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Biomedical subjects

M Atkinson

Publications and source records attributed to M Atkinson.

At least 19 recordsLinked to original sources
PubMed1999

Eradication of pre-established lymphoma using herpes simplex virus amplicon vectors.

Herpes simplex virus amplicon vectors expressing RANTES (HSVrantes) and the T-cell costimulatory ligand B7.1 (HSVB7.1) were studied for their ability to elicit a tumor-specific T-cell response in a murine lymphoma model. HSVB7.1- and HSVrantes-transduced EL4 cells expressed high levels of B7.1 and RANTES as analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. Inoculation of ex vivo HSVB7.1 transduced cells in syngeneic mice resulted in regression of both transduced cells and nontransduced cells inoculated contralaterally. Direct intratumoral injection of HSVB7.1 and/or HSVrantes alone or in combination into established EL4 tumors led to complete tumor regression in injected tumors as well as in nontransduced contralaterally implanted tumor, whereas control tumors or tumors injected with HSVlac expressing beta-galactosidase did not regress. Maximal protection was achieved with combined injection of HSVB7.1 and HSVrantes; mice showing tumor regression were resistant to rechallenge with parental EL4 cells, and tumor cell-specific cytolytic T-cell activity was observed in mice demonstrating regression. HSV amplicon-mediated delivery of immune effector molecules may represent a useful strategy for immunotherapy in the setting of pre-existing tumor.

Animals↗
PubMed1998

Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors.

Recombinant adeno-associated virus (AAV) vectors have been used to transduce murine skeletal muscle as a platform for secretion of therapeutic proteins. The utility of this approach for treating alpha-1-antitrypsin (AAT) deficiency was tested in murine myocytes in vitro and in vivo. AAV vectors expressing the human AAT gene from either the cytomegalovirus (CMV) promoter (AAV-C-AT) or the human elongation factor 1-alpha promoter (AAV-E-AT) were examined. In vitro in C2C12 murine myoblasts, the expression levels in transient transfections were similar between the two vectors. One month after transduction, however, the human elongation factor 1 promoter mediated 10-fold higher stable human AAT expression than the CMV promoter. In vivo transduction was performed by injecting doses of up to 1.4 x 10(13) particles into skeletal muscles of several mouse strains (C57BL/6, BALB/c, and SCID). In vivo, the CMV vector mediated higher levels of expression, with sustained serum levels over 800 micrograms/ml in SCID and over 400 micrograms/ml in C57BL/6 mice. These serum concentrations are 100,000-fold higher than those previously observed with AAV vectors in muscle and are at levels which would be therapeutic if achieved in humans. High level expression was delayed for several weeks but was sustained for over 15 wk. Immune responses were dependent upon the mouse strain and the vector dosage. These data suggest that recombinant AAV vector transduction of skeletal muscle could provide a means for replacing AAT or other essential serum proteins but that immune responses may be elicited under certain conditions.

Animals↗
PubMed1998

Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation.

The MAP kinase ERK2 is widely involved in eukaryotic signal transduction. Upon activation it translocates to the nucleus of the stimulated cell, where it phosphorylates nuclear targets. We find that nuclear accumulation of microinjected ERK2 depends on its phosphorylation state rather than on its activity or on upstream components of its signaling pathway. Phosphorylated ERK2 forms dimers with phosphorylated and unphosphorylated ERK2 partners. Disruption of dimerization by mutagenesis of ERK2 reduces its ability to accumulate in the nucleus, suggesting that dimerization is essential for its normal ligand-dependent relocalization. The crystal structure of phosphorylated ERK2 reveals the basis for dimerization. Other MAP kinase family members also form dimers. The generality of this behavior suggests that dimerization is part of the mechanism of action of the MAP kinase family.

Animals↗
PubMed1998

Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades.

