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Biomedical subjects

A Holmes

Publications and source records attributed to A Holmes.

At least 109 records · Page 6Linked to original sources
PubMed1997

In vitro and in vivo disposition of 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976). Identification of a novel five-carbon cleavage metabolite in rats.

The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration. The major metabolite observed both in vitro and in vivo was identified as the 6-carbon, chain-shortened 5,5-dimethyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid (M-4). M-4 was determined to be formed from the omega-carboxylic acid 11,11-dimethyl-12-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid (M-1) via the 2- and 4-carbon, chain-shortened intermediate metabolites [9,9-dimethyl-10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid (M-2) and 7,7-dimethyl-8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]octanoic acid (M-3)], respectively. M-1 was, in turn, determined to be derived from omega-hydroxy CI-976. A minor metabolite, identified in vitro and in vivo, was a novel 5-carbon, chain-shortened derivative, 6,6-dimethyl-7-oxo-7-[(2,4,6-trimethoxyphenyl)amino]heptanoic acid (M-5). M-5 was shown not to be formed from either M-1 or the omega-hydroxy derivative. Separate incubation of CI-976 (omega-oxidation and beta-oxidation pathways) and M-1 (beta-oxidation only) indicated a potential gender difference in the omega-oxidation of CI-976. Both the omega-oxidation and beta-oxidation pathways were enhanced by clofibrate and phenobarbital induction, and CI-976 metabolism was completely inhibited when coincubated with SKF525A pointing to cytochrome P450-mediated metabolism, presumably CYP4A. Etomoxir and L-carnitine had minor effects on the beta-oxidation of M-1, indicating beta-oxidation occurs predominately within peroxisomes.

Anilides↗
PubMed1997

Hypoadrenocorticism in young related Nova Scotia duck tolling retrievers.

Five cases of hypoadrenocorticism in young related Nova Scotia duck tolling retrievers are discussed. Two were littermates and the others shared one or more common ancestors. No specific mode of inheritance was determined. Clinical and laboratory findings typical of hypoadrenocorticism were observed. Further documentation will be required to confirm a breed predisposition.

Adrenal Glands↗
PubMed1996

Randomised, controlled trial of efficacy of midwife-managed care.

BACKGROUND: Midwife-managed programmes of care are being widely implemented although there has been little investigation of their efficacy. We have compared midwife-managed care with shared care (ie, care divided among midwives, hospital doctors, and general practitioners) in terms of clinical efficacy and women's satisfaction. METHODS: We carried out a randomised controlled trial of 1299 pregnant women who had no adverse characteristics at booking (consent rate 81.9%). 648 women were assigned midwife-managed care and 651 shared care. The research hypothesis was that compared with shared care, midwife-managed care would produce fewer interventions, similar (or more favourable) outcomes, similar complications, and greater satisfaction with care. Data were collected by retrospective review of case records and self-report questionnaires. Analysis was by intention to treat. FINDINGS: Interventions were similar in the two groups or lower with midwife-managed care. For example, women in the midwife-managed group were less likely than women in shared care to have induction of labour (146 [23.9%] vs 199 [33.3%]; 95% CI for difference 4.4-14.5). Women in the midwife-managed group were more likely to have an intact perineum and less likely to have had an episiotomy (p = 0.02), with no significant difference in perineal tears. Complication rates were similar. Overall, 32.8% of women were permanently transferred from midwife-managed care (28.7% for clinical reasons, 3.7% for non-clinical reasons). Women in both groups reported satisfaction with their care but the midwife-managed group were significantly more satisfied with their antenatal (difference in mean scores 0.48 [95% CI 0.41-0.55]), intrapartum (0.28 [0.18-0.37]), hospital-based postnatal care (0.57 [0.45-0.70]), and home-based postnatal care (0.33 [0.25-0.42]). INTERPRETATION: We conclude that midwife-managed care for healthy women, integrated within existing services, is clinically effective and enhances women's satisfaction with maternity care.

Adult↗
PubMed1996

Changes in cervical canal spinal volume during in vitro flexion-extension.

