Knowledge, attitudes and practice (KAP) regarding newborn feeding modalities in HIV-infected and HIV-uninfected pregnant women in sub-Saharan Africa: a multicentre study.

Exclusive formula feeding, exclusive breastfeeding (EBF) with early weaning or the administration of antiretroviral therapy to lactating mothers and/or to breastfed newborns may lower postnatal HIV transmission. The aim of this study was to assess mothers' knowledge, attitudes and practice (KAP) on lactation in various real-life settings in sub-Saharan Africa. A questionnaire survey investigating KAP with regard to breastfeeding in pregnant women of unknown status (Questionnaire A, 16 items) or HIV-infected women (Questionnaire B, 37 items) was administered. Associations between newborn feeding KAP and demographic, socioeconomic, cultural and obstetric variables were investigated. From January 2007 to January 2008, 2112 pregnant women answered Questionnaire A in Burkina Faso, Cameroon, Chad, Tanzania, Uganda and Zambia. Most women (53.0%) declared EBF as the preferred feeding modality. The practice of strictly defined EBF in previous pregnancies was only 11.4%, which was inversely correlated with education and parity. Questionnaire B was answered by 225 HIV-infected pregnant women in Burkina Faso, Tanzania and Uganda. Knowledge about the lactation-associated risk was associated with previous dead children. Significant variability was observed among collaborating sites. The introduction of fluids other than maternal milk within 6 months of age is common practice in sub-Saharan Africa, requiring intensive health education efforts if strictly defined EBF is to be adopted to decrease HIV postnatal transmission. Significant variation in newborn feeding determinants was observed.

Reversible carnitine palmitoyltransferase inhibitors with broad chemical diversity as potential antidiabetic agents.

A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.

Inhibition of tumor necrosis factor-alpha (TNF-alpha)/TNF-alpha receptor binding by structural analogues of suramin.

Suramin, a symmetrical polysulfonated urea derivative, promotes the dissociation of trimeric human tumor necrosis factor-alpha (TNF-alpha) into biologically inactive subunits and prevents the interaction of TNF-alpha with its cellular receptors. The aim of this work was to identify compounds structurally related to suramin which inhibit the binding of TNF-alpha to its receptor. Molecular modeling studies were performed on suramin and TNF-alpha molecules and likely interaction sites were identified in the docked complex. On this basis, Evans blue, trypan blue, sulfonazo III, beryllon II, and 1,3,6-naphthalenetrisulfonic acid trisodium salt were identified as polysulfonated compounds endowed, to various extents, with the structural characteristics responsible for interaction with TNF-alpha. N,N-bis(3,5-di-tert-butylphenyl)-3,4,9,10-perylenedicarboximide was used as an unrelated structure. The capacity of these molecules to inhibit the binding of TNF-alpha with its receptor p55 was tested in vitro by means of a specific immunoenzymatic assay using suramin as reference compound. Evans blue and trypan blue inhibited TNF-alpha/p55 binding with an IC50 of 0.75 and 1.00 mM, respectively (suramin IC50: 0.65 mM); no effect was observed with the other molecules. Molecular modeling analyses on Evans blue and trypan blue docked into the TNF-alpha molecule support these experimental results by demonstrating that these compounds share with suramin a similar binding mode to TNF-alpha. The results of this work provide a new insight into and useful hints for the design of new chemical entities endowed with a potent and selective activity on TNF-alpha.

Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and alpha1 receptor binding affinity.

A series of triazolopyridine derivatives (compounds 2a-l) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT2A and alpha1 receptors. All of the synthesized compounds show a decrease of affinity for both 5HT2A and alpha1 receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an alpha position to the aliphatic nitrogen atom N1. These compounds showed a decrease of affinity only for the alpha1 receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)-2c showed the most significant differences between 5HT2A and alpha1 receptor affinity (IC50 values) and among the corresponding functional properties (pA2 values). Since (S)-2c cannot generate the metabolite 4-(3-chlorophenyl)piperazine this product was selected for further pharmacological studies.

A new approach to the design of novel inhibitors of Na+,K+-ATPase: 17alpha-substituted seco-D 5beta-androstane as cassaine analogues.

A new three-dimensional model for the relative binding mode of cassaine 1 and digitoxigenin 2 at the digitalis receptor site is proposed on the basis of the structural and conformational similarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculation that also 17alpha-substituted derivatives of the digitalis 5beta,14beta-androstane skeleton could efficiently bind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of some related compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3beta, 14-dihydroxy-5beta,14beta-androstane-17alpha-acrylate 6 (IC50 = 5.89 microM) and, much more significantly, by the corresponding 14, 15-seco-14-oxo derivative 9 (IC50 = 0.12 microM) substantiates the new hypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists.

