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Biomedical subjects

M Graham

Publications and source records attributed to M Graham.

At least 19 recordsLinked to original sources
PubMed1992

Measurement of blood-brain barrier permeability in a tumor model using magnetic resonance imaging with gadolinium-DTPA.

Sequential MR imaging with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and sequential measurements of plasma Gd-DTPA concentration by inductively coupled plasma atomic emission spectroscopy (ICP-AES) were used to estimate the blood-to-tissue transport coefficient (Ki) in the 36B-10 rat glioma model. For these measurements, tissue Gd-DTPA concentration was estimated from tumor enhancement by correlation with calibration measurements obtained by ICP-AES analysis of tumor tissue. The 14 animals for which Ki was calculated can be grouped into those imaged at 11 days following tumor implantation, at 13-18 days, and at 20 days. The mean (+SEM) Ki values for these groups were 1.1 + 0.24, 9.2 + 0.8, and 13.4 + 1.7 ml/kg-min, respectively. These results correspond well with published data obtained by quantitative autoradiography. It is concluded that frequent sequential imaging and a graphical approach to Ki calculation are promising methods for determining the blood-to-tissue transport coefficient noninvasively by contrast-enhanced MRI.

Animals↗
PubMed1992

Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues.

The expression of basic fibroblast growth factor (bFGF) and two of its receptors, FGFR1 and FGFR2, was detected using the polymerase chain reaction, and quantified by comparison to the relative amount of product obtained following co-amplification of the ubiquitous glyceraldehyde phosphate dehydrogenase transcript. Varying levels were found in the vast majority of both cancer and non-malignant breast biopsies as well as in samples of several other normal human tissues. Significantly less bFGF was present in cancers (P less than 0.0001). Similarly, FGFR2 product was also much less in cancer tissues (P = 0.0078), as was FGFR1 (P = 0.002). FGFR1 levels in cancers tended to be higher in those which were oestrogen receptor positive (P less than 0.06). Amplification of different coding regions showed evidence of variant forms of FGFR1 RNA. Cancers appeared to have a significantly greater proportion of PCR product corresponding to the region between the third immunoglobulin like domain and the tyrosine kinase domain (P = 0.046). Differential expression was observed in breast cell lines, with bFGF in the normal derived HBL100, HBR SV1.6.1 and 184A1 but little or none in ZR-75-1, MCF-7, T47D and MDA-MB-231. FGFR1 was present in most of these but FGFR2 was absent from T47D, MDA-MB-231 and HBL100. ZR-75-1 cells had a marked preponderance of FGFR1 variants lacking part of the coding sequence. Aberrant receptor processing may provide clues concerning the role of FGF's and their potential involvement in malignancy.

Aged↗
PubMed1992

Vaccination of young Dorset lambs against haemonchosis.

Six Dorset Horn lambs were each vaccinated at age 7 weeks and 9 weeks with 50 micrograms of glycosylated integral membrane proteins, particularly enriched in the protein H11 from the intestinal brush border of adult Haemonchus. At 11 weeks of age the lambs were infected with 10,000 infective third stage Haemonchus larvae. Compared with the average for the control group the vaccinated group of lambs had a 78% reduction in parasite egg output over the patent period, with four of the six better than 93% protected. At autopsy 35 days post-infection the mean total worm burden of the vaccinated lambs was 83% reduced compared with the controls. The serum antibody titres to H11 correlated with the degree of protection.

Animals↗
PubMed1992

Immune response of Clun Forest sheep to vaccination with membrane glycoproteins from Haemonchus contortus.

Clun Forest lambs were injected with a fraction containing integral membrane glycoproteins derived from the intestinal microvilli of Haemonchus contortus in two equal doses of 0.5, 5, 50 or 500 micrograms protein and then challenged with 10,000 infective larvae. The time-course of serum specific antibody responses were determined. Compared to the adjuvant control group, the animals injected with 1000 micrograms protein were better than 84% protected and those injected with 100 micrograms, better than 95% protected by all criteria. For these two groups parasite egg output was reduced 99% on average over the patent period. Two of the animals injected with 10 micrograms protein were partially protected, with 86% reduction in egg output. Two animals in the group injected with 1 microgram protein also showed partial protection. Antibody level correlated with protection.

Animals↗
PubMed1992

Somatosensory evoked potentials and outcome in perinatal asphyxia.

Somatosensory evoked potentials (SEP) can be measured in the term newborn infant and given an index of function in the areas of the brain most likely to be damaged in perinatal asphyxia. We studied the median nerve SEP in 30 asphyxiated term infants over the course of their encephalopathy and until discharge from the neonatal unit. Three types of response were noted: normal waveform, abnormal waveform, or absence of cortical response. Follow up of the survivors was undertaken at a mean age of 12 months by means of a Griffiths' assessment and neurological examination. Nine infants died of their asphyxial illness and one of spinal muscular atrophy. Of the 20 survivors, three have cerebral palsy, four have minor abnormalities, and 13 are neurodevelopmentally normal. There was a close correlation between outcome and SEP. All 13 infants with normal outcome had normal SEP by 4 days of age, whereas those with abnormal or absent responses beyond 4 days had abnormalities at follow up.

