Biomedical subjects

C J Miller

Publications and source records attributed to C J Miller.

At least 19 recordsLinked to original sources

PubMed2003

The glycaemic index of dates and date/yoghurt mixed meals. Are dates 'the candy that grows on trees'?

OBJECTIVE: To determine the glycaemic index of one variety of date, alone and in mixed meals with plain full-milk yoghurt. DESIGN: An experimental study involving the measurement of the glycaemic responses of participants to the ingestion of dates, alone and with yoghurt. SETTING: Within the Department of Family Medicine, Faculty of Medicine and Health Sciences, UAE University. SUBJECTS: Healthy male and female volunteers aged 32-67 y. INTERVENTION: Glycaemic responses to date and date/yoghurt meal ingestion were plotted for each subject. Glycaemic indexes were calculated as the ratios of the incremental areas under these response curves to those for glucose ingestion. Results are presented using means and standard deviations. Glycaemic indexes were compared using paired t-tests. RESULTS: Mean glycaemic indexes of the dates were 47.2, 45.3, 35.5, 37.3, 28.9 for rutab, traditionally stored, commercial, rutab/yoghurt and commercial tamer/yoghurt preparations, respectively. There was a significant difference between the results for rutab vs commercial tamer dates (P<0.05), but other comparisons failed to reach statistical significance. CONCLUSIONS: Khalas dates, when eaten alone or in mixed meals with plain yoghurt have low glycaemic indexes. The consumption of dates may be of benefit in glycaemic and lipid control of diabetic patients. The consumption of dates in mixed meals with yoghurt appears to have, at most, a minimal effect on the glycaemic index.

Adult↗

PubMed2002

Co-immunization of rhesus macaques with plasmid vectors expressing IFN-gamma, GM-CSF, and SIV antigens enhances anti-viral humoral immunity but does not affect viremia after challenge with highly pathogenic virus.

To investigate the adjuvant capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN-gamma), we cloned these rhesus cytokines into a mammalian expression vector. Two groups of six rhesus macaques (Macaca mulatta) received intradermal immunizations of plasmid DNA coding for SIV Eng and Gag, and influenza virus nucleoprotein (Flu-NP), with or without the co-administration of plasmid DNA coding for these cytokines. Humoral immune responses to antigens of both of these viruses and SIV specific T cell proliferative responses were significantly enhanced by co-immunization with the cytokines. These twelve monkeys, and a group of six naive controls, were challenged by the oral mucosal route with the uncloned and highly pathogenic SIVmac251. All monkeys became infected. The early CD4 decline was reduced in the group co-immunized with cytokine and viral plasmids. Unexpectedly, plasma viremia set points were not different in this co-immunized group and the non-immunized control group. On the other hand, monkeys vaccinated with equivalent amounts of empty vector plasmid (i.e. no cytokine inserts) along with plasmids expressing viral antigens demonstrated a slight but significant decrease in acute viremia compared to non-immunized controls (P<0.02). However, viral loads at set points were not significantly different between both the immunized and the non-immunized control group. Thus, although the cytokine vectors demonstrated detectable enhancement of the immune response to different viral antigens, such enhanced response did not translate into better anti-viral control in our experiment. These results underscore the need for further testing of cytokines as vaccine adjuvants in relevant animal models.

Animals↗

PubMed2002

Progress in bioinformatics and the importance of being earnest.

