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Biomedical subjects

M Graham

Publications and source records attributed to M Graham.

At least 73 records · Page 4Linked to original sources
PubMed1994

Double modulation of 5-fluorouracil in the treatment of advanced colorectal carcinoma: report of a trial with sequential methotrexate, intravenous (loading dose) folinic acid, 5-fluorouracil, and a literature review.

5-Fluorouracil (5-FU) modulation with either folinic acid (FA) or methotrexate (MTX) has improved 5-FU's potential cytoreductivity. We combined MTX and FA with 5-FU to further augment 5-FU's cytoreductivity. Patients (n = 34) with advanced colorectal carcinoma were first given intravenous MTX (escalated from 30 mg/m2 to 70 mg/m2). FA (100 mg/m2) was infused 17-24 hr later, followed by 5-FU (600 mg/m2). Oral rescue doses of FA were begun 24 hr after MTX. Patients were treated every 2 weeks. No previously treated patient (n = 6) responded. Eight of the remaining 28 (29%) (95% confidence interval, 15-47%) patients achieved a PR. Median survival was 9.3 months. Toxicity (primarily gastrointestinal) necessitated dosage modification in 10 patients (29%). These results, in addition to a literature review, reveal that the manipulation of 5-FU by two modulating agents does not improve the response rate seen with single-agent modulation.

Adult↗
PubMed1994

The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation.

Over the past 6 years, umbilical cord blood has emerged as an efficacious alternative source of hematopoietic stem cells in related bone marrow transplantation. These encouraging results led us to extend this technology to the mismatched related and unrelated settings in three high-risk leukemic children lacking a matched-related donor for transplantation. Two of the three children also lacked identifiable donors through the National Marrow Donor Program, while the third was in relapse and did not have time to wait for completion of a search. The first child was transplanted with haploidentical umbilical cord blood-derived mononuclear cells from his sister, while the remaining two children were transplanted with partially mismatched, unseparated, unrelated umbilical cord blood banked through the Placental Blood Project at the New York Blood Center. All three children demonstrated trilineage engraftment with donor cells within 6 weeks of transplantation. The patient transplanted with haploidentical marrow developed grade 2 graft vs. host disease (GVHD), which was controlled with steroid and anti-thymocyte globulin (ATG) therapy. One of the two patients grafted with unrelated umbilical cord blood developed mild grade 1 GVHD of the skin, which rapidly cleared with steroid therapy. One patient remains alive, in good health and disease-free 12 months from transplantation.

Acute Disease↗
PubMed1993

Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

BACKGROUND: To prevent drug resistance, the authors designed a protocol that featured early intensive rotating drug pairs as part of the therapy for acute lymphoblastic leukemia (ALL). METHODS: After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were given in 30 weeks: A--intermediate-dose methotrexate (IDMTX) plus intermediate-dose mercaptopurine (MP); B--cytosine arabinoside (AC) plus daunorubicin (DNR); C--AC plus teniposide (VM-26). Triple intrathecal chemotherapy (AC, MTX, and hydrocortisone) was given for central nervous system (CNS) prophylaxis. Continuation therapy consisted of weekly MTX and daily MP until 2.5 years of continuous complete remission had been achieved. RESULTS: Seventy-four children (age range, 1-19 years) at high risk of relapse were treated. Of 55 with B-lineage (early pre-B, pre-B) ALL, 24 have failed (2 induction failures, 2 deaths from infection, and 20 relapses). The event-free survival (EFS) rate at 4 years was 55.5% (standard error [SE] +/- 7.7%). Of 19 patients with T-cell ALL, 12 have failed (2 induction failures and 10 relapses). The EFS rate at 4 years was 32.6% (SE +/- 26.8%). Toxicities were significantly more common after AC and DNR or AC and VM-26 than IDMTX and MP. There were no toxicity-related deaths during intensive treatments. CONCLUSION: Early intensive rotating therapy is tolerable and warrants consideration for additional trials of patients with high-risk, B-lineage ALL.

