Gastric distention during meal ingestion activates vagal afferents, which send signals from the stomach to the brain and result in the perception of fullness and satiety. Distention is one of the mechanisms that modulates food intake. We measured regional brain activation during dynamic gastric balloon distention in 18 health subjects using functional magnetic resonance imaging and the blood oxygenation level-dependent (BOLD) responses. The BOLD signal was significantly changed by both inflow and outflow changes in the balloon's volume. For lower balloon volumes, water inflow was associated with activation of sensorimotor cortices and right insula. The larger volume condition additionally activated left posterior amygdala, left posterior insula and the left precuneus. The response in the left amygdala and insula was negatively associated with changes in self-reports of fullness and positively with changes in plasma ghrelin concentration, whereas those in the right amygdala and insula were negatively associated with the subject's body mass index. The widespread activation induced by gastric distention corroborates the influence of vagal afferents on cortical and subcortical brain activity. These findings provide evidence that the left amygdala and insula process interoceptive signals of fullness produced by gastric distention involved in the controls of food intake.

BACKGROUND

The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated patient-reported outcome (PRO) containing both generic scales and scales specific to cystic fibrosis (CF). The minimal clinically important difference (MCID) score for a PRO corresponds to the smallest clinically relevant change a patient can detect. MCID scores for the CFQ-R respiratory symptom (CFQ-R-Respiratory) scale were determined using data from two 28 day, open-label, tobramycin inhalation solution (TIS) studies in patients with CF and chronic Pseudomonas aeruginosa airway infection. At study enrollment, patients in the study 1-exacerbation had symptoms indicative of pulmonary exacerbation (n = 84; < 14 years of age, 31 patients;>> or = 14 years of age, 53 patients); patients in study 2-stable had stable respiratory symptoms (n = 140; < 14 years of age, 14 patients;>> or = 14 years, 126 patients).

METHODS

The anchor-based method utilized a global rating-of-change questionnaire (GRCQ) that assessed patients' perceptions of change in their respiratory symptoms after TIS treatment. The mean change from baseline CFQ-R-Respiratory scores were mapped onto the GRCQ to estimate the MCID. The two distribution-based methods were as follows: (1) 0.5 SD of mean change in CFQ-R-Respiratory scores (baseline to end of TIS treatment); and (2) 1 SEM for baseline CFQ-R-Respiratory scores. Triangulation of these three estimates defined the MCIDs.

RESULTS

MCID scores were larger for patients in study 1-exacerbation (8.5 points) than for those in study 2-stable (4.0 points), likely reflecting differences in patient disease status (exacerbation/stable) between these studies.

CONCLUSIONS

Patient benefit from new and current CF therapies can be evaluated using changes in CFQ-R-Respiratory scores. Using the MCID provides a systematic way to interpret these changes, and facilitates the identification of CF treatments that improve both symptoms and physiologic variables, potentially leading to better treatment adherence and clinical outcomes. Trial registration (study 1-exacerbation): Australian-New Zealand Clinical Trials Registry Identifier: ACTRN 12605000602628 Trial registration (study 2-stable): ClinicalTrials.gov Identifier: NCT00104520.

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.

OBJECTIVE

To further evaluate the efficacy and safety of an injectable mixed subtype collagenase for the treatment of Dupuytren's contracture (DC).

METHODS

Patients with flexion deformities of the metacarpophalangeal (MCP) and/or the proximal interphalangeal (PIP) joints of 20 degrees or greater were randomized in a double-blind, placebo-controlled trial. Patients completing this phase could enter an open-label extension phase. The primary efficacy variable was clinical success: contracture correction to within 5 degrees of normal (normal, 0 degrees ). Additional efficacy variables included the time and number of injections required to achieve success in the primary joint. Recurrence of contracture to 20 degrees or greater in successfully treated joints and adverse events (AEs) were recorded.

RESULTS

Thirty-three of 35 patients (mean +/- SD, 61 +/- 9 y) entering the double-blind phase completed the study; 19 of them entered the open-label extension. In the double-blind phase, clinical success of the primary joint was achieved in 16 of 23 patients receiving 1 injection and in 21 of 23 patients receiving 3 injections. No placebo-treated patients achieved joint correction. In the open-label extension, 17 of 19 patients achieved clinical success in at least 1 joint. The mean number of injections for clinical success in the double-blind and extension phases was 1.5 and 1.4, respectively; the time to clinical success ranged between 1 and 29 days. Overall, of 62 joints (31 MCP, 31 PIP) treated in 35 patients, 54 joints achieved clinical success. Over the 24-month follow-up period after the last injection, 5 joints had a recurrence. The most frequent treatment-related AEs were local reactions to injections. AEs were mild and resolved over several weeks. There were no serious treatment-related AEs.

