Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone

Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.     

Utility of MMP-1, p53, E-cadherin, and collagen IV immunohistochemical stains in the differential diagnosis of adenomas with misplaced epithelium versus adenomas with invasive adenocarcinoma.

Adenomas with misplaced epithelium in the submucosa of the polyp stalk ("pseudoinvasion") may be difficult to distinguish from adenomas that harbor invasive adenocarcinoma by morphologic analysis. Recently, several epithelial and stromal proteins, such as matrix metalloproteinase-1 (MMP-1), p53, E-cadherin, and collagen IV, have been shown to be altered in colonic adenocarcinomas in comparison with adenomas and normal colonic mucosa. Therefore, the purpose of this study was to evaluate the diagnostic use of several epithelial (p53, E-cadherin) and stromal (MMP-1, collagen IV) markers in distinguishing adenomas with misplaced epithelium from those with invasive adenocarcinoma. Routinely processed polypectomy specimens from 23 patients with an adenoma with misplaced epithelium (male/female ratio 12/11; mean age 65 years) and 23 patients with an adenocarcinoma arising in an adenoma (male/female ratio 13/10; mean age 63 years) were immunohistochemically stained (avidin-biotin complex method) for monoclonal antibodies to MMP-1 (epithelial and stromal cell collagenase), p53 (tumor suppression gene), E-cadherin (intercellular adhesion protein), and collagen IV (basement membrane collagen component), and the results were compared between the two polyp groups. Where appropriate, immunopositivity was evaluated in the epithelium (MMP-1, p53, E-cadherin), stroma (MMP-1), and/or basement membrane (collagen IV). Cases were considered positive if an increase (MMP-1, p53) or decrease (E-cadherin, collagen IV) in either the intensity or proportion of cells staining was noted in the submucosal epithelial component compared with the intramucosal portion of the polyp head for each individual polyp. In adenomas with invasive adenocarcinoma, MMP-1 staining of the stroma surrounding submucosal epithelium and p53 nuclear staining within the epithelium were increased in 21 (91%) and 14 (61%) cases, respectively, whereas decreased or discontinuous E-cadherin and collagen IV staining was noted in 15 (65%) and 22 (96%) cases, respectively. All these values were significantly different (p < 0.005) from those observed in adenomas with misplaced epithelium [MMP-1, 11 of 23 (48%); p53, 1 of 23 (4%); E-cadherin, 0 of 23 (0%); collagen IV, 0/23 (0%)]. Furthermore, in three diagnostically difficult cases that contained foci of misplaced epithelium with high-grade dysplasia, the immunohistochemical results confirmed the impression that the lesions represented epithelial misplacement rather than invasive adenocarcinoma. In conclusion, the degree and/or pattern of MMP-1, p53, E-cadherin, and collagen IV staining in the submucosal epithelial elements in comparison with the intramucosal adenomatous tissue may help distinguish adenomas with misplaced epithelium from those with invasive adenocarcinoma.     

An analysis of glyphosate data from the California Environmental Protection Agency Pesticide Illness Surveillance Program

Glyphosate is among the pesticides most frequently reported to the California EPA Pesticide Illness Surveillance Program. We analyzed glyphosate-related calls to the Pesticide Illness Surveillance Program in order to assess the number of reports involving systemic symptoms and to better understand the nature and severity of reported cases. Data on glyphosate and other pesticides are available for the years 1982-1997 including: type of exposure (agricultural/other); target organ(s) affected (skin/eye/respiratory/systemic); exposure(s); an assessment of causal relationship (possible, probable, or definite); and limited medical text. Of 815 total glyphosate calls, most involved topical irritation of the eye (n = 399), skin (n = 250), upper airway (n = 7), or combinations of these sites (n = 32) without systemic symptoms. Of the 187 systemic cases, only 22 had symptoms recorded as probably or definitely related to glyphosate exposure alone. The reported symptoms were not severe, expected to be limited in duration, and frequently inconsistent with the route of exposure and/or previous experience with glyphosate. We conclude that call volume is not a reliable indicator of the actual incidence or severity of glyphosate-related incidents in California.     

Differences in DNA binding properties between E2F1 and E2F4 specify repression of the Mcl-1 promoter

E2F1 is a potent inducer of apoptosis whereas its relative, E2F4, generally does not promote cell death. Other work from our laboratory has demonstrated that E2F1 can directly bind and represss the Mcl-1 promoter - contributing to E2F1-mediated apoptosis. Here we show that while E2F1 can repress the Mcl-1 promoter, other members of the E2F family (such as E2F4) cannot. Characterization of the Mcl-1 promoter demonstrates that the -143/+10 region is critical for E2F1-mediated downregulation. We demonstrate that the ability of E2F1 to repress the Mcl-1 promoter correlates with its ability to bind within the required -143/+10 region of this promoter. In contrast, E2F4 is unable to bind to the -143/+10 region of the Mcl-1 promoter. We propose that E2F4 is unable to repress the Mcl-1 promoter primarily as a result of insufficient binding to the essential regulatory region. This is the first evidence of DNA binding specificity among E2F family members that results in differential regulation of a naturally occurring promoter.     

