OBJECTIVE

Limited data on patients undergoing Roux-en-Y gastric bypass surgery (RY-GBP) suggest that an improvement in insulin secretion after surgery occurs rapidly and thus may not be wholly accounted for by weight loss. We hypothesized that in obese patients with type 2 diabetes the impaired levels and effect of incretins changed as a consequence of RY-GBP.

METHODS

Incretin (gastric inhibitory peptide [GIP] and glucagon-like peptide-<em>1</em> [GLP-<em>1</em>]) levels and their effect on insulin secretion were measured before and <em>1</em> month after RY-GBP in eight obese women with type 2 diabetes and in seven obese nondiabetic control subjects. The incretin effect was measured as the difference in insulin secretion (area under the curve [AUC]) in response to an oral glucose tolerance test (OGTT) and to an isoglycemic intravenous glucose test.

RESULTS

Fasting and stimulated levels of GLP-<em>1</em> and GIP were not different between control subjects and patients with type 2 diabetes before the surgery. One month after RY-GBP, body weight decreased by 9.2 +/- 7.0 kg, oral glucose-stimulated GLP-<em>1</em> (AUC) and GIP peak levels increased significantly by 24.3 +/- 7.9 pmol x l(-<em>1</em>) x min(-<em>1</em>) (P < 0.000<em>1</em>) and <em>1</em>3<em>1</em> +/- 85 pg/ml (P = 0.007), respectively. The blunted incretin effect markedly increased from 7.6 +/- 28.7 to 42.5 +/- <em>1</em><em>1</em>.3 (P = 0.005) after RY-GBP, at which it time was not different from that for the control subjects (53.6 +/- 23.5%, P = 0.284).

CONCLUSIONS

These data suggest that early after RY-GBP, greater GLP-<em>1</em> and GIP release could be a potential mediator of improved insulin secretion.

BACKGROUND

Insulin resistance is present in the setting of congestive heart failure. Glucagon-like peptide-<em>1</em> (GLP-<em>1</em>) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties.

RESULTS

We investigated the safety and efficacy of a 5-week infusion of GLP-<em>1</em> (2.5 pmol/kg/min) added to standard therapy in <em>1</em>2 patients with New York Heart Association class III/IV heart failure and compared the results with those of 9 patients with heart failure on standard therapy alone. Echocardiograms, maximum myocardial ventilation oxygen consumption (VO2 max), 6-minute walk test, and Minnesota Living with Heart Failure quality of life score (MNQOL) were assessed. Baseline demographics, background therapy, and the degree of left ventricular dysfunction were similar between groups. GLP-<em>1</em> significantly improved left ventricular ejection fraction (2<em>1</em> +/- 3% to 27 +/- 3% P < .0<em>1</em>), VO2 max (<em>1</em>0.8 +/- .9 ml/O2/min/kg to <em>1</em>3.9 +/- .6 ml/O2/min/kg; P < .00<em>1</em>), 6-minute walk distance (232 +/- <em>1</em>5 m to 286 +/- <em>1</em>2 m; P < .00<em>1</em>) and MNQOL score (64 +/- 4 to 44 +/- 5; P < .0<em>1</em>). Benefits were seen in both diabetic and non-diabetic patients. There were no significant changes in any of the parameters in the control patients on standard therapy. GLP-<em>1</em> was well tolerated with minimal episodes of hypoglycemia and gastrointestinal side effects.

CONCLUSIONS

Chronic infusion of GLP-<em>1</em> significantly improves left ventricular function, functional status, and quality of life in patients with severe heart failure.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in <em>1</em>4 normotensive males during <em>1</em>-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- <em>1</em> microU/<em>ml</em> during control, to 72 +/- 8 and <em>1</em>44 +/- <em>1</em>3 microU/<em>ml</em> during the low and high insulin doses, respectively, and fell to <em>1</em>5 +/- 6 microU/<em>ml</em> <em>1</em> h after insulin infusion was stopped. MSNA, which averaged 2<em>1</em>.5 +/- <em>1</em>.5 bursts/min in control, increased significantly (P less than 0.00<em>1</em>) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during <em>1</em>-h recovery (+<em>1</em>5.2 bursts/min). Plasma norepinephrine levels (<em>1</em><em>1</em>9 +/- <em>1</em>9 pg/<em>ml</em> during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.0<em>1</em>) doses of insulin and recovery (3<em>1</em>6 +/- 23; P less than 0.0<em>1</em>). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.00<em>1</em>) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.0<em>1</em>). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.

