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Biomedical subjects

J O'Neil

Publications and source records attributed to J O'Neil.

At least 37 records · Page 2Linked to original sources
PubMed1998

Child fatality review in Georgia: a young system demonstrates its potential for identifying preventable childhood deaths.

BACKGROUND: Child fatality review (CFR) by interagency teams can contribute to the prevention of childhood deaths. We investigated the potential usefulness of Georgia's CFR, legislated in 1990 primarily to prevent death from child maltreatment, for identifying preventable deaths from injury and sudden infant death syndrome (SIDS). METHODS: Using CFR report data and death certificate data, we examined reviewed and nonreviewed childhood deaths in Georgia in 1991 and examined data by etiology, county, risk factors, and preventability. RESULTS: Injury or SIDS caused 33.2% of childhood deaths in Georgia in 1991; CFR reviewed 29.4% of these. Child fatality review was most sensitive for investigating death from intentional injury (40.5%) and SIDS (35.3%). Review teams reassigned the cause of five deaths (2.0%) to child abuse or neglect. County participation was low (31.4%). Overall, 29.0% of deaths were judged preventable. CONCLUSIONS: Georgia's CFR has potential for identifying preventable childhood deaths. Refinements in the system can increase the number and accuracy of death investigations. By participating in the system, physicians may make meaningful contributions to preventing childhood death in their own communities.

Adolescent↗
PubMed1997

Non-conventional modification of low density lipoproteins: chemical models for macrophage recognition of oxidized LDL.

To define the structural and chemical criteria governing recognition of oxidized LDL (oxLDL) by mouse peritoneal macrophages (MPM), we exposed LDL to novel chemical modification agents that induce defined neutralizing and non-neutralizing alterations of lysine as models for distinct apoB adducts present in oxLDL. We found some exceptions to the usual notion that neutralization of lysine positive charges is the principal determinant governing MPM recognition. In addition, competitive binding experiments using chemically modified 125I-LDL preparations revealed that, whereas some modifications engendered recognition principally by the classical scavenger receptor class A (SRA), as seen for acetylated LDL (acLDL), chemical models of advanced aldehydic modifications of LDL led instead to MPM uptake mainly by oxLDL receptors distinct from SRA.

Animals↗
PubMed1997

Activation of human T cells by major histocompatability complex class II expressing neutrophils: proliferation in the presence of superantigen, but not tetanus toxoid.

The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-gamma). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II-expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-gamma, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-gamma under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-gamma.

Antigen Presentation↗
PubMed1997

Information needs and decisional preferences in women with breast cancer.

OBJECTIVE: To determine the degree of involvement women with breast cancer wanted in medical decision making, extent to which they believed they had achieved their preferred level of involvement, and types of information they judged to be most important. DESIGN AND SETTING: Cross-sectional survey at 2 tertiary oncology referral clinics and 2 community hospital oncology clinics in Winnipeg, Manitoba. PATIENTS: Consecutive sample of 1012 women with a confirmed diagnosis of breast cancer who were scheduled for a visit at 1 of 4 hospital oncology clinics. MAIN OUTCOME MEASURES: The following measures were used: (1) Preferences about various levels of participation in treatment decision making; (2) the extent to which subjects believed they had achieved their preferred levels of involvement in decision making; and (3) priority needs for information and how these needs differed by selected sociodemographic, disease, and treatment variables. RESULTS: A total of 22% of women wanted to select their own cancer treatment, 44% wanted to select their treatment collaboratively with their physicians, and 34% wanted to delegate this responsibility to their physicians. Only 42% of women believed they had achieved their preferred level of control in decision making. The 2 most highly ranked types of information were related to knowing about chances of cure and spread of disease. Women younger than 50 years rated information about physical and sexual attractiveness as more important than did older women (P<.001); women older than 70 years rated information about self-care as more important than did younger women (P=.002); and women who had a positive family history of breast cancer rated information about family risk as more important than did other women (P=.03). CONCLUSIONS: The substantial discrepancy between women's preferred and attained levels of involvement in treatment decision making suggests that systematic approaches to assess and respond to women's desired level of participation in treatment decision making need to be evaluated. Priorities for information identified in this study provide an empirical basis to guide communication with women seeking care for breast cancer.

