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Biomedical subjects

J Keith

Publications and source records attributed to J Keith.

At least 19 recordsLinked to original sources
PubMed2003

A retrospective review comparing the use of Gonal-F and Metrodin-HP for in-vitro fertilisation (IVF).

All cycles of IVF with pituitary down-regulation (n = 57) done at the Damansara Fertility Centre in the year 2000 were studied. All the 57 patients had controlled ovarian hyperstimulation, either using Metrodin HP (n = 27) or Gonal-F (n = 30). Of these, 53 patients reached oocyte pick-up, 26 patients in Metrodin HP group and 27 patients in Gonal-F group. Gonal-F resulted in a higher clinical pregnancy rate of 66.6% compared to Metrodin HP 38.5% (p < 0.05). The live birth rate tends to be higher in Gonal-F group (40.7%) compared to Metrodin HP (30.8%), (p > 0.05).

Adult↗
PubMed2002

Pharmacogenomic analysis of rhIL-11 treatment in the HLA-B27 rat model of inflammatory bowel disease.

Recombinant human interleukin-11 (rhIL-11) reduces the clinical signs and histological lesions of inflammatory bowel disease (IBD) in transgenic rats expressing the human major histocompatability complex (MHC) class I allele, HLA-B27. To elucidate the pharmacogenomic effects of rhIL-11 in this model, we examined the global gene expression pattern in inflamed colonic tissue before and following rhIL-11 treatment using oligonucleotide microarrays. In total, 175 disease-related genes were identified. Increased expression of genes involved in antigen presentation, cell death and inflammation, and decreased expression of metabolic genes was associated with disease. A total of 27 disease-related genes returned to normal expression levels following rhIL-11 treatment including the MHC class II gene RT1-DMbeta. rhIL-11 induced the expression of four intestinal epithelial growth factors. These gene expression patterns indicate that treatment of inflammatory bowel disease with rhIL-11 affects class II antigen processing and colonic epithelial cell proliferation and metabolism.

Animals↗
PubMed1998

Preclinical studies of recombinant factor IX.

Recombinant factor IX (rFIX) has been extensively evaluated in preclinical studies. Dog model study of hemophilia B indicated that rFIX was as effective as a highly purified plasma-derived replacement factor in normalizing indices of hemostasis. Pharmacokinetic studies indicated a dose-proportional profile for rFIX. Pharmacokinetic/pharmacodynamic analysis showed that increases in the plasma concentration of rFIX following administration were closely correlated with measured factor IX activity in the plasma. Appropriate in vitro and in vivo toxicology studies have been performed to support the clinical use of rFIX for the treatment of hemophilia B. Finally, experiments in a model of thrombogenicity indicated that in animals rFIX has a low thrombogenic potential. The preclinical results provided a basis for proceeding with human clinical trials.

Animals↗
PubMed1997

Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters.

Ulcerative mucositis is a painful, debilitating and dose-limiting toxicity of cancer chemotherapy. Current treatment is largely palliative and no adequate preventive treatment exists. Recently, we reported that recombinant human(rh) interleukin 11 (IL-11) favourably modified the course of mucositis following a single stomatotoxic regimen of 5-fluorouracil in hamsters. Although potentially beneficial, the clinically relevant issue of mucositis and myelosuppression during multicourse chemotherapy treatment was not addressed. The present study was undertaken to evaluate the effect of rhIL-11 on two consecutive courses of mucositis and myelosuppression in hamsters. Ulcerative mucositis was induced using a standardized protocol consisting of 5-fluorouracil (60 mg/kg) on days 1 and 2 followed by superficial irritation of the buccal mucosa on day 4. Animals treated with 100 microg of rhIL-11 for 12 consecutive days following each regimen of chemotherapy experienced a reduction in the incidence, severity, and duration of mucositis, a reduction in weight loss, and less morbidity and mortality relative to control animals. Bone marrow cellularity and function was not adversely affected by rhIL-11 treatment. The present study is consistent with the potential use of rhIL-11 treating patients at risk of developing ulcerative mucositis while undergoing intensive multicourse chemotherapy treatment.

