Prenatal ethanol exposure disrupts the histological stages of fetal bone development.

Maternal ethanol intake during pregnancy results in impairments in general growth and skeletal development in the offspring. We have previously shown that ethanol retards skeletal ossification at doses lower than those that affect growth. Moreover, skeletal sites vary in their sensitivity to ethanol effects, with more severe effects occurring in bones that undergo a greater proportion of their development in utero. Taken together, these data suggest that ethanol has specific effects on bone development, and that later stages in the ossification process may be particularly affected. Such effects could have important implications for the offspring's long-term bone health, as studies suggest that the intrauterine environment can program the skeleton. The present study examined the histological stages of bone development to determine if prenatal ethanol exposure alters the morphological development of the growth plate in the fetal rat. Rats were fed a liquid diet containing ethanol (Ethanol, E group), or without ethanol (Pair-Fed, PF, or Control, C groups) for 6 weeks: 3 weeks prior to breeding and during 3 weeks of pregnancy. Fetal tibiae were fixed, decalcified and stained for histological analysis on day 21 of gestation. Maternal ethanol intake resulted in a significant decrease in fetal total bone and diaphysis lengths, compared with tibiae from PF and C fetuses. Although the lengths of the epiphyses were not affected, ethanol disrupted the organization of the histological zones within the epiphyses. Prenatal ethanol exposure decreased the length of the resting zone, but increased the length of the hypertrophic zone. Enlargement of the hypertrophic zone is consistent with an effect of ethanol on the later stages of bone development; however, ethanol's effect on the resting zone indicates that earlier stages of bone development may also be disrupted. The functional significance of these morphological changes to long-term bone health remains to be determined.

Interventions in the workplace to support breastfeeding for women in employment.

BACKGROUND: In recent years there has been a rise in the participation rate of women in employment. Some may become pregnant while in employment and subsequently deliver their babies. Most may decide to return early to work after giving birth for various reasons. Unless these mothers get support from their employers and fellow employees, they might give up breastfeeding when they return to work. As a result, the duration and exclusivity of breastfeeding to the recommended age of the babies would be affected. Workplace environment can play a positive role to promote breastfeeding. For women going back to work, various types of workplace support interventions are available and this should not be ignored by employers. Notably, promoting breastfeeding in a workplace may have benefits for the women, the baby and also the employer. OBJECTIVES: To assess the effectiveness of workplace interventions to support and promote breastfeeding among women returning to paid work after the birth of their children, and its impact on process outcomes pertinent to employees and employers. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2006), CINAHL (1982 to November week 1 2006), LILACS (2 August 2006), Social Services Abstracts (1979 to November 2006), Sociological Abstracts (1952 to November 2006), Australian Public Affairs Information Service (2003 to 2006), Australian Family and Society Abstracts (2003 to 2006), International Bibliography of the Social Sciences (1951 to 2006), ProQuest Social Science Journals (1994 to 2006), Middle Eastern and Central Asian Studies (1900 to 2006) and the Campbell Collaboration Register (C2-SPECTR) (November 2006). SELECTION CRITERIA: Two authors independently assessed all identified studies for randomised controlled trials and quasi-randomised controlled trials that compared workplace interventions with no intervention or two or more workplace interventions against each other. DATA COLLECTION AND ANALYSIS: Two authors planned to evaluate the methodological quality of the eligible trials and extract data. MAIN RESULTS: There were no randomised controlled trials or quasi-randomised controlled trials identified. AUTHORS' CONCLUSIONS: No trials have evaluated the effectiveness of workplace interventions in promoting breastfeeding among women returning to paid work after the birth of their child. The impact of such intervention on process outcomes is also unknown. Randomised controlled trials are required to establish the benefits of various types of workplace interventions to support, encourage and promote breastfeeding among working mothers.

A new method for building protein conformations from sequence alignments with homologues of known structure.

We describe a largely automatic procedure for building protein structures from sequence alignments with homologues of known structure. This procedure uses simple rules by which multiple sequence alignments can be translated into distance and chirality constraints, which are then used as input for distance geometry calculations. By this means one obtains an ensemble of conformations for the unknown structure that are compatible with the rules employed, and the differences among these conformations provide an indication of the reliability of the structure prediction. The overall approach is demonstrated here by applying it to several Kazal-type trypsin inhibitors, for which experimentally determined structures are available. On the basis of our experience with these test problems, we have further predicted the conformation of the human pancreatic secretory trypsin inhibitor, for which no experimentally determined structure is presently available.

A molecular-mechanics study of the conformation of the interchain disulfide of human immunoglobulin G4 (IgG4).

