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A genetic map of the Cf-9 to Dmd region of the mouse X chromosome has been established by typing 100 offspring from a Mus musculus × Mus spretus interspecific backcross for the four loci Cf-9, Cdr, Gabra3, and Dmd. The following order and genetic distances in centimorgans were determined: (Cf-9)-2.4 ± 1.7-(Cdr)-2.0 ± 1.4-(Gabra3)-4.1 ± 2.0-(Dmd). Six backcross offspring carrying X chromosomes with recombination events in the Cdr-Dmd region were identified. These recombination events were used to define the position of Fmr-1, the murine homologue of FMR1, which is the gene implicated in the fragile X syndrome in man, and that of DXS296h, the murine homologue of DXS296. Both Fmr-1 and DXS296h were mapped into the same recombination interval as Gabra3 on the mouse X chromosome. These findings provide strong support for the concept that the order of loci lying in the Cf-9 to Gabra3 segment of the X chromosome is highly conserved between human and mouse.

The interaction of different phosphate esters with a series of hydrogen bonding receptors has been studied using UV-visible and NMR spectroscopies and X-ray crystallography. Critical for binding is a combination of an acidic proton and the potential for bidentate hydrogen bonding either between charged or uncharged components. Phosphotriesters show no binding to the receptors. Phosphodiesters bind to both bis-(2, 6–diacylaminopyridine) and mono-(2, 6–diacylaminopyridine) receptors in chlorocarbon solvent via proton transfer to form the pyridinium phosphate ion pair and bidentate hydrogen bonding between the anion and the cation. Titration experiments as well as Job's analyses show that for cyclic and acyclic bis-(2, 6–diacylaminopyridine) receptors 2: 1 complexes can be formed. X-ray crystal structures demonstrate that in the solid state two different binding arrangements are present; either a direct bidentate interaction or intramolecular hydrogen bonding with self-assembly of an oligomeric structure. Phosphomonoesters bind to mono-(2, 6–diacylaminopyridines) in a similar way to the diesters, via proton transfer and bidentate hydrogen bonding. In this, as in the diester case, only a single acid-base interaction is possible and proton transfer is preferred. However, in the interaction of phosphomonoesters with bis-(2, 6–diacylaminopyridine) derivatives two acid-base interactions are possible between the two pyridines and two POH groups, and little proton transfer is seen. Strong binding (Ka = 1.0 × 105M−1) occurs via tetrahydrogen bond formation. Thus, there appears to be a balance between the occurrence of proton transfer and the number of hydrogen bonds formed between receptor and substrate.

Fragment-based hit identification coupled with crystallographically enabled structure-based drug design was used to design potent inhibitors of JAK-2. After two iterations from fragment 1, we were able to increase potency by greater than 500-fold to provide sulfonamide 13, a 78-nM JAK-2 inhibitor.

Fragile X positive, mentally retarded males have been shown to have an insertion or amplification of DNA sequences at, or close to, the site of expression of the fragile site. We show here the application of the detection of such changes to the diagnosis of affected males and female carriers and the identification of normal transmitting males. One fragile X negative male with the clinical features of the Martin-Bell syndrome also possesses an inserted/amplified DNA sequence. The implications of these results for screening for the fragile X syndrome are discussed.

The most common genetic cause of mental retardation after Down's syndrome, the fragile X syndrome, is associated with the occurrence of a fragile site at Xq27.3. This X-linked disease is intriguing because transmission can occur through phenotypically normal males. Theories to explain this unusual phenomenon include genomic rearrangements and methylation changes associated with a local block of reactivation of the X chromosome. Using microdisected markers close to the fragile site, we have been able to test these hypotheses. We present evidence for the association of methylation with the expression of the disease. However, there is no simple relationship between the degree of methylation and either the level of expression of the fragile site or the severity of the clinical phenotype.

The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R(2)=0.30) with a slope of 0.32 (P

Fragment-based hit identification coupled with crystallographically enabled structure-based drug design was used to design potent inhibitors of JAK-2. After two iterations from fragment 1, we were able to increase potency by greater than 500-fold to provide sulfonamide 13, a 78-nM JAK-2 inhibitor.

