Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism.

AIMS/HYPOTHESIS: It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. SUBJECTS AND METHODS: We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. RESULTS: After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. CONCLUSIONS/INTERPRETATION: Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

Acute regulation of plasma leptin by isoprenaline in lean and obese fasted subjects.

AIM: In human obesity, there is some evidence for impaired adrenergic sensitivity with respect to catecholamine-induced lipolysis. The beta-adrenoceptor agonist isoprenaline has been shown to suppress plasma leptin levels in lean humans in vivo. We hypothesized that a reduced adrenergic sensitivity in obese humans would result in impaired suppression of leptin secretion. METHODS: Eight obese [Ob, body mass index (BMI) = 33.3 kg/m2] and seven lean (Ln, BMI = 21.8 kg/m2) men were studied after an overnight fast. Intravenous isoprenaline infusion was initiated at a rate of 8 ng/kg/min, titrated up to 24 ng/kg/min over 30 min and continued at this rate for a further 120 min with continuous electrocardiogram monitoring. RESULTS: Baseline fasting plasma leptin was higher in obese compared with lean subjects (Ob 12.2 +/- 1.8, Ln 2.6 +/- 0.6 ng/ml, p < 0.05 unpaired t-test). Baseline fasting glycerol as a measure of lipolysis was similar in both groups (Ob 62.9 +/- 7.6, Ln 42.4 +/- 8.9 micromol/l) and increased from baseline to 150 min by equivalent amounts (Ob +66.9%, Ln +81.2%, p = NS). Plasma leptin decreased from baseline to 150 min with similar relative changes in both groups (Ob -29.2%, Ln -27.8%). CONCLUSIONS: Obese subjects show a similar lipolytic and leptin response to acute isoprenaline infusion compared with lean subjects. Impaired beta-adrenergic-induced inhibition of leptin secretion does not appear to contribute to hyperleptinaemia in obese human subjects.

The neural substrates of visual implicit memory: do the two hemispheres play different roles?

Identification of visually presented words is facilitated by implicit memory, or visual priming, for past visual experiences with those words. There is disagreement over the neuro-anatomical substrates of this form of implicit memory. Several studies have suggested that this form of priming relies on a visual word-form system localized in the right occipital lobe, whereas other studies have indicated that both hemispheres are equally involved. The discrepancies may be related to the types of priming tasks that have been used because the former studies have relied primarily on word-stem completion tasks and the latter on tasks like word-fragment completion. The present experiments compared word-fragment and word-stem measurements of visual implicit memory in patients with right occipital lobe lesions and patients with complete callosotomies. The patients showed normal visual implicit memory on fragment completion tests, but essentially no visual priming on standard stem completion tests. However, when we used a set of word stems that had only one correct solution for each test item, as was true of the items in the fragment completion tests, the patients showed normal priming effects. The results indicate that visual implicit memory for words is not solely dependent upon the right hemisphere, rather it reflects changes in processing efficiency in bilateral visual regions involved in the initial processing of the items. However, under conditions of high lexical competition (i.e., multiple completion word stems), the lexical processes, which are dominant in the left hemisphere, overshadow the visual priming supported by the left hemisphere.

Form-specific visual priming in the left and right hemispheres.

Word fragment completion performance was examined for items that were presented in the same or different letter case at study and test. During the study phase words and nonwords were presented at central fixation, then during the test phase a divided visual field technique was used in which word fragments were presented briefly to the right hemisphere (left visual field) or the left hemisphere (right visual field). Previous research using the word stem completion task indicated that only the right hemisphere was sensitive to case changes in words from study to test. In contrast, the current results indicate that in the fragment completion task the priming effects for the test items presented to either hemisphere were greater when the fragments were in the same compared to different letter case at study and test. These results indicate that both hemispheres are capable of supporting form-specific visual implicit memory.

Visual implicit memory in the left hemisphere: evidence from patients with callosotomies and right occipital lobe lesions.

Identification of visually presented objects and words is facilitated by implicit memory for past visual experiences with those items. Several behavioral and neuroimaging studies suggest that this form of memory is dependent on perceptual processes localized in the right occipital lobe. We tested this claim by examining implicit memory in patients with extensive right occipital lobe lesions, using lexical-decision mirror-reading, picture-fragment, and word-fragment-completion tests, and found that these patients exhibited normal levels of priming. We also examined implicit memory in patients with complete callosotomies, using standard and divided-visual-field word-fragment-completion procedures, and found that the isolated left hemisphere exhibited normal priming effects. The results indicate that the right occipital lobe does not play a necessary role in visual implicit memory, and that the isolated left hemisphere can support normal levels of visual priming in a variety of tasks.

Hippocampal, parahippocampal and occipital-temporal contributions to associative and item recognition memory: an fMRI study.

