Biomedical subjects

R Smith

Publications and source records attributed to R Smith.

At least 91 records · Page 5Linked to original sources

PubMed2002

A second case of post-transfusion purpura caused by HPA-5a antibodies: successful treatment with intravenous immunoglobulin.

Post-transfusion purpura (PTP) is a rare disorder characterized by severe thrombocytopenia developing seven to 10 days following transfusion of platelet-containing blood components, in a person who was previously sensitized via transfusion or pregnancy. Although most cases of PTP are caused by alloantibodies directed against HPA-1a[(Pl(A1))], this case represents the second example of anti-HPA-5a-associated PTP. A 61-year-old female was diagnosed with acute myocardial infarction and gastrointestinal bleeding and, after receiving six units of packed red cells over 5 days, developed PTP as a result of HPA-5a [Br(b)] antibodies with severe thrombocytopenia (5000/microl). She was successfully treated with intravenous immunoglobulin (IVIG), suggesting that this is a highly effective mode of treatment for PTP, regardless of the antibody implicated.

Antigens, Human Platelet↗

PubMed2002

Investigation of a cyclopic, human, term fetus by use of magnetic resonance imaging (MRI).

Using magnetic resonance imaging (MRI), the internal neural and craniofacial malformations of a cyclopic fetus are described. External facial features were characterized by a tubular proboscis situated above a single eye slit. The brain was recognized as 'pancake' type alobar holoprosencephaly (a condition where the undifferentiated telencephalon partially surrounds a monoventricle). Displacement of some bones that normally contribute to the orbit could be clearly discerned. Absence of neural structures (e.g. falx cerebri, corpus callosum) and missing components of the ethmoid bone indicated a midline deficit. This correlates with proposed theories of cyclopic embryopathy, which suggest that the prechordal plate and the neural crest cells are affected during the third week of gestation in cyclopia.

Abnormalities, Multiple↗

PubMed2002

Corticotrophs and peptides.

Corticotrophs were long thought to be a static, homogeneous population of cells that respond positively to hypothalamic stimulation, are inhibited by glucocorticoid feedback and secrete a single biologically active peptide, ACTH(1-39). Our current understanding is that this is an oversimplification and corticotrophs are a dynamic and more complex group of cells. The biosynthetic precursors of ACTH and other cleavage products of proopiomelanocortin (POMC) have been found to be secreted by anterior pituitary cells, to circulate and to have biological activity. POMC and the biosynthetic intermediate, pro-ACTH, exert activity antagonistic to ACTH(1-39) on glucocorticoid secretion by adrenal cells, and other derivatives of POMC are mitogenic to adrenocortical cells. In terms of responses to hypothalamic and peripheral factors, corticotrophs are functionally heterogeneous. This is reflected in the sensitivity of individual subtypes of corticotrophs to CRH, vasopressin and glucocorticoids. There is a functional plasticity amongst the various types of corticotrophs. During gestation, in fetal sheep, changes occur in the overall ACTH-secretory responses to CRH relative to vasopressin, the proportions of total corticotrophs that respond to the respective peptides and the average secretory response of individual cells. Corticotrophs also respond to locally produced pituitary factors. Local actions of leukaemia inhibitory factor are demonstrated by the effects of immunoneutralization of the peptide in pituitary cells. Urocortin and preproTRH(178-199) are locally produced peptides with potent stimulatory and inhibitory actions on corticotrophs, respectively. The specific roles of these peptides are under investigation.

Adrenocorticotropic Hormone↗

PubMed2002

Pituitary autoantibodies in lymphocytic hypophysitis target both gamma- and alpha-Enolase - a link with pregnancy?

The first target autoantigen to have been identified in lymphocytic hypophysitis is a 49 kDa protein, identified as alpha-enolase. Pituitary autoimmunity is strongly associated with pregnancy and we have shown that pituitary autoantibodies from patients with peripartum lymphocytic hypophysitis also recognise enolase in the placenta. Enolase exists in different forms as a number of isoenzymes, which are homo- or heterodimers of three subunits, alpha, beta and gamma. alphaalpha-enolase is ubiquitous, betabeta-enolase is muscle-specific and gammagamma-enolase, which is restricted to neuronal tissue and neuroendocrine cells, is known as neuron-specific enolase (NSE). NSE is expressed in normal human pituitary and pituitary neoplasms. The current study investigated which isoforms of enolase in pituitary and placenta reacted with the sera of patients with lymphocytic hypophysitis. Immunoblotting of two-dimensional gels of human pituitary cytosolic proteins showed that autoantibodies in patient sera react with both an acidic form, and more neutral forms of enolase. Immunoblotting with a monoclonal antibody to NSE confirmed the identity of the acidic enolase isoform as the gammagamma-isoform in both pituitary and placental samples. Gamma-enolase, i.e. NSE, was detected by immunohistochemistry in term placenta in decidua, syncytiotrophoblasts, anchoring villi and terminal villi. Our study is the first to describe the cellular localisation of NSE in normal human placenta, thus establishing a direct link between pituitary and placental autoantigens. This link provides a theoretical basis for the strong prediliction of lymphocytic hypophysitis to occur during or after pregnancy.

