Biomedical subjects
Publications and source records attributed to H P Adams.
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Although the Philadelphia chromosome (Ph1) has been identified as an adverse prognostic factor in acute lymphoblastic leukemia (ALL), little is known about the incidence and clinical course of relapsed Ph1-positive ALL in children. The incidence was determined by screening of 170 consecutive children with first bone marrow relapse of ALL using the reverse transcriptase-polymerase chain reaction (RT-PCR) and comparison, with cytogenetic analysis. Among these 170 children, 20 (12%) were found to be BCR-ABL-positive, representing a rate that is about three times higher than that reported for newly diagnosed ALL. Ten of the cases were identified by RT-PCR only. In none of the 21 patients with T-cell immunophenotypes could an expression of the BCR-ABL mRNA be detected. BCR-ABL positivity was associated with a significantly shorter duration of first remission (P = .0086) and higher white blood cell (P = .0157) and blast cell counts (P = .0304) at relapse diagnosis. All patients were treated according to the ALL-REZ BFM 87 and 90 relapse trials of the BFM Relapse Study Group. The intensive multiagent chemotherapy induced a second complete remission in only 60% of children with BCR-ABL-positive ALL compared with in 91% of those without BCR-ABL expression (P = .0023). The prognosis of BCR-ABL-positive ALL in children is poor, with a probability of event-free survival at 2 years of 8% versus 50% in those without BCR-ABL mRNA or cytogenetic analysis should become part of the routine diagnostic panel for children with newly diagnosed ALL and is fundamental for children presenting with an early bone marrow relapse.
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To determine the frequency, location, size, and risk factors for silent cerebral infarctions (SCIs) on brain CT, we identified 629 patients without a history of previous stroke who were enrolled in a multicenter clinical trial of therapy for acute ischemic stroke. On the baseline CT, 143 patients (22.7%) had SCIs; 34.3% of the lesions were in the right hemisphere, 38.5% in the left hemisphere, and 27.3% were bilateral. The lesion size was < 1 cm in 65.7%, and the most common site was the basal ganglia (48.3%). Patients with SCI were compared with controls without SCI to determine the odds ratios (ORs) for each risk factor. On univariate analysis, race (black versus white) had an OR of 1.80 (95% confidence interval [CI], 1.14 to 2.85), male sex an OR of 1.68 (95% CI, 1.12 to 2.51), and congestive heart failure an OR of 1.88 (95% CI, 1.07 to 3.31). Significant risk factors on multivariate analysis include age (OR 1.03 per year, p = 0.0070), male sex (OR 1.78, p = 0.0094), and race (OR 2.43, p = 0.0004). After including interaction terms with age and hypertension and age, sex, and race, hypertension was also a significant risk factor.
PURPOSE: We determined whether the classification of interstitial cystitis cases into ulcer and nonulcer categories from cystoscopic findings could be corroborated with epidemiological data relating to demographics, risk factors, symptoms, pain and psychosocial factors. MATERIALS AND METHODS: We surveyed 565 interstitial cystitis patients (111 with and 454 without ulcer), and from univariate analyses we found 10 noninvasive variables to be significantly associated with the presence of Hunner's ulcers. The 3 multivariate statistical methodologies of discriminant analysis, logistic regression and recursive partitioning were used to classify ulcer versus nonulcer cases from these variables. The retrospective and prospective performances from each methodology were also analyzed. RESULTS: Retrospectively, resubstitution error rates of all 3 methodologies were small, with overall misclassification rates of 19.1% with linear discriminant, 14.7% with logistic regression and 8.0% with recursive partitioning. Prospectively, the overall misclassification rates increased slightly to 20.0% with linear discriminant, 15.8% with logistic regression, and 15.9% with recursive partitioning. CONCLUSIONS: The classification of interstitial cystitis into distinct categories of Hunner's ulcer (classic interstitial cystitis) and nonulcer based on cystoscopic findings can be corroborated with epidemiological evidence. The 2 categories may represent different manifestations of the underlying disease pathophysiology.
