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Biomedical subjects

M Dunn

Publications and source records attributed to M Dunn.

At least 55 records · Page 3Linked to original sources
PubMed1998

Association of pulmonary surfactant protein A (SP-A) gene and respiratory distress syndrome: interaction with SP-B.

Deficiency of the lipoprotein complex, surfactant, can lead to respiratory distress syndrome (RDS) in the prematurely born infant. The surfactant proteins (SP) play important roles in the function of surfactant. Previously, we have characterized four allelic variants of the SP-A1 gene (6A, 6A2, 6A3, and 6A4) and five allelic variants of the SP-A2 gene (1A, 1A0, 1A1, 1A2, and 1A3). We hypothesized that specific SP-A alleles/genotypes are associated with increased risk of RDS. Because race, gestational age (GA), and sex are risk factors for RDS, we first studied the distribution and frequencies of SP-A alleles/genotypes while adjusting for these factors as confounders or effect modifiers in control (n = 86 white and 12 black subjects) and RDS (n = 106 white and 37 black subjects) populations with GAs ranging from 24 wk to term. Although the odds ratios of several alleles and genotypes were in the opposite directions for black and white subjects, the homogeneity of odds ratio reached statistical significance only in the case of 6A3/6A3. Although differences were observed in subgroups with different GAs (< or =28 and >28 wk) of the RDS white population, definitive conclusions cannot be made regarding the effect of modification by GA. No differences were observed as a function of sex. Second, we compared the frequencies of SP-A genotypes and alleles between control (n = 83) and RDS (n = 82) patients in the >28-wk white population. Differences between the two groups were observed for the 1A0 allele and 1A0 genotypes. Moreover, a significant synergistic positive association was observed between 1A0 allele + SP-B polymorphic variant and RDS. We conclude that 1) the genetic analyses of RDS and SP-A locus should be performed separately for black and white populations and 2) SP-A alleles/genotypes and SP-B variant may contribute to the etiology of RDS and/or may serve as markers for disease subgroups.

Alleles↗
PubMed1997

Inhibition of endogenous cardiac phosphatase activity and measurement of sarcoplasmic reticulum calcium uptake: a possible role of phospholamban phosphorylation in the hypertrophied myocardium.

The activity of the sarcoplasmic reticulum (SR) CaATPase in cardiac muscle is regulated by phospholamban via its ability to be phosphorylated. It is unclear what role phospholamban phosphorylation plays in cardiac adaptation and disease. The study of the native phospholamban phosphorylation in tissue has been technically difficult because of the presence of endogenous enzymes. Using mobility shifts on SDS PAGE gels we have demonstrated that significant dephosphorylation of phospholamban occurs during tissue homogenisation in the absence of phosphatase inhibitors. Endogenous kinases do not appear to alter phospholamban phosphorylation. When 10 mM NaF (a phosphatase inhibitor) was used in the preparation of crude SR homogenates, CaATPase activity (measured by oxalate stimulated calcium uptake) was stimulated almost 2 fold, p < 0.01. Increased CaATPase activity in NaF was associated with increased phospholamban phosphorylation. Phosphatase inhibitors were used in tissue homogenisation to determine phospholamban phosphorylation in normal hearts and in cardiac hypertrophy induced by abdominal aortic constriction. In 50 mM NaF which completely inhibits endogenous phosphatases, phospholamban from hypertrophied hearts had a slower mobility compared with normal hearts. This suggests that phospholamban was more highly phosphorylated in cardiac hypertrophy. Increased phospholamban phosphorylation following cardiac hypertrophy may enable the myocardium to compensate functionally in the early stages of adaptation.

Animals↗
PubMed1997

Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness.

BACKGROUND: Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS). METHODS AND RESULTS: MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (Sf 0 to 12), IDL (Sf 12 to 20), VLDL (Sf 20 to 400), and HDL (F1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B-containing lipoproteins were measured independently, IDL (r=.21, P<.005) but not VLDL (r=-.09, P=.24) or LDL (r=.09, P=.26) was associated with the progression of carotid artery intimamedia thickness. CONCLUSIONS: These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (Sf 12 to 20) that is included within the traditional measurements of LDL-C.

Adult↗
PubMed1997

Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression.

