2006, Congress passed legislation authorizing the Medicare Medical Home Demonstration (MMHD) project. MHS and MMHD are directed at similar patient populations: high-cost, frail, elderly patients with multiple co-morbid conditions. The medical home concept being advanced by primary care physicians has the potential to be competitive with DM companies. Health plans that have built their own DM programs are more likely to be supportive of the medical home model. Do physicians have the ability to compete at providing care-coordination services? There are strong arguments suggesting ‘no’ and strong arguments suggesting ‘yes’.While the medical home model is focused on primary care reform, its effect could be competitive to DM companies and others. The medical home model could affect the flow of hundreds of billions of dollars — money that over time might flow either to physicians or to private companies.     

Disposition of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in dog and rat

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide (DMPP), an inhibitor of acyl-CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual-labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete, amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG-400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat. DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half-life of 14C was 105 h in the dog and 83 h in the rat, while that of 3H was approximately 32 h in both species.     

Does magnesium sulfate alter the maternal cardiovascular response to vasopressor agents in gravid ewes?

Magnesium sulfate (MgSO4) attenuates the maternal compensatory response to hemorrhage in gravid ewes, perhaps by decreasing the response to endogenous vasopressors. The purpose of this study was to determine whether MgSO4 alters the cardiovascular response of gravid ewes to vasopressor agents. Sixteen gravid ewes underwent a series of experiments consisting of administration of two exogenous and two endogenous vasopressors, each with and without a concurrent MgSO4 infusion. Dose-response curves were constructed for phenylephrine (an alpha 1-adrenergic agonist), ST-91 (an alpha 2-adrenergic agonist), angiotensin II, and arginine vasopressin (AVP). MgSO4 significantly attenuated the increase in maternal mean arterial pressure and systemic vascular resistance and the decrease in cardiac output during ST-91 infusion but not during phenylephrine, angiotensin II, or AVP infusions. MgSO4 significantly attenuated the increase in uterine vascular resistance during phenylephrine, ST-91, and angiotensin II infusions and the decrease in uterine blood flow during phenylephrine and angiotensin II infusions. MgSO4 also appeared to attenuate the decrease in uterine blood flow during ST-91 infusion (P = 0.067). The present study suggests that MgSO4 antagonizes the effects of alpha 1-adrenergic agonists, alpha 2-adrenergic agonists, and angiotensin II on the uterine vasculature, thus providing a level of protection for the fetus in situations of maternal stress.     

Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study

Myoid cells were studied by double immunofluorescence in sections of thymus from 47 patients with myasthenia gravis and 15 control subjects, using polyclonal sheep anti-troponin T and monoclonal antibodies to troponin I, striated muscle myosin, and acetylcholine receptor (AChR). The myoid cells were rare and located mainly in the medulla, and most were clearly positive for AChR; labeling was similar with four individual monoclonal antibodies specific for extrajunctional AChR and five that also recognize endplate AChR. They were mostly keratin-positive and consistently HLA-DR-negative. In the myasthenia gravis samples, the myoid cells were similar but largely confined to medullary epithelial areas; AChR labeling was slightly weaker, but otherwise they did not differ noticeably from those of control subjects. A preliminary finding was of even rarer AChR-positive/HLA-DR-positive antigen-presenting (possibly) cells seen in 9 of 9 myasthenia gravis samples and in none of 9 control samples. Although myoid-cell AChR appears antigenically similar to extrajunctional muscle AChR, and must therefore express the epitopes that myasthenics' antibodies recognize, these cells do not appear to be foci of immunological stimulation in myasthenia gravis.