Suppression of Emittance Growth Using a Shaped Cold Atom Electron and Ion Source.

We demonstrate precise control of charged particle bunch shape with a cold atom electron and ion source to create bunches with linear and, therefore, reversible Coulomb expansion. Using ultracold charged particles enables detailed observation of space-charge effects without loss of information from thermal diffusion, unambiguously demonstrating that shaping in three dimensions can result in a marked reduction of Coulomb-driven emittance growth. We show that the emittance growth suppression is accompanied by an increase in bunch focusability and brightness, improvements necessary for the development of sources capable of coherent single-shot ultrafast electron diffraction of noncrystalline objects, with applications ranging from femtosecond chemistry to materials science and rational drug design.

Detailed observation of space-charge dynamics using ultracold ion bunches.

Control of Coulomb expansion in charged particle beams is of critical importance for applications including electron and ion microscopy, injectors for particle accelerators and in ultrafast electron diffraction, where space-charge effects constrain the temporal and spatial imaging resolution. The development of techniques to reverse space-charge-driven expansion, or to observe shock waves and other striking phenomena, have been limited by the masking effect of thermal diffusion. Here we show that ultracold ion bunches extracted from laser-cooled atoms can be used to observe the effects of self-interactions with unprecedented detail. We generate arrays of small closely spaced ion bunches that interact to form complex and surprising patterns. We also show that nanosecond cold ion bunches provide data for analogous ultrafast electron systems, where the dynamics occur on timescales too short for detailed observation. In a surprising twist, slow atoms may underpin progress in high-energy and ultrafast physics.

High-coherence picosecond electron bunches from cold atoms.

Ultrafast electron diffraction enables the study of molecular structural dynamics with atomic resolution at subpicosecond timescales, with applications in solid-state physics and rational drug design. Progress with ultrafast electron diffraction has been constrained by the limited transverse coherence of high-current electron sources. Photoionization of laser-cooled atoms can produce electrons of intrinsically high coherence, but has been too slow for ultrafast electron diffraction. Ionization with femtosecond lasers should in principle reduce the electron pulse duration, but the high bandwidth inherent to short laser pulses is expected to destroy the transverse coherence. Here we demonstrate that a two-colour process with femtosecond excitation followed by nanosecond photoionization can produce picosecond electron bunches with high transverse coherence. Ultimately, the unique combination of ultrafast ionization, high coherence and three-dimensional bunch shaping capabilities of cold atom electron sources have the potential for realising the brightness and coherence requirements for single-shot electron diffraction from crystalline biological samples.

Non-iterative imaging of inhomogeneous cold atom clouds using phase retrieval from a single diffraction measurement.

We demonstrate a new imaging technique for cold atom clouds based on phase retrieval from a single diffraction measurement. Most single-shot diffractive imaging methods for cold atoms assume a monomorphic object to extract the column density. The method described here allows quantitative imaging of an inhomogeneous cloud, enabling recovery of either the atomic density or the refractive index, provided the other is known. Using ideas borrowed from density functional theory, we calculate the approximate paraxial diffracted intensity derivative from the measured diffracted intensity distribution and use it to solve the Transport of Intensity Equation (TIE) for the phase of the wave at the detector plane. Back-propagation to the object plane yields the object exit surface wave and then provides a quantitative measurement of either the atomic column density or refractive index. Images of homogeneous clouds showed good quantitative agreement with conventional techniques. An inhomogeneous cloud was created using a cascade electromagnetically induced transparency scheme and images of both phase and amplitude parts of refractive index across the cloud were separately retrieved, showing good agreement with theoretical results.

Liquorice and soy sauce, a life-saving concoction in a patient with Addison's disease.

