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Biomedical subjects

A Haynes

Publications and source records attributed to A Haynes.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of intracerebroventricular infusion of leptin in obese Zucker rats.

The obese Zucker rat (OZR) exhibits a missense mutation in the cDNA for the leptin receptor, producing a single amino acid substitution in the extracellular domain of the receptor. A mutation in the leptin receptor gene of the db/db mouse prevents the synthesis of the long splice variant of the receptor. The possibility that the OZR, like the db/db mouse, is refractory to the actions of murine leptin was tested by infusing the protein intracerebroventricularly via a minipump for 7 days. Lean Zucker rats (LZR) infused with leptin acted as positive controls, and other groups of OZR and LZR were infused with vehicle. In LZR, leptin reduced bodyweight and food intake and increased brown adipose tissue (BAT) temperature. Plasma corticosterone increased (61%) in these rats, and plasma triglycerides fell (78%). Leptin treatment improved tolerance to an oral glucose load (16% reduction in the area under the blood glucose curve) while lowering plasma insulin. In OZR, the actions of leptin were blunted. Food intake was slightly, but not significantly, reduced. Although there was a reduction in the rate of increase in body mass, the effect of leptin was about half that seen in LZR. BAT temperature and glucose tolerance were unchanged. In contrast to the elevated plasma corticosterone seen in LZR, leptin reduced the level of this hormone (27%) in OZR. In OZR and LZR treated with leptin, the plasma leptin levels were increased 24-fold and 47-fold, respectively. The results suggest that leptin retains some efficacy in OZR, although these rats are less responsive than LZR.

Adipose Tissue, Brown↗
PubMed1997

The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy.

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56-81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.

Acute Disease↗
PubMed1995

Cancer among special populations: women, ethnic minorities, and the poor.

The study of cancer among women, ethnic minorities, and the poor can yield useful information about etiology and lead to effective recommendations for prevention. Opportunities exist for affecting cancer rates among women by studying and altering hormonal exposures and, possibly, alcohol consumption. The study of diet among ethnic groups may be more informative than among populations with homogeneous diets. The gender and racial differences among lung cancer patients related to tobacco need further research. Innovative multidisciplinary research is needed to reduce the ethnic, gender, and institutional barriers to ensure success in the fight against cancer.

Diet↗
PubMed1995

Engraftment characteristics of peripheral blood stem cells mobilised with cyclophosphamide and the delayed addition of G-CSF.

The optimal protocol for the mobilisation of PBSC remains unknown. We present data on 42 patients mobilised with cyclophosphamide (3 or 4 g/m2) and the delayed addition of a standard 300 micrograms dose of G-CSF (Filgrastim) from day +5. The patients had received a median of 2 previous chemotherapy regimes, 38% had received prior radiotherapy and 38/42 had active disease at the time of mobilisation. The protocol was well tolerated and 38 patients proceeded to transplantation. The median number of CD34+ cells reinfused was 4.3 x 10(6)/kg (range 0.5-30) and CFU-GM 15.8 x 10(4)/kg (range 0-148). The total number of CD34+ cells harvested correlated with the total number of CFU-GM available for reinfusion (P = 0.008). Overall engraftment occurred within median days to neutrophils > 0.5 x 10(9)f/l or platelets > 20 x 10(9)/l of 14 and 13 days, respectively. Patients receiving more than 2.5 x 10(6)/kg CD34+ cells had even more rapid haemopoietic reconstitution with significant reductions in hospital stay and transfusion requirements. Those below this threshold had significantly delayed platelet engraftment. The mobilising dose of cyclophosphamide did not influence the achievement of the threshold CD34+ cell yield for optimal engraftment. The delayed addition of a standard 300 micrograms G-CSF dose after priming chemotherapy resulted in the use of a median 9 days hence 9 vials of G-CSF. This protocol presents the potential for cost saving without compromising the quality or success of PBSC mobilisation.

Adult↗
PubMed1992

The identification, purification, and characterization of a pancreatic beta-cell form of the microtubule adenosine triphosphatase kinesin.

Microtubules have been implicated as being necessary for the secretion of insulin from beta-cells, although the mechanism by which cytoplasmic microtubules contribute to the release of insulin is unknown. Kinesin is a microtubule-dependent adenosine triphosphatase (ATPase) that is thought to be responsible for the intracellular transport of vesicles and organelles. In this manuscript, the purification and preliminary characterization of a beta-cell form of kinesin is described. A 120-kilodalton antikinesin-reactive polypeptide was identified on blots when cultured insulinoma tumor cell lines were subjected to immunoblot analysis using monoclonal antibodies specific for the heavy chain of mammalian kinesin. The beta-cell form of kinesin was isolated from solid rat insulinoma tumors by cosedimentation of the kinesin with microtubules from tissue homogenates in the presence of adenylyl-imidodiphosphate. The beta-cell kinesin was further purified by gel filtration chromatography, and then the pure enzyme was characterized using in vitro assays. Although beta-cell kinesin showed little ATPase activity alone, the enzyme exhibited considerable ATP hydrolysis activity in the presence of taxol-stabilized microtubules. Moreover, in motility assays beta-cell kinesin was able to translocate microtubules across microscope coverslips in the presence of Mg(2+)-ATP. In summary, we report the identity of a novel islet beta-cell form of the microtubule-dependent ATPase kinesin and suggest a possible contribution of the microtubule cytoskeleton in insulin secretion.

