Quasi-planar InGaAsSb p-B-n photodiodes for spectroscopic sensing.

An InGaAsSb p-B-n structure has been designed and characterized for zero bias low power detection applications. Devices were grown by molecular beam epitaxy and fabricated into quasi-planar photodiodes with a 2.25 µm cut-off wavelength. Maximum responsivity was measured to be 1.05 A/W at 2.0 µm, achieved at zero bias. D* of 9.4 × 1010 Jones was determined from room temperature spectra of noise power measurements with calculated D* remaining >1 × 1010 Jones up to 380 K. With a view to simple miniaturized detection and measurement of low concentration biomarkers, optical powers down to 40 pW were detected, without temperature stabilization or phase-sensitive detection, indicating the photodiode's potential.

Systems Biology Model of Cerebral Oxygen Delivery and Metabolism During Therapeutic Hypothermia: Application to the Piglet Model.

Hypoxic ischaemic encephalopathy (HIE) is a significant cause of death and disability. Therapeutic hypothermia (TH) is the only available standard of treatment, but 45-55% of cases still result in death or neurodevelopmental disability following TH. This work has focussed on developing a new brain tissue physiology and biochemistry systems biology model that includes temperature effects, as well as a Bayesian framework for analysis of model parameter estimation. Through this, we can simulate the effects of temperature on brain tissue oxygen delivery and metabolism, as well as analyse clinical and experimental data to identify mechanisms to explain differing behaviour and outcome. Presented here is an application of the model to data from two piglets treated with TH following hypoxic-ischaemic injury showing different responses and outcome following treatment. We identify the main mechanism for this difference as the Q10 temperature coefficient for metabolic reactions, with the severely injured piglet having a median posterior value of 0.133 as opposed to the mild injury value of 5.48. This work demonstrates the use of systems biology models to investigate underlying mechanisms behind the varying response to hypothermic treatment.

Magnetic resonance imaging measurement of placental perfusion and oxygen saturation in early-onset fetal growth restriction.

OBJECTIVE: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR). DESIGN: Case-control study. SETTING: London, UK. POPULATION: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied. METHODS: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation. MAIN OUTCOME MEASURES: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan. RESULTS: The FGR group (mean GA 27+5  weeks, range 24+2 to 33+6  weeks) had a significantly lower EFW compared with the control group (mean GA 29+1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83). CONCLUSION: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies. TWEETABLE ABSTRACT: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity.

Femtosecond few- to single-electron point-projection microscopy for nanoscale dynamic imaging.

Femtosecond electron microscopy produces real-space images of matter in a series of ultrafast snapshots. Pulses of electrons self-disperse under space-charge broadening, so without compression, the ideal operation mode is a single electron per pulse. Here, we demonstrate femtosecond single-electron point projection microscopy (fs-ePPM) in a laser-pump fs-e-probe configuration. The electrons have an energy of only 150 eV and take tens of picoseconds to propagate to the object under study. Nonetheless, we achieve a temporal resolution with a standard deviation of 114 fs (equivalent to a full-width at half-maximum of 269 ± 40 fs) combined with a spatial resolution of 100 nm, applied to a localized region of charge at the apex of a nanoscale metal tip induced by 30 fs 800 nm laser pulses at 50 kHz. These observations demonstrate real-space imaging of reversible processes, such as tracking charge distributions, is feasible whilst maintaining femtosecond resolution. Our findings could find application as a characterization method, which, depending on geometry, could resolve tens of femtoseconds and tens of nanometres. Dynamically imaging electric and magnetic fields and charge distributions on sub-micron length scales opens new avenues of ultrafast dynamics. Furthermore, through the use of active compression, such pulses are an ideal seed for few-femtosecond to attosecond imaging applications which will access sub-optical cycle processes in nanoplasmonics.

Simulating NIRS and MRS measurements during cerebral hypoxia-ischaemia in piglets using a computational model.

