The Development of Technology for Effective Respiratory-Gated Irradiation Using an Image-Guided Small Animal Irradiator.

The development of image-guided small animal irradiators represents a significant improvement over standard irradiators by enabling preclinical studies to mimic radiotherapy in humans. The ability to deliver tightly collimated targeted beams, in conjunction with gantry or animal couch rotation, has the potential to maximize tumor dose while sparing normal tissues. However, the current commercial platforms do not incorporate respiratory gating, which is required for accurate and precise targeting in organs subject to respiration related motions that may be up to the order of 5 mm in mice. Therefore, a new treatment head assembly for the Xstrahl Small Animal Radiation Research Platform (SARRP) has been designed. This includes a fast X-ray shutter subsystem, a motorized beam hardening filter assembly, an integrated transmission ionization chamber to monitor beam delivery, a kinematically positioned removable beam collimator and a targeting laser exiting the center of the beam collimator. The X-ray shutter not only minimizes timing errors but also allows beam gating during imaging and treatment, with irradiation only taking place during the breathing cycle when tissue movement is minimal. The breathing related movement is monitored by measuring, using a synchronous detector/lock-in amplifier that processes diffuse reflectance light from a modulated light source. After thresholding of the resulting signal, delays are added around the inhalation/exhalation phases, enabling the "no movement" period to be isolated and to open the X-ray shutter. Irradiation can either be performed for a predetermined time of X-ray exposure, or through integration of a current from the transmission monitor ionization chamber (corrected locally for air density variations). The ability to successfully deliver respiratory-gated X-ray irradiations has been demonstrated by comparing movies obtained using planar X-ray imaging with and without respiratory gating, in addition to comparing dose profiles observed from a collimated beam on EBT3 radiochromic film mounted on the animal's chest. Altogether, the development of respiratory-gated irradiation facilitates improved dose delivery during animal movement and constitutes an important new tool for preclinical radiation studies. This approach is particularly well suited for irradiation of orthotopic tumors or other targets within the chest and abdomen where breathing related movement is significant.

Identifying the independent effect of HbA1c variability on adverse health outcomes in patients with Type 2 diabetes.

AIMS: To characterize the relationship between HbA1c variability and adverse health outcomes among US military veterans with Type 2 diabetes. METHODS: This retrospective cohort study used Veterans Affairs and Medicare claims for veterans with Type 2 diabetes taking metformin who initiated a second diabetes medication (n = 50 861). The main exposure of interest was HbA1c variability during a 3-year baseline period. HbA1c variability, categorized into quartiles, was defined as standard deviation, coefficient of variation and adjusted standard deviation, which accounted for the number and mean number of days between HbA1c tests. Cox proportional hazard models predicted mortality, hospitalization for ambulatory care-sensitive conditions, and myocardial infarction or stroke and were controlled for mean HbA1c levels and the direction of change in HbA1c levels during the baseline period. RESULTS: Over a mean 3.3 years of follow-up, all HbA1c variability measures significantly predicted each outcome. Using the adjusted standard deviation measure for HbA1c variability, the hazard ratios for the third and fourth quartile predicting mortality were 1.14 (95% CI 1.04, 1.25) and 1.42 (95% CI 1.28, 1.58), for myocardial infarction and stroke they were 1.25 (95% CI 1.10, 1.41) and 1.23 (95% CI 1.07, 1.42) and for ambulatory-care sensitive condition hospitalization they were 1.10 (95% CI 1.03, 1.18) and 1.11 (95% CI 1.03, 1.20). Higher baseline HbA1c levels independently predicted the likelihood of each outcome. CONCLUSIONS: In veterans with Type 2 diabetes, greater HbA1c variability was associated with an increased risk of adverse long-term outcomes, independently of HbA1c levels and direction of change. Limiting HbA1c fluctuations over time may reduce complications.

Brain structure and function in patients after metal-on-metal hip resurfacing.