Glucose tolerance depends on a complex interaction among insulin secretion from the beta-cells, clearance of the hormone, and the actions of insulin to accelerate glucose disappearance and inhibit endogenous glucose production. An additional factor, less well recognized, is the ability of glucose per se, independent of changes in insulin, to increase glucose uptake and suppress endogenous output (glucose effectiveness). These factors can be measured in the intact organism with physiologically based minimal models of glucose utilization and insulin kinetics. With the glucose minimal model, insulin sensitivity (SI) and glucose effectiveness (SG) are measured by computer analysis of the frequently sampled intravenous glucose tolerance test. The test involves intravenous injection of glucose followed by tolbutamide or insulin and frequent blood sampling. SI varied from a high of 7.6 x <em>1</em>0(-4) min-<em>1</em>.microU-<em>1</em>.<em>ml</em>-<em>1</em> in young Whites to 2.3 x <em>1</em>0(-4) min-<em>1</em>.microU-<em>1</em>.<em>ml</em>-<em>1</em> in obese nondiabetic subjects; in all of the nondiabetic subjects, SG was normal. In subjects with non-insulin-dependent diabetes mellitus (NIDDM), not only was SI reduced 90% below normal (0.6<em>1</em> +/- 0.<em>1</em>6 x <em>1</em>0(-4) min-<em>1</em>.microU-<em>1</em>.<em>ml</em>-<em>1</em>), but in this group alone, SG was reduced (from 0.026 +/- 0.008 to 0.0<em>1</em>4 +/- 0.002 min-<em>1</em>); thus, defects in SI and SG are synergistic in causing glucose intolerance in NIDDM. One assumption of the minimal model is that the time delay in insulin action on glucose utilization in vivo is due to sluggish insulin transport across the capillary endothelium. This was tested by comparing insulin concentrations in plasma with those in lymph (representing interstitial fluid) during euglycemic-hyperinsulinemic glucose clamps. Lymph insulin was lower than plasma insulin at basal (<em>1</em>2 vs. <em>1</em>8 microU/<em>ml</em>) and at steady state, indicating significant loss of insulin from the interstitial space, presumably due to cellular uptake of the insulin-receptor complex. Additionally, during clamps, lymph insulin changed more slowly than plasma insulin, but the rate of glucose utilization followed a time course identical with that of lymph (r = .96) rather than plasma (r = .7<em>1</em>). Thus, lymph insulin, which may be reflective of interstitial fluid, is the signal to which insulin-sensitive tissues are responding. These studies support the concept that, at physiological insulin levels, the time for insulin to cross the capillary endothelium is the process that determines the rate of insulin action in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE

The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.

METHODS

This was a <em>1</em>2-month, multicenter, sham-controlled, double-masked study with eyes (age><em>1</em>8 years, type <em>1</em> or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) rando<em>ml</em>y assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=5<em>1</em> each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month <em>1</em>, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.<em>1</em> <em>ml</em> and remained at 0.<em>1</em> <em>ml</em> thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=<em>1</em>5<em>1</em>, patients receiving≥<em>1</em> injection).

RESULTS

At month <em>1</em>2, mean±SD BCVA improved from baseline by <em>1</em>0.3±9.<em>1</em> letters with ranibizumab and declined by <em>1</em>.4±<em>1</em>4.2 letters with sham (P<0.000<em>1</em>). Mean CRT reduction was <em>1</em>94.2±<em>1</em>35.<em>1</em> μm with ranibizumab and 48.4±<em>1</em>53.4 μm with sham (P<0.000<em>1</em>). Gain of ≥<em>1</em>0 letters BCVA from baseline occurred in 60.8% of ranibizumab and <em>1</em>8.4% of sham eyes (P<0.000<em>1</em>). Safety data were consistent with previous studies of intravitreal ranibizumab.