Adult↗
PubMed1997

Macrophage recognition of LDL modified by levuglandin E2, an oxidation product of arachidonic acid.

Levuglandin (LG) E2, a secoprostanoic acid levulinaldehyde derivative, is a product of free radical oxidation that forms covalent adducts with lysyl residues on proteins. Treatment of LDL with LGE2 leads to uptake and degradation by mouse peritoneal macrophages. Oxidized LDL, but not acetyl LDL efficiently competed for binding and uptake of LGE2-modified 125I-LDL. This result suggests that LGE2-modified LDL was recognized by a class of scavenger receptor that demonstrated ligand specificity for oxidized LDL but not for acetyl LDL.

Acetylation↗
PubMed1997

Inactivation of cathepsin B by oxidized LDL involves complex formation induced by binding of putative reactive sites exposed at low pH to thiols on the enzyme.

We recently showed that the poor degradation of apo B in oxidized (ox-) LDL by mouse peritoneal macrophages could be attributed to the inactivation of cathepsin B by ox-LDL. In this current study, we show that enzyme inactivation involves complex formation of ox-LDL with cathepsin B rather than the diffusion of reactive components from ox-LDL to the enzyme. Complex formation between ox-LDL and cathepsin B was far greater at pH 4.5 than at pH 7.4 and far greater with ox-LDL than with LDL. Even though complexes were also formed between ox-LDL and other proteins such as BSA, insulin, and LDL, ox-LDL bound up to 30 times more cathepsin B than BSA, when compared on a molar level and under the same conditions. Unlike ox-LDL alone, complexes of ox-LDL and BSA were unable to inactive cathepsin B, suggesting that BSA was sequestering reactive sites on ox-LDL. The interaction of ox-LDL with proteins such as cathepsin B appears to represent aldehydic modifications of apo B, since treatment of ox-LDL with the reductant NaBH4, which stabilizes such adducts, greatly decreased the binding of ox-LDL to BSA and prevented ox-LDL from inactivating cathepsin B. It is likely that thiols on cathepsin B or other proteins interact with reactive groups on ox-LDL, since BSA in which thiols were blocked with N-ethylmaleimide (NEM), failed to bind to ox-LDL. Moreover, NEM-treated BSA had no effect on the ability of ox-LDL to inactivate cathepsin B. Similar results were obtained with LDL modified with 4-hydroxynonenal (HNE). These data suggest that aldehydic adducts on ox-LDL that are unreactive at neutral pH, possibly HNE bound to apo B, become exposed at acidic pH and then covalently bind thiols on neighboring proteins such as cathepsin B in lysosomes, inducing crosslinking of proteins and enzyme inactivation.

Aldehydes↗
PubMed1997

Levuglandin E2-protein adducts in human plasma and vasculature.

The prostaglandin endoperoxide PGH2 rearranges nonenzymatically to generate prostaglandins and secoprostanoic acid levulinaldehyde derivatives such as PGE2 and levuglandin (LG) E2, respectively. Direct detection of LGE2 in biological samples is complicated because it is rapidly sequestered by covalent adduction to endogenous nucleophiles including proteins, which produces LGE2-derived protein-bound pyrroles. Therefore, to detect LGE2-protein adducts in vivo, antibodies were raised against a covalent adduct of LGE2 with keyhole limpet hemocyanin (KLH). This antigen enabled the production of high-titer antibodies that exhibit minimal cross-specificity and are sensitive for detecting LGE2-derived pyrroles. Although pyrrole yields are low at LG/protein ratios found in vivo, an enzyme-linked immunosorbent assay with the LGE2-KLH antibodies detects LGE2-derived protein-bound pyrrole immunoreactivity in human plasma from specific patient populations. Furthermore, prominent immunocytochemical staining of human brain thin sections revealed the presence of LGE2-derived pyrrole immunoreactivity, especially in the meningeal vessels of some patients. This demonstration of LG-protein adducts in human plasma and vasculature provides the first evidence for the biological occurrence of levuglandins in vivo and further suggests that these antibodies might prove useful in diagnostic and mechanistic studies of various disease conditions.

