Behavioural clusters and predictors of performance during recovery from stroke.

We examined the patterns and variability of recovery post-stroke in multiple behavioral domains. A large cohort of first time stroke patients with heterogeneous lesions was studied prospectively and longitudinally at 1-2 weeks, 3 months and one year post-injury with structural MRI to measure lesion anatomy and in-depth neuropsychological assessment. Impairment was described at all timepoints by a few clusters of correlated deficits. The time course and magnitude of recovery was similar across domains, with change scores largely proportional to the initial deficit and most recovery occurring within the first three months. Damage to specific white matter tracts produced poorer recovery over several domains: attention and superior longitudinal fasciculus II/III, language and posterior arcuate fasciculus, motor and corticospinal tract. Finally, after accounting for the severity of the initial deficit, language and visual memory recovery/outcome was worse with lower education, while the occurrence of multiple deficits negatively impacted attention recovery.

The circuitry of abulia: insights from functional connectivity MRI.

BACKGROUND: Functional imaging and lesion studies have associated willed behavior with the anterior cingulate cortex (ACC). Abulia is a syndrome characterized by apathy and deficiency of motivated behavior. Abulia is most frequently associated with ACC damage, but also occurs following damage to subcortical nuclei (striatum, globus pallidus, thalamic nuclei). We present resting state functional connectivity MRI (fcMRI) data from an individual who suffered a stroke leading to abulia. We hypothesized that, although structural imaging revealed no damage to the patient's ACC, fcMRI would uncover aberrant function in this region and in the relevant cortical networks. METHODS: Resting state correlations in the patient's gray matter were compared to those of age-matched controls. Using a novel method to identify abnormal patterns of functional connectivity in single subjects, we identified areas and networks with aberrant connectivity. RESULTS: Networks associated with memory (default mode network) and executive function (cingulo-opercular network) were abnormal. The patient's anterior cingulate was among the areas showing aberrant functional connectivity. In a rescan 3 years later, deficits remained stable and fcMRI findings were replicated. CONCLUSIONS: These findings suggest that the aberrant functional connectivity mapping approach described may be useful for linking stroke symptoms to disrupted network connectivity.

Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance.

AIMS/HYPOTHESIS: Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. METHODS: We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. RESULTS: Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. CONCLUSIONS/INTERPRETATION: These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.

Independence of anticipatory signals for spatial attention from number of nontarget stimuli in the visual field.

Covertly attending to a location modulates the activity of visual areas even in the absence of visual stimulation. These effects are widespread, being found in the cortical representations of both attended and unattended portions of the visual field. It is not clear, however, whether preparatory modulations depend on subjects' expectation regarding the presence of additional nontarget stimuli in the visual field. Here, we asked subjects to endogenously direct attention to a peripheral location in the upper visual field, to identify the orientation of a low-contrast target stimulus, and we manipulated the number and behavioral relevance of other low-contrast nontarget stimuli in the visual field. Anticipatory (i.e., prestimulus) blood oxygenation level-dependent (BOLD) signal increments in visual cortex were strongest at the contralateral attended location, whereas signal decrements were strongest at the unattended mirror-opposite ipsilateral location/region of visual cortex. Importantly, these strong anticipatory decrements were not related to the presence/absence of nontarget low-contrast stimuli and did not correlate with either weaker target-evoked responses or worse performance. Second, the presence of other low-contrast stimuli in the visual field, even when potential targets, did not modify the anticipatory signal modulation either at target or nontarget locations. We conclude that the topography of spatial attention-related anticipatory BOLD signal modulation across visual cortex, specifically decrements at unattended locations, is mainly determined by processes at the cued location and not by the number or behavioral relevance of distant low-contrast nontarget stimuli elsewhere in the visual field.

Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.

OBJECTIVES: To determine the prevalence of impaired insulin sensitivity among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. METHODS: Eligible subjects were nondiabetic men and women over age 45 years who were hospitalized with a TIA or ischemic stroke. To measure insulin sensitivity, subjects underwent an oral glucose tolerance test between 2 and 6 months after their event. Impaired insulin sensitivity was defined by a value of < or =2.5 on the Composite Insulin Sensitivity Index derived from insulin and glucose values during the test. RESULTS: Between July 2000 and June 2001, we identified 177 eligible patients, among whom 105 declined to participate and 72 enrolled. The median age of participants was 71 years and 46 (64%) were men. The baseline event was stroke for 57 subjects (79%). A history of myocardial infarction (MI) was reported by 14 subjects (19%), and 16 (22%) were obese (body mass index > 30). Fasting glucose was normal (<110 mg/dL) for 58 (80%) participants and impaired (110 to 125 mg/dL) for 14 (20%). Among 72 participants, the median insulin sensitivity index value was 2.6 (range 0.9 to 10.2). The prevalence of impaired insulin sensitivity was 36 of 72 (50%, 95% CI 38% to 62%). Impaired insulin sensitivity was more prevalent among younger patients and patients with obesity, lacunar stroke etiology, and disability (Rankin grade >1). CONCLUSION: Impaired insulin sensitivity is highly prevalent among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. This finding has important therapeutic implications if treatment to improve insulin sensitivity is shown to reduce risk for subsequent stroke and heart disease.

Teaching with a video system improves the training period but not subsequent success of tracheal intubation with the Bullard laryngoscope.

