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Biomedical subjects

M Hunt

Publications and source records attributed to M Hunt.

At least 37 records · Page 2Linked to original sources
PubMed1995

Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.

The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid. Strains C57L, SWR, and A were notable for a high prevalence of cholelithiasis; strains C57BL/6, C3H, and SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 exhibited no cholelithiasis after consuming the diet for 18 weeks. Genetic analysis of the difference in gallstone prevalence rates between strains AKR and C57L was carried out by using the AKXL recombinant inbred strain set and (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least two genes. A major gene, named Lith1, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) was downregulated as expected in the gallstone-resistant strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggests that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. These studies indicate that genetic factors are critical in determining gallstone formation and that the genetic resources of the mouse model may permit these factors to be identified.

Animals↗
PubMed1995

Purification and characterization of phospho enol pyruvate carboxykinase from Trypanosoma brucei.

ATP-dependent phospho enol pyruvate carboxykinase (EC 4.1.1.49; PEPCK, ATP) was purified from glycosomes of cultured procyclic Trypanosoma brucei to electrophoretic homogeneity. The purified enzyme exhibited a mean specific activity of 83 units mg-1, as measured in the carboxylation direction at 30 degrees C. A similar activity was obtained for the decarboxylation reaction. The enzyme was shown to be a homodimer in solution with a subunit molecular mass of 59 kDa. Amino acid sequence analysis suggested that the PEPCK (ATP) is identical to the trypanosomal protein p60, the sequence of which was previously predicted from the corresponding nucleotide sequence by other investigators. The basic nature of the enzyme was indicated by a high isoelectric point (pH 8.9). The enzyme was found to be strictly dependent on adenosine nucleotides for activity, as well as on the presence of Mn2+. Mg2+ was found to be ineffective as activator of the trypanosomal enzyme, but a combination of subsaturating (< or = 300 microM) concentrations of Mn2+ and high concentrations of Mg2+ caused a synergistic effect on the carboxylation activity, indicating a dual cation requirement. Mn2+ is necessary to activate the enzyme and Mn2+ or Mg2+ most likely forms the cation-nucleotide complex as the active form of the substrate. Relatively high (5 mM) levels of ATP were required to produce a significant inhibition of the carboxylation reaction. Quinolinic acid, a structural analogue of oxaloacetate, completely inhibited the decarboxylation reaction at a 1 mM concentration. The apparent Michaelis constants of the enzyme were 490 microM for PEP, 37 microM for oxaloacetate, 40 microM for ADP, 10.3 microM for ATP, 970 microM for Mn2+ and 26 mM for HCO3-. Endogenous substrate concentrations were found to be 327 nmol PEP, 1486 nmol ADP, 4200 nmol ATP and 11.5 nmol Mn2+ (ml cell volume)-1. Our kinetic data suggest that under physiological conditions PEPCK (ATP) in T. brucei is bidirectional and that its activity is regulated primarily by mass action. The physiological relevance of the enzyme in procyclic T. brucei is discussed.

Amino Acid Sequence↗
PubMed1994

Effects of beam modifiers and immobilization devices on the dose in the build-up region.

PURPOSE: To analyze the effect that immobilization devices used in conjunction with beam modifiers may have on the dose to the skin and build-up region. METHODS AND MATERIALS: Central axis depth dose measurements were made in a polystyrene phantom in the build-up regions using the 6 and 15 MV photon beams, at two different source-to-phantom distances, and various field sizes. The effects of acrylic blocking trays, lead wedges, and cerrobend blocks were assessed in conjunction with the enhancement of dose in the build-up region due to immobilizing devices using plaster and thermoplastic casting materials of different thicknesses. RESULTS: For the 6 MV photons, solid (3 mm) thermoplastic casting material was found to have the greatest effect on surface dose: for a 12 x 12 cm field we measured 79% of maximum dose when treating through the material versus 22% of maximum dose when no beam modifiers or immobilization devices are used. Measurements were also made to evaluate the effect of the immobilization of patients receiving three-dimensional conformal treatments using a 15 MV photon beam. CONCLUSIONS: The relevance of these results to treatments in the pelvis, breast, and head and neck regions is discussed. For 6 MV beams, special consideration should be given if the need arises to treat through the immobilization device, as unacceptable skin reactions may result.

