Magnetic Compton scattering study of the magnetocaloric material Gd(7)Pd(3).

The spin-dependent momentum density of Gd(7)Pd(3) was probed by the magnetic Compton scattering technique with elliptically polarized synchrotron radiation. A contribution to the spin moment from Pd 4d electrons was observed, at 2 and 280 K, alongside a large Gd 4f moment and a smaller Gd 5d moment. The total spin moment, at 2 K, was determined as 50.8 ± 0.7 µ(B) (f.u.)(-1). The Gd 4f contribution to the spin moment was determined as 43.4 ± 1.8 µ(B) (f.u.)(-1), the Gd 5d moment as 4.4 ± 0.7 µ(B) (f.u.)(-1) and the Pd 4d spin moment contribution as 2.9 ± 1.1 µ(B) (f.u.)(-1), where f.u. represents a formula unit. At 280 K the total spin moment was 27.3 ± 0.9 µ(B) (f.u.)(-1) with individual contributions determined as a Gd 4f spin moment of 23.8 ± 1.1 µ(B) (f.u.)(-1), a Gd 5d contribution of 2.2 ± 0.5 µ(B) (f.u.)(-1) and a Pd 5d spin moment of 1.2 ± 0.6 µ(B) (f.u.)(-1).

Protein engineering and the study of structure--function relationships in receptors.

Protein engineering is a powerful tool for studying relationships between receptor structure and function--providing that it is used and interpreted appropriately. Site-directed mutagenesis, deletion mutagenesis and construction of chimaeric proteins have all been used to characterize receptors. In this review, Walter Ward, David Timms and Alan Fersht describe the application of protein engineering, illustrating important concepts with experimental data. They explain that detailed study of function requires careful dissection of mechanistic steps. Care must also be taken when selecting replacement residues; mutation should not cause delocalized structural reorganization or else the true significance of functional change will remain unclear.

In situ measurements of the sub-surface gamma dose from Chernobyl fallout.

Methods of estimating external radiation exposure of soil-dwelling organisms are currently of much research and regulatory interest. In this paper, we report the first in situ measurements of the sub-surface gamma dose rate for 137Cs contaminated land that quantify variation in dose rate with depth. Two contrasting sites have been investigated. The first site comprised a mineral type soil with a low percentage of organic matter and the second site chosen was in a peat-bog. The different soil compositions afford different 137Cs mobility and this results in variations in the measured gamma dose-rate with soil depth. For each site the paper reports the measured dose rates, the 137Cs activity depth profile, the 137Cs inventory and a description of the soil-characteristics. It is suggested that these data can be used to produce estimates of the sub-surface gamma dose rate in other sites of 137Cs contamination.

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives.

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

Ponalrestat: a potent and specific inhibitor of aldose reductase.

Many of the complications of diabetes appear to be closely linked to increased conversion of tissue glucose to sorbitol which is catalysed by aldose reductase (aldehyde reductase 2, ALR2). Inhibition of ALR2 could, therefore, lead to a reduction in the development of diabetic complications. Ponalrestat ["Statil" (a trademark, the property of Imperical Chemical Industries PLC), "Prodiax" (a trademark, the property of Merck, Sharp and Dohme), ICI 128436, MK538] inhibits ALR2 from a number of sources. Until now, the mechanism of this inhibition has not been fully elucidated. In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat. Treatment of humans with some ALR2 inhibitors leads to side-effects, some of which may result from interactions with other enzymes. Aldehyde reductase (ALR1) is probably the most closely related enzyme to ALR2. Inhibition of ALR1 from bovine kidney was, therefore, investigated in order to assess the specificity of ponalrestat. The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear fitting of kinetic data. These values indicate that ponalrestat does not compete with binding of glucose of NADPH to ALR2, nor with binding of glucuronate or NADPH to ALR1. Lack of competition and the structural dissimilarity of substrates and inhibitor make it unlikely that ponalrestat will utilize substrate binding sites on other enzymes, and so produce undesirable side-effects via such a mechanism. Ponalrestat is a potent inhibitor (Ki = Kies = 7.7 nM) of ALR2 and follows a pure noncompetitive mechanism with respect to glucose. Efficacy, therefore, will not be decreased by development of hyperglycaemia. The compound is a mixed noncompetitive inhibitor of ALR1 when glucuronate is varied. The values of Ki and Kies are 60 microM and 3 microM, respectively, so that inhibition tends towards uncompetitive. The selectivity of ponalrestat in favour of ALR2, therefore, lies in the range 390 to 7,800-fold, being higher at lower concentrations of glucuronate. The high selectivity of ponalrestat in favour of ALR2 rather than ALR1 suggests that the compound is unlikely to inhibit other enzymes which have less homology with ALR2.