A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.

An investigation is presented of coupled ocean-atmosphere models' behavior in an environment where atmospheric wave speeds are substantially reduced from dry atmospheric values by such processes as condensation-moisture convergence. Modes are calculated for zonally periodic, unbounded ocean-atmosphere systems, emphasizing the importance of an inclusion of prognostic atmosphere equations in simple coupled ocean-atmosphere models with a view to simulations of intraseasonal variability and its possible interaction with interannual variability. The dynamics of low and high frequency modes are compared; both classes are sensitive to the degree to which surface wind anomalies are able to affect the evaporation rate.

Selecting a detector for dosimetry three important factors are sensitivity, energy independence and convenience. Silicon solar cells have high volume sensitivity in the low-energy range associated with mammography, however, the sensitivity becomes dose dependent at low- dose rates. The dose rate dependence of sensitivity appears to be common to all silicon photodiodes but different types exhibit it to different degrees. Fortunately, it is possible to select photodiodes, the dose rate dependence of which is not significant at the levels of exposure encountered in routine mammography. In the energy range 10-50 keV silicon photodiodes with thin detection volumes are relatively energy independent and are well suited for mammography. Silicon photodiodes are much less suitable for general radiographic dosimetry due to the large variation in sensitivity which occurs from 50 keV upwards.

Cyclobutane photodimers of thymine were synthesized and shown, in organic solvent, to bind to mono-and bis-diamidopyridine derivatives.

Transgenic models representing Huntington's disease (HD) have proved useful for understanding the cascade of molecular events leading to the disease. We report an initial characterisation of a novel transgenic mouse model derived from a spontaneous truncation event within the R6/1 transgene. The transgene is widely expressed, carries 89 CAG repeats and the animals exhibit a significantly milder neurological phenotype with delayed onset compared to R6/1. Moreover, we report evidence of progressive somatic CAG expansions in the brain starting at an early age before an overt phenotype has developed. This novel line shares a common genetic ancestry with R6/1, differing only in CAG repeat number, and therefore, provides an additional tool with which to examine early molecular and neurophysiological changes in HD.

Three different estimates of shortwave attenuation depth (SWAD) of photosynthetically active radiation (PAR) derived from remotely sensed ocean colour data have been tested in an ocean general circulation model (OGCM) forced with interannual atmospheric forcings. Two estimates (referred to as and ) are calculated from different algorithms based on the diffusive attenuation coefficient at 490 nm and the third one ( ) is just an average of and . is larger than almost everywhere in the tropical oceans. Our results show that the OGCM with produces warmer sea surface temperature (SST) in the eastern equatorial Pacific and Atlantic and leads to reduce a cold bias in the equatorial cold tongue regions. It has warmer subsurface temperatures in the low latitude, a slower meridional velocity and Pacific equatorial undercurrent (EUC) than the model with . These results are similar to previous studies, although we use a different model and different methods. This study has further analysis and firstly reveals that slower EUC and meridional velocity in the model with are mainly related to the changes of the acceleration due to zonal density gradient. This acceleration driving the EUC eastward in the subsurface becomes smaller in the subsurface along the equatorial Pacific. However, near the sea surface, the zonally averaged accelerations over the different ocean basins are larger in the model with than that with , which pushes back the poleward meridional transport. The interannual variability in the model with is generally weaker than that in the experiment with due to a deeper mixed layer depth. The vertical temperature errors averaged horizontally within the domain of 30°S to 30°N in the experiment with are almost in the middle of errors of the other two experiments. This indicates that the effect of the SWAD on the simulation of the vertical temperature profile is largely linear. Keywords: OGCM, shortwave penetration depth, climate simulation (Published: 23 January 2015) Citation: Tellus A 2015, 67, 25313, http://dx.doi.org/10.3402/tellusa.v67.25313