BACKGROUND AND PURPOSE: Hip prostheses that use a metal-on-metal articulation expose the brain to elevated metal concentrations that, in acute excess due to prosthesis malfunction, is associated with neurologic damage, including visual and hearing loss and motor deficits. Here, we examined whether chronic exposure to lower elevated metal levels, typical of well-functioning prostheses, also affects brain structure and function. MATERIALS AND METHODS: We compared brain volumes, metal deposition, and gray matter attenuation by MR imaging and clinical neurologic function in patients 8 years after receiving a metal-on-metal hip resurfacing versus a matched group of patients with the same duration exposure to a conventional hip prosthesis. RESULTS: Twenty-nine patients (25 men; mean, age 59±7 years) after metal-on-metal hip resurfacing and 29 patients (25 men; 59±8 years) after total hip arthroplasty were compared. Whole blood cobalt and chromium concentrations were 5-10 times higher in the metal-on-metal hip resurfacing group (P<.0001). Occipital cortex gray matter attenuation tended to be lower (P<.005 uncorrected, P>.05 corrected), and the optic chiasm area tended to be lower (mean difference, -2.7 mm2; P=.076) in the metal-on-metal hip resurfacing group. Subgroup analyses in 34 patients (17 per group), after exclusion of primary ocular pathology, showed the same trend in gray matter attenuation in the occipital cortex and basal ganglia and a smaller optic chiasm in the metal-on-metal hip resurfacing group (mean difference, -3.9 mm2; P=.048). No other structural or functional differences were found between the groups. CONCLUSIONS: Chronic exposure to metal-on-metal hip resurfacing is associated with subtle structural change in the visual pathways and the basal ganglia in asymptomatic patients.

The Gray Institute 'open' high-content, fluorescence lifetime microscopes.

We describe a microscopy design methodology and details of microscopes built to this 'open' design approach. These demonstrate the first implementation of time-domain fluorescence microscopy in a flexible automated platform with the ability to ease the transition of this and other advanced microscopy techniques from development to use in routine biology applications. This approach allows easy expansion and modification of the platform capabilities, as it moves away from the use of a commercial, monolithic, microscope body to small, commercial off-the-shelf and custom made modular components. Drawings and diagrams of our microscopes have been made available under an open license for noncommercial use at http://users.ox.ac.uk/~atdgroup. Several automated high-content fluorescence microscope implementations have been constructed with this design framework and optimized for specific applications with multiwell plates and tissue microarrays. In particular, three platforms incorporate time-domain FLIM via time-correlated single photon counting in an automated fashion. We also present data from experiments performed on these platforms highlighting their automated wide-field and laser scanning capabilities designed for high-content microscopy. Devices using these designs also form radiation-beam 'end-stations' at Oxford and Surrey Universities, showing the versatility and extendibility of this approach.

Factors affecting nuclear maturation, cleavage and embryo development of vitrified bovine cumulus-oocyte complexes.

The objective was to investigate the effects of cryodevice, vitrification solutions, and equilibration time on in vitro maturation, cleavage, and embryo development of vitrified bovine oocytes. In Experiment 1, the nuclear maturation (MII) rate of immature bovine COCs vitrified was compared between two equilibration times (0 vs 10 min) in vitrification solution 1 (VS1) and two cryodevices (cryotop vs 0.25 mL straw). The MII rate was higher in the non-vitrified control group than in vitrified groups (61 vs 16%, P < 0.0001). Equilibration time did not affect MII rate (P = 0.964); however, the MII rate was higher for COCs vitrified on cryotops than in straws (23 vs 9%, P = 0.007). In Experiment 2, bovine COCs were vitrified on cryotops using two equilibration times (0 vs 5 min) in VS1 and two kinds of vitrification solutions (freshly prepared vs frozen). Cleavage and blastocyst rates were higher (P < 0.0001) in the non-vitrified control group than vitrified groups (cleavage rate 93 vs 42% and blastocysts rate 31 vs 0.4%). Cleavage rate of COCs vitrified using frozen solutions with 5 min equilibration was higher (P = 0.05) than other treatment groups. However, blastocyst rate did not differ (P = 0.993) among treatment groups. In conclusion, cryotop was a better cryodevice than 0.25 mL straw for vitrification of bovine COCs. Furthermore, 5 min equilibration in VS1 improved cleavage. Compared with control, the vitrification procedure per se damaged bovine COCs, resulting in poor nuclear maturation and embryo development. However, vitrification did not immediately kill oocytes, as the cleavage rate was acceptable.

Tracheal intubation of outpatients with and without muscle relaxants.