CONCLUSIONS

Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

<em>1</em>. Noradrenaline and adrenaline reduce the output of acetylcholine by the guinea-pig ileum longitudinal strip by up to 80%, both in resting conditions and after stimulation. The effect is graded with dose, and is detectable with noradrenaline 2 x <em>1</em>0(-7) g/<em>ml</em>. Adrenaline is approximately 4 times as active as noradrenaline, and its action after being washed out is more persistent.2. If resting output is high, both amines have a proportionately greater effect and their action, as dosage is increased, is to reduce resting output to a basal level, relatively constant from strip to strip, of about <em>1</em>0 ng/g/min.3. With stimulation, the effect of the amine is greater at low frequencies, when the output per volley is high, than at high frequencies. The effect is reduced by increasing the number of shocks delivered. There thus appears to be a basal output per volley, of the order of <em>1</em>-2 ng/g/volley, which can be reached either by relatively rapid stimulation, by prolonged stimulation, or by treatment with these amines.4. If noradrenaline is applied during continued stimulation at 40/min, the depression of acetylcholine output during its presence is followed by an augmented output when the drug is withdrawn. The magnitude of this "overshoot" increases with the duration of noradrenaline exposure.5. Phenylephrine 4 mug/<em>ml</em>. and amphetamine 20 mug/<em>ml</em>. reduced the acetylcholine output, but isoprenaline <em>1</em> mug/<em>ml</em>., dopamine <em>1</em> mug/<em>ml</em>. and methoxamine <em>1</em>0 mug/<em>ml</em>. were ineffective.6. Phenoxybenzamine reduced the resting output and increased the stimulation output. Of the two other blocking agents examined, phentolamine had no effect on either resting or stimulation output and ergotamine transiently reduced stimulation output. The effect of phenoxybenzamine was not due to a reaction with either adrenoceptive or muscarinic receptors.7. Phenoxybenzamine, phentolamine and ergotamine abolished the effect of adrenaline and noradrenaline on both resting output and on output in response to stimulation.8. In strips obtained from animals treated with reserpine and guanethidine, a rise in resting acetylcholine output and in stimulation output at low frequencies was found. In these conditions, noradrenaline was still effective.9. Reducing the hydroxytryptamine content of the strips by treatment with p-chloro-(+/-)-phenylalanine did not significantly affect acetylcholine output.<em>1</em>0. It is concluded that acetylcholine output by the nervous networks of the longitudinal strip is under the normal control of the sympathetic by a species of presynaptic inhibition mediated by alpha receptors. This implies that for a tissue under dual autonomic control, withdrawal of sympathetic control will lead to a parasympathetic response which is not only unopposed but also itself enhanced.

BACKGROUND

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase <em>1</em>/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.

METHODS

In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:<em>1</em> ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-<em>1</em>5 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of <em>1</em> cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of <em>1</em> cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.

RESULTS

<em>1</em><em>1</em>7 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI <em>1</em>5-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·000<em>1</em>). Adverse events were mostly grade <em>1</em> or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [3<em>1</em>%] vs eight [2<em>1</em>%]), convulsion (<em>1</em>8 [23%] vs ten [26%]), and pyrexia (<em>1</em>7 [22%] vs six [<em>1</em>5%]).

CONCLUSIONS

These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.

BACKGROUND

Novartis Pharmaceuticals.

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, <em>1</em>, 2.5, or 5 g) was conducted in <em>1</em>0 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/<em>mL</em> (2.4 micromol/L, mean +/- SD; n = <em>1</em>0), which occurred <em>1</em>.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 micromol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.

Curcumin, the yellow pigment in turmeric and curry, has antioxidative and anticarcinogenic activities. In this study, we investigated the pharmacokinetic properties of curcumin in mice. After i.p. administration of curcumin (0.<em>1</em> g/kg) to mice, about 2.25 microg/<em>ml</em> of curcumin appeared in the plasma in the first <em>1</em>5 min. One hour after administration, the levels of curcumin in the intestines, spleen, liver, and kidneys were <em>1</em>77.04, 26.06, 26.90, and 7.5<em>1</em> microg/g, respectively. Only traces (0.4<em>1</em> microg/g) were observed in the brain at <em>1</em> h. To clarify the nature of the metabolites of curcumin, the plasma was analyzed by reversed-phase HPLC, and two putative conjugates were observed. Treatment of the plasma with beta-glucuronidase resulted in a decrease in the concentrations of these two putative conjugates and the concomitant appearance of tetrahydrocurcumin (THC) and curcumin, respectively. To investigate the nature of these glucuronide conjugates in vivo, the plasma was analyzed by electrospray. The chemical structures of these metabolites, determined by mass spectrometry/mass spectrometry analysis, suggested that curcumin was first biotransformed to dihydrocurcumin and THC and that these compounds subsequently were converted to monoglucuronide conjugates. Because THC is one of the major metabolites of curcumin, we studied its stability at different pH values. THC was very stable in 0.<em>1</em> M phosphate buffers of various pH values. Moreover, THC was more stable than curcumin in 0.<em>1</em> M phosphate buffer, pH 7.2 (37 degrees C). These results, together with previous findings, suggest that curcumin-glucuronoside, dihydrocurcumin-glucuronoside, THC-glucuronoside, and THC are major metabolites of curcumin in vivo.

BACKGROUND

Narcolepsy, a neurological disorder affecting <em>1</em> in 2000 individuals, is associated with HLA-DQB<em>1</em>*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels.

OBJECTIVE

To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-<em>1</em> measurements as a diagnostic tool for narcolepsy.

METHODS

Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-<em>1</em> were studied in a case series of patients with sleep disorders from <em>1</em>999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-<em>1</em> levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-<em>1</em> levels.

METHODS

Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif.

METHODS

There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB<em>1</em>*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders).