Animals↗
PubMed1991

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.

Alzheimer Disease↗
PubMed1990

A phase II trial of murine monoclonal antibody 17-1A and interferon-gamma: clinical and immunological data.

A group of 15 patients with metastatic colorectal adenocarcinoma received a combination of interferon gamma (0.1 mg/m2, days 1-15) and the murine monoclonal antibody 17-1A (400 mg, days 5, 7, 9 and 12). The treatment was tolerated with minimal toxicity. Of the 14 evaluable patients, 13 developed human antibody to murine 17-1A, with 11 patients demonstrating antibody to the variable region of 17-1A (anti-idiotype). Antibody to the variable region was inhibited by 17-1A but not by mouse immunoglobulin. Sera from patients with substantial anti-idiotype reactivity were capable of inhibiting the binding of murine 17-1A to antigen expressing LS174-T cells thus indicating the presence of antibody directed against the 17-1A combining site (mirror-image anti-idiotype). The median survival of the whole group was 56 weeks and there was no correlation between clinical response/survival and the development of anti-idiotype antibody.

Adenocarcinoma↗
PubMed1990

Initial evaluation of a human immunoglobulin M monoclonal antibody (HA-1A) in humans.

A human monoclonal antibody (HA-1A) directed against bacterial endotoxin was administered to 15 patients with incurable malignant disease. No adverse effects were noted following single intravenous infusions of 0.05 to 100 mg. Pharmacokinetics were evaluated in nine patients receiving 10 mg (n = 3), 25 mg (n = 3), and 100 mg (n = 3). Seven of these patients had initial peak serum concentrations greater than 80% of predicted values with plasma disappearance curves fitting a one-compartment system and a plasma half-life of 31.5 h (range of 20.3-44.6 h). The peak serum concentrations and area under the curve values were proportional to the dose of HA-1A administered. One patient had a hypercatabolic state with low levels of serum albumin and IgM. He achieved 65% of the predicted value for peak serum concentration of HA-1A with a plasma half-life of 12.3 h. A second patient had detectable serum HA-1A for only 15 min following infusion without an adequate technical or biologic explanation. We were unable to demonstrate antibody to HA-1A in sera from these nine patients either prior to therapy or during 28 days postinfusion using a "double-antigen" radiometric assay. This study suggests that HA-1A human monoclonal antibody administration is well tolerated by patients. Phase I trials will need to be carried out to characterize further the pharmacokinetics and toxicity of HA-1A in patients with gram-negative sepsis.

Adult↗
PubMed1989

Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.

A mouse/human chimeric monoclonal antibody (mAb) composed of the variable regions of murine 17-1A mAb and the constant regions of human IgG-1K immunoglobulin was administered to 10 patients with metastatic colon cancer. Four patients received single infusion of 10 mg (n = 2) or 40 mg (n = 2). Six patients received three infusion of 10 mg (n = 3) or 40 mg (n = 3) at 2-week intervals. The pharmacokinetics were similar at both dose levels and at the second and third infusions. The plasma disappearance curves were best fit by a two-compartment model having a mean alpha T1/2 of 17.5 hr (range 13-23 hr) and a mean beta T1/2 of 100.5 hr (range 65-139 hr). One patient who received three 40-mg doses of chimeric IgG-1K 17-1A mAb (day 0, 14, and 28) was the only patient to exhibit a detectable but modest antibody reactivity to chimera on days 63 and 84. The antibody reactivity was inhibited by murine 17-1A mAb, indicating that the antibody response was directed to the murine variable region of the chimera. The patients had no toxic or allergic reactions. This chimeric form of 17-1A mAb has an approximate 6-fold longer circulation time and appears to be substantially less immunogenic than its murine counterpart. These characteristics may provide an advantage in the clinical application of such chimeric molecules in therapeutic trials in humans.

Adenocarcinoma↗
PubMedDate not supplied

Parenteral feeding alters the fatty acid composition of serum phospholipids of rabbits.

BACKGROUND: Cholestatic liver disease develops in 30% to 70% of neonates receiving total parental nutrition (TPN). We analyzed the fatty acid composition of serum phospholipids from control and TPN-fed rabbits to determine if TPN altered the fatty acid profile. METHODS: Eleven male New Zealand White rabbits aged 9 to 11 weeks received TPN, whereas 11 other rabbits were offered standard laboratory rabbit chow ad libitum. After 14 days on the prescribed diet, serum samples were analyzed for their phospholipid fatty acid content by gas chromatography. RESULTS: The proportions of palmitolenic (16:2n7), alpha-linolenic (18:3n3), arachidic (20:0), and eicosaenoic (20:1n9) acids were significantly lower in the serum phospholipids of the TPN-fed animals compared with the control group. The proportion of docosahexaenoic acid (22:6n3), a fatty acid that is critical to the development of the nervous system, was increased two- to threefold. CONCLUSIONS: The differences in proportions of fatty acids observed between control and TPN-fed animals indicate that a fatty acid elongation and desaturation pathways are perturbed in rabbits on TPN.

Amino Acids↗