Profiles of respite use

Profiles of long-term respite use are reported for a diverse sample of 4,369 families from seven states who participated in the Alzheimer's Disease Demonstration Grant to States program. Data from service records spanning a period of seven years were analyzed using hierarchical linear modeling techniques. Respite use was examined in both day care and in-home settings using three different measures of use. Client characteristics related to use include the caregiver's gender and relationship to the elder, and the ethnicity, income, functional level, and problem behaviors of the elder. Provider characteristics linked with different patterns of use include level of service, fee structure, and level of capitation. Implications for service delivery are discussed.     

Thoughts about encounters between nondisabled and disabled peers: Situational constraints,states-of-mind,valenced thought categories

This study explores three issues: thoughts and feelings of individuals with and without physical disabilities concerning encounters in different situations, ways of grouping self-statements into valenced categories, and use of states-of-mind (SOM) ratios as an alternative to positive and negative thought frequencies. Data from 127 able-bodied and 46 physically disabled college students indicate that, in everyday social encounters, nondisabled individuals' thoughts and feelings were more negative, while those of disabled individuals were more negative when helping was involved and when encounters centered on the impairment. Thus, problematic encounters between people with and without disabilities may be due to the reactions of individuals with disabilities in situations which involve help, and to reactions of able-bodied persons in everyday contexts. The data also confirm the utility of SOM ratios as an alternative to valenced frequencies in cognitive assessment: SOM scores discriminated groups when situational demands were manipulated and scores were linearly related to criterion measures. However, SOM ratios differed dramatically, depending on the attentional focus of thoughts. The findings illustrate types of thoughts which occur during interaction between people with and without disabilities, demonstrate a simple technique for grouping thoughts into valenced categories on an empirical basis, and highlight the relative contribution of cognitive and affective elements to overall valenced scores. Implications for research on assessment of self-statements are discussed and recommendations are made concerning programming to facilitate the social integration of people with disabilities.This research was supported by grants to the first author from the Social Sciences and Humanities Research Council of Canada and from Fonds F.C.A.R. pour l'aide et le soutien à la recherche. Thanks are due to Meribah Aikens, Maria Barile, Leo Bissonette, Bosco Daude, Jim Dubois, Lillian Fox, Evelyn Gold, Naomi Goodz, Darlene Judd, André Leblanc, John Martos, Sue McKenzie, Irwin Slopak, and Joan Wolforth for their assistance with various stages of this investigation.     

Cerebellar cortical atrophy in experimental autoimmune encephalomyelitis

Brain atrophy measured by MRI is an important correlate with clinical disability and disease duration in multiple sclerosis (MS). Unfortunately, neuropathologic mechanisms which lead to this grey matter atrophy remain unknown. The objective of this study was to determine whether brain atrophy occurs in the mouse model, experimental autoimmune encephalomyelitis (EAE). Postmortem high-resolution T2-weighted magnetic resonance microscopy (MRM) images from 32 mouse brains (21 EAE and 11 control) were collected. A minimum deformation atlas was constructed and a deformable atlas approach was used to quantify volumetric changes in neuroanatomical structures. A significant decrease in the mean cerebellar cortex volume in mice with late EAE (48-56 days after disease induction) as compared to normal strain, gender, and age-matched controls was observed. There was a direct correlation between cerebellar cortical atrophy and disease duration. At an early time point in disease, 15 days after disease induction, cerebellar white matter lesions were detected by both histology and MRM. These data demonstrate that myelin-specific autoimmune responses can lead to grey matter atrophy in an otherwise normal CNS. The model described herein can now be used to investigate neuropathologic mechanisms that lead to the development of gray matter atrophy in this setting.     

Prosthetic intervention effects on activity of lower-extremity amputees

OBJECTIVE: To investigate the effect of prosthetic interventions on the functional mobility of lower-extremity amputees. DESIGN: Crossover with repeated measures. SETTING: Household and community environment. PARTICIPANTS: Twelve transtibial and 5 transfemoral amputees. INTERVENTIONS: For transtibial amputees, shock-absorbing versus rigid pylons. For transfemoral amputees, C-Leg versus Mauch SNS knees. MAIN OUTCOME MEASURES: Daily activity level (step count) and duration (minutes of activity). RESULTS: Pylon type had no effect on the daily activity level or duration of transtibial amputees. Knee type had no effect on the daily activity level or duration of transfemoral amputees. Transtibial amputees were more active on weekdays (3079+/-1515 steps/d) than weekends (2386+/-1225 steps/d) (P=.007). In general, lower-extremity amputees perform numerous short-duration bouts of activity (1-2 min) consisting of fewer than 17 steps/min, but activities of more than 15 minutes in duration were relatively rare (<1 per day). CONCLUSIONS: Intervention had no effect on amputee activity level and duration. Higher weekday activity levels of transtibial amputees suggest their vocational activities are more demanding than recreational activities. The fitting, alignment, and design of prosthetic components should be optimized for 1 to 2 minute bouts of activity consisting of only a few dozen steps.