We present a group analysis of the changes in cerebral haemodynamics, and the oxidation state of cytochrome-c-oxidase measured using broadband near-infrared spectroscopy (NIRS) and intracellular pH measured by phosphorous ((31)P) magnetic resonance spectroscopy (MRS) during and after cerebral hypoxia-ischaemia (HI) in 15 piglets. We use a previously published computational model of cerebral metabolism in the piglet [1] to integrate these measurements and simulate HI. We successfully simulate changes in cellular metabolism including shifts in intracellular pH observed in the piglet brain during HI. In this process, we optimise physiological parameters in the model identified through sensitivity analysis (such as the rate of glucose metabolism and intracellular lactate concentration), to fit simulated and measured data. The model fits the data reasonably and suggests a 20 % drop in glucose consumption, a ~65 % increase in lactate concentration and ~35 % drop in the cerebral metabolic rate of oxygen (CMRO2) during HI.

Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy.

BACKGROUND: Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy ((31)P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and (31)P metabolite peak-area ratios during and after transient cerebral hypoxia-ischemia (HI) in the newborn piglet. METHODS: Twenty-four piglets (aged<24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~20 min). Whole-brain (31)P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by (31)P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp=exchangeable phosphate pool=Pi+PCr+2γ-NTP+ß-NTP). RESULTS: During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between (31)P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and (31)P ratios 1h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] -0.29 ± 0.50 µM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] -2.41 ± 1.48 µM). CONCLUSIONS: Both lowered Δ[oxCCO] and NTP/epp 1h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and (31)P ratios by 1 h after HI.

Quantitative MRI of colonic mural enhancement: segmental differences exist in endoscopically proven normal colon.

OBJECTIVES: Abnormal contrast enhancement on MRI is advocated as a biomarker for inflammation in colitis, although the enhancement kinetics of normal colon are poorly described. Our purpose was to quantitatively assess mural enhancement in normal colon and test for intersegmental differences. METHODS: Eight patients without prior history of inflammatory bowel disease underwent standard MRI colonography followed by normal same-day colonoscopy. Acquired sequences included a volumetric interpolated breath-hold examination (VIBE) to encompass the whole colonic volume, performed at 5°, 10° and 35° flip angles for T(1) quantitation and then at a fixed 35° flip angle three times prior to and every 30 s following intravenous gadoterate meglumine for 220 s. Ascending colon, descending colon and rectal R(1) (1/T(1)) was plotted against time. Mean pre-contrast R(1), initial change of R(1) (ΔR(1)), early and late "plateau phase" enhancement and the area under the R(1)-time (AUC-R(1)) curve were compared between segments using the Student's paired t-test. RESULTS: There was no significant difference of pre-contrast R(1) between segments (p=0.49 to 0.62). ΔR(1) was higher for ascending colon compared with descending colon (0.0023±0.0012 ms(-1) vs 0.0010±0.0011 ms(-1), p=0.03). There was no significant difference for early or late plateau phase R(1) between colonic segments (p=0.08 to 1.00). AUC-R(1) was greater for ascending than descending colon (0.54±0.19 vs 0.30±0.14, p=0.03). CONCLUSIONS: Intersegmental differences in colonic enhancement are present and should be considered when interpreting differential segmental enhancement.

31-Phosphorus magnetic resonance spectroscopy for dynamic assessment of adenosine triphosphate levels in pancreas preserved by the two-layer method.

Cold preservation injury influences islet graft function. Reliable tools for real-time assessment of pancreas viability before islet isolation are lacking. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) was used immediately after organ harvest to study rat pancreases at 4 °C to 6 °C in five randomized preservation groups: Marshall's solution, static two-layer method (TLM), continuous TLM with oxygen perfused at 0.5 L/min, and static TLM or continuous TLM both the latter following 30 minutes of warm ischemia (WI). (31)P spectra were analyzed for phosphomonoesters, inorganic phosphate (Pi) and α-, ß-and γ-nucleotide triphosphate. Intergroup rates of change of [γ-adenosine triphosphate (ATP)]/[Pi] and [ß-ATP]/[Pi] throughout preservation period were significantly different. For continuous TLM there was an increase relative to baseline (0.043 (SD0.033) h(-1) and 0.029 (0.029) h(-1), respectively) but a decrease for both static TLM (-0.023 (0.016) h(-1) and 0.015 (0.026), P < .001 and < .05, respectively) and Marshall's (-0.049 (0.025) h(-1) and -0.036 (0.019) h(-1), respectively, both P < .001) with respect to continuous TLM. Rate of decrease was similar for the Marshall's and static TLM groups. [γ-ATP]/[Pi] and [ß-ATP]/[Pi] increased with WI continuous TLM (0.008 [0.009] h(-1) and 0.007 [0.008] hr(-1), respectively) but decreased for WI static TLM (-0.018 (0.008) h(-1) and -0.014 (0.004) hr(-1), respectively, P < .001). (31)P-MRS is an effective tool for noninvasive assessment of pancreas bioenergetics. Continuous TLM preserves cellular bioenergetics and is superior to current non-perfluorocar bone based solutions for pancreas preservation.

