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Biomedical subjects

I A Cree

Publications and source records attributed to I A Cree.

At least 73 records · Page 4Linked to original sources
PubMed1997

Transmission and protection in leprosy: indications of the role of mucosal immunity.

Recent advances in treatment have achieved a large drop in the prevalence of active leprosy cases, but the incidence is at best decreasing slowly. Most people within leprosy-endemic populations have been exposed to Mycobacterium leprae, but few develop disease and it seems likely that the majority of the population develops protective immunity. If the site of initial infection is in the nose, dissemination of bacilli around the body to skin and nerve implies that the initial infection is bacilliferous and it has been shown that nasal M. leprae are detectable by polymerase chain reaction (PCR) of nasal swabs. Since salivary anti-M. leprae IgA (sMLIgA) levels are correlated with protection, we have surveyed groups of leprosy patients, contacts and the general population for both their sMLIgA and nasal PCR positivity. A total of 304 subjects were enrolled in the study: PCR and mucosal challenge tests were performed in 204 of these individuals. sMLIgA was present in 66% of treated patients, 76% of leprosy workers and 72% of healthy contacts. However, only 33% of indigenous subjects were sMLIgA+, in contrast to the earlier studies showing 74% positivity. PCR for M. leprae was present in both household contacts (2%) and indigenous controls (5%). In a subsequent follow-up study, nasal swabs were taken from 97 of those studied in the first series: three PCR+ individuals followed up after one year became negative, while of the remaining 94 PCR- individuals retested, 2 became positive. Of 112 subjects retested with the mucosal challenge test for sMLIgA: 22 converted from positive to negative and 12 from negative to positive. These results suggest that there is widespread subclinical transmission of M. leprae with transient infection of the nose resulting in the development of a mucosal immune response, despite the fact that few individuals will develop clinical disease. This may explain the current lack of effect of multidrug therapy (MDT) control programmes on incidence, although the reduction in general population immunity is consistent with some effect of MDT on transmission.

Adolescent↗
PubMed1997

Mitoxantrone combined with paclitaxel as salvage therapy for platinum-refractory ovarian cancer: laboratory study and clinical pilot trial.

This report describes preclinical and early clinical investigations of the mitoxantrone/paclitaxel combination (NT) for patients with platinum-refractory ovarian cancer. The preclinical activity of NT was studied ex vivo, evaluating native tumor specimens with the ATP tumor chemosensitivity assay. Of 24 tumors tested, 20 (83%) were sensitive to NT, whereas 7 (29%) responded to mitoxantrone and 8 (33%) responded to paclitaxel. In the majority of tumors assayed (19 of 24), potentiating or major independent effects between both agents were found. Subsequently, a clinical pilot trial of NT was initiated for patients with platinum-refractory ovarian cancer. Patients had failed one to four (median, two) prior chemotherapy regimens. In 11 cases, NT was administered every three weeks with 8 mg/m2 mito-xantrone and 180 mg/m2 paclitaxel (NT-I). Seven patients were treated biweekly with 6 mg/m2 mitoxantrone and weekly with 100 mg/m2 paclitaxel (NT-II). During 92 NT courses, myelosuppression with leucopenia, anemia, and thrombocytopenia was the limiting toxicity, occurring more frequently with NT-II. No patient required hospitalization due to any life-threatening complication. Five complete and nine partial remissions were observed with both NT-I and NT-II, accounting for an overall 78% response rate, with a median progression-free survival of 40 weeks. One patient showed early progression during therapy. Currently, three patients (NT-I, two; NT-II, one) have died due to progressive relapsed ovarian cancer, so that the median overall survival is not reached after a median follow-up of 40.5+ weeks. Both schedules were found to be equal in terms of response rate and overall survival. NT is highly active and practical for salvage treatment of ovarian cancer. NT-II may be preferred due to both clinical activity and patients' acceptance. However, NT-I seems to be a less myelotoxic alternative. Both schedules warrant further clinical investigation.

Adult↗
PubMed1996

Heterogeneity of in vitro chemosensitivity in perioperative breast cancer cells to mitoxantrone versus doxorubicin evaluated by a microplate ATP bioluminescence assay.

