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Biomedical subjects

J H Todd

Publications and source records attributed to J H Todd.

At least 19 recordsLinked to original sources
PubMed1995

Renal brush border membrane vesicle aminoglycoside binding and nephrotoxicity.

The in vitro binding affinity (KD) of aminoglycoside (AG) antibiotics to renal brush border membranes (BBM) has previously been correlated with several variables (sex, age and toxic potential of specific antibiotics) influencing in vivo AG nephrotoxicity in rats. The initial intent of our study was to extend this correlation to the in vivo difference in sensitivity to tobramycin recently observed between two strains of rats. However, the tobramycin binding affinity (KD) failed to correlate with the in vivo strain difference in AG nephrotoxicity. In addition, a comparison of BBM vesicle tobramycin binding affinity between sexes failed to correlate with an earlier report of in vivo gender differences in tobramycin nephrotoxicity. Comparison of binding capacities for male Sprague-Dawley rats and male Fischer rats yielded the only instance where binding parameters correlated with the reports of in vivo nephrotoxicity comparisons. Preliminary examinations of tobramycin binding using renal BBM vesicles derived from a single human kidney revealed binding kinetics and characteristics similar to rat BBM binding. Tobramycin binding was rapid and saturable for each type of BBM vesicle preparation. Scatchard analyses indicated low affinity, high capacity binding characteristics, as well as a single binding site in each case. Polyaspartic acid, which blocks in vitro BBM tobramycin binding as well as in vivo nephrotoxicity in rats, also blocked binding of tobramycin to human BBM vesicles. These data indicate that AG binding is qualitatively similar for rat and human BBM vesicle preparations. However, examination of the quantitative kinetic aspects of AG binding to BBM vesicles (KD and binding capacities) suggests that these parameters may not be critical determinants in the pathogenesis of Ag nephrotoxicity.

Aminoglycosides↗
PubMed1994

Serum-free culture and characterization of renal epithelial cells isolated from human fetal kidneys of varying gestational age.

Cell cultures were initiated from seven human fetal kidneys that varied in gestational age from 90 days to newborn. The growth medium utilized was a 1:1 mixture of Dulbecco's modified Eagle's and Ham's F12 supplemented with selenium (5 ng/ml), insulin (5 micrograms/ml), transferrin (5 micrograms/ml), hydrocortisone (36 ng/ml), triiodothyronine (4 pg/ml), and epidermal growth factor (10 ng/ml). For all the kidney isolates, initial cell attachment occurred within 12 h through multicell spheroids, and by 24 h a rapidly growing population of cells was obtained. Confluency was reached within 3 to 6 days. A combination of light microscopy, immunohistochemistry, and ultrastructural evaluation was utilized to characterize the resulting cultures as epithelial and homogeneous within each isolate and among the isolates. That is, regardless of gestational age of the fetal kidney used as starting material, an identical or highly similar population of cells was obtained. By light microscopy, the cultures were noted to form very few domes, the number being an indication of transport activity. However, ultrastructural examination revealed that the cells were noted to form domes composed of only a few cells or "micro-domes" that would not be visible by light microscopy. Within the micro-domes as well as other areas of the monolayer an apparent absence of tight junctions was noted by routine transmission electron microscopy. However, by freeze fracture analysis cells were shown to possess sealing strands, the structural component of tight junctions. It is postulated that the tight junctions of fetal epithelial cells are structurally altered as compared to tight junctions in adult renal epithelial cell cultures.

Cells, Cultured↗
PubMed1994

Selective exposure of human proximal tubule cells to gentamicin provides evidence for a basolateral component of toxicity.

The goal of the present study was to determine if cultured human proximal tubule (HPT) cells could provide evidence for a basolateral component of gentamicin toxicity. Six isolates of HPT cells were grown on Millicell filters and exposed to gentamicin either apically, basolaterally, or both apically and basolaterally. Toxicity was determined by the release of lactate dehydrogenase into the growth media. The results clearly demonstrated that basolateral exposure and combined apical and basolateral exposure to gentamicin resulted in significant levels of cell toxicity. In contrast, apical exposure to gentamicin elicited only marginal toxicity. The transepithelial flux of gentamicin was shown to be the same in either the apical to basolateral or the basolateral to apical direction. A two-step mechanism of gentamicin toxicity is proposed in order to integrate basolateral toxicity with known features of aminoglycoside nephrotoxicity.

Adult↗
PubMed1993

Electrical and freeze-fracture analysis of the effects of ionic cadmium on cell membranes of human proximal tubule cells.

