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Iain T Cameron

Publications and source records attributed to Iain T Cameron.

14 recordsLinked to original sources
PubMed2007

Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits.

The angiotensin II type 1 receptor (AGTR1) is the main target through which angiotensin II influences cardiovascular tone, cell growth, and fluid and electrolyte balance. AGTR1 polymorphism has been reported to associate with hypertension, myocardial infarction (MI), and metabolic traits. Here we describe a novel approach to quantitation of transcript haplotypes (QTH) of AGTR1. To determine relative allelic expression from haplotypes, within-individual-between-allele ratiometric analyses in placental cDNA were developed for the transcribed SNPs rs5182:C>T (encoding p.L191) and rs5186:A>C (3'-noncoding "A1166C"). Additionally, between-individual comparisons were made using TaqMan assays applied to both homozygous and heterozygous genotypes and haplotypes. In conjunction, linkage disequilibrium (LD) and genomic haplotype associations with metabolic syndrome were examined. There was no significant difference of mRNA level for alleles of rs5182:C>T, but allele and mRNA haplotypes carrying 1166C exhibited reduced abundance. The effect was much greater in CC homozygotes than in heterozygotes. The promoter region was confirmed to be in a separate haplotype block from the AGTR1 3' region containing rs5182:C>T and rs5186:A>C. Metabolic syndrome trait associations were strongest for the 3' block generally and for the C allele of rs5186:A>C specifically. All effects were much more prominent in homozygotes, possibly reflecting interallelic interaction through feedback loops of mRNA regulation. Differential abundance of AGTR1 mRNA haplotypes may mediate clinical phenotypic observations of the AGTR1 genotype.

Aged↗
PubMed2006

In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development.

In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3beta-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Relative contribution of cell contact pattern, specific PKC isoforms and gap junctional communication in tight junction assembly in the mouse early embryo.

In mouse early development, cell contact patterns regulate the spatial organization and segregation of inner cell mass (ICM) and trophectoderm epithelium (TE) during blastocyst morphogenesis. Progressive membrane assembly of tight junctional (TJ) proteins in the differentiating TE during cleavage is upregulated by cell contact asymmetry (outside position) and suppressed within the ICM by cell contact symmetry (inside position). This is reversible, and immunosurgical isolation of the ICM induces upregulation of TJ assembly in a sequence that broadly mimics that occurring during blastocyst formation. The mechanism relating cell contact pattern and TJ assembly was investigated in the ICM model with respect to PKC-mediated signaling and gap junctional communication. Our results indicate that complete cell contact asymmetry is required for TJ biogenesis and acts upstream of PKC-mediated signaling. Specific inhibition of two PKC isoforms, PKCdelta and zeta, revealed that both PKC activities are required for membrane assembly of ZO-2 TJ protein, while only PKCzeta activity is involved in regulating ZO-1alpha+ membrane assembly, suggesting different mechanisms for individual TJ proteins. Gap junctional communication had no apparent influence on either TJ formation or PKC signaling but was itself affected by changes of cell contact patterns. Our data suggest that the dynamics of cell contact patterns coordinate the spatial organization of TJ formation via specific PKC signaling pathways during blastocyst biogenesis.

Animals↗
PubMed2005

Human embryonic germ cells for future neuronal replacement therapy.

Stem cell therapy offers exciting potential for ambitious cellular replacement to treat human (h) disease, such as Parkinson's disease, Alzheimer's disease or even replacement of the cell death that follows thromboembolic stroke. The realisation of these treatments requires cellular resources possessing three essential characteristics: (i) self-renewal, (ii) the ability to differentiate to physiologically normal cell types and (iii) lack of tumourigenicity. Here, we describe work on human embryonic germ cells (hEGCs), a population of cells alongside human embryonic stem cells (hESCs) with the potential to address these issues.

Animals↗
PubMed2005

Evaluating human embryonic germ cells: concord and conflict as pluripotent stem cells.

