Military service and health-related quality of life among gay and bisexual prostate cancer survivors: Results from the Restore -2 study.

INTRODUCTION: There are notable disparities in health-related quality of life (HRQOL) between gay and bisexual men (GBM) and heterosexual patients with prostate cancer (PCa); however, the role of past military service is unclear. This study examines HRQOL differences in GBM PCa survivors based on reported military service history. METHODS: We used data from the 24-month follow-up survey of the Restore-2 study, a clinical trial which evaluated a rehabilitation programme for GBM PCa survivors. PCa HRQOL was assessed using the Expanded Prostate Cancer Index Composite (EPIC-50) and the Functional Assessment of Cancer Treatment-Prostate (FACT-P). Mental health quality of life was assessed using the Brief Symptom Inventory-18 (BSI-18) scale, while sexual functioning was measured using the Sexual Minorities and Prostate Cancer Scale (SMACS). Multivariable linear regression was used to estimate unadjusted and adjusted mean differences in HRQOL between GBM with and without a reported history of military service. RESULTS: In this cross-sectional study of 351 GBM PCa survivors, 47 (13.4%) reported a history of US military service. After adjusting for covariates, participants who reported a history of military service (compared with those with no military service) had clinically better scores on the FACT-P physical, social and emotional well-being domains, as well as higher total FACT-General, EPIC urinary bother and hormonal function scores. Additionally, men with a history of military service reported significantly fewer sexual problems, more sexual confidence and less urinary incontinence in sex. CONCLUSION: This exploratory study provides the first evidence that GBM PCa survivors with a military background may have clinically better outcomes than those without military service. Potential reasons may include the structured support and healthcare access associated with military service, fostering resilience and well-being. These findings underscore the need for further research to elucidate how military service influences PCa HRQOL.

Milk production of cows grazing pasture supplemented with grain mixes containing canola meal or corn grain or both over the first 100 days of lactation.

Grain mixes varying in proportions of wheat grain, barley grain, canola meal, and corn grain were fed to grazing dairy cows in early lactation to determine the contribution of canola meal and corn grain to milk yield, BW, BCS, eating behavior, and blood serum metabolite concentrations. The experiment used 80 multiparous, seasonally calving Holstein-Friesian dairy cows during the first 100 d of lactation, the treatment period, and over the subsequent carryover period of 100 d, during which all cows were fed a common diet. Cows were divided into 4 cohorts (blocks) based on calving date and within each cohort, 5 cows were randomly allocated to each of the 4 treatments. Dietary treatments included disc-milled grain mixes comprising (on a DM basis) (1) a control treatment of wheat (25%) and barley (75%); (2) wheat (25%), barley (50%), and canola meal (25%); (3) wheat (25%), barley (50%), and corn (25%), and (4) wheat (25%), barley (25%), canola meal (25%), and corn (25%). Treatment diets were introduced at 19 DIM ± 4.7 d, which included a 7-d adaptation period and were applied up until 100 DIM. Each grain mix was fed at 9 kg of DM/cow per day, offered twice daily, in equal proportions in the parlor at milking times. In addition to the grain mix, all cows grazed perennial ryegrass pasture at a daily allowance of ∼35 kg of DM/cow per day (measured to ground level). Results were analyzed in terms of corn and canola presence or absence in the diet. Including canola meal in grain mixes increased grain intake and pasture intake by 0.6 and 2.1 kg of DM/cow per day, respectively, resulting in an increased milk yield of 2.6 kg/cow per day during the first 100 d of lactation. Including canola meal also increased yields of milk fat and protein, and concentrations of milk fat, as well as increasing mean BW and BCS over the 100 d. The inclusion of canola meal in the grain mixes also resulted in greater blood serum BHB and urea concentrations, compared with feeding grain mixes that did not contain canola meal. The inclusion of corn grain provided no milk production benefits and did not change BW, BCS, or any feeding behavior variables. There were no carryover effects on milk production from either canola meal or corn grain after the treatment period. In summary, the results demonstrate that the provision of canola meal in grain mixes can improve milk production and increase mean BCS. Further, there are no benefits to milk yield when a proportion of barley is substituted for corn, in a wheat and barley grain mix fed to grazing dairy cows in early lactation. However, these results are dependent on the level of inclusion and the feeding system employed.