STUDY DESIGN: Quasistatic flexion and extension loads were applied in vitro to lower cervical spines. The flexion-extension motion produced was checked for physiologic relevance. OBJECTIVES: To examine the changes in the volume of the cervical spinal canal in flexion-extension motion. SUMMARY OF BACKGROUND DATA: Many papers have been published concerning the cervical canal volume as inferred from standard lateral radiographs. This study compares the inferred (radiographic) volumes and their changes to the physical changes within the spinal canal. METHODS: The lower cervical spines (C2-C7) from 10 cadavers were subject to stepwise flexion and extension in a purpose-built rig. Before this testing, the spinal cord was removed from the canal space of each specimen and replaced by a thin latex tube stoppered and secured at the opening of the canal (at C2) so that the volume of liquid displaced from the tube could be measured. This was done at each loading stage by means of a graduated glass column, and a radiograph of the spine was also taken to allow angular and displacement readings to be taken from C2 to C7. RESULTS: The average recorded change in volume of the spinal canal with flexion-extension motion was 1.9 ml, and showed a significant linear correlation with the dynamic canal width (r = 0.868, P < 0.05) and also with the total angle of flexion or extension (r = 0.979, P < 0.005). The volume of liquid displaced from the canal in lateral bending was much lower than that in flexion-extension motion, and only amounted to about 0.2 ml. The angular ranges of motion produced at each level were compared to previous results obtained in vivo, and no significant differences between the angular displacements found in vivo and in vitro under this experimental arrangement were seen. CONCLUSIONS: The loading regime described in this study causes angular displacements similar to those in vivo, and on this basis is a physiologically relevant loading pattern. The change in the volume of the spinal canal between C2 and C7 shows linear relationships with the angle of flexion and the dynamic canal width.

Adult↗
PubMed1996

Detecting activations in PET and fMRI: levels of inference and power.

This paper is about detecting activations in statistical parametric maps and considers the relative sensitivity of a nested hierarchy of tests that we have framed in terms of the level of inference (voxel level, cluster level, and set level). These tests are based on the probability of obtaining c, or more, clusters with k, or more, voxels, above a threshold u. This probability has a reasonably simple form and is derived using distributional approximations from the theory of Gaussian fields. The most important contribution of this work is the notion of set-level inference. Set-level inference refers to the statistical inference that the number of clusters comprising an observed activation profile is highly unlikely to have occurred by chance. This inference pertains to the set of activations reaching criteria and represents a new way of assigning P values to distributed effects. Cluster-level inferences are a special case of set-level inferences, which obtain when the number of clusters c = 1. Similarly voxel-level inferences are special cases of cluster-level inferences that result when the cluster can be very small (i.e., k = 0). Using a theoretical power analysis of distributed activations, we observed that set-level inferences are generally more powerful than cluster-level inferences and that cluster-level inferences are generally more powerful than voxel-level inferences. The price paid for this increased sensitivity is reduced localizing power: Voxel-level tests permit individual voxels to be identified as significant, whereas cluster-and set-level inferences only allow clusters or sets of clusters to be so identified. For all levels of inference the spatial size of the underlying signal f (relative to resolution) determines the most powerful thresholds to adopt. For set-level inferences if f is large (e.g., fMRI) then the optimum extent threshold should be greater than the expected number of voxels for each cluster. If f is small (e.g., PET) the extent threshold should be small. We envisage that set-level inferences will find a role in making statistical inferences about distributed activations, particularly in fMRI.

Brain↗
PubMed1996

Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo.

At day 10 in mouse gestation, the intraembryonic aorta-gonads-mesonephros (AGM) region generates the first definitive hematopoietic stem cells (HSCs) of the adult blood system. By 11 days postcoitum, the liver contains such HSCs. While HSCs of the adult bone marrow and late-stage fetal liver have been extensively characterized for cell surface markers, there has been no phenotypic description of the first HSCs during embryo development. We report here the temporal cell surface phenotype of HSCs from the AGM region and early fetal liver and show that all HSCs reside in the c-kit+ population. c-kit+ HSCs from AGM and liver are mainly CD34+ and in the AGM are in both Mac-1+ and Mac-1 fractions. These results demonstrate that during mouse ontogeny the first definitive HSCs are similar in cell surface phenotype to the HSCs of adult bone marrow but that spatial localization and developmental time are critical factors in the phenotypic assessment of this functional cell population.

Animals↗
PubMed1996

Emergency hormonal contraception usage in genitourinary medicine clinic attenders.