A photoluminescence (PL) spectroscopy study of the bulk quaternary alloy InAlAsSb is presented. Samples were grown lattice-matched to InP by molecular beam epitaxy and two different growth temperatures of 450 °C and 325 °C were compared. Interpolated bandgap energies suggest that the development of this alloy would extend the range of available direct bandgaps attainable in materials lattice-matched to InP to energies as high as 1.81 eV. However, the peak energy of the observed PL emission is anomalously low for samples grown at both temperatures, with the 450 °C sample showing larger deviation from the expected bandgap. A fit of the integrated PL intensity (I) to an I∝Pk dependence, where P is the incident power density, yields characteristic coefficients k = 1.05 and 1.18 for the 450 °C and 325 °C samples, respectively. This indicates that the PL from both samples is dominated by excitonic recombination. A blue-shift in the peak emission energy as a function of P, along with an S-shaped temperature depe...

We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed based on a desire to access the unique residues in the extended hinge region of Lck.

Predictive genetic testing for Huntington’s disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. We report here a progressive derailment of both LTD and short-term plasticity at perirhinal synapses. Layer II/III neurones gradually lose their ability to support LTD, show early nuclear localization of mutant huntingtin and display a progressive loss of membrane integrity (depolarization and loss of cell capacitance) accompanied by a reduction in the expression of D1 and D2 dopamine receptors visualized in layer I of the perirhinal cortex. Importantly, abnormalities in both short-term and long-term plasticity can be reversed by the introduction of a D2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD.

Duchenne Muscular Dystrophy (DMD) is a devastating, progressive muscle wasting disease for which there is currently no effective treatment. DMD is caused by mutations in the dystrophin gene many of which result in the absence of the large cytoskeletal protein dystrophin at the sarcolemma. Over-expression of utrophin, the autosomal paralogue of dystrophin, as a transgene in the mdx mouse (the mouse model of DMD) has demonstrated that utrophin can prevent the muscle pathology. Thus, up-regulation of utrophin in DMD muscle is a potential therapy for DMD. In this review we discuss recent advances in our understanding of the regulatory pathways controlling utrophin expression and the various approaches that have been applied to increasing the level of utrophin in the mdx mouse. These results are very encouraging and suggest that pharmacological up-regulation of utrophin may well be a feasible approach to therapy for DMD.

We describe the identification, SAR, and pharmacology of the src-family selective lck inhibitor A-770041 that prolongs the survival of major histocompatibility mismatched allografts in models of solid organ transplant rejection for greater than 65 days.

The Src family kinases Lck and Fyn play an important role in T cell development and function. We have synthesized a novel small molecule, A-420983, which inhibits Lck and Fyn, as well as other Src family kinases, but has selectivity with respect to non-Src family kinases. A-420983 completely inhibited antigen-stimulated production of IFN-gamma and IL-4 by mouse Th1 and Th2 cells, respectively. Antigen-induced T cell proliferation was also blocked by treatment with A-420983. In contrast, IL-15-induced proliferation was unaffected by A-420983, suggesting that TCR-independent pathways of T cell activation were not impaired. When mice were dosed orally, A-420983 inhibited TCR-mediated c-jun and ZAP-70 phosphorylation in CD4+ T cells and suppressed the disease course of established EAE. Treatment with A-420983 for 7 days resulted in a block in thymocyte development at the CD4- CD8- stage, consistent with inhibition of Lck and Fyn in vivo. These results demonstrate that a small molecule inhibitor of Lck and Fyn can block TCR-induced T cell activation in vitro and in vivo. Furthermore, CNS demyelination mediated by activated encephalitogenic CD4+ T cells is dependent upon the kinase activity of these Src family members. We conclude that inhibition of Src family kinases may represent a promising strategy for the treatment of T cell-mediated disorders.