The conformation of the interchain disulfide bond between the light and the heavy chains of human immunoglobulin G4 (IgG4) was modeled based on the known structure of a human IgG1 Fab. Exploration of a large number of conformations followed by energy minimization using molecular mechanics methods rendered a plausible model for the disulfide. In this model the disulfide adopts the long, trans-gauche-trans configuration found in immunoglobulin intrachain bridges and not the conformations most commonly observed in other proteins (left-handed spiral or right-handed hook). Heavy chain residues H217 and H218 pack tightly against the disulfide and put restrictions on which sequences can exist in the proposed conformation. Sequence analysis at these positions shows that: (a) all human IgG4 and IgG3 are compatible with the model; (b) IgG2 and human immunoglobulins of other classes cannot adopt the conformation proposed for IgG4.

Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods.

Generation of a three-dimensional pharmacophore model (hypothesis) that correlates the biological activity of a series of farnesyl protein transferase (FPT) inhibitors, exemplified by the prototype 1-(4-pyridylacetyl)- 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 44342, 1, with their chemical structure was accomplished using the three-dimensional quantitative structure-activity relationship (3D-QSAR) software program, Catalyst. On the basis of the in vitro FPT inhibitory activity of a training set of compounds, a five-feature hypothesis containing four hydrophobic and one hydrogen bond acceptor region was generated. Using this hypothesis as a three-dimensional query to search our corporate database identified 718 compounds (hits). Determination of the in vitro FPT inhibitory activity using available compounds from this "hitlist" identified five compounds, representing three structurally novel classes, that exhibited in vitro FPT inhibitory activity, IC50 < or = 5 microM. From these three classes, a series of substituted dihydrobenzothiophenes was selected for further structure-FPT inhibitory activity relationship studies. The results from these studies is discussed.

Affect and cognition in autism.

An array of six photographs of the same woman was used to assess the ability of 18 autistic, 14 nonautistic mentally retarded, and 18 normal preschool subjects to use affect- and activity-related concepts in the solution of cognitive tasks. The Total Performance Level of the autistic and mentally retarded subjects did not differ significantly. Autistic subjects performed imitation, directed action, and description tasks less well in the affect mode. The findings are consistent with other studies, suggesting an impairment in the expression of emotion in autism.

DSM-III and DSM-III-R diagnosis of autism and pervasive developmental disorder in nursery school children.

DSM-III and DSM-III-R diagnoses of 112 developmentally disordered preschool children were compared. There was no significant difference between the DSM-III and DSM-III-R diagnosis of the inclusive category of pervasive developmental disorder, but nearly twice as many cases (58) were diagnosed as autistic disorder by DSM-III-R criteria as were diagnosed as infantile autism (31) by DSM-III. Thirty children met both DSM-III and DSM-III-R criteria for autism (IA/AD) and 23 received a DSM-III diagnosis of atypical PDD (A-PDD) and a DSM-III-R diagnosis of AD (A-PDD/AD). All of the IA/AD children and none of the A-PDD/AD group displayed a marked lack of awareness of others. DSM-III-R criteria have specifically broadened the concept of autism to include children who, although socially impaired, are not pervasively unresponsive to others.

Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation.

OBJECTIVE: To reevaluate platelet serotonin (5-HT) levels in autism, measuring and controlling for effects of race and puberty. The specificity of hyperserotonemia for autism versus cognitive impairment is also assessed. METHOD: Platelet 5-HT levels were measured in 77 individuals, aged 2 through 37 years, with autistic disorder; 65 normal controls; and 22 mentally retarded or otherwise cognitively impaired (MR/CI) prepubertal children. Effects of diagnosis, race, and pubertal status were evaluated by analysis of variance in separate pre- and postpubertal groups. 5-HT levels were expressed as ng/mL blood and ng/microL platelet volume. RESULTS: Among prepubertal children, significant effects of diagnosis (ng/mL; F2,109 = 5.9, p = .004) and race (F2,109 = 14.7, p < .0005) were found. Autistic youngsters had significantly higher 5-HT concentrations than controls, although the elevation (25%) was less than typically reported; MR/CI children had levels very similar to those of controls. White children had significantly lower 5-HT levels than black or Latino youngsters, regardless of diagnosis. Diagnosis and race effects were nonsignificant in the postpubertal group. Postpubertal subjects had lower 5-HT concentrations than prepubertal subjects (ng/mL; F1,114 = 28.5, p < .0005). CONCLUSIONS: The data underscore the importance of matching for race and pubertal status in neuropsychiatric research and suggest that the prevalence of hyperserotonemia in autistic individuals may have been overestimated because of a failure to control for both variables. Hyperserotonemia was not found in MR/CI youngsters without autistic features.