Asphyxia Neonatorum↗
PubMed1992

Impaired motor function (clumsiness) in 5 year old children: correlation with neonatal ultrasound scans.

All 155 surviving children from a cohort of 200 very low birthweight infants originally studied in 1984-5 were traced. These infants had careful sequential ultrasound examinations in the neonatal period. The children were examined again at entry into school at 5 years of age. The test of motor impairment (TOMI) and the vocabulary subscale of the Wechsler preschool and primary scale of intelligence (WPPSI) were administered to 152 of the index cohort and 144 control children of the same age in the same class at school. Twelve of the cohort had cerebral palsy, but eight of these were in mainstream schools. The index group scored significantly higher on both the TOMI and the WPPSI subscale compared with the controls. The index cases were subdivided on the basis of their neonatal ultrasound scans into four groups: group 1, consistently normal; group 2, 'prolonged flare'; group 3, germinal matrix haemorrhage-intraventricular haemorrhage (GMH-IVH), without parenchymal haemorrhage, but no evidence of prolonged flare; and group 4, both GMH-IVH and prolonged flare. The group of index children with consistently normal ultrasound scans had a higher TOMI and lower WPPSI compared with their controls. There was a statistically significant increase in the TOMI subscore 1 (manual dexterity) in group 4 infants compared with group 1, but not differences between the other groups. Regression analysis suggests that neither prolonged flare nor GMH-IVH has an important individual contribution to the variation, but the low birth weight does have a significant relationship with motor impairment. It appears that relatively minor ultrasound appearances such as prolonged flare and GMH-IVH are associated with motor impairment (clumsiness) at 5 years, but this has a small effect compared with low birth weight.

Cerebral Palsy↗
PubMed1992

Islet-reactive T cells are a marker of preclinical insulin-dependent diabetes.

The destruction of pancreatic islet beta cells in insulin-dependent diabetes mellitus (IDDM) is thought to be T cell mediated. To directly identify islet-reactive T cells in asymptomatic, "preclinical" IDDM individuals with islet cell antibodies (ICA), proliferation of peripheral blood mononuclear cells (PBMC) was measured in the presence of sonicated fetal pig proislets. Stimulation indices (mean +/- SD) for [3H]thymidine uptake by PBMC cultured with sonicated proislets were: preclinical IDDM subjects (n = 22) 6.10 +/- 6.50, recent-onset IDDM subjects (n = 29) 3.66 +/- 3.35, Graves' disease subjects (n = 6) 2.17 +/- 0.93, scleroderma subjects (n = 4) 1.65 +/- 0.19 and normal control subjects (n = 14) 1.63 +/- 0.62. 68% (15/22) of preclinical IDDM, 41% (12/29) of recent-onset IDDM and 17% (1/6) of Graves' disease subjects had T cell reactivity greater than the mean + 2 SD of controls. T cell reactivity to proislets was tissue specific, and greater in magnitude and frequency than to human insulin. The majority of preclinical subjects with ICA greater than 20 Juvenile Diabetes Foundation (JDF) units (12/15, 80%) or antibodies to a 64-kD islet autoantigen (11/15, 73%) had significant T cell reactivity to proislets. ICA greater than 40 JDF units, a strong prognostic marker for progression to clinical IDDM, was an absolute index of T cell reactivity. Overall, the frequency of T cell reactivity in preclinical subjects, 68% (15/22), was comparable to that of ICA greater than 20 JDF units or 64-kD antibodies. Greater T cell reactivity to proislets in preclinical subjects accords with the natural history of autoimmune beta cell destruction. The direct assay of islet-reactive T cells in peripheral blood may have prognostic significance for the development of clinical IDDM and should facilitate identification of the primary target autoantigen(s).

Adolescent↗
PubMed1991

Membrane topology of Escherichia coli prolipoprotein signal peptidase (signal peptidase II).

The lsp gene of Escherichia coli encodes the inner membrane enzyme, signal peptidase II (SPase II). SPase II is comprised of 164 amino acid residues and contains four hydrophobic domains. A series of lsp-phoA and lsp-lacZ gene fusions have been constructed in vitro to determine the topology of SPase II. The fusion junction for each of these gene fusions was determined by DNA sequencing. The lengths of the SPase II fragment in the fusions varied from 12 to 159 amino acid residues. Strains containing SPase II-PhoA fusions to the two predicted periplasmic loops exhibited higher levels of alkaline phosphatase activity than fusions to the predicted cytoplasmic domains. In contrast, SPase II-LacZ fusions at the cytoplasmic and the periplasmic domains of SPase II showed high and low levels of beta-galactosidase activity, respectively, a result opposite to those shown by SPase II-PhoA fusions located at precisely the same amino acid of SPase II. Taken together, these results strongly support the predicted model for SPase II topology, i.e. this enzyme spans the cytoplasmic membrane four times with both the amino and the carboxyl termini facing the cytoplasm.