CONCLUSIONS

The collagenase injections safely and effectively corrected MCP and PIP contractures in patients with 1 or more DC-affected joints. Recurrence rates after treatment appear to be low. Data suggest that this collagenase appears to be a viable nonsurgical treatment option for DC.

OBJECTIVE

To relate neuropsychological performance to measures of cerebral injury in persons with MS selected for cognitive impairment.

METHODS

Participants were 37 individuals with relapsing-remitting (59.5%) and secondary progressive (40.5%) MS. They were tested at baseline as part of a clinical trial to enhance cognition with an acetylcholinesterase inhibitor. Eligibility criteria included at least mild cognitive impairment on a verbal learning and memory task. A modified Brief Repeatable Battery of Neuropsychological Tests formed the core of the behavioral protocol. Neuroimaging measures were central (ventricular) cerebral atrophy, lesion volume, and ratios of N-acetyl aspartate (NAA) to both creatine and choline.

RESULTS

A clear, consistent relation was found between cognitive and MR measures. Among neuroimaging measures, central atrophy displayed the highest correlations with cognition, accounting for approximately half the variance in overall cognitive performance. NAA ratios in right hemisphere sites displayed larger correlations than those on the left. Multiple regression models combining the MR measures accounted for well over half the variance in overall cognitive performance. The Symbol Digit Modalities Test was the neuropsychological task most strongly associated with the neuroimaging variables.

CONCLUSIONS

If a strong and stable association can be firmly established between cognitive and MR variables in appropriate subsets of MS patients, it might aid in the investigation of interventions to enhance cognition and modify the course of the disease.

Previous research suggests that many preschoolers meet criteria for psychiatric diagnoses; still, relatively little is known about preschool mental health, particularly emotional problems, in the community. This study investigated the rates of parent-reported DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) disorders in a large community sample of preschoolers using the Preschool Age Psychiatric Assessment (PAPA). Five hundred forty-one parents were interviewed with the PAPA. Of the children, 27.4% met criteria for a PAPA/DSM-IV diagnosis; 9.2% met criteria for 2 or more diagnoses. Oppositional defiant disorder (ODD) (9.4%), specific phobia (9.1%), and separation anxiety disorder (5.4%) were the most common diagnoses; depression (1.8%), selective mutism (1.5%), and panic disorder (0.2%) were the least common. In addition, there was significant comorbidity/covariation between depression, anxiety, and ODD and between ODD and attention-deficit/hyperactivity disorder (odds ratios = 1.81-18.44; P < .05), and significant associations with measures of psychosocial functioning. The stability and clinical significance of diagnoses and patterns of comorbidity must be elucidated in future research.

OBJECTIVE

The purpose of the present study was to evaluate the efficacy of divalproex for reducing aggressive behavior among children 6 to 13 years old with attention deficit hyperactivity disorder (ADHD) and a disruptive disorder whose chronic aggression was underresponsive to a prospective psychostimulant trial.

METHODS

Children received open stimulant treatment during a lead-in phase that averaged 5 weeks. Agent and dose were assessed weekly and modified to optimize response. Children whose aggressive behavior persisted at the conclusion of the lead-in phase were randomly assigned to receive double-blind, flexibly dosed divalproex or a placebo adjunctive to stimulant for 8 weeks. Families received weekly behavioral therapy throughout the trial. The primary outcome measure was the proportion of children whose aggressive behavior remitted, defined by post-trial ratings of negligible or absent aggression.

RESULTS

A significantly higher proportion of children randomly assigned to divalproex met remission criteria (eight out of 14 [57%]) than those randomly assigned to placebo (two out of 13 [15%]). Divalproex was generally well tolerated.

CONCLUSIONS

Among children with ADHD whose chronic aggressive behavior is refractory to optimized stimulant treatment, the addition of divalproex increases the likelihood that aggression will remit. A larger trial is necessary to specify with greater precision the magnitude of benefit for adjuvant divalproex.

Modern imaging techniques enable researchers to observe drug actions and consequences as they occur and persist in the brains of abusing and addicted individuals. This article presents the five most commonly used techniques, explains how each produces images, and describes how researchers interpret them. The authors give examples of key findings illustrating how each technique has extended and deepened our knowledge of the neurobiological bases of drug abuse and addiction, and they address potential clinical and therapeutic applications.

