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Sex Transm Infect 2004;80:35-42. doi: 10.11346/sti. 2003.005413 Background/objectives: There is an urgent need for effective interventions to improve the sexual and reproductive health of adolescents. Reliable data on the sexual [...]

G-protein-coupled receptors (GPCR) participate in many disease pathways and represent the largest family of therapeutic targets. Thus, great investments are made to discover drugs modulating GPCR-mediated events. Among functional assays for screening GPCRs, the Transfluor® imaging assay is based on redistribution of cytosolic β-arrestin to an activated GPCR and has become widely used in high-content screening. However, assessing Transfluor® alone has limitations: relying on a single mechanistic step of β-arrestin redistribution during GPCR activation, providing no information on the stimulated GPCR’s intracellular fate, and using only a single fluorescent color (green fluorescent protein). Taking full advantage of high-content imaging to screen approximately 2000 compounds, the authors multifplexed the Transfluor® assay with an immunofluorescence-based quantification of GPCR internalization. This approach identified and classified 377 compounds interfering with agonist-induced activation of the Transfluor® assay, receptor internalization, or both. In addition, a subset of compounds was analyzed for their performance across imaging, cell-based calcium release (fluorometric imaging plate reader [FLIPR]), and biochemical receptor binding assays (scintillation proximity assay). This indicated that the imaging assays have even better predictive power for direct inhibition of receptor binding than the FLIPR assay. In conclusion, compounds inducing unique responses can suggest novel mechanisms of action and be used as tools to study GPCR activation and internalization.

AbstractRecent studies have indicated that linkage disequilibrium (LD) between single nucleotide polymorphism (SNP) markers can be used to derive a reduced set of tagging SNPs (tSNPs) for genetic association studies. Previous strategies for identifying tSNPs have focused on LD measures or haplotype diversity, but the statistical power to detect disease-associated variants using tSNPs in genetic studies has not been fully characterized. We propose a new approach of selecting tSNPs based on determining the set of SNPs with the highest power to detect association. Two-locus genotype frequencies are used in the power calculations. To show utility, we applied this power method to a large number of SNPs that had been genotyped in Caucasian samples. We demonstrate that a significant reduction in genotyping efforts can be achieved although the reduction depends on genotypic relative risk, inheritance mode and the prevalence of disease in the human population. The tSNP sets identified by our method are remarkably robust to changes in the disease model when small relative risk and additive mode of inheritance are employed. We have also evaluated the ability of the method to detect unidentified SNPs. Our findings have important implications in applying tSNPs from different data sources in association studies.Copyright © 2004 S. Karger AG, Basel

The morphology of the Gulf of Oman Basin, a 3,400 m deep oceanic basin between Oman and southern Pakistan and southern Iran, ranges from a convergent margin (Makran margin) along the north side, a passive type (Oman margin) along the south side, translation types along the basin's west (Zendan Fault-Oman Line) and east (Murray Ridge) sides and a narrow continental rise and a wide abyssal plain in the centre of the basin. Sediment input into the basin during the Late Quaternary has been mainly from the north as a result of the uplift of the Coast Makran Mountains in the Late Miocene-Pliocene. Today most of this detritrus is deposited on the shelf and upper continental slope and perched basins behind the fold/fault ridges on the lower slope. The presence of fans and channels on the continental rise on the north side of the basin indicate, however, that continental derived debris was, and possibly is, being transported to the deep-sea by turbidity currents via gaps in the ridges on the lower slope. In addition to land derived terrigenous sediments, the basin deposits also contain biogenic (organic matter and calcium carbonate), eolian detritus and hydrates and authigenic carbonates from the tectonic dewatering of the Makran accretionary wedge. The eolian sediment is carried into the Gulf of Oman Basin from Arabia and the Mesopotamia Valley by the northwesterly Shamal winds. This type of detritus was particularly abundant during the glacial arid periods 21,000–20,000 and 11,000 (Younger Dryas) years ago when exposure of the Persian (Arabian) Gulf increased the area of dust entrainment and shifted the position of the source of the eolian sediments closer to the basin.

Abstract.: We evolve virtual photon parton densities up to the SUSY threshold and higher using coupled inhomogeneous DGLAP differential equations. Reliable input parameterizations were available from the c-quark threshold. Limited (target photon virtuality) dependence is observed. The difference to the photon structure function is shown to be significant with the introduction of SUSY dependent splitting functions. A negligible difference is observed by letting the gluino mass enter after the squark mass. An effort is made to include the squark threshold effect in such a way that both the renormalization group equations are satisfied and the perturbative calculation is reproduced.