Bar-like structures were investigated in a sample of 186 disk galaxies larger than 0.5 arcsec that are in the I-band image of the Tadpole galaxy taken with the HST ACS. We found 22 clear cases of barred galaxies, 21 galaxies with small bars that appear primarily as isophotal twists in a contour plot, and 11 cases of peculiar bars in clump-cluster galaxies, which are face-on versions of chain galaxies. The latter bars are probably young, as the galaxies contain only weak interclump emission. Four of the clearly barred galaxies at z~0.8-1.2 have grand design spirals. The bar fraction was determined as a function of galaxy inclination and compared with the analogous distribution in the local Universe. The bar fraction was also determined as a function of galaxy angular size. These distributions suggest that inclination and resolution effects obscure nearly half of the bars in our sample. The bar fraction was also determined as a function of redshift. We found a nearly constant bar fraction of 0.23+-0.03 from z~0 to z=1.1. When corrected for inclination and size effects, this fraction is comparable to the bar fraction in the local Universe, ~0.4, as tabulated for all bar and Hubble types in the Third Reference Catalogue of Galaxies. The average major axis of a barred galaxy in our sample is ~10 kpc after correcting for redshift with a LambdaCDM cosmology. Galaxy bars were present in normal abundance at least ~8 Gy ago (z~1); bar dissolution cannot be common during a Hubble time unless the bar formation rate is comparable to the dissolution rate., to appear in ApJ, Sept 1, 2004, Vol 612, 18 pg, 12 figures

International audience; We examine six different coupled climate model simulations to determine the ocean biological response to climate warming between the beginning of the industrial revolution and 2050. We use vertical velocity, maximum winter mixed layer depth, and sea ice cover to define six biomes. Climate warming leads to a contraction of the highly productive marginal sea ice biome by 42% in the Northern Hemisphere and 17% in the Southern Hemisphere, and leads to an expansion of the low productivity permanently stratified subtropical gyre biome by 4.0% in the Northern Hemisphere and 9.4% in the Southern Hemisphere. In between these, the subpolar gyre biome expands by 16% in the Northern Hemisphere and 7% in the Southern Hemisphere, and the seasonally stratified subtropical gyre contracts by 11% in both hemispheres. The low-latitude (mostly coastal) upwelling biome area changes only modestly. Vertical stratification increases, which would be expected to decrease nutrient supply everywhere, but increase the growing season length in high latitudes. We use satellite ocean color and climatological observations to develop an empirical model for predicting chlorophyll from the physical properties of the global warming simulations. Four features stand out in the response to global warming: (1) a drop in chlorophyll in the North Pacific due primarily to retreat of the marginal sea ice biome, (2) a tendency toward an increase in chlorophyll in the North Atlantic due to a complex combination of factors, (3) an increase in chlorophyll in the Southern Ocean due primarily to the retreat of and changes at the northern boundary of the marginal sea ice zone, and (4) a tendency toward a decrease in chlorophyll adjacent to the Antarctic continent due primarily to freshening within the marginal sea ice zone. We use three different primary production algorithms to estimate the response of primary production to climate warming based on our estimated chlorophyll concentrations. The three algorithms give a global increase in primary production of 0.7% at the low end to 8.1% at the high end, with very large regional differences. The main cause of both the response to warming and the variation between algorithms is the temperature sensitivity of the primary production algorithms. We also show results for the period between the industrial revolution and 2050 and 2090.

[1] We have used a marine food-web model, an atmosphere-ocean general circulation model (GCM), and an empirical dimethylsulfide (DMS) algorithm to predict the DMS seawater concentration and the DMS sea-to-air flux in 10° latitude bands from 70°N to 70°S under contemporary and enhanced greenhouse conditions. The DMS empirical algorithm utilizes the food-web model predictions of surface chlorophyll and the GCM's simulation of oceanic mixed layer depth. The food-web model was first calibrated to contemporary climate conditions using satellite-derived chlorophyll data and meteorological forcings. For the climate change simulations, the meteorological forcings were derived from a transient simulation of the CSIRO Mark 2 GCM, using the IPCC/IS92a radiative forcing scenario to the period of equivalent CO2 tripling (2080). The globally integrated DMS flux perturbation is predicted to be +14%; however, we found strong latitudinal variation in the perturbation. The greatest perturbation to DMS flux is simulated at high latitudes in both hemispheres, with little change predicted in the tropics and sub-tropics. The largest change in annual integrated flux (+106%) is simulated in the Southern Hemisphere between 50°S and 60°S. At this latitude, the DMS flux perturbation is most influenced by the GCM-simulated changes in the mixed layer depth. The results indicate that future increases in stratification in the polar oceans will play a critical role in the DMS cycle and climate change.

