Spectroscopy of short-lived radioactive molecules.

Molecular spectroscopy offers opportunities for the exploration of the fundamental laws of nature and the search for new particle physics beyond the standard model1-4. Radioactive molecules-in which one or more of the atoms possesses a radioactive nucleus-can contain heavy and deformed nuclei, offering high sensitivity for investigating parity- and time-reversal-violation effects5,6. Radium monofluoride, RaF, is of particular interest because it is predicted to have an electronic structure appropriate for laser cooling6, thus paving the way for its use in high-precision spectroscopic studies. Furthermore, the effects of symmetry-violating nuclear moments are strongly enhanced5,7-9 in molecules containing octupole-deformed radium isotopes10,11. However, the study of RaF has been impeded by the lack of stable isotopes of radium. Here we present an experimental approach to studying short-lived radioactive molecules, which allows us to measure molecules with lifetimes of just tens of milliseconds. Energetically low-lying electronic states were measured for different isotopically pure RaF molecules using collinear resonance ionisation at the ISOLDE ion-beam facility at CERN. Our results provide evidence of the existence of a suitable laser-cooling scheme for these molecules and represent a key step towards high-precision studies in these systems. Our findings will enable further studies of short-lived radioactive molecules for fundamental physics research.

Isotope Shifts of Radium Monofluoride Molecules.

Isotope shifts of ^{223-226,228}Ra^{19}F were measured for different vibrational levels in the electronic transition A^{2}Π_{1/2}←X^{2}Σ^{+}. The observed isotope shifts demonstrate the particularly high sensitivity of radium monofluoride to nuclear size effects, offering a stringent test of models describing the electronic density within the radium nucleus. Ab initio quantum chemical calculations are in excellent agreement with experimental observations. These results highlight some of the unique opportunities that short-lived molecules could offer in nuclear structure and in fundamental symmetry studies.

The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function.

TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that some mutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating early-to-late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminished mTOR colocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature that may contribute to both pheochromocytoma and RCC pathogenesis.

Progress testing in undergraduate dental education: the Peninsula experience and future opportunities.

BACKGROUND: Progress testing is well established as a longitudinal form of assessment in undergraduate medical programmes to measure growth in knowledge. Peninsula Dental School is the first school to use progress testing and remains the only one to do so. AIMS: To share the experience of developing progress testing in an undergraduate dental programme as a major summative assessment tool at a newly established dental school in the United Kingdom. METHODS: Data were collected for progress tests conducted from 2007 to 14. The tests were formative in the first 2 years of the programme and summative in subsequent years. Each test was based on 100 single best answer multiple-choice items with an appropriate vignette. The students chose their answer from 5 options. A score 1 mark is awarded for each correct answer, minus 0.25 for an incorrect answer and 0 for 'don't know' (DK). The standard setting for each sitting was carried out using Angoff and Hofstee methods. RESULTS: There were two tests per year with each cohort undertaking eight tests in their 4 years of study providing a total 14 test occasions. The reliability of each test for each student cohort tests was measured using Cronbach's alpha. The average reliability over 42 test/cohort combinations was 0.753 (±SD 0.08). Data analyses show growth in knowledge of dental students across successive years with the largest increase in knowledge observed between tests 1 and 5 and concomitant reduction in DK responses. CONCLUSION: This is the first study to report the establishment and use of progress testing as the principle form of written summative testing in an undergraduate dental curriculum. Progress testing is a valid and reliable tool to assess growth in knowledge longitudinally over the duration of a dental programme. Although a labour-intensive process, progress testing merits more widespread use in dental programmes.

Laser spectroscopy of indium Rydberg atom bunches by electric field ionization.