Progressive multifocal leukoencephalopathy: serial high-b-value diffusion-weighted MR imaging and apparent diffusion coefficient measurements to assess response to highly active antiretroviral therapy.

A patient with human immunodeficiency virus-related posterior fossa progressive multifocal leukoencephalopathy had serial diffusion-weighted imaging using b-values of 1000 and 3000 before and during highly active antiretroviral therapy (HAART). High-b-value images provided a superior definition of the leading edge of the lesion and additional information about the integrity of white matter tracts. Following HAART, there was a marked reduction of lesional apparent diffusion coefficient and reconstitution of anisotropy in the affected middle cerebellar peduncle.

Is the secretion of atrial natriuretic peptide in man under neural control?

AIMS: Previous work has described short-term variation in the circulating plasma level of atrial natriuretic peptide (ANP), but the mechanism remains unknown. Our aim was to investigate the role of cardiac innervation in this variability. METHODS AND RESULTS: Blood samples were obtained from the right atrium via a pulmonary artery flotation catheter every 2 min over a 90 min period. Seven patients who underwent cardiac transplantation by the standard biatrial technique (partial innervation) and ten patients who underwent transplantation by the bicaval technique (total denervation) were studied. ANP levels were measured by radioimmunoassay. The median ANP levels were somewhat higher in the biatrial group compared to the bicaval group [470 (150-1095) vs. 216 (100-605) pg. ml(-1); median (range); P = ns], and both were much higher than normal levels in the pulmonary artery (40 (24, 56) pg ml(-1); median and interquartile range). In both transplant groups circulating plasma ANP levels showed considerable variability. The median number of 'peaks' and 'troughs', as counted by visual inspection, were not significantly different between the two groups. Computer analysis identified 12-16 and 6-15 'pulses' in the biatrial and bicaval group, respectively. Further analysis revealed that pulse amplitude, height and area were significantly higher in the biatrial compared to the bicaval group. CONCLUSION: It would appear that variability of circulating plasma levels of ANP is preserved despite complete or partial cardiac denervation, and so a neural mechanism does not appear to account for such variation.

The utility of pacemaker evoked T wave amplitude for the noninvasive diagnosis of cardiac allograft rejection.

Previous work suggested that pacemaker evoked T wave amplitude (ETWA) may be a sensitive noninvasive marker of cardiac allograft rejection. A Topaz QT sensing rate responsive pacemaker (Vitatron Medical) was implanted at transplantation using epicardial ventricular leads in 45 recipients (35 males; median age 51 years, range 20-63). The median duration of follow-up was 129 days (range 4-327). The ETWA at a paced rate of 100 beats/min was measured daily during hospitalization and at each outpatient attendance (900 readings). Endomyocardial biopsies were at routine intervals or when otherwise clinically indicated (257 biopsies with concurrent ETWA data). There were 58 episodes of rejection > or = grade 3a in 28 patients. The biopsies were classed as either no rejection (grade < 3a) or rejection requiring treatment (grade > or = 3a). The median normalized ETWA was 100.8% (range 24.6-239.7) without rejection and 89.9% (17.0-189.7) with rejection (Mann-Whitney U Test: P = 0.028). The performance of ETWA monitoring as a diagnostic test for the individual recipient was evaluated with exponentially weighted moving average quality control charts. For the diagnosis of all rejection episodes, ETWA monitoring had a sensitivity of 55%, a specificity of 62%, a positive predictive value of 30%, and negative predictive value of 83%. It is concluded that although analysis of pooled data showed a significant reduction in normalized ETWA with biopsy proven rejection, ETWA monitoring requires further refinement to improve sensitivity before it can be considered a clinically useful technique for the non-invasive diagnosis of cardiac allograft rejection in individual recipients.