Surgical fasciectomy is the currently accepted treatment of Dupuytren's disease. The goal of this study was to test the clinical safety and efficacy of clostridial collagenase injection as a nonsurgical treatment of Dupuytren's disease in a phase II open-label trial. Thirty-five Dupuytren's disease patients entered the study (32 men and 3 women). The mean age was 65 years. The first 6 patients were treated following a dose escalation protocol and received 300, 600, 1,200, 2,400, 4,800, and 9,600 U collagenase injected into the cord that was causing contracture of the metacarpophalangeal (MCP) joint. There were no beneficial clinical effects of these injections. The remaining 29 patients had collagenase injections at a dose level of 10,000 U, causing contractures of 34 MCP joints, 9 proximal interphalangeal (PIP) joints, and 1 thumb. Twenty-eight of the 34 MCP joint contractures corrected to normal extension (0 degrees ) and 2 of the 34 MCP joint contractures corrected to 5 degrees of normal extension, with full range of motion, within 1 to 14 days of injection. In the patients with PIP joint contractures, 4 of the 9 joints corrected to normal (0 degrees ). One PIP joint corrected to within 10 degrees of normal and 2 corrected to within 15 degrees of normal. There were 2 failures; these patients will require surgery. The mean follow-up period was 20.0 +/- 5.6 months for the MCP joints and 14.1 +/- 6.6 months for the PIP joints. Clostridial collagenase injection of Dupuytren's cords causing MCP and PIP joint contractures appears to have merit as nonsurgical treatment of this disorder. Pending further placebo, double-blind studies, collagenase injection to treat Dupuytren's disease may be a safe and effective alternative to surgical fasciectomy.

OBJECTIVE

Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.

METHODS

We used positron emission tomography and [(11)C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands.

RESULTS

Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005).

CONCLUSIONS

Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.

The error-related negativity (ERN) is an event-related brain potential observed in adults when errors are committed, and which appears to be sensitive to error value. Recent work suggests that the ERN can also be elicited in relatively young children using simple tasks and that ERN amplitude might be sensitive to error value. The current study employed a Go No-Go paradigm in which 5-7-year-old children (N = 18) earned low or high points for correct responses. Results indicated that errors were associated with an ERN; however, the size was not reliably moderated by error value.

Acute alcohol administration decreases overall brain glucose metabolism, which serves as a marker of brain activity. The behavioral effects of alcohol, however, are likely to reflect not only changes in regional brain activity but also the patterns of brain functional organization. Here we assessed the effects of a moderate dose of alcohol on the patterns of brain activity and cerebral differentiation. We measured brain glucose metabolism in 20 healthy controls with positron emission tomography and fluorodeoxyglucose during baseline and during alcohol intoxication (0.75 g/kg). We used the coefficient of variation (CV) to assess changes in brain metabolic homogeneity, which we used as a marker for cerebral differentiation. We found that alcohol decreased the CV in the brain and this effect was independent of the decrements in overall glucose metabolism. Our study revealed marked disruption in brain activity during alcohol intoxication including decreases in global and regional brain differentiation, a loss of right versus left brain metabolic laterality and a shift in the predominance of activity from cortical to limbic brain regions. The widespread nature of the changes induced by a moderate dose of alcohol is likely to contribute to the marked disruption of alcohol on behavior, mood, cognition and motor activity.

The diagnosis of pediatric multiple sclerosis (MS) is challenging due to its low frequency and the overlap with other acquired childhood demyelinating disorders of the central nervous system. To identify potential protein biomarkers which could facilitate the diagnosis, we used two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry to identify proteins associated with pediatric MS. Plasma samples from nine children with MS and nine healthy subjects, matched in aggregate by age and gender, were analyzed for differences in their patterns of protein expression. We found 12 proteins that were significantly up regulated in the pediatric MS group: alpha-1-acid-glycoprotein 1, alpha-1-B-glycoprotein, transthyretin, apoliprotein-C-III, serum amyloid P component, complement factor-I, clusterin, gelsolin, hemopexin, kininogen-1, hCG1993037-isoform, and vitamin D-binding protein. These results show that 2-DE in combination with mass spectrometry is a highly sensitive technique for the identification of blood-based biomarkers. This proteomic approach could lead to a new panel of diagnostic and prognostic markers in pediatric MS.

