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Summary This paper examines the effects of stress on the neuroendocrine production of cortisol and links this to potential changes in food choice, mood and bodyweight. Animal and human studies suggest that stressful conditions can result in low mood, increased energy intake, particularly from fatty acids and non-milk extrinsic sugars (NMES), and potential changes in bodyweight. With current unsustainable rises in obesity in the Western world, tackling predictors of weight increase remains a primary target for intervention. In a longitudinal naturalistic study of 71 healthy women, we found an increase in cortisol secretion during a period of chronic stress to be strongly correlated with changes in food choice and increased energy consumption, as well as an increase in intake of saturated fatty acids and NMES. This resulted in an increase in bodyweight. We also found that anxiety and depression increased significantly during the stress period; however, we could find no correlation with mood, food choice or energy intake. Furthermore, we found that women with a body mass index (BMI) on the higher side of ‘healthy’, who experienced a significant increase in cortisol secretion under chronic stress, were more vulnerable to increases in bodyweight than women with lower BMIs and a smaller increase in cortisol secretion. Further research is needed to investigate whether cognitive behavioural/remedial therapies to reduce the impact of stress can help to minimise changes in diet, bodyweight and mental health.

The sustainability of organic dairying in Canada, with respect to nutrients, remains unexamined. To assess how management affects nutrient status, we documented whole farm nutrient (NPK) budgets over 2 yr (2003 to 2005) and soil (0 to 15 cm) P and K status on 15 long-term Ontario organic dairy farms. Farm size, livestock density and herd productivity averaged 110 ha, 1.00 livestock units ha-1 and 5656 kg milk cow-1 yr-1, respectively. Annual farm nutrient surpluses of 75 (N), 1 (P) and 11 (K) kg ha-1 yr-1 were lower than those reported for confinement-based dairy farms in the United States, pointing to possible environmental benefits from reduced off farm impacts on air and water quality. Weighted average soil test P levels were low (< 10 mg kg-1) on approximately 50% of farms, while exchangeable K levels were moderate to high (76 to 160 mg kg-1) on all farms. Four farms adopting a "self-sufficient" approach, producing most feed on-farm, imported little P as feed (1.37 to 1.90 kg P ha-1 yr-1) and had negative average farm P balances (avg. -1.54 kg P ha-1 yr-1). An integrated nutrient management approach, along with a flexible feed import strategy, fosters the sustainability of organic dairying systems. Key words: Organic dairying, nutrient budget, nitrogen, potassium, phosphorus, soil fertility

We compute hadron masses and nucleon matrix elements in quenched QCD using overlap fermions.

Aims Total wrist arthrodesis (TWA) produces a spectrum of outcomes. We investigated this by reviewing 77 consecutive TWA performed for inflammatory and post-traumatic arthropathies, wrist instability and as a salvage procedure. Patients and Methods All operations were performed by a single surgeon using a specifically designed pre-contoured dorsally applied non-locking wrist arthrodesis plate at a single centre. Results Median post-operative Buck-Gramcko Lohman (BGL), Disabilities of the Arm, Shoulder and Hand and Patient Rated Wrist Evaluation scores at six years (interquartile range (IQR) 3 to 11) were 9 (IQR = 6 to 10), 19 (IQR = 7 to 45) and 13 (IQR = 1 to 31) respectively. Polyarticular inflammatory arthritis and female gender were associated with poorer patient-reported outcomes, although the effect of gender was partly explained by higher rates of inflammatory disease among women. Return to work was negatively influenced by workers’ compensation and non-inflammatory wrist pathology. There was no difference in complication rates for inflammatory and non-inflammatory indications. Take home message: Polyarticular inflammatory arthritis is a risk factor for adverse patient-reported outcomes in TWA. Furthermore, when compared with patients without inflammatory arthritis, dorsally applied pre-contoured plates can be used for wrist arthrodesis in patients with inflammatory arthritis without an increased risk of complications. Cite this article: Bone Joint J 2016;98-B:647–53.

The effects of air agitation on electrolyte conductivity have been considered. Experimental data obtained from a conductivity probe was found to be comparable to theoretical models for conductivity which show that localized reductions of 20–30% are quite normal in an acid copper electrolyte. Such nonuniformity within an electroplating tank could be one cause of the throwing power/metal distribution variations which are normally attributed to surface irregularities or poorly designed agitation systems. These aspects have particular bearing for printed circuit board (PCB) manufacture where consistency in electrodeposition is paramount to ensure low defect or failure rates, especially within high aspect ratio through-holes.