Adolescent↗
PubMed1997

Oxidation of low-density lipoproteins produces levuglandin-protein adducts.

Free-radical oxidation of human low-density lipoprotein (LDL) produces levuglandin (LG)-protein adducts that were detected with an enzyme-linked immunosorbent assay using LGE2-KLH antibodies which recognize LGE2-derived pyrroles. The level of immunoreactivity increases with time of oxidation and reaches a maximum by 8 h. The yield of pyrrole varies nonlinearly with the level of LG adduction to LDL. At low LG:LDL ratios, such as those detected in oxidized LDL, the reaction of primary amino groups with LGE2 produces mostly non-pyrrole adducts that are not immunoreactive. Concomitant phospholipolysis must occur if the generation of immunoreactive epitopes in LDL involves oxidation of arachidonyl phospholipids. Thus, since a protein adduct prepared from synthetic LGE2-2-lysophosphatidylcholine ester showed, at most, only 0.5% cross-reactivity with the LGE2-KLH antibodies, the epitopes detected in oxidized LDL are almost certainly not protein adducts of LG-phospholipid esters. As expected, hydrolysis of the carboxylic ester in the protein adduct of LGE2-2-lysophosphatidylcholine ester by treatment with phospholipase A2 produced a fully immunoreactive LGE2-protein adduct.

Cross Reactions↗
PubMed1997

(Carboxyalkyl)pyrroles in human plasma and oxidized low-density lipoproteins.

Free-radical oxidation of human plasma low-density lipoprotein (LDL) produces (carboxyalkyl)pyrrole (CAP) epitopes that were detected with enzyme-linked immunosorbent assays using antibodies raised against keyhole limpet hemocyanin (KLH)-bound 2-(omega-carboxyheptyl)-pyrrole (CHP) and 2-(omega-carboxypropyl)pyrrole (CPP). These antibodies exhibit high structural selectivity (< 0.5% cross-reactivity) in competitive binding inhibition assays with the corresponding human serum albumin (HSA)-bound pyrroles. No cross-reactivity was detected for HSA-bound 2-pentylpyrrole, an epitope that is generated by a reaction of 4-hydroxy-2-nonenal (HNE) with protein lysyl residues. Oxidation of either arachidonic or linoleic acid in the presence of HSA produced an HNE-derived 2-pentylpyrrole epitope. However, only oxidation of linoleic acid formed HSA-bound CHP, while only oxidation of arachidonic acid generated HSA-bound CPP. Since ester hydrolysis with KOH markedly elevated levels of immunoreactive epitopes detected in oxidized LDL, the CAPs are presumably generated by reactions of oxidized cholesteryl esters, triglycerides, and phospholipids with LDL protein, and only some of these oxidized esters are hydrolyzed, e.g., by phospholipase activity associated with LDL. Protein-bound CHP immunoreactivity was detected in human plasma, and levels are significantly elevated in renal failure and atherosclerosis patients compared with healthy volunteers. This provides the first evidence for the biological occurrence of protein-bound CAPs in vivo and further suggests that free-radical oxidation of polyunsaturated lipids produces hydroxyalkenal carboxylate esters whose gamma-hydroxy-alpha,beta-unsaturated aldehyde functionality and reactivity resemble that of HNE.

Adjuvants, Immunologic↗
PubMed1997

Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer.