The realization of cell replacement therapy derived from human pluripotent stem cells requires full knowledge of the starting cell types as well as their differentiated progeny. Alongside embryonic stem cells, embryonic germ cells (EGCs) are an alternative source of pluripotent stem cell. Since 1998, four groups have described the derivation of human EGCs. This review analyzes the progress on derivation, culture, and differentiation, drawing comparison with other pluripotent stem cell populations.

Animals↗
PubMed2005

Insulin and human chorionic gonadotropin cause a shift in the balance of sterol regulatory element-binding protein (SREBP) isoforms toward the SREBP-1c isoform in cultures of human granulosa cells.

The isoforms of sterol regulatory element-binding proteins (SREBP) (1a, 1c, and 2) are key transcriptional regulators of lipid biosynthesis. We examined their regulation by gonadotropin and insulin in human granulosa cells. After removal of leukocytes, granulosa cells were exposed to hormonal additions for 16 h starting on d 2 of culture. Progesterone, lactate, and IGF binding protein-1 were measured in culture medium and cellular mRNA measured by competitive RT-PCR. Addition of human chorionic gonadotropin (hCG) (100 ng/ml) stimulated progesterone production (7.0-fold, P < 0.001 vs. control), whereas lactate was increased by hCG (1.6-fold, P < 0.001) and insulin (1.4-fold, P < 0.001; 1000 ng/ml). Insulin decreased IGF binding protein-1 production by 85% (P < 0.001). There were no significant effects on the expression of SREBP-1a but significant increases in mRNA for SREBP-1c with insulin (6.3-fold), hCG (10.4-fold) and in combination (15.2-fold; P < 0.01 for all comparisons). No consistent effects on SREBP-2 were observed. The expression of mRNA for fatty acid synthase, a target gene for SREBP-1c, was increased by hCG (24-fold, P = 0.006) and insulin (19-fold, P = 0.024), which also increased the level of cellular, total fatty acid (1.34-fold; P = 0.03). Thus, hCG and insulin cause a switch toward expression of the SREBP-1c isoform with consequent effects on fatty acid synthesis. We suggest that high circulating insulin, associated with clinically defined insulin resistance, may up-regulate SREBP-1c expression in the ovary.

CCAAT-Enhancer-Binding Proteins↗
PubMed2004

Low serine hydroxymethyltransferase activity in the human placenta has important implications for fetal glycine supply.

Glycine is essential for fetal development, but in both sheep and human pregnancy, little is transported directly from the mother to the fetus, indicating that fetal glycine is derived from other sources. In the sheep, placental conversion of maternal serine by serine hydroxymethyltransferase (SHMT) provides almost all the glycine transported to the fetus. Although mRNA for mitochondrial and cytoplasmic SHMT has been detected in human placenta, it is not known whether substantial placental conversion of serine to glycine occurs in species other than sheep. We determined SHMT activity in human, rat, and sheep placenta by measuring conversion of [3-(14)C]serine to (14)C-methylene tetrahydrofolate. Compared with term human placenta, SHMT activity per gram of placenta was 5.1-fold higher in term rat placenta and 24.1-fold higher in term sheep placenta. In sheep placenta, SHMT activity per gram of placenta increased 2.1-fold between mid-gestation and term. In human placenta, placental SHMT activity was similar 8 wk post conception and at term. The low activity of SHMT in the human and rat placenta suggests that, unlike in the sheep, placental conversion of serine to glycine is not a major source of fetal glycine in these species.

Animals↗
PubMed2004

Specific PKC isoforms regulate blastocoel formation during mouse preimplantation development.