Addison's disease is a relatively common disorder to endocrinologists, but is rare and potentially fatal when presenting acutely. Treatment now involves replacement of glucocorticoids and mineralocorticoids with synthetic compounds, although historically patients took common salt and plant-based preparations. We describe the case of a 42-year-old woman who self-treated undiagnosed Addison's disease for several years with soy sauce and liquorice sticks. She presented with a four-week history of decreased energy, malaise and postural dizziness. Our patient described an unusual diet of liquorice sticks and soy sauce, consuming around 46 g of salt per week. There was a family history of Type 1 diabetes mellitus. Physical examination was unremarkable, although subsequent investigation confirmed Addison's disease. Liquorice provided glycyrrhizic acid and glycyrrhetinic acid, which act on 11-beta hydroxysteroid dehydrogenase enzymes. In this case, the net effect was potentiation of glucocorticoid action on renal mineralocorticoid receptors in the context of failing adrenocortical steroid production. The case highlights the importance of taking a dietary history to aid diagnosis.

Best practice in primary care pathology: review 10.

This tenth best practice review examines four series of common primary care questions in laboratory medicine: (i) antenatal testing in pregnant women; (ii) estimated glomerular filtration rate calculation; (iii) safety testing for methotrexate; and (iv) blood glucose measurement in diabetes. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence-based. They will be updated periodically to take account of new information.

Screening for diabetic retinopathy: a cause for concern in people who drive.

AIMS: To report a case of a road traffic accident in a lady driving home from a diabetes clinic after pupillary dilatation. We also present the findings of a questionnaire survey of health professionals to elicit their practice in dealing with such patients. METHODS: We present the case report of a lady having a road traffic accident on her way back from a retinal screening appointment after having had pupillary dilatation. A subsequent postal questionnaire survey was undertaken to find out current practice in screening patients who drive on the day of their retinal screening. RESULTS: A lady was involved in a road traffic accident whilst returning home after retinal screening. Her motor insurance company refused to cover subsequent claims for damage because her pupils had been dilated. She was also prosecuted by the police for driving without valid motor insurance. We conducted a postal survey of 500 health care workers including ophthalmologists, optometrists, diabetologists and general practitioners regarding the use of dilating drops in people with diabetes who intend to drive. Analysis of 320 valid responses confirmed that there is no consistent practice with regard to either the use of dilating drops in drivers or in ensuring that arrangements are made for subsequent adequate visual inspection in those whom dilatory drops are not instilled. CONCLUSIONS: Guidelines, for use by health care professionals and people with diabetes, are clearly required regarding the use of pupillary dilating drops in drivers.

The effectiveness of a primary-care-based diabetes education service.

The efficacy of structured education for 158 Type 2 diabetic patients in primary care (80 male, mean age 63 yr, median diabetes duration 3 yr) was assessed with respect to change in knowledge of diabetes, weight, and haemoglobin A1 over a 6-month period. The programme supplemented a primary care initiative in our semi-rural population. Teaching was carried out by a Diabetes Nurse Educator within primary care health centres (141 patients) and a hospital diabetes clinic (17 patients). For all patients mean baseline questionnaire score (maximum possible 12) was 6.2 rising after the programme to 10.5 (p < 0.01). At 6 months mean score fell to 9.5 (p < 0.01 compared to end of the programme), but still significantly better than baseline (p < 0.01). For patients on the primary-care-based programme mean haemoglobin A1 at baseline was 10.7% (normal range 6%-9%) decreasing after 6 months to 9.6% (p < 0.01). No significant changes were found in mean weight. Unlike many previous studies, these results demonstrate a highly beneficial effect not only on knowledge but also on metabolic control in patients who received their education in the primary-care setting. These results have obvious implications for patients residing in rural or semi-rural populations.

Glucose turnover in compensated hepatic cirrhosis.