Plasma androgens in autism.

Plasma levels of testosterone and the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) were measured in male autistic subjects (31 prepubertal, 8 postpubertal), mentally retarded/cognitively impaired subjects (MR, 12 prepubertal), and normal control subjects (NC, 10 prepubertal, 11 postpubertal). Mean levels of plasma testosterone were similar in the postpubertal autistic (4.54 +/- 1.12 ng/ml) and postpubertal NC (5.02 +/- 1.87 ng/ml) groups. Plasma DHEA-S levels in postpubertal autistic (2170 +/- 1020 ng/ml) and postpubertal NC (1850 +/- 777 ng/ml) groups also were not significantly different. Similarly, no significant group differences were seen for testosterone or DHEA-S in the prepubertal autistic, MR, or NC individuals, although prepubertal MR individuals with cerebral palsy did have increased plasma DHEA-S levels compared to age-matched MR or NC individuals. Significant negative correlations were found between testosterone and whole blood serotonin (5-HT) levels in the combined (all subjects, all ages) groups and in the autistic group, suggesting that the effect of puberty on whole blood 5-HT may deserve further study. Data indicate that altered secretion of the androgens is not a common feature of autism. However, abnormalities of adrenal androgen secretion may be present in individuals with cerebral palsy.

Conditional discrimination learning in the pigeon.

Four pigeons received conditional discrimination training in which reinforcement contingencies were related to specific combinations of color and form, but were unrelated to either color or form considered separately. During discrete-trial training, each response in the presence of two of four color-form displays produced reinforcement and terminated the trial; responding to the other two displays was never reinforced, and each such response prolonged the particular trial on which it occurred. Subsequently, the subjects received multiple-schedule training in which responding to either of the displays previously associated with reinforcement was now reinforced on a variable-interval schedule, and extinction was the schedule again correlated with the other two displays. After differential responding to the stimuli was clearly evident, intensity of the combination displays was changed in subsequent training sessions. Complex stimulus control was generally maintained across variation in intensity, although there were temporary disruptions in performance associated with onset of some of the intensity changes. Finally, a component-stimulus test revealed considerably more responding to the forms than to the colors.

A novel parameterization scheme for energy equations and its use to calculate the structure of protein molecules.

A novel scheme for the parameterization of a type of "potential energy" function for protein molecules is introduced. The function is parameterized based on the known conformations of previously determined protein structures and their sequence similarity to a molecule whose conformation is to be calculated. Once parameterized, minima of the potential energy function can be located using a version of simulated annealing which has been previously shown to locate global and near-global minima with the given functional form. As a test problem, the potential was parameterized based on the known structures of the rubredoxins from Desulfovibrio vulgaris, Desulfovibrio desulfuricans, and Clostridium pasteurianum, which vary from 45 to 54 amino acids in length, and the sequence alignments of these molecules with the rubredoxin sequence from Desulfovibrio gigas. Since the Desulfovibrio gigas rubredeoxin conformation has also been determined, it is possible to check the accuracy of the results. Ten simulated-annealing runs from random starting conformations were performed. Seven of the 10 resultant conformations have an all-C alpha rms deviation from the crystallographically determined conformation of less than 1.7 A. For five of the structures, the rms deviation is less than 0.8 A. Four of the structures have conformations which are virtually identical to each other except for the position of the carboxy-terminal residue. This is also the conformation which is achieved if the determined crystal structure is minimized with the same potential. The all-C alpha rms difference between the crystal and minimized crystal structures is 0.6 A.(ABSTRACT TRUNCATED AT 250 WORDS)

Dimensional oscillation. A fast variation of energy embedding gives good results with the AMBER potential energy function.

The structure of the AMBER potential energy surface of the cyclic tetrapeptide cyclotetrasarcosyl is analyzed as a function of the dimensionality of coordinate space. It is found that the number of local energy minima decreases as the dimensionality of the space increases until some limit at which point equipotential subspaces appear. The applicability of energy embedding methods to finding global energy minima in this type of energy-conformation space is explored. Dimensional oscillation, a computationally fast variant of energy embedding is introduced and found to sample conformation space widely and to do a good job of finding global and near-global energy minima.

A 1.8 A resolution potential function for protein folding.