During early mammalian development, blastocyst morphogenesis is achieved by epithelial differentiation of trophectoderm (TE) and its segregation from the inner cell mass (ICM). Two major interrelated features of TE differentiation required for blastocoel formation include intercellular junction biogenesis and a directed ion transport system, mediated by Na+/K+ ATPase. We have examined the relative contribution of intercellular signalling mediated by protein kinase C (PKC) and gap junctional communication in TE differentiation and blastocyst cavitation. The distribution pattern of four (delta, theta, iota/lambda, zeta) PKC isoforms and PKCmicro/PKD1 showed partial colocalisation with the tight junction marker ZO-1alpha+ in TE and all four PKCs (delta, theta, iota/lambda, zeta) showed distinct TE/ICM staining patterns (predominantly at the cell membrane within the TE and cytoplasmic within the ICM), indicating their potential contribution to TE differentiation and blastocyst morphogenesis. Specific inhibition of PKCdelta and zeta activity significantly delayed blastocyst formation. Although modulation of these PKC isoforms failed to influence the already established programme of epithelial junctional differentiation within the TE, Na+/K+ ATPase alpha1 subunit was internalised from membrane to cytoplasm. Inhibition of gap junctional communication, in contrast, had no influence on any of these processes. Our results demonstrate for the first time that distinct PKC isotypes contribute to the regulation of cavitation in preimplantation embryos via target proteins including Na+/K+ ATPase.

Animals↗
PubMed2004

PKC signalling regulates tight junction membrane assembly in the pre-implantation mouse embryo.

Epithelial differentiation including tight junction (TJ) formation occurs exclusively within the trophectoderm (TE) lineage of the mouse blastocyst. Here we examine mechanisms by which TJ protein membrane assembly might be regulated by protein kinase C (PKC) in the embryo. To overcome the inherent staging asynchrony of individual blastomeres within intact embryos, we have used isolated inner cell masses (ICMs) from early blastocysts to induce epithelial differentiation in their outer cells responding to their new cell contact pattern. Two TJ proteins examined retain their order of membrane assembly in isolated ICMs in culture as during normal development (early-assembling ZO-2 and late-assembling ZO-1alpha(+)), but this process is highly accelerated. Using six chemical modulators of PKC activity, we show here that PKC signalling is involved in the regulation of TJ membrane assembly. While indolactam-mediated PKC activation stimulates membrane assembly of both TJ proteins, TPA-mediated PKC activation stimulates only that of ZO-1alpha(+). The PKC inhibitors Ro-31-8220, Ro-31-8425 and Gö 6983 suppress the stimulatory effect of both PKC activators on membrane assembly to varying extents according to inhibitor and TJ protein examined. Gö 6983 similarly inhibits ZO-2 and ZO-1alpha(+) membrane assembly. PKC inhibition by Gö 6976 appeared to stimulate TJ membrane assembly. Despite the broad PKC isotype specificity of the inhibitors used, these data suggest that the two TJ proteins are differently regulated by PKC isotypes or subfamilies. As Gö 6983 uniquely affects aPKC (particularly PKCzeta) and we find that both PKCdelta and zeta relocate upon activator treatment to colocalise partially with the TJ proteins in isolated ICMs, we suggest that at least PKCdelta and zeta may play a central role in regulating TJ membrane assembly.

Animals↗
PubMed2003

Ovulation induction/intrauterine insemination in infertile couples is associated with low-birth-weight infants.

OBJECTIVE: The study was undertaken to determine the outcome of singleton pregnancies conceived through ovulation induction and intrauterine insemination using a partner's (OI/IUI) or donor sperm (OI/IUID) by comparison with naturally conceived singletons within a national cohort. STUDY DESIGN: Retrospective cohort study in primigravid women who were treated with OI/IUI (n = 97) or OI/IUID (n = 35) at Glasgow Royal Infirmary between March 1993 and March 1997 and identified within the Scottish national cohort (n = 109,443) delivering during the same period. Univariate and multivariate logistic regression models were used to examine outcomes and to determine the factors associated with infertility treatment and low birth weight. RESULTS: OI/IUI singletons were more likely to be lighter, of clinically low birth weight, and born more prematurely than natural conceptions. After adjustment for associated factors, these infants were 4.85 times (95% CI 2.25-10.48) more likely to be of low birth weight. We could not demonstrate any differences between OI/IUID and natural conceptions. CONCLUSION: The perinatal outcome of singletons born to subfertile mothers conceived through OI/IUI is poorer than that of matched natural conceptions. We suggest that intrinsic factors in subfertile couples predispose them to having smaller infants and that "infertility" should be added to the list of recognized factors associated with low birth weight.

