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Biomedical subjects

N Nicholson

Publications and source records attributed to N Nicholson.

At least 19 recordsLinked to original sources
PubMed2001

Xemilofiban/orbofiban: insight into drug development.

A number of studies have reported on the successful use of intravenous glycoprotein IIb/IIIa receptor antagonists in patients with unstable angina or undergoing percutaneous interventions. The promise of interrupting the aggregation of platelets in the setting of unstable plaques on a chronic basis had led to the evaluation of several oral agents for longer-term administration. The development program of two of these agents, xemilofiban and orbofiban, will be reviewed and evaluated to understand the selection process of therapeutic targets for use based upon complex pharmacokinetic and pharmacodynamic responses. A review of the pivotal phase III trial results will also be provided along with insights into the potential reasons for the lack of significant benefit shown with these agents to date.

Alanine↗
PubMed2000

The structure of ribonuclease P protein from Staphylococcus aureus reveals a unique binding site for single-stranded RNA.

Ribonuclease P (RNaseP) catalyses the removal of the 5'-leader sequence from pre-tRNA to produce the mature 5' terminus. The prokaryotic RNaseP holoenzyme consists of a catalytic RNA component and a protein subunit (RNaseP protein), which plays an auxiliary but essential role in vivo by binding to the 5'-leader sequence and broadening the substrate specificity of the ribozyme. We determined the three-dimensional high-resolution structure of the RNaseP protein from Staphylococcus aureus (117 amino acid residues) by nuclear magnetic resonance (NMR) spectroscopy in solution. The protein has an alphabeta-fold, similar to the ribonucleoprotein domain. We used small nucleic acid molecules as a model for the 5'-leader sequence to probe the propensity for generic single-stranded RNA binding on the protein surface. The NMR results reveal a contiguous interaction site, which is identical with the previously identified leader sequence binding site in RNaseP holoenzyme. The conserved arginine-rich motif does not bind single-stranded RNA. It is likely that this peptide segment binds selectively to double-stranded sections of P RNA, which are conformationally more rigid. Given the essentiality of RNaseP for the viability of the organism, knowledge of the S. aureus protein structure and insight into its interaction with RNA will help us to develop RNaseP and RNaseP protein as targets for novel antibiotics against this pathogen.

Amino Acid Sequence↗
PubMed1999

A new model of dual interacting ligand binding sites on integrin alphaIIbbeta3.

The platelet integrin alphaIIbbeta3 mediates platelet aggregation and platelet adhesion. This integrin is the key to hemostasis and also to pathologic vascular occlusion. A key domain on alphaIIbbeta3 is the ligand binding site, which can bind to plasma fibrinogen and to a number of Arg-Gly-Asp (RGD)-type ligands. However, the nature and function of the ligand binding pocket on alphaIIbbeta3 remains controversial. Some studies suggest the presence of two ligand binding pockets, whereas other reports indicate a single binding pocket. Here we use surface plasmon resonance to show that alphaIIbbeta3 contains two distinct ligand binding pockets. One site binds to fibrinogen, and a separate site binds to RGD-type ligands. More importantly, however, the two ligand binding pockets are interactive. RGD-type ligands are capable of binding to alphaIIbbeta3 even when it is already occupied by fibrinogen. Once bound, RGD-type ligands induce the dissociation of fibrinogen from alphaIIbbeta3. This allosteric cross-talk has important implications for anti-platelet therapy because it suggests a novel approach for the dissolution of existing platelet thrombi.

Allosteric Regulation↗
PubMed1995

Late intracytoplasmic sperm injection in unexpected failed fertilization in vitro: diagnostic or therapeutic?

OBJECTIVE: To evaluate fertilization potential of 24-hour-old unfertilized oocytes using intracytoplasmic sperm injection and the pregnancy potential of resultant embryos. DESIGN: Prospective observational study. SETTING: Private infertility clinic, London, United Kingdom. PATIENTS: Fifteen patients with a history of infertility who underwent treatment with IVF and showed failure of fertilization on the day after oocyte retrieval. INTERVENTION: Assisted fertilization with intracytoplasmic sperm injection was carried out at 24 hours after oocyte retrieval. RESULTS: A total of 121 metaphase II oocytes were subjected to intracytoplasmic sperm injection. Of these, 9 were damaged (7%), 2 were polyploidic (2%), and 58 showed normal fertilization (48%). Of the latter, 47 cleaved normally (81%). Forty embryos were transferred and three were cryopreserved. One patient conceived (7%) but in this case only one of three embryos transferred was from intracytoplasmic sperm injection. CONCLUSION: Late (24 hours) intracytoplasmic sperm injection can give good fertilization and cleavage rates but the potential of the generated embryos to achieve pregnancy seems to be low.

