Biomedical subjects
Publications and source records attributed to C Page.
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The antigenic status of vascular endothelium from different sites of the normal adult and fetal human cardiovascular system was investigated. Tissues included aorta (n = 9), pulmonary artery (n = 8), coronary artery (n = 6), ventricle/atrium (n = greater than 10), lymph node (n = 2), fetal whole heart (n = 3), and umbilical cord (n = 7). Frozen sections were studied using monoclonal antibodies recognizing endothelial markers (EN4, vWf, Pal-E, and 44G4), vascular adhesion molecules (ICAM-1, ELAM, VCAM, and PECAM), the monocyte/endothelial marker (OKM5), and major histocompatibility complex (MHC) molecules (class I and class II). Results demonstrate that capillary endothelium is phenotypically different from endothelial cells (EC) lining large vessels. Capillary EC strongly express MHC classes I and II, ICAM, and OKM5, which are variably weak to undetectable on large vessels. In contrast, the large vessels strongly express vWf and appear to constitutively express ELAM-1. This suggests that the capillary EC may be more efficient at antigen presentation or more susceptible to immune attack in vivo. Interestingly, normal coronary arteries, unlike all other large vessels, express MHC class II and VCAM molecules. Future studies should concentrate on comparative functional studies between capillary, coronary, and large vessel EC.
NTera 2/cl.D1 (NT2) cells, a human teratocarcinoma cell line, were manipulated following retinoic acid treatment to yield greater than 95% pure cultures of neuronal cells (NT2-N cells). The commitment of NT2-N cells to a stable neuronal phenotype is irreversible as judged by the lack of mitotic activity or phenotypic reversion over a period of 2 months in culture. Furthermore, NT2-N cells express a variety of neuronal markers including many neuronal cytoskeletal proteins, secretory markers, and surface markers. NT2-N cells resemble primary neuronal cultures from rodents morphologically and in density of process outgrowth and, like primary neurons, go on to elaborate processes that differentiate into axons and dendrites. This culture method yields sufficient highly differentiated postmitotic NT2-N cells for both biochemical and molecular biological studies. Indeed, when undifferentiated NT2 cells were stably transfected with a beta-galactosidase (beta-gal) expression plasmid, beta-gal expression was shown to be present in both undifferentiated NT2 and postmitotic NT2-N cells. Thus, the ability to transfect expression plasmids into undifferentiated NT2 cells will allow the introduction of normal and mutant gene products into cells that can then be induced to become stable, postmitotic human neurons. We conclude that NT2 cells and NT2-N cells represent a unique model system for studies of human neurons, and a novel vehicle for the expression of diverse gene products in terminally differentiated polarized neurons.
Immunocytochemical analysis of endomyocardial biopsies from cardiac transplant patients has defined changes in expression of antigens, expressed on both the myocardium and endothelium which are characteristic of rejection. Biopsies taken from normal donor heart (prior to transplantation) have been compared with biopsies showing histological signs of rejection. There is induction of MHC class I antigen on the normally negative myocardial plasma membrane and induction of the adhesion molecule ICAM-1 on the intercalating discs. Capillary endothelial cells, which constitutively express Class II DR antigen and ICAM-1 in normal heart show increased of endothelial antigens Pal-E and FVIII-RA during rejection. These results demonstrate perturbation of the endothelial system during rejection and possibly indicate damage to the capillary endothelial cells.