Autoantibodies↗

PubMed2002

Protease-activated receptors: a means of converting extracellular proteolysis into intracellular signals.

Protease-activated receptors (PARs) mediate cellular responses to a variety of extracellular proteases. The four known PARs constitute a subgroup of the family of seven-transmembrane domain G protein-coupled receptors and activate intracellular signalling pathways typical for this family of receptors. Activation of PARs involves proteolytic cleavage of the extracellular domain, resulting in formation of a new N terminus, which acts as a tethered ligand. PAR-1, -3, and -4 are relatively selective for activation by thrombin whereas PAR-2 is activated by a variety of proteases, including trypsin and tryptase. Recent studies in mice genetically incapable of expressing specific PARs have defined roles for PAR-1 in vascular development, and for PAR-3 and -4 in platelet activation, which plays a fundamental role in blood coagulation. PAR-1 has also been implicated in a variety of other biological processes including inflammation, and brain and muscle development. Responses mediated by PAR-2 include contraction of intestinal smooth muscle, epithelium-dependent smooth muscle relaxation in the airways and vasculature, and potentiation of inflammatory responses. The area of PAR research is rapidly expanding our understanding of how cells communicate and control biological functions, in turn increasing our knowledge of disease processes and providing potential targets for therapeutic intervention.

Animals↗

PubMed2002

The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease.

BACKGROUND: Osteoclasts are multinucleated cells (MNCs) that form from circulating mononuclear precursors in the presence of the receptor activator of nuclear factor kappa B-ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). AIM: To determine whether cytokines and growth factors influence RANKL/M-CSF induced osteoclastogenesis and bone resorption in Paget's disease. DESIGN: Prospective case-control study. METHODS: Serum levels of M-CSF, interleukin (IL)-1 beta, IL-6 and tumour necrosis factor-alpha (TNFalpha) were measured in 13 Paget's disease patients and 8 normal controls. The effect of serum from Paget's patients on osteoclast formation was also assessed. RESULTS: Serum levels of IL-1 beta, IL-6 and TNFalpha were low or undetectable in Paget's disease patients and normal controls. Levels of M-CSF were significantly increased in Paget's patients who were not currently under treatment. In Paget's patients under treatment, serum M-CSF levels were not significantly different from normal controls. The addition of serum from untreated Paget's patients dose-dependently increased RANKL-induced osteoclast formation and lacunar resorption in normal monocyte cultures; elevated IL-6 levels were found in the supernatant and the addition of a specific antibody to human IL-6 blocked the increase in osteoclast formation and resorption. Serum from untreated Paget's patients also induced osteoclast formation in the absence of exogenous M-CSF; an antibody specific to human M-CSF abolished this effect. DISCUSSION: Both M-CSF and IL-6 play a major role in osteoclast formation and bone resorption in Paget's disease and measurement of serum M-CSF may provide a useful indicator of disease activity.

Adult↗

PubMed2002

Synergistic induction of apoptosis in human myeloid leukemia cells by phorbol 12-myristate 13-acetate and flavopiridol proceeds via activation of both the intrinsic and tumor necrosis factor-mediated extrinsic cell death pathways.

Previous studies have shown that coexposure to marginally toxic concentrations of phorbol 12-myristate 13-acetate (PMA; 10 nM) and the cyclin-dependent kinase inhibitor flavopiridol (FP; 100-200 nM) synergistically induces apoptosis in human myeloid leukemia cells U937 and HL-60 (i.e., >50% apoptotic at 24 h). Attempts have now been made to characterize the cell death pathway(s) involved in this phenomenon. In contrast to cytochrome c release and caspase-3 activation, which occur within 2.5 h of PMA/FP coexposure, caspase-8 activation and Bid cleavage appeared as later events. Such findings implicate the mitochondria-dependent pathway in the initial induction of apoptosis by PMA/FP. However, U937 cells ectopically expressing CrmA, dominant-negative caspase-8, or dominant-negative Fas-associated death domain that were highly resistant to tumor necrosis factor (TNF)/cycloheximide-induced lethality displayed significant, albeit incomplete, resistance to PMA/FP-induced apoptosis after 24 h. Furthermore, coadministration of TNF soluble receptor significantly attenuated PMA/FP-induced apoptosis in U937 (p < 0.02) and HL-60 (p < 0.03) cells at 24 h. PMA/FP coadministration also triggered substantial increases in TNFalpha mRNA and protein secretion compared with the effects of PMA administered alone. The protein kinase C (PKC) inhibitor bisindolylmaleimide (1 microM) completely blocked PMA/FP-induced TNFalpha secretion in U937 cells and attenuated apoptosis. Taken together, these results suggest that coadministration of PMA with FP in myeloid leukemia cells initially triggers mitochondrial damage, an event followed by the PKC-dependent induction and release of TNFalpha, supporting a model in which the synergistic induction of leukemic cell apoptosis by this drug combination proceeds via both mitochondrial- and TNF receptor-related apoptotic pathways.