Animals↗
PubMed1996

Prediction of the in-vitro fertilization (IVF) potential of human spermatozoa using sperm function tests: the effect of the delay between testing and IVF.

To examine the diagnostic significance of several criteria of semen quality and to determine whether their prognostic value is eroded by the time interval between assessment and the attempt at in-vitro fertilization (IVF) with embryo transfer, 73 couples undergoing IVF and embryo transfer therapy were studied. The ability of human spermatozoa to achieve fertilization in vitro was examined in relation to the conventional semen profile, sperm morphology, the computer-aided assessment of sperm movement, ionophore-induced acrosome reaction, acridine orange staining, and chemiluminescent signals induced by phorbol ester and N-formyl-methionyl-leucyl-phenylalanine (FMLP). Spermatozoa were examined both in semen and after preparation on Percoll, some weeks prior to IVF. Fertilization rates were noted to be significantly correlated with elements of sperm movement characteristics, sperm morphology, and reactive oxygen species generation. Prediction of fertilization rates in a stepwise multiple regression analysis was obtained using four variables: sperm morphology, FMLP-induced chemi-luminescence and sperm movement characteristics (beat cross frequency and straightness) (r approximately 0.5). When multiple logistic regression analysis was used to predict which samples would achieve fertilization rates above and below a 50% threshold, three variables of predictive value including linearity, average path velocity and FMLP-induced chemiluminescence were selected. Combination of these variables classified the samples achieving good or poor fertilization with an overall accuracy of 83.6%. The time interval between semen assessment and IVF had little effect on the predictive value of these tests. In conclusion, the fertilizing ability of human spermatozoa is related to sperm morphology, attributes of sperm movement and reactive oxygen species production. The time delay between testing and IVF did not appear to affect predictive accuracy.

Acridine Orange↗
PubMed1996

Dissociation of hypothalamic NPY from BAT uncoupling protein mRNA in rats exposed to 24 h thermoneutrality.

Neuropeptide Y (NPY) is increasingly considered to be involved in the central regulation of energy balance. Our previous studies suggest that hypothalamic NPY neurons of the arcuatoparaventricular (ARC-PVN) projection are inhibited in association with the marked increases in brown adipose tissue (BAT) thermogenesis and uncoupling protein (UCP) gene expression in rats exposed to cold. We therefore hypothesized that the NPYergic ARC-PVN system would be activated in a thermoneutral environment, when energy expenditure falls to a minimum, and that this activation could mediate the fall in BAT activity. We measured regional hypothalamic NPY concentrations, hypothalamic NPY receptor binding, and NPY mRNA together with UCP mRNA levels in rats exposed to thermoneutrality (29 degrees C) for 24 h. At thermoneutrality, UCP mRNA levels fell to 42% of those in controls maintained at 22 degrees C, but there were no significant changes in hypothalamic NPY or NPY mRNA levels or in NPY receptor binding. We conclude that the fall in UCP mRNA expression occurring under short-term thermoneutral condition is mediated by neuroendocrine mechanisms other than increased activity of hypothalamic NPY neurons.

Adipose Tissue, Brown↗
PubMed1995

Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11.

