Biomedical subjects

S A Jones

Publications and source records attributed to S A Jones.

At least 19 recordsLinked to original sources

PubMed2006

Localization of Period 1 mRNA in the ruminant oocyte and investigations of its role in ovarian function.

The clock gene Period 1 (Per1) may be a prolificacy gene, because it localized to the mouse oocyte and Per1-null drosophila shed fewer eggs. Because Per1 mapped to a region of mouse chromosome 11 syntenic to bovine chromosome 19 where a quantitative trait loci (QTL) for ovulation rate existed, we hypothesized that Per1 influenced folliculogenesis and ovulation rate in ruminants. Ovarian cortex was collected at slaughter on days 5, 12, 15, 17, and 20 after estrus for real-time RT-PCR evaluation of Per1 mRNA expression in Dorset (n = 18), Romanov (n = 10), Romanov/Dorset (n = 21), and Composite (n = 22) ewes. Ovarian cortex was also collected from cows selected for increased ovulation rate (n=37) or unselected controls (n = 28) on days 4, 5, and 6 of the estrous cycle for in situ hybridization and real-time RT-PCR. To examine the role of Per1 in early follicular development, ovarian cortex from neonatal calves (n = 5) was cultured for 10 days and Per1 mRNA levels were measured on day 0 and on day 10 of culture. The primers generated a 483bp amplicon with 100% sequence homology to bovine RIGUI-like protein (Per1). In silico mapping of this sequence placed Per1 on bovine chromosome 19; however, it was 20cM from the QTL. Per1 mRNA expression was unaffected by prolificacy, day of the cycle, or pregnancy status in ewes or cows. The riboprobe hybridized to oocytes of bovine preantral and antral follicles. In bovine ovarian cortical cultures on day 0, the tissue contained mostly primordial follicles (5.6+/-0.6 follicles/section); however, after 10 days in culture, the number of primordial follicles per section decreased (0.5 follicles/section) and the number of primary follicles increased as follicles activated (day 0 = 0.5+/- 0.6 versus day 10 = 10.4 +/-0.6 primary follicles/section; P < 0.001). Per1 mRNA did not change over time in culture. We conclude that Per1 mRNA is expressed by ruminant oocytes in preantral and antral follicles; however, its physiological role in mammalian ovarian function remains to be elucidated.

Animals↗

PubMed2006

Interleukin-6 signalling in juvenile idiopathic arthritis is limited by proteolytically cleaved soluble interleukin-6 receptor.

OBJECTIVES: Interleukin-6 (IL-6) exerts multiple effects on chondrocytes and fibroblasts within the joint and is associated with disease activity in juvenile idiopathic arthritis (JIA). Although these cells express the ubiquitous signalling receptor for all IL-6-related cytokines, gp130, they do not express a cognate IL-6 receptor. Consequently, IL-6 responses within these cells occur via IL-6 trans-signalling relying on the presence of a soluble receptor (sIL-6R). Levels of sIL-6R in vivo are governed by either proteolytic cleavage (PC) of cognate receptor or by differential sIL-6R mRNA splicing (DS). The aim of this study was to evaluate the contribution of both isoforms to clinical parameters associated with IL-6 signalling in JIA. METHODS: IL-6, sIL-6R and DS-sIL-6R were measured by ELISA in serum and synovial fluid (SF) samples from 86 JIA patients. These data were related to indicators of inflammation-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and compared between patients stratified by subtype, age and disease duration. RESULTS: SF IL-6 significantly correlated with general indicators of activity (ESR and CRP) and SF PC-sIL-6R to a lesser degree with CRP. When the IL-6:sIL-6R ratio was calculated as an indicator of the potential for IL-6 signalling within the joint, 33% of SF samples showed a ratio >1 indicating saturation of sIL-6R by IL-6. Mean DS-sIL-6R levels were 0.71 ng/ml, whereas PC-sIL-6R levels constituted the majority of sIL-6R at 20.89 ng/ml. CONCLUSIONS: IL-6 trans-signalling within the joints of JIA patients is predominantly governed by the presence of PC-sIL-6R, and the data provided suggest that synovial levels of IL-6 and sIL-6R would be sufficient to drive IL-6 responses in chondrocytes and synovial fibroblasts.

Adolescent↗

PubMed2006

HIV-disclosure in the context of vertical transmission: HIV-positive mothers in Johannesburg, South Africa.