METHODS

Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies.

METHODS

Diagnostic threshold for CSF hypocretin-<em>1</em>, HLA-DQB<em>1</em>*0602 positivity, and clinical and polysomnographic features.

RESULTS

HLA-DQB<em>1</em>*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs <em>1</em>7% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-<em>1</em> levels below <em>1</em><em>1</em>0 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB<em>1</em>*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB<em>1</em>*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and <em>1</em> with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = <em>1</em>94). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions.

CONCLUSIONS

Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-<em>1</em> is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

BACKGROUND

The replication of BK virus (BKV) and JC virus (JCV) is linked to polyomavirus-associated nephropathy, hemorrhagic cystitis, and multifocal leukoencephalopathy in immunodeficient patients, but the behavior of these viruses in immunocompetent individuals has hardly been characterized.

METHODS

We used EIA to study samples obtained from 400 healthy blood donors aged 20-59 years for BKV- and JCV-specific antibodies against virus-like particles. We also studied BKV and JCV loads in plasma and urine among these individuals by use of real-time polymerase chain reaction.

RESULTS

IgG seroprevalence was 82% (328 of 400 donors) for BKV and 58% (23<em>1</em> of400) for JCV. As age increased (age groups were divided by decade), the seroprevalence of BKV decreased from 87% (87 of <em>1</em>00) in the youngest group (aged 20-29 years) to 7<em>1</em>% (7<em>1</em> of <em>1</em>00) in the oldest group (aged 50-59 years) (P = .006), whereas the seroprevalence of JCV increased from 50% (50 of <em>1</em>00) in the youngest group to 68% (68 of <em>1</em>00) in the oldest group (P = .06). Asymptomatic urinary shedding of BKV and JCV was observed in 28 (7%) and 75 (<em>1</em>9%) of 400 subjects, respectively, with median viral loads of 3.5<em>1</em> and 4.64 log copies/<em>mL</em>, respectively (P < .00<em>1</em>). Unlike urinary BKV loads, urinary JCV loads were positively correlated with IgG levels. The shedding of JCV was more commonly observed among individuals who were seropositive only for JCV, compared with individuals who were seropositive for both BKV and JCV, suggesting limited cross-protection from BKV immunity. Noncoding control regions were of archetype architecture in all cases, except for <em>1</em> rearranged JCV variant. Neither BKV nor JCV DNA was detected in plasma.

CONCLUSIONS

Our study provides important data about polyomavirus infection and replication in healthy, immunocompetent individuals. These data indicate significant differences between BKV and JCV with respect to virus-host interaction and epidemiology.

BACKGROUND

Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes.

OBJECTIVE

To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction (E-selectin; intercellular adhesion molecule <em>1</em> [ICAM-<em>1</em>]; and vascular cell adhesion molecule <em>1</em> [VCAM-<em>1</em>]) predict development of type 2 diabetes in initially nondiabetic women.

METHODS

Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in <em>1</em>976.

METHODS

Of <em>1</em>2<em>1</em> 700 women initially enrolled, 32 826 provided blood samples in <em>1</em>989-<em>1</em>990; of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetes by 2000. Controls (n = 785) were selected according to matched age, fasting status, and race.

METHODS

Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-<em>1</em>, and VCAM-<em>1</em>.

RESULTS

Baseline median levels of the biomarkers were significantly higher among cases than among controls (E-selectin, 6<em>1</em>.2 vs 45.4 ng/mL; ICAM-<em>1</em>, 264.9 vs 247.0 ng/mL; VCAM-<em>1</em>, 545.4 vs 526.0 ng/mL [all P values < or =.004]). Elevated E-selectin and ICAM-<em>1</em> levels predicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted for body mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, and postmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs the bottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-<em>1</em> (95% CI, 2.28-5.58), and <em>1</em>.<em>1</em>2 for VCAM-<em>1</em> (95% CI, 0.76-<em>1</em>.66). Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and hemoglobin A(<em>1</em>c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations.

CONCLUSIONS

Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.

BACKGROUND

Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome.

METHODS

We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (ILs) <em>1</em> beta, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days <em>1</em>, 2, 3, 5, 7, <em>1</em>0, and <em>1</em>2 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day <em>1</em> of ARDS and over time.

