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Authorship↗
Biomedical subjects
L A Carey
Publications and source records attributed to L A Carey.
High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms' tumor.
Telomerase is a reverse transcriptase that maintains chromosome ends, compensating for the progressive loss of DNA that occurs during replication. High telomerase enzyme activity is an unfavorable prognostic feature for several types of cancers. We investigated whether telomerase level predicts outcome for patients with the pediatric renal malignancy Wilms' tumor. In a case-cohort study of 78 patients with favorable histology Wilms' tumor, we compared tumor telomerase levels in patients with and without eventual recurrence. Three measures of telomerase were used: (a) telomerase enzyme activity; (b) expression of hTR, the RNA component of telomerase; and (c) mRNA expression of hTERT, the gene that encodes the catalytic component of the enzyme. Of the evaluable samples, 81% had detectable telomerase activity, 97% had detectable hTERT transcript, and 100% had detectable hTR. Weak correlations were observed between telomerase activity and hTR level (r = 0.34, P = 0.02) and between telomerase activity and hTERT mRNA level (r = 0.32, P = 0.04). Of the variables assessed, only hTERT mRNA expression correlated with outcome. The median hTERT mRNA level in tumors with recurrence was higher than that in tumors without recurrence (1.42 versus 0.97 units, P = 0.023, Wilcoxon). Univariate analysis of hTERT mRNA level as a continuous variable suggested that each unit increase in hTERT mRNA level increased the risk of recurrence (RR) by a factor of 1.66 [95% confidence interval (CI), 1.2-2.3; P < 0.005]. Compared with tumors with hTERT mRNA levels of 0-1 units, tumors with hTERT mRNA levels of 1-2 units had a RR of 2.72 (95% CI, 0.91-8.13; P = 0.074), and tumors with hTERT mRNA levels >2 units had a RR of 6.40 (95% CI, 1.49-27.67, P = 0.013). Multivariate analysis of hTERT mRNA level as a predictor of recurrence, adjusted for tumor stage and age at diagnosis, revealed a RR of 1.48 (95% CI, 0.9-2.6; P = 0.16). Measurement of hTERT mRNA level may, therefore, enable clinicians to identify a population of patients at high risk for recurrence and to adjust their therapy accordingly. A larger study will be necessary to determine whether hTERT expression is an independent prognostic indicator. Further biological investigation is warranted to discern whether the link between high hTERT expression and unfavorable prognosis is causative or correlative.
Child, Preschool↗
Telomerase activity in ductal carcinoma in situ and invasive breast cancer.
The increasing number of breast carcinoma in situ detected by screening procedures makes it imperative to develop improved markers to stratify the risk of invasive cancer. Telomerase is detectable in invasive cancer, but not in normal tissues. We have microdissected frozen tissue blocks containing both DCIS and invasive cancer to assay the telomerase activity of these two lesions. The 46 available cases of concurrent DCIS and invasive breast cancer resulted in 43 DCIS samples and 38 invasive cancer samples adequate for analysis. Seventy per cent of the DCIS and all invasive cancer samples tested had detectable telomerase activity. In addition, we analysed telomerase activity in ten cases of DCIS that were not associated with invasive cancer, and detected telomerase activity in seven (70%). Mixing experiments showed no evidence of telomerase inhibitors in telomerase negative samples. Furthermore, periductal inflammatory infiltrates were shown to be a potential confounding source of telomerase activity. Since DCIS lesions appear to be heterogeneous with respect to telomerase activity, and telomerase activation appears to precede the development of invasive cancer, telomerase activity may be a useful adjunct in stratifying the risk of developing invasive breast cancer in patients with DCIS.
Adult↗
Telomerase activity and prognosis in primary breast cancers.