Our understanding of FMRI trinucleotide instability has increased dramatically with knowledge of its detailed structures. While most arrays seem to be protected by interspersions, for a few the price of perfection is instability. Although there remain many unanswered questions, diagnosis in the “grey zone” can be greatly improved by studying array content. For the future, as we strive to delineate normal from premutation, we should increasingly be able to estimate rates of instability for future generations and predict the risk of conversion to the full mutation.

[i] In the Earth's geological record massive marine ecological change has been attributed to the occurrence of widespread anoxia in the ocean [Jahren, 2002; White, 2002; Wignall and Twitchett, 1996]. Climate change projection till the end of this century predict a 4 to 7% decline in the dissolve oxygen in the ocean [Bopp et al., 2002; Matear et al., 2000; Plattner et al., 2001; Sarmiento et al., 1998] suggesting the potential for global warming to eventually drive the deep ocean anoxic. To examine the multicentury impact of protracted global warming on oceanic concentrations of dissolved oxygen, we use a climate system model and a low-order oceanic biogeochemical model. The models are integrated for an atmospheric equivalent CO 2 concentration, which is specified to triple according to a standard scenario from the late nineteenth to the late twenty-first century, and then is subsequently held constant at that elevated level for an additional 6 centuries. For the present day, the model successfully reproduced the large-scale features of the dissolved oxygen field in the ocean. In the global warming simulation, the physical model displays marked changes in high-latitude oceanic stratification and overturning, including near-cessation of deep water renewal for depths greater than about 1.5 km during the period of elevated stable CO 2 concentration. Our model predicts a decline in oxygen concentration through most of the subsurface ocean. Concentration changes in the thermocline waters result mainly from solubility changes in the upstream source waters, while changes in the deep waters result mainly from lack of ventilation and ongoing consumption of oxygen by remineralization of sinking particulate organic matter. Changes in the upper 2 km of the ocean generally show signs ofequi libration by the end ofthe integration, but at greater depths, there occurs a slow but steady decline through to the end of the integration. By the end of the integration, we simulate a doubling ofthe volume ofhypoxic water (less than 10 μmol/kg) in the thermocline of the eastern equatorial Pacific Ocean. During the integration deep ocean oxygen concentrations generally decline by between 20 and 40%, but, significantly, no extensive deep ocean anoxia develops during the period of integration, nor does it appear that it would likely do so for at least a further 4000 years of integration. Subsurface oxygen decline is moderated by an overall reduction in export production of particulate organic matter, which reduces oxygen consumption in the ocean interior due to the remineralization of this material.

Methyl (Z)-3-(Phenylsulfonyl)Prop-2-enoate product: methyl (E)-3-(phenylsulfonyl)prop-2-enoate product: methyl (Z)-3-(phenylsulfonyl)prop-2-enoate Keywords: sulfonation, C-sulfonation; benzene; methyl propiolate, lachrymator

An unambiguous observation of hot-carrier photocurrent from an InGaAs single quantum well solar cell is reported. Simultaneous photo-current and photoluminescence measurements were performed for incident power density 0.04–3 kW cm−2, lattice temperature 10 K, and forward bias 1.2 V. An order of magnitude photocurrent increase was observed for non-equilibrium hot-carrier temperatures >35 K. This photocurrent activation temperature is consistent with that of equilibrium carriers in a lattice at elevated temperature. The observed hot-carrier photo-current is extracted from the well over an energy selective GaAs barrier, thus integrating two essential components of a hot-carrier solar cell: a hot-carrier absorber and an energy selective contact.