Glucose turnover and recycling from glucose derived 3-carbon intermediates were examined in overnight fasted patients with compensated hepatic cirrhosis and in age- and weight-matched normal control subjects. Fasting blood concentrations of glucose, lactate and glycerol were similar in both groups but blood pyruvate (60 +/- 10 vs. 80 +/- mumol/l, P less than 0.05), blood alanine (0.23 +/- 0.02 vs 0.34 +/- 0.02 mmol/l, P less than 0.01) were decreased and serum insulin increased (19 [13-24]v 7 [4-11] mU/l, P less than 0.01) in cirrhotic subjects. Absolute glucose turnover, assessed by analysis of decay of [3H]-3-glucose specific activity was decreased in cirrhotic patients (8.1 +/- 0.6 v 12.1 +/- 0.7 mol/kg-1 min-1). Glucose "recycling", assessed by the difference between absolute glucose turnover and that given by [14C]-1-glucose data, was normal in cirrhotic patients suggesting that Cori cycle (glucose-lactate-glucose) activity was normal. These data support previous findings of decreased peripheral glucose utilisation and insulin resistance in cirrhotic patients.

A trial of the calcium antagonist nisoldipine in hypertensive non-insulin-dependent diabetic patients.

The antihypertensive and metabolic effects of a new calcium antagonist nisoldipine (10 to 20 mg at night) were investigated in 14 mild to moderately hypertensive non-insulin-dependent diabetic patients (median age 62, range 50-70 years). In a 12-week placebo controlled single blind study, sitting and standing blood pressure were significantly lowered (p less than 0.001). Heart rate was unchanged as were blood urea, creatinine, bilirubin, mmol/l (mean +/- SEM) and uric acid concentrations. Plasma sodium levels fell during active therapy (142 +/- 0.5 mmol/l (mean +/- SEM) versus 139 +/- 0.5 (p less than 0.001) and remained lower during the washout period. Plasma calcium concentrations increased during nisoldipine therapy (2.41 +/- 0.02 versus 2.51 +/- 0.03 mmol/l, p less than 0.001) and returned towards baseline during the washout period. Plasma ionized calcium concentrations showed similar changes but plasma sodium and calcium remained within the normal laboratory ranges in all patients at all times. Serum triglyceride concentrations fell (placebo 1.9 +/- 0.02 mmol/l vs nisoldipine 1.6 +/- 0.2, p less than 0.05), but fasting cholesterol was unchanged. Fasting blood glucose, and the blood glucose response to oral glucose challenge (75 g) showed no differences though HbA1 concentrations fell (10.6 +/- 0.7 versus 9.2 +/- 0.05%, p less than 0.05) and tended to rise when the drug was withdrawn. Haemoglobin concentrations also fell during active therapy (14.7 +/- 0.4 vs 14 +/- 0.32 g/dl p less than 0.001) and also remained lower after the washout period (13.9 +/- 0.03 g/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of 3 methods for assessing insulin sensitivity in subjects with normal and abnormal glucose tolerance.

The euglycaemic clamp, insulin sensitivity test with somatostatin, and insulin sensitivity test without somatostatin, were compared as in vivo methods of assessing insulin sensitivity. Fifteen subjects with varying degrees of glucose tolerance were studied. Somatostatin was not found to influence the assessment of insulin sensitivity by the insulin sensitivity test. When glucose disposal was expressed as metabolic clearance rate significant strong correlations were found between the euglycaemic clamp technique and the insulin sensitivity test with (r = 0.90) and without (r = 0.83) somatostatin. The effects of the tests on intermediary metabolism were also similar, and all 3 tests showed a similar impairment of insulin sensitivity in subjects with abnormal glucose tolerance. The insulin sensitivity test without somatostatin thus provides a simple and economical tool for studying insulin sensitivity.

Insulin secretion, adipocyte insulin binding and insulin sensitivity in thyrotoxicosis.