PURPOSE: Recent studies associate telomerase activity with prognostic factors and survival. We compared quantitative telomerase activity in primary tumors with traditional prognostic factors and outcome in a group of invasive but nonmetastatic breast cancers. PATIENTS AND METHODS: Telomerase activity was measured in 203 invasive breast cancers by the quantitative telomeric repeat amplification protocol method. Telomerase expression was compared with 28S rRNA level, tumor content, and clinical variables, including outcome. For clinical correlations, telomerase activity was standardized by two methods: (1) a correction for cellularity using 28S rRNA levels, and (2) a correction for the histologically determined invasive proportion of the specimen. RESULTS: Telomerase activity was found in 82% of breast cancers with measurable 28S rRNA levels. Telomerase activity was associated with the proliferative index (P <.01) of the tumor but not with any other prognostic variable. Neither uncorrected nor corrected telomerase activity was associated with relapse-free or overall survival in this study. CONCLUSION: Telomerase activity level was associated with the proliferative index of invasive breast cancers, but its measurement in samples from this group of nonmetastatic breast cancer patients did not predict survival.
Adult↗
Prevalence of articles with honorary authors and ghost authors in peer-reviewed medical journals.
CONTEXT: Authorship in biomedical publications establishes accountability, responsibility, and credit. Misappropriation of authorship undermines the integrity of the authorship system, but accurate data on its prevalence are limited. OBJECTIVES: To determine the prevalence of articles with honorary authors (named authors who have not met authorship criteria) and ghost authors (individuals not named as authors but who contributed substantially to the work) in peer-reviewed medical journals and to identify journal characteristics and article types associated with such authorship misappropriation. DESIGN: Mailed, self-administered, confidential survey. PARTICIPANTS: A total of 809 corresponding authors (1179 surveyed, 69% response rate) of articles published in 1996 in 3 peer-reviewed, large-circulation general medical journals (Annals of Internal Medicine, JAMA, and The New England Journal of Medicine) and 3 peer-reviewed, smaller-circulation journals that publish supplements (American Journal of Cardiology, American Journal of Medicine, and American Journal of Obstetrics and Gynecology). MAIN OUTCOME MEASURES: Prevalence of articles with honorary authors and ghost authors, as reported by corresponding authors. RESULTS: Of the 809 articles, 492 were original research reports, 240 were reviews and articles not reporting original data, and 77 were editorials. A total of 156 articles (1 9%) had evidence of honorary authors (range, 11%-25% among journals); 93 articles (11%) had evidence of ghost authors (range, 7%-16% among journals); and 13 articles (2%) had evidence of both. The prevalence of articles with honorary authors was greater among review articles than research articles (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6) but did not differ significantly between large-circulation and smaller-circulation journals (OR, 1.4; 95% CI, 0.96-2.03). Compared with similar-type articles in large-circulation journals, articles with ghost authors in smaller-circulation journals were more likely to be reviews (OR, 4.2; 95% CI, 1.5-13.5) and less likely to be research articles (OR, 0.49; 95% CI, 0.27-0.88). CONCLUSION: A substantial proportion of articles in peer-reviewed medical journals demonstrate evidence of honorary authors or ghost authors.
Authorship↗
Careful histological confirmation and microdissection reveal telomerase activity in otherwise telomerase-negative breast cancers.
Studies of invasive breast cancers consistently identify a subset of tumors without telomerase activity, compromising its utility as a tumor marker. Telomerase-negative tumors may represent a biologically different subset, or the result could be attributed to assay imperfections. To resolve this issue, we tested 105 invasive breast cancers for telomerase activity and found that 23 (22%) tumors were telomerase negative. Careful histological confirmation of an adjacent cryosection and/or microdissection of pure tumor cells reduced this number to 5 (5%). Thus, truly telomerase-negative invasive breast cancers are rare, making this enzyme a potentially very useful tumor marker in breast cancer.
Breast Neoplasms↗
Telomerase activity in the normal and neoplastic rat mammary gland.