RESULTS

Of the 27 patients, <em>1</em>3 survived ICU admission and <em>1</em>4 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p < 0.02). The mean initial plasma levels of TNF-alpha, IL-<em>1</em> beta, IL-6, and IL-8 were significantly higher in nonsurvivors (p < 0.000<em>1</em>) and in those patients with sepsis (p < 0.000<em>1</em>). Plasma levels of IL-<em>1</em> beta (p < 0.0<em>1</em>) and IL-6 (p = 0.03) were more strongly associated with patient outcome than cause of ARDS (p = 0.8), lung injury score (LIS), APACHE II score, sepsis (p = 0.<em>1</em>6), shock, or MODS score. Plasma levels of TNF-alpha, IL-<em>1</em> beta, IL-6, and IL-8 remained significantly elevated over time (p < 0.000<em>1</em>) in those who died. Although it was the best early predictor of death (p < 0.00<em>1</em>), plasma IL-2>> 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-<em>1</em> beta or IL-6 level>> 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival.

CONCLUSIONS

Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-alpha, IL-<em>1</em> beta, IL-6, and IL-8 on day <em>1</em> of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day <em>1</em> of ARDS and a rapid reduction over time. Plasma IL-<em>1</em> beta and IL-6 levels were consistent and efficient predictors of outcome.

BACKGROUND

We analyzed the accuracy of multi-detector row spiral computed tomography (MDCT) using a <em>1</em>6-slice CT scanner with improved spatial and temporal resolution, as well as routine premedication with beta-blockers for detection of coronary stenoses.

RESULTS

Seventy-seven patients with suspected coronary disease were studied by MDCT (<em>1</em>2x0.75-mm cross-sections, 420 ms rotation, <em>1</em>00 <em>mL</em> contrast agent IV at 5 <em>mL</em>/s). Patients with a heart rate above 60/min received 50 mg atenolol before the scan. In axial MDCT images and multiplanar reconstructions, all coronary arteries and side branches with a diameter of <em>1</em>.5 mm or more were assessed for the presence of stenoses exceeding 50% diameter reduction. In comparison to invasive coronary angiography, MDCT correctly classified 35 of 4<em>1</em> patients (85%) as having at least <em>1</em> coronary stenosis and correctly detected 57 of 78 coronary lesions (73%). After excluding 38 of 308 coronary arteries (left main, left anterior descending, left circumflex, and right coronary artery in 77 patients) classified as unevaluable by MDCT (<em>1</em>2%), 57 of 62 lesions were detected, and absence of stenosis was correctly identified in <em>1</em>94 of 208 arteries (sensitivity: 92%; specificity: 93%; accuracy: 93%; positive and negative predictive values: 79% and 97%).

CONCLUSIONS

MDCT coronary angiography with improved spatial resolution and premedication with oral beta-blockade permits detection of coronary artery stenoses with high accuracy and a low rate of unevaluable arteries.

Cotinine, a metabolite of nicotine, is widely used to distinguish smokers from nonsmokers in epidemiologic studies and smoking-cessation clinical trials. As the magnitude of secondhand smoke exposure declines because of proportionally fewer smokers and more clean-indoor-air regulations, the optimal cotinine cutpoint with which to distinguish smokers from nonsmokers is expected to change. The authors analyzed data on 3,078 smokers and <em>1</em>3,078 nonsmokers from the National Health and Nutrition Examination Survey for <em>1</em>999-2004. Optimal serum cotinine concentrations for discriminating smokers from nonsmokers were determined using receiver operator characteristic curve analysis. Optimal cotinine cutpoints were 3.08 ng/<em>mL</em> (sensitivity = 96.3%, specificity = 97.4%) and 2.99 ng/<em>mL</em> (sensitivity = 86.5%, specificity = 93.<em>1</em>%) for adults and adolescents, respectively. Among adults, optimal cutpoints differed by race/ethnicity: They were 5.92 ng/<em>mL</em>, 4.85 ng/<em>mL</em>, and 0.84 ng/<em>mL</em> for non-Hispanic blacks, non-Hispanic whites, and Mexican Americans, respectively. Among adolescents, cutpoints were 2.77 ng/<em>mL</em>, 2.95 ng/<em>mL</em>, and <em>1</em>.<em>1</em>8 ng/<em>mL</em> for non-Hispanic blacks, non-Hispanic whites, and Mexican Americans, respectively. Use of the currently accepted cutpoint of <em>1</em>4 ng/<em>mL</em> overestimates the number of nonsmokers in comparison with the proposed new overall cutpoint of 3 ng/<em>mL</em> or the race/ethnicity-specific cutpoints of <em>1</em>-6 ng/<em>mL</em>.

OBJECTIVE

We estimated the prevalence of renal impairment in heart failure (HF) patients and the magnitude of associated mortality risk using a systematic review of published studies.

BACKGROUND

Renal impairment in HF patients is associated with excess mortality, although precise risk estimates are unclear.

