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Biomedical subjects

Jessica Harris

Publications and source records attributed to Jessica Harris.

14 recordsLinked to original sources
PubMed2006

Modified Th2 responses at high-dose exposures to allergen: using an occupational model.

RATIONALE: The relationships between allergen exposures and allergy and asthma are complex. High exposure levels to cat allergen are associated with IgG- and IgG(4)-specific antibody responses without sensitization or risk of asthma, a process described as a "modified Th2 response." Attenuation of risk of allergy and asthma at high exposure levels has been reported in longitudinal studies of both childhood and occupational asthma. OBJECTIVES: To investigate, using an occupational model, the relationships among estimated exposure to aeroallergens, the production of specific IgE, IgG and IgG(4) antibodies, and the prevalence of associated symptoms. METHODS: Cross-sectional survey of employees exposed to rats at work on six pharmaceutical sites across the United Kingdom. A total of 689 (89%) provided a blood sample and completed a questionnaire. MEASUREMENTS AND MAIN RESULTS: At highest exposure to rats, there was an attenuation of the exposure response for sensitization and symptoms. In contrast, the frequency of individuals producing high quantities of specific IgG and IgG(4) increased with exposure intensity. Ratios of IgG(4)/IgE were highest in those handling the greatest number of rats. Risk of developing work-related chest symptoms was lower for those who produced both specific IgE and IgG(4) compared to those with specific IgE only. CONCLUSIONS: High exposure to rats is associated with lower rates of specific IgE and symptoms but an increased frequency of high specific IgG and IgG(4) production. Specific IgG(4) produced together with specific IgE may reduce the risk of developing work-related chest symptoms compared with when specific IgE is produced alone.

Adolescent↗
PubMed2006

Socs2 and elf5 mediate prolactin-induced mammary gland development.

The proliferative phase of mammary alveolar morphogenesis is initiated during early pregnancy by rising levels of serum prolactin and progesterone, establishing a program of gene expression that is ultimately responsible for the development of the lobuloalveoli and the onset of lactation. To explore this largely unknown genetic program, we constructed transcript profiles derived from transplanted mammary glands formed by recombination of prolactin receptor (Prlr) knockout or wild-type mammary epithelium with wild-type mammary stroma. Comparison with profiles derived from prolactin-treated Scp2 mammary epithelial cells produced a small set of commonly prolactin-regulated genes that included the negative regulator of cytokine signaling, Socs2 (suppressor of cytokine signaling 2), and the ets transcription factor, E74-like factor 5 (Elf5). Homozygous null mutation of Socs2 rescued the failure of lactation and reduction of mammary signal transducer and activator of transcription 5 phosphorylation that characterizes Prlr heterozygous mice, demonstrating that mammary Socs2 is a key regulator of the prolactin-signaling pathway. Reexpression of Elf5 in Prlr nullizygous mammary epithelium restored lobuloalveolar development and milk production, demonstrating that Elf5 is a transcription factor capable of substituting for prolactin signaling. Thus, Socs2 and Elf5 are key members of the set of prolactin-regulated genes that mediate prolactin-driven mammary development.

Animals↗
PubMed2006

Depression--what should the doctor ask?

BACKGROUND: There are barriers to doctors detecting depression in general practice. We wondered what questions patients thought the doctor should ask to explore it appropriately. METHODS: One hundred and thirty-six teacher trainees, teachers, and students in the community, most of whom had experienced depression, were studied qualitatively in interviews and focus groups. They were asked to suggest what questions they would find helpful from doctors to elicit their experience of depression. Transcripts were grouped by gender and content analysed. RESULTS: Subjects suggested starting with open questions that act as signals for moving into emotional areas followed by specific questions about specific somatic expressions of depression. Men preferred questions about shorter fuse and anger toward others, while women were happy with questions about increased crying. DISCUSSION: If confirmed in other sectors of the community, these data may allow doctors to increase patients' comfort with their exploration of possible emotional problems such as depression.

Australia↗
PubMed2005

Transcriptional changes underlying the secretory activation phase of mammary gland development.

The secretory activation stage of mammary gland development occurs after parturition and converts inactive lobuloalveoli to active milk secretion. This process is triggered by progestin withdrawal and depends upon augmented prolactin (Prl) signaling. Little is known about the Prl-induced transcriptional changes that occur in the mammary gland to drive this process. To examine changes in the mammary transcriptome responsible for secretory activation, we have used transcript profiling of three mouse models that exhibit failure of secretory activation: knockout of galanin (a regulator of pituitary Prl production and a mammary cell autonomous modulator of Prl action); treatment with S179D Prl (a phosphoprolactin mimic); and knockout of a single Prl receptor allele. A significant reduction in expression was observed in genes belonging to 46 gene ontologies including those representing milk proteins, metabolism, lipid, cholesterol and fatty acid biosynthetic enzymes, immune response, and key transcription factors. A set of 35 genes, commonly regulated in all three models, was identified and their role in lactogenesis was validated by examining their expression in response to Prl stimulation or signal transducer and activator of transcription 5 knockdown in the HC11 mouse mammary cell culture model. The transcript profiles provided by these experiments identify 35 key genes (many for the first time) involved in the secretory activation phase of mammary gland development, show that S179D acts as an antagonist of Prl action, and provide insight into the partial penetrance of failed lactation in Prl receptor heterozygous females.

Alleles↗
PubMed2005

Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation.