OBJECTIVES: This study sought to define the effects of age and gender effects on the normal range of time domain heart rate variability (HRV) over nine decades in healthy subjects. BACKGROUND: Low HRV is considered an independent marker of mortality risk. However, the age-related decline in HRV may limit its predictive value, particularly in the elderly. Delineation of the range of HRV in healthy subjects over the life span is needed. Gender-related differences in HRV also need clarification. METHODS: We determined, according to decade, 24-h heart rate (HR) and HRV of 260 healthy subjects (10 to 99 years old; 112 male, 148 female) by means of five standard time domain measures: standard deviation of all normal sinus RR intervals over 24 h (SDNN), standard deviation of the averaged normal sinus RR intervals for all 5-mm segments (SDANN), mean of the standard deviations of all normal sinus RR intervals for all 5-min segments (SDNN index), root-mean-square of successive normal sinus RR interval difference (rMSSD) and the percentage of successive normal sinus RR intervals >50 ms (pNN50). RESULTS: 1) HRV decreased with aging, the pattern of change being measure dependent. HRV (SDNN and SDANN) decreased only very gradually, reaching 60% of baseline (second-decade values) by the tenth decade. With the SDNN index, HRV decreased linearly with aging, reaching 46% of baseline by the tenth decade. Using pNN50 and rMSSD, HRV decreased most rapidly, reaching 24% and 47% of baseline, respectively, by the sixth decade and then stabilized. 2) Using the SDNN index, rMSSD and pNN50, HRV of subjects >65 years old fell below published cutpoints for increased risk of mortality in 25%, 12% and 4%, respectively. 3) At age <30 years, HRV for all measures was lower in female than male subjects. Gender differences decreased at age >30 years and disappeared at age >50 years. 4) HR also declined with aging but much more slowly. HR at age <50 years was faster in female than in male subjects. Gender differences disappeared thereafter. CONCLUSIONS: 1) Using all measures, HRV of healthy subjects declines with aging, with measure-dependent patterns. 2) Using the SDNN index, rMSSD and pNN50, HRV of healthy subjects, particularly those >65 years old, may decrease to below levels associated with increased risk of mortality. 3) Gender influences HRV. Gender differences in HRV are age and measure dependent. 4) Age and gender also affect heart rate.

Adolescent↗
PubMed1998

Aging and the immune response to tetanus toxoid: diminished frequency and level of cellular immune reactivity to antigenic stimulation.

The period of efficacious immune reactivity afforded by tetanus immunization and the need for continuing some forms of tetanus vaccination programs have been the subjects of recent debates. Our studies demonstrate that the level of antitetanus immunity based on immunological memory (i.e., cellular immune responsiveness) varies dramatically as a function of age, with older individuals constituting a population which is increasingly susceptible to tetanus infection.

Adolescent↗
PubMed1998

The prevalence of posttraumatic stress disorder in an adolescent inpatient unit.

OBJECTIVE: To examine the prevalence and comorbidity of posttraumatic stress disorder (PTSD) in an adolescent inpatient population. A 2-year retrospective chart study was conducted. METHOD: Computer-registered data of discharge records from 1993 and 1994 were recovered. Patients were grouped by diagnosis; frequency and chi-square statistical analyses were performed to ascertain the prevalence and the comorbidity of various diagnoses with PTSD. RESULTS: A total of 187 patients, 114 females and 73 males, with a mean age of 15 years were reviewed, and 42% (79) of all patients had a diagnosis of PTSD using DSM-III-R criteria. There were 54 females and 25 males with PTSD; however, gender effect was not clinically significant. Associated comorbidity reaching clinical significance included other anxiety disorders (P = 0.008) and depressive disorders (P = 0.003). Asthma was diagnosed as a significant clinical disorder (P = 0.05) comorbid with PTSD. PTSD diagnoses correlated strongly with a history of abuse (P = 0.0001). CONCLUSIONS: PTSD occurs frequently in adolescent inpatients and is commonly comorbid with other diagnostic presentations. These findings may affect the management of PTSD and prognosis for this population.

Adolescent↗
PubMed1998

The effects of different types of music on mood, tension, and mental clarity.

This study investigated the impact of different types of music on tension, mood, and mental clarity. A total of 144 subjects completed a psychological profile before and after listening for 15 minutes to four types of music (grunge rock, classical, New Age, and designer). With grunge rock music, significant increases were found in hostility, sadness, tension, and fatigue, and significant reductions were observed in caring, relaxation, mental clarity, and vigor. In contrast, after listening to the designer music (music designed to have specific effects on the listener), significant increases in caring, relaxation, mental clarity, and vigor were measured; significant decreases were found in hostility, fatigue, sadness, and tension. The results for New Age and classical music were mixed. Feeling shifts among subjects were observed with all types of music. Designer music was most effective in increasing positive feelings and decreasing negative feelings. Results suggest that designer music may be useful in the treatment of tension, mental distraction, and negative moods.

Adolescent↗
PubMed1997

Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen.

Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes.

Adult↗
PubMed1997

The method of sib-pair linkage analysis in context of case-control design.