A general method is presented for constructing a potential function for approximate conformational calculations on globular proteins. The method involves solving a nonlinear program that seeks to adjust the potential's parameters in such a way that a minimum near the native remains a minimum and does not move far away, while any alternative minima shift so as to remain local minima but eventually rise higher than the level of the near-native minimum. Although the potential trades computational speed for detail by representing each amino acid residue as only a single point, correct secondary structural preferences and reasonable tertiary folding can be built into the potential in an entirely routine way. The potential has been parameterized to agree with the crystal structure of avian pancreatic polypeptide (having 36 residues) in the sense that the lowest minimum found (-407 arbitrary units) is reasonably close to the native (1.8 A rms interresidue distance deviation). In contrast, the lowest nonnative conformation found after extensive searches by a variety of methods was -399 units and 7.5 A away. Such potentials may prove to be useful in predicting approximate tertiary structure from amino acid sequence, if they can be generalized to apply to more than one protein.

Calculating three-dimensional changes in protein structure due to amino-acid substitutions: the variable region of immunoglobulins.

A procedure (coupled perturbation procedure, CPP) is introduced as a specific method for calculating the detailed three-dimensional structure of a protein molecule which has a number of amino-acid substitutions relative to some previously determined "parent" protein structure. The accuracy of the procedure is tested by calculating the conformation of a region of the human immunoglobulin fragment Fab Kol based on the analogous region of the human immunoglobulin fragment Fab New. Both structures have previously been determined crystallographically. The calculated model is accurate to the extent that both of the sequence differences in the region are modeled correctly and that conformational changes in a number of nearby residues are correctly identified. CPP is shown to give better results than other commonly used modeling procedures when applied to the same problem.

Regression of severe alcoholic cardiomyopathy after abstinence of 10 weeks.

Alcoholic cardiomyopathy usually has a poor prognosis, but the case presented here documents a dramatic regression of left ventricular dysfunction in a patient with alcoholic cardiomyopathy. Ejection fraction determined by echocardiography increased from 12% at the time of presentation to 45% 10 weeks later. This was associated with clinical resolution of congestive heart failure and a decrease in cardiac and left ventricular size documented by chest x-ray and echocardiography.

Prediction of blood-brain partitioning using Monte Carlo simulations of molecules in water.

The brain-blood partition coefficient (log BB) is a determining factor for the efficacy of central nervous system acting drugs. Since large-scale experimental determination of log BB is unfeasible, alternative evaluation methods based on theoretical models are desirable. Toward this direction, we propose a model that correlates log BB with physically significant descriptors for 76 structurally diverse molecules. We employ Monte Carlo simulations of the compounds in water to calculate such properties as the solvent-accessible surface area (SASA), the number of hydrogen bond donors and acceptors, the solute dipole, and the hydrophilic, hydrophobic and amphiphilic components of SASA. The physically significant descriptors are identified and a quantitative structure-prediction relationship is constructed that predicts log BB. This work demonstrates that computer simulations can be employed in a semi-empirical framework to build predictive QSPRs that shed light on the physical mechanism of biomolecular phenomena.

The postcardiotomy syndrome following transvenous pacemaker insertion.

We describe a syndrome of fever, pericarditis, and symptomatic pericardial effusion beginning 2 months after transvenous insertion of a permanent pacemaker in a 75-year-old woman. The syndrome improved dramatically following pericardiocentesis and resolved after subsequent administration of indomethacin. Although right ventricular perforation during pacemaker insertion was not recognized, inadvertent perforation leading to the postcardiotomy syndrome is postulated.

Mechanism of triclosan inhibition of bacterial fatty acid synthesis.

Triclosan is a broad-spectrum antibacterial agent that inhibits bacterial fatty acid synthesis at the enoyl-acyl carrier protein reductase (FabI) step. Resistance to triclosan in Escherichia coli is acquired through a missense mutation in the fabI gene that leads to the expression of FabI[G93V]. The specific activity and substrate affinities of FabI[G93V] are similar to FabI. Two different binding assays establish that triclosan dramatically increases the affinity of FabI for NAD+. In contrast, triclosan does not increase the binding of NAD+ to FabI[G93V]. The x-ray crystal structure of the FabI-NAD+-triclosan complex confirms that hydrogen bonds and hydrophobic interactions between triclosan and both the protein and the NAD+ cofactor contribute to the formation of a stable ternary complex, with the drug binding at the enoyl substrate site. These data show that the formation of a noncovalent "bi-substrate" complex accounts for the effectiveness of triclosan as a FabI inhibitor and illustrates that mutations in the FabI active site that interfere with the formation of a stable FabI-NAD+-triclosan ternary complex acquire resistance to the drug.