A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to the AT1 receptor. Consistency with the previously derived activity models was always checked to contemporarily test the validity of the various hypotheses. The specific conformations chosen for the study, the procedures invoked to superimpose all structures, the conditions employed to generate steric and electrostatic field values and the various PCA/PLS runs are discussed in detail. The effect of experimental design techniques to select objects (molecules) and variables (descriptors) with respect to the predictive power of the QSAR models derived was especially analysed.

[Comparison of 2 low molecular weight heparins in patients undergoing major abdominal surgery]. / Confronto di due eparine a basso peso molecolare nel paziente sottoposto a chirurgia addominale maggiore.

INTRODUCTION AND AIMS: Thromboembolic disease can, in a large number of cases, be prevented in patients undergoing major surgery by using low molecular weight heparin (LMWH). These molecules extracted from standard heparin using a variety of cleavage methods possess different physical and chemical characteristics. The aim of this study was to compare two LMWH in the prevention of thromboembolism and in terms of safety. METHODS: Thirty patients of both sexes were admitted to the study and underwent major abdominal surgery. Fifteen patients were treated with dalteparin sodium, 2500 IU, and fifteen with nadroparin calcium, 3075 IU. Subcutaneous administration was commenced two hours prior to surgery and continued for at least five days after the operation until the complete mobilisation of the patient. Six blood samples were taken from each patient in order to assay: aPTT, heparin, X factor, Quick time, ATIII, platelets and hemoglobin. Intraoperative bleeding and drainage were recorded for each patient. RESULTS: The group treated with nadroparin showed a significant reduction in hemoglobin, correlated with greater blood loss (p < 0.05) compared to the group treated with dalteparin. CONCLUSIONS: Both nadroparin and dalteparin showed good anti-Xa activity and safety, but although they possess the same pharmacodynamic characteristics, they should not be regarded as equal or interchangeable.

Synthesis and quantitative structure-activity relationship of 17 beta-(hydrazonomethyl)-5 beta-androstane-3 beta,14 beta-diol derivatives that bind to Na+,K(+)-ATPase receptor.

A series of 17 beta-(hydrazonomethyl)-5 beta-androstane-3, beta,14 beta-diol derivatives was synthesized and evaluated in the displacement of [3H]ouabain binding from Na+,K(+)-ATPase. The data were explored with multiple linear regression and partial least-squares to find possible quantitatives structure-activity relationships. Good correlations were found between binding to the receptor and van der Waals volumes or molar refractivities of the 17 beta-hydrazonomethyl substituents and pKa values of the compounds. Equivalent results were obtained using the proton affinity (calculated using MOPAC) of the hydrazone residues instead of experimental pKa. As basicity or related electronic factors of the substituents explain a significant portion of the observed changes in the activity, an ion-pair interaction between a carboxylate residue of the enzyme and the protonated 17 beta-hydrazonomethyl group, as postulated by Thomas, plays an important role in the interaction of the ligand to the Na+,K(+)-ATPase receptor.

Beliefs and practices in infant feeding among the Wagogo of Chigongwe (Dodoma rural district), Tanzania. I. Breastfeeding.

PIP: Fieldwork conducted in 1989-91 among the Wagogo, a semipastoral people in central Tanzania, documented the cultural and social contexts of infant nutrition. 120 breast-feeding mothers were observed extensively and 291 mothers of 322 children attending a health center were interviewed. In this setting, repeated pregnancy and lactation are natural conditions for all adult women. Breast milk is perceived as an essential source of nutrition, energy, vigor, and strength. Lactation failure does not occur in this society. All infants nurse within a few hours of delivery and receive colostrum. The infant remains with the mother night and day, even when she is working in the fields. Breast feeding is on demand, generally in response to crying, and lasts for 2-3 years. Any changes in the quality of breast milk are viewed as associated with maternal disease or witchcraft due to jealousy. "Bad" milk is believed to cause diarrhea and withheld from the infant. In many cases, milk in one breast is perceived as bad and that breast is no longer used for feeding. Sexual intercourse is prohibited during lactation, and women who become pregnant before weaning are shamed. The progressive weakening of the child associated with the cessation of breast feeding at the time of a new pregnancy is viewed as a consequence of the breach of sexual taboos ant not recognized as malnutrition.^ieng

Beliefs and practices in infant feeding among the Wagogo of Chigongwe (Dodoma rural district), Tanzania. II. Weaning.