Ninety-five young, male Golden Syrian hamsters were randomly divided into five equally sized groups. One group served as a placebo control while the animals in the others received one of four doses of interleukin-eleven (IL-11) twice daily given by subcutaneous injection beginning on the first day of chemotherapy (day 0) and continuing to day 14. Mucositis was induced with 5-fluorouracil using a standard regimen of 60 mg/kg, intraperitoneally on days 0 and 2 followed by superficial mucosal irritation on day 4. Animals were evaluated daily beginning on day 6. Mucositis was assessed using a standardised technique in which randomly numbered daily mucosal photographs were scored by three blinded independent observers at the conclusion of the experiment. IL-11 favourably affected the frequency, severity and duration of mucositis. This phenomenon appeared to be dose dependent. Hamsters receiving 30 and 100 micrograms per day of IL-11 demonstrated significantly (P < 0.05) lower mucositis scores than did either the control or animals receiving 3 or 10 micrograms per day, although the latter had marginal beneficial effects. Additionally, survival was significantly better for hamsters receiving higher doses of IL-11 (85%) compared to the placebo control (46%). IL-11 administration also favourably affected weight loss. While stimulation of platelet production was noted in animals receiving IL-11, a lack of difference in bone marrow cellularity between test and control animals suggests that the mechanism by which IL-11 modifies mucositis is mediated at the epithelial or connective tissue level rather than through the marrow. The kinetics of IL-11 alteration of mucositis induction supports such a hypothesis. Further investigation is currently underway to establish a definitive mechanism by which IL-11 protects the oral mucosa.

Animals↗
PubMed1995

Predicting the fertilizing potential of human sperm suspensions in vitro: importance of sperm morphology and leukocyte contamination.

OBJECTIVE: To determine the relationships between sperm function tests and fertilization of human oocytes in vitro. DESIGN: Analysis of infertile patients undergoing IVF therapy. SETTING: Diagnostic Andrology Laboratory and Assisted Conception Service. PATIENTS: Forty-one couples who underwent IVF-ET therapy were studied. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The ability of human spermatozoa to achieve fertilization in vitro was examined in relation to numerous criteria of semen quality, including the conventional semen profile, the computer-aided assessment of sperm movement, ionophore-induced acrosome reaction, acridine orange staining, sperm morphology, and chemiluminescent signals induced by phorbol ester and N-formyl-methionyl-leucyl-phenylalanine (FMLP). RESULTS: Significant correlations were observed between fertilization rates and several attributes of the sperm preparations, including elements of sperm function (acrosome reaction), movement (percentage motile, hyperactivation, the amplitude of lateral sperm head displacement), morphology (normal morphology, midpiece defects, multiple anomalies index), nuclear normality (acridine orange staining), and reactive oxygen species generation (chemiluminescence induced by phorbol ester and FMLP). In a stepwise multiple regression analysis, an accurate prediction of fertilization rates was obtained using a multiple regression equation incorporating six variables of which sperm morphology and FMLP-induced chemiluminescence were the most informative. CONCLUSIONS: A set of criteria have been identified that accurately predict the fertilizing potential of human sperm suspensions in vitro and that place particular emphasis on sperm morphology and the degree of leukocyte contamination.

Acridine Orange↗
PubMed1995

Definition of the optimal criteria for identifying hyperactivated human spermatozoa at 25 Hz using in-vitro fertilization as a functional end-point.

Spermatozoa from fertile donors were used to select and validate criteria for the automated classification of hyperactivated (HA) motility using a computer-aided sperm analysis (CASA) system operating at 25 Hz. In the first phase of this analysis, 710 sperm trajectories were analysed and classified as forward progressive (FP), transition phase (TP) or HA. These tracks were then subjected to a CASA analysis and the various attributes of sperm movement defined for each category of motion. From this analysis, criteria were identified and subsequently validated that permitted the automated selection of FP, TP+HA and HA cells, with > 90% accuracy. To determine which attributes of movement best predicted the fertilizing potential of human spermatozoa, a detailed analysis of sperm motion was undertaken in patients undergoing in-vitro fertilization therapy. This analysis indicated that the single most important aspect of sperm movement was the incidence of HA motility (defined as curvilinear velocity > 90 microns/s, linearity < 20%, dancemean [amplitude of lateral head displacement/linearity x 100] > 45.8 microns) after 3 h of incubation. Using the latter criterion as the first incorporated variable, multiple regression equations were created that explained up to 50% of the variance in fertilization rates. None of the other patterns of motion (FP, TP, TP+HA) was correlated with fertilization rates, and none of the other published algorithms for identifying HA cells were as efficient as those described here.