We used sib-pair linkage analysis as part of an epidemiologic approach to solving Problem 2 of the GAW10 data set of nuclear families. We recoded the quantitative trait Q1 into a dichotomous trait using Q1 > or = 40 as the cut-point. In a case-control design of sib-pair analysis, the affected siblings of the proband were the case subjects and the unaffected siblings were the control subjects. Case and control subjects were compared with respect to the number of alleles at one or more loci (0, 1, 2) that were identical-by-descent (IBD) with those of the proband. Odds ratios (ORs) and 95% confidence intervals (95% CI) were then computed with subjects sharing no alleles (share-0) serving as the reference group. Significantly high ORs were taken as indication of linkage between a marker locus and a suspected disease-susceptibility locus. The case-control sib-pair analysis identified marker D5G15 as associated with disease susceptibility (OR of sharing two alleles [share-2] = 7.7 [95% CI 2.5-23.9]). Our results were consistent with the results from Kruglyak and Lander's method of complete multipoint sib-pair analysis for linkage. For the marker (D5G15) identified through sib-pair analysis, we examined the effects of other covariates and evaluated gene-environment interaction using conditional logistic regression.

Case-Control Studies↗
PubMed1997

Development and evaluation of interdisciplinary team standards of patient care.

Interdisciplinary team collaboration is considered an essential component of most health care services. The overall goal of such collaboration in mental health services/ psychiatry is to provide a comprehensive biopsychosocial perspective organized around patient needs and stages of treatment. There is also increasing interest in using an interdisciplinary framework to monitor and evaluate patient care. Unfortunately, little information is available regarding treatment standards that address the issue of interdisciplinary team collaboration. This project was designed to formulate a set of interdisciplinary team standards of patient care. This article presents the standards and provides an overview of the interdisciplinary processes through which they were developed. An empirical evaluation of the standards within one service area--The Affective Disorders Clinic--is also included.

Adult↗
PubMed1997

Characterizing quality of life among patients with chronic mental illness: a critical examination of the self-report methodology.

OBJECTIVE: The purposes of the study were 1) to characterize the quality of life of three patient groups with chronic mental illness, 2) to evaluate differences in reported life quality among the three groups, and 3) to evaluate the validity of a self-report methodology by comparing these results with several objective indicators of life quality. METHOD: The study group consisted of chronically mentally ill patients with schizophrenia (N = 69), bipolar disorder (N = 37), or major depression (N = 35). Subjects were administered the Quality of Life Index, and comparisons of both objective and self-report life quality indices were made among the three groups. Quality of life ratings of these subjects were also compared with those of patients with a chronic physical illness. RESULTS: The two groups with mood disorders reported significantly lower scores on the Quality of Life Index than the patients with schizophrenia. Moreover, the scores on the Quality of Life Index for patients with schizophrenia were very similar to those of the comparison group of physically ill patients. The opposite trend emerged when groups were compared with respect to objective indicators of life quality. Schizophrenic patients experienced more objectively aversive life circumstances than either of the affectively disturbed groups. CONCLUSIONS: The validity of self-report measures of life satisfaction is questioned, particularly for use with affectively disturbed populations, since scores may be influenced by affective bias, poor insight, and recent life events.

Adult↗
PubMed1997

Strategies and outcomes of prenatal diagnosis for osteogenesis imperfecta: a review of biochemical and molecular studies completed in 129 pregnancies.

We completed prenatal diagnostic studies from 129 pregnancies at risk for osteogenesis imperfecta (OI). Studies in 107 pregnancies were completed by analysis of collagen synthesized by cells cultured from chorionic villus biopsies and the remaining 22 used direct mutation identification or analysis of polymorphic restriction sites in the COL1A1 gene of type I collagen. The vast majority of studies (n = 113) were obtained to identify fetuses with OI type II (the perinatal lethal form) and some fetuses affected with OI type III or IV (the deforming varieties). Of the 50 couples who had had one previous affected pregnancy with the lethal form of OI, one had a second affected pregnancy, a rate of 2 per cent. Two of the seven unaffected couples (28 per cent) who had had two previous affected pregnancies with OI type II had a third affected pregnancy; none of the three with two previous pregnancies with OI type III had a third. Pregnancies at risk for OI type I could not be ascertained reliably by biochemical analysis of cultured CVS cells but were identified by direct analysis of the causative mutation or the use of linked markers in families. All prenatal diagnostic studies were undertaken only after earlier diagnostic studies (biochemical or molecular) had been completed on the proband, a necessary strategy for accurate results. In all pregnancies at risk for OI type II, OI type III, and OI type IV studied with biochemical strategies and in pregnancies at risk for OI type I studied with molecular techniques, there were neither false-negative nor false-positive results. Diagnostic information can be obtained within 20-30 days of biopsy using biochemical techniques and within 10-14 days when molecular strategies are used.