Six trained cyclists (high-fitness group) and six untrained individuals (low-fitness group), performed a 20-min cycle ergometer exercise test at 70% of maximum oxygen consumption ( $$\dot VO_{2max} $$ followed by a 30-min rest period and then an incremental ride to exhaustion on two occasions, 1 week apart. Ninety minutes prior to exercise subjects consumed a drink containing either 22.2 g dibasic calcium phosphate (DCP; treatment) or calcium carbonate (placebo). Blood was drawn prior to drink ingestion, during submaximal exercise, during recovery and at exhaustion for determination of blood 2,3-DPG, blood ATP, plasma lactate, plasma phosphate, haemoglobin and haematocrit. Throughout exercise, cardiorespiratory variables [oxygen uptake ( $$\dot VO_2 $$ minute ventilation, ( $$\dot V_E $$ ), respiratory exchange ratio, heart rate and oxygen pulse] were monitored, and ratings of perceived exertion obtained. Although there was a trend for the low-fitness group to have a higher plasma phosphate concentration prior to treatment ingestion, no treatment effects on plasma phosphate were noted at any sample time in either group. 2,3-DPG, $$\dot VO_2 $$ oxygen pulse, $$\dot V_E $$ time to exhaustion and $$\dot VO_{2max} $$ were significantly higher in the high-fitness group; however, no differences in these variables were observed as a result of phosphate ingestion. Plasma lactate was significantly lower in the high-fitness group during the submaximal exercise and the recovery period, but again phosphate ingestion had no effect. These results suggest that acute DCP supplementation is not effective as an ergogenic aid and that aerobic fitness level does not affect the response to phosphate supplementation.

Synthesis of oestrogens within breast tissues makes an important contribution to the high concentrations of oestradiol which are found in breast tumours. The activities of the enzymes involved in oestrogen synthesis, i.e. the aromatase, oestradiol dehydrogenase (E2DH) and oestrone sulphatase (E1-STS), can be stimulated by several growth factors and cytokines. As it is possible that some of these factors may be derived from cells of the immune system (macrophages and lymphocytes), the effects of basic fibroblast growth factor (bFGF) and interleukin-2 (IL-2), which are produced by these cells, on E2DH activity was examined in MCF-7 cells. Treatment of these cells with bFGF resulted in a dose-dependent increase in E2DH reductive activity whereas IL-2 was inactive at the concentration tested. To obtain further evidence that factors produced by macrophages and lymphocytes can modulate the activities of enzymes involved in oestrogen synthesis, conditioned medium was collected from these cells and found to stimulate both E1-STS and E2DH activities. In addition to understanding the control of oestrogen synthesis in breast tumours an inhibitor to block the synthesis of oestrone via the oestrone sulphatase pathway was developed. Oestrone-3-O-sulphamate (EMATE) is a potent, irreversible, inhibitor of E1-STS. A single dose of EMATE (10 mg/kg) inhibited tissue E1-STS activity in rats by more than 95% for up to 7 days, indicating that this compound may have considerable therapeutic potential for the treatment of breast cancer. Evidence is also reviewed that another steroid sulphatase, dehydroepiandrosterone sulphate sulphatase, may have a crucial role in regulating cytokine production and that this may indirectly control tumour oestrogen synthesis.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 μm diameter hot core.

We have utilized wheat germ agglutinin conjugated to iron/dextran particles in conjunction with high gradient magnetic affinity chromatography (HIMAC) to prepare plasma membranes from cultured cells. Membrane-impermeable succinimidyl esters inactivate alkaline phosphodiesterase 1 (APDE-1) and were used to establish the proportion of APDE-1 expressed at the cell surface. The yield of inhibitable APDE-1 provides an accurate indication of plasma membrane yield, which was > 90% for Chinese hamster ovary (CHO) cells. Plasma membranes prepared by HIMAC contained

In vitro studies demonstrate that cannabinoid CB(1) receptors subserve activity-dependent suppression of inhibition in the neocortex. To examine this mechanism in vivo, we assessed the effects of local changes in CB(1) receptor activity on somatosensory cortex neuronal activation by whisker movement in rats.Laser Doppler flowmetry and c-Fos immunohistochemistry were used to measure changes in local blood flow and neuronal activation, respectively. All drugs were applied directly to the cranium above the whisker barrel fields of the primary somatosensory cortex.The CB(1) receptor agonist WIN55212-2 potentiated the hyperaemia induced by whisker movement and this potentiation was occluded by bicuculline. The CB(1) receptor antagonists, rimonabant and AM251, inhibited hyperaemic responses to whisker movement; indicating that activation of endogenous CB(1) receptors increased during whisker movement. Whisker movement-induced expression of c-Fos protein in neurons of the whisker barrel cortex was inhibited by rimonabant. Movement of the whiskers increased the 2-arachidonoylglycerol content in the contralateral, compared to the ipsilateral, sensory cortex.These results support the hypothesis that endocannabinoid signalling is recruited during physiologically relevant activation of the sensory cortex. These data support the hypothesis that the primary effect of CB(1) receptor activation within the activated whisker barrel cortex is to inhibit GABA release, resulting in disinhibition of neuronal activation. These studies provide physiological data involving endocannabinoid signalling in activity-dependent regulation of neuronal activation and provide a mechanistic basis for the effects of cannabis use on sensory processing in humans.