BACKGROUND: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (i.e., formation of new blood vessels) both in vitro and in vivo. Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization. It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known as TP53). PURPOSE: We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer. We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis. METHODS: Tumors from 163 patients (with a median follow-up of 7.7 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP. For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined. TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group. Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test. Reported P values are two-sided. RESULTS: TSP expression was significantly associated with disease recurrence (P = .009) and overall survival (P = .023). Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival. TSP expression was an independent predictor of disease recurrence (P = .002) and overall survival (P = .01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status. TSP expression was significantly associated with p53 expression status (P = .001) and microvessel density counts (P = .001). Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts. Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression. CONCLUSIONS AND IMPLICATIONS: These data support the concept that TSP may possess a tumor-inhibitory function. TSP may act, in part, through the regulation of tumor neovascularity. These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, i.e., through the control of tumor angiogenesis.

Adult↗
PubMed1997

Adverse prognostic features of collagen injection therapy for urinary incontinence following radical retropubic prostatectomy.

PURPOSE: We identified and characterized predictive factors associated with an unfavorable outcome of collagen injection therapy in post-radical prostatectomy incontinence. MATERIALS AND METHODS: A total of 46 patients, 49 to 85 years old (mean age 67) and incontinent after radical retropubic prostatectomy, underwent a mean of 2.8 transurethral injections of collagen (mean cumulative volume injected 31 ml.). Preoperatively, all patients underwent fluoroscopic multichannel video urodynamics including determination of Valsalva's leak point pressure. Stress urinary incontinence was subjectively graded as 1 (0 to 1 pad per day), 2 (2 to 3 pads per day) and 3 (greater than 3 pads per day). Patient age, duration and severity of pretreatment incontinence, presence of detrusor instability and anastomotic strictures, number of injections, total volume of collagen delivered and the impact of a nerve sparing procedure plus adjuvant radiation therapy were assessed and correlated with treatment outcome. RESULTS: Of the patients 11 (24%) became completely dry (9 after 3 or fewer treatments), 21 (41%) improved (17 after 3 or fewer treatments) and 14 (30%) showed no benefit (after more than 3 treatments). Of the 14 patients in whom treatment failed 6 had undergone adjuvant radiation treatment, pretreatment urinary incontinence was grade 3 in all, and concomitant detrusor instability was present in 11 (79%). All patients had received more than 3 treatments (mean total volume injected 37 ml.). CONCLUSIONS: Notwithstanding the need for multiple treatments, the prospect for cure by collagen injection of the post-radical prostatectomy incontinent patient is significantly affected by the severity of pretreatment incontinence, concomitant detrusor overactivity and exposure to radiation therapy. Age, duration of incontinence, presence of mild to moderate anastomotic strictures and a nerve sparing technique did not seem to influence treatment outcome.

Aged↗
PubMed1997

A comparison of quantitative computerized and human panel coronary endpoint measures: implications for the design of angiographic trials.

The Monitored Atherosclerosis Regression Study was a double-blind, 2-year, placebo-controlled, randomized, serial angiographic trial which tested reduction of low density lipoprotein-cholesterol with monotherapy using lovastatin on the progression of coronary atherosclerosis. Angiographic outcome was evaluated both by a panel of human readers who visually inspected matched film pairs to arrive at a global change score and by automated computerized vessel edge finding and lesion measurement (quantitative coronary angiography, QCA). In this paper, we model the association between QCA measures of coronary artery lesion change and the panel-based global change score. QCA measures included: per-patient changes in percent diameter stenosis and minimum lumen diameter averaged over all lesions; per-patient changes in average diameter and percent involvement averaged over all segments; the numbers of progressing and regressing lesions and new total occlusions; and the development of any new lesions. We found that when evaluating coronary artery lesion change, panelists evaluate changes in percent diameter stenosis for both low grade (< 50% diameter stenosis at baseline) and high grade (> or = 50% diameter stenosis at baseline) lesions as well as new total occlusions and the number of progressing lesions. Although computerized quantification of the size of a lesion at baseline and as an endpoint may be a more precise measure than that by human panel interpretation, QCA fails to incorporate many other important aspects of coronary angiographic change visualized over the entire coronary artery tree by a panel of human interpreters. Thus, the global change score provides a "multiple endpoint" for coronary angiographic trials which does not suffer from the problems of statistical analysis and interpretation of multiple hypothesis tests which usually accompany true multiple endpoint measures. Choice of either or both endpoints in preparing angiographic trials depends on careful consideration of the desired information as well as the cost of carrying out the endpoint analysis.

Anticholesteremic Agents↗
PubMed1997

Language disorders in children with autism.