OBJECTIVE: To assess the indications for usage of emergency hormonal contraception amongst a population of London genitourinary medicine clinic attenders. METHODS: In a prospective study, 150 consecutive women receiving emergency hormonal contraception (EHC) were enrolled. The attending doctor completed a questionnaire of patient details and prescribed EHC with prophylactic prochlorperazine. Follow-up was arranged three weeks later, at which time outcomes and side-effects of therapy were recorded. For those women who did not reattended as planned case notes were reviewed at three months. RESULTS: Of 150 women surveyed, 100 (66%) reported contraceptive method failure, 48 (32%) had used no contraception at the time of last sexual intercourse and two requested EHC after sexual assault. Ninety three (62%) reported condom failure, 7 (5%) oral contraceptive pill failure. Seventy five (50%) had used EHC before (range 1-10 times). Seventy one (47%) women reattended within three months. Five (3.3%) of the 150 women were pregnant; none of these cases had experienced nausea or vomiting whilst taking EHC. Side-effects were reported by 22 (31%) of the 71 patients who reattended. Nine (6%) women had been followed-up in the family planning advisory clinic. Of the 71 women who reattended, 39 (55%) reported that their preferred future method of contraception would be condoms. Of the 150 women 19 (13%) underwent tests for sexually transmissible infections within one month of presentation. CONCLUSIONS: EHC usage in this population was associated with a failure rate of at least 3.3% and an overall side effect rate of 31%. Despite requests for emergency contraception because of condom failure many elected to continue using condoms as their preferred method of contraception. The majority of women (53%) did not return for follow-up or family planning advice, and so we believe that future contraceptive plans must be addressed at the time EHC is prescribed.

Adolescent↗
PubMed1996

The Consultant Orthodontists Group 1994 survey of the use of the Index of Orthodontic Treatment Need (IOTN).

A questionnaire, relating to the use and acceptance of occlusal indices and in particular the Index of Orthodontic Treatment Need (IOTN), was sent to all UK hospital consultants in the orthodontics. Of the respondents 74.6 per cent routinely recorded the Dental Health Component of IOTN for their new patient referrals. The reasons for the increased acceptance of the IOTN amongst hospital orthodontic consultants are evaluated and some of the difficulties in usage, reported by respondents, are discussed.

Cephalometry↗
PubMed1996

Roles of diet and physical activity in the prevention of osteoporosis.

In recent years, much attention has been directed toward the prevention of osteoporosis, since this disease has become a leading cause of morbidity and mortality in elderly women. Research has demonstrated that the prevention of osteoporosis and osteoporosis-related fractures may best be achieved by initiating sound health behaviors early in life and continuing them throughout life. Evidence suggests that osteoporosis is easier to prevent than to treat. In fact, healthy early life practices, including the adequate consumption of most nutrients, regular physical activity, and other health behaviors, contribute to greater bone mineral measurements and optimal peak bone mass by the fourth decade of life of females, and, perhaps, also of males. Several reports have shown that the adequate consumption of nutrients, calcium in particular, during the pre-pubertal and early post-pubertal years of females contribute to increased peak bone mass. Indeed, skeletal benefits from long-term calcium supplementation have been reported for females at practically every period of the life cycle. Vitamin D, which may be either consumed or produced endogenously through the action of sunlight, promotes calcium absorption and thereby enhances bone mineralization. Thus, the adequate consumption of calcium, in conjunction with vitamin D, in early life will likely optimize peak bone mass, and adequate intakes of these two nutrients should continue through the remainder of life to help maintain bone mass. On the other hand, excess phosphorus consumption may deter bone mineral accrual because of the resultant elevation of serum parathyroid hormone levels. Additionally, high intakes of protein, sodium, and caffeine may decrease bone mineral mass through increased urinary excretion of calcium. Vitamin K may also have an important positive effect on the development and maintenance of bone through its role in promoting carboxylations of the matrix protein, osteocalcin. In conclusion, the prevention of osteoporosis needs to begin during the pre-pubertal years and it should be continued throughout life. Bone mass can better be maintained later in life through adequate consumption of several nutrients with specific roles in calcium and bone metabolism, regular physical activity, and the practice of a healthy lifestyle. Mechanisms through which the nutrients and exercise affect bone mass will be explored.

Bone Development↗
PubMed1995

A functional neuroanatomy of hallucinations in schizophrenia.

Hallucinations, perceptions in the absence of external stimuli, are prominent among the core symptoms of schizophrenia. The neural correlates of these brief, involuntary experiences are not well understood, and have not been imaged selectively. We have used new positron emission tomography (PET) methods to study the brain state associated with the occurrence of hallucinations in six schizophrenic patients. Here we present a group study of five patients with classic auditory verbal hallucinations despite medication, demonstrating activations in subcortical nuclei (thalamic, striatal), limbic structures (especially hippocampus), and paralimbic regions (parahippocampal and cingulate gyri, as well as orbitofrontal cortex). We also present a case study of a unique, drug-naive patient with visual as well as auditory verbal hallucinations, demonstrating activations in visual and auditory/linguistic association cortices as part of a distributed cortical-subcortical network. Activity in deep brain structures, identified with group analysis, may generate or modulate hallucinations, and the particular neocortical regions entrained in individual patients may affect their specific perceptual content. The interaction of these distributed neural systems provides a biological basis for the bizarre reports of schizophrenic patients.