Multiple frequency bioelectrical impedance analysis (MFBIA) has previously been shown to provide accurate relative measures of lymphedema in the upper limb of patients (1). This paper reports the results of a three year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in patients following treatment for breast cancer. Bioelectrical impedance measurements and circumferential measurements of each upper limb were recorded in healthy control subjects (n = 60) to determine the normal range of the ratio (dominant/non-dominant) of extracellular and total limb volumes respectively. Patients undergoing surgery for the treatment of breast cancer were recruited as the study group; MFBIA and circumferential measurements were recorded pre-surgery, one month post-surgery and then at two month intervals for 24 months. One hundred and two patients were recruited into the study. Twenty patients developed lymphedema in the 24 months follow up period of this study. In each of these 20 cases MFBIA predicted the onset of the condition up to 10 months before the condition could be clinically diagnosed. Estimates of the sensitivity and specificity were both approximately 100%. At the time of detection by MFBIA, only one of the patients returned a positive test result from the total limb volumes determined from the circumferential measures. These results confirmed the suitability of the MFBIA technique as a reliable diagnostic procedure for the early detection of lymphedema.

Fragile X syndrome is one of 14 trinucleotide repeat diseases. It arises due to expansion of a CGG repeat which is present in the 5'-untranslated region of the FMR1 gene, disruption of which leads to mental retardation. The mechanisms involved in trinucleotide repeat expansion are poorly understood and to date, transgenic mouse models containing transgenic expanded CGG repeats have failed to reproduce the instability seen in humans. As both cis-acting factors and the genomic context of the CGG repeat are thought to play a role in expansion, we have now generated a knock-in mouse Fmr1 gene in which the murine (CGG)8 repeat has been exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models, this model shows moderate CGG repeat instability upon both in maternal and paternal transmission. This model will now enable us to study the timing and the mechanism of repeat expansion in mice.

International audience; This paper presents some research developments in primitive equation ocean models which could impact the ocean component of realistic global coupled climate models aimed at large-scale, low frequency climate simulations and predictions. It is written primarily to an audience of modellers concerned with the ocean component of climate models, although not necessarily experts in the design and implementation of ocean model algorithms.

The fragile X syndrome is one of the most common familial causes of mental retardation. It is associated with the expression of a fragile site at Xq27.3, although not all individuals carrying the mutation are fragile-X-positive. Recently, the mutation causing this disease has been identified as the amplification of, or insertion into, a CGG repeat sequence at the fragile site. The mutated chromosome can be recognised by the decrease in mobility of the EcoRI fragment that covers the mutated region. Analysis of lymphocytes of affected males often gives a number of different sized fragments indicating somatic heterogeneity. We have investigated this mosaicism in various tissues of an affected fetus in order to determine the extent of the variation between tissues, and to ascertain how to interpret the results in lymphocytes. Our results suggest that the heterogeneity occurs in all fetal tissues, but that the pattern of fragments observed varies between tissues. Methylation across the region also varies. These differences may be reflected in the cellular phenotypes and may influence the ultimate expression of the clinical phenotype.

[1] Climate models predict that increasing greenhouse gases in the atmosphere will change our climate. However, the range of observations available to assess these model predictions is limited. We have utilized an ocean biogeochemical model to project the impact of climate change on the oxygen cycle in the ocean and the air-sea exchange of oxygen. With climate change, our model predicts an outgassing of oxygen from the ocean. In the model, the Southern Ocean is the region that displays the largest change in the air-sea exchange of oxygen with climate change. The reduced oxygen uptake in the Southern Ocean is dominated by a reduction in convective mixing and in the subduction rate of bottom water which decreases the amount of dissolved oxygen in the Southern Ocean. Our model results suggest that dissolved oxygen is sensitive to changes in Southern Ocean circulation revealing the potential to use dissolved oxygen to test model predictions of climate change. From Southern Ocean observations collected 28 years a part we observed a decrease in dissolved oxygen that was consistent with model climate change simulation. This provides credibility to the climate model predictions. Additional analysis and observations of dissolved oxygen are needed to substantiate our climate model simulations.

Breast disease in the adolescent female is fortunately uncommon, with most presenting lesions being benign. The type and frequency of breast problems in young women less than 20 years of age are discussed in this paper. There were 634 adolescent females (9-19 years) referred to the Wesley Breast Clinic between January 1990 and December 1999. Of these, 62.6% were aged 18-19 years. The commonest reason for referral was a lump or thickening in the breast (n=554, 87.4%). Six hundred and nineteen females had ultrasound performed, with 59% showing no abnormality. The commonest abnormality in the remainder was probable fibroadenoma (n=162). Twenty-two percent of the females in the study had fine needle aspiration performed; none showed suspicious cytology. Twenty-three females had an excision biopsy following their initial visit. Three of these were found to have benign phyllodes tumour. There were no malignancies detected, although one female had previous DCIS diagnosed elsewhere.