PURPOSE: To compare intubating conditions and postoperative myalgias in outpatients after intubation with propofol/alfentanil compared with propofol/alfentanil/succinylcholine with and without precurarisation with d-tubocurarine. METHODS: 144 ASA I-II ambulatory patients for dental extraction under anesthesia were studied. Subjects received either 3 mg d-tubocurarine (Group II) or saline (Groups I, III) i.v. prior to induction of anesthesia with 20 microg x kg(-1) alfentanil and 2.5 mg x kg(-1) propofol followed by 1.5 mg x kg(-1) succinylcholine (II and III) or saline 0.9% (I) for muscle relaxation. The ease of airway management and the postoperative incidence, severity and distribution of muscle pains were examined. RESULTS: Intubation was successful in all patients and there were no differences in jaw mobility, ease of bag-mask ventilation, visualization of the vocal cords or cord position. Limb movement was more common during intubation in Group I (37.5%) than in Group III (8.3%) or Group II (2%), P < 0.05. At home, VAS scores for myalgia were higher in Group III than in Group I and II. Neck myalgia was more common in Group II (72%) than in Groups II (44%) and I (41%), P < 0.05. Myalgias were also more common in Group III patients (P < 0.05). CONCLUSION: Acceptable intubating conditions were achieved with propofol and alfentanil alone. Succinylcholine reduced limb movement during intubation but was associated with postoperative myalgias for up to five days. Precurarisation with tubocurarine reduced the severity of succinylcholine myalgia.

Quantitative, low cycle, crack initiation fatigue testing of fine wires and CENELEC standard pacing coil.

Uniaxial fatigue testing was performed on different diameters of fine wires made from MP35N. The fatigue limits of the wires differed from each other based on the diameter of the wire. Multiaxial (shear) fatigue testing was also performed on a benchmark coil used to evaluate the fatigue life of all modern pacemaker leads (the CENELEC standard coil). A computer algorithm was used to quantify the maximum shear stress and strain on the coil. The bend radius, coil diameter, wire diameter, and pitch of the coil all affect the shear stress and strain and therefore the fatigue properties of conductor coils. Based on the analysis presented, it was determined that the portion of the CENELEC standard dealing with fatigue, when used in its present format, is not a valid fatigue test for pacemaker leads.

Inhibition of PS II photochemistry by PAR and UV radiation in natural phytoplankton communities.

The effects of PAR and UV radiation on PS II photochemistry were examined in natural phytoplankton communities from coastal waters off Rhode Island (USA) and the subtropical Pacific. The photochemical energy conversion efficiency, the functional absorption cross section and the kinetics of electron transfer on the acceptor side of PS II were derived from variable fluorescence parameters using both pump and probe and fast repetition rate techniques. In both environments, the natural phytoplankton communities displayed marked decreases in PS II photochemical energy conversion efficiency that were correlated with increased PAR. In the coastal waters, the changes in photochemical energy conversion efficiency were not statistically different for samples treated with supplementary UV-B radiation or screened to exclude ambient UV-B. Moreover, no significant light-dependent changes in the functional absorption cross section of PS II were observed. The rate of electron transfer between QA (-) and QB was, however, slightly reduced in photodamaged cells, indicative of damage on the acceptor side. In the subtropical Pacific, the decrease in photochemical energy conversion efficiency was significantly greater for samples exposed to natural levels of UV-A and/or UV-B compared with those exposed to PAR alone. The cells displayed large diurnal changes in the functional absorption cross section of PS II, indicative of non-photochemical quenching in the antenna. The changes in the functional absorption cross section were highly correlated with PAR but independent of UV radiation. The time course of changes in photochemical efficiency reveals that the photoinhibited reaction centers rapidly recover (within an hour or two) to their preillumination values. Thus, while we found definitive evidence for photoinhibition of PS II photochemistry in both coastal and open ocean phytoplankton communities, we did not find any effect of UV-B on the former, but a clear effect on the latter. The results of this study indicate that the effects of UV-B radiation on phytoplankton photosynthesis are as dependent on the radiative transfer properties of the water body and the mixing rate, as on the wavelength and energy distribution of the radiation and the absorption cross sections of the biophysical targets.

Ketorolac trometamol for postoperative analgesia after orthopaedic surgery.