Dose-Response Relationship, Radiation↗
PubMed1994

Studies on compounds promoting the in vitro transformation of Trypanosoma brucei from bloodstream to procyclic forms.

In vitro differentiation of pleomorphic blood-stream forms of Trypanosoma brucei to procyclic culture forms occurred rapidly and at high rates at 27 degrees C in a culture medium containing 1 mM cis-aconitate as the transformation-inducing agent. Citrate was required at a much higher concentration (10 mM) to produce a similar transformation rate. The highest percentage of transformed cells was obtained when bloodstream-form trypanosomes were treated with pronase in the absence of a feeder-cell layer. However, under these conditions, the amount of procyclic forms obtained after 72 h was lower than that obtained in the presence of cis-aconitate. Trypsin was also capable of inducing transformation in the absence of a feeder-cell layer, but this treatment again resulted in low numbers of transformed cells. Blood-stream-form trypanosomes were incapable of taking up citrate to any significant extent and the citrate content of these stages was negligible. After 72 h of exposure to citrate (3 mM), intracellular levels of this compound remained very low (< 1 nmol (10(9) cells)-1), increasing in established procyclic stages to approximately 1.7 nmol (10(9) cells)-1. These observations suggest that the tricarboxylic acid (TCA)-cycle metabolite-dependent transformation may be initiated externally to the trypanosome cell membrane. The ability of both citrate and cis-aconitate to bind calcium and, thus, to reduce the concentration of this cation in the culture medium was found not to be responsible for the triggering effect on trypanosome transformation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitic Acid↗
PubMed1994

Recombinant human erythropoietin for the treatment of the anaemia associated with autologous bone marrow transplantation.

Patients with solid tumours undergoing high-dose chemotherapy with autologous bone marrow transplantation use an average of 10 units of packed red blood cells (PRBC) while awaiting haemopoietic reconstitution. They are also known to have inappropriately low endogenous erythropoietin levels for their degree of anaemia. This pilot study was designed to determine the effects of recombinant human erythropoietin (rHuEPO) on erythroid recovery and PRBC transfusion requirements. Ten patients received high-dose chemotherapy (days -7 to -3), bone marrow reinfusion (day 0), and then rHuEPO (day 1 onward). RHuEPO (200 units/kg intravenous bolus daily), along with iron supplementation, was administered for 28 d or until a haematocrit (Hct) of 35% (independent of transfusions) was reached, whichever occurred first. PRBCs were routinely given for Hct < or = 25% and platelets for counts < 20,000/microliters. Eight (80%) patients developed a brisk reticulocytosis (median peak reticulocyte count 0.32 x 10(9)/l) and a haematocrit > or = 30% independent of red blood cell transfusions within 32 d of receiving marrow, as compared to 20/37 (54%) similarly treated controls. An unexpected finding was the more rapid engraftment in myeloid and platelet lineages in a subset of rHuEPO-treated patients. Quick return of red blood cells (17 v 33 d) (P = 0.0001), platelets (14 v 19 d) (P = 0.04), and neutrophils (13 v 25 d) (P = 0.01) (with circulating myeloblasts and early myeloid forms) characterized recovery from an ifosfamide-based intensification with rHuEPO support. Similar trilineage enhancement of haemopoiesis did not occur with the possibly more myeloablative cyclophosphamide-based regimens. Despite the enhancement by rHuEPO on reticulocytosis, there was no significant decrease in PRBC transfusion requirements. RHuEPO proved to be a well-tolerated agent in enhancing reticulocytosis following high-dose chemotherapy. Further study to elucidate the activity of erythropoietin on both erythroid and non-erythroid growth and maturation appears warranted.

Adult↗
PubMed1994

Using the Delphi survey technique to develop a professional definition of nursing for analysing nursing workload.

This paper describes the use of the Delphi survey technique to develop a professional definition of nursing which is used as a framework for analysing the contribution made to care by learner nurses prior to the introduction of Project 2000. A detailed account is provided of the importance of generating a theoretical nursing perspective to structure the first round of the Delphi survey. The paper goes on to question the validity of developing a consensus about nursing priorities in subsequent rounds of the Delphi survey and argues instead that priorities about nursing care needs can only be determined in the context of practice.

Activities of Daily Living↗
PubMed1994

Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.