We previously reported that cell cultures of human proximal tubule (HPT) cells respond to ionic cadmium in a manner consistent with well-defined Cd(2+)-elicited responses reported for in vivo systems. However, one unique finding was that the transepithelial electrical resistance and tight junction sealing strands were altered as a result of Cd2+ exposure at micromolar concentrations. These alterations are reexamined in detail in the present report to determine whether the Cd(2+)-induced alterations are specific alterations in the tight junction structure or reflect a general alteration in the cell membrane. Exhaustive analysis of tight junction sealing strands demonstrated no significant alterations due to Cd2+ exposure, even at the concentration that elicited a significant reduction in transepithelial resistance. Further analysis of intramembrane particle distribution demonstrated a significant increase in apical intramembrane particles, indicating that Cd2+ exposure altered the characteristics of the apical cell membrane. Overall, the results were consistent with evidence of Cd(2+)-induced alteration in the apical cell membrane of the HPT cell.

Cadmium↗
PubMed1992

In situ freeze-fracture of monolayer cell cultures grown on a permeable support.

The growth of cultured epithelial cells on permeable supports allows increased cell differentiation and the assessment of a variety of transcellular and paracellular transport processes. The need to assess the corresponding ultrastructural characteristics of these cells under identical conditions prompted this laboratory to develop a reliable method for producing freeze-fracture replicas of these cultures. Sections of filter inserts with the cell-side facing up are placed between layers of polyvinyl alcohol with a strip of mylar positioned on the layer of polyvinyl alcohol. Following freezing, the monolayer is fractured by lifting the mylar strip from the assembly. The result is a consistent fracture of the apical membrane sufficient for analysis of tight junction sealing strands, microvilli distribution, and intramembranous particle (IMP) distribution between apical and lateral membrane domains. This method utilizes standard equipment and readily available materials and, most importantly, allows the freeze-fracture and replication of an undisturbed cell monolayer.

Cells, Cultured↗
PubMed1992

Aminoglycoside antibiotics alter the electrogenic transport properties of cultured human proximal tubule cells.

Monolayers of human proximal tubule (HPT) cells, when grown on permeable supports and mounted in Ussing chambers, spontaneously display a transepithelial potential difference (PD) and short-circuit current (Isc). These electrical parameters were used in the present study to determine if aminoglycoside exposure altered electrogenic sodium transport by HPT cells. The results of this determination demonstrated that exposure to gentamicin, at levels below that producing cell necrosis, caused a marked reduction in Isc and that this reduction followed the known in vivo nephrotoxicities of the aminoglycosides streptomycin, gentamicin, and neomycin. It was concluded through a similar analysis on a total of 14 isolates of HPT cells that the aminoglycosides repeatably reduced the electrogenic sodium transport of HPT cells. It was further determined that this alteration in electrogenic transport by gentamicin was mediated through exposure of the drug to the basolateral cell surface and that apical exposure had little effect. Evidence was obtained against the involvement of Na+, K(+)-ATPase, adenosine 3',5'-cyclic monophosphate, and sodium-coupled substrate transport in this alteration in electrogenic transport by the aminoglycosides. The basolaterally located Na+: CO3(-2):HCO3(-1) symporter is a possible site for aminoglycoside-induced nephrotoxicity.

Adult↗
PubMed1990

Expression of epidermal growth factor receptor in breast carcinoma.

A series of 90 patients with primary operable breast cancer and with up to 36 months of follow up were investigated for expression of epidermal growth factor receptor (EGFR) in their tumours by immunocytochemical staining with the monoclonal antibody EGFR 1. Tumour samples were snap frozen in liquid nitrogen immediately after resection and subsequently stained using a standard indirect immunocytochemical method. Tumour staining was assessed by two observers and scored on a four point scale (0-3). Thirteen (14%) tumours showed positive immunoreactivity. A strong correlation between distinct EGFR expression and short disease free interval was observed. Significant correlations were also shown with oestrogen and progesterone receptor expression and tumour nuclear size. No significant association was found with tumour size, lymph node stage, and histological grade. The association with disease free interval remained significant in multivariate analysis.

Antibodies, Monoclonal↗
PubMed1989

Carcinoembryonic antigen immunocytochemistry in primary breast cancer.

We studied the immunoreactivity by immunohistology of two carcinoembryonic antigens (CEA) with specific and two CEA antibodies with nonspecific cross-reacting antigen (NCA) cross reactivity (CEA/NCA) in 180 primary breast carcinomas. Positive tissue staining was found in more than 90% of the specimens with CEA/NCA antibodies, compared with less than 30% for both CEA-specific antibodies. There was no correlation between the positivity of CEA immunocytochemistry for any of the four antibodies and histologic grade, lymph node stage, locoregional recurrence, disease-free interval (DFI), or patient survival. This large study with a long follow-up period for patients has shown that CEA and CEA/NCA immunocytochemistry have no relation to prognosis in breast cancer. An extensive review of the literature that confirms these findings should end the controversy over the place of CEA and CEA/NCA immunocytochemistry in breast cancer.

Animals↗
PubMed1989

Mitoxantrone--a useful palliative therapy in advanced breast cancer.