METHODS

A systematic search of MEDLINE (through May 2005) identified 16 studies characterizing the association between renal impairment and mortality in 80,098 hospitalized and non-hospitalized HF patients. All-cause mortality risks associated with any renal impairment (creatinine >1.0 mg/dl, creatinine clearance [CrCl] or estimated glomerular filtration rate [eGFR] <90 ml/min, or cystatin-C >1.03 mg/dl) and moderate to severe impairment (creatinine>> or =1.5, CrCl or eGFR <53, or cystatin-C>> or =1.56) were estimated using fixed-effects meta-analysis.

RESULTS

A total of 63% of patients had any renal impairment, and 29% had moderate to severe impairment. After follow-up>> or =1 year, 38% of patients with any renal impairment and 51% with moderate to severe impairment died versus 24% without impairment. Adjusted all-cause mortality was increased for patients with any impairment (hazard ratio [HR] = 1.56; 95% confidence interval [CI] 1.53 to 1.60, p < 0.001) and moderate to severe impairment (HR = 2.31; 95% CI 2.18 to 2.44, p < 0.001). Mortality worsened incrementally across the range of renal function, with 15% (95% CI 14% to 17%) increased risk for every 0.5 mg/dl increase in creatinine and 7% (95% CI 4% to 10%) increased risk for every 10 ml/min decrease in eGFR.

CONCLUSIONS

Renal impairment is common among HF patients and confers excess mortality. Renal function should be considered in risk stratification and evaluation of therapeutic strategies for HF patients.

BACKGROUND

Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.

OBJECTIVE

To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.

METHODS

We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 6<em>1</em>6 Costa Rican children between the ages of 6 and <em>1</em>4 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.

RESULTS

Of the 6<em>1</em>6 children with asthma, <em>1</em>75 (28%) had insufficient levels of vitamin D (<30 ng/<em>ml</em>). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log(<em>1</em>0) unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004-0.7<em>1</em>; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.<em>1</em>8; 95% CI, 0.05-0.67; P = 0.0<em>1</em>), and increased airway responsiveness (a < or =8.58-mumol provocative dose of methacholine producing a 20% fall in baseline FEV(<em>1</em>) [OR, 0.<em>1</em>5; 95% CI, 0.024-0.97; P = 0.05]).

CONCLUSIONS

Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.

OBJECTIVE

Despite poor performance, guaiac-based fecal occult blood tests (G-FOBT) are most frequently implemented for colorectal cancer screening. Immunochemical fecal occult blood tests (I-FOBT) are claimed to perform better, without randomized comparison in screening populations. Our aim was to randomly compare G-FOBT with I-FOBT in a screening population.

METHODS

We conducted a population-based study on a random sample of 20,623 individuals 50-75 years of age, randomized to either G-FOBT (Hemoccult-II) or I-FOBT (OC-Sensor). Tests and invitations were sent together. For I-FOBT, the standard cutoff of 100 ng/ml was used. Positive FOBTs were verified with colonoscopy. Advanced adenomas were defined as>>or=10 mm, high-grade dysplasia, or>>or=20% villous component.

RESULTS

There were 10,993 tests returned: 4836 (46.9%) G-FOBTs and 6157 (59.6%) I-FOBTs. The participation rate difference was 12.7% (P < .01). Of G-FOBTs, 117 (2.4%) were positive versus 339 (5.5%) of I-FOBTs. The positivity rate difference was 3.1% (P < .01). Cancer and advanced adenomas were found, respectively, in 11 and 48 of G-FOBTs and in 24 and 121 of I-FOBTs. Differences in positive predictive value for cancer and advanced adenomas and cancer were, respectively, 2.1% (P = .4) and -3.6% (P = .5). Differences in specificities favor G-FOBT and were, respectively, 2.3% (P < .01) and -1.3% (P < .01). Differences in intention-to-screen detection rates favor I-FOBT and were, respectively, 0.1% (P < .05) and 0.9% (P < .01).

CONCLUSIONS

The number-to-scope to find 1 cancer was comparable between the tests. However, participation and detection rates for advanced adenomas and cancer were significantly higher for I-FOBT. G-FOBT significantly underestimates the prevalence of advanced adenomas and cancer in the screening population compared with I-FOBT.

OBJECTIVE

Positron emission tomography (PET) with choline tracers has found widespread use for the diagnosis of prostate cancer (PC). However, choline metabolism is not increased in a considerable number of cases, whereas prostate-specific membrane antigen (PSMA) is overexpressed in most PCs. Therefore, a (68)Ga-labelled PSMA ligand could be superior to choline tracers by obtaining a high contrast. The aim of this study was to compare such a novel tracer with standard choline-based PET/CT.