We have examined several aspects of neurotransmitter function in the brains of mice carrying a deletion mutation in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). During the first 6 weeks of postnatal development, dopamine levels in whole-brain extracts from the mutant mice (HPRT-) failed to increase at rates comparable to normal animals, resulting in 40% lower dopamine levels throughout adulthood. Regional analysis in adult animals showed the caudoputamen to be the most severely affected region, with dopamine deficits of 48-64%. Dopamine levels in other regions were normal or less severely affected. The decrease in dopamine was accompanied by a decrease in tyrosine hydroxylase (TH) activity, the rate-limiting step in dopamine synthesis. Kinetic analysis of TH extracted from the caudoputamen of normal and HPRT- mice demonstrated a 45% decrease in Vmax with an increased affinity for the tetrahydropterin cofactor in the mutants. Labeling of midbrain dopamine neurons using TH immunohistochemistry revealed no obvious deficits in the number of midbrain dopamine neurons, but quantitative autoradiographic studies revealed significant reductions in the binding of 3H-N-[1-(2-benzo(beta)thiophenyl)cyclohexyl]piperidine (3H-BTCP) to dopamine uptake sites in the forebrain of the mutants. In contrast to these abnormalities of the dopamine systems in the mutant mice, other neurotransmitter systems appeared relatively unaffected. Norepinephrine, 5-HT, tryptophan hydroxylase, and glutamic acid decarboxylase were present at normal levels in the brains of the mutants. ChAT activity was slightly lower than normal in the caudoputamen of the mutant animals, but was normal in all other brain regions examined. These results indicate that HPRT deficiency is associated with a relatively specific deficit in basal ganglia dopamine systems that emerges during the first 2 months of postnatal development.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Intensive combined modality therapy for limited-stage small-cell lung cancer.

BACKGROUND: Conventional-dose chemotherapy for small-cell lung cancer has resulted in high response rates but rarely in a cure. The addition of thoracic radiotherapy (chemoradiotherapy) has improved survival for patients having limited disease, resulting in a median survival of 14-18 months. Previous trials evaluating high-dose chemotherapy and autologous bone marrow transplantation have demonstrated enhanced complete response rates without documenting overall survival benefit. PURPOSE: The purpose of this phase II trial was to determine the disease-free and overall survival, toxic effects, and relapse patterns in patients with limited small-cell lung cancer who were in partial or complete response to first-line conventional-dose chemotherapy and then received intensive systemic combined modality therapy. METHODS: Adults with stage III small-cell lung cancer who had achieved at least a partial response to conventional-dose induction chemotherapy were treated with high-dose cyclophosphamide, cisplatin, and carmustine combined with autologous bone marrow transplantation. Cumulative doses of the three drugs were 5625, 165, and 480 mg/m2, respectively. After recovery, patients received thoracic radiotherapy (50-60 Gy in 25-30 fractions over 5-6 weeks) and cranial radiotherapy (30 Gy in 15 fractions during 3 weeks). RESULTS: Of 19 patients in the study, six had achieved complete response, eight had a greater than 90% reduction in tumor size, and five had a 50%-90% reduction in tumor size. After high-dose therapy, 15 of the 19 were in complete response. Overall, median time to treatment failure after high-dose therapy was 12 months. Overall survival was 73% (95% confidence interval [CI] = 42%-89%) at 1 year and 53% (95% CI = 22%-77%) at 2 years. Of the 14 patients in or near complete response before high-dose therapy, 10 remain disease free with no further chemotherapy a median of 15 (4-69+) months after therapy. Actuarial 2-year disease-free survival is 57% (95% CI = 20%-82%). One patient died of Candida sepsis. Morbidity was low, and most patients returned to full-time work. With the exception of herpes zoster, there were no complications more than 3 months after high-dose therapy. CONCLUSIONS: The majority of the patients in this study are experiencing prolonged and unmaintained disease-free survival. Our findings suggest that patients in or near complete response before high-dose therapy have the most favorable prognosis. IMPLICATIONS: A randomized comparison between this approach and conventional-dose therapy is planned to define the utility of dose intensification with autologous bone marrow transplantation in the treatment of patients with limited-stage small-cell lung cancer who are in or near complete response.

Actuarial Analysis↗
PubMed1993

Purging the emotions: the lack of emotional expression in subfertility and in the care of the dying.