Apart from clinical trials, mitoxantrone (MX) is rarely used in breast cancer (BC) due to the anticipated anthracycline cross-resistance. We have examined this drug versus doxorubicin (DOX) using data obtained from in vitro microplate ATP tumor chemosensitivity assays (ATP-TCA) of BC cells which were derived from 55 chemotherapy-naive patients at time of primary surgery. Both drugs were tested at 6 different concentrations ranging from 6.25% to 200% peak plasma concentration in vivo (PPC). Differences between DOX and MX observed for mean IC50, IC90, and a sensitivity index (SI) were not statistically significant. In vitro response rates were 44% for DOX and 52% for MX. 34 of 52 eligible assays (65%) showed comparable activity of both drugs whereas a lack of cross-resistance was observed in the remaining 18 (35%) tumors as indicated by differences for SI. Cumulative concentration-response plots of tumors responding in vitro with a > or = 50 percent or > or = 90 percent tumor cell inhibition showed a strong dose-dependence for both DOX and MX at concentrations which normally can be achieved within clinical tumors (i.e. 6.25%-50% PPC). At higher concentrations, however, cytotoxicity of DOX and MX could not be improved by further in vitro dose escalation. Moreover, a substantial proportion of BC specimens (DOX: 48.1%; MX: 40.4%) did not experience a > or = 90 tumor cell inhibition at 200% PPC. In conclusion, in vitro results obtained by ATP-TCA indicate that there is no cross-resistance between MX and DOX in a substantial proportion of BC patients. This may be clinically useful and suggests that combinations including MX should be tested in patients clinically resistant to DOX containing regimens. Since both drugs produced sigmoidal concentration-response curves, dose escalation beyond a certain point may not produce increased sensitivity.

Adenosine Triphosphate↗
PubMed1996

Phagocyte chemiluminescence in pre-term infants.

Intact phagocyte function is a pre-requisite for successful defence against infection, but paradoxically, these cells may also play a major role in the pathogenesis of the infant respiratory distress syndrome. Phagocyte function is known to be deficient in pre-term infants, who are at risk of infection as a result, but these infants are also at risk of respiratory distress syndrome as a result of surfactant deficiency. Despite this, few longitudinal studies of phagocyte function have been performed in pre-term infants. We have used lucigenin-enhanced chemiluminescence to examine the respiratory burst of mixed samples containing polymorphonuclear leucocytes and monocytes of 100 pre-term infants at 48- to 72-h intervals during their admission to a neonatal care unit. Increased polymorphonuclear leucocyte chemiluminescence was associated with respiratory distress syndrome and the use of intermittent positive pressure ventilation. Multiple linear regression analysis revealed a slight, but significant depression of chemiluminescence in association with the use of gentamicin and penicillin when stronger influencing factors such as the presence of respiratory distress syndrome were taken into consideration. Measurement of phagocyte function by sensitive luminescence assays requires very little blood and may be useful in pre-term infants to follow the severity of respiratory distress syndrome. However, it is probable that other factors such as antioxidant capacity also have an important influence on the degree of tissue damage.

Anti-Bacterial Agents↗
PubMed1996

The effect of cefodizime on phagocyte function in non-patient volunteers and patients with chronic renal failure. In vitro and ex vivo studies.