In silico biology has gathered momentum as, worldwide, scientists have united in a common quest to sequence, store and analyse complete genomes. This year, a pivotal achievement of this cooperative endeavour was realised in the release of a public draft of the human genome, and with it the promises to improve our understanding of diverse aspects of biology and to yield a healthier future with safe personalized medicines. Key to these goals will be the need to elucidate and characterise the genes and gene products encoded not just in the human genome, but in many genomes. These tasks are underpinned by the concepts and processes of genome and gene/protein evolution, regulation of gene expression, mechanisms of protein folding, the manifestation of protein function, and so on, all of which must be understood in the context of complex, dynamic biological systems. Our use of computers to model such concepts and systems must be placed in the context of the current limits of our understanding of them:- it is important to recognise, for example, that we don't have a common understanding either of what constitutes a gene or a protein function; we can't invariably say that a particular sequence or fold has arisen via divergent or convergent evolution; and we don't fully understand the rules of protein folding. Accepting what we can't do in silico is essential in appreciating what we can do. Without this understanding, it is easy to be misled, as notions of what particular computational approaches can achieve are sometimes rather optimistic. There are valuable lessons to be learned here from the field of Artificial Intelligence, principal among which is the realisation that capturing and representing complex knowledge is time consuming, expensive and hard. Thus, we argue here that if bioinformatics is to tackle biological complexity in earnest, it would be wise to absorb the experience distilled from decades of artificial intelligence research, and to approach the road ahead with caution, rigour and pragmatism.

Artificial Intelligence↗

PubMed2002

The strength of B cell immunity in female rhesus macaques is controlled by CD8+ T cells under the influence of ovarian steroid hormones.

To understand more clearly how mucosal and systemic immunity is regulated by ovarian steroid hormones during the menstrual cycle, we evaluated the frequency of immunoglobulin- and antibody-secreting cells (ISC, AbSC) in genital tract and systemic lymphoid tissues of normal cycling female rhesus macaques. The frequency of ISC and AbSC was significantly higher in tissues collected from animals in the periovulatory period of the menstrual cycle than in tissues collected from animals at other stages of the cycle. The observed changes were not due to changes in the relative frequency of lymphocyte subsets and B cells in tissues, as these did not change during the menstrual cycle. In vitro, progesterone had a dose-dependent inhibitory effect, and oestrogen had a dose-dependent stimulatory effect on the frequency of ISC in peripheral blood mononuclear cell (PBMC) cultures. The in vitro effect of progesterone and oestrogen on ISC frequency could not be produced by incubating enriched B cells alone with hormone, but required the presence of CD8+ T cells. Following oestrogen stimulation, a CD8+ enriched cell population expressed high levels of IFN-gamma and IL-12. The changes in B cell Ig secretory activity that we document in the tissues of female rhesus macaques during the menstrual cycle is due apparently to the action of ovarian steroid hormones on CD8+ T cells. Thus, CD8+ T cells control B cell secretory activity in both mucosal and systemic immune compartments. Understanding, and eventually manipulating, the CD8+ regulatory cell-B cell interactions in females may produce novel therapeutic approaches for autoimmune diseases and new vaccine strategies to prevent sexually transmitted diseases.

Animals↗

PubMed2002

The introduction of a ten-week general practice clerkship in the United Arab Emirates.

Clerkships in general practice have become established in medical curricula around the world. The reorganization of the clinical course at the United Arab Emirates University Faculty of Medicine and Health Sciences was an opportunity to design and introduce a new 10-week clerkship in general practice. This article reports the aims, structure and educational processes of the clerkship including the student assessment methods adopted. Early student feedback on the clerkship is positive.

Clinical Clerkship↗

PubMed2001

Anatomic site and immune function correlate with relative cytokine mRNA expression levels in lymphoid tissues of normal rhesus macaques.

Reverse transcriptase real-time polymerase chain reaction was used to determine pro-inflammatory, anti-viral and immunoregulatory cytokine mRNA expression levels in peripheral blood mononuclear cells (PBMC) of healthy juvenile, adolescent and adult rhesus macaques. Few age-related changes in cytokine mRNA expression levels were observed. Expression of interleukin 2 and Mx, a type I interferon-inducible gene, decreased with age, whereas interleukin 4 and macrophage inflammatory protein 1 (MIP-1) alpha and beta mRNA levels increased in older monkeys. Independent of age, the pro-inflammatory cytokines [tumour necrosis factor alpha (TNF-alpha) and chemokines] were expressed at higher mRNA levels in PBMC than the immunoregulatory cytokines (interleukins 2, 4, 12). Pro-inflammatory cytokine mRNA expression levels were highest in lymphoid tissues draining mucosal surfaces. Thus, a correlation exists between cytokine mRNA levels in lymphoid tissues and the anatomical site.