Cohort Studies↗
PubMed2003

Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel.

BACKGROUND: The levonorgestrel intrauterine system (LNG-IUS) is a contraceptive device that is used for treatment of menorrhagia. The system induces inter-menstrual bleeding within the first few months after insertion. We hypothesized that this bleeding might be associated with a change in vascular development. METHODS: A randomized, controlled study was undertaken on 48 women. RESULTS: Hysterectomy specimens were obtained and immunocytochemistry was carried out with antibodies to CD31, alpha-smooth muscle actin and myosin. Stereological measurement of blood vessels was also undertaken. Most vessels appeared normal, including the arterioles. Large thin-walled vessels were present in the superficial endometrium of the treated group but were almost completely absent in the controls. The distribution of cytoskeletal markers revealed well-formed basal arterioles with more widespread expression in the superficial stroma than was found in untreated tissue. The volume fraction of blood vessels (P = 0.0001), the number of vessel cross-sections per unit area (P = 0.0003) and the cross-sectional diameters of the largest vascular lumens (P = 0.0001) were significantly increased following treatment with LNG-IUS. However, there was no difference in the median values of vessel diameter or the vascular surface density. CONCLUSION: These findings suggest that the LNG has a localized effect on some vessels within the superficial endometrium.

Actins↗
PubMed2003

The Mirena levonorgestrel system.

The levonorgestrel intrauterine system is a safe, efficacious, long-term contraceptive device. Additionally, it results in a decrease in the volume of menstrual blood loss in women with normal periods and those with menorrhagia. It may also have a role in the treatment of other benign gynecological disorders, such as adenomyosis or endometriosis, and it has been advocated as a means of delivering progestogen to the endometrium as part of combined hormone replacement therapy. Despite the beneficial effect on menstrual volume, compliance is sometimes limited by breakthrough bleeding during the first months of use. The precise mechanism of this bleeding is unclear, but it may be related to a direct effect of levonorgestrel on endometrial vascular development. Detailed counseling is crucial to explain this anticipated side effect in order to reduce unnecessary discontinuation of treatment.

Contraceptive Agents, Female↗
PubMed2003

Derivation of human embryonic germ cells: an alternative source of pluripotent stem cells.

Based on evidence suggesting similarities to human embryonic stem cells, human embryonic germ (hEG) cells have been advocated as an alternative pluripotent stem cell resource but have so far received limited attention. To redress this imbalance, human fetal gonads were collected for the isolation and culture of primordial germ cells at 7-9 weeks postconception. We provide evidence for the derivation, culture, and differentiation of hEG cells in vitro. This evidence includes the expression of markers characteristic of pluripotent cells, the retention of normal XX or XY karyotypes, and the demonstration of pluripotency, as suggested by the expression of markers indicative of differentiation along the three germ lineages (ectoderm, mesoderm, and endoderm) and an associated loss of pluripotent markers. In assessing this differentiation, however, we also demonstrate a hitherto unacknowledged overlap in gene expression profiles between undifferentiated and differentiated cell types, highlighting the difficulty in ascribing cell lineage by gene expression analyses. Furthermore, we draw attention to the problems inherent in the management of these cells in prolonged culture, chiefly the difficulty in preventing spontaneous differentiation, which hinders the isolation of pure, undifferentiated clonal lines. While these data advocate the pursuit of pluripotent hEG cell studies with relevance to early human embryonic development, culture limitations carry implications for their potential applicability to ambitious cell replacement therapies.

Biomarkers↗