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Biomedical subjects

M Graham

Publications and source records attributed to M Graham.

At least 37 records · Page 2Linked to original sources
PubMed1999

Local intramural heparin delivery during primary angioplasty for acute myocardial infarction: results of the Local PAMI Pilot Study.

The feasibility and safety of local heparin delivery during acute infarct angioplasty was evaluated in a prospective, multicenter, 120-patient series. Angioplasty was performed using standard techniques, after which heparin (4,000 U) was delivered locally; 25% of patients received stents. Procedural success was reported in 98% of patients; 6.7% of patients suffered death, reinfarction, recurrent ischemia, or stroke during the index hospitalization. The 6-month target vessel revascularization rate was 12.5%. Local heparin therapy with provisional stenting in acute myocardial infarction patients is safe, feasible, associated with a low rate of infarct artery revascularization at 6 months, and may potentially eliminate the need for systemic heparin following the procedure.

Aged↗
PubMed1998

Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein.

The agouti-related protein gene (Agrp) is a novel gene implicated in the control of feeding behavior. The hypothalamic expression of Agrp is regulated by leptin, and overexpression of Agrp in transgenic animals results in obesity and diabetes. By analogy with the known actions of agouti, these data suggest a role for the Agrp gene product in the regulation of melanocortin receptors expressed in the central nervous system. The availability of recombinant, highly purified protein is required to fully address this potential interaction. A nearly full-length form of AGRP (MKd5-AGRP) was expressed in the cytosolic or soluble fraction of Escherichia coli and appeared as large intermolecular disulfide-bonded aggregates. Following oxidation, refolding, and purification, this protein was soluble, and eluted as a single symmetric peak on RP-HPLC. Circular dichroism studies indicated that the purified protein contains primarily random coil and beta-sheet secondary structure. Sedimentation velocity studies at neutral pH demonstrated that MKd5-AGRP is monomeric at low micromolar concentrations. Mobility shifts observed using SDS-PAGE under reducing and nonreducing conditions for bacterially expressed and mammalian expressed AGRP were identical, an indication of a similar disulfide structure. The purification to homogeneity of a second, truncated form of AGRP (Md65-AGRP) which was expressed in the insoluble or inclusion body fraction is also described. Both forms act as competitive antagonists of alpha-melanocyte stimulating hormone (alpha-MSH) at melanocortin-3 (MC-3) and melanocortin-4 receptors (MC-4). The demonstration that AGRP is an endogenous antagonist with respect to these receptors is a unique mechanism within the central nervous system, and has important implications in the control of feeding.

Agouti Signaling Protein↗
PubMed1998

Protection against allograft rejection with intercellular adhesion molecule-1 antisense oligodeoxynucleotides.

BACKGROUND: We designed an antisense phosphorothioate oligodeoxynucleotide (oligo) to specifically inhibit the expression of rat intercellular adhesion molecule-1 (ICAM-1) mRNA (IP-9125). METHODS: IP-9125 oligo was delivered intravenously by osmotic pump alone or in combination with cyclosporine (CsA) to recipients in order to prevent the rejection of kidney or heart allografts. In additional experiments, kidney allografts were perfused with IP-9125 before grafting. RESULTS: IP-9125 inhibited ICAM-1 mRNA and ICAM-1 protein expression in rat aortic endothelial cells; scrambled controls IP-12140 and IP-13944 were ineffective. Untreated ACI (RT1a) recipients rejected Lewis (RT1l) kidney allografts at a mean survival time of 8.5+/-1.1 days. A 14-day intravenous administration of 2.5 mg/kg/day IP-9125 prolonged the survival of kidney allografts to 39.2+/-16.4 days; 5.0 mg/kg/day, to 43.0+/-17.5 days; and 10.0 mg/kg/day, to 50.4+/-21.6 days. In contrast, a scrambled control IP-12140 was not effective. A combination of 10 mg/kg/day IP-9125 and 1.0 mg/kg/day CsA delivered for 14 days synergistically extended kidney allograft survival times 88.5+/-7.5 days. In contrast, the combination of 10.0 mg/kg/day control IP-12140 with CsA was ineffective (20.7+/-3.2 days) when compared with CsA alone (20.2+/-4.0 days). Similar results were obtained for heart transplants in recipients treated with IP-9125 alone or in combination with CsA. Furthermore, in situ immunostaining showed that IP-9125 significantly reduced the expression of ICAM-1 protein in kidney allografts. Finally, perfusion of kidney grafts alone with 20.0 mg per 2 ml of IP-9125 protected kidney allografts from rejection (37.5+/-7.5 days; P < 0.001), whereas perfusion with 20 mg per 2 ml of control IP-12140 was ineffective (12.6+/-5.0 days). CONCLUSIONS: Rat ICAM-1 IP-9125 oligo inhibits ICAM-1 protein expression in vitro and in vivo as well as blocks allograft rejection when used for pretreatment of donors, graft perfusion, or postoperative treatment of recipients.