The half-time of transfer of 99mTc DTPA (T50) is a useful method of assessing lung epithelial permeability, which has been shown to be altered in patients with acquired immunodeficiency syndrome (AIDS) who have Pneumocystis carinii pneumonia (PCP). The present study was designed to assess the usefulness of the T50 measurement in evaluating patients with renal transplants, breathlessness, and fever. An assessment was also made of the effect of renal failure on the T50 result. Sixty-eight non-smokers (12 normal subjects, ten patients with chronic renal failure not requiring dialysis (CRF), ten patients on haemodialysis (HD), ten patients on chronic ambulatory peritoneal dialysis (CAPD), 13 patients with functioning renal transplants (Tx), seven transplanted patients with PCP, two transplanted patients with cytomegalovirus pneumonia, and four transplanted patients with other lung infections), and 30 smokers (ten normal subjects, five CRF, five HD, five CAPD, five Tx) were studied. The lung epithelial permeability of the patients with renal failure, as judged by the whole lung T50, was not significantly different from that of the normal subjects. The T50 of transplanted smokers was significantly longer than that of the normal subjects who smoked and not significantly different from the transplanted non-smokers. Patients with PCP and CMV pneumonitis had significantly faster T50 values compared with all other patients with renal disease. This fast T50 suggests that the test may be of use in identifying patients who have an alveolitis as a cause for their fever when immunosuppressed following a renal transplant.
The nature of class II-positive cells in normal and transplanted human heart has been investigated using immunoperoxidase and dual-immunofluorescent techniques. In normal heart approximately 83% of DR expression can be accounted for by EN4+ endothelial cells, most of which express intercellular adhesion molecule 1 constitutively. Few cells bearing the leukocyte common antigen are found in normal heart; most of them are RFD7+ macrophages or T cells. There is a paucity of RFD1+ dendritic cells. In transplanted heart showing signs of rejection, the infiltrate consists of RFD7+, RFD1+, RFD7+, RFD1+ cells and T lymphocytes. The increased class II expression within these biopsies is confined to the infiltrating cells. Dual-immunofluorescence demonstrates that nearly all the RFD1+ cells are from the recipient. In conclusion, in normal heart presentation of allogeneic class II is by the intercellular adhesion molecule-1-positive endothelial cells. After transplantation, there is an influx of recipient cells of the macrophage/dendritic series which are probably able to process allogeneic class II.
Interest in the endothelium as a possible initiator or target of the antiallograft response prompted the following study. Immunocytochemical techniques have been used to investigate the expression of the endothelial markers EN4, Pal-E, and FVIII-RA in normal human heart, cardiac biopsies from patients with various cardiac diseases (dilated cardiomyopathy [DCM] and myocarditis [MCO]), and cardiac biopsies from heart-transplant recipients undergoing acute rejection or free of rejection. Quantitative data demonstrated greater preponderance of EN4 cells in normal heart than the other markers. In biopsies showing histologic signs of rejection, there was no difference in the number of EN4 positive cells compared to normal. In contrast, there was found a striking increase in the proportion of cells that are Pal-E positive and a significant increase in the proportion of FVIII-RA positive cells in these biopsies. The patient details provided suggest these results do not reflect vascular damage due to cyclosporine but may well reflect damage caused by the rejection process.
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An estimate of the absolute pulmonary deposition of nebulised pentamidine isethionate was obtained in nine patients with AIDS. Two nebuliser systems were compared, System 22 Mizer (Medic-Aid) and Respirgard II (Marquest), with 50 and 150 mg doses of pentamidine in a 3 ml solution driven by an air flow of 6 l/min with the patient in the sitting position. The 50 mg pentamidine dose was repeated with a 6 ml fill with both devices. The nebuliser cloud was labelled with technetium-99m human serum albumin (Ventocol) and lung deposition was measured with a gamma camera. Of the two nebulisers studied, System 22 Mizer delivered more drug to the lungs as a whole and to each individual lung region, including the peripheral and upper zones. For the 50 mg dose the mean (SEM) total pulmonary deposition with the 3 and the 6 ml fill respectively was 2.63 (0.34) and 3.71 (0.41) mg for the System 22 Mizer and 1.37 (0.26) and 1.45 (0.18) mg for the Respirgard II. For the 150 mg dose the System 22 Mizer delivered 7.16 (1.02) mg and the Respirgard II 4.34 (0.57) mg. Increasing the volume of fill from 3 to 6 ml increased pulmonary deposition with System 22 Mizer, and this was related to an increase in nebuliser output. Neither pulmonary deposition nor nebuliser output was increased by using a 6 ml solution in the Respirgard II. Increasing the volume of fill prolonged the time required for nebulisation with both nebulisers. The System 22 Mizer produced more nonpulmonary (gastric and oropharyngeal) deposition of drug, more frequent local adverse effects (cough, burning in the throat, and a metallic taste), and small reductions in lung function, particularly with the 150 mg pentamidine dose. Thus nebuliser type, volume of fill, and nebuliser dose affect the pulmonary deposition of pentamidine. A 300 mg dose of pentamidine via a Respirgard II is generally recommended as providing effective prophylaxis; our results suggest that similar pulmonary deposition can be produced with System 22 Mizer and 150 mg pentamidine. A clinical trial would be needed to show whether this regimen provides similar prophylactic benefit.
