Pre-oxygenation with facemask oxygen vs high-flow nasal oxygen vs high-flow nasal oxygen plus mouthpiece: a randomised controlled trial.

High-flow nasal oxygen used before and during apnoea prolongs time to desaturation at induction of anaesthesia. It is unclear how much oxygenation before apnoea prolongs this time. We randomly allocated 84 participants to 3 minutes of pre-oxygenation by one of three methods: 15 l.min-1 by facemask; 50 l.min-1 by high-flow nasal cannulae only; or 50 l.min-1 by high-flow nasal cannulae plus 15 l.min-1 by mouthpiece. We then anaesthetised and intubated the trachea of 79 participants and waited for oxygen saturation to fall to 92%. Median (IQR [range]) times to desaturate to 92% after pre-oxygenation with facemask oxygen, high-flow nasal oxygen only and high-flow nasal oxygen with mouthpiece, were: 309 (208-417 [107-544]) s; 344 (250-393 [194-585]) s; and 386 (328-498 [182-852]) s, respectively, p = 0.014. Time to desaturation after facemask pre-oxygenation was shorter than after combined nasal and mouthpiece pre-oxygenation, p = 0.006. We could not statistically distinguish high-flow nasal oxygen without mouthpiece from the other two groups for this outcome. Median (IQR [range]) arterial oxygen partial pressure after 3 minutes of pre-oxygenation by facemask, nasal cannulae and nasal cannulae plus mouthpiece, was: 49 (36-61 [24-66]) kPa; 57 (48-62 [30-69]) kPa; and 61 (55-64 [36-72]) kPa, respectively, p = 0.003. Oxygen partial pressure after 3 minutes of pre-oxygenation with nasal and mouthpiece combination was greater than after facemask pre-oxygenation, p = 0.002, and after high-flow nasal oxygen alone, p = 0.016. We did not reject the null hypothesis for the pairwise comparison of facemask pre-oxygenation and high-flow nasal pre-oxygenation, p = 0.14.

Real-Time Electron Solvation Induced by Bursts of Laser-Accelerated Protons in Liquid Water.

Understanding the mechanisms of proton energy deposition in matter and subsequent damage formation is fundamental to radiation science. Here we exploit the picosecond (10^{-12} s) resolution of laser-driven accelerators to track ultrafast solvation dynamics for electrons due to proton radiolysis in liquid water (H_{2}O). Comparing these results with modeling that assumes initial conditions similar to those found in photolysis reveals that solvation time due to protons is extended by >20 ps. Supported by magnetohydrodynamic theory this indicates a highly dynamic phase in the immediate aftermath of the proton interaction that is not accounted for in current models.

Noncollinear Polarization Gating of Attosecond Pulse Trains in the Relativistic Regime.

High order harmonics generated at relativistic intensities have long been recognized as a route to the most powerful extreme ultraviolet pulses. Reliably generating isolated attosecond pulses requires gating to only a single dominant optical cycle, but techniques developed for lower power lasers have not been readily transferable. We present a novel method to temporally gate attosecond pulse trains by combining noncollinear and polarization gating. This scheme uses a split beam configuration which allows pulse gating to be implemented at the high beam fluence typical of multi-TW to PW class laser systems. Scalings for the gate width demonstrate that isolated attosecond pulses are possible even for modest pulse durations achievable for existing and planned future ultrashort high-power laser systems. Experimental results demonstrating the spectral effects of temporal gating on harmonic spectra generated by a relativistic laser plasma interaction are shown.

The development of a patient partnership programme and its impact on quality improvements in a comprehensive haemophilia care service.

It has long been advocated that patient input in service quality development is essential. We have developed a model of quality evaluation and improvement within a comprehensive haemophilia service, and describe the issues and improvements that resulted from the process. The project utilized an action research methodology. Seven patients were recruited from the haemophilia service for the initial focus groups. The main themes initially explored were as follows: patient experience of the outpatient, inpatient and weekend services and provision of information. The focus group data were analysed using basic content analysis. The main themes the initial focus group identified were the need to optimize the annual review, emergency care and inpatient facilities. Following this, the haemophilia care team worked on improving these issues. At the second focus group the patients contributed at a higher level - patient participation. Patients assisted in addressing outstanding issues such as ID alert card content and the algorithm of care for emergency services. Finally, a patient panel was developed and the relationship became one of direct negotiation and partnership with the haemophilia team to address issues within the service. The expectations and needs of patients attending the haemophilia comprehensive care service are complex. The process of including patients as partners at the highest level of patient involvement evolved and proved an effective method of service evaluation and development, facilitating lateral decision-making, not only improving care directly, but also improving the user experience.

