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Biomedical subjects

K McCarthy

Publications and source records attributed to K McCarthy.

At least 37 records · Page 2Linked to original sources
PubMed2000

Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for phase I trial.

rPSGL-Ig is a recombinant, soluble, and chimeric form of P-selectin glycoprotein ligand-1, which is developed as an antagonist to P-selectin. Allometric and pharmacokinetic/pharmacodynamic modeling was used to select doses for human clinical trials. Pharmacokinetic parameters of rPSGL-Ig such as clearance (CL), volume of distribution (Vc), and t(1/2) across animal species are well described by power functions with body weight as an independent variable. The power functions for CL, Vc, and t(1/2) were CL = 0.37. W(0.93) ml/h (r(2) = 0.94), Vc = 45.0.W(1.064) ml (r(2) = 0.988), and t(1/2) = 190.W(0.159) h (r(2) = 0.75), respectively. These functions provide a means to predict pharmacokinetics of rPSGL-Ig in humans. For a 70-kg human, the values of CL, Vc, and t(1/2) are predicted to be 19.9 ml/h, 4138 ml, and 15.5 days, respectively. The predicted pharmacokinetics in humans is used in conjunction with pharmacological data to estimate appropriate doses for clinical trials. The doses that may provide potential effects in humans range from 0.13 to 4.7 mg/kg. The predicted doses produce concentrations above those that are associated with efficacy in animal disease models and, maintain concentrations above the EC(50) of in vitro binding between rPSGL-Ig and stimulated human platelets. Hence, rPSGL-Ig in clinical trials may provide therapeutic activities for P-selectin-mediated diseases.

Algorithms↗
PubMed1999

High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer.

Studies from model systems suggest that matrix metalloproteinases (MMPs) are causally involved in tumor progression while tissue inhibitors of MMPs (TIMPs) prevent this progression. Here, we show that concentrations of TIMP-1 are significantly higher in breast carcinomas than in fibroadenomas. In primary breast cancers, TIMP-1 concentrations increased with increasing tumor size but showed an inverse relationship with estrogen receptor concentrations. In primary breast cancers also, TIMP-1 levels were weakly but significantly correlated with those for MMP-1, proMMP-2, active MMP-2, MMP-3 and proMMP-9. Contrary to what might be expected from published data on model systems, high concentrations of TIMP-1 predicted a poor outcome in patients with breast cancer. We conclude that in human breast cancer, endogenous TIMP-1 does not inhibit tumor progression but may enhance the process.

Biomarkers, Tumor↗
PubMed1999

Irradiation of the tumor bed alone after lumpectomy in selected patients with early-stage breast cancer treated with breast conserving therapy.

BACKGROUNDS AND OBJECTIVES: We present the interim findings of our in-house protocol treating the tumor bed alone after lumpectomy with low-dose-rate (LDR) interstitial brachytherapy in selected patients with early-stage breast cancer treated with breast conserving therapy (BCT). METHODS: From 1 March 1993 through 1 January 1995, 50 women with early-stage breast cancer were entered into a protocol of tumor bed irradiation alone using an interstitial LDR implant. Patients were eligible if their tumor was an infiltrating ductal carcinoma < or =3 cm in diameter, surgical margins were clear by at least 2 mm, the tumor did not contain an extensive intraductal component, the axilla was surgically staged with < or =3 nodes involved with cancer, and a postoperative mammogram was performed. Implants were positioned using a template guide delivering 50 Gy over 96 hr to the lumpectomy bed plus a 1-2-cm margin. Local control, cosmetic outcome, and complications were assessed. RESULTS: Patients ranged in age from 40 to 84 years (median, 65). The median tumor size was 10 mm (range, 1-25). Seventeen of 50 patients (34%) had well-differentiated tumors, 22 (44%) had moderately differentiated tumors, and in 11 (22%) the tumor was poorly differentiated. Forty-five patients (90%) were node-negative while five (10%) had 1-3 positive nodes. A total of 23 (46%) patients were placed on tamoxifen and 3 (6%) received adjuvant systemic chemotherapy. No patient was lost to follow-up. The median follow-up for surviving patients is 47 months (range, 37-59). No patient has experienced a local, regional, or distant failure. Three patients have died at 19, 33, and 39 months after treatment. All were without clinical evidence of recurrent disease and all deaths were unrelated to treatment. Good-to-excellent cosmetic results have been observed in 49 of 50 patients (98%) (median cosmetic follow-up was 44 months with a range of 19-59). No patient has experienced significant sequelae related to their implant. CONCLUSIONS: Interim results with treatment of the tumor bed alone with an LDR interstitial implant appear promising. Long-term follow-up of these patients and additional studies will be necessary to establish the equivalence of this treatment approach compared to standard BCT.

