Changes in peak fat oxidation in response to different doses of endurance training.

The effect of different doses of endurance training on the capacity to oxidize fat during exercise in sedentary, overweight men and assessment of variables associated with changes in peak fat oxidation (PFO) were evaluated. Young, sedentary, overweight men were randomized to either the high-dose (HIGH, 600 kcal/day, n = 17) or moderate-dose (MOD, 300 kcal/day, n = 18) endurance training groups or controls (CON, n = 15). PFO and peak oxygen uptake (VO2 peak) were measured using indirect calorimetry, body composition using dual-energy x-ray absorptiometry, and protein levels of mitochondrial enzymes determined by Western blotting. PFO increased in both MOD [1.2 mg/kg fat-free mass (FFM)/min, 95% confidence interval (CI): 0.08:2.3, P = 0.03] and HIGH (1.8 mg/kg FFM/min, CI: 0.6:2.9, P < 0.001) compared with CON. Skeletal muscle expression of citrate synthase, ß-hydroxyacyl-CoA dehydrogenase, and mitochondrial oxphos complexes II-V increased similarly in MOD and HIGH. Stepwise multiple linear regression analysis with backward elimination of individual variables correlated with changes in PFO revealed increases in cycling efficiency, FFM, and VO2 peak as the remaining associated variables. In conclusion, PFO during exercise increased with both moderate- and high-dose endurance training. Increases in PFO were mainly predicted by changes in VO2 peak, FFM, and cycling efficiency, and less with skeletal muscle mitochondrial enzymes.

Only minor additional metabolic health benefits of high as opposed to moderate dose physical exercise in young, moderately overweight men.

OBJECTIVE: The dose-response effects of exercise training on insulin sensitivity, metabolic risk, and quality of life were examined. METHODS: Sixty-one healthy, sedentary (VO2max: 35 ± 5 ml/kg/min), moderately overweight (BMI: 27.9 ± 1.8), young (age: 29 ± 6 years) men were randomized to sedentary living (sedentary control group; n = 18), moderate (moderate dose training group [MOD]: 300 kcal/day, n = 21), or high (high dose training group [HIGH]: 600 kcal/day, n = 22) dose physical exercise for 11 weeks. RESULTS: The return rate for post-intervention testing was 82-94% across groups. Weekly exercise amounted to 2,004 ± 24 and 3,774 ± 68 kcal, respectively, in MOD and HIGH. Cardiorespiratory fitness increased (P < 0.001) 18 ± 3% in MOD and 17 ± 3% in HIGH, and fat percentage decreased (P < 0.001) similarly in both exercise groups (MOD: 32 ± 1 to 29 ± 1%; HIGH: 30 ± 1 to 27 ± 1%). Peripheral insulin sensitivity increased (P < 0.01) (MOD: 28 ± 7%; HIGH: 36 ± 8%) and the homeostasis model assessment of insulin resistance decreased (P < 0.05) (MOD: -17 ± 7%; HIGH: -18 ± 10%). The number of subjects meeting the criteria of the metabolic syndrome decreased by 78% in MOD (P < 0.01) and by 80% in HIGH (P < 0.05). General health assessed by questionnaire increased similarly in MOD (P < 0.05) and HIGH (P < 0.01). CONCLUSIONS: Only minor additional health benefits were found when exercising ∼3,800 as opposed to ∼2,000 kcal/week in young moderately overweight men. This finding may have important public health implications.

Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: a randomized study using FDG PET imaging.