The decision to shorten the time spent in most areas of hospital care is extremely complex and hinges on the balance of numerous resulting credits and debits, which are largely unknown. The length of stay in hospital can be stabilized for many categories of medical care but the likely benefits may be disappointingly small in the face of unchanged demand for health care. Furthermore, a sustained reduction in length of stay could bring with it logistic contractual and personal problems, the costs of which could outweigh the benefits of stabilization. The best delivery of health care in a closed financial system seems to depend on a joint consideration of output per unit time and a provision of a service that comes near to satisfying the true need for that service. The appropriate level of service will be decided from a study of the true prevalence of the need and the ability of the service to satisfy it. The enthusiastic pursuit of traditional efficiency without adequate information may be counterproductive--by increasing demand, by demoralizing the health personnel and by diverting some of the demand into private practice. Our first priority is the rationalization of demand; this will need the combined efforts and goodwill of the consumer and the supplier. Only when demand has been rationalized may we expect a net benefit from shortening length of stay.

An experiment that investigated the establishment of seven grass and legume seed mixes on opencast coal mining spoil in South Wales is described. After three years, mixtures containing Poa pratensis and Festuca rubra var. rubra were the most successful in covering the spoil; the ‘Johnson JR33’ seed mix proved the best of those commercially available that was tested. Tree growth was not detrimentally affected by the establishment of a grass ground cover. Erosion was not an important process at the experimental site, though slumping occurred locally from plough ridge to plough furrow.

Insulin-like growth factor-1 could be a useful marker in the horse for diagnostic, selection, or forensic purposes, provided its physiological regulation is well understood. The objective of this study was to investigate factors, such as acute exercise, fitness training, time of day, sex, and age, that may influence serum IGF-1 in normal, healthy horses. Throughout a 9-wk training program, 6 geldings maintained a mean (+/- SEM) IGF-1 concentration of 302 +/- 29 ng/mL. Moderate or high intensity exercise had no effect on IGF-1 concentrations, when pre- and postexercise values were compared. Over a 24-h period, there was some variation in IGF-1 concentrations but no clear diurnal rhythm. Concentrations of IGF-1 were measured in a large population of thoroughbred horses (1,880) on 3 continents. The population deviated slightly from a normal distribution (P0.001) because of large IGF-1 concentrations in 10 horses. The global mean IGF-1 concentration was 310 +/- 2.2 ng/mL, with a greater mean value (P0.001) in gonad-intact males (336 +/- 5.6 ng/mL) than in females (303 +/- 3.2 ng/mL) or geldings (302 +/- 3.2 ng/mL). However, the greatest IGF-1 concentrations observed for all stallions, mares, and geldings were 627, 676, and 709 ng/mL, respectively. In mares and geldings, IGF-1 concentrations showed a gradual decrease with advancing age (P0.001), but the effect was much less marked in stallions. This study confirms that IGF-1 concentrations are stable, compared with GH concentrations, in the horse and that a meaningful measure of IGF-1 status can be obtained from a daily serum sample.

This study examined the prevalence and severity of ocular pain in eye casualty patients. All new patients presenting over a 1 month period were invited to indicate their pain level using a visual analogue scale. The results for 352 patients were analysed, and median pain levels calculated for 29 common diagnoses. Of those responding, 94% (= 47% of all new patients) had ocular pain at presentation. While many results were predictable, some diagnoses were associated with higher pain scores than expected. Junior ophthalmologists also were asked to indicate their perceptions of pain severity for the 29 diagnoses using the same visual analogue scale.

Theoretical Physics Division, Department of Mathematical Sciences, University of LiverpoolLiverpool L69 3BX, UKE-mail:galletly@ph.ed.ac.uk, martin.guertler@desy.de,rhorsley@ph.ed.ac.uk, karl.koller@lrz.uni-muenchen.de,volkard.linke@physik.fu-berlin.de,rakow@amtp.liv.ac.uk,cjr@amtp.liv.ac.uk, gerrit.schierholz@desy.de,thomas.streuer@desy.deQCDSF CollaborationWe compute the lowest moments of the nucleon’s structure functions using quenched overlapfermions at two different lattice spacings. The renormalisation is done nonperturbatively in theRI