Adult↗
PubMed1995

Effects of granulocyte colony-stimulating factor and interferon-gamma on antifungal activity of human polymorphonuclear neutrophils against pseudohyphae of different medically important Candida species.

Polymorphonuclear neutrophils (PMNs) are the major host defense against pseudohyphae, the invasive form of Candida species. We studied the effects of granulocyte colony-stimulating factor (G-CSF) and interferon-gamma (IFN-gamma) on the PMN-induced damage of pseudo-hyphae of Candida albicans, Candida tropicalis, and Candida parapsilosis in vitro by using two antifungal assays: a modified limiting dilution assay and a colorimetric metabolic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. PMNs from healthy volunteers were incubated with either G-CSF (100-10,000 U/ml) or IFN-gamma (10-5000 U/ml) or buffer at 37 degrees C for 90 min and their capacity to damage nonopsonized pseudohyphae was then measured. C. tropicalis appeared to be the most susceptible species, whereas C. parapsilosis showed the highest rate of resistance to PMN damage. G-CSF (500-10,000 U/ml) and IFN-gamma (100-1000 U/ml) enhanced the antifungal activity of PMNs against C. albicans pseudo-hyphae (P < .01 and P < .05). Among the others, G-CSF enhanced PMN-induced damage of C. parapsilosis at concentrations 500-10,000 U/ml (P < .05), whereas it enhanced damage of C. tropicalis only at 10,000 U/ml (P < .01). IFN-gamma (100-1000 U/ml)-primed PMNs also caused augmented damage of C. parapsilosis (P < .05) but not of C. tropicalis at the same concentrations. Species-dependent differences exist in the responses of PMNs to Candida pseudohyphae and G-CSF as well as IFN-gamma are important immunomodulators of phagocytic host defenses against them.

Adult↗
PubMed1995

The emergence of a highly transmissible lineage of cbl+ Pseudomonas (Burkholderia) cepacia causing CF centre epidemics in North America and Britain.

The rapid increase in Pseudomonas (Burkholderia) cepacia infection in cystic fibrosis (CF) patients suggests epidemic transmission, but the degree of transmissibility remains controversial as conflicting conclusions have been drawn from studies at different CF centres. This report provides the first DNA sequence-based documentation of a divergent evolutionary lineage of P. cepacia associated with CF centre epidemics in North America (Toronto) and Europe (Edinburgh). The involved epidemic clone encoded and expressed novel cable (Cbl) pili that bind to CF mucin. The sequence of the cblA pilin subunit gene carried by the epidemic isolates proved to be invariant. Although it remains to be determined how many distinct, highly transmissible lineages exist, our results provide both a DNA sequence and chromosomal fingerprint that can be used to screen for one such particularly infectious, transatlantic clone.

Amino Acid Sequence↗
PubMed1995

Effects of macrophage colony-stimulating factor on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus.

The effects of recombinant human macrophage colony-stimulating factor (M-CSF) on antifungal activity of human monocytes (MNC), MNC-derived macrophages (MDM), and rabbit pulmonary alveolar macrophages (PAM) against Aspergillus fumigatus were studied. MNC-induced hyphal damage was augmented by incubation with M-CSF (P = .027); PAM-induced hyphal damage was moderately enhanced by M-CSF (P = .046). Phagocytosis of Aspergillus conidia by MDM and PAM was strongly enhanced by M-CSF (P < .01). MNC pretreated with M-CSF exhibited enhanced superoxide anion production in response to PMA (P = .026). This effect was not associated with increased levels of mRNA transcripts of the components of NADPH oxidase, the enzyme responsible for superoxide anion production. M-CSF augments antifungal activity of mononuclear phagocytes against both conidia and hyphae of Aspergillus fumigatus partly by enhancement of oxidation-dependent mechanisms and may have an important immunomodulatory role in prevention and treatment of invasive aspergillosis in leukopenic patients.

Animals↗
PubMed1995

Relation between cerebral activity and force in the motor areas of the human brain.

