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Biomedical subjects

D A Albert

Publications and source records attributed to D A Albert.

At least 37 records · Page 2Linked to original sources
PubMed1988

The diagnosis of polyarteritis nodosa. II. Empirical verification of a decision analysis model.

We evaluated our literature-based estimates of diagnostic test characteristics and aggressive and conservative strategies for the diagnosis of polyarteritis nodosa (PAN) by reviewing 1980 through 1985 data from the University of Chicago Medical Center, Michael Reese Hospital, and Northwestern University Medical School. Test specificity was calculated by reviewing pathology and radiology reports on all relevant procedures done at the University of Chicago Medical Center in 1984 and 1985. There were no reports of false-positive findings (including angiography); thus, test specificity was 100% for muscle, nerve, kidney, liver, and testicular biopsy, which was comparable with our literature-based estimate of 97%. Test sensitivity was based on the 18 confirmed cases of PAN from the 3 institutions and was similar to that in published reports, ranging from 0% for liver biopsy to 100% for visceral angiography. Review of each case for diagnostic test sequence showed an average of 2 diagnostic procedures to confirm the diagnosis (range 1-6). Eight of 18 patients were evaluated according to the conservative strategy we proposed from our literature-based decision analysis approach. No patient was evaluated with the aggressive strategy, although 1 patient had 6 invasive procedures. Of the remaining 10 patients, 9 represented cases that might have been confirmed had the conservative approach been used, and if it had been used, 6 patients would have had the diagnosis confirmed. Thus, the minimum sensitivity of our conservative strategy is 78%, although based on these data, it could be as high as 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation Studies as Topic↗
PubMed1988

Deoxyadenosine toxicity and cell cycle arrest in hydroxyurea-resistant S49 T-lymphoma cells.

Hydroxyurea-resistant S49 T-lymphoma cells have increased ribonucleotide reductase activity and deoxyribonucleoside triphosphate pools when compared with wild-type cultures. If ribonucleotide reductase inhibition is the mechanism by which deoxyadenosine is cytotoxic, then hydroxyurea (HU)-resistant S49 cells might be more resistant to deoxyadenosine toxicity when adenosine deaminase is inhibited than wild-type cells. Five S49 cell lines resistant to varying concentrations of HU were compared with wild-type cells by measuring CDP reductase activity, deoxyribonucleoside triphosphate pools, and deoxyadenosine toxicity. All five cell lines resistant to increasing concentrations of HU exhibited a twofold increase in resistance to deoxyadenosine toxicity when compared to wild type, and the resistance was proportional to the twofold increased pools of dNTPs in these cell lines but was less than the six- to eight fold increase in ribonucleotide reductase activity. In both wild-type and mutant cell lines, deoxyadenosine toxicity was accompanied by the accumulation of deoxyadenosine triphosphate and reduction of the other dNTPs; however, only dGTP greatly diminished. Exogenous addition of deoxycytidine decreased the dATP accumulation by about 20%, but also resulted in increases in the dCTP, dTTP, and dGTP pools. The S49 cells arrested in G1 phase when exposed to dAdo, although hydroxyurea-resistant cells required higher dAdo concentrations to elicit G1-phase arrest than wild-type cells. Deoxycytidine prevented dAdo-induced G1 arrest in all cell types. In summary, these data support the hypothesis that deoxyadenosine-induced dATP accumulation results in inhibition of ribonucleotide reductase and that this may be the mechanism for both cell cycle arrest and cytotoxicity in S49 T-lymphoma cells.

Animals↗
PubMed1988

Prognosis in SLE: comparison of Markov model to life table analysis.

A Markov model of prognosis was evaluated by comparing the duration of disease activity states and life expectancy with Kaplan-Meier survival curves for 98 patients with systemic lupus erythematosus with 1080 patient-years of observation. A four state (remission, active, flare and death) homogeneous Markov chain was constructed to determine the transition probabilities between disease states, the probability of disease states over the subsequent 25 years, time in each disease state, and life expectancy. Approximately 85% of the clinical course of patients was in the active disease state; no patient made a transition directly between remission and flare; virtually all deaths occurred from the flare disease state. The proportion of the patient population in each disease state over time provided a convenient graphic summary of the natural history of SLE that supplemented the Kaplan-Meier survival curves. A Markov model analysis yields a clinically useful description of outcome for multistate diseases that supplements survival curves.