Divergent structure activity relationships in series of enkephalin agonists and cognate antagonists.

Diallylation of the amino group of [Leu]enkephalin methyl ester yields a moderately potent, delta-selective opiate receptor antagonist. The diallyl congeners of a larger range of potent mu-and delta-selective enkephalin agonists have been prepared and were found to be weak, non-selective antagonists as assessed by their ability to antagonise the effects of normorphine and [Leu]enkephalin on the field-stimulated mouse vas deferens. Conversely, whereas [Gly3 psi (CH2S)Phe4,Leu5]enkephalin and [Gly3 psi(CH2S)-D-Phe4,Leu5]enkephalin are virtually inactive as opiate agonists the corresponding diallyl analogues are moderately potent, highly selective delta-antagonists. Analogues of diallyl[Leu]enkephalin in which the Gly2 and Gly3 residues have been replaced by D- and L- Ala have also been prepared and tested as delta-receptor antagonists. In addition, the empiric energy program ECEPP has been used to derive eighteen low energy conformations of diallyl[Leu]enkephalin and to estimate the effect of the D- and L-Ala substitutions on the conformer energies. Two conformers were identified for which there was a partial correlation between the variations in conformational energy and delta-antagonist potency.

Gender, social mobility and psychiatric diagnoses.

Data from a Swedish cohort born in 1953 and studied through to 1983 is used to examine the relationship between the incidence of psychiatric disorder, parental socio-economic status and intergenerational social mobility. No difference is found in the over-all incidence of in-patient treatment between men and women, but there are considerable differences in the incidence of individual diagnoses. As found in other studies, rates of schizophrenia and substance abuse are greater among men than women, while rates of neurosis are greater among women. The data generally support the drift explanation of inequalities in health rather than the social causation hypothesis, but there is some variation by both gender and diagnosis. Little association is found between parental status, measured when cohort members were aged 10, and the incidence of disorder, except in the case of substance abuse, but there is a strong association between disorder and own status, measured at age 27 yr. By far the highest rates of disorder are found among those members of the cohort who are not in the workforce. Both schizophrenia and neurosis exhibit strong drift effects; there is some evidence that the children of higher status parents have a heightened risk of being diagnosed as schizophrenic; in the case of substance abuse both downwards social mobility and low class origins appear to be implicated in the cumulative incidence of in-patient treatment.

Final-state effects in neutron Compton scattering measurements on zirconium deuteride and beryllium.

We report inelastic neutron scattering measurements of the neutron Compton profile, J(y), for Be and for D in polycrystalline [Formula: see text] over a range of momentum transfers, q between 27 and [Formula: see text]. The measurements were performed using the inverse geometry spectrometer eVS which is situated at the UK pulsed spallation neutron source ISIS. We have investigated deviations from impulse approximation (IA) scattering which are generically referred to as final-state effects (FSEs) using a method described by Sears. This method allows both the magnitude and the q dependence of the FSE to be studied. Analysis of the measured data was compared with analysis of numerical simulations based on the harmonic approximation and good agreement was found for both [Formula: see text] and Be. Finally we have shown how [Formula: see text], where V is the interatomic potential, can be extracted from the antisymmetric component of J(y).

Teenage mothers and the adult mental health of their sons: evidence from a Stockholm cohort

Data from a Swedish male cohort born in 1953 is used to investigate the effects of teenage motherhood on later mental health and illness. Measures of coping ability and psychiatric impairment at the age of 19 years and of hospitalization with a psychiatric diagnosis at ages 20-30 show that the sons of teenage mothers have a poorer health record than those born to older women. The differences disappear, however, when controls are introduced for the marital and socio-economic status of the boys' mothers, and the data suggest that teenage motherhood is not associated with poor outcomes in the absence of other predisposing factors.