Animals↗

PubMed2001

Titration of an SIVmac251 stock by vaginal inoculation of Indian and Chinese origin rhesus macaques: transmission efficiency, viral loads, and antibody responses.

The purpose of this study was to determine whether rhesus monkeys of Chinese origin are suitable for studies of mucosal lentivirus transmission by comparing the relative ability of these animals and rhesus macaques of Indian origin to become infected by vaginal (IVAG) inoculation with SIVmac251. In addition, we sought to test the hypothesis that differences in viral load during the first few weeks after inoculation were due to the relative strength of the anti-SIV immune responses in the two populations of rhesus macaques. Significant difference was not observed between the number of Indian and Chinese origin monkeys that were infected after IVAG SIV inoculation in this study. For 8-9 weeks after infection there was considerable overlap in the range of viral loads among the Indian and Chinese animals and the variation among the Indian origin animals was greater than the variation among the Chinese origin monkeys. By 6 weeks postinfection, viral loads in SIV-infected Chinese origin monkeys tended to be at the lower end of the range of viral loads observed in SIV-infected Indian origin monkeys. The strength of the anti-SIV antibody response was also more variable in the Indian origin rhesus macaques, but at 6-8 weeks postinfection, Chinese and Indian origin rhesus macaques had similar titers of anti-SIV antibodies. Microsatellite allele frequencies differed between Chinese and Indian rhesus macaques; however, the majority of alleles present in Indian-origin animals were also found in Chinese macaques. Together these results show that host factors, other than geographic origin, determine the ability of a rhesus macaque to be infected after IVAG SIV exposure and that geographic origin does not predict the viral load of SIV-infected animals during the first 8-9 weeks after IVAG inoculation.

Animals↗

PubMed2001

Acoustic oscillations in the early universe and today.

During its first approximately 100,000 years, the universe was a fully ionized plasma with a tight coupling by Thompson scattering between the photons and matter. The trade-off between gravitational collapse and photon pressure causes acoustic oscillations in this primordial fluid. These oscillations will leave predictable imprints in the spectra of the cosmic microwave background and the present-day matter-density distribution. Recently, the BOOMERANG and MAXIMA teams announced the detection of these acoustic oscillations in the cosmic microwave background (observed at redshift approximately 1000). Here, we compare these CMB detections with the corresponding acoustic oscillations in the matter-density power spectrum (observed at redshift approximately 0.1). These consistent results, from two different cosmological epochs, provide further support for our standard Hot Big Bang model of the universe.

Journal Article↗

PubMed2001

The number and distribution of immune cells in the cervicovaginal mucosa remain constant throughout the menstrual cycle of rhesus macaques.

A number of studies have shown that the ovarian hormone cycle affects genital tract immunoglobulin (Ig) levels and T cell function in both humans and rhesus monkeys. We hypothesized that shifts in immune cell populations occurring in response to hormone cycles are involved in the observed changes in genital tract immunity. To test this hypothesis, we characterized the type, number, and distribution of immune cells in the cervicovaginal mucosa at different stages of the menstrual cycle. Tissues from 18 normal female rhesus macaques were studied by immunohistochemistry and computerized morphometric analysis. The number and distribution of CD1a+ Langerhans' cells, CD2+, CD3+, CD4+, and CD8+ T cells, CD20+ B cells, and surface Ig+ plasma cells did not change in samples collected at the different stages of the cycle. However, in no relation to the stage of the menstrual cycle, the number of Langerhans' cells and other immune cell types was different in the various regions of the cervicovaginal mucosa examined. In addition, variation in thickness of the ectocervical and vaginal epithelium during a normal menstrual cycle of rhesus macaques is not accompanied by changes in intraepithelial immune cell populations. We conclude that steroid hormones do not influence genital mucosal immunity by changing the number or distribution of immune cells in the lower reproductive tract.

Animals↗

PubMed2001

Which craft is best in bioinformatics?