The 1-methyl-1-nitrosourea-induced rat mammary tumor model system is well studied, reproducible, and widely used. We have investigated whether these tumors possess higher telomerase activity than normal mammary tissue. Using the telomeric repeat amplification protocol assay, we found significantly higher telomerase activity in 36 mammary carcinomas than in 72 mammary glands of virgin rats. The level of telomerase activity in virgin rats was unaffected by strain, age, stage of the estrous cycle, or ovariectomy. However, mammary glands obtained from pregnant rats exhibited telomerase activity comparable to that found in the tumors, possibly reflecting the high epithelial content of these tissues. Indeed, isolated epithelial cells from virgin and pregnant mammary glands and from carcinomas had similar telomerase activities. Thus, telomerase activity is constitutive in the rat mammary epithelium and is not a unique characteristic of malignant transformation in this tissue. These results underscore the importance of attributing biochemical properties to specific cell types in a tissue, a situation not paralleled in the interpretation of data from in vitro models.
Animals↗
Peptide mimicry of carbohydrate epitopes on human immunodeficiency virus.
Cancer-related, mucin-type carbohydrate epitopes, principally mannose and sialo-syl residues, are expressed on the envelope protein gp 160 of the human immunodeficiency virus (HIV). Anticarbohydrate antibodies directed toward these and other carbohydrate epitopes are known to neutralize HIV-1 infection by cell-free virus. Carbohydrates, however, being T cell-independent antigens, typically elicit diminished immune responses. To overcome this potential draw back, we have examined the ability of peptides that mimic such epitopes to elicit immune responses that cross-react with carbohydrate structures. We report that mouse polyclonal antisera generated against peptides that mimic mucin-related carbohydrate epitopes have anti-HIV-1 activity. Generation of antibodies was not lr-gene restricted, as at least two different strains of mice. Balb/c (H-2d) and C57Bl/6 (H-2b), responded equally to the peptides. The antipeptide sera displayed neutralizing activity against HIV-I/MN and HIV-I/3B viral strains. This neutralization was as good as human anti-HIV sera. These results indicate that peptide mimics of carbohydrates provide a novel strategy for the further development of reagents that elicit immune responses to carbohydrate epitopes associated with many infectious organisms and tumor cells.
Acquired Immunodeficiency Syndrome↗
Neutrophil recruitment as a factor limiting injury or promoting recovery from acute lung injury.
We studied 1) neutrophil mobilization in sheep given endotoxin (10 ng.kg-1.min-1, n = 5) for 4 h, 2) surviving (n = 17) and nonsurviving sheep (n = 8) during a 12-h infusion of endotoxin, and 3) adult sheep (n = 8) or lambs (n = 8) infused with endotoxin for 12 h. Bone marrow cells of sheep declined from a baseline value of 10,533 +/- 1,784 to 5,966 +/- 1,980 cells/microliter (P < 0.05) 4 h after endotoxin. After 12 h of endotoxin infusion, circulating neutrophils remained reduced from baseline values of 2,000-4,000 cells/microliter to 343 +/- 70 in lambs and 484 +/- 236 in nonsurviving sheep, while beginning to recover in surviving sheep to 1,838 +/- 467 cells/microliter. In lambs and nonsurviving sheep, a 12-h infusion of endotoxin increased lung lymph protein clearance tenfold compared with a fivefold increase in surviving sheep. Neutrophils cultured from sheep bone marrow exposed to lamb postendotoxin plasma failed to increase in cell number (609 +/- 229 to 610 +/- 182 cells/microliter), whereas similar cells exposed to adult sheep postendotoxic plasma showed a significant increase in cell number (1,069 +/- 101 to 2,293 +/- 448 cells/microliter, P < 0.05). Our results are consistent with the hypothesis that the ability to recruit neutrophils to the circulation during periods of inflammation is important in limiting the severity of acute lung injury.
Acute Disease↗
Tuberculin skin test reactivity, anergy, and HIV infection in hospitalized patients. Longcope Firm of the Osler Medical Housestaff.