Amniocentesis↗
PubMed1996

Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes.

Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 Mr. Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD65, glima 38, and IA2 antibodies in the same groups was 91 and 84%, respectively. GAD65, IA2, and glima 38 represent three distinct targets of immunoprecipitating IgG autoantibodies associated with beta cell destruction and type 1 diabetes.

Adolescent↗
PubMed1996

Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition.

Glutamic acid decarboxylase (GAD) is an autoantigen in two autoimmune diseases, insulin-dependent diabetes mellitus (IDDM) and stiff-man syndrome (SMS). However, most individuals with one of these diseases do not have the other disease. Prior studies have suggested that the natures of the GAD Abs associated with each of these diseases are different, which may have implications for the autoimmune pathogenesis. We have compared the GAD autoantibody profile and have mapped GAD protein epitope regions in the two diseases using an immunoprecipitation assay with recombinant GAD 65 and GAD 67 proteins, GAD protein fragments, and synthetic GAD peptides, as well as chimeric GAD proteins. Our results indicate that individuals with SMS have GAD Abs in 100- to 500-fold higher titer than individuals with IDDM. The population of GAD Abs in SMS sera is quite complex and includes those that recognize at least three GAD 65 epitope regions located between amino acids 1-16, 188-442, and 442-563. These types of GAD Abs are not found in IDDM sera. All SMS sera also had Ab specificity that binds GAD 67 in a region highly homologous to amino acids 188-442 of GAD 65. In contrast to prior studies that used immunoblotting to measure GAD Abs, we find GAD Abs in SMS sera also target two conformation-dependent regions of GAD 65, one located in the middle and one near the C-terminus of the protein. These two regions of the GAD 65 protein are similar to regions targeted by GAD 65-specific Abs found in individuals with IDDM. These results indicate that although disease-specific epitopes may exist, there is also overlap in the humoral response between the two diseases.

Autoantibodies↗
PubMed1996

A psychometric comparison of the Calgary Depression Scale for Schizophrenia and the Hamilton Depression Rating Scale.

This study compared two measures of depression in a population with schizophrenia. Inpatients (n = 112) with schizophrenia, were assessed on the Hamilton (HDRS), and Calgary (CDSS) depression scales and the Positive and Negative Syndrome Scale (PANSS). Eighty-nine were reassessed 3 months later. A principal components factor analysis was applied to each depression scale. The relationship between measures of depression and positive and negative symptoms was explored using correlation, factor and regression analyses. There were no significant correlations between the total CDSS and positive or negative symptoms at either time. In contrast, the HDRS total score was correlated with both positive and negative syndromes at time 2. Moreover, a number of HDRS factors correlated significantly with the PANSS positive scale at both times and with the negative subscale score at time 2. Multiple regression analysis showed that the HDRS accounted for more of the variance in positive and negative symptoms scores than did the CDSS. The CDSS has fewer factors and less overlap with positive and negative symptoms than the HDRS. This suggests that it is a more specific measure of level of depression than the HDRS for individuals with schizophrenia.

Adult↗
PubMed1996

Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes.

A new marker for cells of the osteoblastic lineage was identified by raising monoclonal antibodies against an immortalized rat osteoblastic cell line. Among the different antibodies one was selected which, on tissue sections, strongly reacts with osteoblasts, preosteocytes, and osteocytes. This antibody, designated E11, recognizes an antigen localized at the cell surface. The cDNA encoding the E11 antigen was cloned from a cDNA library prepared from ROS 17/2.8 cells, using a eukaryotic expression system. The E11 cDNA sequence revealed homology with the murine OTS-8/gp38 sequence. In situ hybridization confirmed that E11 mRNA expression in bone is restricted to osteoblasts and osteocytes. The tissue specificity of the E11 expression was studied by immunohistochemistry and Northern blot analysis. Apart from bone, E11-positive cells were also found in lung: namely, the alveolar cells of type I. Epithelial cells of the choroid plexus and endothelial cells of lymphatic vessels were also labeled with mAb E11. These results were confirmed by Northern blot, as the 1.8 kb E11 mRNA transcript was detected in bone and also in lung, brain, and skin. In conclusion, we describe a novel osteoblastic product which is expressed by mature osteoblasts and newly formed osteocytes.

Adenylyl Cyclases↗