We have compared the postoperative morphine requirements and analgesic efficacy of four doses of i.m. ketorolac 30 mg administered 6-hourly with placebo in a double-blind study of patients undergoing major or minor orthopaedic surgery. During the 24-h postoperative study period which began at the end of surgery, patients were prescribed i.m. morphine 10 mg as required 2-hourly and assessments were made of pain at 4 and 24 h. After major surgery, the median morphine consumption over 24 h was 10 mg in patients who received ketorolac, compared with 30 mg in those who received placebo (P = 0.008). Visual analogue pain scores and verbal pain assessments were better than placebo at 4 h (P = 0.028 and P = 0.008, respectively), but were not statistically different between the groups at 24 h. Overall assessment of pain was similar in both groups who had undergone major surgery. In the minor surgery groups, median morphine consumption was 0 mg in patients who received ketorolac, compared with 10 mg in those given placebo (ns). Visual analogue pain scores at 24 h after surgery were significantly less in patients who had received ketorolac compared with placebo (P = 0.046) and the overall assessment of pain relief was better in the ketorolac group (P = 0.0007). Mandatory administration of ketorolac appeared to be of benefit in both major and minor orthopaedic surgery, although the principal effects were reduction in requirement for supplementary morphine for major surgery and better overall analgesia for minor surgery.

Baseline assessment. Report of a company wide risk factor survey.

CVD accounts for the highest rates of morbidity and mortality among the general population. Unhealthy lifestyle practices are largely responsible for this occurrence. Risk factor prevalence of smoking, uncontrolled high blood pressure, and high serum cholesterol levels contribute to the likelihood of developing CVD. Two or more of these risk factors can place individuals at higher risk of developing CVD. Completing a heart health survey of risk factor prevalence among a working population will give occupational health professionals a basis on which to set goals and objectives for effective CVD intervention programs.

Postoperative nefopam and diclofenac. Evaluation of their morphine-sparing effect after upper abdominal surgery.

The aim of the study was to assess the relative morphine-sparing effects of nefopam and diclofenac when used singly or in combination after upper abdominal surgery. Eighty-four patients of ASA grade 1 or 2 were allocated randomly to one of three groups. Group A received nefopam 20 mg by intramuscular injection 6 hourly after surgery for the 24-hour study period. Group B received diclofenac 75 mg 12-hourly and placebo injections at 6 and 18 hours after surgery. Group C received both 6-hourly nefopam and 12-hourly diclofenac. Supplemental analgesia was given on demand via a patient-controlled analgesia system which delivered intravenous morphine. Morphine requirements in the diclofenac group were significantly lower than in either of the other groups (p less than 0.01). Patients who received the combination of nefopam and diclofenac required significantly less morphine than those who received nefopam alone (p less than 0.01). Pain scores assessed 6 hours after surgery were significantly lower in the diclofenac and combination groups compared with the nefopam group (p less than 0.01).

Simian scribbles: a reappraisal of drawing in the chimpanzee (Pan troglodytes).

Three chimpanzees (Pan troglodytes) were provided with 18 different stimulus pages for drawing. The resulting 618 drawings were coded for drawn marks, and results were compared with early reports on ape drawing (Morris, 1962; Schiller, 1951) and with more recent systematic studies (Smith, 1973). The findings of the present study confirm Smith's observations of a tendency for the animals to draw closer to the center and toward the bottom of the page. No evidence for perceptual balancing was observed in drawings produced on pages with lateral figures, nor was any evidence for closure apparent with complex figures. The present results agree with earlier findings that chimpanzees will engage in drawing activities without training or reinforcement, and this behavior may reflect their intrinsic interest in exploratory and manipulative play.

Medical student attitudes to computer-assisted learning in anaesthesia.

Two methods of data entry for computer-assisted learning (CAL) programs were assessed and the acceptability of two forms of CAL to 100 medical students determined. Sixty-two per cent preferred keyboard entry of data compared with 26% who preferred the light-pen. There was not preference for dynamic simulation programs over patient management programs. The majority of the students preferred using CAL in groups with a supervisor to provide further explanation when required. Ninety-three per cent of students favoured more teaching using this method.

Microcomputer-based anaesthetic record system.

A system, based on the Apple II microcomputer, has been developed to collect cardiovascular data on-line from a non-invasive arterial pressure monitor. Off-line data are entered as far as possible, with a light pen. All information is stored on disc for subsequent analysis. A coloured trend graph can be displayed on the screen. The trend graph and all the information entered off-line can be printed out at the end of the operation to form a complete anaesthetic record.