The paper briefly discussed different statistical analysis in functional magnetic resonance imaging (fMRI). Multivariate regression analysis with multiple comparisons corrections allows the determination of activated voxels that can then be grouped into regions of interest (ROIs). Principal component analysis (PCA) is useful in extracting common temporal response features of an ROI as well as differentiating the temporal response of groups of commonly responding ROI. It can also be used to examine differences in the temporal response of subgroups of subjects in the study. Structural equation modeling (SEM) is a technique that requires a priori knowledge of the connections and their direction between ROIs. It is particularly useful in identifying changes in connectivity that result from different interventions or different classes of patients.

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.

An ongoing sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of FS, has revealed important information about this autoimmune disease. During surveillance of this population of approximately 1,200, which began in 1994, we documented 43 FS cases and studied the transition from the normal state to the disease state in several of these individuals. Furthermore, we established that FS patients as well as a large number of normal individuals on the reservation possess anti-dsg1 autoantibodies. The following interesting observations were made: (1) the ectodomain of dsg1 contains epitopes recognized by both autoantibodies and T cells from FS patients; (2) pathogenic anti-dsg1 autoantibodies in FS belong to the IgG4 subclass; (3) nonpathogenic anti-dsg1 autoantibodies of the IgG1 subclass were detected in normal individuals from Limao Verde and in patients in the preclinical stage of the disease; (4) anti-dsg1 autoantibodies from normal individuals and patients in the preclinical stage of FS recognize the EC5 domain of dsg1, whereas pathogenic anti-dsg1 autoantibodies bind the EC1/EC2 domains; (5) houses of FS patients are rustic, with thatched roofs and walls and dirt floors; (6) there was a high frequency of hematophagous insects (bedbugs and kissing bugs) in the houses of FS patients; (7) previous studies revealed that the predominant black fly on this reservation belongs to the species Simunlium nigrimanum. These findings suggest that the environmental antigen(s) triggering the autoimmune response in FS may be linked to exposure to hematophagous insects.

Studies involving brain-lesioned subjects have used the paced finger tapping (PFT) task to investigate the neural systems that govern motor timing. Patients with Parkinson's disease (PD), for example, demonstrate abnormal performance on the PFT, characterized by decreased accuracy and variability changes, suggesting that the basal ganglia may play a critical role in motor timing. Consistent with this hypothesis, an fMRI study of healthy participants demonstrated that the medial frontostriatal circuit (dorsal putamen, ventrolateral thalamus, SMA) correlated with explicit time-dependent components of the PFT task. In the current fMRI study, PD patients and healthy age-matched controls were imaged while performing the PFT. PD patients underwent 2 imaging sessions, 1 on and the other off dopamine supplementation. Relative to controls, PD patients were less accurate and showed greater variability on the PFT task relative to controls. No PFT performance differences were observed between the on and off medication states despite significantly greater motor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) in the off medication state. Functional imaging results demonstrated decreased activation within the sensorimotor cortex (SMC), cerebellum, and medial premotor system in the PD patients compared to controls. With dopamine replacement, an increase in the spatial extent of activation was observed within the SMC, SMA, and putamen in the PD patients. These results indicate that impaired timing reproduction in PD patients is associated with reduced brain activation within motor and medial premotor circuits. Despite a lack of improvement in PFT performance, PD patient's brain activation patterns were partially “normalized” with dopamine supplementation. These findings could not be attributed to greater head movement artifacts or basal ganglia atrophy within the PD group. (JINS, 2003, 9, 1088–1098.)

Mice with disruptions of the red blood cell (RBC) cytoskeleton provide severe hemolytic anemia models in which to study multiorgan thrombosis and infarction. The incidence of cerebral infarction ranges from 70% to 100% in mice with alpha-spectrin deficiency. To determine whether mutant RBCs abnormally bind adhesive vascular components, we measured adhesion of mouse and human RBCs to immobilized human thrombospondin (TSP) and laminin (LM) under controlled flow conditions. Mutant RBCs had at least 10-fold higher adhesion to TSP compared with normal RBCs (P <.006). Mutant relative to unaffected RBC adhesion to LM was significantly (P <.01) increased as well. Treatment of RBCs with the anionic polysaccharide dextran sulfate inhibited mutant RBC adhesion to TSP (P <.001). Treatment of RBCs with antibodies to CD47 or the CD47-binding TSP peptide 4N1K did not inhibit TSP adhesion of RBCs. Previously, we have shown that infarcts in alpha-spectrin-deficient sph/sph mice become histologically evident beginning at 6 weeks of age. TSP adhesion of RBCs from 3- to 4- and 6- to 8-week-old sph/sph mice was significantly higher than RBCs from adult mice (> 12 weeks old; P <.005). While the mechanism of infarction in these mice is unknown, we speculate that changes in RBC adhesive characteristics contribute to this pathology.