PURPOSE: We performed a phase I study to determine the appropriate dose of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluorouracil (FU) and than to determine the maximum-tolerated dose (MTD) of FU when given with PN401. PATIENTS AND METHODS: Patients with advanced cancer received oral PN401 as either a suspension or a tablet in escalating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD > or = 50 mumol/L. In the first phase of the study, all patients received a fixed dose of FU 600 mg/m2 as a rapid intravenous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN401 therapy commenced 24 hours after FU. After determination of the appropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. RESULTS: Thirty-eight patients with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g given in tablet form resulted in high bioavailability of URD, with sustained plasma concentrations greater than 50 mumol/L. In the second phase of the study, FU doses were escalated from 600 to 1,000 mg/m2. FU was given as a rapid intravenous bolus weekly for 6 weeks with a 2-week rest. The MTD of FU given in this fashion with PN401 rescue was 1,000 mg/m2, at which level two of six patients had neutropenic fever. FU at doses of 800 mg/m2 for 6 weeks was well tolerated without significant toxicity when given with PN401 rescue. CONCLUSION: Oral PN401 is well tolerated and total doses of 6 g every 6 hours yield sustained levels of URD in the target range of 50 mumol/L. The MTD of FU with PN401 rescue is 1,000 mg/m2 and the recommended dose for phase II trials is 800 mg/m2 given weekly for 6 weeks with dose escalation. Further studies to define better the appropriate interval for PN401 rescue and the appropriate dose of FU when given with biochemical modulation, such as with leucovorin, are indicated.

Acetates↗
PubMed1997

Rehabilitation of foot and ankle injuries.

Rehabilitation of foot and ankle injuries is essential for full functional recovery and prevention of chronic disease. Rehabilitation includes the usage of physical therapy modalities and rehabilitative exercise whose goals are the reduction of pain and edema and the increase of strength and proprioception. Physical therapy modalities may be classified as thermal, mechanical or electrical agents and include the use of ice, heat, ultrasound, phonophoresis, iontophoresis, intermittent compression, therapeutic massage and a variety of electrical currents. Rehabilitative exercises are primarily designed to increase flexibility, range of motion, strength, proprioception and sport-specific development prior to resumption of full activity. Proper rehabilitation of the lateral ankle (inversion) sprain is critical due to its frequency and potential for chronic pain and recurrence.

Ankle Injuries↗
PubMed1996

Risk factors for injuries from in-line skating and the effectiveness of safety gear.

BACKGROUND: Of the estimated 22.5 million people participating in in-line skating in the United States in 1995, about 100,000 were sufficiently injured so as to require emergency department care. We investigated the effectiveness of wrist guards, elbow pads, knee pads, and helmets in preventing skating injuries. METHODS: We used data from the 91 hospital emergency departments participating in the National Electronic Injury Surveillance System, a national probability sample of randomly selected hospitals with 24-hour emergency departments. Injured in-line skaters who sought medical attention between December 1992 and July 1993 were interviewed by telephone. We conducted a case-control study of skaters who injured their wrists, elbows, knees, or heads as compared with skaters with injuries to other parts of their bodies. RESULTS: Of 206 eligible injured subjects, 161 (78 percent) were interviewed. Wrist injuries were the most common (32 percent); 25 percent of all injuries were wrist fractures. Seven percent of injured skaters wore all the types of safety gear; 46 percent wore none. Forty-five percent wore knee pads, 33 percent wrist guards, 28 percent elbow pads, and 20 percent helmets. The odds ratio for wrist injury, adjusted for age and sex, for those who did not wear wrist guards, as compared with those who did, was 10.4 (95 percent confidence interval, 2.9 to 36.9). The odds ratio for elbow injury, adjusted for the number of lessons skaters had had and whether or not they performed trick skating, was 9.5 (95 percent confidence interval, 2.6 to 34.4) for those who did not wear elbow pads. Non-use of knee pads was associated with a nonsignificant increase in the risk of knee injury (crude odds ratio, 2.2; 95 percent confidence interval, 0.7 to 7.2). The effectiveness of helmets could not be assessed. CONCLUSIONS: Wrist guards and elbow pads are effective in protecting in-line skaters against injuries.