1. Positron emission tomography (PET) studies were performed in six normal right-handed male volunteers (age 30 +/- 3) to investigate the relationship between cerebral activation as measured by relative regional cerebral blood flow (rCBF) and force peak exerted during right index finger flexion. The purpose was to determine in which central motor structures activity is directly correlated with force for repeatedly executed movements. 2. Twelve PET rCBF measurements were performed in each volunteer with the use of H2(15)O as a perfusion tracer. Volunteers pressed a Morse-key repetitively with their right index finger for 2 min while lying in a supine position in the PET camera. The device was fitted with strain gauges to measure the force peaks exerted upon it. Scans were collected twice each at five different levels of exerted force peak and in a resting state. Individual and group results were co-registered with anatomic magnetic resonance images (MRI). 3. Group analysis revealed four major regions with a high correlation between rCBF and different degrees of repetitively exerted force peaks. One was located in the arm area of the left lateral surface [primary somatosensory and motor cortex (SI, MI)]. The second area was situated on the left mesial surface of the brain, posterior to the anterior commissure (AC) and encompassing the first gyrus dorsal to the cingulate sulcus. This area is thought to be homologous to the posterior part of the supplementary motor area (SMA) in the monkey. The third area was the dorsal bank of the posterior cingulate sulcus. The fourth area showing a significant correlation between rCBF and force peaks was in the cerebellar vermis. 4. Individual PET data were co-registered with each individual's MRI in order to identify precisely the locations of structures demonstrating a positive correlation between rCBF and force peak. Activated areas on the mesial surface consisted of the same two distinct regions seen in the group data. In three subjects the focus on the lateral surface of the cortex appeared to extend into the caudal premotor area; in two it extended into the rostral part of the superior parietal area. In no subject did blood flow in the anterior cingulate areas and anterior SMA show a correlation with the force exerted. Cerebellar correlations were present in the vermis in all subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

The range and nature of flexion-extension motion in the cervical spine.

OBJECTIVE: The full flexion to full extension angular ranges of motion (ROM) from C2 to C7 were measured for 78 normal subjects and 50 cervical myelopathic cases to examine the cervical motions for these two groups in a Chinese population. METHODS: Measurements were all taken from standard lateral radiographs. RESULTS: The normal group showed an average total ROM slightly less than in Western subjects, but a similar distribution of motion throughout C2 to C7. The proportion of motion at levels C4:C5 and C5:C6 were functions of the total ROM, the greatest proportion of motion being at C4:C5 for low (< 50 degrees) total ROM and moving to C5:C6 for high (> 90 degrees) total ROM. The myelopathic group showed a similar but less clearly established pattern of motion to this. A significantly lower average total ROM than in the normal group was also found. CONCLUSIONS: This work suggests that the reduction in total angular ROM concomitant with aging results in the emphasis of cervical flexion-extension motion moving from C5:C6 to C4:C5, both in normal cases and those suffering from cervical myelopathy.

Adult↗
PubMed1994

Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity.

We recently described our initial structure-activity relationship (SAR) studies on a series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). From this series of analogs, compound 1 (PD 129337) was identified as a potent inhibitor of ACAT with an IC50 value of 17 nM. It was also shown to dose-dependently lower plasma cholesterol in cholesterol-fed rats. However, further investigation led to the suggestion that this compound was poorly absorbed, due to a lack of efficacy when administered by gavage in an aqueous vehicle. To overcome this deficiency, we continued our SAR study on this novel series of ACAT inhibitors using an acute in vivo screen in which the compounds are administered to rats in an aqueous, CMC/Tween suspension vehicle. Modification of the N'-phenyl moiety by incorporating functional groups which were amenable to forming salts and/or polar groups to reduce lipophilicity led to the identification of several inhibitors which displayed excellent efficacy employing this protocol. Overall, substitution on the phenyl ring in the ortho, meta, or para positions led to inhibitors with only a slight decrease in potency in vitro compared to the parent unsubstituted compound. Bulkier groups in the para position tended to lower the ACAT inhibitory activity in vitro. Polar groups, such as carboxyl (33,34), lowered in vitro activity significantly, suggesting that polar-ionic interactions are disfavored for the enzyme activity. From this series, compound 28 was evaluated further in secondary in vivo screens. In a chronic cholesterol-fed rat model of hypercholesterolemia, compound 28 dose-dependently reduced nonHDL cholesterol and significantly elevated HDL cholesterol. It showed significantly greater aqueous solubility than the parent compound 1. However, it was shown to cause adrenal toxicity in guinea pigs. This led us to design a series of homologs (44-51) with increased basicity and lower lipophilicity. Some of these compounds were more potent ACAT inhibitors in vitro and demonstrated excellent hypocholesterolemic activity in vivo. Interestingly, compound 45, unlike 28, did not produce adrenal toxicity in guinea pigs and demonstrated excellent lipid-modulating activity in the chronic model of preestablished dyslipidemia in rats.

Adrenal Gland Diseases↗