Physical exercise increases peripheral insulin sensitivity, but regional differences are poorly elucidated in humans. We investigated the effect of aerobic exercise training on insulin-stimulated glucose uptake in five individual femoral muscle groups and four different adipose tissue regions, using dynamic (femoral region) and static (abdominal region) 2-deoxy-2-[¹8F]fluoro-d-glucose (FDG) PET/CT methodology during steady-state insulin infusion (40 mU·m⁻²·min⁻¹). Body composition was measured by dual X-ray absorptiometry and MRI. Sixty-one healthy, sedentary [V(O2max) 36(5) ml·kg⁻¹·min⁻¹; mean(SD)], moderately overweight [BMI 28.1(1.8) kg/m²], young [age: 30(6) yr] men were randomized to sedentary living (CON; n = 17 completers) or moderate (MOD; 300 kcal/day, n = 18) or high (HIGH; 600 kcal/day, n = 18) dose physical exercise for 11 wk. At baseline, insulin-stimulated glucose uptake was highest in femoral skeletal muscle followed by intraperitoneal visceral adipose tissue (VAT), retroperitoneal VAT, abdominal (anterior + posterior) subcutaneous adipose tissue (SAT), and femoral SAT (P < 0.0001 between tissues). Metabolic rate of glucose increased similarly (~30%) in the two exercise groups in femoral skeletal muscle (MOD 24[9, 39] µmol·kg⁻¹·min⁻¹, P = 0.004; HIGH 22[9, 35] µmol·kg⁻¹·min⁻¹, P = 0.003) (mean[95% CI]) and in five individual femoral muscle groups but not in femoral SAT. Standardized uptake value of FDG decreased ~24% in anterior abdominal SAT and ~20% in posterior abdominal SAT compared with CON but not in either intra- or retroperitoneal VAT. Total adipose tissue mass decreased in both exercise groups, and the decrease was distributed equally among subcutaneous and intra-abdominal depots. In conclusion, aerobic exercise training increases insulin-stimulated glucose uptake in skeletal muscle but not in adipose tissue, which demonstrates some interregional differences.

International exercise on 124Sb activity measurements.

An international exercise, registered as EUROMET project no. 907, was launched to measure both the activity of a solution of (124)Sb and the photon emission intensities of its decay. The same solution was sent by LNE-LNHB to eight participating laboratories. In order to identify possible biases, the participants were asked to use all possible activity measurement methods available in their laboratory and then to determine their reference value for comparison. Thus, measurement results from 4pibeta-gamma coincidence/anti-coincidence counting, CIEMAT/NIST liquid-scintillation counting, 4pigamma counting with well-type ionization chambers and well-type crystal detectors were given. The results are compared and show a maximum discrepancy of about 1.6%: possible explanations are proposed.

International exercise on 124Sb photon emission intensities determination.

An international exercise, registered as EUROMET project no. 907, was launched to measure both the activity of a solution of (124)Sb and the photon emission intensities of its decay. The same solution was sent by LNE-LNHB to eight participating laboratories, six of which sent results for photon emission intensities both in absolute and in relative terms. From these results and including previous published values, a consistent decay scheme was worked out, proving that problems in activity measurements have not been due to decay scheme data.

Application of "wet" extrapolation method for activity standardisation of electron capture radionuclides.

The activity of electron capture radionuclides is usually determined by 4pi(proportional counter, PC)-gamma coincidence counting. The corrections necessary for the final activity value calculation are obtained by an extrapolation method. Variation of the PC detection efficiency can be achieved through different methods, e.g. by changing the self-absorption of the source using absorbing foils or by adding carriers. Another possibility is a "wet" extrapolation method, which utilises an absorption change during the drying of a water droplet added onto the source surface. In this paper, slopes of extrapolation curves and resulting activity values obtained by different methods are compared for several radionuclides ((54)Mn, (139)Ce, (88)Y, (57)Co). In some cases a digital coincidence system was used for the analysis of measured data. The "wet" extrapolation, due to its very simple procedure, seems to be convenient for routine measurement and its accuracy is similar to the other methods.

The ventral hippocampal regulation of prepulse inhibition and its disruption by apomorphine in rats are not mediated via the fornix.

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is impaired in schizophrenia. We have reported that PPI is regulated by the ventral hippocampus (VH) and that the PPI disruptive effects of the dopamine agonist apomorphine are enhanced 4 weeks after excitotoxic lesions of the VH. The mechanisms responsible for the VH influence on PPI are not understood, but have been ascribed to interactions between the VH and nucleus accumbens. In the present study, we examined whether the VH influence on PPI and its dopaminergic regulation is dependent on the integrity of the VH-accumbens projection via the fornix. First, the PPI-disruptive effects of intra-VH NMDA infusion were assessed after sham or electrolytic transection of the fornix. Second, the PPI-disruptive effects of apomorphine were assessed 1 month after excitotoxic or electrolytic lesions of the VH, or after fornix transection. Intra-VH N-methyl-D-aspartate infusion significantly disrupted PPI; this effect was unaffected by fornix lesions. The PPI-disruptive effects of apomorphine were significantly enhanced by excitotoxic or electrolytic lesions of the VH, but not by fornix transection. The influence of the VH on PPI and its dopaminergic regulation does not appear to be mediated via the fornix. The enhanced sensitivity to the PPI-disruptive effects of apomorphine after VH lesions is not dependent on excitotoxin-induced changes in the VH or its downstream projections.