Language development is delayed in most children on the autistic spectrum. The children are dysphasic as well as autistic. Comprehension and pragmatics are invariably affected. Lower level mixed receptive/expressive disorders involve phonological and syntactical processing, whereas higher level processing disorders involve semantics and formulation of discourse. In some children, lower level disorders may be so severe as to preclude speech, whereas in others phonology may be deficient in spontaneous production but not in repetition. Abnormal features of autistic language include aberrant prosody, immediate and delayed echolalia (scripts), and perseveration. Electrophysiological studies indicate that brainstem-evoked potentials are normal. Even in fully verbal individuals with autism, early and late cortical components of auditory, but not visual, event-related potentials are abnormal. Appropriate intervention must address language and behavioral issues. In children with severely defective auditory language, provision of visual language to supplement speech is essential.

Autistic Disorder↗
PubMed1997

Remediation of children with developmental language disorders.

There is no single approach to intervention in children with developmental language disorders. Remedial approaches differ in that they are based on differing theoretical perspectives. Four theoretical frames are reviewed. Neuropsychologically driven remediation, which tailors intervention to a child's profile of cognitive and linguistic strengths and weakness, is emphasized. Concrete examples of compensatory techniques suited to specific profiles are presented.

Child↗
PubMed1996

Diagnosis and classification in autism.

This study compared four systems for the diagnosis of autism (DSM-III, DSM-III-R, DSM-IV, and ICD-10) with two empirically derived taxa of autism, and with three social subgroups of autism (Aloof, Passive, and Active-but-Odd) in 194 preschool children with salient social impairment. There were significant behavior and IQ differences between autistic and other-PDD groups for all four diagnostic systems, and a significant association was found (a) for Taxon B, diagnoses of autism, and the Aloof subgroup, and (b) for Taxon A, other-PDD, and the Active-but-Odd subgroup. Findings offer support for two major overlapping continua within idiopathic Pervasive Developmental Disorder.

Algorithms↗
PubMed1996

The use of spontaneous language measures as criteria for identifying children with specific language impairment: an attempt to reconcile clinical and research incongruence.

Criteria for identification of children as specifically language impaired (SLI) vary greatly among clinicians and researchers. Standardized psychometric discrepancy criteria are more restrictive and perhaps less sensitive to language impairment than is clinical judgment based on a child's language performance in naturalistic contexts. This paper examines (a) differences in groups of preschool children clinically diagnosed as SLI who were and were not identified as SLI through standard psychometric discrepancy criteria, and (b) the validity of quantitative measures of mean length of utterance (MLU), syntax, and pragmatics derived from a spontaneous language sample as criteria for discriminating clinically diagnosed preschoolers from normally developing preschoolers. Spontaneous language data indicated that children clinically identified as SLI produced a significantly higher percentage of errors in spontaneous speech than normal children whether they met psychometric discrepancy criteria or not. Logistic regression analysis indicated that a combination of MLU, percent structural errors, and chronological age was the optimal subset of variables useful for predicting a clinical diagnosis of SLI. This combined criterion captured a larger proportion of the clinically identified SLI children than even the best psychometric discrepancy criteria.

Child↗
PubMed1996

Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure.

We conducted a case-control study of the possible association of occupations with likely exposure to electromagnetic fields and Alzheimer's disease (AD) with patients from the Alzheimer Disease Treatment and Diagnostic Center, Rancho Los Amigos Medical Center, Downey, CA. Patients with definite or probable AD were the case subjects (86 male, 240 female). Patients with cognitive impairment/dementia other than vascular dementia were control subjects (76 male, 76 female). The study was limited to patients who were at least age 65 at the time of their first examination at Rancho Los Amigos. The odds ratio for both sexes combined was adjusted for sex, education, and age at onset. The odds ratio for males was adjusted only for age at onset, and the odds ratio for females was adjusted for both education and age at onset. The adjusted odds ratio for both sexes was 3.93 (p = 0.006), 95% CI = (1.5 to 10.6). For males the adjusted odds ratio was 4.90 (p = 0.01), 95% CI = (1.3 to 7.9), and for females the adjusted odds ratio was 3.40 (p = 0.10), 95% CI = (0.8 to 16.0). These results are consistent with previous findings regarding the hypothesis that electromagnetic field exposure is etiologically associated with the occurrence of AD.

Aged↗
PubMed1995

Exon scanning for mutations of the NF2 gene in pediatric ependymomas, rhabdoid tumors and meningiomas.