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes.

AIMS/HYPOTHESIS: This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. METHODS: We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. RESULTS: The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. CONCLUSIONS/INTERPRETATION: These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor.

AIMS/HYPOTHESIS: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. METHODS: Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. RESULTS: With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. CONCLUSIONS/INTERPRETATION: RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.

Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes.

The biochemical process of advanced glycation appears to play a central role in the development and progression of diabetic vascular complications. A number of strategies to influence this pathway have been designed, one of which involves the putative advanced glycation end-product (AGE) crosslink breaker, alagebrium which has been shown in in vitro studies to cleave preformed AGE crosslinks. This agent has been studied in various models of diabetic complications and has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis. In addition to the ability of alagebrium to reduce tissue levels of AGEs, this drug appears to inhibit activation of certain protein kinase C isoforms. Planned clinical studies in diabetic subjects at risk of complications should assist in determining the role of alagebrium in the prevention, retardation, and reversal of diabetic micro- and macrovascular disease.

A potential hidden layer of meteorites below the ice surface of Antarctica.

Antarctica contains some of the most productive regions on Earth for collecting meteorites. These small areas of glacial ice are known as meteorite stranding zones, where upward-flowing ice combines with high ablation rates to concentrate large numbers of englacially transported meteorites onto their surface. However, meteorite collection data shows that iron and stony-iron meteorites are significantly under-represented from these regions as compared with all other sites on Earth. Here we explain how this discrepancy may be due to englacial solar warming, whereby meteorites a few tens of centimetres below the ice surface can be warmed up enough to cause melting of their surrounding ice and sink downwards. We show that meteorites with a high-enough thermal conductivity (for example, iron meteorites) can sink at a rate sufficient to offset the total annual upward ice transport, which may therefore permanently trap them below the ice surface and explain their absence from collection data.

Picosecond metrology of laser-driven proton bursts.

Tracking primary radiation-induced processes in matter requires ultrafast sources and high precision timing. While compact laser-driven ion accelerators are seeding the development of novel high instantaneous flux applications, combining the ultrashort ion and laser pulse durations with their inherent synchronicity to trace the real-time evolution of initial damage events has yet to be realized. Here we report on the absolute measurement of proton bursts as short as 3.5±0.7 ps from laser solid target interactions for this purpose. Our results verify that laser-driven ion acceleration can deliver interaction times over a factor of hundred shorter than those of state-of-the-art accelerators optimized for high instantaneous flux. Furthermore, these observations draw ion interaction physics into the field of ultrafast science, opening the opportunity for quantitative comparison with both numerical modelling and the adjacent fields of ultrafast electron and photon interactions in matter.

Differential sensitivity of proximal and distal coronary arteries to a nitric oxide donor following reperfusion injury or inhibition of nitric oxide synthesis.

OBJECTIVE: The effect of the nitric oxide donor, SIN-1, in proximal and distal coronary arteries with normal endothelium was characterised before and after inhibition of NO synthesis with L-nitroarginine methyl ester (L-NAME). The effect of reperfusion injury in vivo in similar vessels on the response to SIN-1 was also assessed. METHODS: In vitro reactivity of preconstricted coronary arterial rings was studied in control dogs (group 1), and dogs in which the left circumflex coronary artery was subjected in vivo to four acute occlusions of 5 min duration, with three intervening reperfusion periods of 5 min and a final reperfusion period of 60 min (group 2). The effects of acetylcholine and SIN-1 on the tone of left circumflex and left anterior descending coronary vascular rings were examined before and after treatment with L-NAME. RESULTS: Proximal [1851 (SEM 82) microns] and distal [477(19) microns] vessels were studied. In control dogs (group 1) acetylcholine caused relaxation in proximal and distal coronary arteries (p > 0.05). No difference in responsiveness of left circumflex or left anterior descending coronary arteries was observed in the control group. In group 2 the response to acetylcholine was significantly (p < 0.05) attenuated in left circumflex coronary arteries exposed to ischaemia and reperfusion compared with left anterior descending control rings from the same heart. Proximal vessels in group 1 and group 2 showed greater sensitivity to the vasodilator effects of SIN-1 than distal vessels. Proximal left circumflex vessels exposed to ischaemia and reperfusion showed enhanced sensitivity to the relaxant effects of SIN-1 compared to control proximal vessels obtained from the same hearts. Reperfusion was not associated with any alteration in sensitivity of distal vessels to SIN-1. Similarly, inhibition of the synthesis of endothelium derived relaxing factor (EDRF) by L-NAME resulted in an enhanced response to SIN-1 in proximal vessels only. CONCLUSIONS: Endothelium dependent vasodilatation is attenuated by ischaemia and reperfusion in both proximal and distal coronary arteries of the size studied. The response to direct nitric oxide donation (bypassing vascular endothelial synthesis of EDRF) is inhibited by a basal endothelial process present in proximal coronary arteries only. This inhibition is abolished following reperfusion injury or inhibition of NO synthesis.