Actuarial Analysis↗
PubMed1987

Deoxyribonucleotide metabolism and cyclic AMP resistance in hydroxyurea-resistant S49 T-lymphoma cells.

We investigated the cell cycle regulation of deoxyribonucleoside triphosphate (dNTP) metabolism in hydroxyurea-resistant (HYUR) murine S49 T-lymphoma cell lines. Cell lines 10- to 40-fold more hydroxyurea-resistant were selected in a stepwise manner. These HYUR cells exhibited increased CDP reductase activity (5- to 8-fold) and increased dNTP pools (up to 5-fold) that appeared to result from increased activity of the M2 subunit (binding site of hydroxyurea) of ribonucleotide reductase. These characteristics remained stable when the cells were grown in the absence of hydroxyurea for up to 2 years. In both wild type and hydroxyurea-resistant cell populations synchronized by elutriation, dCTP and dTTP pools increased in S phase, whereas dATP and dGTP pools generally remained the same or decreased, suggesting that allosteric effector mechanisms were operating to regulate pool sizes. Additionally, CDP reductase activity measured in permeabilized cells increased in S phase in both wild type and hydroxyurea-resistant cells, suggesting a nonallosteric mechanism of increased ribonucleotide reductase activity during periods of active DNA synthesis. While wild type S49 cells could be arrested in the G1 phase of the cell cycle by dibutyryl cyclic AMP, hydroxyurea-resistant cell lines could not be arrested in the G1 phase by exogenous cyclic AMP or agents that elevate the concentration of endogenous cyclic AMP. These data suggest that cyclic AMP-generated G1 arrest in S49 cells might be mediated by the M2 subunit of ribonucleotide reductase.

Animals↗
PubMed1986

Selection and characterization of mutant S49 T-lymphoma cell lines resistant to phosphonoformic acid: evidence for inhibition of ribonucleotide reductase.

Phosphonoformic acid (PFA) and its congener phosphonoacetic acid (PAA) are inhibitors of viral replication whose mechanism of action appears to be the inhibition of viral DNA polymerase. These drugs inhibit mammalian DNA polymerase to a lesser extent. We sought to characterize the effects of phonoformic acid on mammalian cells by examining mutants of S49 cells (a mouse T-lymphoma line), which were selected by virtue of their resistance to phosphonoformic acid. The 11 mutant lines that were resistant to growth inhibition by 3 mM PFA had a range of growth rates, cell cycle distribution abnormalities, and resistance to the inhibitory effects of thymidine, acycloguanosine (acyclovir), aphidicolin, deoxyadenosine, and novobiocin. Most mutant lines had pools of ribonucleoside triphosphates and deoxyribonucleoside triphosphates similar to those of wild-type S49 cells. However, one line (PFA 3-9) had a greatly elevated dCTP pool. When this mutant line was further characterized, no apparent defect in DNA polymerase alpha activity was seen, but an increased ribonucleotide reductase activity, as assayed by CDP reduction in permeabilized cells, was observed. The CDP reductase activity in the PFA 3-9 cells decreased to wild-type control levels, and the CDP reductase activity of wild-type cells was also greatly reduced when PFA (2-3 mM) was added to permeabilized cells during the enzyme assay. These results demonstrate that PFA can directly inhibit ribonucleotide reductase activity in permeabilized cells. In addition, when PFA was added to exponentially growing cultures of either wild-type or PFA 3-9 mutant cells, the drug caused an arrest in S phase of the cell cycle and a decrease in all four deoxyribonucleotide pools, with the most dramatic decrease in the dCTP pools. The reduction in the dCTP pool level could be reversed by addition of exogenous deoxycytidine, but this reversed PFA toxicity only marginally. These observations suggest that PFA is an inhibitor of mammalian ribonucleotide reductase and that partial resistance to PFA can be effected by mutation to increased CDP reductase activity resulting in a large dCTP pool. This mutation results in less than twofold resistance to PFA, suggesting that other sites of inhibition coexist.

Animals↗
PubMed1985

Ribonucleotide reductase activity and deoxyribonucleoside triphosphate metabolism during the cell cycle of S49 wild-type and mutant mouse T-lymphoma cells.