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The binding of antigenic peptide sequences to major histocompatibility complex (MHC) molecules is a prerequisite for stimulation of cytotoxic T cell responses. Neural networks are here used to predict the binding capacity of polypeptides to MHC class I molecules encoded by the gene HLA-A*0201. Given a large database of 552 nonamers and 486 decamers and their known binding capacities, the neural networks achieve a predictive hit rate of 0.78 for classifying peptides which might induce an immune response (good or intermediate binders) vs. those which cannot (weak or non-binders). The neural nets also depict specific motifs for different binding capacities. This approach is in principle applicable to all MHC class I and II molecules, given a suitable set of known binding capacities. The trained networks can then be used to perform a systematic search through all pathogen or tumor antigen protein sequences for potential cytotoxic T lymphocyte epitopes.
OBJECTIVES: To describe the likely causes of ischemic stroke in a population of young adults and to report the influence of strict algorithms on the diagnosis of the likely cause of stroke in this cohort. DESIGN: Between July 1, 1977, and January 1, 1993, we registered 329 young adults with ischemic stroke in our registry. Diagnostic studies were selected on a case-by-case basis. Presumed causes of stroke were determined using clinical information and the results of diagnostic tests. In each case, a second causative diagnosis was made using the criteria developed for a large clinical trial. SETTING: Patients referred to the Division of Cerebrovascular Diseases in the Department of Neurology at the University of Iowa Hospitals and Clinics, Iowa City, by physicians in Iowa and adjacent states. PATIENTS: Three hundred twenty-nine young adults (182 men and 147 women) aged 15 to 45 years with ischemic stroke; 102 persons, 48 men and 54 women, were aged 30 years or younger. RESULTS: Cerebral arteriography was performed in 227 cases, and the findings were abnormal in 146. Transthoracic echocardiography revealed abnormalities in 82 of 221 patients examined. We identified approximately 60 different disorders that were presumed to be the cause of stroke. There were no major changes in the frequency of subtype diagnoses between the first 144 patients and the subsequent 185. Use of strict diagnostic criteria increased the number of cases of stroke of undetermined etiology (from 45 to 113), and the number attributed to large artery atherosclerosis declined from 71 to 32. CONCLUSIONS: The causes of ischemic stroke in young adults are numerous. Because treatment options in this group are influenced by a presumed cause, an evaluation on a case-by-case basis is warranted. Our experience suggests that a likely cause will be detected in most cases and that a regimented battery of tests may not be required. If strict diagnostic criteria are used, the diagnosis of stroke of undetermined etiology considerably increases. While such strict criteria are important in clinical trials that test new interventions, the value of the application of such methodologies to an unusual population, such as stroke in young adults, needs clarification. In particular, the usefulness of categorizing a stroke as undetermined when two or more possible causes are identified needs to be explored.
Mutants were recovered in a population of cybrids formed following protoplast fusion between tomato (Lycopersicon esculentum Mill.) cv UC82 and Lycopersicon pennellii Corr. The cybrids were identified as individuals with recombinant cytoplasmic genomes but only tomato nuclear genomes. The mutants were identified based on two features, a variegated sectoring of light and dark green regions on their leaves, stems, and fruit, and reduced growth in the field. The mutants produced 50% of the shoot fresh weight and 20% of the fruit fresh weight of the parental type, UC82. The variegated sectoring was maternally inherited. The chloroplast genome in the mutants was indistinguishable from the chloroplast genome in UC82, when distribution of restriction endonuclease sites was used as an assay. The mitochondrial genome in the mutants, however, was recombinant, containing genes from UC82 and L. pennellii. Light microscopic analysis of the leaves of the mutants demonstrated an absence of the palisade layer in the variegated sectors. Electron microscopic analysis of these same regions demonstrated an absence of normal inner membranes in the mitochondria of these cells.