AimsThe study measured the prevalence of eye diseases in primary school children between 7 and 19 years of age in a rural area of Tanzania, and investigated whether teachers could successfully provide the first component of a school eye screening service.MethodsTeachers from each of three primary schools in Mwanza Region tested visual acuity using a Snellen's E chart in 1438 pupils. 1386 of these pupils were then interviewed and underwent a full eye examination by an eye team.Results10 pupils (0.7%) had bilateral poor eyesight (visual acuity worse than 6/12), and an additional 14 pupils (1.0%) had unilateral poor eyesight. Significant refractive errors causing visual acuity less than 6/12 (1.0%), strabismus (0.5%), and amblyopia (0.2%) were uncommon. Overall, 76 pupils (5.5%) had active trachoma, though the prevalence was 15.5% in the poorest school. 73 pupils (5.3%) reported night blindness, eight (0.6%) had Bitot's spots, and 11 (0.8%) had corneal scars. Simple screening by teachers correctly identified 80% of the pupils who were found to have bilateral poor eyesight by the eye team, with 91% specificity.ConclusionThe prevalence of significant refractive errors was not high enough to justify a school eye screening programme solely for this purpose. However, a programme may be justified in areas where trachoma is common. Further research is needed to validate the frequent reports of night blindness and to establish the public health importance of vitamin A deficiency in this age group.

We investigated the contribution of plasma and red blood cells to amino acid (AA) supply for milk protein synthesis during a combination of treatments that included abomasal infusion of casein and AA and utilization of a hyperinsulinemic-euglycemic clamp. Treatments resulted in substantial differences in circulating concentrations of AA, mammary uptake of AA, and rates of milk protein synthesis. Arterial concentrations of all AA in plasma were highly correlated with that of whole blood. Concentrations of AA in red blood cells were either higher (Asn+Asp, Gly, His, Leu, Met, Orn, Ser, Tau, Thr, and Tyr), lower (Ala, Arg, Cit, Cys, Ile, and Val), or similar (Gln+Glu, Phe, and Pro) to that of plasma. Arteriovenous difference measurements demonstrated that interorgan transfer of AA to the mammary gland was primarily by plasma. There was little involvement of red blood cells except for small quantities of Leu, Met, and Thr to the mammary gland; this contribution was greatest for Met and accounted for 14% of the total mammary uptake. Countercurrent transport of Gln + Glu, Asn + Asp, and Pro was also evident where these AA were extracted from plasma, but were released into red blood cells as blood passed through the mammary gland. This net influx of Gln+Glu, Asn+Asp, and Pro into red blood cells was equivalent to 26, 17, and 30% of their mammary uptake from plasma. Overall, the interorgan transport of free AA for the mammary gland was predominantly by plasma, and red blood cells were limited to minor contri butions in mammary uptake for a few AA. Furthermore, arteriovenous differences of essential AA across the mammary gland were highly correlated between plasma and whole blood.

We examined the relationships between amino acid supply, net utilization of amino acid by the mammary gland, and milk protein yield, in investigations that utilized a hyperinsulinemic-euglycemic clamp. A two-way crossed factorial design was employed. There were two 12-d periods involving abomasal infusions of either water or a mixture of casein (500 g/d) plus branched-chain amino acids (88 g/d), with a hyperinsulinemic-euglycemic clamp during the last 4 d of each period. During the clamp, insulin was infused at 1.0μg·kg BW–1·h–1to increase circulating levels fourfold, and euglycemia was maintained by infusion of glucose. The insulin clamp treatments increased milk protein yield by 15 and 25% during abomasal infusion of water or casein plus branched-chain amino acids, respectively. Circulating concentrations of essential amino acids were reduced (33%) during insulin clamp treatments, especially branched-chain amino acids (41%). Arteriovenous difference of essential amino acids across the mammary gland was linearly related to their arterial concentrations. However, milk protein yield was not related to either arterial concentration or arteriovenous difference, for any of the essential amino acids. During insulin clamp treatments, the mammary gland was able to support the increased milk protein yields by increasing extraction efficiency of essential amino acids, mammary blood flow, and glucose uptake. Furthermore, a positive mammary balance of total amino nitrogen and carbon was maintained for all treatments. These adaptations demonstrate the unique ability of the mammary gland to adjust local conditions to allow for an adequate nutrient supply.