Hungary: a change from decay.

At the end of October a group of dentists departed for Hungary. They arrived without mishap--then came the difficult part, getting to their hotel. Once this had been overcome, the group enjoyed an informative and entertaining Study Tour, learning about the state of dentistry in the country, as well as sampling its more obvious attractions. Donald Timms, a member of the group reports.

An analysis of the environmental mobility of radiostrontium from weapons testing and Chernobyl in Finnish river catchments.

The mobility of radiostrontium within the Arctic environment and surrounding area has been studied by analysing the mobility of 90Sr in river catchments that are within Finland. The environmental mobility of 90Sr deposited by both nuclear weapons testing and the Chernobyl accident has been investigated in five Finnish river catchments. Different models assessing the time-dependent mobility of 90Sr have been evaluated. No significant differences were found between the mobility of 90Sr from nuclear weapons tests and from the Chernobyl accident. Model parameters obtained by fitting to the measurements of the deposition and runoff rates of the nuclear weapons test fallout gave predictions which were consistent with the mid- and long-term contamination by the Chernobyl fallout. A comparison of 90Sr with 137Cs showed that they had similar mobility on deposition but, as time passed, the relative mobility of 90Sr increased with respect to 137Cs over a period of 5-8 years. Once the relative migration of 90Sr with respect to 137Cs reached equilibrium, its runoff rate was, on average, approximately an order of magnitude greater than 137Cs.

A new method to account for the depth distribution of 137Cs in soils in the calculation of external radiation dose-rate.

This work reports a new method for calculating the external dose-rate as a function of height above land that has been contaminated with a surface deposition of (137)Cs. Unlike previous work this method accounts for vertical migration of (137)Cs using the Advection Dispersion Equation (ADE) with appropriate parameters. The results have been successfully verified with field measurements from the (137)Cs contaminated regions within the Republic of Belarus. The method also correctly predicts the observed variation of dose-rate with elevation above the soil surface and it is shown how this method can be used to predict the reduction in surface dose-rate after remediation measures such as deep ploughing have taken place.

Rapid maxillary expansion in the treatment of nocturnal enuresis.

There is growing consensus that upper airway obstruction is a causative factor in nocturnal enuresis. This phenomenon has an unhappy history, although some surgeons in the past have touched on its treatment through the relief of upper airway obstruction. Only recently have sleep laboratory investigations presented a clearer, though still incomplete, picture of the etiology of nocturnal enuresis through disturbed sleep patterns. The obstruction is usually an adenoidal hypertrophy or, less commonly, an anterior nasal stenosis. While the otolaryngologist can readily cope with the former, surgical difficulties make treating the latter problematic. In many cases, the constriction can be reduced by rapid maxillary expansion. In the ten cases examined in this study, nocturnal enuresis ceased within a few months of maxillary expansion.

The dawn of rapid maxillary expansion.

The first report of lateral maxillary expansion by separation of the maxilla, written by Angell and published in 1860, was discredited. Applying our present-day knowledge of the technique to the original documents indicates that the case history agrees in general with current observations. The arguments mounted against Angell, especially by McQuillen, may be dismissed as irrelevant and Angell's thesis is upheld. In addition, good reason exists to accept three further "firsts" in this unprecedented work: (1) The significance of the first permanent molars in occlusal development, (2) the use of a double-action jackscrew, and (3) the use of a retention plate.

Relationship of the functional oropharynx to craniofacial morphology.

The association between the functional oropharyngeal airway (defined as the minimal sagittal dimension at right angles to the airstream) and craniofacial morphology was investigated using 16 craniofacial variables taken from lateral cephalometric radiographs. The sample consisted of 70 subjects (31 males and 39 females) 10 to 13 years of age. There was no difference in ages between males and females, and no correlation with age except upper face height. Oropharyngeal airway was positively correlated with length of the mandible (Gon-Men), the distance between the third cervical vertebra and the hyoid bone (C3-Hy), and cranial base angle (NSBa). Although short mandibular length is a characteristic finding in patients with obstructive sleep apnea, none of the subjects in this study had this diagnosis.

Residues within the transmembrane domain of the glucagon-like peptide-1 receptor involved in ligand binding and receptor activation: modelling the ligand-bound receptor.

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9-39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9-39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.