This work reports on the application of a novel electric field-ionization setup for high-resolution laser spectroscopy measurements on bunched fast atomic beams in a collinear geometry. In combination with multi-step resonant excitation to Rydberg states using pulsed lasers, the field ionization technique demonstrates increased sensitivity for isotope separation and measurement of atomic parameters over previous non-resonant laser ionization methods. The setup was tested at the Collinear Resonance Ionization Spectroscopy experiment at ISOLDE-CERN to perform high-resolution measurements of transitions in the indium atom from the [Formula: see text] and [Formula: see text] states to [Formula: see text]p [Formula: see text]P and [Formula: see text]F Rydberg states, up to a principal quantum number of [Formula: see text]. The extracted Rydberg level energies were used to re-evaluate the ionization potential of the indium atom to be [Formula: see text]. The nuclear magnetic dipole and nuclear electric quadrupole hyperfine structure constants and level isotope shifts of the [Formula: see text] and [Formula: see text] states were determined for [Formula: see text]In. The results are compared to calculations using relativistic coupled-cluster theory. A good agreement is found with the ionization potential and isotope shifts, while disagreement of hyperfine structure constants indicates an increased importance of electron correlations in these excited atomic states. With the aim of further increasing the detection sensitivity for measurements on exotic isotopes, a systematic study of the field-ionization arrangement implemented in the work was performed at the same time and an improved design was simulated and is presented. The improved design offers increased background suppression independent of the distance from field ionization to ion detection.

Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome.

CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.

Measurement of haemolysis in patients with prosthetic heart valves.

Haemolysis following prosthetic heart valve insertion can be precisely and sensitively measured by means of a 59Fe ferrokinetic technique. Results obtained in a small series of patients with either Starr-Edwards or Brunwald-Cutter valve replacement are presented.

Changes in the molecular composition of circulating hydroxyethyl starch.

1. Hydroxyethyl starch (HES) of molecular weight 450,000 has been extensively investigated as a plasma volume expander and HES of molecular weight 60,000 has been proposed for use as a cryoprotective agent in the freezing for preservation of red blood cells. In these applications considerable amounts of HES may be injected intravenously and it is therefore desirable to understand its behaviour in vivo.2. After intravenous injection into rabbits, plasma levels of HES and clinical dextrans were determined using anthrone. HES persisted longer in the circulation than did the dextrans.3. HES was recovered from the bloodstream of rabbits and shown by gel filtration to be of a narrower molecular size distribution than the injected material. Smaller molecules were removed, presumably by filtration at the glomerulus. Larger molecules may have been removed by cells of the reticuloendothelial system or possibly through the action of amylase.4. The amylase in saliva was shown to break down HES into molecules of intermediate size with very little production of maltose units.

An evaluation of two methods of laboratory quality control.

Two methods for quality control of automated blood counters have been compared: (1) monitoring results from patients' samples, and (2) analysis of results of a stable whole-blood control. The latter method proved better able to distinguish calibration changes from patient variation.

Automated quality control for the haematology laboratory.

Two simple methods of using sophisticated statistical techniques to analyse intralaboratory quality control data are described. One method uses a plastic grid to assess the cumulative sum (cusum) graph. An equivalent procedure, which may be carried out by a laboratory computer, gives automated on-line quality control of the Coulter S blood counter. The possible development of simple apparatus to carry out the same function is discussed.

Urinary excretion kinetics of hydroxyethyl starch 350/0.60 in normovolaemic man.

Rates of urinary excretion concomitant with the molecular size distribution of filtered polymer fragments were determined in five normovolaemic men dosed with 30 g/m2 BSA of a species of HES (HES 350/0.60) possessing a M-W of 350 000 combined with an MS of 0.60. Approximately 13% of the total injected dose of HES 350/0.60 was excreted in urine 1 hr after dosing, and 45% by 72 hours. Gel filtration of Sepharose CL-4B revealed that aliquots of urine collected 1 hour after injection contained polymer fragments of HES 350/0.60 with values of Kav ranging between 0.88 and 0.84, and possessed a Stokes radius (r = 32A) similar to that of Dextran 20 (M-W 22 700). Polymer fragments of HES 350/0.60 excreted 6 to 48 hours after dosing, however, possessed a Kav ranging between 0.78 and 0.73 with a Stokes radius (r = 45A) similar to that of Dextran 40 (M-W 41 000). All filtered polymer fragments were less polydisperse relative to both the injection solution (Kav 0.60) and residual material recovered from blood immediately after injection (Kav 0.72). These data support the hypothesis that the excretion of HES 350/0.60 occurs in two distinct phases: a rapid phase of elimination dependent on the M-n of the injected solution, and a slower phase dependent on the MS (degree of resistance to alpha-amylase attack). This study, in conjunction with our previous investigation of the changes in circulating HES 350/0.60, define the basic differences between clearance and excretion of the dextrans and of the rapidly degraded species of HES. These data are relevant to the utilisation of HES 350/0.60 during centrifugal leucapheresis.