'Silicon-based' biology has gathered momentum as the world-wide sequencing projects have made possible the investigation and comparative analysis of complete genomes. Central to the quest to elucidate and characterise the genes and gene products encoded within genomes are pivotal concepts concerning the processes of evolution, the mechanisms of protein folding, and, crucially, the manifestation of protein function. Our use of computers to model such concepts is limited by, and must be placed in the context of, the current limits of our understanding of these biological processes. It is important to recognise that we do not have a common understanding of what constitutes a gene; we cannot invariably say that a particular sequence or fold has arisen via divergence or convergence; we do not fully understand the rules of protein folding, so we cannot predict protein structure; and we cannot invariably diagnose protein function, given knowledge only of its sequence or structure in isolation. Accepting what we cannot do with computers plays an essential role in forming an appreciation of what we can do. Without this understanding, it is easy to be misled, as spurious arguments are often used to promote over-enthusiastic notions of what particular programs can achieve. There are valuable lessons to be learned here from the field of artificial intelligence, principal among which is the realisation that capturing and representing complex knowledge is time consuming, expensive and hard. If bioinformatics is to tackle biological complexity meaningfully, the road ahead must therefore be paved with caution, rigour and pragmatism.

Amino Acid Sequence↗

PubMed2001

The use of an objective structured clinical examination (OSCE) for formative and summative assessment in a general practice clinical attachment and its relationship to final medical school examination performance.

OBJECTIVES: To report the use of OSCEs for both formative and summative purposes within a general practice undergraduate clinical attachment and to compare student performance in the departmental OSCEs with that of their final medical school examinations. METHODS: Twenty-eight students rotated through the attachment and undertook pre- and post-attachment OSCEs of similar format but different content. Results were analysed to determine relationships between mean scores in the two OSCEs and student performance in their final medical school MBBS examinations. RESULTS: There was a marked improvement in all OSCE station scores. Pre-attachment scores for those stations measuring physical examination and problem-solving skills were unrelated to prior clinical experience. Post-attachment OSCE mean scores were significantly correlated with final examination OSCE and total mean scores. CONCLUSION: The general practice attachment appears to upgrade those clinical skills measured by the pre- and post-attachment OSCE, however, there was no control group of students. Problem-solving and focused physical examination skills need to be targeted by all undergraduate clinical departments. The department's post-attachment OSCE and total assessment results are predictors of final examination OSCE and total results. The use of pre- and post-attachment OSCEs facilitates both students' formative learning processes and the department's evaluation of its educational programme.

Clinical Competence↗

PubMed2001

Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.

Unraveling the molecular basis of inherited disorders of epithelial fragility has led to understanding of the complex structure and function of keratin intermediate filaments. Keratins are organized as a central alpha-helical rod domain flanked by nonhelical, variable end domains. Pathogenic mutations in 19 different keratin genes have been identified in sequences corresponding to conserved regions at the beginning and end of the rod. These areas have been recognized as zones of overlap between aligned keratin proteins and are thought to be crucial for proper assembly of keratin intermediate filaments. Consequently, all keratin disorders of skin, hair, nail, and mucous membranes caused by mutations in rod domain sequences are characterized by perinuclear clumping of fragmented keratin intermediate filaments, thus compromising mechanical strength and cell integrity. We report here the first mutation in a keratin gene (KRT1) that affects the variable tail domain (V2) and results in a profoundly different abnormality of the cytoskeletal architecture leading to a severe form of epidermal hyperkeratosis known as ichthyosis hystrix Curth-Macklin. Structural analyses disclosed a failure in keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failed translocation of loricrin to the desmosomal plaques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament organization and barrier formation.

Amino Acid Sequence↗

PubMed2001

Knowledge, attitudes, and practices related to breast cancer screening: a survey of Arabic women.

