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Biomedical subjects

R A Graham

Publications and source records attributed to R A Graham.

At least 37 records · Page 2Linked to original sources
PubMed1994

A method for calculating the distribution of pH in tissues and a new source of pH error from the 31P-NMR spectrum.

The true distribution of the pH in tissues can be determined from the in vivo 31P-nuclear magnetic resonance (NMR) spectrum by converting the parts per million (PPM) axis of the pH responsive resonance to pH using the Henderson-Hasselbalch equation. In addition, the intensity axis of the resonance must be divided by the derivative of the Henderson-Hasselbalch equation to correct for the nonlinear relationship between pH and PPM. This nonlinear relationship causes the apparent center of the resonance in PPM to be dependent not only on the center of the pH distribution but also on its width and distance from the pKa, where Ka is the association constant. Therefore, the pH determined from uncorrected spectra may be in significant error, particularly if the pH distribution is distant from the pKa and is broad. The method was applied to the isolated perfused Morris hepatoma 5123C to determine the distribution of intracellular pH (pHi) using resonances from two intracellular compounds. The two resonances did not report the same pHi unless the spectral data were properly corrected. The method should be of interest to anyone interested in pHi.

Animals↗
PubMed1994

The polymorphic epithelial mucin MUC1 in human endometrium is regulated with maximal expression in the implantation phase.

After ovulation, progesterone stimulates a temporally regulated secretory transformation in human endometrial epithelium. Using a combination of immunohistochemistry, and Western and Northern blotting, we demonstrate that 1) the polymorphic epithelial mucin MUC1 is secreted by human endometrial epithelium; 2) low levels of both mRNA and core protein are present in the preovulatory phase of the menstrual cycle; 3) mRNA levels increase several-fold after ovulation, consistent with transcriptional regulation by progesterone; 4) there is an increase in translation product in postovulatory endometrium; and 5) the tandem repeat domain of the MUC-1 polypeptide is glycosylated in endometrium.

Antibodies, Monoclonal↗
PubMed1994

The efficacy of specimen radiography in evaluating the surgical margins of impalpable breast carcinoma.

OBJECTIVE: The purpose of this study was to determine if the presence or absence of tumor at the surgical margin in cases of impalpable breast carcinoma could be predicted accurately with specimen radiography. MATERIALS AND METHODS: We obtained single-view radiographs of 119 consecutive surgical biopsy specimens of impalpable invasive or in situ ductal carcinoma. Radiographic lesions were classified as a mass with moderately well defined margins, a mass with poorly defined margins, or microcalcifications without an associated mass. The radiographic appearance of the impalpable cancer, the margin as judged from the specimen radiograph, the tumor's histologic appearance, and the histologic appearance of the tumor margin were then correlated. RESULTS: Specimen radiographs showed tumor at the surgical margin in 63 cases; 62 of these were confirmed histologically (positive predictive value, 98%). Specimen radiographs showed tumor-free surgical margins in 56 cases; 18 of these were confirmed histologically (negative predictive value, 32%). These results were independent of the radiographic appearance of the lesion or the tumor's histologic appearance. CONCLUSION: Decisions based on findings on specimen radiographs were valid only if the radiographs showed tumor at the margin of the specimen.

Biopsy↗
PubMed1992

Regional DNA content heterogeneity in colonic adenocarcinoma: prognostic significance in patients with liver metastases.

We retrospectively examined by flow cytometry the DNA ploidy pattern in tissue blocks from 25 primary colon adenocarcinomas and their lymph node and liver metastases. Intratumoral heterogeneity was present in 22% of primary tumors and 21% of metastatic liver deposits. Intertumoral heterogeneity, measured between the primary tumor and its lymph node and liver metastases, was 0% and 20%, respectively. Of 24 patients who underwent successful resection of their liver metastases, 8 neoplasms had uniformly diploid DNA content, while 16 tumors had aneuploid DNA pattern in either the primary tumor, the metastases, or both. Five-year survival was better in the diploid group (38% vs. 7%, P = 0.10 by log rank analysis). Three of eight patients in the diploid group remain free of disease, while all 16 patients with aneuploid cell populations have died of recurrent disease.

Adenocarcinoma↗
PubMed1992

Endometrial responses in artificial cycles: a prospective study comparing four different oestrogen dosages.