OBJECTIVES:We studied the maturation of esophageal body and upper esophageal sphincter (UES) motor responses that protect against reflux in newborns.STUDY DESIGN:The responses of esophageal body and UES on midesophageal provocation were quantified using a micromanometric water perfusion system and a specially designed catheter with a UES sleeve and 5 side-hole recording sites. Eighteen healthy premature infants were studied twice, at 33.4 weeks' and 35.7 weeks' mean postmenstrual ages (PMAs).RESULTS:Mean threshold volumes and the distribution of responses including secondary peristalsis, UES pressure increase, and primary peristalsis were similar for air and liquids. Secondary peristalsis and UES pressure increases were volume dependent for both studies, but their characteristics changed as PMA increased in that (1) completely propagated secondary peristalsis with liquids increased; (2) proximal esophageal contraction duration was shorter for air and liquids; and (3) propagating velocity for liquids was faster.CONCLUSIONS:Esophageal and UES motor responses to abrupt midesophageal provocation are present as early as 33 weeks' PMA, and the response-characteristics improve during development. Reflexes that may facilitate esophageal clearance include (1) secondary peristalsis; (2) esophago-UES-contractile reflex; and (3) esophago-deglutition response.

Objective To define epidemiologic and clinical characteristics of newly diagnosed pediatric inflammatory bowel disease (IBD) in a large population-based model. Study design All pediatric gastroenterologists providing care for Wisconsin children voluntarily identified all new cases of IBD during a 2-year period. Demographic and clinical data were sent to a central registry prospectively for analysis. Results The incidence of IBD in Wisconsin children was 7.05 per 100,000, whereas the incidence for Crohn's disease was 4.56, more than twice the rate of ulcerative colitis (2.14). An equal IBD incidence occurred among all ethnic groups, and children from sparsely and densely populated counties were equally affected. The majority (89%) of new IBD diagnoses were nonfamilial. Conclusions This study provides novel, prospective, and comprehensive information on pediatric IBD incidence within the United States. The surprisingly high incidence of pediatric IBD, the predominance of Crohn's disease over ulcerative colitis, the low frequency of patients with a family history, the equal distribution of IBD among all racial and ethnic groups, and the lack of a modulatory effect of urbanization on IBD incidence collectively suggest that the clinical spectrum of IBD is still evolving and point to environmental factors contributing to the pathogenesis.

The purpose of this study was to evaluate the association of the insulin resistance syndrome with both blood pressure and target organ damage in blacks and whites with essential hypertension. Eighty-two black and 63 white French Canadian patients were studied. None had diabetes, and antihypertensive medications had been discontinued for ≥1 week. Measurements included 24-hour blood pressure monitoring, fasting plasma lipids, insulin sensitivity determined with the Bergman minimal model, echocardiogram, microalbumin excretion, and inulin and lithium clearances. Compared with the white French Canadians, black patients had an attenuated nighttime reduction in blood pressure ( P <0.02), increased cardiac dimensions ( P <0.001), greater microalbumin excretion ( P <0.05), increased inulin clearance (indicative of glomerular hyperfiltration; P <0.001), and decreased lithium clearance (indicative of increased sodium reabsorption in the proximal tubule; P <0.001). Blood pressure levels were not related to insulin resistance; although in blacks, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin ( r =−0.18, P <0.04). In a stepwise multivariate analysis (including blood pressure levels and components of the insulin resistance syndrome as independent variables), race was the strongest predictor of left ventricular mass ( r =0.53, P <0.000), relative wall thickness ( r =0.49, P <0.000), and both inulin ( r =0.53, P <0.000) and lithium ( r =0.41, P <0.000) clearances. Nighttime systolic blood pressure was also a significant determinant of concentric left ventricular hypertrophy ( r =0.37, P <0.000). In blacks, microalbumin excretion was related to insulin resistance. These observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in blacks with essential hypertension.