The hypothalamic-pituitary-adrenal axis is thought to play a role in the pathogenesis of depression. In the study reported here, we tested the hypothesis that parenting behavior moderates the relation between parents' lifetime history of depression and their offspring's cortisol reactivity to a psychosocial stressor. We exposed 160 preschool-age children to stress-inducing laboratory tasks, during which we obtained four salivary cortisol samples. Parents completed clinical interviews and an observational parent-child interaction task. The results confirmed our hypothesis: The offspring who evidenced high and increasing cortisol levels were those whose parents had a history of depression and demonstrated hostility toward their child. This moderating effect was specific to offspring who were exposed to maternal depression during the first few years of life. As do findings in animals, results of this study underscore the importance of the early rearing environment in the intergenerational transmission of stress sensitivity.

Behavioral inhibition (BI) has generally been treated as a unitary construct and assessed by combining ratings of fear, vigilance, and avoidance to both novel social and non-social stimuli. However, there is evidence suggesting that BI in social contexts is not correlated with BI in non-social contexts. The present study examined the distinction between social and non-social BI in a community sample of 559 preschool-age children using a laboratory assessment of child temperament, a diagnostic interview, and parent-completed questionnaires. Social and non-social BI were not significantly correlated and exhibited distinct patterns of associations with parent reports of temperament and anxiety symptoms. This study suggests that BI is heterogeneous, and that distinguishing between different forms of BI may help account for the variation in trajectories and outcomes exhibited by high BI children.

BACKGROUND

Despite growing interest in depression in young children, little is known about which variables predict the onset of depression in early childhood. We examined a range of predictors of the onset of depression diagnoses in a multi-method, multi-informant longitudinal study of a large community sample of young children from ages 3 to 6.

METHODS

Predictors of the onset of depression at age 6 were drawn from five domains assessed when children were 3 years old: child psychopathology (assessed using a parent diagnostic interview), observed child temperament, teacher ratings of peer functioning, parental psychopathology (assessed using a diagnostic interview), and psychosocial environment (observed parental hostility, parent-reported family stressors, parental education).

RESULTS

A number of variables predicted the onset of depression by age 6, including child history of anxiety disorders, child temperamental low inhibitory control, poor peer functioning, parental history of mood, anxiety, and substance use disorders, early and recent stressful life events, and less parental education.

CONCLUSIONS

Predictors of the onset of depression in early childhood tend to be similar to those identified in older youth and adults, and support the feasibility of identifying children in greatest need for early intervention.

BACKGROUND

Scrotal hyperthermia has been identified as a risk factor for male infertility. Laptop computers (LC) have become part of a contemporary lifestyle and have gained popularity among the younger population of reproductive age. LC are known to reach high internal operating temperatures. We evaluated the thermal effect of LC on the scrotum.

METHODS

Right and left scrotal temperature (ScT) was measured in 29 healthy volunteers in two separate 60 min sessions. ScT was recorded from thermocouples on a digital datalogger every 3 min with the working LC in a laptop position and in the same sitting position with approximated thighs without LC.

RESULTS

ScT increased significantly on the right and left side in the group with working LC (2.8 degrees C and 2.6 degrees C, respectively; P<0001) and without LC (2.1 degrees C, P<0.0001). However, ScT elevation with working LC was significantly higher (P<0.0001).

CONCLUSIONS

Working LC in a laptop position causes significant ScT elevation as a result of heat exposure and posture-related effects. Long-term exposure to LC-related repetitive transient scrotal hyperthermia is a modern lifestyle feature that may have a negative impact upon spermatogenesis, specifically in teenage boys and young men. Further studies of such thermal effects on male reproductive health are warranted.

OBJECTIVE

This study is a preliminary test of the hypothesis that the pathophysiology of irritable bowel syndrome (IBS) derives from pharyngeal collapse during sleep.

METHODS

We studied inspiratory airflow dynamics during sleep in 12 lean females with IBS and 12 healthy female controls matched for age and obesity. A standard clinical polysomnogram (airflow measured with a nasal/oral pressure catheter) was performed to assess the impact of pharyngeal collapse on the participants' natural sleep. A second polysomnogram with a pneumotachograph and a supraglottic pressure catheter to measure airflow and effort was performed to compare the maximal inspiratory airflow and effort and the prevalence of inspiratory airflow limitation (IFL) during supine stage 2 sleep between groups.