BACKGROUND: Incorporating breast cancer screening into day-to-day clinical care leads to early diagnosis and decreases mortality. Patients' participation in screening depends on their knowledge and attitudes, other barriers, and physician behavior. METHODS: A cross-sectional questionnaire survey was conducted to evaluate knowledge, attitudes, barriers, and practices related to breast cancer screening among Arabic women. A convenience sample was selected from 1,750 women aged 40-65 years who, for any reason, attended primary health care (PHC) clinics in Al-Ain, United Arab Emirates (UAE). RESULTS: Of the 1,750 invited women, 1,445 agreed to participate; 78 were excluded from analysis because of histories of breast cancer. Breast self-examination (BSE) was practiced by 12.7% of the study population, clinical breast examination (CBE) by 13.8%, and mammography by 10.3%. Knowledge about breast cancer screening was low in the study population. Women were infrequently instructed about or offered screening for breast cancer by health professionals. Being employed was an independent predictor for participation in the three screening examinations. CONCLUSIONS: Health workers infrequently offered screening examinations and women lacked adequate knowledge about breast cancer screening. Acquired information about barriers to screening may help in the design of effective screening programs for Arabic women.

Adult↗

PubMed2001

Human diploid fibroblasts that undergo a senescent-like differentiation have elevated ceramide and diacylglycerol.

Senescent human diploid fibroblasts (HDF) have elevated levels of ceramide and diacylglycerol (DAG) compared with young HDF. DNA fragmentation analysis demonstrated the increased ceramide in senescent HDF was not associated with apoptosis, whereas in young HDF, exogenous ceramide induced apoptosis. In young HDF treated with both exogenous ceramide and DAG, less DNA fragmentation was observed. Thus, elevated DAG levels in senescent HDF might protect against ceramide-induced apoptosis. To determine which characteristics of senescent HDF (aging per se, cell cycle arrest, elevated p21Sdi1,Waf1,Cip1, and senescent-like differentiation) might influence ceramide and DAG, we examined transformed or mitomycin C-treated HDF that shared some of these properties with senescent HDF. The elevation of ceramide and DAG did not depend on aging per se, cell cycle arrest, or elevation of p21. Rather, ceramide and DAG may be elevated as part of a program of differentiation that is induced by either aging or DNA damage.

Apoptosis↗

PubMed2001

Protection against simian immunodeficiency virus vaginal challenge by using Sabin poliovirus vectors.

Here we provide the first report of protection against a vaginal challenge with a highly virulent simian immunodeficiency virus (SIV) by using a vaccine vector. New poliovirus vectors based on Sabin 1 and 2 vaccine strain viruses were constructed, and these vectors were used to generate a series of new viruses containing SIV gag, pol, env, nef, and tat in overlapping fragments. Two cocktails of 20 transgenic polioviruses (SabRV1-SIV and SabRV2-SIV) were inoculated into seven cynomolgus macaques. All monkeys produced substantial anti-SIV serum and mucosal antibody responses. SIV-specific cytotoxic T-lymphocyte responses were detected in three of seven monkeys after vaccination. All 7 vaccinated macaques, as well as 12 control macaques, were challenged vaginally with pathogenic SIVmac251. Strikingly, four of the seven vaccinated animals exhibited substantial protection against the vaginal SIV challenge. All 12 control monkeys became SIV positive. In two of the seven SabRV-SIV-vaccinated monkeys we found no virological evidence of infection following challenge, indicating that these two monkeys were completely protected. Two additional SabRV-SIV-vaccinated monkeys exhibited a pronounced reduction in postacute viremia to <10(3) copies/ml, suggesting that the vaccine elicited an effective cellular immune response. Three of six control animals developed clinical AIDS by 48 weeks postchallenge. In contrast, all seven vaccinated monkeys remained healthy as judged by all clinical parameters. These results demonstrate the efficacy of SabRV as a potential human vaccine vector, and they show that the use of a vaccine vector cocktail expressing an array of defined antigenic sequences can be an effective vaccination strategy in an outbred population.

Animals↗

PubMed2001

Route of simian immunodeficiency virus inoculation determines the complexity but not the identity of viral variant populations that infect rhesus macaques.