PURPOSE: Detection of latent tuberculosis infection is an important step in the control of tuberculosis because high-risk persons may be given preventive therapy. The value of tuberculin skin testing in individuals with human immunodeficiency virus (HIV) infection, however, is limited by anergy. We evaluated the prevalence of tuberculin skin test reactivity, anergy, and HIV infection in a group of hospitalized patients in an area where both tuberculosis and HIV infection are prevalent. PATIENTS AND METHODS: Three hundred fifty-one patients consecutively admitted to a medical service of a large urban teaching hospital were enrolled in the study. All those with no documented history of a positive tuberculin skin test were evaluated on admission with purified protein derivative (PPD) by the Mantoux test, and with anergy testing using a multiple-puncture device. HIV testing was offered to all patients who did not have a known history of HIV infection, and was performed when informed consent was obtained. RESULTS: Forty-one patients (12%) had a documented history of a positive PPD. Of the remaining 310 patients, 62 (20%) had a PPD response of > or = 10 mm induration. Fifty-two (15%) of the 351 patients were HIV positive. None of the HIV-infected patients was PPD positive. Anergy was found in 63% of the HIV-infected patients and 28% of the HIV-seronegative patients. Independent risk factors for a positive PPD included age > 55, male sex, and hypertension. HIV infection, current steroid use, and a history of cancer were associated with a negative PPD. Independent risk factors for anergy included HIV infection, current corticosteroid use, renal failure pneumonia, and a history of cancer. Of the 62 new PPD-positive patients, 30 (48%) were candidates for chemoprophylaxis. Additionally, 30 (63%) of 48 HIV-seropositive patients who were completed testing were anergic and might be candidates for chemoprophylaxis. Almost all of the patients eligible for chemoprophylactic therapy would have been detected if only patients at increased risk for developing tuberculosis were screened. CONCLUSIONS: Tuberculosis infection, HIV infection, and anergy were common in patients admitted to this medical service. Interpretation of PPD reactivity was confounded by a high prevalence of anergy, particularly in HIV-infected patients. A large proportion of patients tested were candidates for chemoprophylaxis. Routine tuberculin skin testing with anergy testing for high-risk patients on admission to the hospital is useful for identifying patients who might benefit from prophylaxis to help control the spread of tuberculosis.
Adult↗
Endotoxin infusion in anesthetized sheep is associated with intrapulmonary sequestration of leukocytes that immunohistochemically express tumor necrosis factor-alpha.
Plasma levels of tumor necrosis factor-alpha (TNF-alpha) peak between 2 and 4 h during a 12-h continuous infusion of endotoxin in awake sheep. We hypothesized that a source of this TNF-alpha is the pool of leukocytes that accumulate in the pulmonary circulation. To test this hypothesis, we physiologically monitored six anesthetized sheep during baseline and 4-h endotoxin infusion periods (10 ng/kg x min). We obtained open-lung biopsies at baseline and at 20 min and 2 and 4 h during the endotoxin infusion period for immunohistochemical localization of TNF-alpha. The plasma concentration of TNF-alpha increased from an average baseline concentration of 0.06 +/- 0.03 ng/ml (mean +/- SD) to a peak of 1.40 +/- 0.28 ng/ml at 2 h of the endotoxin infusion. We observed increased cytoplasmic TNF-alpha immunoreactivity in situ among neutrophils and intravascular mononuclear phagocytes during the endotoxin infusion compared with baseline. Also, the number of immunopositive leukocytes increased in the pulmonary circulation during the continuous infusion of endotoxin. We conclude that TNF-alpha-producing leukocytes accumulate in the pulmonary circulation during endotoxemia. These cells probably contribute to both the rise in the circulating levels of TNF-alpha and the development of acute lung injury.
Anesthesia↗
Microplate reader assay for measurement of opsonized zymosan-stimulated superoxide anion production by neutrophils.
We report a microplate reader assay for the measurement of superoxide anion (O2-) production from opsonized zymosan-stimulated sheep polymorphonuclear leukocytes (PMNs). This method, for use with the particulate neutrophil activator, is a modification of the cytochrome c reduction system that measures O2- release from adherent neutrophils stimulated with soluble mediators such as phorbol-myristate-acetate (PMA). We measured O2- release from PMNs (250,000 per well) stimulated with opsonized zymosan over a dose range from 0.0625 mg/mL to 0.5 mg/mL. A dose of 0.125 mg/mL was shown to stimulate maximal superoxide production while having little effect on the optical density of the reagent blank. O2- values obtained using this method were not statistically different from values measured using cell-free supernatants. This system was useful in demonstrating PMN priming, as evidenced by the 2.7 times increase in O2- production above baseline from neutrophils isolated from sheep given a 12-hour, low-dose endotoxin infusion. This is a convenient and sensitive method for measurement of neutrophil O2- production in response to a receptor-mediated, particulate stimulus.