Using non-perturbative techniques we have found the renormalisation factor, Z, in the RI-MOM scheme for quark bilinear operators in quenched QCD. We worked with overlap fermions using the Luescher-Weisz gauge action. Our calculation was performed at beta=8.45 at a lattice spacing of 1/a=2.1 GeV using a value of rho=1.4. Our results show good agreement between the vector and the axial vector in the zero mass limit. This shows that overlap fermions have good chiral properties. To attempt to improve the discretisation errors in our results we subtracted the O(a^2) terms in one-loop lattice perturbation theory from the Monte Carlo Green functions. In particular we paid attention to the operators for the observable . We found a value for the renormalisation constants Z^msbar_(v_2b) and Z^msbar_(v_2a) just less than 1.9 at mu=1/a=2.1 GeV., Comment: 6 pages, 3 figures, uses PoS style, poster presented at Lattice 2005 (Chiral Fermions), to be published in Proceedings of Science

Poster at College Congress, Birmingham 2001. Oral presentation at European Strabismus Association, Florence 2001. Purpose Anisometropia of more than one dioptre during the sensitive visual period may cause amblyopia. Its management requires refractive correction, and occlusion. Compliance with treatment is critical if visual improvement is to obtained. High anisometropia, poor initial acuity and mixed strabismic/anisometropia amblyopia are predictive factors for a poor outcome. We evaluated contact lens use in the management of high anisometropic amblyopia. Methods Retrospective analysis of anisometropic amblyopia managed in a paediatric contact lens clinic (July 1996–July 2000), after standard amblyopia therapy of spectacles and occlusion therapy had been tried. Presenting age, acuity and refraction, duration of lens wear and occlusion, and final visual outcomes were noted. Results Seven children (four male, three female) presented at age 3.5–6 years (mean 4.5). Six had myopic anisometropia 6.0–18.4 dioptres (mean 10.4 dioptres) and one 6.75 dioptres hypermetropic anisometropia. The initial corrected acuities of the amblyopic eyes were 6/18 to 1/60. Five patients used contact lenses with a range from 5 months to 4 years. Final acuities were 6/12–1/60. Two myopes with 6 dioptres anisometropia improved three to four Snellen lines, one with 8.8 dioptres improved one line. Three with >10 dioptres anisometropia did not improve. The hypermetropic patient improved part of one Snellen line. Conclusions High anisometropic amblyopia is challenging to treat. In our study contact lenses improved visual acuity in myopic anisometropia of up to 9 dioptres.

Poly(lactic acid)-poly(ethylene glycol)-biotin (PLA-PEG-biotin) is a degradable polymer with protein resistant properties that can undergo rapid surface engineering in aqueous media to create biomimetic surfaces. Surface engineering of this polymer is dependent on biomolecular interactions between the biotin end group and the protein avidin. Given the vigorous conditions of synthesis, it is essential that the manufacture of the polymer does not alter the biotin structure or its molecular recognition. Equally, it is important that the incorporation of biotin does not adversely affect the physicochemical properties of the polymer. (1)H NMR provides evidence of biotin attachment and structural integrity. (1)H NMR, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC) analysis shows there is no significant effect on bulk properties induced by the biotin end group. Surface plasmon resonance (SPR) and fluorescent spectroscopy studies using the 2-(4'-hydroxyazobenzene) benzoic acid (HABA)/avidin complex show that the biotin moieties binding capabilities are not impaired by the synthesis.

Signal transduction pathways with shared components must be insulated from each other to avoid the inappropriate activation of multiple pathways by a single stimulus. Scaffold proteins are thought to contribute to this specificity by binding select substrates.We have studied the ability of scaffold proteins to influence signaling by the yeast kinase Ste11, a MAPKKK molecule that participates in three distinct MAP kinase pathways: mating, filamentation, and HOG. We used protein fusions to force Ste11 to associate preferentially with a subset of its possible binding partners in vivo, including Ste5, Ste7, and Pbs2. Signaling became confined to a particular pathway when Ste11 was covalently attached to these scaffolds or substrates. This pathway bias was conferred upon both stimulus-activated and constitutively active forms of Ste11. We also used membrane-targeted derivatives of the mating pathway scaffold, Ste5, to show that stimulus-independent signaling initiated by this scaffold remained pathway specific. Finally, we demonstrate that loss of pathway insulation has a negative physiological consequence, as nonspecific activation of both the HOG and mating pathways interfered with proper execution of the mating pathway.The signaling properties of these kinase fusions support a model in which scaffold proteins dictate substrate choice and promote pathway specificity by presenting preferred substrates in high local concentration. Furthermore, insulation is inherent to scaffold-mediated signaling and does not require that signaling be initiated by pathway-specific stimuli or activator proteins. Our results give insight into the mechanisms and physiological importance of pathway insulation and provide a foundation for the design of customized signaling proteins.