BACKGROUND: The Bullard laryngoscope is useful for the management of a variety of airway management scenarios. Without the aid of a video system, teaching laryngoscopy skills occurs with indirect feedback to the instructor. The purpose of this study was to determine if use of a video system would speed the process of learning the Bullard laryngoscope or improve the performance (speed or success) of its use. METHODS: Thirty-six anesthesia providers with no previous Bullard laryngoscope experience were randomly divided into two groups: initial training (first 15 intubations) with looking directly through the eyepiece (n = 20), or with the display of the scope on a video monitor (n = 16). The subjects each then performed 15 Bullard intubations by looking directly through the eyepiece. RESULTS: There was not an overall significant difference in laryngoscopy or intubation times between the groups. When only the first 15 intubations were considered, the laryngoscopy time was shorter in the video group (26 +/- 24) than in the nonvideo group (32 +/- 34; P< 0.04). In the first 15 patients, there were fewer single attempts at intubation (67.9% vs 80.3%; P< 0.002) and more failed intubations (17.2% vs 6.0%; P< 0.0001) in the nonvideo group. CONCLUSIONS: In conclusion, the authors have shown that use of a video camera decreases time for laryngoscopic view and improves success rate when the Bullard laryngoscope is first being taught to experienced clinicians. However, these benefits are not evident as more experience with the Bullard laryngoscope is achieved, such that no difference in skill with the Bullard laryngoscope is discernible after 15 intubations whether a video system was used to teach this technique.

Cellular mechanism of insulin resistance: potential links with inflammation.

Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.

Bilateral pneumothoraces in a pediatric patient undergoing Hickman catheter placement.

IMPLICATIONS: The laryngeal mask airway (LMA) is often used for airway management in pediatric patients. We report bilateral pneumothoraces in a patient who underwent neck surgery whose airway was managed with a LMA. We recommend that the LMA be used with caution in small children undergoing deep-neck dissection.

AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat.

Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that alpha-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.

Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.

Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.

Intraoperative autotransfusion in hip arthroplasty.

Two groups of patients having primary or revision total hip replacement were studied during a period of 11 months. The first group of 40 consecutive patients consented to have whole blood collected coincident with acute normovolemic hemodilution. An inventory of autologous red blood cells, plasma, and platelets was prepared in the operating room as a preliminary to surgery. Subsequently, the same supplies and equipment were used for autotransfusion intraoperatively. In a case-control study, another 40 patients having total hip replacements were matched for age, gender, and weight. The second group of patients refused hemodilution and received autotransfusion alone. The perioperative transfusion requirements of the two groups were compared. The total blood product donor exposure rate of the first group was 1/4 of the controls (0.6 and 2.4 donor units per patient, respectively). The average length of stay in the hospital after surgery for the first group was shortened significantly (6.2 versus 8.4 days), possibly from less immunogenic insult associated with increased transfusions of autologous blood products. Hemodilution, followed by autotransfusion, was cost effective in primary and revision total hip replacements, autotransfusion alone was cost effective only in revision arthroplasty.

Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis.

The underlying mechanism by which skeletal muscle adapts to exercise training or chronic energy deprivation is largely unknown. To examine this question, rats were fed for 9 wk either with or without beta-guanadinopropionic acid (beta-GPA; 1% enriched diet), a creatine analog that is known to induce muscle adaptations similar to those induced by exercise training. Muscle phosphocreatine, ATP, and ATP/AMP ratios were all markedly decreased and led to the activation of AMP-activated protein kinase (AMPK) in the beta-GPA-fed rats compared with control rats. Under these conditions, nuclear respiratory factor-1 (NRF-1) binding activity, measured using a cDNA probe containing a sequence encoding for the promoter of delta-aminolevulinate (ALA) synthase, was increased by about eightfold in the muscle of beta-GPA-fed rats compared with the control group. Concomitantly, muscle ALA synthase mRNA and cytochrome c content were also increased. Mitochondrial density in both extensor digitorum longus and epitrochlearis from beta-GPA-fed rats was also increased by more than twofold compared with the control group. In conclusion, chronic phosphocreatine depletion during beta-GPA supplementation led to the activation of muscle AMPK that was associated with increased NRF-1 binding activity, increased cytochrome c content, and increased muscle mitochondrial density. Our data suggest that AMPK may play an important role in muscle adaptations to chronic energy stress and that it promotes mitochondrial biogenesis and expression of respiratory proteins through activation of NRF-1.

Effect of triiodothyronine on mitochondrial energy coupling in human skeletal muscle.

The mechanism underlying the regulation of basal metabolic rate by thyroid hormone remains unclear. Although it has been suggested that thyroid hormone might uncouple substrate oxidation from ATP synthesis, there are no data from studies on humans to support this hypothesis. To examine this possibility, we used a novel combined (13)C/(31)P nuclear magnetic resonance (NMR) approach to assess mitochondrial energy coupling in skeletal muscle of seven healthy adults before and after three days of triiodothyronine (T(3)) treatment. Rates of ATP synthesis and tricarboxylic acid (TCA) cycle fluxes were measured by (31)P and (13)C NMR spectroscopy, respectively, and mitochondrial energy coupling was assessed as the ratio. Muscle TCA cycle flux increased by approximately 70% following T(3) treatment. In contrast, the rate of ATP synthesis remained unchanged. Given the disproportionate increase in TCA cycle flux compared with ATP synthesis, these data suggest that T(3) promotes increased thermogenesis in part by promoting mitochondrial energy uncoupling in skeletal muscle.

Prevention of fat-induced insulin resistance by salicylate.

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-(3)H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-(14)C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.

Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes.

Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. Expression of KR-IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic beta-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.

Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.

beta cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of beta cell glucose sensing, and as a critical link between obesity, beta cell dysfunction, and type 2 diabetes.

Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4.

Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin's ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.

Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta).

Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.