PIP: Anthropologic research conducted among the Wagogo, a semipastoral people in central Tanzania, elaborated the critical role that mothers play in the growth and development of their infants during the periods of breast feeding and weaning. 114 mothers recruited from a local health facility were interviewed. Most breast-fed infants are provided with additional foods after 3-4 months, but breast feeding on demand continues. The first traditional baby food is a thin soup of millet flour and water. Over time, more ingredients are added to the gruel and it is thickened. At about 12 months, the infant is given uwugali--a stiff sorghum or millet porridge that is the staple of the adult diet. Many children are completely weaned at 24-30 months for a range of reasons: desire for another pregnancy, the general developmental level of the child, the mother's assessment that her milk supply is dwindling. The weaning process lasts just 1 day. Mothers often place noxious substances on their breasts to repel the child or tell the child an animal defecated on her breasts. When possible, weaning occurs during the rainy season when more food is available. Immediate weaning also occurs if a mother violates the postpartum sex taboo and becomes pregnant again.^ieng

Conformational properties of topoisomerase II inhibitors and sequence specificity of DNA cleavage.

The sequence specificity of topoisomerase-II-mediated DNA cleavage, stimulated by 2-methyl-9-hydroxy ellipticinium and 4',5,7-trihydroxyflavone (genistein) was investigated by sequencing analysis of DNA cleavage sites and molecular modeling techniques. The former drug exhibits a marked preference for a T base at the position immediately preceding the cleavage site (-1). The latter shares the preference for the same base, with an additional preference for a thymine at position +1. The cleavage intensity patterns in the presence of the two drugs differ considerably. From a conformational point of view, ellipticinium and genistein exhibit similar overall shape and dimensions. However, the fused ring system in the former generates a planar structure whereas the single bond, connecting the two aromatic portions in the latter, allows internal rotation. The most stable conformation of genistein corresponds to a deviation of about 40 degrees from planarity. A computer-assisted analysis was carried out to compare the steric and electrostatic properties of the two compounds. Two types of preferred (energetically almost degenerate) alignment for the two molecules were found. One corresponds to overlapping of the 9-hydroxyl containing ring of ellipticinium with the 4'-hydroxyphenyl moiety of genistein, the other envisages the same moiety of ellipticine superimposed to the hydroxyl-benzopyrone portion of genistein. The structural similarities of the test drugs might account for the common preference for stimulation of DNA cleavage at position +1, whereas the different possible arrangements of genistein in the cleavable complex could explain both the additional +1 specificity exhibited by this compound and the differences in cleavage intensity patterns observed in comparison to ellipticinium.

Conformational drug determinants of the sequence specificity of drug-stimulated topoisomerase II DNA cleavage.

To gain further knowledge of the molecular features of topoisomerase II inhibitors required for drug-receptor complex formation, we investigated the conformational drug determinants of the sequence specificities of drug-stimulated DNA cleavage by computer-aided molecular modeling techniques. DNA sequence specificities of bisantrene, genistein, piroxantrone and ellipticinium were determined by using simian virus 40 DNA and compared to those of mitoxantrone, 4-demethoxydaunorubicin, VM-26 and mAMSA. DNA cleavage intensity patterns of bisantrene and mAMSA were virtually identical in sequencing gels, although these drugs are of distinct chemical classes. Genistein and ellipticinium showed drug-specific DNA cleavage intensity patterns with no apparent similarity to other drugs or to each other. From 54 to 72 drug-stimulated sites were sequenced, and local base sequence specificities were established by statistical analyses. In complete agreement with mAMSA requirements, bisantrene required an adenine at position +1. Ellipticinium required a thymine and excluded a cytosine at position -1. Genistein was the only drug showing base requirements (thymines) at both positions -1 and +1. Piroxantrone (structurally related to mitoxantrone) required a pyrimidine at position -1. Since the common sequence specificity of bisantrene and mAMSA could not be simply explained by the nature of some chemical substituents, a comparative molecular modeling analysis of the drugs was carried out based on their steric and electronic attributes. Energy-minimized structures of mAMSA and bisantrene were very similar, since their planar aromatic domains and pendant side-chains overlapped to a very good approximation. In contrast, their most stable conformations were different from other drug structures. In particular, the planar system and pendant sugar moiety of doxorubicin, which also required an adenine but at position -1, was not superimposed to the corresponding moieties of mAMSA and bisantrene even when considering computer-generated conformations with higher energy contents. The most stable conformations of the other drugs studied revealed specific three-dimensional motifs. Therefore, since in a simple model of drug action each spatial region has a single chemical-pharmacological function, these results suggest that bisantrene and mAMSA share common steric and electronic features that may constitute a specific pharmacophore. We suggest that the molecular properties of this pharmacophore may be critical determinant of the +1 position specificity shown by mAMSA and bisantrene.

Azapsoralens-DNA interactions: crystal structure characterization of furan-side monoadduct and computer-aided studies.