Animals↗
In vivo endotoxin exposure increases neutrophil counts without maintenance of primed superoxide anion release in short-term cultures of sheep bone marrow.
A short-term bone marrow culture was established to determine the functional and proliferative responses of neutrophils sampled from sheep exposed to endotoxin in vivo. Iliac crest bone marrow was drawn from surgical control animals and from sheep given a 12-h infusion of endotoxin. In these bone marrow aspirates, neutrophils from endotoxin-treated sheep showed primed superoxide anion release compared with controls when stimulated with phorbol myristate acetate. Priming was no longer present in neutrophils tested after 2 days in culture. The neutrophil cell count, however, was higher after 2 days in culture than in controls. Increased neutrophil production/viability was reproduced in naive bone marrow cultures by replacing part of the normal serum medium with plasma taken from sheep several hours after endotoxin infusion. These data suggest that a dissociation exists between priming and increased neutrophil production/viability in response to endotoxin.
Animals↗
Quantifying the effect of ischemia on epiphyseal growth in an extremity replant model.
Warm ischemia (21 degrees C) of 0, 2, 4, 6, or 8 hours was produced in a modified hindlimb preparation of 35 10-week-old Lewis rats by amputation. Subsequent microvascular anastomoses of each hindlimb to a syngeneic animal was done after which fluorochrome bone labels were administered 5 minutes after operation and on day 14 after operation. Epiphyseal plate growth (that between bone labels) was analyzed histomorphometrically and statistically. Epiphyseal plate growth was found to have a linear inverse relationship to ischemia time with a correlation coefficient (r) of -0.653 and high statistical significance (p less than 0.001). Overgrowth occurred at all ischemic periods except 8 hours, and vascular pedicle patency decreased as ischemia time progressed.
Anastomosis, Surgical↗
Oxygen radical scavengers improve vascular patency and bone-muscle cell survival in an ischemic extremity replant model.
We examined the use of oxygen radical scavengers in preventing the no-reflow phenomenon and improving bone-muscle cell survival in an ischemic extremity replant model. A total of 70 Lewis rat modified hindlimb replants were performed after specific periods of cold ischemia and intraarterial perfusion with either superoxide dismutase and catalase, specific oxygen free-radical scavengers, or a control solution. Ischemic hindlimbs treated with superoxide dismutase and catalase showed a statistically significant (p less than 0.05) improvement in vascular patency after prolonged cold ischemia when compared to controls. Histologically, experimental extremities demonstrated greater osteoblast, osteocyte, and muscle cell survival in replanted hindlimbs with patent vascular anastomoses. The perfusion of severed limbs and digits and free vascularized tissue transfers with superoxide dismutase and catalase after a period of ischemia has already occurred may prolong the ischemic "time window" tolerated for successful tissue survival.
Animals↗
Acute resetting of arterial baroreflexes in hypertensive rats.