OBJECTIVE: To measure the safety and efficacy of antenatal treatment with anti-D immunoglobulin. DESIGN: Open study with historical controls. SETTING: Multicentre study in 17 hospitals in West Yorkshire. PATIENTS: 1238 Rh negative women who delivered Rh positive infants after 34 weeks in their first pregnancy in 1980-1 (group 1) and 2000 similar primigravidas from 1978-9 (group 2). Obstetric data were collected for 616 women in group 1 who had a subsequent pregnancy, 536 similar women in group 2, and 410 Rh positive but otherwise similar primigravidas who delivered in the same hospitals in 1978-81 (group C). INTERVENTIONS: Anti-D immunoglobulin 100 micrograms intramuscularly was given at 28 and 34 weeks to the mothers in their first pregnancy who delivered in 1980-1. END POINTS: Detection of anti-D antibody in the first or any subsequent pregnancy in groups 1 and 2. For all three groups having subsequent pregnancies gestation at delivery, birth weight, fetal survival at one month, pre-eclampsia defined as blood pressure greater than 140/90 on two occasions more than 12 hours apart, and proteinuria greater than 0.25 milligram. MEASUREMENTS AND MAIN RESULTS: Antenatal immunisation to Rh(D) occurred in six mothers in group 1 and 32 group 2. Most immunisations occurred in the first or second pregnancy. The rates of abortion, gestation at delivery, birth weight, and fetal survival were not significantly different among the three groups. The incidence of pre-eclampsia was lower in mothers given antenatal anti-D immunoglobulin, but the difference was not significant. CONCLUSIONS: Antenatal prophylaxis with anti-D immunoglobulin is effective, and the effect of giving it in the first pregnancy persists into at least the second pregnancy. It seems to be safe for the fetus in the index and subsequent pregnancies.
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Nebulized pentamidine has been used as therapy for Pneumocystis carinii pneumonia. The lung dose delivered using different nebulizer systems and doses of pentamidine from 50-600 mg is unknown. To measure this a marker which does not alter the characteristics of the nebulized pentamidine solution must be found. We have assessed the aerosol characteristics of four jet nebulizers (System 22, System 22 Mizer, Optimist, Respigard II) and one ultrasonic device (Pulmosonic) using two concentrations of pentamidine isethionate (50 mg and 300 mg) in 3 ml of solution. The jet nebulizers were operated at a flow rate of 6 l min-1, a rate suitable for home use. These measurements were repeated with 99Tcm labelled human serum albumin (HSA) added to the solutions. A linear relationship between 99Tcm-HSA activity and pentamidine concentration was demonstrated by using a nine stage cascade impactor. The Respigard II and Optimist produced the best results in terms of particle size (96% less than 5 microns), but the addition of the tracer to the latter led to a smaller particle size range and a reduction in the amount of aerosol present at the mouthpiece. The Mizer system had 52% of particles less than 5 microns, the Pulmosonic 46%. The Respigard II had a total output of 8.7 mg for the 50 mg concentration and 30.9 mg for the 300 mg concentration. The System 22 produced corresponding outputs of 18.0 mg and 67.1 mg with 54% of the aerosol particles less than 5 microns.(ABSTRACT TRUNCATED AT 250 WORDS)
The study compared the pulmonary deposition of nebulised pentamidine when inhaled by way of different nebuliser systems by nine human-immunodeficiency-virus-positive patients with a history of previous Pneumocystis carinii pneumonia. Pentamidine, 50 mg or 300 mg, mixed with technetium-99m-labelled human serum albumin in a total volume of 3 ml, was administered by way of three jet nebulisers (System 22', 'System 22 Mizer', and 'Respigard II') operated with a gas flow of 6 l/min, and one ultrasound nebuliser ('Pulmosonic'). Pulmonary and non-pulmonary isotope deposition was measured for each apparatus and adverse effects and lung function tests were recorded. For both doses of pentamidine, the system 22 mizer produced the largest pulmonary isotope deposition and it was completed in the shortest time. Oropharyngeal and gastric deposition were least with the respigard II, which also caused the fewest adverse effects. The adverse effects were greatest with the system 22 mizer and pulmosonic and the higher pentamidine dose, which also caused significant reductions in measurements of pulmonary function. It is concluded that either the system 22 mizer or the respigard II should be used to administer nebulised pentamidine.