A system for data processing in haematology.

The data processing problems which arise in the provision of a modern haematology service are discussed in the light of available resources, and the basic requirements of any automated data processing system are defined. The differences between the needs of haematology and those of other pathology specialities are emphasized. A strategy for the development of a simple system which covers data capture, analysis, and retrieval is described. Separation of the short-and long-term functions of the system provides a relatively simple, inexpensive solution which can be modulated to meet the particular circumstances of each laboratory.

Changes in the molecular size distribution and post-transfusion survival of hydroxyethyl starch 350/0.60 as influenced by a lower degree of hydroxyethylation: a study in normal man.

The need to provide a greater rate of colloid clearance from blood than is presently available with the long-acting dosage form of HES 450/0.70 prompted the clinical investigation of a new species of hydroxyethyl starch (HES) possessing a M-w of 350000 concomitant with a molar substitution of 0.60 (HES 350/0.60). The concentration of HES 350/0.60 in serum fell to half its peak value in 10.2 +/- 0.7 (SD) hour (in contrast to an IT50 of approximately 25 hours with HES 450/0.70). Levels of glucose in serum remained elevated in normal fasted subjects after dosing, suggesting that catabolism of the infused HES 350/0.60 was occurring. Hydrolysis of residual HES 350/0.60 was confirmed by Sepharose CL-4B gel filtration analysis of material obtained from serum, showing continual production of smaller molecules relative to the injected solution (in contrast to HES 450/0.70, in which intermediate polymer fragments are recovered). Recovered HES 350/0.60 material displayed a Kav ranging between 0.74 and 0.72 and possessed a Stokes radius (r = 45A) similar to that of dextran 40 (M-w 41000). HES 350/0.69 appears to offer the same advantages as the currently available long-acting HES 450/0.70 but is removed from blood approximately twice as rapidly. This more rapid hydrolysis of HEs 350/0.60 may be useful, for example, in avoiding cumulative build-up of colloid in the blood of normal donors undergoing consecutive leucapheresis procedures.

Post-transfusion survival of hydroxyethyl starch 450/0.70 in man: a long-term study.

Intravascular persistence concomitant with changes occurring in the circulating molecular size distribution were determined in five healthy normovolaemic men dosed with 7 ml/kg of a 6% (w/v) solution of a species of hydroxyethyl starch (HES 450/0.70) possessing a M(w)- of 450 000 daltons combined with a molar hydroxyethyl group substitution (MS) of 0.70 (70 hydroxyethyl groups/100 glucose residues). The concentration of HES 450/0.70 in serum fell to 24% of its peak value (measured 2 minutes post injection) one week after the infusion. By 17 weeks after injection, < 1.0% remained in the intravascular space. The HES 450/0.70 material recovered from the bloodstream 2 minutes after injection was shown by gel filtration on a column of Sepharose CL-4B to be less polydisperse than the injected solution. The K(av) calculated for the peak of material eluted after one week showed a definite shift of molecular size toward that of a lower molecular weight composition. However, at four weeks the value of K(av) indicated a shift toward the high molecular weight region of the injected solution, and by seven weeks this movement was quite pronounced. These data clearly indicate the complex nature of the removal of HES 450/0.70 from the intravascular space of man and appear to substantiate previous clinical studies reporting that the MS plays the major role influencing the rate of elimination of this material from the bloodstream.

The distribution of leukaemia in association with domestic water quality in south west England.

This study assessed whether there is any variation in the incidence of haematological malignancies between geographical areas of differing water supplies in the South West peninsula of the United Kingdom (1984 to 1988 inclusive). The possibility of correlations existing between variation in water quality and variation in the incidence of haematological malignancies was examined. Haematological incidence data, taken from the Leukaemia Research Fund's Data Collection Study, were mapped into 46 geographical areas of differing water supply. The distribution of the mapped cases was then tested for homogeneity using the Potthoff and Whittinghill (1966) test score. The age-adjusted incidence ratios calculated during the heterogeneity testing were examined for correlations with water quality indicators using correlation and stepwise regression. Significant heterogeneity in the incidence rates among water supply areas was observed for two groups of disease-acute leukaemias and myeloproliferative disorders. Three water quality indicators-pH, nitrate concentration and aluminium concentration-varied considerably over the study period. Significant correlations were observed between the standardized incidence ratios of five disease categories and some water quality indicators, especially aluminium and trihalomethane concentrations. The standardized incidence ratios of some haematological malignancies differed between geographical areas of water supply in South West England, and the evidence suggests that this variation may be associated with variation in water quality indicators. Although this lends support to similar findings in the United States of America, the pattern of correlations are affected by disease latency and statistical methodology.