BACKGROUND AND PURPOSE: This study was an attempt to determine whether CT and MRI are comparable or if one is superior to the other in the early detection of ischemic stroke or hematoma. METHODS: Patients with acute stroke were sought within 3 hours of onset for clinical examination and prospective evaluation by concurrently performed CT and MRI. Repeated clinical and imaging studies were undertaken when possible immediately after imaging and at 24 hours, 3 to 5 days, and 3 months. The study neurologists were blinded to the results of imaging, as were the study radiologists to the clinical findings. The study radiologists read the scans in sequence, mapping each imaging on standard templates before viewing a later scan. No retrospective revisions of imaging mapping of earlier images were undertaken. RESULTS: Sixty-eight patients were recruited within 4 hours and an additional 12 patients within 24 hours. Seventy-five strokes were due to infarction and five to hemorrhage. The median time to first scan was 132 minutes. Although some of the infarctions in 75 patients were detected within 1 hour, the fraction of positive first scans approached an asymptote at 2 to 3 hours. Overall, with the use of conventional non-contrast-enhanced CT and T1- and T2-weighted MRI, neither was superior in the very early detection of either hematoma or infarction. There was a marginally significant correlation between early positive brain imaging and the severity of the stroke. Some patients had initially positive CT and/or MRI scans, but their neurological examination had returned to normal by 24 hours. Overall, CT was better than baseline MRI at predicting 24-hour outcome. After 24 hours, both CT and MR more conspicuously defined the lesion limits than they did at baseline. CONCLUSIONS: With the technology available through 1991, neither CT nor MRI proved superior in the detection of the earliest signs of stroke.
Rapid identification of stroke subtype is valuable for both practicing clinicians and the optimal design of clinical stroke trials. Mechanisms of ischemic injury might differ among different stroke subtypes. Certain subtypes might be clinically identified as suboptimal for future therapeutic or prophylactic stroke trials. Some subtypes might be so clinically distinct that extensive laboratory investigation is unwarranted. Investigators in the ongoing Trial of ORG 10172 in Acute Stroke Treatment are using criteria to categorize stroke etiology among enrolled patients into one of five subtypes: large-artery atherothromboembolic, cardioembolic, small-vessel thrombotic, other etiology, or undetermined etiology. As part of the study, physicians initially predict the most likely subtype of stroke based on clinical features and baseline CT. Three months after stroke, investigators use the criteria, which also incorporate results of diagnostic testing, to reclassify stroke subtype. Initial clinical impression of subtype agreed with final determination in 62% of patients, and the rate was similar for all stroke subtypes. No stroke subtype was more accurately diagnosed than others by initial assessment. No subtype was more commonly identified by diagnostic studies. Fifteen percent of patients remained without a clear etiologic subtype diagnosis at 3 months. We conclude that clinical trials in stroke should not attempt to restrict entry into trials based on presumed stroke subtype. A careful evaluation for etiology is justified in all patients presenting with stroke, regardless of presumed subtype.
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In the vast majority of studies that address the role of surgery in the management of high-grade gliomas, the degree of tumor removal accomplished is solely based on the intraoperative perception of the neurosurgeon. Despite its fundamental importance for a comparison of different treatment modalities, little systematic effort has been made to evaluate the residual gross tumor by neuroimaging methods immediately after surgery. We report the results of a prospective study using contrast-enhanced computed tomography and magnetic resonance imaging (MRI) to monitor 60 patients after the resection of a high-grade glioma. In each case, the first scans were obtained between Days 1 and 5 after surgery, followed by serial imaging every 2 to 3 months, usually until the condition of the patient deteriorated severely or the patient died. Gadolinium-enhanced MRI proved to be extremely valuable for assessing gross residual tumor when performed during Days 1 to 3 after the resection of a preoperatively enhancing high-grade glioma. This timing avoided surgically induced contrast enhancement and minimized interpretative difficulties. In delineating residual tumor, MRI was vastly superior to computed tomography. About 80% of tumor "recurrences" emerged from definitely enhancing remnants, as revealed by early postoperative MRI. The neurosurgeon's estimation of gross tumor burden reduction could be shown to be much less accurate (by a factor of 3) than the postoperative assessment by modern neuroimaging. In our series, residual tumor enhancement was the most predictive prognostic factor of survival in patients with glioblastoma, followed by radiotherapy. Patients with a residual tumor postoperatively had a 6.595-times higher risk of death in comparison to patients without a residual tumor. Patients undergoing radiotherapy had a 0.258-times lower risk of death in comparison to patients who were not treated with radiation. Concerning survival, the prognostic significance of both variables surpassed age and performance.
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BACKGROUND: HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS: Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS: In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.