Antineoplastic Agents↗

PubMed2002

Exposure to crystalline silica, silicosis, and lung disease other than cancer in diatomaceous earth industry workers: a quantitative risk assessment.

OBJECTIVES: To estimate excess lifetime risk of (a) mortality from lung disease other than cancer (LDOC), and, (b) onset of radiographic silicosis, arising from occupational exposure to respirable crystalline silica dust. METHODS: Data from a cohort of California diatomaceous earth mining and processing workers exposed to crystalline silica dust (mainly as cristobalite) were reanalyzed with Poisson regression methods with internal and external adjustments for potential confounding by calendar time, age, smoking, Hispanic ethnicity, and time since first observation. Model fit was evaluated by comparing deviances and fitting cubic spline models. Lifetime risks of death from LDOC and radiographic silicosis were estimated up to age 85 with an actuarial approach accounting for competing causes of death. RESULTS: For deaths due to LDOC, a linear relative rate model gave the best fit in Poisson regression analyses. At the mean cumulative exposure of LDOC cases to silica, after adjustment for smoking, the estimated rate ratio was 4.2 (p<0.0001); at the maximum cumulative exposure of cases, the rate ratio was 18.4. The excess lifetime risk for white men exposed to respirable cristobalite dust for 45 years at the current permissible exposure limit (PEL; about 0.05 mg/m(3)) of the Occupational Safety and Health Administration was 54/1000 (95% confidence interval (95% CI) 17 to 150). For 70 incident cases of radiographic silicosis largely manifest before the end of employment, the best fit was also the linear relative rate model, predicting a rate ratio of 25.6 for silicosis at the mean cumulative exposure of the cases (p<0.0001). The excess lifetime risk for silicosis at the current PEL was 75/1000. CONCLUSION: Current occupational health standards for crystalline silica permit risks of lung disease other than cancer far in excess of what is usually considered acceptable by the Occupational Safety and Health Administration (a lifetime risk of less than one in a thousand deaths).

Adult↗

PubMed2002

Molecular genetic delineation of a deletion of chromosome 13q12-->q13 in a patient with autism and auditory processing deficits.

In a sporadic case of autism and language deficit due to auditory processing defects, molecular genetic studies revealed that a chromosomal deletion occurred in the 13q12-->q13 region. No chromosome abnormalities were detected in the parents. We determined that the deletion occurred on the paternally derived chromosome 13. There are two previous reports of chromosome 13 abnormalities in patients with autism. The deletion in the subject described in this paper maps between the two chromosome 13 linkage peaks described by Bradford et al. (2001) in studies of subjects with autism and language deficits. The 9-Mb region deleted in the patient described here contains at least four genes that are expressed in brain and that play a role in brain development. They are NBEA, MAB21L1, DCAMKL1 and MADH9. These genes therefore represent candidate genes for autism and specific language deficits.

Autistic Disorder↗

PubMed2002

Microvascular effects of CRH in human skin vary in relation to gender.

Males and females have a significantly different life expectancy because of the cardioprotective effects of estrogen. The mechanisms that result in this difference between the sexes are not fully understood. However, stress is a contributing factor to the development of cardiovascular disease, and stress-related factors derived from central or peripheral sources may have differential effects in the modulation of cardiovascular function in males and females. CRH is a central modulator of the stress response and is known to have vasodilator effects in a number of vascular beds. We have examined whether CRH has vasodilator effects in human skin and whether this effect is different between males and females using laser Doppler and iontophoresis. CRH (1 nM) had vasodilatory effects in the skin circulation of both premenopausal females (n = 6) and age-matched males (n = 5), but CRH-induced dilation was significantly more potent in females than males. Acetylcholine (1 nM) and sodium nitroprusside (0.74 nM) induced dilation was not significantly different between males (n = 6) and females (n = 6). This is the first study to demonstrate that CRH acts locally as a vasodilator in human skin circulation and that this response is augmented in premenopausal females. The mechanism by which CRH causes dilation in human skin is presently unknown. However, these data suggest that CRH-induced dilation may be one mechanism by which cardiovascular risk is reduced in premenopausal women.