Adult↗
PubMed1999

Clinical impact of preoperative respiratory syncytial virus testing.

The purpose of this study was to determine if preoperative assessment (i.e., physical examination and history review) of pediatric patients can predict positive test results for respiratory syncytial virus (RSV) infection, surgery cancellations, and adverse anesthetic outcomes. Approximately 400 pediatric patients were identified for the study from infection control statistics and classified by RSV test result and surgery cancellation status into three groups for analyses. Researchers analyzed retrospective chart data of preoperative histories and physical findings using one way analysis of variance to compare age among the groups and Fisher's exact test to compare patient characteristics and signs and symptoms of illness. The results show that active RSV infection cannot be predicted by history and physical findings alone. In addition, patients who had a history of pulmonary disease and who were wheezing at the time of their examinations were more likely to have their surgeries cancelled, independent of positive test results for RSV infection.

Ambulatory Surgical Procedures↗
PubMed1998

Rothia dentocariosa endocarditis and aortic root abscess.

We report a case of endocarditis and associated paravalvular abscess due to Rothia dentocariosa which did not respond to antibiotic therapy. Nine case reports describing endocarditis caused by this organism, formerly thought to be non-pathogenic, have been recorded in the literature. The isolates were extremely sensitive to penicillin, and eight patients responded to this agent which, in most cases, was used in combination with an aminoglycoside. Surgery is recommended for an associated abscess, as the outcome in the two recorded cases has been fatal.

Abscess↗
PubMed1998

Dendritic cell precursors are enriched in the vascular compartment of the lung.

The vast mucosal interface separating external from internal compartments of the lung is under the surveillance of a population of blood-borne, bone marrow-derived dendritic cells (DC) characterized by constant turnover. Because these sentinel cells process foreign antigens that have penetrated the epithelial barrier and transport them to local lymph nodes, they require continuous replenishment by blood-borne cells. In the present study, the phenotype and function of DC and their precursors isolated from the vascular compartment of the lung were examined and compared with those in vena cava blood. Intravascular leukocytes were retrieved by exhaustive perfusion of the lung vasculature. Leukocytes harvested from the subdiaphragmatic vena cava of the same animal served as a source of DC in prepulmonary blood. Typical, large, major histocompatibility class II+ antigen (MHC II+) DC constituted < 1% of leukocytes from either vascular compartment. These cells expressed intercellular adhesion molecule [ICAM]-1 and lymphocyte function-associated antigen [LFA]-1 and many were ED1(+) (lysosomal antigen in monocytes, macrophages, and some DC). No ED2(+) cells (macrophages) were identified. Very few of the circulating DC expressed the alpha-like subunit of integrin recognized by the OX62 monoclonal antibody. A striking difference appeared when neutrophil-depleted leukocytes were cultured with granulocyte macrophage colony-stimulating factor (GM-CSF) for 3 d; the number of MHC II+ DC generated from pulmonary vascular leukocytes was 76% greater than that from the vena cava population. After pulse-labeling with tritiated thymidine ([3H]TdR) followed by 3 d of culture with GM-CSF, DC from either source remained virtually unlabeled, as determined by autoradiography. On the day of harvest, DC and their precursors obtained from either vascular compartment were poor stimulators of the mixed leukocyte reaction and required GM-CSF for development of their full accessory cell capability. These data suggest that, relative to leukocytes in vena cava blood, those in the lung vascular compartment are enriched in a population of mononuclear cells that are capable of differentiating into MHC II+ DC when exposed to the appropriate growth factors, including GM-CSF. This enriched population of DC precursors could represent a source from which lung DC may be readily recruited not only to replenish the normally turning-over mucosal DC, but also to participate in inflammatory reactions occurring in the lung.

Animals↗
PubMed1998

Albuterol delivered by metered-dose inhaler (MDI), MDI with spacer, and Rotahaler device--a comparison of efficacy and safety.

