Rydberg-Dressed Magneto-optical Trap.

We propose and demonstrate the laser cooling and trapping of Rydberg-dressed Sr atoms. By off-resonantly coupling the excited state of a narrow (7 kHz) cooling transition to a high-lying Rydberg state, we transfer Rydberg properties such as enhanced electric polarizability to a stable magneto-optical trap operating at <1 µK. Simulations show that it is possible to reach a regime where the long-range interaction between Rydberg-dressed atoms becomes comparable to the kinetic energy, opening a route to combining laser cooling with tunable long-range interactions.

Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial.

AIMS: To evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D). METHODS: We conducted a randomized crossover study comparing closed-loop therapy with standard prandial insulin boluses versus closed-loop therapy with prandial boluses reduced by 25%. Eight adolescents with T1D [3 males; mean (standard deviation) age 15.9 (1.5) years, glycated haemoglobin 74 (17) mmol/mol; median (interquartile range) total daily dose 0.9 (0.7, 1.1) IU/kg/day] were studied on two 36-h-long visits. In random order, subjects received closed-loop therapy with either standard or reduced insulin boluses administered with main meals (50-80 g carbohydrates) but not with snacks (15-30 g carbohydrates). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd). RESULTS: The median (interquartile range) time spent in target (3.9-10 mmol/l) was similar between the two interventions [74 (66, 84)% vs 80 (65, 96)%; p = 0.87] as was time spent above 10 mmol/l [21.8 (16.3, 33.5)% vs 18.0 (4.1, 34.2)%; p = 0.87] and below 3.9 mmol/l [0 (0, 1.5)% vs 0 (0, 1.8)%; p = 0.88]. Mean plasma glucose was identical during the two interventions [8.4 (0.9) mmol/l; p = 0.98]. Hypoglycaemia occurred once 1.5 h post-meal during closed-loop therapy with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9 (55.2, 75.0) vs 72.5 (63.6, 80.3) IU; p = 0.01] and resulted in lower mean plasma insulin concentration [186 (171, 260) vs 252 (198, 336) pmol/l; p = 0.002]. Lower plasma insulin was also documented overnight [160 (136, 192) vs 191 (133, 252) pmol/l; p = 0.01, pooled nights]. Ra_total was similar [26.3 (21.9, 28.0) vs 25.4 (21.0, 29.2) µmol/kg/min; p = 0.19] during the two interventions as was Rd [25.8 (21.0, 26.9) vs 25.2 (21.2, 28.8) µmol/kg/min; p = 0.46]. CONCLUSIONS: A 25% reduction in prandial boluses during closed-loop therapy maintains similar glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with a 25% reduction in prandial boluses would prevent postprandial hypoglycaemia.

Metabolic effects of intensive insulin therapy in critically ill patients.

Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7-9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4-6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU . kg(-1).min(-1) plus insulin requirement from study 1), BG of 7-9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU.kg(-1).min(-1) plus insulin requirement from study 1), BG of 4-6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 (P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI (P < 0.01) and HI (P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (R(a)), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose R(a) and lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI (P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7-9 mmol/l is sufficient to limit lipolysis and endogenous glucose R(a) and increase glucose R(d). Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.

Leucine-enriched essential amino acid supplementation in mechanically ventilated trauma patients: a feasibility study.

BACKGROUND: Critically ill patients lose up to 2% of muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. METHODS: A randomised feasibility study was performed over six months in intensive care (ICU). Patients received 5 g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) for up to 14 days. C-reactive protein, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz and Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness were measured sequentially. RESULTS: Eight patients (9.5% of screened patients) were recruited over six months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC sum score could not be performed as patients were not able to respond to the screening questions. The Katz and Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future randomised controlled trial. CONCLUSION: L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN79066838 . Registered on 25 July 2012.

Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study.

BACKGROUND/OBJECTIVE: Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy). SUBJECTS/METHODS: Sixteen participants were randomised to 4 g/day EPA+DHA (n=8) or placebo (n=8) for 15-18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers (2H2O and [U13C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention). RESULTS: Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13C from dietary fat into plasma 3-hydroxybutyrate (all P<0.05). CONCLUSIONS: The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.

Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study.

This corrects the article DOI: 10.1038/ejcn.2017.9.

Measurement of hepatic insulin sensitivity early after the bypass of the proximal small bowel in humans.