To observe in situ and on individual aspirin crystal faces the comparative rates and processes of dissolution of the dominant faces.The kinetics of the dissolution rate of two aspirin crystal planes (001) and (100) under 0.05M HCl are studied in situ at room temperature using Atomic Force Microscopy. The dissolution process of each crystal plane was followed by observed changes in topographic features.The results revealed that crystal plane (001) dissolves by receding step edges, and has a dissolution rate of 0.45 nm s(-1). Conversely. plane (100) displays crystal terrace sinking at an average rate of 2.93 nm s(-1). Calculated intrinsic dissolution values (g s(-1) cm(-2)) for planes (001) and (100) are 1.37 x 10(-7) gs(-1) cm(-2) and 8.36 x 10(-7) gs(-1) cm(-2), respectively.These values indicate that the rate of flux of material from plane (100) is approximately six times greater than that from plane (001), under 0.05M HCl. Interpretation of the data, based upon intrinsic dissolution rates and dissolution rate velocities, correlate with reported variations in the dissolution behavior of commercial aspirin products. These observations illustrate the suitability of the technique for characterizing the dissolution behavior of crystalline drugs.

To evaluate the use of the MTI photoscreener (Medical Technology Inc, Iowa City, Iowa) in assessing and documenting lens abnormalities in the pediatric ophthalmology clinic.MTI photoscreener photographs of pediatric patients with lens abnormalities were taken to assess and document lens opacities and subluxation, to assist with explanations to parents, and to monitor progression of abnormalities. Postoperative photographs were taken to assess opacification of the posterior capsule and contact lens fit.Nineteen children with lens abnormalities were examined. Twelve patients underwent surgery and 9 patients had postoperative photoscreener pictures. Illustrative cases are reported.The MTI photoscreener is a useful adjunct to clinical examination in the assessment and documentation of pediatric lens abnormalities.

In response to elevated levels of HMG-CoA reductase, an integral endoplasmic reticulum (ER) membrane protein, cells assemble novel ER arrays. These membranes provide useful models for exploration of ER structure and function, as well as general features of membrane biogenesis and turnover. Yeast express two functional HMG-CoA reductase isozymes, Hmg1p and Hmg2p, each of which induces morphologically different ER arrays. Hmg1p induces stacks of paired nuclear-associated membranes called karmellae. In contrast, Hmg2p induces peripheral ER membrane arrays and short nuclear-associated membrane stacks. In spite of their ability to induce different cellular responses, both Hmg1p and Hmg2p have similar structures, including a polytopic membrane domain containing eight predicted transmembrane helices. By examining a series of recombinant HMG-CoA reductase proteins, our laboratory previously demonstrated that the last ER-lumenal loop (Loop G) of the Hmg1p membrane domain contains a signal needed for proper karmellae assembly. Our goal was to examine the primary sequence requirements within Loop G that were critical for proper function of this signal. To this end, we randomly mutagenized the Loop G sequence, expressed the mutagenized Hmg1p in yeast, and screened for inability to generate karmellae at wild-type levels. Out of approximately 4000 strains with Loop G mutations, we isolated 57 that were unable to induce wild-type levels of karmellae assembly. Twenty-nine of these mutants contained one or more point mutations in the Loop G sequence, including nine single point mutants, four of which had severe defects in karmellae assembly. Comparison of these mutations to single point mutations that did not affect karmellae assembly did not reveal obvious patterns of sequence requirements. For example, both conservative and non-conservative changes were present in both groups and changes that altered the total charge of the Loop G region were observed in both groups. Our hypothesis is that Loop G serves as a karmellae-inducing signal by mediating protein-protein or protein-lipid interactions and that amino acids revealed by this analysis may be important for maintaining the proper secondary structure needed for these interactions.

Atomic force microscopy has been utilized to probe, at a molecular level, the interaction between purified pig gastric mucin (PGM) and a mucoadhesive cationic polymer, chitosan (sea cure 210+), with a low degree (approx. 11%) of acetylation. Images were produced detailing the structures of both PGM and chitosan in 0.1 M acetate buffer (pH 4.5), followed by the complex of the two structures in the same buffer. PGM in 0.1 M acetate buffer revealed long linear filamentous structures, consistent with earlier electron microscopy and scanning tunnelling micoscopy studies. The chitosan molecules also adopted a linear conformation in the same buffer, although with a smaller average length and diameter. They appeared to adopt a stiff-coil conformation consistent with earlier hydrodynamic measurements. The complexes formed after mixing PGM and chitosan together revealed large aggregates. In 0.1 M ionic strength buffer they were of the order of 0.7 microm in diameter, consistent with previous electron microscopy studies. The effect of ionic strength of the buffer on the structure of the complex was also studied and, together with molecular hydrodynamic data, demonstrates that the interaction is principally electrostatic in nature.

In chemical processing, it is important to distinguish between and identify polymorphic forms. We demonstrate the novel use of scanning thermal microscopy (SThM) and localized thermal analysis to distinguish and identify polymorphic forms of the drug cimetidine. These forms cannot be resolved by classical bulk thermal analysis. SThM reveals a sample consisting of a 50 : 50 mixture of the polymorphs contains regions of different thermal conductivity, corresponding to the different polymorphs. Localized thermal analysis of small volumes of pure polymorphic samples (approximately 50 microm3) shows that the origin of the thermal conductivity contrast lies, at least in part, with the presence of a surface water layer on the more hydrophilic polymorph.