OBJECTIVE: To examine the endometrial response to four different regimens of oestrogen. DESIGN: A prospective, randomized cross-over study. SETTING: Jessop Hospital for Women, Sheffield. SUBJECTS: Twenty one women with premature ovarian failure divided into three equal groups. INTERVENTIONS: Four different regimens of hormone replacement therapy: variable, fixed 1 mg, fixed 2 mg and fixed 4 mg oestrogen dosages. Each woman received the variable dosage regimen in one cycle and crossed over to receive one of the three fixed dose regimens (1 mg, Group 1; 2 mg, Group 2; 4 mg Group 3) in another cycle. MAIN OUTCOME MEASURE: Ultrasonographic measurement of endometrial thickness and outpatient endometrial biopsy on day 19 of the artificial cycle; analysis of endometrial specimens by three separate methods: traditional histological criteria, morphometry and immunohistochemistry. RESULTS: The endometrial response was similar in those treated with the variable and the fixed 2 mg or 4 mg dosage regimens. The response was suboptimal in those treated with the fixed 1 mg dosage regimen. CONCLUSIONS: Normal endometrial development requires adequate priming of the endometrium by oestrogen, which may be administered in a sequential, variable dosage fashion, or simply by a fixed daily dosage regimen. However, the minimum daily dose required is likely to be 2 mg of oestradiol valerate. No adverse effect on the endometrium was observed at a daily dose of 4 mg oestradiol valerate, which produced plasma levels of oestradiol above the reference ranges of the natural cycle.

Adult↗
PubMed1991

Cyclic hydrolase-transfected 3T3 cells have low levels of inositol 1,2-cyclic phosphate and reach confluence at low density.

The cDNA that encodes inositol-1,2-cyclic phosphate 2-phosphohydrolase (cyclic hydrolase), an enzyme that converts inositol 1,2-cyclic phosphate (cIns(1,2)P) to inositol 1-phosphate, was expressed in 3T3 cells to investigate the function of inositol cyclic phosphates. Cells with increased cyclic hydrolase activity had lower levels of cIns(1,2)P and grew to a lower density at confluence than control cells. This relationship was strengthened by the demonstration that several cell types with differences in cyclic hydrolase activity had levels of cIns(1,2)P and saturation densities that also correlated inversely with cyclic hydrolase activity. In addition, cyclic hydrolase activity is higher in cells at confluence compared to subconfluence. These results suggest that cellular cIns(1,2)P levels are determined by cyclic hydrolase activity and play a role in the control of cell proliferation.

Animals↗
PubMed1991

An ex vivo model for the study of tumor metabolism by nuclear magnetic resonance: characterization of the phosphorus-31 spectrum of the isolated perfused Morris hepatoma 7777.

We have developed an isolated perfused tumor model to study the metabolism of solid tumors by nuclear magnetic resonance spectroscopy. Morris hepatomas (7777) were implanted in the inguinal region of Buffalo rats, such that they developed an isolated blood supply. These tumors were perfused with a RBC perfusate, removed from the animal, and studied by 31P nuclear magnetic resonance spectroscopy. ATP levels, as determined from the spectra, were stable for as long as the tumors were maintained in the magnet (7 h) only if the perfusate contained inosine, adenosine, and insulin. The adenosine and inosine were also required for recovery from ischemia. Under these conditions, ischemia did not result in a change in tumor pH. The gamma nucleoside triphosphate resonance was significantly larger than the beta nucleoside triphosphate resonance in spectra of some of the perfused tumors, suggesting that ADP above about 300 nmol/g wet weight was not complexed in these tumors. The adenylate levels determined from extracts, O2 consumption, histology, and 31P nuclear magnetic resonance spectra of extracts of perfused tumors and tumors in situ were all similar, indicating the perfused tumor is a reasonable model of the tumor in vivo.

Adenosine Diphosphate↗
PubMed1991

The effects of the antiprogesterone RU486 (Mifepristone) on an endometrial secretory glycan: an immunocytochemical study.

OBJECTIVE: To examine the effects of progesterone (P) receptor blockade by RU486 (Mifepristone; Roussel-Uclaf, Paris, France) on a secretory endometrial glycan recognized by monoclonal antibody D9B1. DESIGN: Retrospective comparison of endometrial biopsies from treated and untreated women from 2 to 8 days after the luteinizing peak (LH) peak. SETTING: Infertility clinic, Jessop Hospital for Women, Sheffield. PATIENTS: Twenty-two normal fertile women received the RU486. A control group of 44 normal fertile women were also assessed. INTERVENTIONS: RU486 was administered to 22 normal women during the first half of the luteal phase and an endometrial biopsy examined 3 days later. MAIN OUTCOME MEASURES: Immunohistochemistry was used to assess the production and secretion of the D9B1 epitope. RESULTS: When the drug was given 2 days after the LH peak, it prevented appearance of the epitope. When RU486 was administered 5 days after the LH peak, epitope already present in gland cells was subsequently secreted. CONCLUSIONS: These data suggest that production of the sialo-oligosaccharide is P-dependent, but secretion through established intracellular pathways is P-independent.

