Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans.

AIM: To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. METHODS: As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n = 48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps. RESULTS: Body mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects. CONCLUSIONS: Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating.

Neuromagnetic assessment of pathophysiologic brain activity induced by minor head trauma.

BACKGROUND AND PURPOSE: Patients with mild traumatic brain injury (TBI) often show significant neuropsychological dysfunction despite the absence of abnormalities on traditional neuroradiologic examinations or EEG. Our objective was to determine if magnetic source imaging (MSI), using a combination of MR imaging and magnetoencephalography (MEG), is more sensitive than EEG and MR imaging in providing objective evidence of minor brain injury. METHODS: Four subject groups were evaluated with MR, MSI, and EEG. Group A consisted of 20 neurologically normal control subjects without histories of head trauma. Group B consisted of 10 subjects with histories of mild head trauma but complete recovery. Group C consisted of 20 subjects with histories of mild head injury and persistent postconcussive symptoms. The 15 subjects included in group D underwent repeat examinations at an interval of 2 to 4 months. RESULTS: No MR abnormalities were seen in the normal control group or the asymptomatic group, but five (20%) of the patients with persistent postconcussive symptoms had abnormal MR findings. EEG was abnormal for one subject (5%) from the normal control group, one (10%) from the asymptomatic group, and five (20%) from the group with persistent postconcussive symptoms. MSI was abnormal for one subject (5%) from the normal control group, one (10%) from the asymptomatic group, and 13 (65%) from the group with persistent postconcussive symptoms. There was a direct correlation between symptom resolution and MSI findings for the symptomatic head trauma group. CONCLUSION: MSI indicated brain dysfunction in significantly more patients with postconcussive symptoms than either EEG or MR imaging (P < .01). The presence of excessive abnormal low-frequency magnetic activity provides objective evidence of brain injury in patients with postconcussive syndromes and correlates well with the degree of symptomatic recovery.

Quantitative proton MRS predicts outcome after traumatic brain injury.

OBJECTIVE: To determine whether proton MRS (1H-MRS) neurochemical measurements predict neuropsychological outcome of patients with traumatic brain injury (TBI). BACKGROUND: Although clinical indices and conventional imaging techniques provide critical information for TBI patient triage and acute care, none accurately predicts individual patient outcome. METHODS: The authors studied 14 patients with TBI soon after injury (45+/-21 days postinjury) and again at 6 months (172+/-43 days) and 14 age-, sex-, and education-matched control subjects. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and gray matter using quantitative 1H-MRS. Outcome was assessed with the Glasgow Outcome Scale (GOS) and a battery of neuropsychological tests. A composite measure of neuropsychological function was calculated from individual test z-scores probing the major functional domains commonly impaired after head trauma. RESULTS: Early NAA concentrations in gray matter predicted overall neuropsychological performance (r = 0.74, p = 0.01) and GOS (F = 11.93, p = 0.007). Other metabolite measures were not related to behavioral function at outcome. CONCLUSION: 1H-MRS provides a rapid, noninvasive tool to assess the extent of diffuse injury after head trauma, a component of injury that may be the most critical factor in evaluating resultant neuropsychological dysfunction. 1H-MRS can be added to conventional MR examinations with minimal additional time, and may prove useful in assessing injury severity, guiding patient care, and predicting patient outcome.

Expression and characterization of recombinant murine cytomegalovirus protease.

The protease domain of the murine cytomegalovirus (MCMV) M80 open reading frame was expressed in and purified from Escherichia coli. The recombinant enzyme was recovered as a mixture of active one- and two-chain forms. The two-chain enzyme was formed by internal cleavage of the one-chain enzyme at the I site. Activity measurements showed that MCMV protease cleaves R- and M-site peptide mimics with kinetics similar to those of recombinant human cytomegalovirus (HCMV) protease. Both the MCMV and HCMV proteases cleave I-site peptide substrates very poorly, but the crystal structure of the HCMV protease indicates that the cytomegalovirus I site likely resides on a solvent-exposed loop close to the active site.

Thrombosed dialysis grafts: comparison of treatment with transluminal angioplasty and surgical revision.

PURPOSE: To compare the usefulness of transluminal angioplasty coupled with thrombectomy versus surgical revision coupled with thrombectomy in the restoration and maintenance of flow in thrombosed dialysis access grafts. MATERIALS AND METHODS: Twenty-four patients undergoing 28 angioplasty procedures were retrospectively compared to 24 patients who underwent 33 surgical revisions with a minimum 12-month follow-up period. All patients had thrombosed upper-arm expanded polytetrafluoroethylene (ePTFE) grafts. RESULTS: Initial success rates were 88% for angioplasty and 87% for surgery. Mean primary patency for angioplasty and surgery was 4.6 and 3.3 months, respectively. Mean secondary patency for angioplasty and surgery was 5.4 and 4.5 months, respectively. These differences were not statistically significant. A significantly shorter hospital stay and lower anesthesia requirement were noted in the angioplasty group. CONCLUSION: Transluminal angioplasty coupled with Fogarty thrombectomy is an effective alternative to surgical revision for thrombosed dialysis access grafts. Angioplasty extends graft life, thereby preserving proximal venous outflow sites for future use.