The pattern of insulin secretion following an oral glucose load and the insulin receptor status and insulin sensitivity of adipocytes have been studied in patients with thyrotoxicosis and in matched controls. Thyrotoxic subjects showed normal basal and peak levels of serum immunoreactive insulin (peak, 69.0 +/- 6.8 vs 54.3 +/- 8.8 mU/l) and serum C-peptide (peak, 1.95 +/- 0.13 vs 1.71 +/- 0.12 nmol/l for thyrotoxic and control subjects, respectively). Peak serum proinsulin was higher in the thyrotoxic group (64.8 +/- 7.3 vs 39.0 +/- 3.7 pmol/l; P less than 0.01). Maximum specific insulin binding to adipocytes was decreased in the thyrotoxic group (1.80 +/- 0.18 vs 2.62 +/- 0.27%; P less than 0.025) and half-maximum displacement of tracer insulin was similar in the two groups, suggesting that reduced receptor number rather than reduced affinity accounted for the difference. However, adipocyte insulin sensitivity was normal as judged by half-maximal stimulation values of 13.9 +/- 3.6 vs 11.4 +/- 2.1 pmol/l, respectively for lipogenesis and 24.3 +/- 2.2 vs 24.6 +/- 3.6 pmol/l, respectively for glucose transport. Hence, thyroid hormone excess appears to affect adipocyte insulin receptor number directly, but change in receptor number is not associated with change in adipocyte insulin sensitivity in hyperthyroidism. The normal insulin secretion together with the failure to demonstrate abnormal insulin sensitivity of one of the major peripheral tissues suggests that disturbed hepatic rather than peripheral insulin responsiveness may be responsible for the glucose intolerance of hyperthyroidism.

The effect of vasopressin infusion on glucose metabolism in man.

Studies on intact animals and isolated rat hepatocytes have shown that arginine vasopression (AVP) stimulates glycogen phosphorylase to break down glycogen and raise plasma glucose concentrations. Since no similar work has been performed on healthy human adults, the effect of moderate (25 pmol/min) and high (75 pmol/min) dose AVP infusion on plasma glucose, intermediary metabolites, glucose kinetics, and circulating glucagon and insulin concentrations was investigated. After AVP infusion, plasma glucose rose from 4.9 +/- 0.1 to a peak of 5.7 +/- 0.2 mmol/l (P less than 0.001), but no changes in blood lactate, pyruvate, alanine, glycerol or 3-hydroxybutyrate concentrations were observed. The glucose rise was accounted for entirely by an increase in the rate of appearance of glucose from 11.19 +/- 0.43 to 13.38 +/- 0.63 mu mol/kg/min (P less than 0.001). Infusion of AVP also increased plasma glucagon concentrations from 38 +/- 8 to 79 +/- 20 pg/l (P less than 0.01). The hyperglycaemic effect of AVP may be mediated solely by stimulation of glucagon release, but we cannot exclude direct stimulation of glycogen phosphorylase activity.

Enhanced gluconeogenic capacity from glycerol in hyperthyroid man: evidence in favour of a beta-adrenergic mechanism.

We have previously shown that gluconeogenesis, assessed by glycerol clearance, is increased in hyperthyroid man. The mechanism underlying this change is uncertain but many of the metabolic changes found in hyperthyroidism are thought to be due to increased catecholamine sensitivity of peripheral tissues. To test the hypothesis that enhanced gluconeogenic capacity from glycerol in hyperthyroidism might be mediated via a beta-adrenergic mechanism we have estimated glycerol clearance in thyrotoxic subjects before and during treatment with a non-selective beta-adrenergic blocking drug propranolol (Inderal LA). Control subjects of similar age and weight were also tested. In hyperthyroid subjects, blood glucose and blood glycerol concentrations were increased but blood lactate, pyruvate and alanine concentrations were normal. Glycerol clearance was increased and followed a double exponential decay with a shortened second component half-time. Endogenous glycerol production was increased three fold. Following beta-blockade blood glucose and blood glycerol concentrations fell although blood glucose concentrations remained above normal values. Glycerol clearance and endogenous glycerol production were also decreased but remained significantly higher than in control subjects. Serum thyroxine and serum triiodothyronine concentrations showed no significant change although mean values fell by 10% and 17% respectively. We conclude that the increase in gluconeogenic capacity from glycerol in hyperthyroid subjects is mediated in part by a beta-adrenergic mechanism.