The temporal lobe regions involved in memory retrieval were examined using fMRI. During an associative recognition test, participants made memory judgments about the study color of previously presented drawings of objects, and during item recognition tests they made old/new judgments about previously studied objects or new objects. Associative recognition compared with old item recognition led to activations in bilateral hippocampal and parahippocampal regions, as well as in the left middle occipital gyrus. Old item recognition compared with new item recognition led to activation in the left middle occipital gyrus and the left middle temporal gyrus, and relative deactivations in bilateral hippocampal regions. The results indicate that partially distinct temporal lobe regions are involved during recognition memory for item and associative information.

Anterior and posterior callosal contributions to simultaneous bimanual movements of the hands and fingers.

In order to study the role of the corpus callosum in two-handed coordination we tested callosotomy subjects while they attempted to initiate simultaneous discrete movements with both hands. We observed four split-brain patients, including one pre- and post-operatively, as well as normal and epileptic control subjects. Split-brain patients made button presses that were less synchronous than either normal or epileptic controls. Although split-brain patients' average performance did not always differ from control subjects, callosotomy resulted in a 3-fold increase in the variability with which 'simultaneous' movements were initiated. The one subject tested pre- and post-callosotomy showed distinct changes in movement initiation synchrony after both the anterior and the posterior stages of the surgery. These changes suggest that anterior and posterior callosal fibres may make unique contributions to bimanual synchronization, depending on whether responses are self-initiated or in reaction to a visual stimulus. This study demonstrates that neural communication across anterior and posterior fibres of the corpus callosum strongly influences the temporal precision of bimanual coordination. Specifically, callosal transmission affects the degree of bilateral synchrony with which simple simultaneous hand and finger movements are initiated.

Auditory scene analysis in dyslexics.

It has been argued that dyslexics suffer from temporal sensory processing deficits which affect their ability to discriminate speech in quiet environments. The impact of auditory deficits on non-language aspects of perception, however, is poorly understood. In almost every natural-listening environment, one must constantly construct scenes of the auditory world by grouping and analyzing sounds generated by multiple sources. We investigated whether dyslexics have difficulties grouping sounds. The results demonstrate that dyslexics have an impairment in grouping auditory objects that depends both on the sounds' frequency and presentation rate (i.e. the spectrotemporal context of the sound). We conclude that dyslexics have difficulty constructing scenes of the auditory world, and that these deficits can contribute to learning impairments.

Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity.

AIMS/HYPOTHESIS: Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported. METHODS: Phosphoinositide 3-kinase p85 alpha regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85 alpha were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85 alpha-GST fusion proteins were examined by surface plasmon resonance. RESULTS: The common p85 alpha variant, Met326I1e, was identified in 9 of the 20 subjects. Functional studies of the Met326Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85 alpha. A novel heterozygous mutation, Arg409Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg409Gln p85 alpha subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15%, p < 0.05, n = 5). The recruitment of Arg409Gln p85 alpha into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85 alpha showed identical binding to phosphopeptides in surface plasmon resonance studies. CONCLUSION/INTERPRETATION: Mutations in p85 alpha are uncommon in subjects with syndromes of severe insulin resistance. The Met326Ile p85 alpha variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg409Gln mutant suggests that it could contribute to the insulin resistance seen in this family.

Direction information coordinated via the posterior third of the corpus callosum during bimanual movements.

We examined bimanual coordination in a patient before and after each stage of callosotomy surgery. We tested how well the patient coordinated movement direction between the hands. The patient drew symmetrical or asymmetrical figures simultaneously with both hands. Before surgery, symmetrical figures were drawn well and asymmetrical figures were drawn poorly. Following anterior callosotomy, the drawings improved slightly. Symmetrical figures were still drawn well, and asymmetrical ones were still drawn poorly. Thus, spatial integration remained intact despite the loss of interhemispheric communication between frontal cortical sites. After posterior callosotomy, spatial coordination deteriorated significantly. Mirror-image drawings became less symmetrical, while asymmetrical drawings improved. These data indicate that the posterior callosum mediates the coordination of direction information between the hands during bimanual movements. Given the topographical organization of the corpus callosum, this integration is likely carried out by parietal cortex.

Chronic auditory agnosia following Landau-Kleffner syndrome: a 23 year outcome study.

We report a 27-year-old woman with chronic auditory agnosia following Landau-Kleffner Syndrome (LKS) diagnosed at age 4 1/2. She grew up in the hearing/speaking community with some exposure to manually coded English and American Sign Language (ASL). Manually coded (signed) English is her preferred mode of communication. Comprehension and production of spoken language remain severely compromised. Disruptions in auditory processing can be observed in tests of pitch and duration, suggesting that her disorder is not specific to language. Linguistic analysis of signed, spoken, and written English indicates her language system is intact but compromised because of impoverished input during the critical period for acquisition of spoken phonology. Specifically, although her sign language phonology is intact, spoken language phonology is markedly impaired. We argue that deprivation of auditory input during a period critical for the development of a phonological grammar and auditory-verbal short-term memory has limited her lexical and syntactic development in specific ways.