HIV-disclosure among childbearing women remains poorly understood, particularly in sub-Saharan Africa. This paper chronicles disclosure experiences of 31 women attending prevention of mother-to-child HIV transmission services in Johannesburg. Data collection entailed repeat in-depth interviews over a nine-month period. Virtually all women (93.5%) had told at least one person (usually a partner), most voluntarily and within a week of the test result. Secondary disclosure was most likely with female family members, through indirect means and involuntary. Confidentiality breach by primary targets likely contributed to the observed high rates of involuntary secondary disclosure and negative secondary disclosure experiences. For most mothers, voluntary disclosure was driven by the desire to ensure adequate infant care and avoid vertical HIV transmission. The impact of disclosure was not always clear-cut. While most primary disclosure experiences were ultimately constructive, secondary disclosure more likely led to rejection, stigmatization and the withholding of financial support. Our data illustrate the influence of social contextual factors on disclosure patterns and impact. For these mothers, socio-cultural norms, the current media and political environment surrounding HIV/AIDS, household composition and social networks and childbearing status shaped disclosure experiences; sometimes constraining disclosure circumstances and sometimes creating a safe space to disclose. Programmatic implications are also discussed.

Adaptation, Psychological↗

PubMed2005

High-pressure aerosol suspensions--a novel laser diffraction particle sizing system for hydrofluoroalkane pressurised metered dose inhalers.

In this study, a novel laser diffraction particle size analysis dispersion system, capable of sizing particles in situ within suspension hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs), was developed and tested. The technique was compared to four indirect particle sizing methods commonly used to determine the size of particles suspended in HFA pMDIs. The median volume diameter obtained using laser diffraction of both the salbutamol sulphate and fluticasone propionate suspended either in 2H, 3H-decafluoropentane or perfluoropentane (employed as surrogate propellants) was over one-order of magnitude larger than the particle sizes of the drugs suspended in HFA 134a. In contrast, the "in-flight" particle size using the Sympatec inhaler 2000 laser diffraction equipment undersized the particles, predicting higher delivery efficacy compared to the other sizing methods. However, the size of particles suspended in HFAs derived using the novel pressurised dispersion system, showed a linear correlation with the impaction results, r2=0.8894 (n=10). The novel pressure cell sizing technique proved to be simple to use, has the ability to be automated and was accurate, suggesting it could be an essential tool in the development of new suspension-based pMDI formulations.

Aerosol Propellants↗

PubMed2005

Computer three-dimensional reconstruction of the sinoatrial node.

BACKGROUND: There is an effort to build an anatomically and biophysically detailed virtual heart, and, although there are models for the atria and ventricles, there is no model for the sinoatrial node (SAN). For the SAN to show pacemaking and drive atrial muscle, theoretically, there should be a gradient in electrical coupling from the center to the periphery of the SAN and an interdigitation of SAN and atrial cells at the periphery. Any model should include such features. METHODS AND RESULTS: Staining of rabbit SAN preparations for histology, middle neurofilament, atrial natriuretic peptide, and connexin (Cx) 43 revealed multiple cell types within and around the SAN (SAN and atrial cells, fibroblasts, and adipocytes). In contrast to atrial cells, all SAN cells expressed middle neurofilament (but not atrial natriuretic peptide) mRNA and protein. However, 2 distinct SAN cell types were observed: cells in the center (leading pacemaker site) were small, were organized in a mesh, and did not express Cx43. In contrast, cells in the periphery (exit pathway from the SAN) were large, were arranged predominantly in parallel, often expressed Cx43, and were mixed with atrial cells. An approximately 2.5-million-element array model of the SAN and surrounding atrium, incorporating all cell types, was constructed. CONCLUSIONS: For the first time, a 3D anatomically detailed mathematical model of the SAN has been constructed, and this shows the presence of a specialized interface between the SAN and atrial muscle.

Animals↗

PubMed2005

Psychosocial consequences of early diagnosis of HIV status in vertically exposed infants in Johannesburg, South Africa.

Mother-to-child transmission (MTCT) is the most common source of HIV infection in children. One topic that has received virtually no attention in MTCT-related research and programming is the psychosocial consequences among parents and families of receiving a definitive diagnosis of infant HIV status. This study explored experiences of HIV-infected mothers in Johannesburg, South Africa, regarding infant testing and diagnosis. Data collection entailed a key informant workshop and repeat interviews with a convenience sample of 31 HIV-infected mothers. While early testing was desirable, diagnosis had both beneficial and detrimental psychosocial effects, especially in instances of serodiscordance. Programmatic implications are discussed.