Most cytotoxic anticancer agents damage DNA directly, interfere with DNA metabolism or chromosome segregation, and are particularly toxic in dividing cells. Although a considerable amount of information on the mechanisms of action of these agents is available, the molecular bases for selective tumor cell killing by chemotherapy are largely unknown. Many genetic alterations found in sporadic and hereditary cancers affect functions in DNA repair and cell cycle control and result in sensitivity to DNA damaging agents. We have therefore set out to determine the effects of these cancer mutations on sensitivity or resistance to various chemotherapeutic agents. Because most of the affected genes are well conserved among eukaryotes, we have carried out a comprehensive analysis of a panel of isogenic yeast strains, each defective in a particular DNA repair or cell cycle checkpoint function, for sensitivity to the Food and Drug Administration-approved cytotoxic anticancer agents. Widely different toxicity profiles were observed for 23 agents and X-rays, indicating that the type of DNA repair and cell cycle checkpoint mutations in individual tumors could strongly influence the outcome of a particular chemotherapeutic regimen.

The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P

An oesophageal pH electrode was used to record gastro-oesophageal reflux in 73 women who had elective laparoscopy for various gynaecological procedures. No refluxes were recorded during the 63 procedures from which results could be analysed; the upper 95% confidence limit from this observation is 3 in 63 (4.8%). Two of the excluded women refluxed during episodes of hiccough that occurred shortly after induction of anaesthesia. Tracheal intubation may be required during laparoscopy, although the need to protect against the possibility of aspiration of gastric contents may not be a valid reason unless, with the same logic, it is suggested that all patients who hiccough should be intubated.

The objective of this study was to determine whether abdominal ultrasound and plain film radiography (evaluated by senior radiologists) substantially enhances senior surgical assessment in reducing surgical admissions. A randomized controlled trial was carried out in a teaching hospital; ninety-five emergency referrals to general surgery (mean age 51 years, 37% males), presenting with intrabdominal disturbances not requiring immediate surgery, were selected for study. The major outcome measure was the number of patients not admitted as in-patients. Thirty per cent of the intervention group and 10% of the controls did not need admission (95% confidence interval on this 29% difference, 12-38%). There were no important differences in the mean waiting time in casualty (26 min vs. 25 min), length of admission (4.1-5.9 days), surgical intervention (seven vs. 11 patients), readmission with similar pathology within 3 months (seven vs. three patients), and mortality as an in-patient or within 3 months of discharge. Abdominal ultrasound and plain film radiography, assessed by senior radiologists, enhances senior surgical assessment in reducing unnecessary surgical admissions.

Pluronic surfactants, PEO-PPO-PEO triblock copolymers, have been investigated widely due to their protein-resistant properties in applications as coatings for implants and in controlled drug release systems. We have studied a wide range of these copolymers, varying in both PEO and PPO block size, by adsorbing them to a polystyrene surface and investigating their subsequent resistance to human serum albumin adsorption. This investigation has been carried out in real time, using surface plasmon resonance, with the surfaces subsequently visualized by atomic force microscopy. This approach has allowed determination of the effect of the lengths of the PEO and PPO polymer chains on protein resistivity. For low-molecular-weight Pluronics a significant, yet not complete, reduction in albumin adsorption has been observed whereas higher molecular weight Pluronics appear to completely inhibit adsorption within the time frame of this experiment. An increase in the PPO block size of the copolymer also appears to increase its protein resistance. This work further confirms that the binding strength of the anchoring block to the hydrophobic surface, rather than the length of the protruding hydrophilic PEO chains, determines a copolymer's protein resistance capability.

Mutants that show reduced DNA methylation were identified in a mutant screen based on the assumptions that (i) the nucleoside analog 5-azacytidine (5-azaC) promotes the formation of potentially lethal DNA-methyltransferase adducts; (ii) reduction in DNA methyltransferase will decrease the sensitivity of cells to 5-azaC; and (iii) this potential selective advantage will be enhanced in mutants that are deficient in the repair of 5-azaC-induced DNA damage. Of fifteen potential repair mutants screened for sensitivity to 5-azaC, five (mus-9, mus-10, mus-11, mus-18, and uvs-3) showed moderately increased sensitivity and two (mus-20, mei-3) showed highly increased sensitivity. A mus-20 mutation was used to isolate three non-complementing methylation mutants. The mutations, named dim-1 (defective in methylation), reduced female fertility, reduced methylation by 40–50%, and altered patterns of methylation. In wild-type strains hypomethylation perse fails to alter methylation specificity. We demonstrate a growth-phase-dependent change in methylation patterns, detectable only in hypomethylated DNA from dim + cultures. This may represent a growth-phase-dependent change in the relative amounts of distinct species of methyltransferase, one of which may be encoded by the dim-1 gene.