Adult↗
PubMed1990

An endometrial factor in unexplained infertility.

OBJECTIVE: To study a group of women with unexplained infertility to see whether they have a defect that is intrinsic to the endometrium. DESIGN: Evaluation of the functional response of the endometrium by examining endometrial biopsy specimens using immunohistochemical methods in a group of women with unexplained infertility and in a control group of women with normal fertility. PATIENTS: 27 Women with unexplained infertility (average age 33.2); median duration of infertility five years. A control group of 44 women with normal fertility (average age 33.8) who were requesting sterilisation or reversal of sterilisation. SETTING: Infertility clinic, Jessop Hospital for Women, Sheffield. INTERVENTION: Secretory phase endometrial biopsy specimens were taken, with informed consent, as an outpatient procedure. MAIN OUTCOME MEASURES: Immunohistochemistry with monoclonal antibody D9B1, was used to assess the production and secretion of an oligosaccharide epitope produced by endometrial gland cells between two and seven days after the luteinising hormone surge. A reflected light measuring system was used to assess the amount of epitope within the gland cells, and in the gland lumen. RESULTS: In the control group of women, mean reflected light measurements at the cell base and cell apex peaked at three and five days after the luteinising hormone surge respectively, and in the gland lumen the epitope accumulated rapidly from three days, reaching a peak at seven days. In the women with infertility the peaks of epitope at the cell base and cell apex were lower, broader, and delayed in onset, and the build up of epitope in the gland lumen was retarded. The synthesis and secretion of the epitope in the women with infertility was therefore significantly reduced and delayed, even in the presence of normal concentrations of circulating progesterone. CONCLUSIONS: The results suggest that a primary dysfunction of the endometrium might be associated with hitherto unexplained infertility.

Adult↗
PubMed1990

Management of inguinal lymph node metastases from adenocarcinoma of the rectum.

Forty patients with inguinal lymph node metastases from rectal adenocarcinoma were reviewed. Patients were divided into three groups based on the extent of their disease: (1) patients with unresectable primary tumors; (2) patients with recurrent disease after abdominoperineal resection; and (3) patients with isolated inguinal lymph node metastases after abdominoperineal resection. Patients in Groups 1 and 2 underwent biopsy of their nodal metastases. Patients in Group 3 were treated by inguinal node dissection. Survival data were examined for each group, and four clinical and pathologic features were analyzed to determine their impact on prognosis: depth of invasion of the primary tumor (T1-2 vs. T3-4), number of positive lymph nodes in the rectal specimen (0-2 vs. greater than 2), extent of the inguinal lymph node metastases (unilateral vs. bilateral), and timing of the inguinal lymph node metastases (less than 1 vs. greater than 1 year after abdominoperineal resection). There were no five-year survivors in any group. Median survival was highest in those with isolated lymph node metastases, with 2 patients remaining free of disease, and was lowest in those with unresectable primary disease (7 months). Median survival was increased when inguinal LNM were unilateral (17 vs. 6 months; P less than 0.01) and when they occurred more than 1 year after abdominoperineal resection (21 vs. 7 months; P = 0.02). Stage of the primary lesion (depth of invasion and number of positive lymph nodes) did not affect survival. Of the 32 patients who underwent biopsy alone, only 1 developed a tumor-related groin complication. For patients with isolated inguinal lymph node metastases, inguinal node dissection is recommended for the purposes of local control and possible cure. For patients with extranodal disease, prophylactic excision of inguinal lymph node metastases is not warranted.

Adenocarcinoma↗
PubMed1990

Extracorporeal hemofiltration: a model for decreasing systemic drug exposure with intra-arterial chemotherapy.

Cisplatin (3 mg/kg) was infused through the hepatic artery in nine mongrel dogs. Four of these dogs underwent simultaneous extracorporeal hemofiltration (ECH) of the hepatic venous effluent using a high-flow, dual-lumen catheter placed in the vena cava at the level of the hepatic veins. Platinum levels were measured in the plasma, urine, and ultrafiltrate and in kidney and liver tissue. ECH significantly reduced systemic drug exposure as measured by the AUC for free and total platinum, by urinary excretion, and by 24-h kidney levels. Regional liver levels were minimally affected. Recovery of platinum in the ultrafiltrate was 40% +/- 14%. ECH resulted in efficient extraction of platinum and reduced systemic drug exposure with relative preservation of regional hepatic drug exposure.