Cefodizime has previously been shown to possess a number of immunomodulating properties in vivo and in vitro using several different test systems. Since most in vitro studies have been performed with cells from normal individuals, we first investigated whether cells from chronic renal failure patients would respond in vitro to cefodizime in the same way as healthy subjects. Subsequently, we investigated the effect of cefodizime (10 g over 10 days in 2-g doses) on phagocyte function ex vivo in an open study of 26 chronic renal failure patients and 16 healthy subjects. Polymorphonuclear leukocytes were tested for their ability to polarize in response to cefodizime and/or f-met-leu-phe peptide. Polymorphonuclear leukocytes and monocytes were tested for their ability to produce chemiluminescence on stimulation with either phagocytic (zymosan) or soluble phorbol myristate acetate stimuli. Phagocyte and lymphocyte membrane receptor expression was compared after exposure to cefodizime. Exposure to cefodizime in vitro causes a significant increase in polarization of polymorphonuclear leukocytes from both normal individuals and renal failure patients (both P < 0.001). It also caused increased chemotaxis and chemokinesis in a modified Boyden chamber assay. Cefodizime did not affect lucigenin-enhanced chemiluminescence and there were only minor effects on cell membrane antigen levels. In the ex vivo study there was a significant increase in polymorphonuclear leukocyte polarization (P < 0.001) attributable to cefodizime, but other investigations showed no significant differences. The results suggest that cefodizime may act as a mild priming agent for some functions, particularly chemotaxis.

Adult↗
PubMed1996

Correlation of the clinical response to chemotherapy in breast cancer with ex vivo chemosensitivity.

Chemotherapy for breast cancer is given on the basis of empirical information from clinical trials, an approach which falls to take into account the known heterogeneity of chemosensitivity between patients. Previous attempts to determine chemosensitivity ex vivo have been disappointing, but in this study results from a newly developed tumor chemosensitivity assay (TCA) have been correlated prospectively with patient response. In this study, we have used heterogeneity data for standard regimens obtained from 116 breast TCAs to set sensitivity/resistance thresholds which were then used to interpret the results from those with known clinical responses. Assay evaluability was 97% in surgical biopsies. Clinical follow-up of stage III/ IV assessable disease was obtained from 27 breast tumors which were successfully tested for chemosensitivity, including 13 needle biopsies. The ATP-TCA assay predicted response correctly in 22 out of 29 (76%) tumors with clinically evaluable disease, suggesting that it is capable of predicting outcome in individual patients. Assays were performed in seven patients before and after chemotherapy using residual or recurrent tumor tissue. Four cases with initial sensitivity showed a decrease in sensitivity within 6 months of starting chemotherapy, while two others without clinical resistance were still sensitive by TCA. All nine courses of therapy given on the basis of TCA sensitivity resulted in partial or complete responses. Controlled trials of TCA-directed treatment against standardized empirical therapy should be conducted before this technology is widely adopted to assess its impact on rates of response, survival and the cost of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

The immunoalkaline phosphatase technique in immunohistochemistry: the effect of permanganate-oxalate melanin bleaching upon four final reaction products.

Melanin bleaching prior to the application of primary antibody can alter the immunoreactivity of a number of antigens. The effect of melanin bleaching subsequent to antigen visualisation by four different chromogens used with an immunoalkaline phosphatase technique was investigated. Vector black was the only final reaction product that withstood exposure to the permanganate-oxalate sequence for a time sufficient to bleach melanin.

Choroid Neoplasms↗
PubMed1995

Development of a mucosal challenge test for leprosy using leprosin A.

There is little information about the mucosal immune response in leprosy. We have developed a nasal provocation test with leprosin A which will be used to investigate mucosal immunity to Mycobacterium leprae. Initial studies were performed with increasing doses of leprosin A (1.0 pg/ml-10 micrograms/ml) to determine the optimal safe dose of leprosin A. Anti-M. leprae IgA antibody and normal IgA concentrations were measured in the saliva of leprosy contacts and controls before and after instillation of leprosin A. Nasal leprosin A was well tolerated up to a concentration of 10 micrograms/ml without side effects. None of the six subjects who had not been exposed to leprosy had salivary IgA against whole M. leprae, whereas IgA was detected from 64 h to 140 h following instillation of leprosin A in all of the leprosy hospital workers and in 15 out of 18 healthy household contacts tested. There was no correlation between serum and salivary anti-M. leprae IgA levels before and after testing. Salivary IgA anti-lipoarabinomannan responses were seen in 12 out of 20 household contacts. Normal salivary IgA concentrations varied from 8 to 240 mg/l. The leprosin A nasal provocation test appears to be a safe method for the investigation of the role of mucosal immunity in the pathogenesis of leprosy.

Adolescent↗
PubMed1995

Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma.