Effect of forage type on swallowed bolus mass and a method for counting swallows in dairy cattle.

Dry matter intake (DMI) is a primary determinant of milk production in grazing dairy cows and an ability to measure the DMI of individual cows would allow herd managers to formulate supplementary rations that consider the amount of nutrients ingested from grass. The 2 related aims of this experiment were to define the mean number of swallowed boli and mass of the swallowed boli in Holstein-Friesian dairy cattle offered a variety of forages commonly fed in the dairy industry of southeastern Australia, and to evaluate 2 indirect methods for counting the number of swallows. Twelve ruminally-fistulated, lactating Holstein-Friesian cows were randomly assigned to 3 replicated 4 × 4 Latin square designs and offered 4 forages: fresh chicory (FC), fresh perennial ryegrass (RP), alfalfa hay (AH), and perennial ryegrass silage (RS). The experiment was conducted over 28 d with each of 4 periods consisting of 7 d with 3 d of measurement. Forage diets were offered to individual cows following the partial evacuation of the rumen. The first 20 min after forage was offered constituted the measurement period, during which all swallowed boli were manually captured by samplers who placed their hand through the ruminal fistula and over the cardia entrance of the rumen of each cow. Concurrently, microphones and video cameras were used for the indirect measurement of swallows. The average swallowed bolus mass overall was 17.4 g dry matter (DM) per bolus with the lowest mass observed in cows offered FC (8.9 g DM/bolus), followed by RP (14.9 g DM/bolus), compared with cows offered AH (23.6 g DM/bolus) and RS (22.3 g DM/bolus). The swallowing rate was greater in cows offered FC (78 swallows/20 min) than in cows offered RP, AH, and RS (62.3 swallows/20 min). The audio recording method showed greater concordance (Lin's concordance correlation coefficient = 0.90) with the physical capturing of the boli through the rumen, than the video recording method did (Lin's concordance correlation coefficient = 0.54). It is concluded that the mass of the swallowed boli is related to forage type and that using a microphone attached to the cow's forehead can provide an accurate measure of the number of swallows when verified against the actual number of swallows counted by manual interception of the boli at the rumen cardia.

Comparison of sheep and dairy cows for in vivo digestibility of perennial ryegrass.

Sheep are often used as a proxy for dairy cows when measuring the digestibility of a feed. In recent years grassland management guidelines for ruminant animals have been re-evaluated in accordance with the progression in animal genetics and the acknowledgement that genetic potential has an influence on both feed intake and digestibility. Recommended pre-grazing herbage mass (HM) targets are now much lower with improved perennial ryegrass varieties available for grazing swards. The objective of this study was to compare the in vivo digestibility of perennial ryegrass in wether sheep and lactating dairy cows. The experimental design was selected to measure the effect of animal species (cows, sheep), sward HM measured cutting herbage at 4 cm above ground level (low: 1 700 kg DM/ha and high: 4 000 kg DM/ha) and season (Spring: Apr-May, Summer: Jul-Aug) on the digestibility of perennial ryegrass. Each HM treatment was offered to each animal within species and season for 12 d using a 2 HM × 2 period changeover Latin square design. There were eight cows and eight sheep, so there were four 2 × 2 Latin squares for each animal species (two) at each season (two), giving 64 observations. During each 12 d experimental period, the first 6 d were used for adaptation (adaptation phase) and the final 6 d were used for measurement (measurement phase). In vivo organic matter digestibility (OMD) in spring did not differ between animal species but in summer sheep had higher in vivo OMD than cows. The results described herein highlight the suitability of wether sheep as an alternative to dairy cows for determining the digestibility of perennial ryegrass in spring but not in summer. Stage of growth of the plant, which is intrinsically linked to season, should be considered as results show that digestibility in the ruminant was affected by season but not differentially affected by changing sward HM.