Animals↗
PubMed1990

Local excision of rectal carcinoma.

Sixteen published series were reviewed in which local excision was used as definitive treatment for patients with invasive rectal carcinoma located within 6 cm of the anal verge. Ninety-four percent of tumors were T1 or T2 adenocarcinomas with no identified regional metastases. Five-year cancer-specific survival was 89%. Local recurrence was 19%, although more than half of these patients were cured with additional surgery. These results were comparable with those for historical controls treated with abdominoperineal resection (APR). Four pathologic features of the surgical specimen were analyzed to assess their correlation with patient outcome. Positive surgical margins, poorly differentiated histology, and increasing depth of bowel wall invasion were associated with increased local recurrence and decreased survival. Tumor size greater than 3 cm was not a significant factor. When criteria for appropriate patient selection are followed, local excision may provide survival and recurrence rates comparable with those achieved with APR with less morbidity and operative mortality.

Adenocarcinoma↗
PubMed1987

Observation of inositol pentakis- and hexakis-phosphates in mammalian tissues by 31P NMR.

In analyzing the 31P NMR spectra of extracts of mammalian tissues and cells we have identified inositol pentakis- and hexakis-phosphates in essentially all of the samples examined. These compounds were present at concentrations of at least 5-15 microM. While the sources and functions of these compounds in mammalian cells are not clear, they may play an important role in phosphoinositol metabolism. For example, one obvious possibility is that these compounds may be sources of or sinks for the Ca++ mobilizing inositol tris- and tetrakis-phosphates.

Animals↗
PubMed1987

Observation of myo-inositol 1,2-(cyclic) phosphate in a Morris hepatoma by 31P NMR.

We have identified an unusual resonance at 16.5 ppm in the 31P NMR spectrum of a Morris (7777) hepatoma grown in the inguinal fossa of a Buffalo rat as myoinositol 1,2-(cyclic) phosphate. This compound has been observed in all of the 32 tumors examined as well as in cultured cells derived from the tumor, but it has not been observed in normal rat tissues. Its level in the aqueous phase of chloroform/methanol/water extracts of the tumor is 70 +/- 40 nmol/g, wet weight (n = 4). The presence of a breakdown product of phosphatidylinositol at such high levels in a fast growing tumor may provide an important clue for understanding the metabolic defect that results in the malignant growth of this tumor.

Animals↗
PubMed1986

A comparison of imaging, clinical, and pathologic aspects of space-occupying lesions within the brain in patients with acquired immune deficiency syndrome.

Patients with acquired immune deficiency syndrome (AIDS) often have central nervous system mass lesions. Since clinical signs, symptoms, and results of imaging techniques are generally nonspecific, brain biopsy has been considered to be the optimal method for establishing a definitive diagnosis. In an effort to define better the imaging characteristics of such lesions, we retrospectively analyzed 24 patients with AIDS who had intracerebral space-occupying lesions, with subsequent definitive histologic diagnosis and/or a diagnostic response to empiric therapy for toxoplasmosis. We employed computerized tomography (CT), double-dose-delay CT (DDD-CT), and nuclear magnetic resonance imaging (NMRI) of the brain. Sixteen patients had toxoplasmosis, seven had high-grade non-Hodgkins lymphoma, and one had progressive multifocal leukoencephalopathy that was due to herpes simplex virus II (HPML). Toxoplasmosis generally occurred as multiple, small (2 cm or smaller), hypodense or isodense lesions with variable enhancement. Malignant lymphomas appeared as single lesions, always larger than 3 cm, which were isodense or hyperdense, with internal enhancement. The combined radiologic criteria of size, multiplicity, and pre- and postcontrast appearance were useful in differentiating these two pathologic processes. The best single discriminant of toxoplasmosis versus lymphoma was the average lesion size of less than 3 cm. In our experience, diagnostic brain biopsy may be averted when lesions typical of toxoplasmosis are seen. DDD-CT and NMRI may be useful in identifying lesions that are not seen optimally on routine CT.

Acquired Immunodeficiency Syndrome↗
PubMed1985

A model for L-lactate binding to Cancer magister hemocyanin.

L-Lactate raises the oxygen affinity of Cancer magister hemocyanin. The L-lactate analogs, D-lactate, glycolate and 2-methyl-lactate cause smaller increases in an oxygen binding affinity. Other analogs have no detectable effect. These data suggest that L-lactate binds to the hemocyanin at all four positions around the chiral carbon. The carboxyl and hydroxyl groups are required for activity. The protein can only partially distinguish between the methyl group and hydrogen atom.

Allosteric Site↗