Amino Acid Sequence↗
PubMed1991

Carotid endarterectomy in a community hospital: a change in physicians' practice patterns.

A total of 243 consecutive carotid endarterectomies (CEA) performed at Providence Medical Center in Portland, Oregon, were retrospectively reviewed over a 22-month period. Of these, 137 patients (56%) underwent CEA for asymptomatic disease, 52 (37%) of whom had stenotic lesions of 79% or less. There were 6 deaths (3%) and 12 strokes (5%). Four strokes were in asymptomatic patients. These data prompted development of criteria for CEA: (1) hemisphere-specific transient ischemic attacks, reversible ischemic neurologic deficits, or amaurosis fugax with an appropriate carotid lesion; (2) completed stroke with major recovery and significant carotid stenosis; (3) asymptomatic lesion with greater than 80% stenosis (D+) either by carotid arteriogram or non-invasive lab evaluation; and (4) other indications only with a supporting second opinion from a disinterested vascular surgeon, neurosurgeon or neurologist. A prospective review followed institution of the guidelines. In 21 months, 148 operations were performed, a 36% reduction over the initial study period. Of these, 46 (31%) were for asymptomatic lesions. Two patients (4%) did not fulfill the guideline criteria. There were six strokes (4%) and no deaths. The reduction of CEAs appears to be related to a significant decrease in "inappropriate" operations being performed. Surgeons' familiarity with the data rather than external pressures seems to be the major factor in changing practice patterns. The decrease in stroke/death rate is not statistically significant.

Aged↗
PubMed1991

Mitomycin-C/5-FU and radiation therapy for locally advanced uterine cervical cancer.

To assess the feasibility and effectiveness of combined therapy on locally advanced cervical cancer, we entered 38 patients into a study. The patients were treated with mitomycin-C (10 mg/m2) on Days 1 and 30 and 5-FU (1000 mg/m2) on Days 1 to 4 and Days 30 to 33. In 5 weeks 4500-5000 cGy was given concurrently, followed by radioactive implants. Twenty-six patients had an early-stage disease (IB-IIB) and twelve had a late-stage disease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring 5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-proven positive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response, complete (CR) vs partial (PR), was assessed in 36 patients 3 months after completion of therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic disease control (PDC), disease-free survival (DFS), and survival (S) while late stage correlated with the development of distant metastases (DM) and a poor DFS. PDC was obtained in 93% (27/29) of the patients who had a CR, as compared to only 43% (3/7) of those with a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for those with a PR; respective P values were 0.0340 and 0.0002. Eleven percent (3/26) of the patients with an early stage developed DM, as compared to 50% (6/12) of those with late stage, (P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developed transient neutropenia and one had transient thrombocytopenia. The second dose of mitomycin-C was omitted in 4 patients due to persistent neutropenia in 3 and to transfusion-related hepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence. Three patients developed non-cancer-related small bowel obstruction requiring surgery. We concluded that this combined regimen was well tolerated. Although it was effective in controlling the cancer in the pelvis, this regimen failed to control DM in late-stage patients.

Adult↗
PubMed1991

Technical challenges associated with the radiolabeling of monoclonal antibodies utilizing short-lived, positron emitting radionuclides.

Many factors, both physical and chemical, affect the radiolabeling of a chemical compound. These factors add a new dimension of complexity when the labeling of monoclonal antibodies is attempted with short-lived, positron emitting radionuclides. A lack of appreciation for the unique chemical separations associated with the radionuclide incorporated into the synthetic precursor can often lead to unexpected or non-reproducible results.

Antibodies, Monoclonal↗
PubMed1991

The differential expression of protein kinase C genes in normal human neonatal melanocytes and metastatic melanomas.