In this paper a theoretical study, concerning molecular mechanics optimised structures, obtained by quantum mechanics as well as molecular mechanics calculations was carried out with the aim of correlating the theoretical model of the interactions between azapsoralens and DNA with the data experimentally obtained. The theoretical model suggests that both furan-side and pyrone-side double bonds may be involved in the cycloaddition with pyrimidines (although the cycloaddition at the level of furan is preferred), and is in line with the capacity of these compounds to form inter-strand cross-links. Moreover, concerning the theoretical intercalation model calculations on 3,4,4',5'-tetramethylazapsoralen intercalated inside a polynucleotide, they suggest a cis-syn arrangement between furan-side of the intercalated ligand and the above situated thymine, with which, under light activation, a cycloadduct may take place, having a cis-syn steric arrangement. Also this datum is in agreement with the cis-syn regio and stereochemistry of the isolated 4,4',5'-trimethylazapsoralen-thymine cycloadduct. Finally, from theoretical data, the role of nitrogen seems not important: in fact only small differences were found with the corresponding methylpsoralens so that the small differences observed may be mainly attributed to steric rather than to electronic effects. In general a good correlation between the theoretical model and the experimental data was observed.

[Anesthesiologic problems in excessive obesity]. / Problemi anestesiologici nella obesità grave.

Clinical problems to consider in excessive obesity are numerous. Careful preparation before surgery is indispensable to reduce complications during and after surgery. Choice of volatile anesthetic may be important for the good results of narcosis. In the reported case anesthetic management is considered in an obese patient who had undergone a gastric operation.

Conformations of complexes between pyrrolo[1,4]benzodiazepines and DNA segments.

The molecular mechanics program AMBER, assisted by CHEMLAB II, was used to model the covalent and noncovalent binding of anthramycin, tomaymycin, and neothramycin A to the hexanucleotide conformation. Structures covalently bonded at N2 of guanine gave excellent fits when placed in either direction in the minor groove. However, energy analysis showed a preference for the direction wherein the side chain points toward the 5' end of the covalently bound strand. This preference agrees with published NMR studies. Noncovalent binding of anthramycin in the minor groove near guanine gave good fits with almost no distortion in the helix, and the reactive center of the ligand was close enough to N2 for subsequent covalent bond formation. Anthramycin also gave a good noncovalent complex near adenine in the minor groove, but binding in the major groove had decreased dispersion attractions. Binding of tomaymycin was similar to that of anthramycin, although the smaller size of tomaymycin resulted in less binding energy. Neothramycin noncovalent binding was characterized by strong electrostatic interactions, partly involving the 3-OH group, and by part of the molecule lying outside the minor groove. AMBER was used for the exploratory design of an anthramycin analogue that theoretically would bind as well as anthramycin but not cause cardiotoxicity. A related study involving anthramycin, tomaymycin, and the pentanucleotide duplex d(AAGAA/TTCTT) was undertaken to evaluate further the ability of AMBER to predict sequence specificity. It indicated a preferred direction of binding toward 5' in the minor groove of the duplex, but rather weak interaction with the noncovalently bound strand. This prediction agreed with experiments on tomaymycin that showed separation of the duplex and alignment of the drug toward the 5' end of the covalently bound strand.

Structural homology of corticotropin-releasing factor, sauvagine, and urotensin I: circular dichroism and prediction studies.

Three recently isolated peptides, whose sequences have been determined--the corticotropin (adrenocorticotropic hormone)-releasing factor of ovine origin, sauvagine, from the skin of the frog Phyllomedusa sauvagei, and urotensin I from the teleost fish, Catostomus commersoni--show high (greater than 50%) sequence homology. CD spectra of the three peptides in trifluoroethanol indicate predominantly helical character for these peptides. Analysis of the secondary structures by the Chou-Fasman method predicts that the overall structural organization of the peptides is the same. All three possess a long internal helix, spanning about 25 residues, connected by a turn region to a COOH-terminal structural element that is an alpha-helix in corticotropin-releasing factor and urotensin I and a beta-sheet in sauvagine. The values for helical content estimated from the prediction method agree reasonably well with those computed from the CD spectra. This agreement as well as the CD spectra of corticotropin-releasing factor fragment 5-33 support the specific assignments of helical regions derived from the Chou-Fasman analysis. The three peptides exhibit significantly less helical structure in water than in trifluoroethanol as indicated by CD spectra. Hydrophilicity profiles provided comparison of the three peptides in terms of their overall hydrophilicity and the location of the regions of maximal hydrophilicity. A unique distribution of hydrophilic and hydrophobic residues within the internal helices is revealed by helical wheel analysis. Patches of both types of residues are formed following a heptad (four/three) rule. Since the two patches are shifted by one residue relative to one another, together they occupy only one face of the helical surface, a feature distinct from other amphiphilic structures.