Administration, Oral↗
PubMed1993

The potential value of integral membrane proteins in the vaccination of lambs against Haemonchus contortus.

An extract of adult Haemonchus contortus enriched in the parasite's intestinal microvillar membrane protein H11 and other integral membrane proteins but free of the protein contortin was evaluated as a potential vaccine in two breeds of sheep. The worm burdens of Clun Forest sheep injected with the extract and challenged with 25,000 infective larvae were reduced 89% by weight compared to the average for the controls. The worm burdens of Dorset sheep (challenged with 10,000 infective larvae) were reduced 72%. In both breeds the reduction in the number of female worms, 92 and 71.8%, respectively, was greater than the reduction in the males (86.5 and 46%). Parasite egg output, determined only for the Dorsets, was reduced 92% protection correlated with serum antibody titre. Most of the antibodies were directed against H11.

Animals↗
PubMed1993

Purification and evaluation of the integral membrane protein H11 as a protective antigen against Haemonchus contortus.

A detergent extract of adult Haemonchus contortus enriched in the integral membrane protein H11, previously shown to give protective immunity against the parasite, was fractionated by lectin and ion-exchange chromatography. The fractions were evaluated for their ability to immunize Clun Forest and Dorset Horn sheep against experimental haemonchosis. Most of the protective activity was associated with H11. Used in an approximately 95% pure form it gave a mean reduction in parasite egg output of 94.6% and reduced male and female worm numbers by 86.5 and 93.5%, respectively. Level of protection correlated with serum antibody titre to H11.

Animals↗
PubMed1993

Vaccination of merino lambs against haemonchosis with membrane-associated proteins from the adult parasite.

Groups of South African, farm-reared merino lambs about 4 months old were vaccinated with extracts of adult Haemonchus contortus enriched with H11, an integral membrane protein from the parasite's intestinal microvilli, or with proteins soluble in Tween 20. The lambs were challenged with 5000 infective 3rd-stage larvae. Compared to the adjuvant-injected controls, lambs vaccinated with 350 micrograms/kg liveweight of the H11-enriched extract showed an 89% reduction in parasite egg production and an 88% reduction in total worm burden at post-mortem 35 days post-challenge. The H11-enriched extract contained some protein also present in the Tween 20 extract. Lambs vaccinated with 600 micrograms/kg of protein soluble in Tween 20 showed a 40% reduction in faecal egg counts and 51% reduction in total worm numbers 35 days post-challenge. Animals injected with 20 micrograms/kg of a sub-fraction containing H11 obtained from the H11 extract, showed a 71% reduction in egg output and total worm numbers.

Animals↗
PubMed1993

Effects of acute and chronic alprazolam treatment on cerebral blood flow, memory, sedation, and plasma catecholamines.

The effects of 0.014 mg/kg intravenous alprazolam administration on cerebral blood flow (CBF), memory, sedation, and plasma norepinephrine and epinephrine were determined in eight healthy males at baseline levels and following 1 week of daily oral alprazolam treatment. At baseline, intravenous alprazolam administration caused acute reductions in whole-brain CBF (25% to 30% decrease), memory, plasma epinephrine, and self-rated alertness. Following 1 week of alprazolam treatment, tolerance developed to the acute effects of intravenous alprazolam on CBF, memory, and plasma epinephrine. There were no consistent regional neuroanatomic differences in the CBF effects of acute alprazolam, or in the development of tolerance to these effects, and no correlations between the various measures of acute alprazolam effects on either test day.

Administration, Oral↗
PubMed1993

Phase I dose-escalation trial of iodine 131-labeled monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma.