Abstract.: We consider the flavour non-singlet Reggeon within the context of perturbative QCD. This consists of ladders built out of “reggeized” quarks. We propose a method for the numerical solution of the integro-differential equation for the amplitude describing the exchange of such a Reggeon. The solution is known to have a sharp rise at low values of Bjorken-x when applied to non-singlet quantities in deep-inelastic scattering. We show that when the running of the coupling is taken into account this sharp rise is further enhanced, although the dependence is suppressed by the introduction of the running coupling. We also investigate the effects of simulating non-perturbative physics by introducing a constituent mass for the soft quarks and an effective mass for the soft gluons exchanged in the t-channel.

A reversed radial forearm fascial flap has been used as a vascularized tube through which tendon grafts may glide and in which nerve grafts may rest. It may have applications in the treatment of the severely damaged flexor system at wrist level. A further advantage of this technique is that it does sacrifice of the radial artery in an already injured hand.

Patients with melanoma who develop nodal metastatic disease represent a group with heterogeneous clinical outcome. Nodal positivity remains the most accurate prognostic marker for regional melanoma although it fails to predict outcome in a significant number of patients. Recent studies have illustrated the prognostic potential of c-myc oncogene expression in melanoma. The aim of this study was to measure c-myc oncoprotein in a series of regional metastatic specimens from 48 patients, and evaluate its use as a marker of clinical outcome. Oncoprotein expression was detected in 46 (96%) of the tumours with a median positivity of 68% (range 0-98%). Survival analysis revealed a significant association between oncoprotein positivity and survival (Log-Rank test,@g^2 = 15.2, P < 0.001). Multivariate analysis of outcome showed c-myc oncoprotein to be an independent prognostic marker more accurate than all other clinicopathological parameters including nodal positivity (@g^2 = 8.34, P = 0.003). Estimation of c-myc oncoprotein is therefore recommended as a powerful prognostic marker for regional metastatic melanoma.

Background Mutation of the p53 tumour suppressor gene is thought to represent a significant step in the development of over half of all human cancers. Qualitative investigations of p53 protein in cutaneous melanoma suggest that overexpression is more common than in other tumours. This study analysed p53 protein expression using flow cytometry as a quantitative assay.
Methods Expression of p53 protein was assayed in ten benign melanocytic naevi (BMN) and 50 surgically excised ethanol-fixed melanomas. Nuclei were stained for the p53 protein with Pab1801 and analysed using flow cytometry. Protein expression was further correlated with clinicopathological parameters.
Results None of the BMN was immunopositive for p53. Forty-one of the 50 melanomas stained positively. The overall median positivity for p53 in primary melanoma was 12·8 per cent compared with 22·5 per cent in metastatic disease. No association was found between p53 expression and Breslow thickness or presence of nodal and skin metastases. Overexpression of p53 was associated with ulceration, mitotic figures and lymphocytic infiltration, and there was a striking increase of p53 expression with age. Expression of p53 was inversely correlated with disease-free interval.
Conclusion Although overexpression of p53 is common in melanoma, there was no association with major clinical parameters such as Breslow thickness and overall survival. The association found between p53 and other clinicopathological features suggests that the tumour suppressor gene does play a role in the evolution of melanoma.

Starting from the dipole representation of small-xevolution we implement the running of the coupling in a self-consistent way. This results in an evolution equation for the dipole density in Borel (b) space. We show that the Borel image of the dipole density is analytic in the neighbourhood of b= 0 and that it is equal to the BFKL solution at b= 0. We study the Borel singularity structure of the dipole cascade emanating from a virtual photon at small xand find a branch cut on the positive b-semiaxis starting at b = 1β0. This indicates the presence of 1Q2power corrections to the small-xstructure functions. Finally we present numerical results in the context of DIS.

We reduce the theoretical uncertainties in the prediction of the proton lifetime in the simplest SU(5) model to an uncertainty reflecting our lack of precise knowledge of the QCD coupling constant, of the mass of color Higgs' bosons, and of the proton wave function at the origin. This enables us to put a confident upper bound on the lifetime in this model. Our analysis includes all renormalization prescription dependence effects and phase-space effects. Branching ratios to experimentally significant decay modes are also discussed.