Effects of pergolide on sensorimotor gating of the startle reflex in rats.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders, including schizophrenia. This study was designed to assess the effects of the D2-family agonist pergolide in rats, in anticipation of human studies of the dopaminergic regulation of PPI. METHODS: The effects of pergolide (0.0001-0.5 mg/kg) on PPI of the acoustic startle reflex were studied in rats using a wide range of prepulse intensities [1-15 dB(A) over background] and prepulse intervals (5-100 ms, onset to onset). Studies also examined the effects of the D2 antagonist haloperidol on pergolide-induced changes in PPI. RESULTS: Pergolide exhibited dose- and stimulus-dependent effects on PPI. Pergolide increased PPI when startle stimuli were preceded by weak prepulses [1-5 dB(A) over background] at the longest prepulse interval (100 ms), or intense prepulses [15 dB(A) over background] at short prepulse intervals (5-20 ms). Pergolide (0.5 mg/kg) also decreased PPI elicited by intense prepulses at long intervals (60-100 ms). Both PPI-enhancing and PPI-disruptive effects of pergolide were reversed by the D2 antagonist haloperidol. CONCLUSIONS: These effects of pergolide suggest that D2 substrates mediate opposing influences on PPI under different stimulus conditions. The dopaminergic regulation of sensorimotor gating appears to interact with stimulus characteristics such as relative intensity and temporal separation, allowing for dynamic shifts in both the quantity and quality of "gated" information.

Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Reported strain and supplier-based differences in sensitivity to PPI-disruptive effects of DA agonists presumably reflect the differential impact of genetics and/or environment on DAergic substrates regulating PPI. In 2000, Harlan Laboratories established a Texas Sprague-Dawley line (SDHt; facility 211) using breeders from Indianapolis (SDHi; facility 202A). SDHi rats had been used, approximately 11 years earlier, to establish a colony in San Diego (SDHsd; facility 235). SDHt and SDHi rats are thus genetically similar, but raised in distinct environments; approximately 11 years of genetic "drift" separates SDHsd rats from both SDHi and SDHt rats. Harlan Long-Evans hooded rats (LEH; Madison, WI; facility 207) are genetically distinct from albino SDH. All except SDHsd rats were shipped to our facility by air freight. We used SDHt, SDHi, SDHsd, and LEH rats to assess genetic and environmental contributions to the DAergic regulation of PPI. Acoustic startle/PPI were assessed in rats treated with the D1/D2 agonist apomorphine (APO), the D2 agonist quinpirole, or the D1 agonist SKF 82958. The relative sensitivities to the PPI-disruptive effects were: APO: SDHt=SDHsd=SDHi>>LEH; SKF 82958: SDHt=SDHsd=SDHi (LEH not sensitive); quinpirole: SDHt=SDHsd=SDHi; SDHi>LEH. Strain/supplier differences in sensitivity to drug effects on startle magnitude did not correspond to patterns of PPI sensitivity. In these rats, strain differences in the DAergic regulation of PPI are most easily explained by genetic, rather than environmental influences that differentially impact both D1 and D2 substrates. This finding is consistent with published reports in other strains. Pharmacogenetic studies of PPI in rats may identify a genetic basis for a model of deficient sensorimotor gating in schizophrenia.

Lesion size and amphetamine hyperlocomotion after neonatal ventral hippocampal lesions: more is less.

Neonatal hippocampal lesions in rats produce behavioral and neurochemical abnormalities post-puberty that are used in animal models for developmentally linked pathology in schizophrenia. In one model, adult rats exhibit enhanced sensitivity to the locomotor-activating effects of amphetamine, if they had sustained excitotoxic lesions of the ventral hippocampus on post-natal day 7. The hippocampal elements responsible for these lesion-induced developmental changes have not been fully characterized. The present study assessed the locomotor-activating effects of amphetamine in adult rats that on day 7 had sustained either sham or ibotenic acid lesions of the ventral hippocampus alone ("standard lesions"), or the ventral hippocampus plus surrounding portions of entorhinal cortex and dorsal hippocampus ("large lesions"). "Standard lesions" produced the expected "supersensitive" locomotor response to amphetamine, while "large lesions" did not. No differences between these lesion groups were observed in baseline levels of locomotor activity or habituation. These data suggest that models of enhanced behavioral sensitivity to dopamine agonists after neonatal hippocampal lesions require functionality in the entorhinal cortex and/or dorsal hippocampus. It is possible that the behavioral abnormalities in the "neonatal hippocampal lesion model" reflect, at least in part, aberrant function within spared elements of the hippocampal complex.