Using estimated nutrient intake from pasture to formulate supplementary concentrate mixes for grazing dairy cows.

In pasture-based dairy systems, feeding a complex concentrate mix in the parlor during milking that contains cereal grains and protein supplements has been shown to have milk production advantages over feeding straight cereal grain. This experiment had the aim of testing whether further milk production advantages could be elicited by adjusting the composition of the concentrate mix in an attempt to match the expected nutrient intake from pasture during late spring. The experiment used 96 lactating dairy cows, grazing perennial ryegrass pasture offered at a target allowance of 30 kg of dry matter/cow per day (to ground level) during late spring (mid October to November) in southeastern Australia. Cows were allocated into 3 replicates of 4 treatment groups, with 24 cows in each treatment. Each treatment group was offered 1 of 4 dietary treatments in the parlor at milking: control consisting of crushed wheat and barley grains; formulated grain mix (FGM) consisting of crushed wheat, barley, and corn grains and canola meal; designer grain mix 1 (DGM1) consisting of the same ingredients as the FGM grain mix but formulated using the CPM Dairy nutrition model to take into account the expected nutrient intake from pasture; and designer grain mix 2 (DGM2) consisting of the same ingredients as DGM1 but with canola meal replaced by urea and a fat supplement (Megalac, Volac Wilmar, Gresik, Indonesia). Concentrate mixes were offered at 8.0 kg of dry matter/cow per day, except for DGM2 cows, which were offered 7.5 kg of dry matter/cow per day. The experiment ran for a total of 28 d; after a 14-d adaptation period, nutrient intake, milk production, and body weight were measured over a 14-d measurement period. Milk yield (kg) of cows fed the FGM diet was greater than that of the control cows but was not different from that of the DGM1 and DGM2 cows. However, milk fat and protein yields (kg) were greater for cows fed the FGM diet than for all other diets. There was no difference in estimated daily pasture or total dry matter intakes between the 4 treatment groups, despite cows fed the DGM2 treatment consuming less of the concentrate mix (average 6.5 kg of dry matter/cow per day when offered 7.5 kg of dry matter/cow per day). This research has demonstrated the potential for using a nutrition model to take into account the expected nutrient intake from pasture to formulate a concentrate mix (DGM1) to achieve similar milk yields, but also highlighted the need for near real-time analyses of the pasture to be grazed so as to also capture benefits in terms of milk fat and protein yield.

Variation in feeding behavior and milk production among dairy cows when supplemented with 2 amounts of mixed ration in combination with 2 amounts of pasture.

Variation in feeding behavior and milk production of grazing dairy cows fed a mixed ration was measured. Experiments were conducted in spring (early lactation) and autumn (late lactation) with 48 Holstein-Friesian dairy cows. Pasture allowance (low vs. high) and amounts of supplement (low vs. high) were applied to determine the effect on variation among cows in feeding behavior and milk production. The experiments investigated 4 dietary treatments in a 2×2 factorial arrangement of treatments. Daily pasture allowances were 15kg of DM/cow per day (low) and 37kg of DM/cow per day (high; to ground level); and 12kg of DM/cow per day (low) and 31kg of DM/cow per day (high; to ground level), for the spring and autumn experiments, respectively. Supplements were offered at 6kg of DM/cow per day (low) and 14kg of DM/cow per day (high); and 6kg of DM/cow per day (low) and 12kg of DM/cow per day (high), for the spring and autumn experiments, respectively. There were 2groups of 6 cows per treatment. All treatments received a partial mixed ration, defined as a total mixed ration fed between periods of grazing that contained wheat grain, corn grain, alfalfa hay, and canola meal. The grain-to-forage ratio of the supplements was 78:22 (DM basis) in both spring and autumn. In both experiments, the pre-experimental period was 14d followed by a 10-d experimental period. The variation among cows within a group in feeding behavior was influenced by the amount of supplement but not the amount of pasture offered. The variation among cows in pasture eating time approximately doubled when the amount of supplement offered increased, indicating that to reduce the variability among cows, supplement feeding management strategies need to be considered. Increasing pasture allowance had no effect on pasture eating time although pasture intake increased as a result of increased grazing intensity compared with the low pasture allowance. However, increasing the amount of supplement in the partial mixed ration feeding system reduced pasture eating time by 51min/cow per day.