For the assessment of radiation risk at low doses, it is presumed that the shape of the low-dose-response curve in humans for cancer induction is linear. Epidemiological data alone are unlikely to ever have the statistical power needed to confirm this assumption. Another approach is to use oncogenic transformation in vitro as a surrogate for carcinogenesis in vivo. In mid-1990, six European laboratories initiated such an approach using C3H 10T1/2 mouse cells. Rigid standardisation procedures were established followed by collaborative measurements of transformation down to absorbed doses of 0.25 Gy of x-radiation resulting in a total of 759 transformed foci. The results clearly support a linear dose-response relationship for cell transformation in vitro with no evidence for a threshold dose or for an enhanced, supralinear response at doses approximately 200-300 mGy. For radiological protection this represents a large dose, and the limitations of this approach are apparent. Only by understanding the fundamental mechanisms involved in radiation carcinogenesis will further knowledge concerning the effects of low doses become available. These results will, however, help validate new biologically based models of radiation cancer risk thus providing increased confidence in the estimation of cancer risk at low doses.

The frequency of dicentrics + ring (dic/cell) and total chromosome aberrations (dicentrics, rings and excess acentrics, etc.) per cell (TAb/cell) has been studied in 50 male and female volunteers after high or low dose rate (HDR, LDR) irradiation of peripheral blood lymphocytes. The mean male aberration frequencies per cell after HDR irradiation were 0.38 dic/cell and 0.61 TAb/cell; following LDR irradiation, the mean aberration frequencies were 0.28 dic/cell and 0.45 TAb/cell. Equivalent female values after HDR irradiation were 0.42 dic/cell and 0.71 TAb/cell; after LDR irradiation, the mean aberration frequencies were 0.30 dic/cell and 0.48 TAb/cell. Analysis of variance showed that there was a highly significant difference between males and females have a greater HDR, but not LDR, irradiation It is concluded from this study that females have a greater variability in their radioresponse, and that this variability is related to progesterone, which has a profound effect upon radiosensitivity, as measured by cytogenetic end points.

To quantify the protein binding of velnacrine in healthy individuals and investigate potential sources of variability.Medical School Unit, Southmead Hospital, Bristol.Plasma samples were obtained from the following groups: a) 11 healthy volunteers aged 18 to 30 years; b) 10 healthy volunteers aged 73 to 87 years; c) 10 patients aged 65 to 85 years hospitalised for a variety of acute illnesses.Aliquots of plasma from the above subjects were incubated with various concentrations of velnacrine, in the presence and absence of tacrine hydrochloride. Standard solutions of human serum albumin and alpha 1 acid glycoprotein were incubated with velnacrine. The degree of protein binding was determined using the Amicon centrifree micropartition system.1) Over the range of concentrations from 10 to 320 ng.ml-1, there was a decrease in protein binding from 59.1 to 46.7%. 2) At 40 ng.ml-1 the plasma protein binding of velnacrine was 54.8% in the group a subjects, 51.9% in the group b subjects and 53.0% in the group c subjects (NS). 3) The mean total plasma protein concentration was significantly lower in the samples from elderly subjects. The mean albumin and alpha 1 acid glycoprotein concentrations were lower and higher respectively in patients with acute disease. 4) Velnacrine was shown to bind to both albumin and alpha 1-acid glycoprotein, but together they did not account for total binding. 5) The binding of velnacrine was significantly decreased from 59.3 to 43.9% in the presence of a therapeutic concentration (25 ng.ml-1) of THA. There was no evidence that velnacrine displaced THA.Protein binding can be discounted as a major source of variation in the relationship between drug concentration and effect.

Many tumours in endocrine-sensitive tissues, such as the breast and endometrium, are hormone-dependent and the hydrolysis of oestrone sulphate (EIS) to oestrone by oestrone sulphatase (EI-STS) is a major source of oestrogen in such tumours. Oestrone-3-O-sulphamate (EMATE) has been shown to be a potent EI-STS inhibitor in vitro, and in this study its ability to inhibit enzyme activity in vivo was examined. EMATE was initially administered to female rats for 7 days, after which liver EI-STS activity was measured. As EMATE also inhibits a related sulphatase in vitro, dehydroepiandrosterone sulphatase (DHA-STS), its effect on the activity of this enzyme in vivo was also investigated. DHA-STS has a pivotal role in regulating the synthesis of another steroid with potent oestrogenic properties, androstenediol. Administration of EMATE almost completely inhibited liver EI -STS (99%) and DHA-STS (99%) activities and was active when given by the oral or subcutaneous routes. After a single dose of EMATE or following the cessation of multiple doses for 10 days, liver EI-STS activity remained inhibited (>95%) for up to 7 and 10 days, respectively. Other compounds, such as 4-hydroxytamoxifen and the “pure” anti-oestrogen ICI 182,780, which are reported to inhibit EI-STS activity in vitro, did not inhibit activity in vivo. In a preliminary study, EMATE, when injected over a 12-day period, effectively reduced the growth of EI S-stimulated nitrosomethyl-urea-induced mammary tumours in ovariectomised rats and inhibited tumour sulphatase activity in treated animals.