Effects of caffeine on sensorimotor gating of the startle reflex in normal control subjects: impact of caffeine intake and withdrawal.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. This study was designed to assess caffeine effects on PPI in normal humans, as part of an effort to understand cross-species differences and similarities in the neurochemical regulation of PPI. METHODS: Startle was measured during a screening session; 7 days later, subjects were retested after placebo or caffeine (200 mg; double-blind design). Subjects were characterized as low versus high caffeine drinkers based on established scales (range 11-628 mg/day), and either maintained ad libitum caffeine intake (Ad lib study; n=18) or refrained from caffeine consumption for > or =15 h prior to testing (Withdrawal study; n=12). Autonomic and self-rating measures, acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in divided sessions for 3 h post-treatment. RESULTS: There were significant effects of caffeine and/or caffeine withdrawal on several self-rating and autonomic measures, and on startle reflex habituation, but not on acoustic or tactile startle magnitude or PPI. Difference scores of startle data from screening versus test days revealed no group effects on startle magnitude, but PPI difference scores revealed that caffeine had opposite effects on low versus high caffeine drinkers (means=57 versus 258 mg/day) in the two withdrawal states. In the absence of withdrawal, caffeine reduced PPI in heavy caffeine drinkers; during withdrawal, caffeine increased PPI in heavy caffeine drinkers. The opposite pattern was evident in low caffeine drinkers. CONCLUSIONS: While a physiologically active dose of caffeine has no simple effects on PPI in normal humans, both withdrawal states and normal levels of caffeine consumption may be important factors in understanding this drug's effects on sensorimotor gating.

Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Hippocampal lesions enhance startle gating-disruptive effects of apomorphine in rats: a parametric assessment.

Prepulse inhibition of the startle reflex is an operational measure of sensorimotor gating that is impaired in schizophrenia patients and dopamine agonist-treated rats. Previous reports demonstrated an enhanced sensitivity to the prepulse inhibition-disruptive effects of the D(1)/D(2) agonist apomorphine in adult rats four weeks after cytotoxic lesions of the hippocampus, but left unanswered several important questions regarding the nature of this apparent lesion-induced dopamine supersensitivity. Because of the potential importance of this model to current theories of the pathophysiology of schizophrenia, studies now assessed specific features of this effect of hippocampus lesions on prepulse inhibition in rats. The enhanced prepulse inhibition-disruptive effects of apomorphine in ventral hippocampus-lesioned rats were unaffected by startle pulse intensity, suggesting an independence of this lesion effect from potential ceiling effects of elevated startle magnitude. These lesion effects were observed four weeks post-lesion, but not two weeks post-lesion, suggesting a delayed development of this phenomenon. No enhancement of apomorphine sensitivity was observed in rats four weeks after lesions restricted to the dorsal hippocampus; in contrast, these lesions significantly increased "no-drug" levels of prepulse inhibition. Ventral hippocampus-lesioned rats exhibited a significant reduction in prepulse inhibition after subthreshold doses of either the selective D(2)-family agonist quinpirole or the partial D(1) agonist SKF 38393, suggesting that activation of either receptor family is adequate for the expression of this effect of ventral hippocampus lesions. This may be an important paradigm for understanding the contribution of ventral hippocampus dysfunction to the neurobiology of impaired sensorimotor gating in neuropsychiatric populations.

Sex differences in sensorimotor gating of the human startle reflex: all smoke?

RATIONALE: A recent report described sex differences in the effects of nicotine use and withdrawal on prepulse inhibition of acoustic startle (PPI), but no sex differences in PPI in non-smokers. OBJECTIVE: To determine whether previously reported male>female acoustic PPI reflect sex differences in smoking effects on PPI, rather than simple sex differences in the regulation of PPI. A retrospective analyses of >600 carefully screened normals tested over the past 12 years was completed. RESULTS: Male>female acoustic PPI was detected in analyses that included: 1) all subjects; or 2) self-declared non-smokers. CONCLUSIONS: Sex differences in PPI cannot be accounted for by smoking history, because they are present across a large sample of non-smoking normal controls.

The effect of pacing of experimental stimuli on observed functional MRI activity.

