Role of the extracellular matrix in neural crest cell migration

Development of the neural crest involves a remarkable feat of coordinated cell migration in which cells detach from the neural tube, take varying routes of migration through the embryonic tissues and then differentiate at the end of their journey to participate in the formation of a number of organ systems. In general, neural crest cells appear to migrate without the guidance of long-range physical or chemical cues, but rather they respond to heterogeneity in the extracellular matrix that forms their migration substrate. Molecules such as fibronectin and laminin act as permissive substrate components, encouraging neural crest cell attachment and spreading, whereas chondroitin sulphate proteoglycans are nonpermissive for migration. A balance between permissive and nonpermissive substrate components seems to be necessary to ensure successful migration, as indicated by a number of studies in mouse mutant systems where nonpermissive molecules are over-expressed, leading to inhibition of neural crest migration. The neural crest expresses cell surface receptors that permit interaction with the extracellular matrix and may also modify the matrix by secretion of proteases. Thus the principles that govern the complex migration of neural crest cells are beginning to emerge.     

AUTOMATED LOCATION OF DYSPLASTIC FIELDS IN COLORECTAL HISTOLOGY USING IMAGE TEXTURE ANALYSIS

Automation in histopathology is an attractive concept and recent advances in the application of computerized expert systems and machine vision have made automated image analysis of histological images possible. Systems capable of complete automation not only require the ability to segment tissue features and grade histological abnormalities, but must also be capable of locating diagnostically useful areas from within complex histological scenes. This is the first stage of the diagnostic process. The object of this study was to develop criteria for the automatic identification of focal areas of colorectal dysplasia from a background of histologically normal tissue. Fields of view representing normal colorectal mucosa (n=120) and dysplastic mucosa (n=120) were digitally captured and subjected to image texture analysis. Two features were selected as being the most important in the discrimination of normal and adenomatous colorectal mucosa. The first was a feature of the co-occurrence matrix and the second was the number of low optical density pixels in the image. A linear classification rule defined using these two features was capable of correctly classifying 86 per cent of a series of training images into their correct groups. In addition, large histological scenes were digitally captured, split into their component images, analysed according to texture, and classified as normal or abnormal using the previously defined classification rule. Maps of the histological scenes were constructed and in most cases, dysplastic colorectal mucosa was correctly identified on the basis of image texture: 83 per cent of test images were correctly classified. This study demonstrates that abnormalities in low-power tissue morphology can be identified using quantitative image analysis. The identification of diagnostically useful fields advances the potential of automated systems in histopathology: these regions could than be scrutinized at high power using knowledge-guided image segmentation for disease grading. Systems of this kind have the potential to provide objectivity, unbiased sampling, and valuable diagnostic decision support. © 1997 John Wiley & Sons, Ltd.     

Long-Term Protection against HIV-1 Infection Conferred by tat or rev Antisense RNA Was Affected by the Design of the Retroviral Vector

We have constructed a series of retroviral vectors in which the expression of antisense RNA targeted at the full length coding sequence of HIV-1 tat or rev was driven by three different promoters and in the context of double-copy or single-copy vectors. Jurkat cells transduced by these vectors were shown to express the expected tat or rev antisense RNA without alteration in cell proliferation or surface CD4 expression. After challenge with HIV, four patterns of protection were identified, with the degree of protection being determined primarily by the design of the expression system. In those patterns showing long-term complete protection, we could detect no HIV p24 in the culture supernatants or in the cells, and no HIV RNA or HIV proviral DNA (by PCR), during a 23-week follow-up. Experiments designed to rescue any live virus still formed in the culture after 20 weeks’ challenge demonstrated that, with some constructs, infectious virus could no longer be isolated, while with other constructs, only a low level of infectious virus was still being formed and providing a continuing virus challenge, although all other markers of infection remained undetectable. Our results demonstrated that antisense RNA expression driven by tRNA promoter in the context of a double-copy vector conferred better long-term protection against HIV infection compared to that driven by HIV LTR or MLV LTR promoters, and that the optimized vectors may be useful in developing a gene therapy against HIV-1 infection and AIDS.     