Incorporating mixed rations and formulated grain mixes into the diet of grazing cows: Effects on milk composition and coagulation properties, and the yield and quality of Cheddar cheese.

Effects of different strategies for feeding supplements to grazing dairy cows on the composition and coagulation properties of milk and the subsequent yield and quality of Cheddar cheese were measured. The experiment used milk from 72 Holstein-Friesian cows, averaging 45d in milk, fed according to 1 of 3 feeding strategies: (1) cows grazed a restricted allowance of perennial ryegrass pasture [approximately 14kg of dry matter (DM)/cow per day, to ground level] supplemented with milled wheat grain fed in the milking parlor and alfalfa hay offered in the paddock (control); (2) same pasture and allowance as control, supplemented with a formulated grain mix containing wheat grain, corn grain, and canola meal fed in the parlor and alfalfa hay fed in the paddock (FGM); or (3) same pasture and allowance as control, supplemented with a partial mixed ration comprising the same formulated grain mix but mixed with alfalfa hay and presented on a feed pad after each milking (PMR). For all strategies, supplements provided the same metabolizable energy and grain:forage ratio (78:22, DM basis). Within each feeding strategy, milk was sampled from cows receiving either 8 or 16kg (DM) of supplement/cow per day. There were 2 replicated groups of 6 cows per supplement amount per dietary strategy; approximately 250L of milk was sampled from each for analyses of composition and coagulation properties and the manufacture of Cheddar cheese. The experiment had a 14-d adaptation period and a 14-d measurement period. For cows fed according to the control strategy, those fed 16kg/cow per day produced milk with lower concentrations of milk fat than cows fed 8kg/cow per day. This effect was not observed for cows fed according to the FGM and PMR strategies. Milk from cows fed 16kg of DM/cow per day according to the control strategy yielded less Cheddar cheese than milk from cows fed according to the PMR strategy, with cheese yields from FGM cows being intermediate. Amount of supplement offered had minor effects on percentages of some fatty acids. We observed few other effects of feeding strategy on milk composition, types of milk protein, milk coagulation properties, or the composition and quality of the resultant Cheddar cheese. These data show that, compared with the traditional control strategy, feeding PMR or FGM may increase milk fat concentration and the subsequent yield of Cheddar cheese without compromising cheese composition or quality.

Milk production responses to different strategies for feeding supplements to grazing dairy cows.

Milk production responses of grazing cows offered supplements in different ways were measured. Holstein-Friesian cows, averaging 45 d in milk, were allocated into 8 groups of 24, with 2 groups randomly assigned to each of 4 feeding strategies. These were control: cows grazed a restricted allowance of perennial ryegrass pasture supplemented with milled wheat grain fed in the milking parlor and alfalfa hay offered in the paddock; FGM: same pasture and allowance as the control supplemented with a formulated grain mix containing wheat grain, corn grain, and canola meal fed in the parlor and alfalfa hay fed in the paddock; PMRL: same pasture and allowance as the control, supplemented with a PMR consisting of the same FGM but mixed with alfalfa hay and presented on a feed pad after each milking; and PMRH: same PMR fed in the same way as PMRL but with a higher pasture allowance. For all strategies, supplements provided the same metabolizable energy and grain:forage ratio [75:25, dry matter (DM) basis]. Each group of 24 cows was further allocated into 4 groups of 6, which were randomly assigned to receive 8, 12, 14, or 16 kg of DM supplement/cow per d. Thus, 2 replicated groups per supplement amount per dietary strategy were used. The experiment had a 14-d adaptation period and a 14-d measurement period. Pasture allowance, measured to ground level, was approximately 14 kg of DM/d for control, FGM, and PMRL cows, and 28 kg of DM/d for the PMRH cows, and was offered in addition to the supplement. Positive linear responses to increasing amounts of supplement were observed for yield of milk, energy-corrected milk, fat, and protein for cows on all 4 supplement feeding strategies. Production of energy-corrected milk was greatest for PMRH cows, intermediate for FGM and PMRL cows, and lowest for control cows. Some of these differences in milk production related to differences in intake of pasture and supplement. Milk fat concentration decreased with increasing amount of supplement for all feeding strategies, but the decline was most marked for the control cows. Milk protein concentration increased for all groups as the amount of supplement increased, but was greater for FGM, PMRL, and PMRH cows than control cows. It is concluded that when supplements are fed to grazing dairy cows, inclusion of corn grain and canola meal can increase milk production even at similar metabolizable energy intakes, and that it does not matter whether these supplements are fed as a PMR or in the parlor and paddock.