Protease treatment of nuclear extracts distinguishes between class II MHC X1 box DNA-binding proteins in wild-type and class II-deficient B cells.

The X box region is critical for directing the expression of class II major histocompatibility complex genes in B lymphocytes. Although several class II promoter-specific DNA binding factors have been described, only the X box region factor, RFX, shows a genetic correlation with class II expression, being deficient in some B cell lines derived from patients with class II-deficient congenital immunodeficiency. To further evaluate the role of X box DNA-binding proteins in class II gene expression, the role of the X box region was examined in both class II-positive and -negative lymphoid cells. In addition to the wild-type B cell line Raji, two class II transcriptional mutant cell lines, SJO and RJ2.2.5, and Jurkat, a class II negative T cell line, were examined. In contrast to wild-type B cells, neither of the class II mutant cell lines could use the X box region to direct the expression of a transiently transfected reporter gene, indicating that the X box-dependent transcriptional pathway is defective in these cells. The binding activity of the X1 box DNA-binding protein RFX was examined and found to be present in wild-type B cells and the mutant RJ2.2.5 but was absent in SJO and Jurkat. However, other X1 box-specific activities were detected in all these cell lines. To determine whether these different X1 box activities represented distinct DNA binding proteins or multimeric forms of the same factor(s), protease treatment of the crude nuclear extracts followed by DNA-binding assays were carried out and demonstrated that B cell extracts contain at least two X1-specific factors. One of these cleaved products (band 1 pk) correlates with RFX activity. A similar comparison with protease-treated extracts prepared from Jurkat cells demonstrated the presence of the band 1pk activity despite an absence of the native RFX activity. In contrast, protease treatment and analysis of SJO extracts showed no detectable levels of the band 1pk activity. These results demonstrate that multiple X1 box-specific DNA-binding activities exist in all lymphoid cells, but the presence of an actively binding RFX species correlates with class II transcription.

Single base pair substitutions within the HLA-DRA gene promoter separate the functions of the X1 and X2 boxes.

The class II MHC genes are expressed on the surfaces of B cells, activated T cells, and macrophages and may be induced in other cell types by IFN-gamma. The control of class II gene expression has been shown to be mediated by a series of conserved cis-acting sequences (W, X1, X2, and Y boxes) located immediately 5' to the genes. Although these sequences are conserved, the bp that are important for transcriptional regulation have yet to be identified. To address this issue with regard to the MHC gene HLA-DRA, a series of single bp substitutions spanning the conserved upstream sequences was created and analyzed for their effects on transcription in both B cells and IFN-gamma-treated fibroblasts. In addition, the effects of X1 and X2 box mutations on DNA/protein interactions were examined and compared to the transcriptional data. The results of these studies show that each of the conserved elements participate in maximal expression in B cells and that W, X1, and X2 boxes are important for IFN-gamma induction and expression in fibroblasts. Interestingly, some of the bp changes that altered B cell expression did not alter expression and IFN-gamma induction in fibroblasts, suggesting that different or altered factors control the expression of these genes in the different cell types. Mutant templates designed to eliminate the binding of X1- and X2-specific DNA binding proteins in vivo suggest that these elements and their factors may interact to promote transcription.

Regulatory factor-X binding to mutant HLA-DRA promoter sequences.

The class II genes of the major histocompatibility complex (MHC) encode a family of cell surface glycoproteins that present processed antigen to the T cell receptor. Class II genes are regulated coordinately, responding to both immunologic and developmental signals. Conserved sequence elements 5' to class II genes have been shown to be important in transcriptional control. One of these sequences, the X box, is a specific target for the binding of the factor RF-X. In the hereditary HLA class II deficiency, a form of primary immunodeficiency, a regulatory defect in expression of class II genes is associated with a defect in the binding of RF-X. To determine the basepairs that are important for this binding interaction, a series of single basepair substitutions spanning the X box motif of the DRA gene was constructed and tested for binding of RF-X by gel electrophoresis mobility shift assays (EMSAs). Several, but not all, of the mutants severely affected binding of RF-X. In addition, the binding of both the natural and the recombinant form of RF-X was affected with the same specificity. A comparison of X box basepair positions important for RF-X binding to DRA with sequences conserved between X boxes of other class II alpha chain genes suggests that high affinity RF-X binding is important for a high level of expression and may explain differences in the levels of class II expression of different class II alpha chains.

Firearm regulations and rates of suicide. A comparison of two metropolitan areas.