Neuroimaging activation studies typically observe signals during two or more periods of differing cognitive activity which are then analyzed by a subtraction to test for localized neuroanatomical dissociations between cognitive tasks. Significant activity found between task conditions is frequently assumed to reflect a novel cognitive process present in one task and not the other. We present a conceptual framework that considers the neural mechanisms underlying such observed neuroimaging changes. We propose that neuroimaging experiments which present stimuli at a fixed pace (where each trial takes the same amount of time) will be sensitive to changes in both duration and intensity of neural processing. In contrast, the signal observed during a self-paced design is derived from neural processing averaged over the reaction time and hence could be less sensitive to differences in duration of neural processing. As an empirical demonstration of these ideas, we studied normal subjects using echoplanar functional MRI during two visuospatial tasks (matching of either ROTATED or NONROTATED stimuli) performed using FIXED and SELF-PACED designs. In both pacing designs, reaction times were greater in the ROTATED than NONROTATED task, interpreted as a greater duration of neural processing during the ROTATED compared to the NONROTATED task. In the FIXED-PACED design, significantly greater signal was present within a parieto-occipital cortical region during the ROTATED task compared to the NONROTATED task. This difference was not observed during the SELF-PACED design. This result illustrates the importance of considering trial pacing in the interpretation of functional neuroimaging activation studies.

Changes in sensorimotor inhibition across the menstrual cycle: implications for neuropsychiatric disorders.

The startle reflex is inhibited when the starting noise is preceded 30-500 msec by a weak prepulse. "Prepulse inhibition" (PPI) is reduced in specific neuropsychiatric disorders characterized clinically by impaired inhibition of sensory, motor, or cognitive information. PPI is sexually dimorphic, with men exhibiting significantly more PPI than women. We examined possible neuroendocrine substrates for this sex difference in PPI. The startle reflex, and a measure of visuospatial priming, were measured in 10 men, and in 46 normal women at different points in their menstrual cycle. In women, PPI was significantly reduced in the luteal vs follicular phase of the menstrual cycle. This reduction in PPI was most notable during the period corresponding to midluteal elevations of both estrogen and progesterone. In a task of visuospatial priming, follicular-phase women demonstrated a predominance of inhibition over facilitation, but this pattern reversed across the menstrual cycle.

Environmental injuries.

Environmental injuries and illnesses can happen in home, work, or recreational settings. The variety and severity of these injuries might require the clinician to call on skills from internal medicine, emergency medicine, and toxicology. Diseases of thermoregulation are hypothermia and hyperthermia. In each instance, treatment is based on the need to restore the patient's core temperature to normal and on monitoring for complications. The victim of a fire might suffer inhalation injury in addition to burns, and it is more likely that the inhalation injury will be fatal. Oxygen deprivation and inhalation of irritant or asphyxiant chemicals contribute to injury. Toxic plants can be the source of poisoning emergencies, especially in children. Misinformation and myths that surround common plants can create diagnostic problems (i.e., which plants really are toxic and require emergency measures). Venomous marine organisms can cause a wide range of injury, from cutaneous eruption to fatal envenomation. Most are encountered in a recreational setting, such as water sports, but keepers of home aquariums are subject to stings from venomous fish. Lightning injury can present many diagnostic and treatment dilemmas. An important point in this regard is that lightning injury and high-voltage electrical injury are different in pathology and require different approaches for treatment. A discussion of electrical, chemical, and thermal burns makes such differences apparent.

Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine.

Whether the primary mechanisms of migraine are vascular or neurogenic is, as yet, unresolved. In humans it is still unclear whether sumatriptan acts via constriction of dilated arteries or through other mechanisms. Doppler sonography is a non-invasive method for measuring blood flow velocities (BFV), an indirect marker of vessel diameter. This double-blind crossover placebo-controlled trial investigated changes in BFV in extra- and intracranial arteries in 132 migraine attacks (66 patients) before and after treatment with either 6 mg sumatriptan s.c. or placebo. Significant increases in BFV were observed only in the middle cerebral artery (MCA) and the basilar artery (BA) after administration of sumatriptan. However, the majority of the patients showed no change in BFV following sumatriptan. No difference in BFV could be detected between headache and non-headache side or between migraine and headache free periods. Despite a slight increase in BFV in intracerebral arteries, this study does not support the concept that vasoconstriction is sumatriptan's principal mechanism in pain relief.