An ATP luminescence assay (TCA 100) was used to measure chemotherapeutic drug sensitivity and resistance of dissociated tumor cells cultured for 6 days in serum-free medium and 96-well polypropylene microplates. Studies were performed with surgical, needle biopsy, pleural, or ascitic fluid specimens using 10,000-20,000 cells/well. ATP measurements were used to determine tumor growth inhibition. Single agent and drug combinations were evaluated using the area under the curve and 50% inhibitory concentration (IC50) results for a series of test drug concentrations. The ATP luminometry method had high sensitivity, linearity, and precision for measuring the activity of single agents and drug combinations. Assay reproducibility was high with intraassay and interassay coefficients of variation of 10-15% for percentage of tumor growth inhibition, 5-10% for area under curve, and 15-20% for IC50 results. Good correlation (r = 0.93) between the area under the curve, and IC50 results was observed. Cytological studies with 124 specimens demonstrated selective growth of malignant cells in the serum-free culture system. Studies with malignant and benign specimens also showed selective growth of malignant cells in the serum-free medium used for assay. The assay had a success rate of 87% based on criteria for specimen histopathology, magnitude of cell growth, and dose-response drug activity. Cisplatin results for ovarian carcinoma are presented for 81 specimens from 70 untreated patients and 33 specimens from 30 refractory patients. A model for interpretation of these results based on the correlation of clinical response with the area under the curve and IC50 results indicates that the assay has > 90% accuracy for cisplatin resistance of ovarian carcinoma. Additional studies are in progress to evaluate the clinical efficacy of this assay.

Adenosine Triphosphate↗
PubMed1995

Monocyte aggregation around agarose beads in collagen gels: a 3-dimensional model of early granuloma formation?

Granulomas consist of organised collections of macrophages showing evidence of activation in response to an agent localised within a tissue. To date, in vitro models of granuloma formation have failed to reproduce the histological appearance of a granuloma, which forms a characteristic three-dimensional structure. The use of 3-D collagen gels allows agarose beads and human mononuclear cells to be suspended together in a milieu which permit the two to interact. The interaction between agarose beads and mononuclear cells produces monocyte-macrophage aggregates within 24 h which resemble an early granuloma. The monocytes show evidence of activation by direct microscopy, electron microscopy and immunohistochemistry. This model should permit the laboratory testing of hypotheses describing granuloma formation.

Animals↗
PubMed1995

Antibiotic effects on phagocyte chemiluminescence in vitro.

Phagocytes are an essential defence against infection. Since drugs which affect their function may alter the outcome of infections, we have studied the effect of nine antibiotics on phagocyte function in vitro. The effects of antibiotics on the respiratory burst function of phagocytes from healthy adult donors were investigated using lucigenin-enhanced chemiluminescence in response to serum-opsonised zymosan. Aminoglycosides showed dose-dependent suppression of polymorphonuclear leucocyte chemiluminescence, except streptomycin which caused enhancement. Erythromycin caused profound suppression of chemiluminescence from both polymorphonuclear leucocytes and monocytes. Benzylpenicillin and the cephalosporins caused variable suppression of phagocyte chemiluminescence: cefotaxime increased monocyte chemiluminescence in some experiments. None of the drugs produced suppression at clinically relevant plasma concentrations, but erythromycin and some other drugs are preferentially concentrated in phagocytes to levels which suppress their oxidative metabolism in vitro. It is therefore possible that some antibiotics alter phagocyte function: ex vivo studies of phagocyte function in patients taking antibiotics would be valuable.

Adenosine Triphosphate↗
PubMed1995

Methotrexate chemosensitivity by ATP luminescence in human leukemia cell lines and in breast cancer primary cultures: comparison of the TCA-100 assay with a clonogenic assay.