The paper examines emotional expression by drawing on data from patients in two contrasting situations; interview data from couples attending fertility clinics, and audio-recorded conversations with terminally ill patients being cared for at home. Although the literature on subfertility and terminal illness frequently uses a bereavement model to argue for the importance of overt grieving, patients in these studies did not express a wish to discuss their feelings. This finding raises questions about how patients' needs are defined, and whether emotions may be created by discourse.

Adaptation, Psychological↗
PubMed1993

Phase II trial of carboplatin in patients with metastatic malignant melanoma. A report from the Eastern Cooperative Oncology Group.

Thirty patients with pathologically proven, measurable metastatic melanoma without prior chemotherapy were treated with carboplatin 400 mg/m2 by intravenous infusion for 30 minutes every 4 weeks. Twenty-seven patients were evaluable for response and toxicity. Two complete responses and one partial response (3 of 27 = 11%, 90% confidence intervals: 3-26%) were documented. The median survival was 4.7 months. The most common toxicity was myelosuppression. One drug-related death was observed due to renal failure. Prior radiotherapy and liver metastasis were the poor prognostic indicators identified in our study. Carboplatin in the dose and schedule reported in our trial has only modest antitumor activity in patients with advanced malignant melanoma.

Adult↗
PubMed1993

Quality of life and dissociation in anxiety disorder patients with histories of trauma or PTSD.

OBJECTIVE: The purpose of this analysis was to examine quality of life and dissociation in anxiety disorder subjects with histories of trauma, some of whom met criteria for posttraumatic stress disorder (PTSD). METHOD: Subjects came from a prospective, longitudinal study of anxiety disorders. Information was gathered on role, social life, suicide attempts, psychiatric hospitalization, alcohol and substance abuse, depression, and dissociation. RESULTS: Subjects with PTSD had the worst functioning on all of the measures examined except social life. Those with histories of trauma but no PTSD differed from subjects who reported no history of trauma, primarily in high rates of alcoholism and minor depression. CONCLUSIONS: PTSD has severe effects on quality of life in virtually all spheres of life. The high levels of depression, suicide attempts or gestures, and alcohol abuse are of particular concern and show that trauma can have long-lasting effects.

Adolescent↗
PubMed1992

Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer.

High-dose therapy with autologous marrow support results in durable complete remissions in selected patients with relapsed lymphoma and leukemia who cannot be cured with conventional dose therapy. However, substantial morbidity and mortality result from the 3- to 6-week period of marrow aplasia until the reinfused marrow recovers adequate hematopoietic function. Hematopoietic growth factors, particularly used after chemotherapy, can increase the number of peripheral blood progenitor cells (PBPCs) present in systemic circulation. The reinfusion of PBPCs with marrow has recently been reported to reduce the time to recovery of adequate marrow function. This study was designed to determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized PBPCs alone (without marrow) would result in rapid and reliable hematopoietic reconstitution. Sixteen patients with metastatic breast cancer were treated with four cycles of doxorubicin, 5-fluorouracil, and methotrexate (AFM induction). Patients responding after the first two cycles were administered GM-CSF after the third and fourth cycles to recruit PBPCs for collection by two leukapheresis per cycle. These PBPCs were reinfused as the sole source of hematopoietic support after high doses of cyclophosphamide, thiotepa, and carboplatin. No marrow or hematopoietic cytokines were used after progenitor cell reinfusion. Granulocytes greater than or equal to 500/microL was observed on a median of day 14 (range, 8 to 57). Transfusion independence of platelets greater than or equal to 20,000/microL occurred on a median day of 12 (range, 8 to 134). However, three patients required the use of a reserve marrow for slow platelet engraftment. In retrospect, these patients were characterized by poor baseline bone marrow cellularity and poor platelet recovery after AFM induction therapy. When compared with 29 historical control patients who had received the same high-dose intensification chemotherapy using autologous marrow support, time to engraftment, antibiotic days, transfusion requirements, and lengths of hospital stay were all significantly improved for the patients receiving PBPCs. Thus, autologous PBPCs can be efficiently collected during mobilization by chemotherapy and GM-CSF and are an attractive alternative to marrow for hematopoietic support after high-dose therapy. The enhanced speed of recovery may reduce the morbidity, mortality, and cost of high-dose treatment. Furthermore, PBPC support may enhance the effectiveness of high-dose therapy by facilitating multiple courses of therapy.