Comparison of 2-Year Weight Loss Trends in Behavioral Treatments of Obesity: Diet, Exercise, and Combination Interventions

Objective The effects of three cognitive-behavioral weight control interventions for adults were compared: diet only, exercise only, and a combination of diet and exercise. This article reports 2-year follow-up data.Design The three interventions were compared in a randomized, experimental design.Subjects A total of 127 men and women who were at least 14 kg overweight (according to height-weight tables) were recruited from an urban community and assigned randomly to the experimental conditions.Intervention The dietary intervention was a low-energy eating plan adjusted to produce a 1 kg/week loss of weight. The exercise component involved training in walking and a home-based program of up to five exercise periods per week. There were 12 weekly instructional sessions, followed by 3 biweekly and 8 monthly meetings. All sessions were led by registered dietitians.Outcome measures Changes in body weight.Statistical analyses Analysis of variance for weight changes and repeated measures analysis of variance for weight change trends.Results At 1 year, no significant differences were noted among the three groups. The diet-only group lost 6.8 kg, the exercise-only group lost 2.9 kg, and the combination group lost 8.9 kg (P=.09). During the second year, the diet-only group regained weight — reaching 0.9 kg above baseline; the combination group regained to 2.2 kg below baseline; and the exercise-only group regained slightly to 2.7 kg below baseline (P=.36). Repeated measures analysis of variance showed a group-by-time interaction (P=.001); data for the dieting groups best fit a U-shaped regain curve (P=.001).Applications The results suggest that dieting is associated with weight loss followed by regain after treatment ends, whereas exercise alone produced smaller weight losses but better maintenance. The large outcome variability and unequal difficulty of the regimens across groups limit the generalizability of the findings. J Am Diet Assoc. 1996; 96:342-346.     

A Decade of Clinical Trial Developments in Postmyocardial Infarction, Congestive Heart Failure, and Sustained Ventricular Tachyarrhythmia Patients: From CAST to AVID and Beyond

A Decade of Clinical Trials. Multiple trials using antiarrhythmic drugs, pharmacologic therapy, and implantable cardioverter defibrillators have been performed in an attempt to improve survival in patients: (1) postmyocardial infarction; (2) with congestive heart failure, with and without nonsustained ventricular tachycardia; and (3) with sustained ventricular tachycardia and those who have survived an out-of-hospital cardiac arrest. This article reviews some of the key findings and limitations of completed and ongoing trials. We also make recommendations for the current treatment of such patients based on the results of these trials.     

ATP1A3 mutations in infants: a new rapid‐onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.     

Language mixing in bilingual speakers with Alzheimer's dementia: a conversation analysis approach

Bilingual speakers with Alzheimer s disease (AD) may use the wrong language for the setting interlocutor or produce what appears to be an inappropriate mixture of their two languages. The few published studies to date examining this phenomenon have investigated it within a discourse analysis framework, interpreting the behaviour either as a problem of language choice (choosing the appropriate language in which to converse) or language separation (keeping two languages separate in production). These authors contend that while such a distinction is theoretically feasible, it is extremely problematic to apply these labels to actual conversational data. Using examples from free conversations of four bilingual women with AD, some of the difficulties inherent in a discourse analytic approach to this question are illustrated. Applying principles from conversation analysis (CA) it is argued that a methodology that is data driven and context relevant offers more valuable insights into individuals language use and interaction. It avoids the inconclusiveness of the choice-separation dichotomy and offersmore constructive accounts of whether and how language behaviour is appropriate or not.     

TEENAGE DRINKING: A 4-YEAR COMPARATIVE STUDY

Two adolescent drinking surveys carried out within 4 years inthe same region of the UK were compared on three aspects ofdrinking behaviour. The results showed that there was a higherproportion of non-drinkers in 1992 as compared with 1988 formales aged 11–15 and females aged 11–13; more 11–13year-old females in 1992 reported their home as the locationof their first alcoholic drink without their parents; and youngerboys were less likely, in 1992, to report ever being drunk.The relative increase in the proportion of non-drinking adolescentsis in line with similar recent trends in national sample surveysof young adults.     

Factor analysis of ICD-10 symptom items in the 1988 National Health Interview Survey on Alcohol Dependence

The present paper analyzes data from the 1988 National Health Interview Survey (NHIS88) of US adults. This general population survey is important in that it is the largest survey to date that collects detailed information on alcohol consumption and alcohol problems. The NHIS88 is a multi-stage complex sample household study with a sample size of about 44 000 adults of which about 20 000 reported that they were current drinkers. Symptom items were used for classification of individuals into categories of alcohol abuse and alcohol dependence based on the DSM-III-R, DSM-IV, and ICD-10 classification. The present analyses are based on 20 items corresponding to the ICD-10 classification, the elements of which are closely related to the Edwards–Gross alcohol dependence syndrome concepts. A single dimension corresponding to alcohol problems in general accounted for much of the correlations among these items, but additional dimensions of interest were also identified. Of the ICD-10 elements only Impaired Control, Tolerance, and Withdrawal could be identified as separate dimensions.