Involvement of nitric oxide synthase in the delayed vasodilator response to ultraviolet light irradiation of rat skin in vivo.

1. The role of nitric oxide synthase and cyclo-oxygenase in the skin blood flow response to ultraviolet light B (u.v.B) irradiation was investigated in the rat in vivo. 2. Local skin blood flow changes were measured in the shaved dorsal skin of anaesthetized male Sprague-Dawley rats with a laser Doppler flow probe. 3. u.v.B irradiation caused delayed onset vasodilation and by 18 h basal blood flow increased by 125 +/- 25% (P < 0.05, n = 12 rats, mean +/- s.e. mean). 4. Indomethacin, 3 nmol per site, NG-nitro-L-arginine methyl ester (L-NAME) 100 nmol per site, but not D-NAME 100 nmol per site, injected locally 17.5 h after u.v.B irradiation abolished the 18 h increase in blood flow. 5. The nitric oxide synthase inhibitor L-NAME, NG-monomethyl-L-arginine (L-NMMA) and canavanine, 10 and 100 nmol per site injected at 17.5 h, suppressed significantly the u.v.B 18 h response in a dose-dependent manner. The order of potency was L-NAME > canavanine = L-NMMA. The effect of L-NAME was reversed partially by the co-injection of an excess of L-arginine. 6. Topical application of the corticosteroid, clobetasol 17-propionate, immediately after irradiation inhibited the 18 h u.v.B response in a dose-dependent manner. 7. The delayed onset microcirculatory vasodilation induced by u.v.B involves both nitric oxide synthase and cyclo-oxygenase in this in vivo model. Topical corticosteroids may attenuate the response by inhibiting both prostaglandin and nitric oxide synthesis pathways.

Endotoxin-induced vasodilatation in anaesthetized rat skin involves nitric oxide and prostaglandin synthesis.

1. The effect of intradermally injected endotoxin on skin blood flow was investigated in anaesthetized male Wistar rats in vivo. 2. Local skin blood flow changes were measured hourly for 6 h in the shaved dorsal skin with a laser-Doppler flow probe and compared to changes in control sites which had been injected with 100 microliters of phosphate-buffered saline. By 3 h, skin blood flow increased above basal by 129 +/- 27% and 186 +/- 29% with 1 and 10 micrograms of endotoxin respectively. Blood flow remained significantly elevated at 6 h, the corresponding figures being 129 +/- 24% and 154 +/- 31% (P less than 0.05, n = 6 rats, mean +/- s.e.mean). 3. In further experiments, the response to 3 micrograms of endotoxin was measured at 4 h and treatment with a cyclo-oxygenase inhibitor, nitric oxide synthase inhibitors or a topical steroid all significantly inhibited this response (P less than 0.05 in each case, n = 6 rats in each group with duplicate sites in each animal). 4. Indomethacin 3 x 10(-9) mol per site injected 3.5 h after injection of endotoxin suppressed the mean 4 h response to endotoxin by 78%; NG-nitro-L-arginine methyl ester (L-NAME) 10(-7) mol per site suppressed the response by 95%; NG-monomethyl-L-arginine (L-NMMA) 10(-7) mol per site suppressed the response by 50%; whereas the D-isomer of NG-monomethyl-arginine 10(-7) mol per site had no significant effect.5. Topical application of the corticosteroid, betamethasone 17-valerate (1% solution) 18 h before injection of endotoxin inhibited the mean 4 h response to endotoxin by 66% and the 6 h response by 48%.6. In the same model, the vasodilator response to arachidonic acid was inhibited by both indomethacin and nitric oxide synthase inhibitors (P<0.05 in each case).7. These data suggest that the microcirculatory vasodilator response to endotoxin and arachidonic acid injected locally involves both nitric oxide synthase and cyclo-oxygenase in this in vivo model.