OBJECTIVE: Unlike gastric banding or sleeve gastrectomy procedures, intestinal bypass procedures, Roux-en-Y gastric bypass in particular, lead to rapid improvements in glycaemia early after surgery. The bypass of the proximal small bowel may have weight loss and even caloric restriction-independent glucose-lowering properties on hepatic insulin sensitivity. In this first human mechanistic study, we examined this hypothesis by investigating the early effects of the duodeno-jejunal bypass liner (DJBL; GI Dynamics, USA) on the hepatic insulin sensitivity by using the gold standard euglycaemic hyperinsulinaemic clamp methodology. METHOD: Seven patients with obesity underwent measurement of hepatic insulin sensitivity at baseline, 1 week after a low-calorie liquid diet and after a further 1 week following insertion of the DJBL whilst on the same diet. RESULTS: Duodeno-jejunal bypass liner did not improve the insulin sensitivity of hepatic glucose production beyond the improvements achieved with caloric restriction. CONCLUSIONS: Caloric restriction may be the predominant driver of early increases in hepatic insulin sensitivity after the endoscopic bypass of the proximal small bowel. The same mechanism may be at play after Roux-en-Y gastric bypass and explain, at least in part, the rapid improvements in glycaemia.

Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance But Not VLDL Production in NAFLD.

CONTEXT: Randomized controlled trials in nonalcoholic fatty liver disease (NAFLD) have shown that regular exercise, even without calorie restriction, reduces liver steatosis. A previous study has shown that 16 weeks of supervised exercise training in NAFLD did not affect total very low-density lipoprotein (VLDL) kinetics. OBJECTIVE: The objective of the study was to determine the effect of exercise training on intrahepatocellular fat (IHCL) and the kinetics of large triglyceride (TG)-rich VLDL1 and smaller denser VLDL2, which has a lower TG content. DESIGN: This was a 16-week randomized controlled trial. PATIENTS: A total of 27 sedentary patients with NAFLD participated in the trial. INTERVENTION: The intervention was composed of supervised exercise with moderate-intensity aerobic exercise or conventional lifestyle advice (control). MAIN OUTCOME: VLDL1 and VLDL2-TG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes before and after the intervention. RESULTS: In the exercise group, maximal oxygen uptake increased by 31% ± 6% (mean ± SEM) and IHCL decreased from 19.6% (14.8%, 30.0%) to 8.9% (5.4%, 17.3%) (median [interquartile range]) with no significant change in maximal oxygen uptake or IHCL in the control group (change between groups, P < .001 and P = .02, respectively). Exercise training increased VLDL1-TG and apoB fractional catabolic rates, a measure of clearance, (change between groups, P = .02 and P = .01, respectively), and VLDL1-apoB production rate (change between groups, P = .006), with no change in VLDL1-TG production rate. Plasma TG did not change in either group. CONCLUSION: An increased clearance of VLDL1 may contribute to the significant decrease in liver fat after 16 weeks of exercise in NAFLD. A longer duration or higher-intensity exercise interventions may be needed to lower the plasma TG and VLDL production rate.

Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM.

In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.

The effect of recombinant human growth hormone on glucose and leucine metabolism in Cushing's syndrome.

Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P < 0.005 and P < 0.001), C peptide (P < 0.01 and P < 0.005), insulin-like growth factor I (P < 0.001), and glucose concentrations (P < 0.01 and P < 0.005) and a decrease in the leucine concentration (P < 0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P < 0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P < 0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.

Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Eletriptan Steering Committee.