Animals↗
PubMed1998

Extending the indications for breast-conserving treatment to patients with locally advanced breast cancer.

PURPOSE: Breast-conserving therapy (BCS) has generally been limited to T1 and T2 lesions because it has been thought impossible to achieve good local control with satisfactory cosmesis in patients with more advanced disease. However, many patients with T3 and T4 lesions will exhibit dramatic tumor downstaging with neoadjuvant chemotherapy. It is our hypothesis that for these patients BCS can be performed with good local control and cosmesis. METHODS AND MATERIALS: Between February 1991 and November 1995, 34 patients with T3/T4, N0-N2, M0 breast cancer completed treatment consisting of 90 mg/m2 of doxorubicin every 21 weeks x 4, surgery (a local excision if sufficiently downstaged, or mastectomy if not), high dose cyclophosphamide (CMF) every 2 weeks x 4, and radiation therapy. Radionuclide ventriculograms were performed on all patients pre- and postdoxorubicin, and at 6-12 months post radiation therapy. Patients were evaluated for toxicity, local control, cosmesis, disease-free and overall survival. RESULTS: Median follow-up is 30 months. 15/34 (44%) patients underwent BCS with only one local-regional failure and actuarial 3-year disease-free and overall survival of 77% and 88%. Cosmetic results were good to excellent in 80% of the patients. Left ventricular ejection fraction, which predictably declined following doxorubicin, did not further decline after radiation therapy. CONCLUSIONS: These results suggest that with this regimen a subset of patients with locally advanced breast cancer can preserve their breast with acceptable cosmesis without compromising local control or survival.

Adult↗
PubMed1998

A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial.

OBJECTIVES: The purpose of this study was to determine if early triage angiography with revascularization, if indicated, favorably affects clinical outcomes in patients with suspected acute myocardial infarction who are ineligible for thrombolysis. BACKGROUND: The majority of patients with acute myocardial infarction and other acute coronary syndromes are considered ineligible for thrombolysis and therefore are not afforded the opportunity for early reperfusion. METHODS: This multicenter, prospective, randomized trial evaluated in a controlled fashion the outcomes following triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Eligible patients (n=201) with <24 h of symptoms were randomized to early triage angiography and subsequent therapies based on the angiogram versus conventional medical therapy consisting of aspirin, intravenous heparin, nitroglycerin, beta-blockers, and analgesics. RESULTS: In the triage angiography group, 109 patients underwent early angiography and 64 (58%) received revascularization, whereas in the conservative group, 54 (60%) subsequently underwent nonprotocol angiography in response to recurrent ischemia and 33 (37%) received revascularization (p=0.004). The mean time to revascularization was 27+/-32 versus 88+/-98 h (p=0.0001) and the primary endpoint of recurrent ischemic events or death occurred in 14 (13%) versus 31 (34%) of the triage angiography and conservative groups, respectively (45% risk reduction, 95% CI 27-59%, p=0.0002). There were no differences between the groups with respect to initial hospital costs or length of stay. Long-term follow-up at a median of 21 months revealed no significant differences in the endpoints of late revascularization, recurrent myocardial infarction, or all-cause mortality. CONCLUSIONS: Early triage angiography in patients with acute coronary syndromes who are not eligible for thrombolytics reduced the composite of recurrent ischemic events or death and shortened the time to definitive revascularization during the index hospitalization. Despite more frequent early revascularization after triage angiography, we found no long-term benefit in cardiac outcomes compared with conservative medical therapy with revascularization prompted by recurrent ischemia.

Adult↗
PubMed1998

The Epilepsy Outcome Scale: the development of a measure for use with carers of people with epilepsy plus intellectual disability.

This paper describes the development of a new scale for the assessment of epilepsy in people with learning disabilities. The scale was developed and validated in consultation with principal carers, and reflects their concerns about seizures, their impact and their treatment. Further testing of the scale revealed high internal consistency, testretest reliability and a robust factor structure. The scale can be completed in 5-10 min and may be useful as an outcome measure both in clinical practice and in research trials.

Adaptation, Psychological↗
PubMed1998

Identity, place, and erotic community within gay leather culture in Stockholm.