A prospective randomized trial of complete atrioventricular transplantation versus ventricular transplantation with atrioplasty.

BACKGROUND: The standard technique of ventricular transplantation with atrioplasty (SOHT) distorts atrial anatomy. This may compromise diastolic ventricular function, impair atrioventricular valve competence and elevate resting ANP secretion. In contrast, complete atrioventricular anastomosis (CAVT) preserves atrial geometry. METHODS: We evaluated long term outcome in a prospective randomized trial of CAVT vs. SOHT. The primary outcome measures were peak oxygen uptake, atrioventricular valve regurgitation and ANP secretion. RESULTS: 58 recipients (median age 49 years; range 21-64) were consecutively randomized (29 CAVT; 29 SOHT). There were no differences in total ischaemic time, cardiopulmonary bypass time, postoperative bleeding or immunosuppression. Cardiopulmonary exercise tolerance testing was performed by 29 recipients at 742 to 1825 days. Pulmonary function was equivalent. Peak oxygen consumption expressed as a percentage of predicted maximum was 53.5% with CAVT and 63.8% with SOHT (p = 0.14). Echocardiography was performed on 41 recipients at 944 to 1665 days. There was less tricuspid regurgitation with CAVT (3/22 [13.6%] CAVT vs. 10/19 [52.6%] SOHT; p = 0.019). The incidence of mitral regurgitation was similar (5/22 [22.7%] CAVT vs. 4/19 [21.1%] SOHT; p = 0.803). Resting ANP secretion was assessed in 17 recipients at 1013 to 1812 days. All were hemodynamically stable and none had concurrent rejection. Resting ANP secretion was less with CAVT (CAVT: 283 pg/ml; SOHT: 521.4; p = 0.041). CONCLUSIONS: Peak oxygen consumption was not influenced by implantation technique. However, CAVT reduced the incidence of tricuspid regurgitation and attenuated the elevation in resting ANP secretion.

A clinical pharmacological assessment of doxazosin and enalapril in combination.

This study in 12 normotensive males investigated potential pharmacokinetic and pharmacodynamic interaction mechanisms resulting from the combination of enalapril and doxazosin. Blood pressure reductions were consistently greater with the combination but there was no evidence of a significant pharmacodynamic interaction (as determined by heart rate changes, renal function tests or by pressor responsiveness indices) and there was no evidence of a pharmacokinetic interaction with either drug. Responsiveness to each drug i.e. blood pressure reduction per unit drug concentration was not significantly altered in the combination regimen. In conclusion, these results suggest that the combination of enalapril and doxazosin produces a usefully additive hypotensive effect but there was no evidence of synergism i.e an effect which was more than additive.

The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension.

1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.

A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices.

This study investigated potential therapeutic differences between Amlodipine 5 mg and Felodipine ER 10 mg in 12 normotensive/borderline hypertensive subjects by comparison of the plasma drug concentration-time profiles and the blood pressure and heart rate responses. There was significantly less trough-to-peak variability in plasma drug concentrations with amlodipine with a ratio of 67%, compared to 37% for felodipine. Correspondingly there was less variability with amlodipine in the blood pressure reductions across the dosage interval. Overall, amlodipine displayed a more consistent hypotensive effect across 24 hours and lower blood pressure values at trough, i.e. 24 hours post-dose.

The structural and neurochemical development of the fetal guinea pig retina and optic nerve in experimental growth retardation.