Adolescent↗
PubMed1996

Outcome of femoral shaft fractures in the elderly.

Published literature on fractures of the femoral shaft has reported results of treatment stratified by fracture type or treatment type. The current study analyzes the outcome of fractures of the femoral shaft in elderly patients. One hundred thirty-eight patients older than the age of 65 years sustained femoral shaft fractures. Ten percent of the patients had associated injuries. The majority of the patients had significant prefracture medical problems. Nonsurgical treatment was used in 29 cases. Surgical treatment in 109 patients consisted of cerclage wires in 13 cases, plates and screws in 58 cases, intramedullary nails in 26 cases, and long stem prostheses in 12 cases. Complications of treatment occurred in 46% of patients. The type of treatment did not influence the frequency of complications. Twenty percent of patients died within 6 months of the fracture. There was a significant difference in the age of the patients who survived compared with those who did not survive. The mental status of the patient was also a major determinant of survival. Alert and oriented patients had a much better chance of survival. The outcome of fractures of the femoral shafts cited in the literature is different from the results seen in this population of elderly patients. The observed complication rate of 46% and mortality rate of 20% in this series is similar to those reported for intertrochanteric fractures and femoral neck fractures. Age and mental status are important determinants in the survival of the patient regardless of the treatment administered.

Aged↗
PubMed1995

Induction by herpes simplex virus of free and heteromeric forms of E2F transcription factor.

We have determined that HSV causes rapid and large increases in cell-cycle-regulated free E2F and S-phase p107/E2F DNA binding activities in asynchronous cultures of C33A cells. Induction occurred by 4 hr postinfection and coincided with the appearance of viral encoded immediate-early and delayed-early proteins, i.e., when viral DNA replication normally commences. No increase in E2F activities occurred when cells were infected with viruses expressing mutant regulatory proteins ICP4 or ICP27, or mutant replication proteins ICP8, pol or helicase, or when cells were infected with wild-type virus in the presence of inhibitors of DNA synthesis. In contrast, ICP8 mutant-infected cells contained elevated amounts of NF kappa B activity equivalent to WT virus, no induction of Sp1 relative to WT virus, and reduced ATF/CREB activity relative to WT virus. Results of transient expression assays with E2F-responsive reporters indicated that the net effect of induction of both active (free E2F) and repressive (p107/E2F) complexes was a decrease in AdE2 promoter activity and an increase in c-myc promoter activity. Taken together these results suggest that HSV can cause unscheduled changes in the amount and functional status of a cell-cycle-regulated transcription factor. These results are discussed in light of possible roles for viral-induced alterations in E2F, especially as related to imposing or overriding cell-cycle checkpoints.

Activating Transcription Factor 1↗
PubMed1995

Injuries from falls on playgrounds. Effects of day care center regulation and enforcement.

OBJECTIVES: To measure the incidence of playground fall injuries among children attending licensed US day care centers and to evaluate how injury incidence varies with center characteristics and with the regulatory and enforcement climate in which centers operate. DESIGN: Telephone surveys of directors of day care centers and enforcement agencies and review of written day care regulations. SETTING: Probability sample of licensed day care centers in 50 states and the District of Columbia. PARTICIPANTS: Children attending day care centers with playgrounds. MAIN OUTCOME MEASURES: Medically attended playground fall injuries. RESULTS: Among the 1740 day care centers studied, a weighted total of 89.2 injuries occurred during the 2-month study period (0.25/100,000 child-hours in day care). The most important risk factor for injury was height of the tallest piece of climbing equipment on the playground in both bivariate (P = .01) and multivariate (P = .02) analyses. Neither regulations addressing playground safety or playground surfaces nor enforcement patterns were associated with lower injury rates. CONCLUSIONS: Additional effort is needed to develop and evaluate regulations and enforcement that reduce injury risks for children while minimizing burden on day care centers. In the meantime, limiting climbing equipment heights may reduce playground injury rates.

Accidental Falls↗