We investigated deoxyribonucleoside triphosphate metabolism in S49 mouse T-lymphoma cells synchronized in different phases of the cell cycle. S49 wild-type cultures enriched for G1 phase cells by exposure to dibutyryl cyclic AMP (Bt2cAMP) for 24 h had lower dCTP and dTTP pools but equivalent or increased pools of dATP and dGTP when compared with exponentially growing wild-type cells. Release from Bt2cAMP arrest resulted in a maximum enrichment of S phase occurring 24 h after removal of the Bt2cAMP, and was accompanied by an increase in dCTP and dTTP levels that persisted in colcemid-treated (G2/M phase enriched) cultures. Ribonucleotide reductase activity in permeabilized cells was low in G1 arrested cells, increased in S phase enriched cultures and further increased in G2/M enriched cultures. In cell lines heterozygous for mutations in the allosteric binding sites on the M1 subunit of ribonucleotide reductase, the deoxyribonucleotide pools in S phase enriched cultures were larger than in wild-type S49 cells, suggesting that feedback inhibition of ribonucleotide reductase is an important mechanism limiting the size of deoxyribonucleoside triphosphate pools. The M1 and M2 subunits of ribonucleotide reductase from wild-type S49 cells were identified on two-dimensional polyacrylamide gels, but showed no significant change in intensity during the cell cycle. These data are consistent with allosteric inhibition of ribonucleotide reductase during the G1 phase of the cycle and release of this inhibition during S phase. They suggest that the increase in ribonucleotide reductase activity observed in permeabilized S phase-enriched cultures may not be the result of increased synthesis of either the M1 or M2 subunit of the enzyme.

Allosteric Regulation↗
PubMed1984

DNA synthesis inhibitors block protein synthesis in the human lymphocyte.

We examined the requirement for early DNA synthetic events in the protein synthetic response of PHA-stimulated human lymphocytes using specific DNA synthesis inhibitors. The incorporation of H3-thymidine into DNA and H3-leucine into protein was assessed in PHA-stimulated lymphocytes cultured with cytosine arabinoside (8.5 X 10(-6)M), hydroxyurea (1.0 X 10(-2)M) or mitomycin-C (1.5 X 10(-2)M), each of which reduced DNA synthesis to the level of unstimulated lymphocytes. Under those conditions, protein synthesis was suppressed to 2, 14 and 1% of uninhibited cells at 48 h, respectively. Delaying addition of these inhibitors to 6, 12 and 24 h after initiation of PHA stimulation resulted in a parallel loss of inhibition of both RNA and protein synthesis. However, during the first 24 h of uninhibited mitogen stimulation, there is no DNA synthesis as measured by either H3-thymidine uptake or by flow cytometry. In contrast to the inhibition of protein synthesis when measured after 48 h, PHA-stimulated H3-leucine incorporation during the first 24 h was not affected by DNA synthesis inhibition. These results suggest that early events related to DNA synthesis are required for optimum mitogen-induced protein and RNA synthesis, but that new DNA synthesis does not occur until after 24 h of mitogen stimulation.

Blood Proteins↗
PubMed1984

The risk ratio is insufficient for clinical decisions. The case of prophylactic cholecystectomy.

The medical literature contains studies that recommend both for and against prophylactic cholecystectomy when cholelithiasis is present. To investigate whether differing analytic techniques contribute to these disparate recommendations, we analyzed the decision to "wait and see" or "operate now," using both risk ratio and life expectancy analysis on the same data base. With intermediate symptom incidence estimates the risk ratio strongly favored an "operate now" approach, because it lessened the risk of death from gallbladder disease by up to 19-fold. In the group most favored by immediate surgery, 25-year-old men, risking death with immediate surgery increased life expectancy by only one percent (168 days). The risk ratio increased to over 30 for this group with the low incidence estimates, but the difference in life expectancy decreased to 120 days. With the high incidence estimates, the risk ratio declined to 16.4 and the life expectancy difference increased to 186 days. These data demonstrate that (1) the risk ratio can imply a course of action that is different from that implied by life expectancy analysis, and (2) the maximum expected return on the risk of immediate death with elective surgery for silent gallstones is only a one percent increase in life expectancy. This analysis suggests that single measures of effect such as the risk ratio and life expectancy do not capture all the information necessary to make an informed decision.

Adult↗
PubMed1982

A multicenter study of outcome in systemic lupus erythematosus. I. Entry variables as predictors of prognosis.