OBJECTIVE: To compare the efficacy, safety, and tolerability of oral eletriptan (20 mg, 40 mg, and 80 mg) with that of oral sumatriptan (100 mg) and placebo for the acute treatment of migraine. BACKGROUND: Eletriptan is a potent and selective agonist at human recombinant 5HT1B/1D receptors, with efficacy in animal models that predict antimigraine activity. In healthy volunteers, the pharmacokinetics of eletriptan are characterized by linear and rapid oral absorption. METHODS: Randomized, double-blind, parallel-group study conducted in 857 outpatients with a diagnosis of migraine according to the International Headache Society (IHS) criteria. Of these, 692 took study medication for one acute migraine attack and provided on-drug efficacy data. Subjects received either placebo, 100 mg of sumatriptan or 20 mg, 40 mg, or 80 mg of eletriptan for the treatment of an acute migraine attack. The primary endpoint was the percentage of patients with a headache response (improvement in pain intensity from moderate or severe to mild or none) at 2 hours after treatment. RESULTS: At the primary endpoint (2 hours after dosing), headache response rates were 24% (30/126) for placebo; 55% (63/115) for sumatriptan, 100 mg; 54% (70/129) for eletriptan, 20 mg; 65% (76/117) for eletriptan, 40 mg; and 77% (91/118) for eletriptan, 80 mg. There was a difference compared with placebo (p<0.001) for all doses of eletriptan, and at 2 hours there was a difference between sumatriptan, 100 mg, and eletriptan, 80 mg (p<0.001). Headache-free rates at 2 hours were superior to placebo (6%; p<0.001) for both the 80-mg dose of eletriptan (37%) and the 40-mg dose (29%), with the 80-mg dose also being superior to 100 mg of sumatriptan (23%; p<0.05). Eletriptan and sumatriptan were well tolerated, and the majority of adverse events were mild or moderate in intensity and transient. CONCLUSION: In this placebo-controlled trial, eletriptan, at selected doses, demonstrated superior efficacy, onset of action and patient acceptability in the acute treatment of migraine when compared with oral sumatriptan and placebo.

Efficacy of a new calcium antagonist PN 200-110 (isradipine) in angina pectoris.

Angina pectoris is one of the major syndromes against which to test the therapeutic effectiveness of any new calcium antagonist. An interim analysis of the efficacy and safety of a new dihydropyridine calcium antagonist (PN 200-110 [isradipine]) in patients with confirmed coronary artery disease is reported. The study was carried out in 3 centers; 50 patients of an anticipated 96 have completed the double-blind comparative phases in 3 separate studies. Preliminary results from the placebo-controlled study indicate that PN 200-110 was significantly more effective than placebo in reducing the anginal attack rate and glyceryl trinitrate consumption in the 15 patients so far enrolled. Dose-response comparisons against nifedipine in 21 patients and against isosorbide dinitrate in 14 patients demonstrate that PN 200-110 has a similar antianginal efficacy profile to both drugs. No significant change in any of the monitored safety factors was noted in any of the patients taking PN 200-110. The side-effects profile compared favorably with that of nifedipine. These interim results suggest that PN 200-110 will prove to be an effective and safe drug for the treatment of angina pectoris.

Hemodynamic comparison of dopexamine hydrochloride and dopamine in ischemic left ventricular dysfunction.

The hemodynamic dose-response effects of intravenous dopexamine hydrochloride (0.5 to 2.0 micrograms/kg/min) have been compared with dopamine (2.5 to 10 micrograms/kg/min) in 12 patients with ischemic left ventricular dysfunction in an open randomized crossover study. Both drugs increased cardiac output and decreased systemic vascular resistance. Dopexamine hydrochloride appeared to increase heart rate more than dopamine although this did not reach statistical significance. Dopexamine hydrochloride produced small increases in systolic and decreases in diastolic blood pressure, whereas dopamine had a biphasic effect resulting in a decrease in mean blood pressure at low doses and an increase at the highest dose studied. With increasing dosage, there was a trend toward more vasodilator activity with dopexamine hydrochloride than with dopamine. Dopexamine hydrochloride produced fewer adverse effects than dopamine.

Intravenous amrinone in left ventricular failure complicated by acute myocardial infarction.

Hemodynamic dose-response effects of intravenous amrinone were studied in 22 male patients aged 38 to 62 years with left ventricular failure occurring within 18 hours of acute myocardial infarction. After hemodynamic confirmation of a raised left-sided cardiac filling pressure--pulmonary artery occluded pressure greater than 20 mm Hg--patients were randomized to either low-dose infusion of amrinone (200 micrograms/kg/hr for 30 minutes, 400 micrograms/kg/hr for 30 minutes and then 800 micrograms/kg/hr for 30 minutes) or high-dose infusion of the drug (800, 1,600 and 3,200 micrograms/kg/hr sequentially, each for 30 minutes). Hemodynamic measurements were obtained at 1 hour before amrinone and at the end of each infusion step. Low-dose infusion of amrinone resulted in a progressive increase in cardiac output (p less than 0.05) and stroke volume (p less than 0.05) and progressive reductions in pulmonary artery occluded pressure (p less than 0.01) and systemic vascular resistance (p less than 0.05). Systemic blood pressure and heart rate were unchanged. High-dose infusion resulted in a similar increase in cardiac output (p less than 0.05) but no change in stroke volume owing to associated tachycardia (p less than 0.01). There was a significantly greater decrease in pulmonary artery occluded pressure compared with the low-dose infusion (p less than 0.05), and systemic arterial diastolic and mean pressures were also decreased (p less than 0.05). The decrease in systemic vascular resistance was of a similar order to that induced by the low-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of corticosterone on protein degradation in isolated rat soleus and extensor digitorum longus muscles.