The quantitative distribution of planktonic foraminifera, pteropods, and coccolithophorids, as well as oxygen-isotope variations were analyzed in four deep-sea cores from the Gulf of Aqaba (Elat) and the northernmost Red Sea. The core record covers about 150,000 yr. Detailed stratigraphic subdivision is facilitated by combining all calcareous plankton groups. Time-stratigraphic correlation and dating beyond the radiocarbon range are possible by comparison of the oxygen-isotope curves. During the glacial maximum salinity rose to more than 50‰, while winter temperature of the upper waters fell by at least 4°C compared to the present. The rise in salinity can be accounted for by sea-strait dynamics and lowering of sea level. The Gulf of Aqaba and the Red Sea were continuously connected through the Straits of Tiran, and there is no indication of desiccation during the glacial maximum.

The results of the calculation of the metric β-function for the heterotic string sigma model up to three loops are presented and it is shown that although this β-function is non-vanishing it is compatible with an O((α′)2) effective action in which there are no terms cubic in the Riemann tensor or gauge field strength.

A gravimetric estimation of the amount of medulla in wool can be made by determining the amount of residue left after samples of known dry weight have been treated with a 1.6% solution of peracetic acid for 48 hr. at 25° C, followed by a 1.0 Nsolution of am monia for 24 hr. at 25° C. A correction must be applied for the amount of residue given by nonmedullated wools, which is approximately the same for Merino and crossbred wools. Samples which are to be used for analysts should not be dried at a high tempera ture before use. because the amount of residue increases with increasing temperature of drying, especially when the moisture content of the wool is high, owing to the formation of resistant cross-linkages between the peptide chains.

The gene for renin, previously mapped to human chromosome 1, was further localized to 1q12→qter using human-mouse somatic cell hybrid DNAs. The renin DNA probe used (λHR5) could detect a HindIII restriction fragment length polymorphism. When used in studies of 12 informative families, no linkage could be found between the renin gene and Charcot-Marie-Tooth disease. Furthermore, an association of any renin allele with hypertension was not apparent.

A uniform diffraction solution is given for an electromagnetic wave incident on perfectly conducting surface having a discontinuity in curvature. The solution is derived from an asymptotic evaluation of the physical-optics integral, and correction factors are deduced to retrieve the rigorous nonuniform result away from the reflection boundary.

We present Molecular Dynamics (MD) simulations of liquid water confined within nanoscale geometries, including slit-like and cylindrical graphitic pores. These equilibrium results are used for calculating friction coefficients, which in turn can be used to calculate slip lengths. The slip length is a material property independent of the fluid flow rate. It is therefore a better quantity for study than the fluid velocity at the wall, also known as the slip velocity. Once the slip length has been found as a function of surface curvature, it can be used to parameterise Lattice Boltzmann (LB) simulations. These larger scale simulations are able to tell us about how fluid transport is affected by slip in complex geometries; not just limited to single pores. Applications include flow and transport in nano-porous engine valve deposits and gas shales. The friction coefficient is found to be a function of curvature and is higher for fluid on convex surfaces and lower for concave surfaces. Both concave and convex surfaces approach the same value of the friction coefficient, which is constant above some critical radius of curvature, here found to be 7.4 ± 2.9 nm. The constant value of the friction coefficient is 10,000 ± 600 kg m−2s−1, which is equivalent to a slip length of approximately 67 ± 4 nm.

Breslow Depth remains the most accurate prognostic marker for primary melanoma though it fails to predict outcome in a significant number of patients. The aim of this study was to establish the prognostic value of c-myc oncoprotein using multivariate analysis.C-myc oncoprotein was measured in 92 primary melanomas (0.75–2.49mm) using flow cytometry. Median follow up was 81 months. Oncoprotein was detected in 87 (95%) of rumours Survival curves constructed using the Kaplan-Meier method showed significantly shorter survival in tumours with high c-myc (P<0.01). Multivariate analysis using Cox's proportional hazards model showed c-myc expression to be an independent prognostic marker more powerful in determining outcome than all others, including Breslow depth (Chi squared=9.68, P<0.01).The results of this study indicate the powerful prognostic value of c-myc oncoprotein. Further consideration of this oncogene and its manipulation may provide an objective platform for the design of future therapy.