A retrospective study of factors influencing survival in 1,103 patients with systemic lupus erythematosus (SLE) was carried out at 9 university centers diverse in geographic, socioeconomic, and racial characteristics. The mortality and disease characteristics of the patients at study entry varied widely among centers. The survival rates from the time patients with a diagnosis of SLE were first evaluated at the participating center was 90% at 1 year, 77% at 5 years, and 71% at 10 years. Patients with a serum creatinine greater than 3 mg/dl at study entry had the lowest survival rates: 48%, 29%, and 12% at 1, 5, and 10 years, respectively. Survival rate also correlated independently with the entry hematocrit, degree of proteinuria, number of preliminary American Rheumatism Association criteria for SLE satisfied, and source of funding of medical care. When data were corrected for socioeconomic status, race/ethnic origin did not significantly influence survival. Survival rates varied widely at different participating institutions, generally due to differences in disease severity. Place of treatment was independently associated with survival only in the second year after study entry. Disease duration before study entry did not account for the differences in disease severity.

Academic Medical Centers↗
PubMed1982

A multicenter study of outcome in systemic lupus erythematosus. II. Causes of death.

Causes of death were examined for 1,103 systemic lupus erythematosus patients who were followed from 1965 to 1978 at 9 centers that participated in the Lupus Survival Study Group. A total of 222 patients (20%) died. Lupus-related organ system involvement (mainly active nephritis) and infection were the most frequent primary causes of death. Causes of death were similar throughout the followup period. Hemodialysis had little impact on the length of survival for patients with nephritis. Active central nervous system disease and myocardial infarction were infrequent causes of death. There were no deaths from malignancy.

Academic Medical Centers↗
PubMed1981

Deciding whether the conclusions of studies are justified: a review.

Critical review of original studies is a major source of medical information for the physician; it necessitates a clear understanding of the research objective of the study. The design of the study, whether experimental or observational, should be appropriate to answer the research question and, further, the study should employ accurate and precise measurements on a suitable group of subjects. The critical reader, aware of the principle of study design and analysis, can assess the validity of the author's conclusions through careful review of the article. A guide to the analysis of an original article is presented here. The reader is asked to formulate questions about a study from the abstract. The answers to these questions, which form the basis for acceptance or rejection of the author's conclusions, are in general available in the body of an article. This technique is demonstrated with two fictional studies about patients with angina.

Information Services↗
PubMed1980

The rheumatic manifestations of leprosy (Hansen disease).

Leprosy is a rare disorder in the United States, yet the rheumatic features of the disease appear to be common and frequently are the primary complaint. We observed rheumatic syndromes of erythema nodosum leprosum (ENL) occurring with and without arthritis, a swollen hands syndrome, cutaneous vasculitis, or myositis in the majority (15 of 21) of our patients. These syndromes were distinctive, sometimes dramatic, and appeared to "mimic" idiopathic rheumatic diseases, substantially delaying an accurate diagnosis of leprosy in some patients. These complications were the major cause of morbidity in our 21 patients and became dominant clinical problems requiring additional chemotherapy.

Adult↗
PubMed1979

Does corticosteroid therapy affect the survival of patients with systemic lupus erythematosus?

The hypothesis that corticosteroid therapy is responsible for the striking improvement in survival of patients with systemic lupus erythematosus (SLE) was investigated with two approaches: Of 250 published papers on SLE, 52 were chosen for the first analysis because they included sufficient information on diagnostic criteria and survival but were not limited to patients selected for a particular target organ. From each article percent survival by series, average duration to death, and 1 and 5 year survival curves were abstracted. Each statistic showed linear improvement in survival since the 1930s without a significant change (P greater than 0.10) in slope for the time period following the introduction of corticosteroids. The second analysis examined the effect of corticosteroid therapy on 142 patients with SLE followed at the Massachusetts General Hospital between 1922 and 1966. Although the steroid use was conservative, the patients' survival, from year of entry, was comparable to the 52 abstracted series. A prognostic index was used to stratify patients admitted in the steroid era (after 1950) for life table analysis of survival with and without steroids. Steroids had no discernible effect on overall survival in low and medium risk groups. Use of steroids was associated with improved survival among high rish patients (P less than 0.05).

Adrenal Cortex Hormones↗