Acetylcholine↗

PubMed2002

Human myometrial genes are differentially expressed in labor: a suppression subtractive hybridization study.

Human parturition is effected by a cascade of factors, of which many are unknown. We aim to identify the genes that are changed by labor in the human myometrium by suppression subtractive hybridization. We also seek to ascertain whether these genes are differentially expressed in the myometrium at the upper or fundal and lower segments of the uterus. Term myometrial tissues were obtained from laboring and nonlaboring women undergoing cesarean section after obtaining informed consent. Total RNA was used in suppression subtractive hybridization (CLONTECH PCR Select) to produce two subtracted cDNA libraries enriched for genes expressed during or before labor, labor and not-in-labor libraries, respectively. Dot blot screening of 400 positive clones, constituting 20% of the two subtracted libraries, revealed 30 differentially expressed clones, 14 of which were up-regulated by labor. Among the 10 known genes that were up-regulated in labor, 6 had apparent immune regulatory and inflammatory roles. Three are well-known inflammatory mediators and modulators that were previously linked with parturition: IL-8, manganese superoxide dismutase (MnSOD), and metalloproteinase-9. Three others, interferon-inducible 1-8d gene, elongation factor 1alpha, and nucleophosmin, have not been previously linked with labor. Constitutively expressed genes, including cyclophilin and alpha-actin, were found to be altered by labor. Quantitative real-time RT-PCR using Taqman probes further confirmed the up-regulation of some of these genes. The amounts of the specific genes assayed were standardized to 18S ribosomal RNA and are expressed as mean +/- SEM. Quantitative real-time RT-PCR showed that IL-8 mRNA rose from 0.003 +/- 0.002 in nonlaboring samples (n = 38) to 0.24 +/- 0.11 (n = 20) in gestational-age-matched spontaneously laboring women (P = 0.035). Similarly, MnSOD rose from 0.11 +/- 0.02 (n = 24) to 1.23 +/- 0.56 (n = 24) in gestational-age-matched women (P = 0.047). Additionally, cyclophilin, often used as a constitutive or housekeeping gene marker, increased from 0.0008 +/- 0.0002 (n = 6) to 0.002 +/- 0.0004 (n = 6; P = 0.008) during labor. Notably, MnSOD mRNA was differentially distributed between the upper (0.63 +/- 0.18) and lower (0.15 +/- 0.05; n = 15; P = 0.022) segments of the uterus, but IL-8 was not (n = 17; P = 0.97). Induced labor further showed significantly higher levels of IL-8 (0.63 +/- 0.21; n = 14) than spontaneous labor (0.22 +/- 0.11; n = 20; P = 0.046), but not MnSOD (P = 0.1). This work identifies novel as well as known genes that were not previously associated with parturition. It extends previous data indicating that there is differential expression of some, but not all genes within the gravid human uterus. Inflammatory genes constitute a major proportion of the known genes found to be up-regulated in labor, lending support to the hypothesis of an inflammatory mechanism for human parturition. This work further indicates that many factors associated with human labor and their complex interactions remain to be elucidated.

Computer Systems↗

PubMed2002

Lead pollution and amelioration measures in the community of Frazers Content, St Catherine, Jamaica.

Lead poisoning, especially in children, is a preventable disease. Many children are exposed to this hazard, especially in poor communities, because of a paucity of information on lead poisoning and increasing economic hardships. In 1994, the case of the poor suburban community of Frazers Content, St Catherine, Jamaica, came to the public attention because of the high frequency of hospital admissions, or outpatient treatment, of children for lead poisoning. This paper reviews a Blue Cross of Jamaica-led-initiative aimed at the clean up and education of the Frazers Content community. The following four-pronged approach was employed: environmental and biological sampling and sample analysis, health education, decontamination and community clean up and entrepreneurial activities. The project outputs included: training of 17 community wardens and 22 schoolteachers; the clean up of 64 residences which had lead levels in excess of 500 ppm; the establishment of an entombment site for the contaminated soil in accordance with the Jamaica Natural Resources Conservation Authority and training of residents in entrepreneurial skills, chicken and rabbit rearing and nursery establishment. The paper includes discussion of the lessons learnt and recommendations for future action.

Child↗

PubMed2001