Lymphedema is an accumulation of lymph fluid in the limb resulting from an insufficiency of the lymphatic system. It is commonly associated with surgical or radiotherapy treatment for breast cancer. As with many progressively debilitating disorders, the effectiveness of treatment is significantly improved by earlier intervention. Multiple frequency bioelectrical impedance analysis (MFBIA) previously was shown to provide accurate relative measures of lymphedema in the upper limb in patients after treatment for breast cancer, This presentation reports progress to date on a three-year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in breast cancer patients following treatment. Bioelectrical impedance measurements of each upper limb were recorded in a group of healthy control subjects (n = 50) to determine the ratio of extracellular limb-fluid volumes. From this population, the expected normal range of asymmetry (99.7% confidence) between the limbs was determined, Patients undergoing surgery to treat breast cancer were recruited into the study, and MFBIA measurements were recorded presurgery, at one month and three months after surgery, and then at two-month intervals for up to 24 months postsurgery, When patients had an MFBIA measure outside the 99.7% range of the control group, they were referred to their physician for clinical assessment. Results to date: Over 100 patients were recruited into the study over the past two years; at present, 19 have developed lymphedema and, of these, 12 are receiving treatment. In each of these 19 cases, MFBIA predicted the onset of the condition up to four months before it could be clinically diagnosed. The false-negative rate currently is zero, The study will continue to monitor patients over the remaining year to accurately ascertain estimates of specificity and sensitivity of the procedure.

Background: A proportion of the cancers ‘missed’ at mammography are invisible even with the benefit of hindsight. The aim of the present study was to identify a group of women with proven breast cancer whose mammograms did not show a suspicious lesion even in retrospect (i.e. the truly mammographically occult cancers), and to compare them with mammogram-positive cancers. Methods: A total of 1757 breast cancers was diagnosed at the Wesley Breast Clinic’s Screening or Diagnostic Services between July 1987 and August 1997. One hundred and twenty cases were identified where, after independent review by two of the authors, no mammographic abnormality could be found in the region where the cancer was subsequently found. These 120 cases were compared with 1548 cancers considered to have a lesion visible on mammography, whether benign, indeterminate, suspicious or malignant in appearance. Results: In 90% of the mammogram-negative cancers, a clinical abnormality led to further investigation, while the remainder were found incidentally on ultrasound. There were a higher proportion of dense breasts, and of women aged 40–49, in the mammogram-negative cancers than in the mammogram-positive cancers. The mammogram-negative cancers were of smaller size overall, but three of them were surprisingly large (7–11 cm). In both the mammogram-positive and -negative cancers ~ 60% were ductal invasive cancers. Conclusions: Where factors are present that make mammographically occult malignancy more likely (e.g. age 40–49 and dense breasts), women may be targeted for further investigation by other modalities. This is essential in the presence of a clinical abnormality.

Currently there are major initiatives in a number of research institutions to develop operational long-lead climatic prediction schemes. These schemes are all based on the intrinsic predictability of El Nino/Southern Oscillation events occurring in the low latitude Pacific Ocean. The physical processes that provide this long-lead predictability are identified and briefly discussed here. These processes have now been incorporated into a range of climatic models, extending from highly parameterised two-level models to extremely complicated coupled atmospheric-oceanic global climatic models. The manner in which the various models are used for predictions is discussed, and some results from an extensive series of hindcasts are presented to illustrate present levels of predictability, particularly for rainfall. The paper concludes with a list of major problems that need to be resolved in order to enhance predictability, especially the critical requirement to extend oceanic feedbacks beyond the low latitude Pacific Ocean.