Adult↗
PubMed1995

Percutaneous epididymal sperm aspiration and intracytoplasmic sperm injection in the management of infertility due to obstructive azoospermia.

OBJECTIVE: To evaluate the recovery rate of spermatozoa from the epididymis using a percutaneous aspiration technique and to examine the fertilization rate after intracytoplasmic sperm injection. DESIGN: Prospective observational study. SETTING: Private infertility clinic, London. SUBJECTS: Twenty patients with obstructive azoospermia who each had an attempt at IVF. The sperm used for intracytoplasmic sperm injection was retrieved by percutaneous epididymal sperm aspiration in 16 patients. In one patient, microepididymal sperm aspiration was performed in addition because the quality of the sperm obtained by percutaneous epididymal sperm aspiration was not considered suitable for microinjection. In the remaining three patients, neither percutaneous epididymal sperm aspiration nor microepididymal sperm aspiration resulted in the recovery of sperm, which was obtained by testicular biopsy in one of them. INTERVENTION: Assisted fertilization with intracytoplasmic sperm injection. MAIN OUTCOME MEASURES: Normal fertilization and pregnancy rates. RESULTS: A total of 179 eggs were collected and 157 subsequently were microinjected. Normal fertilization occurred in 22 oocytes (14%) and the total number of embryos cleaved was 30. Twelve patients underwent ET in which three conceived (pregnancy rate 25% per transfer). The implantation rate was 10% and failed fertilization occurred in four cycles. CONCLUSION: Percutaneous epididymal sperm aspiration can be used successfully to recover sperm in men with obstructive azoospermia for use in assisted fertilization IVF cycles. The technique is simple, effective, and less traumatic compared with an open microsurgical operation.

Adult↗
PubMed1994

Experience with subzonal insemination (SUZI) and intracytoplasmic sperm injection (ICSI) on unfertilized aged human oocytes.

OBJECTIVE: The aim of this study was to assess the fertilizability of unfertilized aged human oocytes from failed in vitro fertilization (IVF) cycles using SUZI and ICSI. METHODS: A total of 363 oocytes which showed no fertilization after conventional IVF was subjected to assisted fertilization using SUZI or ICSI. The microinjected oocytes which were derived from 72 patients undergoing their first IVF treatment had an intact polar body and no signs of degeneration. SUZI was carried out in 265 oocytes and ICSI in the remaining 98. RESULTS: Significantly more oocytes were damaged after ICSI (9 vs 0.3%, P < 0.01). Normal fertilization rates were higher at 24 hr in both groups and occurred more frequently after ICSI, although the difference did not reach statistical significance. Abnormal fertilization occurred significantly more often after SUZI at 48 hr (P < 0.005), but not at 24 hr. Cleavage rates were significantly higher after ICSI (94.4 vs 57.1%, P < 0.025) at 24 hr, but this was not observed at 48 hr, although the ICSI group still showed better cleavage rates (33.3 vs 19.1%). There was no difference in embryo quality in either group. CONCLUSIONS: Our results indicate that micromanipulation rather than reinsemination should be carried out on unfertilized human oocytes from failed IVF attempts. Both techniques can be used to achieve fertilization which occurs more often after ICSI. However, the trauma from the former technique on the microinjected oocytes may impair the potential of the generated embryos to achieve pregnancy compared to SUZI. Prospective randomized trials are necessary to address the problem.

Adult↗
PubMed1994

Assisted fertilization with intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the significance of intracytoplasmic sperm injection in severe male factor infertility and previous failed fertilization. DESIGN: Prospective observational study. SETTING: Private infertility clinic, London. SUBJECTS: Sixty-nine patients with a long-standing history of infertility of which 48 had previous failed fertilization, 15 had < 1 million progressive motile sperm per ejaculate, and the remaining 6 had obstructive azoospermia. INTERVENTION: Assisted fertilization with primary intracytoplasmic sperm injection was carried out in 69 IVF. OUTCOME: Normal (two pronuclei [2PN]) fertilization and pregnancy rates. RESULTS: A total of 967, oocytes were collected and 785 were subsequently microinjected. Normal fertilization (2PN) occurred in 410 oocytes (52%) and 90.5% of those cleaved. Sixty-four patients underwent ET, with a total of 181 embryos transferred. Twenty-five patients conceived with a pregnancy rate of 39% per transfer. The implantation rate was 16% and the total pregnancy loss rate 24%. Failed fertilization after intracytoplasmic sperm injection occurred in four cases. CONCLUSIONS: Intracytoplasmic sperm injection is increasingly becoming the treatment of choice in infertile couples where assisted fertilization is indicated. The high fertilization and pregnancy rates observed with this technique, together with a low risk of abnormalities, has revolutionized treatment of male factor infertility.