Acute baroreflex resetting was studied in one-kidney, one-clip renal hypertensive (HT) and normotensive (NT) control male Wistar-Kyoto rats. Systolic blood pressure (SBP) was monitored weekly in conscious rats by the indirect tail-cuff occlusion method. At the time of experimentation (4-6 wk after placement of the clip), SBP in the HT rats (238 +/- 9 mmHg) was elevated compared with NT rats (117 +/- 5 mmHg). Baroreflex control of lumbar sympathetic nerve activity (LSNA) was assessed in alpha-chloralose (120 mg/kg)-urethan (600 mg/kg)-anesthetized rats by raising and lowering mean arterial pressure (MAP) between 50 and 200 mmHg (phenylephrine and nitroprusside infusions). The baroreflexes of the hypertensive rats were less sensitive to increments in pressure compared with normotensive rats as evidenced by a decreased slope of the baroreflex curve (-0.396 +/- 0.064 HT vs. -0.637 +/- 0.042 NT). In both groups, curves were obtained before (control) and after (reset) base-line MAP was increased by 30-55 mmHg for 15 min. The MAP for 50% maximum inhibition of LSNA (EP50) was increased in both groups of rats after exposure to the elevated pressure (NT, control = 109 +/- 5.2, reset = 120 +/- 5.0 mmHg; HT, control = 114 +/- 6.5, reset = 131 +/- 10.0 mmHg) with no significant change in slope. There was no significant difference in degree of upward resetting between the two groups (NT, 21 +/- 4%; HT, 30 +/- 7%). Thus, although hypertensive rats exhibited the depressed baroreflex function associated with chronic resetting, the ability to reset acutely was maintained.
Animals↗
Treatment of melanoma metastases in the brain.
Melanoma is prone to spread to the brain and is the third most common source of intracranial metastasis. Patients usually present with signs and symptoms of increased intracranial pressure, a new focal neurologic deficit, or seizures. Contrasted magnetic resonance imaging (MRI) is the single most valuable imaging modality. Surgical therapy is the appropriate choice for single lesions that are accessible, especially if they are causing significant mass effect or are located in the posterior fossa. Patients with several intracranial metastases who undergo resection of all lesions may have a similar prognosis to those with single resected lesion. Stereotactic radiosurgery appears to provide good local control of small lesions. External beam radiotherapy may provide some benefit to patients, and is often used in conjunction with surgery or stereotactic radiosurgery. To date, chemotherapy has been limited because of chemo-resistance and drug delivery issues. Future directions for treatment may include local sustained delivery of either chemotherapy or immunoregulatory molecules.
Antineoplastic Agents↗
Lumbar puncture for evaluation of latent syphilis in hospitalized patients. High prevalence of cerebrospinal fluid abnormalities unrelated to syphilis.
OBJECTIVE: To determine the prevalence of abnormal neurologic findings and cerebrospinal fluid abnormalities in hospitalized patients with serologic evidence of latent syphilis. DESIGN: Cross-sectional survey. METHODS: Consecutively admitted hospital inpatients from an inner-city population were screened for serologic evidence of syphilis with reactive plasma reagin and confirmatory fluorescent treponemal antibody absorption assays. In those with reactive tests, such clinical findings as a history of treatment for syphilis, neurologic abnormalities, presence of human immunodeficiency virus infection, and rapid plasma reagin titer were correlated with cerebrospinal fluid white blood cell count, protein level, and VDRL result. RESULTS: Of 490 consecutive patients, 52 (11%) had serologic evidence of syphilis. Forty-three (83%) of these underwent lumbar puncture. Of the 43, 31 (72%) were seronegative for human immunodeficiency virus and 12 (28%) were seropositive. No patient had a reactive cerebrospinal fluid VDRL test. Cerebrospinal fluid abnormalities were seen in 32% of human immunodeficiency virus-seronegative patients and in 67% of human immunodeficiency virus-seropositive patients. Cerebrospinal fluid abnormalities were not predicted by history of treatment for syphilis, abnormal neurologic findings, or an elevated rapid plasma reagin titer. Cerebrospinal fluid IgG indexes in patients with elevated cerebrospinal fluid protein levels suggested that the protein abnormalities were not caused by local antibody production. Nonreactive cerebrospinal fluid fluorescent treponemal antibody absorption tests suggest that the cerebrospinal fluid abnormalities were not the result of neurosyphilis. CONCLUSIONS: There was a high prevalence of cerebrospinal fluid abnormalities in hospitalized patients with latent syphilis detected by routine screening. Because of the nonspecificity of the cerebrospinal fluid findings, routine lumbar puncture for such patients appears to contribute little to the treatment of latent syphilis.
Adolescent↗