Adolescent↗
PubMed1992

Prenatal diagnosis of tetrasomy 12p by in situ hybridization: varying levels of mosaicism in different fetal tissues.

Prenatal diagnosis of tetrasomy 12p is complicated by the discrimination of the 12p isochromosome from the duplication 21q as well as the level of mosaicism demonstrated in the particular tissue sampled. In this disease, a high percentage of chromosomally abnormal cells are generally found in fibroblastic cells, but lymphocyte karyotypes from the same individual may be normal. We report on the pregnancy of a 37-year-old female who presented to our centre at 16 weeks' gestation for genetic amniocentesis. Sonography of the fetus revealed dextrocardia and diaphragmatic hernia. Chromosome analysis of amniocytes demonstrated mosaicism of a 47,XY,+i(12p) line in 80 per cent of cells and a normal male line (20 per cent), consistent with the Pallister-Killian syndrome. Following termination, a 220 g male fetus of 18 weeks was examined. A flattened nose and low-set ears were noted. In situ hybridization with a chromosome 12 centromeric probe in lymphocytes and skin cells unequivocally confirmed the karyotype and showed the presence of a single centromere in the abnormal chromosome, suggesting a true isochromosome. Chromosome analysis of various fetal tissues was performed and the following percentages of abnormal cells were found: skin 100 per cent, chorion 50 per cent, placenta 30 per cent, and blood 80 per cent. The high frequency of tetrasomic cells in fetal blood at this early gestational age is noteworthy, since most reports of this syndrome show a very low percentage of abnormal cells postnatally.

Adult↗
PubMed1992

An extended phase II trial of ifosfamide plus mesna in malignant mesothelioma.

Forty three patients with histologically confirmed malignant mesothelioma were entered onto an Eastern Cooperative Oncology Group phase II study of ifosfamide given with mesna. Eligibility criteria included adequate performance status, hemogram and renal functions. Ifosfamide was given at 1.5 g/m2 in 200 ml of normal saline over 30 minutes by intravenous infusion on days 1 to 5 of each 21 day cycle. Mesna was given at 300 mg/m2 on each day of ifosfamide at 0, 4 and 8 hours. Two patients were cancelled and one patient was ineligible. The most common toxicity was haematologic. More than 50% of the patients had at least one episode of severe or life threatening toxicity and 2 patients had lethal toxicity (1 renal and 1 pulmonary oedema attributed to treatment), and an additional 4 patients died while on study (2 of cardiac and 2 of cerebral vascular disease not considered directly related to treatment). Of the 40 eligible patients one was unevaluable for response, and one patient had a partial response lasting 6.3 months. Twenty four patients had a no change status with a median duration of 5 months. The median time to treatment failure for all eligible patients was 2.5 months. The median overall survival time (from registration) for all eligible patients was 6.9 months. In multi variable models, factors that predicted for a statistically significant poorer survival were age > or = 62, stage > or = 3, performance status poorer than 0 to 1 and prior surgery (i.e.: more than biopsy).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Administration Schedule↗
PubMed1992

CNS distribution of D1 receptors: use of a new specific D1 receptor antagonist, [3H]SCH39166.

D1 dopamine receptors have been localized using a radioactive form of a new specific antagonist, [3H]SCH39166. This compound has been shown, in in vitro binding studies, to be highly selective for the D1 receptor subtype; more so than its predecessor, [3H]SCH23390. These ligand binds saturably, reversibly and with high affinity. Use of appropriate conditions produces a high signal to noise binding ratio to D1 receptors in slide-mounted tissue sections. Autoradiographic localization of radiolabeled receptors shows high densities of the D1 receptor subtype in such brain structures as the caudate-putamen, nucleus accumbens, entopeduncular nucleus, and the substantia nigra pars reticulata. A lower density of receptors is found in a few other areas including lamina VI of the cerebral cortex. A distinct paucity of binding was apparent in lamina IV of the cerebral cortex and in the choroid plexus, two areas thought to have D1 receptors. SCH39166 thus represents a superior ligand for obtaining selective labeling of D1 receptors in autoradiographic and binding studies.

Animals↗