Expanded trinucleotide repeats underlie a growing number of human diseases. The human FMR1 (CGG)(n) array can exhibit genetic instability characterized by progressive expansion over several generations leading to gene silencing and the development of the fragile X syndrome. While expansion is dependent upon the length of uninterrupted (CGG)(n), instability occurs in a limited germ line and early developmental window, suggesting that lineage-specific expression of other factors determines the cellular environment permissive for expansion. To identify these factors, we have established normal- and premutation-length human FMR1 (CGG)(n) arrays in the yeast Saccharomyces cerevisiae and assessed the frequency of length changes greater than 5 triplets in cells deficient in various DNA repair and replication functions. In contrast to previous studies with Escherichia coli, we observed a low frequency of orientation-dependent large expansions in arrays carrying long uninterrupted (CGG)(n) arrays in a wild-type background. This frequency was unaffected by deletion of several DNA mismatch repair genes or deletion of the EXO1 and DIN7 genes and was not enhanced through meiosis in a wild-type background. Array contraction occurred in an orientation-dependent manner in most mutant backgrounds, but loss of the Sgs1p resulted in a generalized increase in array stability in both orientations. In contrast, FMR1 arrays had a 10-fold-elevated frequency of expansion in a rad27 background, providing evidence for a role in lagging-strand Okazaki fragment processing in (CGG)(n) triplet repeat expansion.

Background: Fifty-one cases of de novo fibroadenoma in women aged 35 years and older were found during an analysis of 117 729 visits to the Wesley Breast Clinic from 1990 to 1996. Methods: The clinical, mammographic and ultrasound diagnosis of fibroadenoma was confirmed by either fine needle aspiration cytology or histology of an open biopsy specimen. In all cases there was a well-documented previous visit available for review, at which there was no clinical or radiological evidence of the fibroadenoma. Results: Thirty-seven of the de novo fibroadenomas were palpable, the remainder satisfying strict mammographic and/or ultrasound criteria. Four of the new fibroadenomas were in women aged 50–52. Conclusions: This study provides information about the natural history of fibroadenomas, confirming that they can appear for the first time in middle-aged women. This has important clinical implications, since new lesions appearing in women over 35 have tended to be automatically categorized as suspicious of carcinoma. However, a multidisciplinary approach involving clinical examination, mammography, ultrasound, and fine needle aspiration cytology or core biopsy can result in a confident diagnosis of fibroadenoma. This will allow some women with new lesions to be managed conservatively rather than by open biopsy.

We compared haemoglobin concentration values obtained using a portable haemoglobinometer, the HemoCue, in the operating theatre with the results obtained by the Coulter Max-M in the laboratory. Haemoglobin concentrations were measured on 52 arterial blood samples obtained from 13 patients during aortic surgery, in theatre with the HemoCue and again by the Coulter Max-M. Twenty routine samples from the laboratory were also analysed by both methods. There was no significant difference between results, with a mean of 10.94 g.dl-1 and 10.90 g.dl-1 for the HemoCue and Coulter, respectively (p = 0.12, t = -1.99, df = 70). The limits of agreement of the two methods (mean difference +/- 2 SD) were -0.37 and +0.45 g.dl-1. The coefficients of repeatability of the 20 samples analysed in duplicate on each device were 0.26 g.dl-1 and 0.33 g.dl-1, respectively. The coefficients of variance were 0.74% (HemoCue) and 0.93% (Coulter). With adequate training and monitoring, the HemoCue provides comparable haemoglobin results for near-patient testing in theatre.

Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.

Expansion and methylation of CGG repeat sequences is associated with Fragile X syndrome in humans. We have examined the consequences of CGG repeat expansion and methylation for nucleosome assembly and positioning on the Fragile X Mental Retardation gene 1 (FMR1) gene. Short unmethylated CGG repeats are not particularly favored in terms of affinity for the histone octamer or for positioning of the reconstituted nucleosome. However, upon methylation their affinity for the histone octamer increases and a highly positioned nucleosome assembles with the repeat sequences found adjacent to the nucleosomal dyad. Expansion of these CGG repeats abolishes the preferential nucleosome assembly due to methylation. Thus, the expansion and methylation of these triplet repeats can alter the functional organization of chromatin, which may contribute to alterations in the expression of the FMR1 gene and the disease phenotype.