There has been much recent attention to the relationship between the construction of place, identity, and the body. This paper examines some of these themes in a presentation of the gay leather scene in Stockholm, Sweden. Based on ethnography of Stockholm's only true leather club, it shows how identity and spatial location are implicated in one another. It also looks at social and cultural processes of containment and dispersion within leather culture, the creation of erotic bodies, and forms of erotic interaction. These processes are seen as reflecting features of the wider Swedish gay scene and society in general, which is sometimes less tolerant than it is imagined to be. Aspects of current and possible future transformations of leather culture and style are also briefly considered.

Body Image↗
PubMed1997

Cloning and characterization of a microsomal aminopeptidase from the intestine of the nematode Haemonchus contortus.

In order to characterise the integral membrane glycoprotein H11 from the intestinal microvilli of the nematode Haemonchus contortus, cDNA libraries prepared using mRNA from adult worms from the UK and Australia were immunoscreened with anti-H11 sera. Antibodies affinity purified on the protein expressed by insert DNA (295 bp) of a positive clone from a UK library bound specifically to H11. A longer clone (948 bp) was obtained from the Australian library by hybridisation. Using a primer based on sequence common to these, a polymerase chain reaction product of 3.3 kb was generated from cDNA from UK H. contortus. The sequences from the UK and Australian nematodes were essentially identical over the 929 bp region in which both were represented. All three cloned DNAs hybridised to mRNA of about 3.5 kb. Analysis of the deduced amino acid sequence, which showed 32% identity with those of mammalian microsomal aminopeptidases, indicated that H11 has a short N-terminal cytoplasmic tail, a single transmembrane region and a long extracellular region with putative N-linked glycosylation sites and the HEXXHXW motif characteristic of microsomal aminopeptidases. Microsomal aminopeptidase activity co-purifies with H11. It is inhibited by bestatin, phenanthroline and amastatin. The recombinant protein has been expressed in active form in insect cells.

Amino Acid Sequence↗
PubMed1997

Anemia and perinatal death result from loss of the murine ecotropic retrovirus receptor mCAT-1.

The mCAT-1 gene encodes a basic amino acid transporter that also acts as the receptor for murine ecotropic leukemia viruses. Targeted mutagenesis in embryonic stem cells has been used to introduce a germ-line null mutation into this gene. This mutation removes a domain critical for virus binding and inactivates amino acid transport activity. Homozygous mutant pups generated from these cells were approximately 25% smaller than normal littermates, very anemic, and died on the day of birth. Peripheral blood from homozygotes contained 50% fewer red blood cells, reduced hemoglobin levels, and showed a pronounced normoblastosis. Histological analyses of bone marrow, spleen, and liver showed a decrease in both erythroid progenitors and mature red blood cells. Mutant fetal liver cells behaved normally in in vitro hematopoietic colony-forming assays but generated an anemia when transplanted into irradiated C.B.-17 SCID mice. Furthermore, reconstitution of the white cell compartment of SCID mice by mutant fetal liver cells was less complete than that observed with a mixed population of wild-type and heterozygous fetal liver cells. Primary embryo fibroblasts from mutant mice were completely resistant to ecotropic retrovirus infection. Thus, mCAT-1 not only appears to be the sole receptor for a group of murine ecotropic retroviruses associated with hematological disease but also plays a critical role in both hematopoiesis and growth control during mouse development.

Anemia↗
PubMed1997

Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.

We have isolated cDNA clones that encode a novel human gene related to agouti. Sequence analysis of this gene, named ART, for agouti-related transcript, predicts a 132-amino-acid protein that is 25% identical to human agouti. The highest degree of identity is within the carboxyl terminus of both proteins. Like agouti, ART contains a putative signal sequence and a cysteine rich carboxyl terminus, but lacks the region of basic residues and polyproline residues found in the middle of the agouti protein. Both agouti and ART contain 11 cysteines, and 9 of these are conserved spatially. ART is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of expression occurring in testis, lung, and kidney. The murine homolog of ART was also isolated and is predicted to encode a 131-amino-acid protein that shares 81% amino acid identity to humans. The mouse was found to have the same expression pattern as human when assessed by RT-PCR. Examination by in situ hybridization using mouse tissues showed localized expression in the arcuate nucleus of the hypothalamus, the median eminence, and the adrenal medulla. In addition, the hypothalamic expression of ART was elevated approximately 10-fold in ob/ob and db/db mice. ART was mapped to human chromosome 16q22 and to mouse chromosome 8D1-D2. The expression pattern and transcriptional regulation of ART, coupled with the known actions of agouti, suggests a role for ART in the regulation of melanocortin receptors within the hypothalamus and adrenal gland, and implicates this novel gene in the central control of feeding.

