Children with autism adapt normally during a catching task requiring the cerebellum

The cerebellum, which has been found to be abnormal in histopathological studies of autism, is important for motor adaptation. We studied controls and children with high functioning autism (HFA) performing a catching adaptation test that is known to be impaired following cerebellar damage. Results showed no differences in adaptation rates or after-effects for HFA subjects versus controls. The findings indicate normal motor adaptation in HFA, suggesting normal or compensated cerebellar function for this task.     

Beta-cell response to intravenous glucagon in African-American and Hispanic children with type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemic control up to one year later. Thus, the fasting and glucagon-stimulated serum C-peptide levels provide an estimate of the potential insulin secretory capacity of the beta-cell and may predict glycemic control in pediatric type 2 DM.     

Genes with linkage or association with type 2 diabetes mellitus

Complex diseases, such as type 2 diabetes mellitus (T2DM), arise from metabolic disruptions with genetic and environmental components. Multiple genes are responsible for the genetic susceptibility to T2DM. The contribution of these genes to the diabetic phenotype may be modest, variable among different populations, and dependent on interactions with other genes and the environment. The methods of genetic dissection based on linkage, allele sharing, and linkage disequilibrium may lack the statistical power to detect weak associations in heterogeneous populations. Nevertheless, genes involved in insulin signaling, insulin secretion, insulin resistance, glucose metabolism, obesity, diabetes comorbidity and the hormone processing protease genes have been associated with T2DM. New research strategies are improving the methods of genetic dissection and include genomic sequence information to characterize profiles of sequence variants that predispose to T2DM.     

Linking actions and their perceivable consequences in the human brain

Voluntary action is goal-directed and therefore depends on the ability to learn associations between movements and their perceivable consequences. The neural substrate of this ability was investigated with H2(15O) positron emission tomography (PET). Healthy adults first learned that self-initiated keypresses were consistently followed by certain tones (i.e., action effects). During PET imaging, participants listened to varied ratios of action-effect tones and neutral tones without performing any movement. The caudal supplementary motor area and the right hippocampus increased their activity with the frequency of action-effect tones, suggesting that both cortical areas play a role in linking the consequences of an action and the action itself. This integration process represents a highly flexible mechanism that helps to promote the learning, automatization, and control of voluntary     

Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis

OBJECTIVE: To identify the role of RelA/nuclear factor-kappa B, an important inhibitor of apoptosis in colorectal tumorigenesis, we examined the expression of RelA in normal colorectal mucosa (n = 10), colorectal adenomas (n = 30) and colorectal adenocarcinomas (n = 30). Furthermore, the association of RelA expression with tumor cell apoptosis, proliferation, and expression of Bcl-2/Bcl-x(L )was also studied. METHODS: Paraffin sections were stained with monoclonal antibodies directed against RelA, Bcl-2, Bcl-x(L), and Ki-67 to assess protein expression patterns in normal, adenomatous and colon cancer tissue. Apoptotic cells were detected by terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling (TUNEL) using an in situ detection kit. RESULTS: The results of immunohistochemical staining revealed that expression of RelA, Bcl-2, Bcl-x(L), and Ki-67 labeling index (LI) significantly increased in the transition from adenoma with low dysplasia to adenocarcinoma. This transition was associated with a significant decrease in the apoptotic index (AI) and a significant increase in the Ki-67 LI. The expression of RelA correlated inversely with the AI and correlated positively with the expression of Bcl-2, Bcl-x(L), and Ki-67 LI in the transition from low-grade dysplasia to adenocarcinoma. CONCLUSION: Our results suggest that increased expression of RelA/nuclear factor-kappa B plays an important role in the transition from colorectal adenoma with low-grade dysplasia to adenocarcinoma in the pathogenesis of colon cancer in humans.     

Preshaping and continuous evolution of motor cortical representations during movement preparation

While a goal-directed movement is prepared, motor cortical neurons selectively change their activity in relation to prior information about movement direction. Only little is known, however, about the neuronal representation of partial information about this parameter. We investigated this question by training monkeys in a multidirectional centre-out pointing task. A preparatory signal provided prior information about one, two or three possible adjacent targets, thus manipulating the level of certainty about movement direction. After a 1-s delay, the response signal specified one of the precued targets to indicate the actual movement to be performed. Based on the directional tuning curves of individual motor cortical neurons determined during the reaction time interval, we constructed distributions of the population activation (DPAs), which we were then able to estimate as well during the preparatory period. We found that these distributions were preshaped by prior information, with peaks of activation centred over the range of precued movement directions. These peaks sharpened as the response signal approached, and shifted to the specified movement direction subsequent to that signal. Wider ranges of precued movement directions were represented by broader DPAs. Trials in which monkeys produced short reaction times were characterized by narrower distributions than trials with long reaction times. Our study thus provides evidence for (i) a graded preshaping of the neuronal population representation of movement direction by partial information about this parameter, and (ii) the continuous evolution of the preshaped population representation during the preparatory period towards movement initiation.     

Fractures of the mandibular condyle. Part 2: results of treatment of 348 patients

This study was designed to record the results of conservative treatment of condylar fractures and to find out if there were any variables that were predictive of complications. Data were analysed in our computer department. During the period 1984-1996, all patients who presented with a fracture of the mandibular condyle and who attended for control examination one year after treatment were recorded at the end of treatment and one year later. The ability to open the mouth, deviation and occlusion were recorded. After one year 45 of the 348 patients (13%) had minor physical complaints such as reduced ability to open the mouth, deviation, or dysfunction. Ten of them (3%) had pain in the joint or muscles or both. Eight patients (2%) had malocclusion, which in seven could be related to dislocation of the condylar head out of the fossa. Five of the eight patients had had bilateral fractures. We conclude that conservative treatment of condylar fractures is non-traumatic, safe, and reliable and in only a few cases may cause disturbances of function and malocclusion. The risk associated with the latter is greatest with bilateral fractures and dislocation of the condylar head from the fossa.     

Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors.

Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.