Pituitary adenylate cyclase activating polypeptide is a potent vasodilator and oedema potentiator in rabbit skin in vivo.

1. The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on microvascular blood flow and plasma protein leakage were investigated in rabbit skin in vivo. 2. Intradermal injection of PACAP38, the 38 amino acid form of the peptide, caused a dose-dependent increase in blood flow measured by a 133Xe clearance technique. An equivalent increase in blood flow was induced by 10(-12) mol per site of PACAP38, 10(-12) mol per site of human alpha-calcitonin gene-related peptide (CGRP) and 10(-10) mol per site of vasoactive intestinal polypeptide (VIP). 3. The vasodilator activity of PACAP38 was not significantly different from that of the 27 amino acid form of the peptide, PACAP27, when measured with a laser Doppler flow meter, causing a 104 +/- 14% compared with 110 +/- 18% increase above basal blood flow at 10(-12) mol per site respectively. 4. At 10(-12) mol per site the effect of PACAP38 was longer lasting than that of CGRP. Blood flow remained significantly increased above control at 2 h with PACAP38 (P less than 0.05) whereas blood flow after intradermal CGRP had returned to control values by this time. 5. PACAP38 injected alone had no significant effect on microvascular leakage of 125I-labelled albumin. However, PACAP38 significantly potentiated bradykinin-induced oedema where it was approximately 100 fold more potent than VIP. 6. Oedema potentiation induced by PACAP38 was not inhibited by indomethacin at a dose which did inhibit potentiation of bradykinin-induced oedema by arachidonic acid.7. PACAP38 is at least as potent as other peptides which have been postulated to be involved in the inflammatory response when tested in rabbit skin in vivo. PACAP may contribute to both the hyperaemia and oedema components of inflammation.

Altered placental oxidative stress status in gestational diabetes mellitus.

Oxidative stress has been clearly linked to type 2 diabetes mellitus, however, limited data are available on the involvement of oxidative stress in gestational diabetes mellitus (GDM), a disease of similar pathophysiology. The aim of this study was to investigate the status of placental oxidative stress in healthy pregnant women and women with GDM. The hypothesis to be tested was that tissue markers of oxidative stress are significantly increased in GDM compared to normal placental tissues. Markers of oxidative stress measured were the release of 8-isoprostane (8-epi-prostaglandin F(2alpha)) from human term placental explants (n=11), the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase (n=10), and protein carbonyl content (n=12). Placental release of 8-isoprostane was 2-fold greater from women with GDM (P<0.001) compared to healthy pregnant women. Superoxide dismutase activity and protein carbonyl content were elevated in placentae obtained from women with GDM (P<0.04 and P<0.004 respectively), whilst there was no significant difference in the activity of glutathione peroxidase. These data demonstrate the presence of oxidative stress in the placenta from women with GDM, in addition to the induction of a key antioxidant, collectively indicating a state of existing oxidative stress in this condition.

Comparison of cardiac output determinants in response to upright and supine exercise in patients with cystic fibrosis.

This study characterizes cardiac output response to progressive submaximal upright cycling in CF patients. Thirty-one CF patients as well as 11 aged-matched CF control subjects completed cardiac output determinations (CO2-rebreathing) at rest, and at submaximal exercise corresponding to 30, 50 and 75 percent VO2max, in both upright and supine positions. The VO2max was similar in three of four groups, but lower in those with severe CF. The cardiac output generally increased with exercise intensity in both positions, except in severe CF. The change from upright to supine posture resulted in a significant increase in SI at rest and for every submaximal exercise in control subjects, but not CF patients. These observations may suggest that the abnormal cardiac output response observed in severe CF could be related to a potential limitation in ventricular diastolic reserve found in all CF patients independent of disease severity which becomes more apparent under increased ventricular preload.

Use of ondansetron in palliative medicine.