The net catabolic effect of glucocorticoids on protein metabolism is well documented but the acute and chronic effect of glucocorticoids on protein breakdown remains controversial. In the present studies protein breakdown was measured by the release of tyrosine from the isolated soleus and extensor digitorum longus (EDL) muscles of control rats and rats treated with corticosterone (10 mg/100 g body weight/day) for 5 days. The effect of corticosterone in arresting growth was confirmed since corticosterone-treated rats weighed significantly less than control rats after 2, 3, 4 and 5 days of treatment (P < 0.001). Furthermore, the weights of soleus and EDL muscles from corticosterone-treated rats were significantly reduced (P < 0.001, at least P < 0.05 respectively) compared with muscles from control rats on days 3-5. In the EDL muscle tyrosine release was significantly elevated after corticosterone treatment for 2 days (257 +/- 21 nmol/g tissue/h, P < 0.05), 3 days (205 +/- 9 nmol/g tissue/h, P < 0.01), 4 days (255 +/- 20 nmol/g tissue/h, P < 0.005) and 5 days (218 +/- 8 nmol/g tissue/h, P < 0.05) compared with EDL from control rats (192 +/- 13, 171 +/- 7, 187 +/- 7, 180 +/- 12 nmol/g tissue/h respectively). In the soleus muscle, tyrosine release was significantly elevated after corticosterone treatment for 2 days (226 +/- 14 nmol/g tissue/h, P < 0.001), 3 days (223 +/- 16 nmol/g tissue/h, P < 0.001) and 4 days (199 +/- 10 nmol/g tissue/h, P < 0.001) compared with control rats (158 +/- 7, 132 +/- 6 and 153 +/- 7 nmol/g tissue/h respectively). After 5 days there was no significant difference in tyrosine release from soleus muscle between corticosterone-treated (176 +/- 15 nmol/g tissue/h) and control rats (157 +/- 6 nmol/g tissue/h). Plasma glucose concentrations were not significantly different in rats treated with corticosterone and control rats whilst insulin levels were significantly raised in the corticosterone-treated rats on all days compared with control rats (P < 0.05 on day 1; P < 0.001 on days 2, 3, 4 and 5). It is suggested that insulin may have prevented hyperglycaemia developing in the corticosterone-treated rats. Results from these studies indicate that the acute effect of glucocorticoids is to increase muscle proteolysis but this is not maintained with longer-term treatment.

Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo.

Existing methods of measuring glucose kinetics are subject to errors. There is considerable interest in improved methods of measuring glucose kinetics to allow the development of new regimes for the treatment of diabetes mellitus. 3-O-Methyl-D-glucose is transported but not metabolized and therefore allows independent estimation of transport parameters. We describe a method by which 3-O-methyl-D-glucose in plasma samples can be measured in protocols during which glucose flux is assessed with simultaneous use of two isotopically labeled glucoses to quantitate and validate measurements of the rate of glucose appearance and disappearance. Quantitative gas chromatographic/mass spectrometric (GC/MS) analysis of 3-O-methyl-D-glucose, D-glucose, D-[U-13C] glucose and D-[6,6-2H2] glucose in human plasma using methoxime-trimethylsilyl ether derivatives is described. Measurements of all four derivatives were performed together in a small sample volume (50 microliters) with high precision. The intra-assay (inter-assay) coefficients of variation at an isotope content of 0.25 atom% excess for D-[6,6-2H2] glucose, D-[U-13C] glucose and 3-O-methyl-D-glucose were 0.8% (1.0%), 0.5% (4.0%) and 0.1% (3.7%), respectively. This method provides the basis for quantitative estimation of parameters of glucose kinetics in man and the rates of glucose flux across the cell membrane.