Agouti Signaling Protein↗
PubMed1997

Preliminary study of the effect of iron dextran on a non-regenerative anaemia of housed lambs.

A study of the effects of iron dextran supplementation on anaemia in indoor lambs was carried out on one commercial flock of 525 lambs from January to June 1993. The lambs were randomly allocated into two groups, one of which was given a parenteral injection of 300 mg iron dextran and the other was left untreated. Blood was collected from 22 12-day-old lambs and 106 24-day-old lambs, in each case half treated and half untreated. The supplemented lambs had significantly improved haematological values than the unsupplemented lambs. There were also significant differences in the total serum iron concentration, the unsaturated iron binding capacity and the percentage serum saturation with iron between the treated and untreated lambs. At 12 days, the untreated lambs had a total serum iron below the accepted normal range for sheep whereas the treated lambs had values within the normal range. At weaning, lambs injected with iron dextran were significantly heavier (1.0 kg) than those not injected. The daily liveweight gain to slaughter was greater and the proportion of deaths was lower in the treated lambs but these differences were not statistically significant.

Anemia↗
PubMed1997

A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): preliminary toxicity report.

PURPOSE: A multi-institutional, prospective study was designed to determine the feasibility and tolerance of external beam irradiation plus concurrent chemotherapy and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. METHODS AND MATERIALS: Planned treatment was 50 Gy external beam radiation (25 fractions/5 weeks) followed 2 weeks later by EB [either high dose rate (HDR) 5 Gy, weeks 8, 9, and 10, for a total of 15 Gy, or low dose rate (LDR) 20 Gy, week 8]. The protocol was later revised to delete the LDR alternative, owing to poor accrual, and to decrease the HDR dose to 10 Gy (i.e. 5 Gy, weeks 8 and 9). Chemotherapy was given weeks 1, 5, 8, and 11 with cisplatin 75 mg/m2 and 5-fluorouracil 1000 mg2/m per 24 h, 96-h infusion. The study closed in January 1995 after 56 patients had been entered on the HDR arm. Six patients were declared ineligible owing to tumor extension to the gastroesophageal junction (three patients) or involved celiac lymph nodes (three patients). Of the 50 eligible patients, the planned EB dose was 15 and 10 Gy in 40 and 10 patients, respectively. Forty-six (92%) of the eligible patients had squamous histology, and three (6%) adenocarcinoma. RESULTS: Life-threatening toxicity or treatment-related death occurred in 13 (26%) and 4 (8%) of the 50 eligible patients, respectively. Treatment-related esophageal fistulas occurred in three patients (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in three. The fourth death was secondary to renal toxicity and infection attributed to chemotherapy. No correlation was found between the development of fistula and location of primary tumor, brachytherapy active length or applicator diameter. So far, 5 of the 6 treatment-related fistulas have occurred following 15 Gy EB. The other fistula occurred after only 5 Gy of a planned 15 Gy was delivered. CONCLUSION: Thirty-five patients (70%) were able to complete external beam, EB, and at least two courses of chemotherapy. Estimated survival rate at 12 months is 48%, with an estimated 11-month median survival rate. Survival following external beam radiation plus concurrent chemotherapy and EB does not appear to be significantly different from survival seen following external beam radiation and chemotherapy only. The development of six fistulas in the 35 patients completing EB is of concern. Based on the high incidence of fistulas, we urge extreme caution in employing EB as a boost following concurrent external beam radiation and chemotherapy.

Adenocarcinoma↗
PubMed1997

Management of chronic pain with epidural steroids.

Perioperative nurses need to be aware of the multiple treatment modalities associated with chronic back problems. Patients who undergo back surgeries often have been and may continue to be pain therapy patients. In addition, many conditions other than back problems are treated in pain clinics. Perioperative nurses may be in a position to refer patients for pain therapy and are encouraged to do so. Patients may look to nurses for guidance when making decisions about using pain therapy clinics. Pain management programs vary from small single-discipline or modality clinics to large multidisciplinary centers. Regardless of the type of clinic, team members should place a strong emphasis on assessing patients' physical, mental, and psychosocial statuses so that coherent treatment plans can be developed. Patients should be encouraged to participate in all decision making because they have much of the responsibility for their treatment. Patients also should be cautioned not to expect miracles but to look for significant improvement and the opportunity to lead more effective and satisfying lives with minimal pain.

Anesthetics, Local↗
PubMed1997

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Adult↗