Expression of protein kinase C (PKC) genes (alpha, beta, gamma and epsilon) was measured in cultured normal human neonatal melanocytes and metastatic melanoma cell strains. Three of the PKC isotypes (alpha, beta and epsilon) were constitutively expressed in neonatal melanocytes. Protein kinase C beta RNA transcripts were induced in neonatal melanocytes cultivated in medium with serum and 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, PKC alpha and epsilon RNA transcripts were detected in melanocytes cultivated in medium without serum and TPA, but were repressed in melanocytes cultivated in medium with serum and TPA. Only PKC alpha and epsilon RNA transcripts were detected in the melanoma cell strains and the PKC RNA transcript expression levels varied among the five metastatic melanomas. In four metastatic melanoma cell strains, PKC alpha and epsilon RNA transcript expression levels were repressed by serum, but in one melanoma cell strain, PKC alpha and epsilon RNA transcript expression levels were induced by serum. Protein kinase C gamma RNA transcripts were not detected in either the melanocytes or melanoma cell strains. These data suggest an alteration of PKC isotype gene expression in the progression of primary melanocytes to metastatic melanoma. The absence of the PKC beta RNA transcripts and altered expression of PKC alpha and epsilon isotypes in particular may be a feature in the transformation of human primary melanocytes.

Gene Expression↗
PubMed1990

31P NMR spectra of extremity sarcomas: diversity of metabolic profiles and changes in response to chemotherapy.

We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.

Animals↗
PubMed1990

The metabolic effects of aspirin in fasting and fed subjects: relevance to the aetiology of Reye's syndrome.

As a possible model for the mechanism of precipitation of Reye's Syndrome in children the metabolic effects of oral aspirin were studied in normal subjects in the fasted and fed states, to determine whether aspirin altered fatty acid oxidation. Starvation increased blood 3-hydroxybutyrate concentrations, but aspirin had no effect on this or other metabolite concentrations in either the fasted or fed states.

3-Hydroxybutyric Acid↗
PubMed1990

Frequency and duration of handwashing in an intensive care unit.

The effects on hand decontamination of the introduction of an antiseptic handrub lotion in an intensive care unit was studied. To obtain baseline data, nursing, medical, physiotherapy, radiology, and orderly staff members were observed. Further observations were carried out after the introduction of the handrub lotion. Patient care activities were classified as high or low, according to the degree of contact with the patients or their equipment. A total of 884 patient contacts and 341 hand decontamination episodes was observed: 440 contacts and 140 handwashes in stage one (32%) and 444 contacts and 201 handwashes in stage two (45%). There was an increase of 13% in hand decontamination frequency after the introduction of the handrub lotion. The data indicate that the frequency of hand decontamination is below levels recommended by infection control authorities. Increasing the accessibility of hand decontamination facilities did result in a slight increase in handwashing compliance.

Cross Infection↗
PubMed1990

Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity.

Lymphokine activity in seven myelin basic protein (MBP)-specific T cell clones was examined. All of the clones recognize MBP peptide 1-9 in the context of I-Au. A strong positive correlation was found between levels of lymphotoxin (LT) and tumor necrosis factor alpha (TNF-alpha) mRNA and biological activity on L929 cells and their capacity to induce paralysis, the clinical hallmark of experimental allergic encephalomyelitis (EAE). No correlation was found between interleukin-2 or gamma interferon production and encephalitogenicity. LT and/or TNF-alpha may play a central role in the pathogenesis of EAE.

Animals↗
PubMed1990

A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression.

Eighteen patients with relapsed non-Hodgkin's lymphoma (NHL) were infused with escalating doses of monoclonal antibody (mAb) OKB7, trace-labeled with iodine-131 (131I), in order to study toxicity, pharmacology, antibody localization, and dosimetry of radioiodine. OKB7 is a noncytotoxic mouse immunoglobulin G2b (IgG2b) mAb reactive with B cells and most B-cell NHL. Three patients each were treated at six dose levels ranging from 0.1 mg to 40 mg. All patients had radionuclide imaging and counting daily, had serial blood sampling to study pharmacokinetics, human antimouse antibody (HAMA), and circulating antigen, and had a biopsy of accessible lymphoma to determine delivery of isotope to tumors and assess the effect of tumor antigen expression on mAb delivery. Bone marrow biopsies were also done in the majority of patients. There was no toxicity. Serum clearance showed a median early phase half-life of 1.9 hours and a later phase half-life of 21.7 hours. Median total body clearance half-life was 22 hours. Pharmacokinetics were not dose-related. HAMA was detected in five patients. Circulating blocking antigen was detected in the serum of four patients, but at levels that were of pharmacologic consequence only in one. Biopsied tumor tissue from five patients did not express OKB7 antigen. No significant uptake of antibody was seen in these tumor sites. Mean total uptake of isotope into lymphoma measured in biopsies correlated linearly over the 400-fold increase in injected mAb dose. However, the percent of injected dose found per gram of tumor was unrelated to dose, but correlated inversely with tumor burden. In two patients with minimal tumor burden, 1.0 mg and 5.0 mg doses of OKB7 resulted in tumor to body radioisotope dose ratios of 22 and 7, which would theoretically permit tolerable delivery of 4,400 and 1,400 rads to these tumors, respectively, if OKB7 were conjugated with higher doses of 131I.

Adult↗