The testis. A protected environment for leukaemic cells against cyclophosphamide in a mouse model.

Groups of BDF1 mice, inoculated either IM or by the intratesticular (IT) route with comparable numbers of L1210 cells, died within the same time range from the disseminated disease. Cyclophosphamide (100 mg/kg IP) given on day 6 after inoculation, when the disease was advanced, increased the lifespan by about 100%, but all the mice died. The same dose on day 3 effectively cured all mice inoculated IM, whereas those injected with cells into the testicular lymphatic sinusoidal system died with only a short prolongation of lifespan. The study indicates that L1210 cells present in the testis are relatively protected from the action of cyclophosphamide, and the experimental results are consistent with clinical evidence for the occurrence of relapse in children with ALL due to malignant lymphoblasts persisting in the testicular environment.

Haemodynamic dose-response actions of cicloprolol in left ventricular dysfunction due to ischaemic heart disease.

Cicloprolol is a cardioselective beta-1 partial agonist; its haemodynamic and radionuclide (nuclear stethoscope) effects were determined in 22 patients with impaired left ventricular function due to coronary artery disease. Following a 20 min stable control period, the effects of four doses of cicloprolol (0.025, 0.025, 0.05 and 0.1 mg/kg at 10 min intervals) were measured at rest 5-10 min after each intravenous injection. The effects of the cumulative 0.2 mg/kg dosage were assessed during supine bicycle exercise and compared with a control exercise period. At rest there were significant increases in systolic arterial without change in mean blood pressure. The heart rate and cardiac index were unchanged. There was a significant increase in left ventricular ejection fraction with a reduction in filling pressure and volume. Patients with resting heart rate below 75 beats/min and with ejection fraction greater than 35% showed the greatest improvement. During supine bicycle exercise, ejection fraction was increased compared to control (31 +/- 2 to 36 +/- 2; P less than 0.01), cardiac volume reduced and exercise tachycardia attenuated. These data suggest that cicloprolol may be of value where beta-blockade is considered in the presence of underlying left ventricular dysfunction due to ischaemic heart disease.

Spleen-targeted 114In(m) via normal and heat-damaged red cells in the mouse: isotope distribution and bone marrow damage.

114In(m)-labelled heat-damaged erythrocytes (HDRBC) in BDF1 mice were quantitatively much less successful in spleen targeting than in the rat. Unheated labelled cells (NRBC) were an even less effective vector. Radiobiological effects manifest in the spleen (weight loss) and white cell count were nevertheless substantial, comparable in both groups and unchanged after 14 days. Considerable early renal loss of indium is inferred in the NRBC animals, but in the HDRBC group a high proportion was retained in the liver. Progenitor cell marrow cultures indicated acute transitory lethal effects with only partial recovery at termination; the marrow concentration of indium was the same in both groups.

A turnover study in the male rat of plasma-bound 59Fe, 114Inm and 109Cd with particular reference to the gonad.

After intravenous doses of the plasma-bound radionuclides 59Fe, 114Inm and 109Cd, only a minute percentage localizes in the rat testis and remains largely unchanged with time. Intratesticular injection of appropriately reduced volumes led to much higher proportionate percentage retention of 14, 65 and 11 for 59Fe, 114Inm and 109Cd, respectively. By this route, significant feedback of the elements escaping initial binding was prevented. Distinct but different testicular turnovers were now discernible. As a receptor of fluid and spermatozoa from the testicular tubules, the epididymis provides an indication of entry into and interaction of the metals with spermatogenic cells. For 59Fe no measurable changes were detected, whereas a progressive increase in epididymal 114Inm occurred, which had not reached a plateau by 70 days. 109Cd, now demonstrated within the testicular tubules by autoradiography, remained at constant organ level for upwards of 16 days but had declined by 25% by 57 days. At this point, the epididymis showed a five-fold increase in the radionuclide, declining to one-half this value by 126 days. Since 109Cd is carrier free, the data reflect a body turnover of dietary cadmium. These results, overall, are compatible with the entry of a proportion of each radionuclide into the seminiferous tubules and reaction with spermatogenic cells. Possible interpretations of the observed differences are presented.