We have treated 76 patients with advanced breast cancer with single-agent mitoxantrone: all had previously received hormone therapy and 30 patients had also received prior chemotherapy. The overall response rate at 6 months was 15%, with a further 22% having static disease. Responding and static patients had similar survival curves and were grouped together as patients with "stable disease." Patients with stable disease had a significantly longer survival than patients with progressive disease (p less than 0.001); the median difference in survival was 9 months.

Breast Neoplasms↗
PubMed1988

Breast self-examination for the early detection of breast cancer.

The early results are presented from a programme of education for Breast Self-Examination (BSE) for self-referral; 32,000 women in one health district, between the ages of 40 and 65 years, were invited by letter for education in BSE. Since the study began (1981-85), 153 breast cancers have been diagnosed, and they have been compared with the 153 breast cancers in the same age group presenting in the same health district immediately prior to the start of the study. A significant amelioration of prognostic factors is seen in the study group. However, at this time there is no significant difference in survival between the Study and the Control groups. The benign to cancer biopsy ratio is 1.2:1.

Adult↗
PubMed1987

Helix pomatia and Ulex europeus lectin binding in human breast carcinoma.

Formalin fixed, paraffin embedded tissue from 100 consecutive cases of breast carcinoma were studied for binding with Helix pomatia (HPA) and Ulex Europeus (UEA1) lectins. Serial sections were pretreated with trypsin or neuraminidase to determine the effect of these enzymes on lectin binding. The lectins were visualized by the peroxidase antiperoxidase technique and the cell staining proportion assessed in a semi-quantitative manner under the light microscope. Correlating staining with prognostic factors and patient follow-up details showed that UEA1 related to disease-free interval and survival, and HPA to lymph node stage, time to loco regional recurrence and to survival. Relationships with both lectins were abolished by pretreatment with neuraminidase. The study demonstrates that a simple assessment of lectin binding can provide prognostic information in breast cancer. This may be useful particularly when conservational surgical practice restricts the amount of nodal tissue for staging.

Animals↗
PubMed1987

Oestrogen receptors in primary and advanced breast cancer: an eight year review of 704 cases.

ER content of primary tumour tissue has been examined in 704 patients presenting with operable breast cancer. The median follow-up is now 84 months and no patient has received adjuvant therapy of any kind. ER status is related to histological grade, menopausal status, initial site of metastases and subsequent response to endocrine therapy. A significant advantage in terms of survival is found in ER positive patients which is confined to those lymph node positive at mastectomy. DFI is also significantly related to ER status in lymph node positive patients. Survival after the symptomatic presentation of metastases and the institution of endocrine therapy is prolonged in patients with ER positive tumours. The overall response rate to endocrine therapy in assessable patients with ER positive tumours is 32%. By combining the ER status and histological grade of tumour tissue, a group of patients comprising 28% of those assessable to endocrine therapy can be identified (ER positive, grade I and II) with a response rate of 46%.

Aged↗
PubMed1987

Confirmation of a prognostic index in primary breast cancer.

A prognostic index, previously derived in a group of 387 patients with primary breast cancer, has been recalculated for the same patients with over 5 years further follow-up and shown to be unchanged. The prognostic index has also been applied prospectively to a further group of 320 patients and shown to be similarly effective in identifying patients with either a very good or a very poor prognosis. It has been verified that the index applies to patients with primary breast cancer. Patients have now been divided into 5 prognostic groups, predicting 11% of patients with an almost normal survival and a further 10% with a very poor prognosis. The index is used to stratify patients to study the effects of treatment regimes within groups of similar patients.

Breast Neoplasms↗
PubMed1986

Survival patterns in hormone treated advanced breast cancer.

This study investigates a series of factors, all recordable by the time of presentation of distant metastases from primary breast cancer and relates these to survival after the initiation of endocrine therapies. One hundred and ninety-one patients have received endocrine therapy as initial treatment for distant metastases. In all patients both the histological grade and oestrogen receptor (ER) status of primary tumour tissue; the lymph node stage and menopausal status at mastectomy and the disease-free interval and sites of initial metastases are available for analysis. Four of these factors have been found to contribute independently towards prolonged survival after the initiation of treatment: tumour grade, ER status, disease-free interval and sites of metastases. Employing a multivariate analysis incorporating these four factors, three groups of patients have been identified with survivals of 67, 37 and 0 per cent at 18 months on therapy. These three groups of patients contain 37, 41 and 22 per cent of the patient population respectively.

Breast Neoplasms↗
PubMed1985

The prediction of local or regional recurrence after simple mastectomy for operable breast cancer.

Both the histological grade of the primary tumour and lymph node status have been found to contribute significantly towards the development of a local or regional recurrence after simple mastectomy for operable breast cancer. No other factor, from a series of seven studied, has been found to be of independent significance. A small group of patients with grade III tumours, lymph node positive at mastectomy, has been identified in whom more than 40 per cent of all symptomatic local or regional recurrences occurred. The chance a patient in this group has of developing a local or regional recurrence requiring treatment within 4 years approaches 50 per cent.

Breast Neoplasms↗