Deletions of chromosome 22 have been identified in 3 types of childhood primary brain tumor: meningiomas, rhabdoid or atypical teratoid tumors (ATT) and ependymomas. This implicates the involvement of tumor suppressor genes on chromosome 22 in the genesis of these rare tumors. One such candidate tumor suppressor gene is the recently cloned neurofibromatosis 2 (NF2) locus. The purpose of our study was to determine the frequency of germ-line and somatic NF2 mutations in a selected group of brain tumors in children. Using single-strand conformation polymorphism (SSCP) assays we screened 17 exons of the NF2 gene in 13 pediatric brain tumors and 9 matched normal blood DNA samples. Tumors included 3 meningiomas, 2 rhabdoid or ATTs, 7 ependymomas and 1 malignant tumor of glial lineage. In addition, lymphoblastoid cell lines from 3 patients with rhabdoid/ATT in whom no tumor tissue was available were analyzed for germ-line mutations. Migration shifts were not detected in any of the normal DNA samples analyzed. Of the 13 tumors screened by SSCP, 1 meningioma with monosomy 22 produced a migration shift in exon 13. DNA sequencing of exon 13 revealed a deletion of a single guanine nucleotide (base 1397) in codon 466, causing a frame shift. While not all mutations might have been picked up by this technique, the data suggest that, similar to adult sporadic meningiomas, some pediatric meningiomas may result from somatic mutations in the NF2 gene. For rhabdoid tumors and ependymomas it appears that a locus distinct from NF2 might be responsible for tumorigenesis.

Base Sequence↗
PubMed1995

p53 gene mutations in pediatric brain tumors.

We investigated the frequency of p53 mutations in 47 pediatric brain tumors of various histologic subtypes that were collected over a period of 5 years. The specimens included 15 primitive neuroectodermal tumors (PNETs), 17 low grade astrocytomas, one anaplastic astrocytoma, three glioblastomas (GBMs), one mixed glial tumor, eight ependymomas, one choroid plexus carcinoma, and one gangliocytoma/ganglioneuroma. Mutations were identified by single strand conformation polymorphism analysis of exons 4-8 and verified by sequencing. Mutations were present in 2 of 3 cases of GBM, but not in 17 low grade astrocytomas (P = 0.02, Fisher's exact test). One GBM demonstrated a germline GGC to AGC transition (gly to ser) at codon 245 with loss of the wild-type allele. A second GBM contained a CGG to TGG transition (arg to trp) at codon 248, also with loss of the wild-type allele, but normal tissue was not available for comparison. In addition, one of 15 PNETs retained heterozygosity but demonstrated a somatic CGT to TGT transition (arg to cys) at codon 273. p53 mutations were absent in other histologic subtypes and in two cases with multiple primary cancers. These data are consistent with earlier findings that p53 mutations are rare in PNETs, which are primarily pediatric tumors. In contrast to adult gliomas, p53 mutations in pediatric gliomas appear restricted to the GBMs. The lack of p53 mutations in pediatric low grade astrocytomas suggests not only histological differences, but also a different molecular pathogenesis in adult and pediatric patients.

Adolescent↗
PubMed1995

Fermentative and aerobic metabolism in Rhizobium etli.

Strains of Rhizobium etli, Rhizobium meliloti, and Rhizobium tropici decreased their capacity to grow after successive subcultures in minimal medium, with a pattern characteristic for each species. During the growth of R. etli CE 3 in minimal medium (MM), a fermentation-like response was apparent: the O2 content was reduced and, simultaneously, organic acids and amino acids were excreted and poly-beta-hydroxybutyrate (PHB) was accumulated. Some of the organic acids excreted into the medium were tricarboxylic acid (TCA) cycle intermediates, and, concomitantly, the activities of several TCA cycle and auxiliary enzymes decreased substantially or became undetectable. Optimal and sustained growth and a low PHB content were found in R. etli CE 3 when it was grown in MM inoculated at a low cell density with O2 maintained at 20% or with the addition of supplements that have an effect on the supply of substrates for the TCA cycle. In the presence of supplements such as biotin or thiamine, no amino acids were excreted and the organic acids already excreted into the medium were later reutilized. Levels of enzyme activities in cells from supplemented cultures indicated that carbon flux through the TCA cycle was maintained, which did not happen in MM. It is proposed that the fermentative state in Rhizobium species is triggered by a cell density signal that results in the regulation of some of the enzymes responsible for the flux of carbon through the TCA cycle and that this in turn determines how much carbon is available for the synthesis and accumulation of PHB. The fermentative state of free-living Rhizobium species may be closely related to the metabolism that these bacteria express during symbiosis.

Aerobiosis↗