Despite numerous studies, the in vivo regulation of plasma leptin levels in response to nutritional factors continues to remain unclear. We investigated temporal and dose-response relationships of plasma leptin in response to physiological changes in insulin/glucose. After an overnight fast of 10 h, lean, healthy subjects were investigated for an additional 16 h of either extended fasting or one of three levels of glycemia/insulinemia induced by stepwise increasing iv glucose infusions. During extended fasting, plasma leptin values declined steadily and significantly. Plasma leptin levels remained constant at glucose concentrations between 5.8-6.5 mmol/liter, which maintained normoinsulinemia at 41.5-45.4 pmol/liter and FFA at 106-123 mg/liter, but leptin concentrations were increased at higher rates of glucose infusion (with plasma glucose rising to 8.7 mmol/liter). Concentrations of serum leptin were inversely related to FFA levels during extended fasting and at all levels of glycemia. Our data indicate that in lean healthy subjects, physiological changes in glycemia and insulinemia significantly alter plasma FFA and leptin concentrations. The increases in leptin concentrations demonstrate dose-dependent relationships that appear to relate to changes in FFA levels as well as to changes in glycemia/insulinemia.

BACKGROUND:Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies against desmoglein 1. The endemic form is thought to have an environmental cause. The Terena reservation of Limão Verde in Mato Grosso do Sul, Brazil, is a recently identified focus of the disease, with a prevalence of 3.4 percent in the population. We tested the hypothesis that normal subjects living in an endemic area have antibodies against desmoglein 1. METHODS:We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus (fogo selvagem) who lived in Limão Verde or elsewhere in Brazil, 372 normal subjects (without pemphigus foliaceus) from Limão Verde and surrounding locations, and 126 normal subjects from the United States and Japan. RESULTS:Antibodies against desmoglein 1 were detected in 59 of the 60 patients with fogo selvagem (98 percent) but in only 3 of the 126 normal subjects from the United States and Japan (2 percent). Antibodies were also detected in 51 of the 93 normal subjects from Limão Verde (55 percent) and in 54 of the 279 normal subjects from surrounding areas (19 percent). Serum samples obtained one to four years before the onset of disease were available for five patients; all five had antibodies in the initial serum samples, and the onset of disease was associated with a marked increase in antibody values. CONCLUSIONS:The prevalence of antibodies against desmoglein 1 is high among normal subjects living in an area among where fogo selvagem is endemic, and the onset of the disease is preceded by a sustained antibody response. These findings support the concept that the production of antibodies against desmoglein 1 is initiated by exposure to an unknown environmental agent.

As the applications of functional magnetic resonance imaging (fMRI) expand, there is a need for the development of new strategies for data extraction and analysis that do not require the presentation of stimuli in a repeated on/off pattern. A description and evaluation of a method and computer algorithm for the detection and analysis of brain activation patterns following acute drug administration using fMRI are presented. A waveform analysis protocol (WAP) input function has been developed that is based upon the single-dose pharmacokinetics of a drug of interest. As a result of this analysis, regional brain activation can be characterized by its localization and intensity of activation, onset of action, time to peak effect, and duration of action. A global statistical test for significant drug effects based upon the probability of a voxel being activated by a saline vehicle injection is applied to grouped data on a voxel by voxel basis. Representative data are presented using nicotine as a prototypical agent. Using this method, statistically significant drug-induced brain activation has been identified in several key cortical and subcortical brain regions. (C) 1999 Wiley-Liss, Inc.

Objective: To identify possible contributors to the seasonal variation in stroke mortality. Background: Stroke and respiratory disease mortality rates were calculated from vital statistics and census data for the United States from 1938 to 1988. State-specific average temperatures by month were derived from data obtained from the National Climatic Data Center for 1938 to 1987. Methods: Each time series was decomposed into a trend, a seasonal effect, and a residual effect. Multiple regression was used to fit both a trend and a seasonal harmonic series. Cross-correlation was used to assess the relationship between the residual time series. Results: There is a strong and consistent seasonal pattern of high stroke and respiratory disease mortality in the colder winter months. Stroke mortality was significantly and independently both positively associated with respiratory disease mortality and inversely associated with temperature. The sharp initial increases in both respiratory disease and stroke mortality in the late fall and early winter are synchronous, and the amplitudes are strongly associated, except for a saturation effect with extreme respiratory disease amplitudes. Conclusions: Seasonal change in stroke mortality is associated with seasonal variation in both respiratory disease and temperature. Respiratory disease and temperature may influence stroke mortality nonspuriously by affecting stroke case fatality, incidence, or both.