Adult↗

PubMed2005

Exploring socio-economic conditions and poor follow-up rates of HIV-exposed infants in Johannesburg, South Africa.

In 2002, more than 280,000 HIV-exposed babies were born in South Africa. According to international PMTCT guidelines, these children require follow-up to 12 months of age. Worldwide, the high loss to follow-up rates experienced by PMTCT programs precludes them from identifying and managing HIV-infected children. Socio-economic factors have been identified as potential contributors to poor follow-up. A small descriptive study to examine socio-economic circumstances of women attending the Coronation Women and Children's Hospital PMTCT program was undertaken. Cross-sectional data from 176 women, interviewed at their infants' 12-month visit, was collected using a semi-structured questionnaire. Socio-economic factors such as poverty, geographical relocation and a lack of paternal support may affect the capacity of families to comply with the PMTCT follow-up program. Fifty-seven percent of mothers were unemployed, 25% of fathers did not support their children and only 58% of children remained resident in Johannesburg at the 12-month visit. The lack of follow-up of HIV-infected children denies them access to adequate medical care. Understanding the socio-economic factors that affect the ability of communities to comply with PMTCT programs will assist resource-poor countries in devising strategies to achieve follow-up of HIV-exposed infants.

Child Health Services↗

PubMed2005

Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin.

Hyaluronic acid (HA) is a naturally occurring polyanionic, polysaccharide that consists of N-acetyl-D-glucosamine and beta-glucoronic acid. It is present in the intercellular matrix of most vertebrate connective tissues especially skin where it has a protective, structure stabilizing and shock-absorbing role. The unique viscoelastic nature of HA along with its biocompatibility and non-immunogenicity has led to its use in a number of clinical applications, which include: the supplementation of joint fluid in arthritis; as a surgical aid in eye surgery; and to facilitate the healing and regeneration of surgical wounds. More recently, HA has been investigated as a drug delivery agent for various routes of administration, including ophthalmic, nasal, pulmonary, parenteral and topical. In fact, regulatory approval in the USA, Canada and Europe was granted recently for 3% diclofenac in 2.5% HA gel, Solaraze, for the topical treatment of actinic keratoses, which is the third most common skin complaint in the USA. The gel is well tolerated, safe and efficacious and provides an attractive, cost-effective alternative to cryoablation, curettage or dermabrasion, or treatment with 5-fluorouracil. The purpose of this review is to describe briefly the physical, chemical and biological properties of HA together with some details of its medical and pharmaceutical uses with emphasis on this more recent topical application.

Administration, Cutaneous↗

PubMed2005

Establishing a practical blood platelet threshold to avoid reporting spurious potassium results due to thrombocytosis.

BACKGROUND: Thrombocytosis is one of several pre-analytical factors which contribute to spuriously high serum potassium concentrations, yet there is little published data to guide analysts in the selection of a specific platelet count threshold above which serum potassium results become unreliable. We have studied the sensitivity and specificity of blood platelet count as a predictor of false elevations in potassium. METHODS: Paired serum and plasma potassium measurements together with full blood count were performed for 300 patients. All samples were stored at room temperature and analysed within 4 h of collection. The difference between serum and plasma potassium was plotted against blood platelet count. RESULTS: When the difference (serum-plasma) in potassium concentration was plotted against platelet count, there was a direct linear relationship. Blood platelet counts of >500 x 10(9)/L will detect elevations in serum relative to plasma potassium of >0.5 mmol/L, with a sensitivity of 71% and a specificity of 89%. CONCLUSION: It is recommended that where blood platelet count is above 500 x 10(9)/L, potassium measurements should be repeated using lithium heparin plasma. When serum potassium results of >5.4 mmol/L are obtained, it is our policy to check the platelet count if a sample is available before reporting results. If available and above 500 x 10(9)/L, potassium results are withheld and plasma requested.

Adult↗

PubMed2004

Differential effects of estrogen and raloxifene on messenger RNA and matrix metalloproteinase 2 activity in the rat uterus.