METHODS

Thirty-seven patients with biochemical relapse of PC [mean prostate-specific antigen (PSA) <em>1</em><em>1</em>.<em>1</em> ± 24.<em>1</em> ng/<em>ml</em>, range 0.0<em>1</em>-<em>1</em><em>1</em>6] were retrospectively analysed after (<em>1</em>8)F-fluoromethylcholine and (68)Ga-PSMA PET/CT within a time window of 30 days. Radiotracer uptake that was visually considered as PC was semi-quantitatively analysed by measuring the maximum standardized uptake values (SUVmax) of the scans acquired <em>1</em> h after injection of (68)Ga-PSMA complex solution (median <em>1</em>32 MBq, range 59-263 MBq) and (<em>1</em>8)F-fluoromethylcholine (median 237 MBq, range <em>1</em><em>1</em>4-374 MBq), respectively. In addition, tumour to background ratios were calculated.

RESULTS

A total of 78 lesions characteristic for PC were detected in 32 patients using (68)Ga-PSMA PET/CT and 56 lesions were detected in 26 patients using choline PET/CT. The higher detection rate in (68)Ga-PSMA PET/CT was statistically significant (p=0.04). In five patients no lesion was found with both methods. All lesions detected by (<em>1</em>8)F-fluoromethylcholine PET/CT were also seen by (68)Ga-PSMA PET/CT. In (68)Ga-PSMA PET/CT SUVmax was clearly >><em>1</em>0 %) higher in 62 of 78 lesions (79.<em>1</em> %) and the tumour to background ratio was clearly >><em>1</em>0 %) higher in 74 of 78 lesions (94.9 %) when compared to (<em>1</em>8)F-fluoromethylcholine PET/CT.

CONCLUSIONS

(68)Ga-PSMA PET/CT can detect lesions characteristic for PC with improved contrast when compared to standard (<em>1</em>8)F-fluoromethylcholine PET/CT, especially at low PSA levels.

OBJECTIVE

The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects.

METHODS

Dabigatran etexilate or placebo was administered orally at single doses of <em>1</em>0-400 mg (n = 40) or at multiple doses of 50-400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded.

RESULTS

Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8-<em>1</em>0 h and <em>1</em>4-<em>1</em>7 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (V(z)/F) of <em>1</em>860 l (range <em>1</em>430-2400 l) and the apparent total clearance after oral administration (CL(tot)/F) of 203<em>1</em> <em>ml</em> min(-<em>1</em>) (range <em>1</em>480-2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration-time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.<em>1</em> (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < <em>1</em>0%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups.

CONCLUSIONS

These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.

We have studied various factors involved in the optimal use of a tetrazolium (MTT) based colorimetric assay for cell growth and chemosensitivity. The assay is dependent on the ability of viable cells to metabolise a water-soluble tetrazolium salt into a water-insoluble formazan product. We have found that DMSO is the best solvent for dissolving the formazan product, especially where a significant amount of residual medium is left in the wells of the microtitre tray used for the assay. A reaction occurs between medium and a solution of MTT formazan in DMSO which changes the shape of the absorbance spectrum of the solution. The resulting optical density is not however greatly dependent upon the volume of added medium in the range <em>1</em>-<em>1</em>0 microliters. Between <em>1</em>0 and 40 microliters of added medium results in a gradually lower optical density than that produced by the smaller volumes. Above 40 microliters, the optical density increases again due to turbidity as protein precipitation occurs. When cells are incubated with MTT, the resulting optical density of the formazan product is dependent upon both the concentration of MTT and the incubation time. The optical density is stable for several hours after solution of the formazan in DMSO. A linear relationship is seen between optical density and cell number for incubation times of 2, 4, 6 or 24 h with 20 microliters of MTT (5 mg <em>ml</em>-<em>1</em>) added to 200 microliters medium. We have adopted 4 h as the standard incubation time for the assay. Only a small amount of MTT formazan product can be detected in the growth medium of wells in which cells have been exposed to MTT. Comparative chemosensitivity data for EMT6 mouse tumour cells show good agreement between results obtained using the MTT assay and results based on total cell count after a fixed period of growth.

An antioxidant fraction of Chinese green tea (green tea antioxidant; GTA), containing several catechins, has been previously shown to inhibit <em>1</em>2-O-tetradecanoylphorbol-<em>1</em>3-acetate (TPA)-induced tumor promotion in mouse skin. In the present study, GTA was shown to have antioxidative activity toward hydrogen peroxide (H2O2) and the superoxide radical (O2-). GTA also prevented oxygen radical and H2O2-induced cytotoxicity and inhibition of intercellular communication in cultured B6C3F<em>1</em> mouse hepatocytes and human keratinocytes (NHEK cells). GTA (0.05-50 micrograms/<em>ml</em>) prevented the killing of hepatocytes (measured by lactate dehydrogenase release) by paraquat (<em>1</em>-<em>1</em>0 mM) and glucose oxidase (0.8-40 micrograms/<em>ml</em>) in a concentration-dependent fashion. GTA (50 micrograms/<em>ml</em>) also prevented the inhibition of hepatocyte intercellular communication by paraquat (5 mM), glucose oxidase (0.8 micrograms/<em>ml</em>), and phenobarbital (500 micrograms/<em>ml</em>). In addition, GTA (50 micrograms/<em>ml</em>) prevented the inhibition of intercellular communication in human keratinocytes by TPA (<em>1</em>00 ng/<em>ml</em>). Cytotoxicity and inhibition of intercellular communication, two possible mechanisms by which tumor promoters may produce their promoting effects were therefore prevented by GTA. The inhibition of these two effects of pro-oxidant compounds may suggest a mechanism by which GTA inhibits tumor promotion in vivo.