Chemosensitivity assays are widely used to predict the ability of tumor cell lines to respond to potential or existing cytotoxic drugs. In this study we have compared the cell cloning assay first described by Salmon and Hamburger with a recently developed assay which measures viable cell number by ATP luminescence. Methotrexate (MTX) was chosen as the test agent, since cell lines with varying degrees of sensitivity to this agent were readily available. The results shown good correlation between the two assays, both of which are able to discriminate between the various cell lines used. MTX inhibition of primary breast carcinomas and cell lines shows a steep dose-response curve with a threshold concentration above which increasing dose does not increase sensitivity. In solid tumors, the plateau is usually reached at a level well below 100% inhibition. The ATP luminescence assay allows discrimination of MTX sensitivity between breast carcinomas and has considerable technical advantages over the cloning assay.

Adenocarcinoma↗
PubMed1995

Histological fate of cortical bone autografts in the middle ear.

Histological studies have been carried out on six cortical bone autografts and three ossicular grafts removed between 6 and 232 months after implantation in ossicular reconstructions. Both types of graft consisted mainly of dead bone, with some areas of viable osteocytes. Four out of six cortical bone grafts showed evidence of new bone formation and only one had reduced in size during the period in the middle ear. Fibrosis and inflammation were also noted in some specimens. In most cases cortical bone autografts appear to survive as well as ossicular grafts in the middle ear.

Bone Transplantation↗
PubMed1995

Effects of treatment on the histopathology of leprosy.

AIMS: To identify the histological changes in leprosy skin lesions over the first few weeks after the start of leprosy treatment and to examine their relationship to reversal reaction. METHODS: Sequential skin biopsy during treatment with multiple drug therapy. In this study, a series of 28 patients was studied, from whom two or more biopsies were taken at two week intervals. Fourteen patients had paucibacillary leprosy (PBL) and 14 had multibacillary leprosy (MBL). RESULTS: In most cases, granuloma fraction and bacterial index fell during treatment, the bacterial index being less sensitive than the granuloma fraction. Since the biopsies were fixed in buffered formalin and processed through to paraffin wax, little immunohistochemistry was feasible. However, there was strong evidence of immune activation, with increased expression of HLA-DR in the granulomas of MBL and PBL cases: the epidermis also expressed HLA-DR in several patients. Such changes may reflect gamma IFN production from granuloma lymphocytes. Patients with reversal reaction often showed HLA-DR expression on admission which decreased with corticosteroid treatment. CONCLUSIONS: The results suggest that activation of cell mediated immunity in leprosy lesions occurs during treatment with multiple drug therapy and may not be restricted to those with clinical evidence of reversal reaction.

Adolescent↗
PubMed1995

C-reactive protein. A clinical marker in community-acquired pneumonia.

STUDY OBJECTIVE: To assess the range of plasma C-reactive protein (CRP) in patients presenting with community-acquired pneumonia and to compare the serial changes of this acute-phase protein with clinical outcome. DESIGN: Prospective hospital-based study, including separate retrospective case series. PATIENTS: Twenty-eight consecutive patients (mean age, 60 years) admitted to our hospital with community-acquired pneumonia were studied. Serial daily plasma samples were taken and assayed for CRP, tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6). Clinical parameters, laboratory data, and response to treatment were recorded. Four other patients considered to be antibiotic failures (three empyemas, one death) were studied separately. RESULTS: Two patients died. Of those who survived, mean (+/- SD) CRP values for days 1,2,3,4, and 5 were as follows: 136 +/- 43, 96 +/- 44, 53 +/- 36, 54 +/- 43, and 44 +/- 31 mg/L. CRP levels on day 1 in patients who had received antibiotics prior to hospital admission were significantly lower than those who had not, 107 +/- 42 and 152 +/- 44 mg/L (p < 0.05). CRP levels did not correlate with other laboratory parameters or with recognized predictors of mortality. A CRP value that continued to rise despite antibiotic treatment was associated with infective complications or death. Only 52% of patients had detectable TNF-alpha and 24% detectable IL-6 at some point during their hospital stay. CONCLUSIONS: CRP is a sensitive marker of pneumonia. A persistently high or rising CRP level suggests antibiotic treatment failure or the development of an infective complication. These results suggest that CRP, rather than TNF-alpha or IL-6, may have a role as a clinical marker in pneumonia.

Adult↗