Patients suffering from unipolar and bipolar affective illness, who began treatment with prophylactic lithium carbonate during a 5-year period, were followed up and 59 out of 101 interviewed. Most had been taking lithium for at least 13 years: 49% had a complete remission, 41% a partial but significant response, and 10% no response. No specific individual or illness factor was found to correlate with favourable outcome, and no correlation between average serum lithium level and outcome. No side-effects could be associated specifically with the long-term use of lithium, but there was a surprisingly high incidence of clinical hypothyroidism.
Results of a study concerned with maternal self-esteem and prenatal attachment in women experiencing a high-risk pregnancy and women experiencing a normal pregnancy are presented. A statistically significant difference between the two groups was found in self-esteem as measured by scores on the Rosenberg Self-Esteem Scale. No significant differences were found on prenatal attachment as measured by a subscale of the Prenatal Tool developed by Rees.
The relationship between placental and peripheral concentrations of pregnancy-associated plasma protein A (PAPP-A) was investigated, using specific radioimmunoassay techniques. At term, placental concentrations of PAPP-A were significantly lower in diabetic pregnancies; 1.9 +/- 0.2 micrograms/mg (mean +/- SE) placental protein as compared with controls (3.2 +/- 0.3). Similar findings were noted when results were analyzed per total placental weight. Patients with classes C-R (1.2 +/- 0.3) had significantly lower PAPP-A levels than in classes A, B (2.4 +/- 0.3 micrograms/mg protein, P = .02). Peripheral PAPP-A levels were measured in patients with chronic hypertension, toxemia, diabetes mellitus, and healthy controls. Overall, the distribution of PAPP-A values in patients with diabetes mellitus were different from controls. In addition, concentrations of PAPP-A in patients with classes B-D were significantly lower than in class A (P less than .001). In patients with chronic hypertension, some values of PAPP-A were lower than the tenth percentile, while patients with toxemia had a distribution which was similar to that of controls.
Production of gamma-interferon (gamma-IFN) in vitro by peripheral blood mononuclear cells (PBMC) from 15 breast-fed and 15 bottle-fed infants has been studied from birth to 9 months of age and compared with production by adult cells. Using a Terasaki plate microculture system with serum-free medium, PBMC were stimulated with staphylococcal enterotoxin A (SEA) and gamma-IFN production was assessed by an immunoradiometric assay. Cord blood mononuclear cells (CBMC) and PBMC from all infants secreted large quantities of gamma-IFN. The levels secreted did not change significantly with age over the 9 months of the study, nor did they differ from the levels secreted by adult cells. Cells from the bottle-fed infants secreted slightly more gamma-IFN than cells from breast-fed infants, but this difference was not significant. These results indicate that the potential for PBMC to secrete gamma-IFN in vitro is fully developed at birth in full-term infants and cannot therefore be further influenced by subsequent breast- or bottle-feeding. In addition, the greater susceptibility of infants than adults to certain bacterial and viral infections cannot be attributed to a deficiency in the potential of infant cells to secrete gamma-IFN in vitro.