The expression of prostate-specific membrane antigen (PSMA) is increased in prostate cancer. Recently, (68)Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]) was developed as a PSMA ligand. The aim of this study was to investigate the detection rate of (68)Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy.

Two hundred forty-eight of 393 patients were evaluable for a retrospective analysis. Median prostate-specific antigen (PSA) level was 1.99 ng/mL (range, 0.2-59.4 ng/mL). All patients underwent contrast-enhanced PET/CT after injection of 155 ± 27 MBq of (68)Ga-PSMA ligand. The detection rates were correlated with PSA level and PSA kinetics. The influence of antihormonal treatment, primary Gleason score, and contribution of PET and morphologic imaging to the final diagnosis were assessed.

Two hundred twenty-two (89.5%) patients showed pathologic findings in (68)Ga-PSMA ligand PET/CT. The detection rates were 96.8%, 93.0%, 72.7%, and 57.9% for PSA levels of ≥2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL, respectively. Whereas detection rates increased with a higher PSA velocity (81.8%, 82.4%, 92.1%, and 100% in <1, 1 to <2, 2 to <5, and ≥5 ng/mL/y, respectively), no significant association could be found for PSA doubling time (82.7%, 96.2%, and 90.7% in >6, 4-6, and <4 mo, respectively). (68)Ga-PSMA ligand PET (as compared with CT) exclusively provided pathologic findings in 81 (32.7%) patients. In 61 (24.6%) patients, it exclusively identified additional involved regions. In higher Gleason score (≤7 vs. ≥8), detection efficacy was significantly increased (P = 0.0190). No significant difference in detection efficacy was present regarding antiandrogen therapy (P = 0.0783).

Hybrid (68)Ga-PSMA ligand PET/CT shows substantially higher detection rates than reported for other imaging modalities. Most importantly, it reveals a high number of positive findings in the clinically important range of low PSA values (<0.5 ng/mL), which in many cases can substantially influence the further clinical management.

Brain-derived neurotrophic factor (BDNF) is one of a family of neurotrophic factors that participates in neuronal transmission, modulation and plasticity. Previous studies using animals have demonstrated that acute and chronic exercise leads to increases in BDNF in various brain regions.

OBJECTIVE

To determine the effects of acute exercise on serum BDNF levels in humans, and to determine the relationship between exercise intensity and BDNF responses. Additionally, the relationship between changes in BDNF and cognitive function was examined.

METHODS

Fifteen subjects (25.4 +/- <em>1</em>.0<em>1</em> yr; <em>1</em><em>1</em> male, 4 female) performed a graded exercise test (GXT) for the determination of VO2max and ventilatory threshold (VTh) on a cycle ergometer. On separate days, two subsequent 30-min endurance rides were performed at 20% below the VTh (VTh - 20) and at <em>1</em>0% above the VTh (VTh + <em>1</em>0). Serum BDNF and cognitive function were determined before and after the GXT and endurance rides with an enzyme-linked immunosorbent assay (ELISA) and the Stroop tests, respectively.

RESULTS

The mean VO2max was 2805.8 +/- <em>1</em>64.3 <em>mL</em> x min(-<em>1</em>) (<em>1</em>04.2 +/- 7.0% pred). BDNF values (pg x <em>mL</em>(-<em>1</em>)) increased from baseline (P<0.05) after exercise at the VTh + <em>1</em>0 (<em>1</em>3%) and the GXT (30%). There was no significant change in BDNF from baseline after the VTh - 20. Changes in BDNF did not correlate with VO2max during the GXT, but they did correlate with changes in lactate (r=0.57; P<0.05). Cognitive function scores improved after all exercise conditions, but they did not correlate with BDNF changes.

CONCLUSIONS

BDNF levels in humans are significantly elevated in response to exercise, and the magnitude of increase is exercise intensity dependent. Given that BDNF can transit the blood-brain barrier in both directions, the intensity-dependent findings may aid in designing exercise prescriptions for maintaining or improving neurological health.