To investigate a possible association between firearm regulations and suicide, we compared the incidence of suicide from 1985 through 1987 in King County, Washington, with that in the Vancouver metropolitan area, British Columbia, where firearm regulations are more restrictive. The risk of death from suicide was not found to differ significantly between King County and the Vancouver area (relative risk, 0.97; 95 percent confidence interval, 0.87 to 1.09). The rate of suicide by firearms, however, was higher in King County (relative risk, 2.34; 95 percent confidence interval, 1.90 to 2.88), because the rate of suicide by handguns was 5.7 times higher there. The difference in the rates of suicide by firearms was offset by a 1.5-fold higher rate of suicide by other means in the Vancouver area. Persons 15 to 24 years old had a higher suicide rate in King County than in the Vancouver area (relative risk, 1.38; 95 percent confidence interval, 1.02 to 1.86). Virtually all the difference was due to an almost 10-fold higher rate of suicide by handguns in King County. We conclude that restricting access to handguns might be expected to reduce the suicide rate in persons 15 to 24 years old, but that it probably would not reduce the overall suicide rate.

Conserved upstream sequences of human class II major histocompatibility genes enhance expression of class II genes in wild-type but not mutant B-cell lines.

Class II major histocompatibility genes contain a conserved upstream sequence (CUS) that is important in the expression of these genes. This region has been divided into two major elements, the X box and the Y box. The ability of these elements to mediate transcription of a heterologous promoter was assayed upon transfection into a B-cell line (Raji), a class II-specific trans-acting factor-deficient B-cell line (RJ2.2.5 cells), and a T-cell line (Jurkat). The results showed that the X box element was responsible for directing tissue-specific expression when Raji cells were compared to Jurkat cells. The X box could not direct expression of the heterologous promoter in the trans-acting factor-deficient cell line, indicating that the X box is an ultimate target of the missing or defective factor in the RJ2.2.5 cell line. The Y box directed an equal but extremely low level of transcription in this system in both the mutant and wild-type B-cell lines, suggesting that this element is not involved in B-cell expression or as a target of the mutant factor.

Handgun regulations, crime, assaults, and homicide. A tale of two cities.

To investigate the associations among handgun regulations, assault and other crimes, and homicide, we studied robberies, burglaries, assaults, and homicides in Seattle, Washington, and Vancouver, British Columbia, from 1980 through 1986. Although similar to Seattle in many ways, Vancouver has adopted a more restrictive approach to the regulation of handguns. During the study period, both cities had similar rates of burglary and robbery. In Seattle, the annual rate of assault was modestly higher than that in Vancouver (simple assault: relative risk, 1.18; 95 percent confidence interval, 1.15 to 1.20; aggravated assault: relative risk, 1.16; 95 percent confidence interval, 1.12 to 1.19). However, the rate of assaults involving firearms was seven times higher in Seattle than in Vancouver. Despite similar overall rates of criminal activity and assault, the relative risk of death from homicide, adjusted for age and sex, was significantly higher in Seattle than in Vancouver (relative risk, 1.63; 95 percent confidence interval, 1.28 to 2.08). Virtually all of this excess risk was explained by a 4.8-fold higher risk of being murdered with a handgun in Seattle as compared with Vancouver. Rates of homicide by means other than guns were not substantially different in the two study communities. We conclude that restricting access to handguns may reduce the rate of homicide in a community.

Effects of training on delayed muscle soreness and serum creatine kinase activity after running.

We studied the effects of progressive, short-term training on the delayed muscle soreness (DMS) and serum creatine kinase (SCK) responses to downhill (-10%) running for 45 min. Prior to the experimental run, subjects in training groups (N = 38) ran for 5 min to 15 min.d-1 on either -10% or +10% incline for either 1 wk (5 d) or 2 wk (10 d). Twelve control subjects did not train. DMS was reduced, although not totally prevented, by the 1 wk, and especially, 2 wk of downhill running training. Training by uphill running had little effect in preventing DMS. Mean SCK values 24 h after the experimental run were not significantly different among the groups (range: 99 to 340% of pre-exercise values), indicating no effect of any training regimen. Relatively large differences existed among subjects in terms of soreness and SCK responses to the experimental running. It was suggested that DMS may be difficult to totally avoid if exercise with a large eccentric component is performed. Prevention of such DMS may be most likely if prior training involves exercise with a substantial eccentric component, starts with bouts of very small quantities, and progresses in small increments over more than 2 wk.

Efficacy of EMG biofeedback in relaxation training: a controlled stury.

Electrical activity in the right elbow flexors has been shown to have a high relationship with a general resting muscular tension factor. It was our purpose to evaluate the efficacy of EMG biofeedback in reducing electrical activity in this muscle group. It was found that EMG voltages were significantly reduced (P less than 0.001) due both to biofeedback treatment and to time of day (construed as a practice and/or restbreak effect). Replication of the experiment without biofeedback and designed to minimize the "restbreak" effect induced by repetitive testing produced no change in the EMG voltages. It was concluded that EMG biofeedback training is effective with the elbow flexor group, and the possibility for training subjects in overall deep relaxation through feedback from this one muscle group is suggested. The importance of the practice effect/restbreak is emphasized.