A better understanding of the host and viral factors associated with human immunodeficiency virus (HIV) transmission is essential to developing effective strategies to curb the global HIV epidemic. Here we used the rhesus macaque-simian immunodeficiency virus (SIV) animal model of HIV infection to study the range of viral genotypes that are transmitted by different routes of inoculation and by different types of viral inocula. Analysis of transmitted variants was undertaken in outbred rhesus macaques inoculated intravenously (IV) or intravaginally (IVAG) with a genetically heterogeneous SIVmac251 stock derived from a well-characterized rhesus macaque viral isolate. In addition, we performed serial IV and IVAG passage experiments using plasma from SIV-infected macaques as the inoculum. We analyzed the V1-V2 region of the SIV envelope gene from virion-associated RNA in plasma from infected animals by the heteroduplex mobility assay (HMA) and by DNA sequence analysis. We found that a more diverse population of SIV genetic variants was present in the earliest virus-positive plasma samples from all five IV SIVmac251-inoculated monkeys and from two of five IVAG SIVmac251-inoculated monkeys. In contrast, we found a relatively homogeneous population of SIV envelope variants in three of five monkeys inoculated IVAG with SIVmac251 stock and in two monkeys infected after IVAG inoculation with plasma from an SIV-infected animal. In some IVAG-inoculated animals, the transmitted SIV variant was the most common variant in the inoculum. However, a specific viral variant in the SIVmac251 stock was not consistently transmitted by IVAG inoculation. Thus, it is likely that host factors or stochastic processes determine the specific viral variants that infect an animal after IVAG SIV exposure. In addition, our results clearly demonstrate that the route of inoculation is associated with the extent and breadth of the genetic complexity of the viral variant population in the earliest stages of systemic infection.

Administration, Intravaginal↗

PubMed2001

Tracking prostate carcinoma micrometastasis to multiple organs using histochemical marker genes and novel cell systems.

Studies of human prostate carcinoma (PCA) have been hampered by only a few cell systems from already-metastatic human disease. We have developed a novel cell system by using tissue cultured CWR22R cells from a xenograft of a primary tumor from a human patient. These cells were transfected with the bacterial lacZ gene to maximize their detection during progression and metastasis in nude mice. LZ-CWR22R cells are extremely stable for lacZ expression over 25 passages and metastasize to lung, liver, and bone from the subcutis - major sites of metastasis of the human disease. A matrigel vehicle facilitated development of primary tumors and micrometastases in all organs. While some micrometastases developed into overt metastases, others remained as micrometastases for long periods of time, possibly providing a model of latency of metastatic disease. An experimental metastasis model (tail vein injection) also generated micrometastases in lung, liver, and bone with differing kinetics of formation and stability. Serial sections of many individual lung micrometastases within one hour of injection indicated considerable heterogeneity in cellular composition (from 1 to 19 cells/site) while liver sites at later times were comprised of only 1 or 2 cells (the size of bone sites were comparable to those of liver). By combining use of these histochemically-tagged PCA cell systems with high resolution molecular analyses (laser-capture microdissection), it will now be possible to analyze gene expression patterns characteristic of micrometastases developing in several different organs.

Androgens↗

PubMed2000

Direct voltammetric investigation of the electrochemical properties of human hemoglobin: relevance to physiological redox chemistry.

Voltammetric measurements on solutions of human hemoglobin using gold electrodes modified with omega-hydroxyalkanethiols have yielded the first direct measure of the reorganization energy of the protein. The value obtained based on extrapolation of the experimentally measured currents, 0.76 eV, is independent of pH (i.e., over the physiologically relevant rage, pH 6.8-7.4) and is remarkably similar to values obtained for myoglobin. This result is perhaps surprising given the marked dependence of the measured reduction potential of hemoglobin on pH (i.e., the redox Bohr effect). Electron transfer rates from the electrode to hemoglobin were also measured. Using similarly measured heterogeneous electron-transfer rates for cytochrome b(5), it is possible to predict the magnitude of the homogeneous electron-transfer rate from cytochrome b(5) to methemoglobin using a formalism developed by Marcus. These predicted rates are in reasonable agreement with reported rates of this physiological reaction based on stopped-flow kinetics experiments. These results suggest that the intrinsic electroreactivity of these heme proteins is sufficient to account for physiologically observed rates. Residual differences between homogeneous phase kinetics and those predicted by heterogeneous phase reactions are suggested to be due to small reductions in the outer-sphere reorganization energy of both component proteins which arise due to solvent exclusion at the interface between the two proteins in complex.

Cytochromes b5↗