A detailed analysis of the differential effects of estrogen (E) compared to raloxifene (Ral), a selective estrogen receptor modulator (SERM), following estrogen receptor (ER) binding in gynecological tissues was conducted using gene microarrays, Northern blot analysis, and matrix metalloproteinase (MMP) 2 activity studies. We profiled gene expression in the uterus following acute (1 day) and prolonged daily (5 wk) treatment of E and Ral in ovariectomized rats. Estrogen regulated twice as many genes as Ral, largely those associated with catalysis and metabolism, whereas Ral induced genes associated with cell death and negative cell regulation. Follow-up studies confirmed that genes associated with matrix integrity were differentially regulated by Ral and E at various time points in uterine and vaginal tissues. Additional experiments were conducted to determine the levels of MMP2 activity in uterus explants from ovariectomized rats following 2 wk of treatment with E, Ral, or one of two additional SERMs: lasofoxifene, and levormeloxifene. Both E and lasofoxifene stimulated uterine MMP2 activity to a level twofold that of Ral, whereas levormeloxifene elevated MMP2 activity to a level 12-fold that of Ral. These data show that one of the significant differences between E and Ral signaling in the uterus is the regulation of genes and proteins associated with matrix integrity. This may be a potential key difference between the action of SERMs in the uterus of postmenopausal women.

Animals↗

PubMed2004

Determination of polyvinylpyrrolidone using high-performance liquid chromatography.

Polyvinylpyrrolidone (PVP) is a versatile polymer with innate surface activity. It is very difficult to accurately assay due to its wide molecular weight range and amphiphilic nature. This study evaluated a reversed-phase HPLC method to separate and quantify PVP K15. The assay used a Hicrome C18 150 mm x 3 microm HPLC column in combination with an 80/20 propanol-1-ol: deionised water, 0.01% TFA mobile phase, which resolved the polymer as a single peak, tR = 10.69+/-0.17 min (n=120) at 243 nm. The column's performance was constant throughout the study, N (theoretical plates) = 1729+/-22 and the peak symmetry remained good (As ranged from 0.74 to 0.92, n=10 over the calibration range). The developed assay proved to be accurate, sensitive and capable of recovering PVP K15 from pharmaceutical formulations. The limits of quantification and detection were calculated statistically as 2.40 and 0.72 mg ml(-1), respectively. Assay reproducibility assessed at five concentrations gave an average coefficient of variance <3.5% and the accuracy of the analytical method was 102.62+/-2.04%. The recovery of PVP K15 from directly compressed tablets and Refresh eye drops was 98.02+/-2.73 and 108.35+/-6.52%, respectively.

Chromatography, High Pressure Liquid↗

PubMed2004

PMTCT from research to reality--results from a routine service.

OBJECTIVES: Assessment of the efficacy of a prevention of mother-to-child transmission (PMTCT) programme in a routine service setting in comparison to a research environment. DESIGN: Descriptive study over a 13-month period utilising retrospective data obtained from hospital records complemented by prospective data on a sample of patients enrolled in a study to determine an affordable HIV diagnostic protocol for infants. SETTING: Routine PMTCT service at Coronation Women and Children's Hospital (CWCH) situated in Johannesburg and affiliated to the University of the Witwatersrand. SUBJECTS: Pregnant women known to be HIV infected who delivered at CWCH from 1 October 2001 to 31 October 2002. OUTCOME MEASURES: The HIV transmission rate to infants, which reflects nevirapine (NVP) delivery and infant feeding practices, and follow-up rates of perinatally exposed children. RESULTS: Of the 8,221 deliveries, 1,234 (15%) occurred in women known to be HIV infected. HIV transmission rates of 8.7% at 6 weeks and 8.9% at 3 months of age in the study population verifies the high rate of NVP administration and the ability of women to formula-feed their babies and abstain from breast-feeding. More than one-third of infants never return for follow-up and more than 70% are lost to follow-up by 4 months of age. CONCLUSIONS: The low HIV transmission rate confirms the efficacy of this routine service PMTCT programme. HIV-infected children are not being identified for medical management as part of PMTCT follow-up. It is imperative that record keeping is improved to facilitate ongoing monitoring.

Anti-HIV Agents↗

PubMed2003

Sarcoplasmic reticulum Ca2+ release is not a dominating factor in sinoatrial node pacemaker activity.