Analysis and purification of eugenol.

The purity of several brands of eugenol was compared by using high performance liquid chromatography with a UV detector. Greater than 95% of the impurities seen in the USP eugenols were removed by preparative liquid chromatography. NMR spectroscopy suggests that there may be a difference in chemical reactivity between purified and stock eugenol.

Residence of college students affects dietary intake, physical activity, and serum lipid levels.

OBJECTIVE: Dietary intake, physical activity, and serum lipid levels of college students living on and off campus were compared. DESIGN: Subjects completed a questionnaire regarding lifestyle factors and a 3-day food record. Lipid levels were determined. SUBJECTS: College students enrolled in an introductory nutrition class. MAIN OUTCOME MEASURES: Energy and nutrient intakes and serum lipid levels. STATISTICAL ANALYSES PERFORMED: Analysis of variance and Student's t tests were used to determine differences in energy and nutrient intakes and serum lipid levels between men and women living on and off campus; chi 2 analysis was used to determine whether there were associations between residence and lifestyle factors; stepwise multiple regression analysis was used to investigate relationships among serum lipid levels, nutrient intakes, and exercise levels. RESULTS: Of the 104 participants, 81% were women and 19% were men; 51% lived on campus. In women, there was a statistically significant difference in age based on residence. Reported percentage of energy from protein was significantly higher in subjects living off campus. Serum triglyceride level and the ratio of total cholesterol to high-density lipoprotein were also significantly higher in students living off campus. APPLICATIONS/CONCLUSIONS: Residence may affect serum lipid levels; living arrangements influence lifestyle factors such as food choices, nutrient content of the diet, and activity patterns. University foodservice directors are challenged to offer low-fat foods that students will choose to eat. Nutrition education is important for all students because their lifestyle may predispose them to development of chronic disease.

Fat preferences, dietary fat intake and body composition in children.

OBJECTIVE: To examine the relationship between fat preference, dietary intake data and body composition in children. SUBJECT AND METHODS: Subjects studied were 88 children aged 9-12 y from two elementary schools in Ohio. Measures for dietary intake and body composition were obtained by 3 day diet records, anthropometrics, triceps and subscapular skinfolds. Fat preference data was assessed by hedonic rating of high and low fat snack foods. RESULTS: Data indicate that children who preferred the high fat snack items had high dietary fat intakes (r = 0.57, P < 0.05). Tricep skinfold measurement and BMI correlated positively with high fat food preferences (r = 0.51 and r = 0.46 P < 0.05). CONCLUSIONS: These data suggest preference for high fat foods may occur due to diet composition and that increased adiposity may be associated with higher relative fat intakes.

Age-related temporal processing speed deterioration in auditory cortex.

A common problem among the elderly is a difficulty in discriminating speech sounds. One factor that may contribute to this is a deterioration in the ability to process dynamic aspects of speech such as formant transitions. For the aging auditory system, this deterioration in temporal processing speed may be manifest as a deficit in encoding time-varying sounds that contain rapidly changing frequencies such as formant transitions. The primary goal of this study was to explore the neural basis of the effects of aging on temporal processing speed. To this end, single units were recorded from the auditory cortex of young and aged rats in response to frequency-modulated (FM) sweeps that changed from trial to trial in both direction and speed. Results showed that the majority of cells recorded from young rats responded most vigorously to fast and medium speeds. By contrast, the majority of units recorded from aged animals responded best to slow speeds. For preferred direction of FM sweep, similar results were observed for both age groups, namely, approximately half of the units exhibited a direction-selective response. The results of the present study demonstrate an age-related decrease in the rate of change of frequency that can be processed by the auditory cortex.

Responses to time-varying stimuli in rat auditory cortex.

Responses to frequency modulated (FM) sweeps were recorded in rat primary auditory cortex. Forty-four percent of the cells were direction-selective. For speed selectivity, the majority of the cells preferred faster sweeps. The results suggest that rat auditory cortex may be used for processing communication signals of their predators or for detecting spectral changes in acoustic signals.