Selective oestrogen receptor modulators: a new paradigm for HRT.

Selective oestrogen receptor modulators are a range of compounds which mimic some, but not all, agonist actions of oestrogen in different tissues. They were developed with the aim of maximizing the benefits of oestrogen-like drugs in a number of important conditions whilst reducing adverse side-effects. The molecular biology of oestrogen receptor signalling is discussed in relation to the pharmacological effects of this class of drugs. The results of clinical trial data with one member of this group (raloxifene) are documented and future developments outlined.

Modular organization of cognitive systems masked by interhemispheric integration.

After resection of the corpus callosum, V.J., a left-handed woman with left-hemisphere dominance for spoken language, demonstrated a dissociation between spoken and written language. In the key experiment, words flashed to V.J.'s dominant left hemisphere were easily spoken out loud, but could not be written. However, when the words were flashed to her right hemisphere, she could not speak them out loud, but could write them with her left hand. This marked dissociation supports the view that spoken and written language output can be controlled by independent hemispheres, even though before her hemispheric disconnection, they appeared as inseparable cognitive entities.

Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance.

Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.

Isolation of a right hemisphere cognitive system in a patient with anarchic (alien) hand sign.

We report evidence of isolated conceptual knowledge in the right hemisphere of a woman with chronic anarchic hand sign after ischemic infarction of the central four-fifths of the corpus callosum. Limited visual information was available to the right hemisphere, access to medial temporal structures subserving memory was disrupted and disconnection from left hemisphere language structures was complete. Still, the right hemisphere could build mental representations of objects via tactile input and use them in cross-modal matching. These representations were not accessed consistently in auditory comprehension or naming tasks. This functional specificity and its pathoanatomical correlates demonstrate that the study of anarchic hand sign can illuminate not just motor control issues but may inform our understanding of the representation and lateralization of conceptual knowledge as well.

Vitamin D, glucose tolerance and insulinaemia in elderly men.

Vitamin D status was assessed in 142 elderly Dutchmen participating in a prospective population-based study of environmental factors in the aetiology of non-insulin-dependent diabetes mellitus. Of the men aged 70-88 years examined between March and May 1990, 39% were vitamin D depleted. After adjustment for confounding by age, BMI, physical activity, month of sampling, cigarette smoking and alcohol intake the 1-h glucose and area under the glucose curve during a standard 75-g oral glucose tolerance test (OGTT) were inversely associated with the serum concentration of 25-OH vitamin D (r = -0.23, p < 0.01; r = -0.26, p < 0.01, respectively). After excluding newly diagnosed diabetic patients total insulin concentrations during OGTT were also inversely associated with the concentration of 25-OH vitamin D (r = -0.18 to -0.23, p < 0.05). Hypovitaminosis D may be a significant risk factor for glucose intolerance.

Memory encoding following complete callosotomy.

Three patients with complete resection of the corpus callosum were tested in a series of memory tasks to determine the effects of callosotomy on the encoding and retrieval of information in memory. Verbal and pictorial conjunction tests were administered to measure patients' ability to consolidate the elements of a stimulus into an accurate composite memory. Patients were also tested in a paired-associate learning task to determine the consequences of callosotomy on the encoding and retrieval of associations between stimuli. Although callosotomy patients were unimpaired in the verbal conjunction task, results from both the pictorial conjunction task and the paired-associate learning task suggest that the absence of callosal cross-talk impairs encoding in these patients. In addition, the pattern of results in the paired-associate learning task suggests that callosotomy impairs retrieval processes. The role of the callosum in the formation of memory traces for nonverbal material and associations between verbal stimuli is discussed.

Collaboration between the hemispheres of a callosotomy patient. Emerging right hemisphere speech and the left hemisphere interpreter.

Split brain patients who are initially unable to produce speech in their right hemispheres sometimes develop the ability to do so. Patient J.W., the subject of this report, is such a patient. At the time of his callosotomy, J.W. had a language dominant left hemisphere; his right hemisphere could understand both spoken and written language, but he was unable to speak. Fourteen years after his surgery, we found that J.W. was capable of naming approximately 25% of the stimuli presented to his left visual field (LVF). Now, 1 year later, we find that he can name about 60% of such stimuli. This late-developing speech ability appears to be consequence of long-term neural plasticity. However, the subject's extended verbal responses to LVF stimuli seem to result from a collaboration between the hemispheres and to involve the left hemisphere interpreter.