PURPOSE: Eighteen patients with recurrent or refractory CD21-positive, non-Hodgkin's lymphoma (NHL) were treated in a phase IA dose-escalation therapeutic trial of iodine 131 labeled to a fixed dose of OKB7. METHODS: Individual doses of 30 to 50 mCi of 131I on 25 mg OKB7 were administered 2 to 3 days apart to achieve four total 131I-OKB7 dose levels of 90, 120, 160, and 200 mCi. Pharmacology, dosimetry, therapeutic effects, toxicity, human anti-mouse antibody (HAMA) response, and maximum-tolerated dose (MTD) were determined. Patients were evaluated by imaging studies (including whole-body gamma camera or single-photon emission computed tomography [SPECT] scans), flow cytometric analysis, bone marrow biopsy, and serial blood sampling. RESULTS: Median plasma and whole-body half-lives (T1/2) were 16 hours and 14 hours, respectively. Plasma and whole-body radiation doses were 0.0081 Gy/mCi and 0.0022 Gy/mCi, respectively. Specific tumor visualization was noted in eight of 18 patients. HAMA was detected in 12 of 16 patients. Nonhematologic toxicity was limited to asymptomatic elevations of thyroid-stimulating hormone (TSH) in five of 15 patients. Hematologic toxicity was observed in six of 18 patients, but was severe in only two patients. MTD in patients with diffuse lymphomatous bone marrow involvement was determined to be 200 mCi in four divided doses of 50 mCi 131I/25 mg OKB7. Antitumor activity was observed in 13 of 18 patients (one partial response [PR] and 12 mixed responses) and was dependent on the 131I-OKB7 dose administered. In general, palpable peripheral lymphadenopathy, enlarged spleens, skin lesions, and circulating OKB7-positive peripheral lymphocytes responded most readily to treatment. 131I-OKB7 was safely administered to a patient in leukemic phase of NHL with prompt subsequent loss of approximately 1 kg of tumor cells from the peripheral blood without associated tumor lysis syndrome. CONCLUSION: Because antitumor activity with tolerable toxicity was observed in the majority of this group of heavily pretreated patients, phase II investigation of mAb OKB7 radioconjugates in the therapy of NHL is warranted.

Adult↗
PubMed1993

The effect of coffee consumption on serum cholesterol levels.

OBJECTIVE: Studies investigating the association of coffee consumption and serum cholesterol levels report conflicting results. In an attempt to resolve this controversy, we reviewed the literature to answer the question: Is there a true positive association between coffee consumption and serum cholesterol levels? DATA SOURCES: A Medline database search dating back to 1965 was utilized. Key words used in the search were coffee, caffeine and cholesterol. Cholesterol was expanded to include lipoproteins and LDL-, HDL- and VLDL-cholesterol. All articles that presented cholesterol data in association with coffee consumption were examined for references missed by Medline. Recently published articles were located by a hand search through Current Contents and the latest monthly editions of Index Medicus. STUDY SELECTION: Three reviewers made the decision to include all publications that met the following criteria: a) reported original experimental results; b) reported total serum cholesterol levels; and c) were published in peer-reviewed journals. DATA EXTRACTION: Two to four articles were read and analyzed each week in chronological order. Independent data extraction was performed by three reviewers, who then met as a group once a week to cross-check the analyses. DATA SYNTHESIS: A trend, representing the association between coffee consumption and serum cholesterol, was calculated for each study. The trend was based on the percent difference in cholesterol values between subjects drinking four or more cups of coffee per day in comparison to those drinking zero or less than one cup of coffee each day. In order to compare studies that reported different cup sizes and different levels of intake, weighted mean cholesterol levels were calculated. In studies discussing the data in terms of correlations, trends were established according to the r values provided by the authors. CONCLUSIONS: The majority of studies demonstrated a positive trend in at least one subpopulation of their subjects, indicating that serum cholesterol levels increase with increasing coffee consumption. Stronger trends were seen among subjects drinking boiled coffee than in those drinking filtered, decaffeinated or instant coffee. However, most studies were not randomized clinical trials, and results can be countered by a number of biases prevalent in the studies, indicating the need for additional well-designed investigations to resolve remaining issues.

Bias↗
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↗