Recent work on isolated sinoatrial node cells from rabbit has suggested that sarcoplasmic reticulum Ca2+ release plays a dominant role in the pacemaker potential, and ryanodine at a high concentration (30 micromol/L blocks sarcoplasmic reticulum Ca2+ release) abolishes pacemaking and at a lower concentration abolishes the chronotropic effect of beta-adrenergic stimulation. The aim of the present study was to test this hypothesis in the intact sinoatrial node of the rabbit. Spontaneous activity and the pattern of activation were recorded using a grid of 120 pairs of extracellular electrodes. Ryanodine 30 micromol/L did not abolish spontaneous activity or shift the position of the leading pacemaker site, although it slowed the spontaneous rate by 18.9+/-2.5% (n=6). After ryanodine treatment, beta-adrenergic stimulation still resulted in a substantial chronotropic effect (0.3 micromol/L isoproterenol increased spontaneous rate by 52.6+/-10.5%, n=5). In isolated sinoatrial node cells from rabbit, 30 micromol/L ryanodine slowed spontaneous rate by 21.5+/-2.6% (n=13). It is concluded that sarcoplasmic reticulum Ca2+ release does not play a dominating role in pacemaking in the sinoatrial node. The full text of this article is available at http://www.circresaha.org.

Action Potentials↗

PubMed2002

Effects of micronutrient supplements on u.v.-induced skin damage.

Development of an orally-administered systemic agent that could reduce the effects of u.v. exposure on skin could potentially have a major effect on the incidence of skin cancers and photo-ageing. A number of micronutrients have been suggested to have metabolic properties that could induce this protection, and our data indicate that n-3 polyunsaturated fatty acids are particularly effective in this role. The mechanisms of action of n-3 polyunsaturated fatty acids appear to depend on their anti-inflammatory properties, acting to reduce the u.v.-induced release of cytokines and other mediators from a variety of skin cell types.

Aging↗

PubMed2001

2-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptor.

We have prepared a novel series of 2-amino-4,6-diarylpyridines that function as ligands of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). These compounds bind to both ERalpha and ERbeta with a modest selectivity for the alpha subtype. The most potent of these analogues, compound 19, has a K(i)=20nM at ERalpha. These molecules represent a novel template for designing potentially useful ligands for the estrogen receptor.

Bacteria↗

PubMed2001

Differential regulation of chemokine production in human peritoneal mesothelial cells: IFN-gamma controls neutrophil migration across the mesothelium in vitro and in vivo.

Leukocyte recruitment into the infected peritoneal cavity consists of an early, predominant polymorphonuclear leukocyte (PMN) influx and subsequent, prolonged mononuclear cell migration phase. Although chemokine secretion by resident peritoneal cells plays a primary role in mediating this migration, the mechanisms involved in controlling the switch in phenotype of cell infiltrate remain unclear. The present study investigates a potential role for the Th1-type cytokine IFN-gamma in the process of leukocyte recruitment into the peritoneal cavity. Stimulation of cultured human peritoneal mesothelial cells with IFN-gamma (1-100 U/ml) alone or in combination with IL-1beta (100 pg/ml) or TNF-alpha (1000 pg/ml) resulted in significant up-regulation of monocyte chemoattractant protein-1 and RANTES protein secretion. In contrast, IFN-gamma inhibited basal and IL-1beta-, and TNF-alpha-induced production of IL-8. The modulating effects of IFN-gamma on chemokine production occurred at the level of gene expression, and the degree of regulation observed was dependent on the doses of IL-1beta and TNF-alpha used. Analysis of the functional effects of IFN-gamma on IL-1beta-induced transmesothelial PMN migration with an in vitro human transmigration system and an in vivo murine model of peritoneal inflammation demonstrated that IFN-gamma was able to down-regulate PMN migration induced by optimal doses of IL-1beta. These effects were mediated in vivo via down-regulation of CXC chemokine synthesis. These findings suggest that IFN-gamma may play a role in controlling the phenotype of infiltrating leukocyte during the course of an inflammatory response, in part via regulation of resident cell chemokine synthesis.

Adjuvants, Immunologic↗

PubMed2001

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

Animals↗

PubMed2001

Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism.

Chemical genomics is the name we have given to the analysis of gene function through use of small molecule chemical tools. Orphan nuclear receptors are ideally suited to this technique of functional analysis, since their activity as transcription factors is regulated by small hydrophobic ligands. GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor FXR (NR1H4). Using GW4064 as a chemical tool, we have identified genes regulated by FXR in the liver, including those involved in bile acid synthesis and transport. We have also discovered that PXR (NR1I2) is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids. Together FXR and PXR cooperate to control biliary and urinary bile acid excretion. These functions suggest that potent PXR and FXR ligands may offer a new approach to the treatment of cholestatic liver disease.

Bile Acids and Salts↗