OBJECTIVE:Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates.METHOD:Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials.RESULTS:Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans.CONCLUSIONS:The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

We investigated whether the male offspring of a parent with early coronary artery disease (before the age of 60; n = 61) exhibit decreased insulin sensitivity compared with controls matched for age and body mass index (BMI) (n = 39). The insulin sensitivity index (SI) was determined by the minimal modeling method of Bergman from a frequently sampled intravenous glucose tolerance test with intravenous tolbutamide. Offspring and controls had a similar SI, insulin-independent glucose utilization (SG), first-phase insulin response (AIRG), and area under the glucose curve. When subjects were separated into two age groups, younger subjects aged 15 to 30 years and older subjects aged 31 to 45 years, important differences were seen. SG was significantly increased in younger offspring compared with controls (22.8 ± 2.3 v 16.8 ± 2.3 × 10−3 · min−1, P < .05). Older offspring had a significantly increased area under the glucose curve compared with controls (18,250 ± 322 v 17,225 ± 347 mg/dL · min−1, P < .05). Older offspring also had decreased SI compared with younger offspring (5.0 ± 0.4 v 6.6 ± 0.9 × 10−4 · min−1, · μ U/mL, P < .05), but this difference was eliminated after adjusting for BMI and waist to hip ratio (5.5 ± 0.4 v 5.8 ± 0.9 × 10−3 · min−1, nonsignificant). This study does not support the concept that insulin resistance is an early atherogenic risk factor in offspring at risk for coronary disease because of their family history. However, it does point to the importance of maturational changes in glucose homeostasis in these offspring.

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.

Meta-analysis of the Randomized controlled trials (RCT's) of Recombinant human Erythropoietin (EPO) in Anemia of Prematurity (AOP). ▴ 1731

The recently cloned adipose tissue hormone leptin has been proposed to be involved in the neuroendocrine regulation of adiposity and its metabolic sequelae. Visceral fat is known to predict reduced insulin sensitivity and associated adverse metabolic profiles. In this study, we report the first evaluation of the relationships between leptin levels and total body fat, visceral fat, and insulin sensitivity in a cohort of premenopausal African-American women. Thirty-four subjects were analyzed for total fat mass and visceral fat by dual-energy X-ray absorptiometry and computerized axial tomography, respectively. Insulin sensitivity (SI) was assessed using Bergman's minimal model. Results showed that fasting leptin levels strongly correlated with total body fat mass (r = 0.797, P < 0.001). Correlations of leptin with visceral fat (r = 0.54, P < 0.001) and SI (r = −0.419, P = 0.02) were dependent on total body fat. In conclusion, leptin levels reflect total body fat mass, and although visceral fat is known to predict reduced insulin sensitivity independently, leptin did not. Our data thus suggest that diverse mechanisms are responsible for the regulation of total body versus visceral fat distribution, with its metabolic and health risks.

Although specific patterns of technetium-99m exametazime [Tc-99m-hexamethylpropylene amine oxime (HMPAO)] brain single-photon emission tomography (SPET) uptake have been described for patients with dementia, no multi-institutional study has evaluated interobserver agreement. Interobserver agreement for Tc-99m-HMPAO brain SPET uptake patterns in 50 clinically diagnosed demented subjects from four institutions were studied. Neurologists classified these subjects as presumed Alzheimer's disease (n=21), confirmed Alzheimers's disease (n=10), multi-infarct dementia (n=9), HIV-related dementia (n=7), or "mixed" (n=3). In addition 20 normal (five per institution) Tc-99m-HMPAO studies were included in a randomized blinded evaluation by three readers each from a different institution. Readers classified the general appearance of the images in one of four categories: normal, globally decreased uptake, focal areas of decreased uptake, and patchy changes in uptake. Consensus results show a sensitivity of 72% and specificity of 79% for identifying abnormalities in scans of demented subjects. Readers also rated Tc-99m-HMPAO uptake in eight designated regions in each hemisphere. Significant reader agreement (P<0.01) for the classification by general appearance and the ratings of regional uptake was obtained. This study demonstrates that interpretation of regional cerebral blood flow/SPET images is concordant across multiple institutions and readers.