The initial screening by senior surgical staff of surgical patients referred for emergency hospital admission should result in improved patient management. The present study was undertaken to determine the effects of this policy. The primary outcome measure was hospital admission rates. The number of operations, diagnostic investigations, initial treatments, deaths, length of stay and bed days per 100 referrals were also measured. The results suggest a 20 per cent reduction in emergency surgical admissions, an important potential benefit to the health service, and to individual patients.

Summary This prospective, double-blind study examined the antiemetic effectiveness of the addition of droperidol to a morphine solution for use in patient-controlled analgesia in a group of 50 patients undergoing elective lumbar laminectomy. The addition of 20 mg droperidol to 120 mg morphine in 60 ml saline given by a Baxter‘Infusor’ patient-controlled analgesia device reduced the incidence of vomiting as compared to the addition of sodium chloride from 42.8% to 12.5% (p = 0.028) and of nausea from 71.4% to 29.2% (p = 0.005). The proportion of patients requiring rescue antiemetic therapy was reduced from 47.6% to 16.7% (p = 0.025) and the time interval to the first use of rescue antiemetic agent was significantly prolonged (p = 0.029). The use of droperidol was associated with an increased degree of sedation during the first 12 h after operation.

In vivo, recombinant human interleukin 1 alpha (rHuIL-1 alpha) + recombinant human macrophage colony-stimulating factor (rHuM-CSF) (IL-1 + M-CSF) effectively serves as a rescue agent for myelosuppression by enhancing the recovery of hematopoietic stem cell (HSC) subpopulations following treatment with 5-fluorouracil (5-FU). Because in vitro studies have suggested that hematopoietic recovery in 5-FU-treated bone marrow (FUBM) may proceed from a 5-FU resistant, (IL-1 + IL-3 + M-CSF-responsive) high proliferative potential HSC subpopulation of colony forming cells (HPP-CFC), studies were carried out to determine whether the addition of recombinant murine interleukin 3 (rMuIL-3) (IL-3) to either IL-1 or IL-1 + M-CSF would further enhance the recovery of HSC subpopulations in myelosuppressed C57Bl/6 mice. With the exception of the HPP-CFC, IL-3 dampened, rather than enhanced, the accelerated recovery of 8 d and 12 d colony forming units-spleen (8 d and 12 d CFU-S) and the committed macrophage progenitor (CFU-M) associated with in vivo treatment with IL-1 alone. Similarly, IL-3 interfered with the enhanced recovery of those HSC subpopulations in FUBM influenced by the synergistic interaction of IL-1 + M-CSF. This interference, however, was observed only when the rMuIL-3 was administered on day 2 or 3 of a four-day treatment with IL-1 + M-CSF. There was, however, no evidence that IL-3 exerted a negative influence on the restoration of granulocytes in the myelosuppressed animals. Moreover, sequencing studies provided data suggesting that the dampening effects of IL-3 on the synergistic interaction of IL-1 + M-CSF resulted from both an enhanced differentiation of the more primitive HSC subpopulations and a significant, but preferential, mobilization of the more mature 8 d CFU-S and CFU-M to extramedullary organs and that the mobilization of these more mature HSC subpopulations was temporally linked to their generation from the recovering HPP-CFC and 12 d CFU-S subpopulations.

World health depends upon our field of vision. If we selectively view the world from a narrow perspective, we will be unable to function effectively as nurses. The sobering reality of health conditions throughout the world should awaken our consciousness and sharpen our focus on priorities for the future. We can agree with Lindquist, that "nursing must be viewed from a global perspective if it is to influence the quality of health care provided in the future." Although not every student has the means and availability to travel overseas in a volunteer capacity, students may begin to examine the possibilities and start their own correspondence with an international agency. Regardless of our realm of service, the opportunity to provide care for individuals of all cultures, whether abroad or at home, remains the highest privilege of our profession.

We will demonstrate a computerised system that we have developed to monitor trends and changes in referral practice for imaging investigations. The objective was to try to help encourage clinicians to comply with guidelines of good radiological practice and thereby achieve the benefits of improved patient care, effective use of resources and reduced radiology dosage. The work has been carried out at the University of Wales College of Medicine under the auspices of the Royal College of Radiologists Working Party on the more effective use of diagnostic radiology and we have been supported by the UK Department of Health and the Kings Fund, London. Six other U.K. Centres have collaborated in the pilot development stage.