Adult↗
PubMed1992

A successful transport scenario for the health sector in developing countries.

The role and operation of transport in the health sector in developing countries is important, costly but often taken for granted. This article suggests the need for a fresh look at the policy, planning and management of transport through the analysis of the essential components of a successful transport scenario for health services in developing countries i.e. transport and health planning; transport and organisational responsibility; the role of health sector donors; decision-making and procurement of transport and spares; transport and human resources; monitoring and control of transport and information; maintenance and repair; the budget. The article concludes with a checklist of key questions that may be used in assessing the contribution of transport to the health services.

Decision Making, Organizational↗
PubMed1990

To the lighthouse.

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Administrative Personnel↗
PubMed1989

Self-regulatory treatment of headache in the elderly.

We examined the utility of various combinations of relaxation, cognitive coping, and feedback in an uncontrolled series of 16 older headache patients (aged 60 to 77) diagnosed as having tension, mixed, or migraine headache. At 1-month follow-up, statistically and clinically significant reductions were observed in both overall headache activity and medication intake; 10 patients (63%) were more than 50% improved in both headache reduction and medication reduction. Female headache suffers were more improved than males. These results are inconsistent with our past findings with geriatric headache sufferers but consistent with other, more recent favorable findings. The efficacy of nondrug treatment for geriatric headache clearly warrants further attention.

Adaptation, Psychological↗
PubMed1984

Distribution of a proteinase inhibitor of epididymal origin in the tissues and secretions of the male reproductive tract of mice.

Monoclonal antibodies to a low molecular weight, acid-stable acrosin-trypsin inhibitor isolated from epididymal homogenates were used to localize the inhibitor in tissues and secretions of the male reproductive tract of mice. The inhibitor, identified by indirect immunofluorescence, is present in the testes and in the apical portion of the epithelial cells from the caput region of the epididymis of both intact and efferentiectomized animals. Sperm isolated from the testes and caput epididymal region show inhibitor-positive fluorescence on the anterior acrosomal region. The inhibitor could not be localized on ductus or electroejaculated sperm or ductus sperm previously incubated in a purified inhibitor solution. Furthermore, the inhibitor was not visible in the copulatory plug of recently inseminated animals or on sperm recovered from the uterus or from an artificial capacitating medium. The inhibitor could be detected by an enzyme-linked immunosorbent assay in the supernatants of detergent treated or frozen-thawed caput sperm but not of ductus sperm. The data suggest that the inhibitor, made in both the testes and caput epididymis where it associates with the sperm, is lost from the sperm or irreversibly masked during the epididymal sojourn.

Animals↗
PubMed1983

Home comforts.

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Home Care Services↗
PubMed1983

Immunofluorescent localization of a seminal vesicle proteinase inhibitor in the female reproductive tract of naturally inseminated mice.

The indirect immunofluorescent technique was used to localize a low molecular weight, acid-stable proteinase inhibitor of seminal vesicle origin in the female reproductive tract of mice. In recently inseminated animals (0, 2, and 4 hr postcoitus) the inhibitor was localized in the copulatory plug, on the epithelia of the vaginal fornix and cervix, in the uterine lumen, and on the apical surface of the uterine epithelium. Ten hours postcoitus the inhibitor was found in localized areas on the uterine epithelium, in a sperm-leucocyte mass in the uterine lumen, and in the copulatory plug. The inhibitor was not found in females 24 hr postcoitus. The inhibitor could not be localized in the oviducts of any of the animals tested. The data are interpreted to mean that the inhibitor, transported to the female at ejaculation, coats the surface of the female reproductive tract protecting it from acrosomal enzymes or from invasion by spermatozoa or pathogens.

Animals↗
PubMed1983

Immunofluorescent localization of a murine seminal vesicle proteinase inhibitor.

The indirect immunofluorescent technique was used to localize a proteinase inhibitor isolated from murine seminal vesicles. The inhibitor was found in the lumen and in the apical epithelium of the seminal vesicle but not in the testes, epididymides, ductus deferens or Cowper's glands. It was also associated with the anterior acrosomal region of ejaculated sperm and sperm recovered from the female tract within 5 min of coitus. The inhibitor is removed from uterine sperm between 2 to 4 h postcoitus, however sperm recovered from the uterus 2 h postcoitus will rebind inhibitor. The inhibitor is not normally associated with epididymal or ductus sperm although these sperm will bind purified inhibitor in vitro.

Animals↗