Effects of partial mixed rations and supplement amounts on milk production and composition, ruminal fermentation, bacterial communities, and ruminal acidosis.

Late-lactation Holstein cows (n=144) that were offered 15kg dry matter (DM)/cow per day of perennial ryegrass to graze were randomized into 24 groups of 6. Each group contained a fistulated cow and groups were allocated to 1 of 3 feeding strategies: (1) control (10 groups): cows were fed crushed wheat grain twice daily in the milking parlor and ryegrass silage at pasture; (2) partial mixed ration (PMR; 10 groups): PMR that was isoenergetic to the control diet and fed twice daily on a feed pad; (3) PMR+canola (4 groups): a proportion of wheat in the PMR was replaced with canola meal to produce more estimated metabolizable protein than other groups. Supplements were fed to the control and PMR cows at 8, 10, 12, 14, or 16kg of DM/d, and to the PMR+canola cows at 14 or 16kg of DM/d. The PMR-fed cows had a lower incidence of ruminal acidosis compared with controls, and ruminal acidosis increased linearly and quadratically with supplement fed. Yield of milk fat was highest in the PMR+canola cows fed 14 or 16kg of total supplement DM/d, followed by the PMR-fed cows, and was lowest in controls fed at these amounts; a similar trend was observed for milk fat percentage. Milk protein yield was higher in the PMR+canola cows fed 14 or 16kg of total supplement DM/d. Milk yield and milk protein percentage were not affected by feeding strategy. Milk, energy-corrected milk, and milk protein yields increased linearly with supplement fed, whereas milk fat percentage decreased. Ruminal butyrate and d-lactate concentrations, acetate-to-propionate ratio, (acetate + butyrate)/propionate, and pH increased in PMR-fed cows compared with controls for all supplement amounts, whereas propionate and valerate concentrations decreased. Ruminal acetate, butyrate, and ammonia concentrations, acetate-to-propionate ratio, (acetate + butyrate)/propionate, and pH linearly decreased with amounts of supplement fed. Ruminal propionate concentration linearly increased and valerate concentration linearly and quadratically increased with supplement feeding amount. The Bacteroidetes and Firmicutes were the dominant bacterial phyla identified. The Prevotellaceae, Ruminococcaceae, and Lachnospiraceae were the dominant bacterial families, regardless of feeding group, and were influenced by feeding strategy, supplement feeding amount, or both. The Veillonellaceae family decreased in relative abundance in PMR-fed cows compared with controls, and the Streptococcaeae and Lactobacillaceae families were present in only minor relative abundances, regardless of feeding group. Despite large among- and within-group variation in bacterial community composition, distinct bacterial communities occurred among feeding strategies, supplement amounts, and sample times and were associated with ruminal fermentation measures. Control cows fed 16kg of DM of total supplement per day had the most distinct ruminal bacterial community composition. Bacterial community composition was most significantly associated with supplement feeding amount and ammonia, butyrate, valerate, and propionate concentrations. Feeding supplements in a PMR reduced the incidence of ruminal acidosis and altered ruminal bacterial communities, regardless of supplement feeding amount, but did not result in increased milk measures compared with isoenergetic control diets component-fed to late-lactation cows.

