The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 microM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.     

Usefulness of the N-Terminal Fraction of Brain Natriuretic Peptide for Deciding When to Refer Patients With Sleep Apnea-Hypopnea Syndrome to the Cardiologist

Introduction and objectiveWhen sleep apnea-hypopnea syndrome (SAHS) and cardiovascular disease occur concurrently, prognosis is affected. Echocardiography can detect structural cardiac abnormalities but using this technique in all patients would place a heavy burden on resources. The objective of this study was to investigate whether the N-terminal fraction of brain natriuretic peptide (NT-proBNP) can be used as a marker for silent heart disease.Patients and methodsNT-proBNP concentration was measured in the 114 consecutive patients with SAHS who underwent echocardiography before starting treatment. Left and right ventricular systolic and diastolic function, as well as structural abnormalities, were studied. Correlations between NT-proBNP concentration and the abnormalities detected were investigated. A receiver operating characteristics (ROC) curve was plotted for NT-proBNP concentration and cardiac abnormalities.ResultsData for 98 patients were finally analyzed. NT-proBNP concentration was significantly correlated with ventricular septal thickness (r=0.63), posterior wall thickness (r=0.45), and left ventricular enddiastolic diameter (r=0.51) (P<.0001 for all correlations). The area under the ROC curve was significant (0.870; 95% confidence interval, 0.801-0.939; P<.0001). Assuming that specificity would be more useful for clinical practice, we calculated that NT-proBNP concentrations below 100 and 200 pg/mL could rule out structural abnormalities with a reliability of 90% and 100%, respectively.ConclusionsNT-proBNP concentration was strongly correlated with echocardiographic abnormalities and so could be a useful tool for identifying patients who should be referred to the cardiologist.     

Effects of 2,4-dichlorophenoxyacetic acid on Rhizobium sp. in pure culture

The effects of 2,4-Dichlorophenoxyacetic acid on the growth rate, chemical composition, ¹⁴C-2,4-dichlorophenoxyacetic acid and ⁴⁵Ca²⁺ uptake by Rhizobium sp. M 4 able to nodulate Arachis hypogaea were determined. Cellular growth was diminished by the presence of 10^?3 M 2,4-dichlorophenoxyacetic acid in the medium. Alterations in cellular chemical composition, in ¹⁴C-2,4-dichlorophenoxyacetic acid and in ⁴⁵Ca²⁺ uptake were found.     

Solitary ileocolic arteriovenous malformation: spongostan and silk therapeutic embolisation.

A debilitated patient with liver cirrhosis and poor haemostasis had a severe lower gastrointestinal haemorrhage. A superior mesenteric arteriogram revealed an early persistent and promiment draining vein in the ileocolic artery. Two fragments of Spongostan and silk were used to embolise the bleeding artery and the haemorhage ceased immediately. No infarction of the embolised area was observed and the bleeding was controlled.     

Variation at 10 protein coding loci in the mbenzele pygmies from the central african republic and a comparison with microsatellite data

Ten protein coding loci (6‐PGD, A1‐AT, ACP1, CaII, ESD, GC, GPX1, Hbβ, PGM1, and TF) were analyzed in the Mbenzele Pygmies from the Central African Republic. The frequency data were used to calculate the genetic distances between Mbenzele Pygmies and other African groups. In the principal coordinate plot of F_ST genetic distances, the Mbenzele cluster together with other Pygmies of the western cluster, the Biaka from C.A.R., Gielli from Cameroon, and Babinga from Congo. By contrast, they are considerably distanced from other Pygmy groups of the eastern cluster (Twa from Rwanda, Mbuti from Zaire). Genetic distances obtained using protein loci were compared with those based on microsatellite loci. The two distance matrices are insignificantly correlated (r = 0.268; one tail probability = 0.332), and the main difference is in the higher genetic affinity between the Mbenzele and Biaka Pygmies observed at the protein level. Although reasons underlying the discrepancy between inter‐populational variation at protein and DNA loci are not established with certainty, the comparison suggests that the genetic distance between the Mbenzele and Biaka Pygmies at microsatellite loci could have been shaped by genetic drift. Am. J. Hum. Biol. 14:9–14, 2002.© 2002 Wiley‐Liss, Inc.     

Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.