Ondansetron was the first of several selective 5-hydroxytryptamine (5-HT3) antagonists to be available as an antiemetic. Its uses in the setting of highly and moderately emetogenic chemotherapy and radiotherapy are well established. Ondansetron has also been used to manage nausea and vomiting in other patients. We report a retrospective analysis of its use in all 16 patients who were commenced on ondansetron after admission to our institution for nausea and/or vomiting over a 4-year period. Nine patients had advanced human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and seven had malignancy. These patients were not undergoing disease-modifying treatment and had inadequate responses to therapeutic doses of standard antiemetics, used either singly or in combination. Responses were independently reviewed and graded by two investigators. Response was judged at 48 hr after commencing therapy. Potential causes of nausea were also reviewed. Overall, 13 of 16 [81%, 95% confidence interval (CI) 54%-96%] derived benefit. Twelve of 15 patients (80%) with nausea had a demonstrable improvement, and ten of 14 patients (71%) with vomiting also improved. Eight of ten patients (80%) admitted with nausea and/or vomiting as one of their presenting problems had the symptom controlled within 48 hr of ondansetron therapy. Treatment with ondansetron was well tolerated, onset of action was rapid, and response rates were high and sustained over time. Seven of the 16 patients continued ondansetron therapy for more than 10 days. With minimal reductions in inpatient bed stays, the total costs of ondansetron could be met while at the same time better supporting patients remaining in the community.

A convenient procedure for the estimation of cellulase activity.

The extent of clarification of cellulose-containing agar by "complete' cellulase is a linear function of the logarithm of the enzyme activity. This fact allows a convenient and quantitative estimation of cellulase activity in culture filtrates to be made without the need for tedious dilution. Moreover, such activity can be determined even in the presence of inhibitors such as cellobiose.

Prevalence of hysterectomy in Ireland.

OBJECTIVES: To assess factors influencing the prevalence of hysterectomy in Ireland. METHODS: Analysis of results of a questionnaire completed by a population-based cohort of 17735 women aged 50-65 years attending for breast screening. RESULTS: Prevalence of hysterectomy was 22.2%, was increased in proportion to parity and was higher in younger women, those who had previously used oral contraception and those who had private health insurance; peak age at operation was 45-49 years. CONCLUSION: The relatively high prevalence parity reflects contraceptive practices and utilization of health service resources.

Analysis of endometrial carcinoma.

Between 1980/86 there were 58 cases of uterine cancer reviewed at the Mater Misericordiae Hospital, of which 49 (84.5%) had endometrial adenocarcinoma. The median survival in Stage I disease was 30 months and where applicable the overall five-year survival rate was 43.75%. These survival rates are less than those reported from most other centres. This reduced survival rate was not related to presentation with more advanced disease. However, patients were of an older age and had a greater number of poorly differentiated tumours than in other reported series. Comparative results with other centres in Ireland would be assisted by the establishment of a National Tumour Registry.

Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?

Diabetic nephropathy (DN) is a progressive microvascular complication arising from diabetes. Within the kidney, the glomeruli, tubules, vessels and interstitium are disrupted, ultimately impairing renal function and leading to end-stage renal disease (ESRD). Current pharmacological therapies used in individuals with DN do not prevent the inevitable progression to ESRD; therefore, new targets of therapy are urgently required. Studies from animal models indicate that disturbances in mitochondrial homeostasis are central to the pathogenesis of DN. Since renal proximal tubule cells rely on oxidative phosphorylation to provide adequate ATP for tubular reabsorption, an impairment of mitochondrial bioenergetics can result in renal functional decline. Defects at the level of the electron transport chain have long been established in DN, promoting electron leakage and formation of superoxide radicals, mediating microinflammation and contributing to the renal lesion. More recent studies suggest that mitochondrial-associated proteins may be directly involved in the pathogenesis of tubulointerstitial fibrosis and glomerulosclerosis. An accumulation of fragmented mitochondria are found in the renal cortex in both humans and animals with DN, suggesting that in tandem with a shift in dynamics, mitochondrial clearance mechanisms may be impaired. The process of mitophagy is the selective targeting of damaged or dysfunctional mitochondria to autophagosomes for degradation through the autophagy pathway. The current review explores the concept that an impairment in the mitophagy system leads to the accelerated progression of renal pathology. A better understanding of the cellular and molecular events that govern mitophagy and dynamics in DN may lead to improved therapeutic strategies.