Reproducibility and agreement in evaluating retinal nerve fibre layer thickness between Stratus and Spectralis OCT.

PURPOSE: To evaluate intra-device reproducibility of retinal nerve fibre layer (RNFL) measurements obtained using Stratus and Spectralis optical coherence tomography, and to analyze inter-device correlation and agreement for these measurements. DESIGN: Prospective observational study. METHODS: A total of 30 normal individuals participated in the study. One eye of each participant was scanned three times during one session by the same operator using Spectralis and Stratus. Intra-class correlation coefficients (ICCs), correlation coefficients (R), and Bland-Altman plots (BAPs) were used to assess reproducibility, correlation, and agreement between the two devices, respectively. RESULTS: A significant difference in mean RNFL thickness was seen between Stratus and Spectralis (106.2 ± 6.9 µm vs 100.0 ± 7.3 µm, P = 0.0001). ICCs of RNFL thickness measurements ranged from 0.69 (clock hour 2; 95% confidence interval (95% CI): 0.54, 0.85) to 0.91 (inferior quadrant; 95% CI: 0.86, 0.96) for Stratus and were higher for Spectralis, ranging from 0.87 (temporal-superior sector; 95% CI: 0.79, 0.94) to 0.96 (global and nasal-inferior sector; 95% CI: 0.94, 0.99). Rs of RNFL thickness measurements between the two instruments ranged from 0.61 (temporal quadrant) to 0.87 (superior quadrant). BAPs demonstrated a systematic difference in RNFL values between the two devices, with Spectralis producing thinner RNFL values than Stratus. CONCLUSIONS: Spectralis demonstrated higher ICCs and thinner RNFL measurements than Stratus. Although the inter-device correlation was good, differences in RNFL measurements obtained by the two devices indicate that these measurements would not be interchangeable in clinical evaluations.

The myth of tracheomalacia and difficult intubation in cases of retrosternal goitre.

Although it is widely believed that management of the airway is difficult in surgery for retrosternal goitre, a review of the literature, revealing management of 1969 patients with retrosternal goitre, provided scant evidence of difficult intubation or post-operative tracheomalacia resulting in tracheal collapse. This was reflected in our own series of 18 thyroidectomies for retrosternal goitre performed at our hospitals.

Lipidomic analysis of the molecular specificity of a cholinephosphotransferase in situ.

Dynamic lipidomics using ESI-MS (tandem electrospray ionization mass spectrometry) of 9-deuterated choline (choline-d(9)) incorporation into mammalian cell PtdCho (phosphatidylcholine) permits assessment of the molecular specificity of synthesis. Bulk cell PtdCho synthesis occurs in spatially distinct locations, using separate CPTs (1,2 diacylglycerol CDP:choline cholinephosphotransferases). We assessed whether in vitro molecular selectivity of DAG (diacylglycerol) incorporation between CPTs is manifest in situ, by monitoring choline-d(9) incorporation into PtdCho and lyso-PtdCho molecular species over 3 h in control cells and in CHO-K1 cells overexpressing hCEPT1. Compared with controls, the basal molecular species composition of hCEPT1 overexpressors was significantly enriched in arachidonate. This was not due to net accretion of cellular PtdCho arguing against effects of inadequate unsaturated PtdCho degradation or remodelling. Rather, time-course analyses of PtdCho and lyso-PtdCho pools showed that both arachidonate-containing DAG incorporation and turnover of PtdCho is increased in hCEPT1 overexpressors. Increased choline-d(9) incorporation into arachidonyl lyso-PtdCho shows that both phospholipase A(1)- and A(2)-mediated turnover is involved. Spatially distinct molecular specificity of DAG incorporation into cellular PtdCho at the level of hCEPT1 exists in situ.

Antibiotic-treated infections in intensive care patients in the UK.