Cohort Studies↗
PubMed1995

Interleukin-11 enhances gastrointestinal absorption of iron in rats.

The effect of parenteral administration of IL-11 on gastrointestinal iron absorption was evaluated. A significant increase in the absorption of 59Fe-tagged food iron fed to fasting rats was observed when two subcutaneous injections of IL-11 were given 48 and 24 h prior to testing. Relatively similar increases of 25% were observed with IL-11 doses of 300, 600 and 1000 micrograms/kg for each injection. The increase in absorption did not appear to be related to changes in erythropoiesis. These findings raise the possibility that the enhanced absorption of iron which occurs with ineffective erythropoiesis may in part be mediated by multifunctional haemopoietic growth factors.

Animals↗
PubMed1994

First meiotic division abnormalities in human oocytes: mechanism of trisomy formation.

Trisomy is the single most frequent type of chromosome abnormality in humans and has considerable impact on many aspects of human pathology. It arises most commonly through "nondisjunction" at maternal meiosis I, but the underlying mechanism of formation remains obscure. Analysis of 100 haploid oocytes at second meiotic metaphase shows that the only type of chromosome abnormality compatible with trisomy formation after fertilisation is the presence of single chromatids in addition to, or replacing, whole chromosomes. The mechanism resulting in the presence of single chromatids is considered to be precocious division of univalents or dyads at first meiotic anaphase.

Adult↗
PubMed1993

Chromosome anomalies in human oocytes in relation to age.

Cytogenetic analysis of oocytes remaining unfertilized after in-vitro fertilization showed that the source of data obtained could be divided into degenerating and 'healthy' oocytes. The degenerating oocytes, which showed different degrees of chromosome breakage, accounted for a quarter of the total. They were found in older patients with a mean age of 35.0 years. The healthy oocytes without chromosome breaks were mostly haploid and fell into two main groups, those with a normal MII,23,X chromosome complement, and those abnormal in which single chromatids replaced a whole chromosome. No oocytes hyperhaploid for an extra whole chromosome were found. We hypothesize that the single chromatids at second meiotic metaphase arise by precocious division of chromosome univalents at anaphase I (predivision) and that this may be the major mechanism for trisomy formation in man, rather than the non-disjunction of whole bivalents as generally assumed.

Aging↗
PubMed1992

Effects of a 48 hour continuous intravenous infusion of CGS 13080-primagrel, a selective thromboxane synthetase inhibitor, on the perinatal and early postnatal period in the guinea pig.

CGS 13080, imidazo[1,5-a]pyridine-5-hexanoic acid, was evaluated for perinatal and postnatal effects in third trimester pregnant guinea pigs and their offspring. The compound was administered via 48 hour continuous intravenous infusion to a group of pregnant guinea pigs (n = 16) at a dose of 3 mg/kg/hr starting on gestational day 52 (via chronically implanted indwelling jugular venous cannulas). A saline control group (n = 12) received equivalent volumes of normal saline 0.5 ml/kg/hr throughout the dosing period. A third group (surgery-sham, n = 16) was subjected to cannulation but not infused. A gross examination of each dam and piglets was conducted at necropsy on day 5 of lactation. The neonatal brains and all gross lesions (maternal and neonatal) were removed and fixed for histopathological examination. Compound-related clinical signs were noted in dams during the dosing phase of gestation. Six guinea pigs developed cephalic lymphatic swelling during the infusion. This observation may be correlated to the reported redistribution of fluid volume to the thorax of guinea pigs given intravenous injections of CGS 13080. There were no compound-induced effects on labor, delivery, or any of the examined reproductive parameters. There were no compound-related clinical signs, or effects on survival, body weight and developmental parameters in the F1 generation. Histopathological examination of the brains and other organs did not reveal any compound-related abnormalities. Based on these results, it was concluded that CGS 13080 did not elicit adverse perinatal and postnatal effects in guinea pigs.

Animals↗