RESULTS

During clinical polysomnography, IBS participants did not differ significantly from controls in sleep architecture or respiration. The difference in apnea-hypopnea index between IBS participants and controls, however, approached statistical significance (2.8 +/- 2.7 vs 1.1 +/- 1.5, respectively; p = 0.079). Although nine of the 12 IBS participants had a prevalence of IFL of at least 33% during supine stage 2 sleep, they did not differ from controls in maximal inspiratory airflow, inspiratory effort, or the prevalence of IFL. Controls, however, differed from IBS participants in having their prevalence of IFL during stage 2 sleep positively correlated with age (r = 0.86; p = 0.0003) while IBS participants demonstrated no relationship between the prevalence of IFL and age.

CONCLUSIONS

Our findings, while less than definitive, suggest a prevalence pattern of pharyngeal collapse during sleep among females with IBS that differs from that of healthy females, providing necessary background to inform further work on the relationship of pharyngeal collapse during sleep to IBS.

MT1-MMP is a key integral membrane protease, which regulates tumor growth by cleaving extracellular matrix components, activating growth factors and receptors, and consequently, triggering downstream signals. To study what genes or pathways are mediated by endogenous MT1-MMP during tumor growth in vivo, we stably suppressed endogenous MT1-MMP in human tumor cells using RNA interference (RNAi). Tumor growth was significantly reduced in tumors derived from MT1-MMP-suppressed cells relative to control cells; the effect was rescued in cells engineered to re-express MT1-MMP expression. Gene expression profiling of cultured and tumor-derived cells by DNA microarray and real-time RT-PCR revealed that Smad1 expression was upregulated in MT1-MMP-expressing cells and rapidly growing tumors; this was confirmed in 4 additional tumor cell lines. Furthermore, tumor growth of MT1-MMP-expressing cells was reduced when Smad1 was suppressed by RNAi. We also found that the active form, but not the latent form, of TGF-beta was capable in promoting Smad1 expression and 3D cell proliferation in MT1-MMP-suppressed cells. In addition, a dominant-negative form of the TGF-beta Type II receptor reduced Smad1 expression in MT1-MMP-expressing cells. Thus, we propose that MT1-MMP functions, in part, to promote tumor growth by inducing the expression of Smad1 via TGF-beta signaling.

Human immunodeficiency virus (HIV) infection is associated with insulin resistance. HIV type 1 Nef downregulates cell surface protein expression, alters signal transduction, and interacts with the cytoskeleton and proteins involved in actin polymerization. These functions are required for glucose uptake by insulin-stimulated adipocytes. We sought to determine whether Nef alters adipocyte glucose homeostasis. Using radiolabeled glucose, we found that adipocytes exposed to recombinant Nef took in 42% less glucose after insulin stimulation than did control cells. This reduction resulted from a Nef-dependent inhibition of glucose transporter 4 (GLUT4) trafficking, as assessed by means of immunofluorescence microscopy. Immunoblot analysis revealed a decrease in phosphorylation of signal transducing proteins after Nef treatment, and fluorescence microscopy showed a dramatic alteration in cortical actin organization. We conclude that Nef interferes with insulin-stimulated processes in adipocytes. We have identified HIV Nef, which is detectable and antigenic in serum samples from HIV-infected people, as a novel contributor to the development of insulin resistance.

The P300 is a known ERP component assessing stimulus value, including the value of a monetary reward. In parallel, the incentive value of reinforcers relies on the PFC, a major cortical projection region of the mesocortical reward pathway. Here we show a significant positive correlation between P300 response to money (vs. no money) with PFC gray matter volume in the OFC, ACC, and dorsolateral and ventrolateral PFC in healthy control participants. In contrast, individuals with cocaine use disorders showed compromises in both P300 sensitivity to money and PFC gray matter volume in the ventrolateral PFC and OFC and their interdependence. These results document for the first time the importance of gray matter structural integrity of subregions of PFC to the reward-modulated P300 response.

Proton magnetic resonance spectroscopy ((1)H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo (1)H-MRS from frontal lobe white matter of 27 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials.

Epidermal growth factor receptor (EGFR) is a target in head and neck cancer. High EGFR expression and phosphorylated EGFR predicts poor survival in head and neck cancer patients, but does not correlate with advanced stage disease. The aim of this study is to determine if clinical biological correlates are more accurate when different aspects of EGFR are evaluated in combination. We analyzed the EGFR phosphorylation, expression, and mutations in 60 primary head and neck tumors. We not only found that head and neck tumors with either truncated or activated EGFR tend to have higher tumor and nodal stage but also discovered two novel EGFR truncations.