The purpose of this audit was to study reasons for starting antibiotic therapy, duration of antibiotic treatment, reasons for changing antibiotics and the agreement between clinical suspicion and microbiological results in intensive care practice. We conducted a multicentre observational audit of 316 patients. Data on demographic details, site, treatment and nature of infection were collected. The median duration of antibiotic therapy was 7 days. Infections were community-acquired in 160 patients (55%). Antibiotics were started on clinical suspicion of infection in 237 patients (75%). Pulmonary infections were the most common, representing 52% of all proven infections. Gram-negative organisms were the most common cause of proven infections (n = 90 (50%)). The antibiotic spectrum was narrowed in light of microbiology results in 78 patients (43%) and changed due to antibiotic resistance in 38 patients (21%). We conclude that the mean duration of treatment contrasts with existing published guidelines, highlighting the need for further studies on duration and efficacy of treatment in intensive care.

Intraocular pressure measurement at the choroid surface: a feasibility study with implications for implantable microsystems.

AIMS: To demonstrate that a sensor, which is inserted through the sclera and placed in intimate contact with the choroid, can reliably detect changes in the intraocular pressure (IOP). METHODS: A manometer was used to control the IOP of three cadaver eyes in steps of 7 mm Hg. A piezoresistive pressure sensor was used to measure the pressure at the choroid through a 2.5 mm diameter hole that was surgically removed from the sclera. Data were collected for two configurations; with the sensor: (i) rigidly attached to a miniature positioning stage, and (ii) sutured to the sclera. RESULTS: Both configurations accurately tracked the manometer pressure from 10 mm Hg to 47 mm Hg. For the fixed sensor cases, the average difference between the pressure measured at the choroid and in the anterior chamber was 0.8 mm Hg for the three eyes. For the sutured sensor case, the average difference was 2.1 mm Hg-although a significant portion of this was attributed to an initial offset. The standard deviations at each pressure level for all of the choroid measurements were under 1.0 mm Hg. CONCLUSIONS: Small changes in IOP can be accurately measured by a sensor in contact with the surface of the choroid, for both a fixed sensor configuration and for a sensor sutured to the sclera. These results are the first step in the realisation of a surgically implantable microsensor to monitor IOP for patients suffering from low tension and other difficult to manage forms of glaucoma.

Snapshots of five clinical ethics committees in the UK.

Each of the following papers gives an account of a different UK clinical ethics committee. The committees vary in the length of time they have been established, and also in the main focus of their work. The accounts discuss the development of the committees and some of the ethical problems that have been brought to them. The issues raised will be relevant for other National Health Service (NHS) trusts in the UK that wish to set up such a committee.

Uncoupling farnesol-induced apoptosis from its inhibition of phosphatidylcholine synthesis.

Genetic inactivation of the synthesis of phosphatidylcholine, the most abundant membrane lipid in eukaryotic cells, induces apoptosis. Administration of farnesol, a catabolite within the isoprenoid/cholesterol pathway, also induces apoptosis. The mechanism by which farnesol induces apoptosis is currently believed to be by direct competitive inhibition with diacylglycerol for cholinephosphotransferase, the final step in the phosphatidylcholine biosynthetic pathway. Our recent isolation of the first mammalian cholinephosphotransferase cDNA has enabled us to more precisely assess how farnesol affects phosphatidylcholine synthesis and the induction of apoptosis. Induced over-expression of cholinephosphotransferase in Chinese hamster ovary cells prevented the block in phosphatidylcholine biosynthesis associated with exposure to farnesol. However, induced over-expression of cholinephosphotransferase was not sufficient for the prevention of farnesol-induced apoptosis. In addition, exogenous administration of diacylglycerol prevented farnesol-induced apoptosis but did not relieve the farnesol-induced block in phosphatidylcholine synthesis. We also developed an in vitro lipid mixed micelle cholinephosphotransferase enzyme assay, as opposed to the delivery of the diacylglycerol substrate in a detergent emulsion, and demonstrated that there was no direct inhibition of cholinephosphotransferase by farnesol or its phosphorylated metabolites. The execution of apoptosis by farnesol appears to be a separate and distinct event from farnesol-induced inhibition of phosphatidylcholine biosynthesis and instead likely occurs through a diacylglycerol-mediated process that is downstream of phosphatidylcholine synthesis.

Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors.

Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.