In this study we have examined structural and neurochemical aspects of retinal and optic nerve development in experimentally growth-retarded fetal guinea pigs following maternal unilateral artery ligation. Eye weight (n = 4) and total retinal area (n = 6) at 62 days gestation (term approximately 66 days) were both relatively spared when expressed as a percentage of body weight but in absolute terms were significantly reduced by 18% (P less than 0.001) and 13% (P less than 0.05) respectively when compared with age-matched controls. The numerical density of neurons in the ganglion cell layer was significantly higher at both 52 days (n = 4) and 62 days (n = 4) in growth-retarded fetuses compared with controls. However, there was no difference between the groups in the total number of neurons in this retinal layer at either age, since retinal areas are reduced in growth retardation. The area of neuronal somata in the ganglion and inner nuclear layers was significantly reduced in growth-retarded fetuses compared with controls. There was a concomitant reduction in the width of the cellular layers in the retina and also in the plexiform (synaptic) and photoreceptor layers. The growth of the outer segments of the photoreceptor layer was particularly affected in peripheral retina. The higher packing density of cells and the reduced growth of the plexiform layers suggests a reduction in the growth of the neuropile in growth-retarded fetuses compared with controls. The radial bundling of ganglion cell axons coursing across the retina to enter the optic nerve head was poorly defined in growth retardation. In addition myelination was delayed in the optic nerve with the numerical density of myelinated axons being significantly reduced (P less than 0.005) in growth-retarded fetuses compared with controls. There was a significant reduction (P less than 0.01) in the number of amacrine cells in the inner plexiform layer expressing Substance P-like immunoreactivity in growth-retarded fetuses compared with controls. Glutamate-like immunoreactivity was most intense in the five laminae of the inner plexiform layer and in the outer plexiform layer and less pronounced in photoreceptors, ganglion cells and their axons. There was no qualitative difference in glutamate immunoreactivity between control and growth-retarded fetuses in any of these structures. Thus we have shown that intrauterine growth retardation has specific effects on the development of the fetal guinea pig retina, reducing the growth of several types of neurons and their processes and affecting the expression of the neuropeptide substance-P in amacrine cells.

The contribution of ambulatory blood pressure measurement to the evaluation of new antihypertensive drugs.

Ambulatory blood pressure recording can provide information on blood pressure changes throughout the day and night and during normal daily activities. The former features are of particular use in evaluating the duration of action and dose-response relationships for new antihypertensive drugs, especially those developed for once daily dosing. Improved precision and multiple measurements through the dose interval may reduce the number of patients required in trials. We have recently used ambulatory blood pressure recording to assess the magnitude and duration of the first dose of an angiotensin converting enzyme (ACE) inhibitor, quinapril, compared to placebo. In addition, the effects on blood pressure of long-acting calcium antagonists, alone and in combination, have been measured. Ambulatory blood pressure recording can complement conventional approaches in determining the dose range, frequency of administration and concentration-effect relationships of new and existing antihypertensive drugs.

The response to the first dose of an angiotensin converting enzyme inhibitor in uncomplicated hypertension--a placebo controlled study utilising ambulatory blood pressure recording.

1. The importance of total dose to the initial hypotensive response with an angiotensin converting enzyme inhibitor (quinapril) was assessed using a suggested 'maintenance' dose (20 mg) or matched placebo in a randomised double-blind study in patients with uncomplicated hypertension. 2. Thirty-two patients were recruited who were not on therapy or had not received diuretic therapy in their existing drug treatment in the preceding 4 weeks. Secondary causes of hypertension had previously been excluded and sustained clinic blood pressures of SBP greater than 160 mmHg and/or DBP greater than 90 mmHg were taken as indications for a trial of adjuvant or monotherapy with an ACE inhibitor. 3. After uneventful supervised therapy with quinapril in an open pilot study (n = 5) 27 patients entered a double-blind, randomised, crossover study of quinapril or placebo using ambulatory monitoring to assess BP response. 4. All patients remained asymptomatic and both therapy and monitoring were well tolerated. A smooth onset of antihypertensive effect was noted with an overall 24 h placebo corrected fall in systolic BP of 9.9 mmHg (7.2-12.6 95% CI) and diastolic BP of 6.4 mmHg (4.2-8.8) with no significant effect on heart rate. Individual placebo corrected maximal responses during the first 8 h following quinapril showed a wide range for both systolic (+1.56 to 44.0 mmHg) and diastolic (+2.3 to -35.6 mmHg) pressure. Larger falls tended to be associated with higher baseline pretreatment pressures but in no case did absolute systolic pressure fall below 100 mmHg during the first 8 h following administration of placebo or quinapril.(ABSTRACT TRUNCATED AT 250 WORDS)