A randomized double-blind, triple crossover study was conducted on 20 asthmatic patients (7 males and 13 females; age 40.9 +/- 14.2 Caucasians, 11 blacks, and 1 oriental. Criteria for admission included FEV1 < or = 80% of predicted when inhaled beta-agonists were witheld for at least 6 hrs and oral beta-agonists for 12 hr, in addition to at least 15% increase in FEV1, 15 min after treatment with albuterol with spacer delivery. Each of the study patients were tested on each of 3 separate days (within the same week) at baseline, 15, 30, 60, 120, 180, 240, 300, and 360 min post treatment. On each day albuterol was delivered by one of the 3 delivery devices and the other two methods delivered placebo. Albuterol was administered at the maximum recommended dosages of two puffs for MDI. Two puffs for MDI with spacer, and two capsules for Rotahaler. Spirometry, blood pressure and heart rate were measured at each testing interval. The mean percentage in FEV1 was higher in Rotahaler group compared to MDI with spacer (p < 0.001) and no significant difference in FEV1 was found between Rotahaler and MDI alone (p = 0.31). No significant changes in heart rate or blood pressure were associated with albuterol delivery by any of the three methods. Albuterol inhaled as a microfine powder was more effective than the same drug delivered as an aerosol by either MDI or MDI with spacer.

Adult↗
PubMed1998

Matrix metalloproteinases in cancer: prognostic markers and targets for therapy (review).

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which catalyse degradation of diverse substrates in the extracellular matrix. The family can be loosely divided into 4 subgroups, i.e., interstitial collagenases, gelatinases, stromelysins and membrane-type MMPs. Data from model systems suggest that MMPs are involved in both stimulating tumor cell growth and promoting invasion and metastasis. Consistent with their role in tumor progression, high levels of certain MMPs have been shown to correlate with poor prognosis in different human cancers. Inhibitors of MMPs prevent or decrease tumor progression in model systems and are currently undergoing evaluation for the treatment of human cancers.

Antineoplastic Agents↗
PubMed1997

Epstein-Barr virus induced virus-associated hemophagocytic syndrome and monoclonal TCR-beta rearrangement: a case report.

Virus-associated hemophagocytic syndrome (VAHS) is a rare histiocytic proliferative disorder secondary to viral infection affecting children and young adults and in which there is both a poor prognosis and no specific treatment. We report a case of VAHS in a 22-year-old woman secondary to infection with Epstein Barr virus in which multiorgan failure developed with a fatal outcome 3 weeks after presentation. Clonal analysis showed EBV incorporation into the T cell genome accompanied by monoclonal rearrangement of the TCR beta gene. Treatment with cyclosporin A resulted in hematological improvement but the patient died of disseminated fungal infection. We propose that bone marrow ablation and allografting should be available for these rare cases and suggest that a protocol should be developed with designated transplant centres to aid early referral.

Adult↗
PubMed1997

Cervical abnormality and sexually transmitted disease screening in human immunodeficiency virus-positive women.

OBJECTIVE: To determine the incidence of genital tract infections and cervical abnormalities in 185 human immunodeficiency virus (HIV)-positive outpatients with a view toward establishing an effective policy for gynecology screening. METHODS: Gynecology results were reviewed for 185 HIV-positive women seen as outpatients at the Royal Free Hospital in London. All subjects underwent screening for cervical abnormalities (smear and colposcopy) and sexually transmitted disease (STD) at 6-month intervals for 6 years. The STD prevalence was calculated, and the relationship between the occurrence of STDs and the demography and sexual lifestyle of the women was examined to determine whether these factors were predictive for women at risk for STDs. The incidence of cervical intraepithelial neoplasia (CIN) was determined. We reviewed the use of colposcopy in addition to cytology as a primary screening test to see whether it improved the detection rate of CIN. RESULTS: Sixty-five (35.1%) women had a history of previous STDs, and new STDs were detected in 18 women at their first visits. None were detected at subsequent visits. Sexual lifestyle details did not predict women at risk for STDs. Ninety-eight (53%) cervical smears were reported as normal at the first visit, but there was a 3.1% (95% confidence interval 0, 6.6) false-negative rate when compared with colposcopy and directed biopsy. Five of fifty women (10%) with CIN I had progressed to higher-grade lesions by 6-month follow-up. CONCLUSIONS: Given the low prevalence of STDs detected, except for initial screening at presentation, regular, repeat STD screening of HIV-positive women appears to be unnecessary. Because of the high incidence of cervical abnormalities, screening for cervical biopsy improved the detection rate of cervical abnormalities.

Adult↗