Elf5 is an epithelial-specific ETS factor. Embryos with a null mutation in the Elf5 gene died before embryonic day 7.5, indicating that Elf5 is essential during mouse embryogenesis. Elf5 is also required for proliferation and differentiation of mouse mammary alveolar epithelial cells during pregnancy and lactation. The loss of one functional allele led to complete developmental arrest of the mammary gland in pregnant Elf5 heterozygous mice. A quantitative mRNA expression study and Western blot analysis revealed that decreased expression of Elf5 correlated with the downregulation of milk proteins in Elf5(+/-) mammary glands. Mammary gland transplants into Rag(-/-) mice demonstrated that Elf5(+/-) mammary alveolar buds failed to develop in an Elf5(+/+) mammary fat pad during pregnancy, demonstrating an epithelial cell autonomous defect. Elf5 expression was reduced in Prolactin receptor (Prlr) heterozygous mammary glands, which phenocopy Elf5(+/-) glands, suggesting that Elf5 and Prlr are in the same pathway. Our data demonstrate that Elf5 is essential for developmental processes in the embryo and in the mammary gland during pregnancy.

Animals↗
PubMed2004

A prospective study of Fel d1 and Der p1 exposure in infancy and childhood wheezing.

The impact of domestic exposure to cat allergen (Fel d1) and house dust mite (Der p1) on wheezing from birth to the age of 4 years was investigated in a multicenter prospective birth cohort; 1,611 mothers were recruited before delivery in Ashford, England, and Barcelona and Menorca, Spain. Exposures were gathered via dust sample collection at children's home in their first year of life. Families provided complete outcome data (wheezing status in all 4 years) for 1,289 children. Domestic allergen levels varied substantially between centers. Six hundred three (47%) children never wheezed during their first 4 years of life. Der p1 did not correlate with any type of wheezing outcome. Fel d1 significantly increased the risk of wheezing in 3- and 4-year-olds in comparison to 1-year-olds. Distinct risk profiles were found for wheezing at different ages. Multivariate analysis revealed an interaction between Fel d1 and maternal asthma among children who wheeze in Year 4 (relative risk = 2.77; 95% confidence interval = 1.19-6.46). Our data support the idea that several patterns of wheezing with different risk profiles exist among young children. The effect of Fel d1 exposure varied according to age and maternal asthma.

Animals↗
PubMed2004

Prolactin and the prolactin receptor: new targets of an old hormone.

Prolactin (PRL) is one of a family of related hormones including growth hormone (GH) and placental lactogen (PL) that are hypothesized to have arisen from a common ancestral gene about 500 million years ago. Over 300 different functions of PRL have been reported, highlighting the importance of this pituitary hormone. PRL is also synthesized by a number of extra-pituitary tissues including the mammary gland and the uterus. Most of PRL's actions are mediated by the unmodified 23 kDa peptide, however, PRL may be modified post-translation, thereby altering its biological effects. PRL exerts these effects by binding to its receptor, a member of the class I cytokine receptor super-family. This activates a number of signaling pathways resulting in the transcription of genes necessary for the tissue specific changes induced by PRL. Mouse knockout models of the major forms of the PRL receptor have confirmed the importance of PRLs role in reproduction. Further knockout models have provided insight into the importance of PRL signaling intermediates and the advent of transcript profiling has allowed the elucidation of a number of PRL target genes.

Alternative Splicing↗
PubMed2003

Using gene expression arrays to elucidate transcriptional profiles underlying prolactin function.

Prolactin is an ancient hormone, with different functions in many species. The binding of prolactin to its receptor, a member of the cytokine receptor superfamily, results in the activation of different intracellular signaling pathways, such as JAK2/STAT5, MAP kinase, and PI3K/AKT. How prolactin elicits so many different biological responses remains unclear. Recently, microarray technology has been applied to identify prolactin target genes in different systems. Here, we attempt to summarize and compare the available data. Our comparison of the genes reported to be transcriptionally regulated by prolactin indicates that there are few genes in common between the different tissues. Among the organs studied, mammary and prostate glands displayed the largest number of overlaps in putative prolactin target genes. Some of the candidates have been implicated in tumorigenesis. The relevance and validation of microarray data, as well as comparison of the results obtained by different groups, will be discussed.

Animals↗
PubMed2003

HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?

BACKGROUND: Laboratory animal allergy is a common occupational health problem affecting between 11% and 44% of exposed researchers. Allergy to rats and mice is most common, probably because these are the animals most frequently used. OBJECTIVE: We hypothesized that HLA class II molecules, involved in the presentation of allergen to the T cell and likely candidates for controlling the immune response, might be associated with sensitization to rat urinary proteins among laboratory animal handlers. METHODS: We undertook a cross-sectional study of 741 employees at 6 pharmaceutical sites across the United Kingdom who had contact at work with laboratory rats. In all, 109 cases with specific sensitization to rat proteins and 397 referents were HLA-typed for DRB1 and DQB1 loci. Amino acid analyses of significantly associated HLA molecules were carried out. RESULTS: HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI, 1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and, most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65). HLA-DR3 was protective against sensitization (OR, 0.55; CI, 0.31-0.97). Amino acid analyses of these 2 molecules indicated a biologically plausible explanation for the associations. CONCLUSION: HLA phenotype is an important determinant of individual susceptibility to sensitization and asthma among laboratory animal workers. Similar mechanisms might apply in other animal allergies.

Adolescent↗
PubMed2003

Prostate development and carcinogenesis in prolactin receptor knockout mice.

Hyperprolactinemia results in prostatic hypertrophy and hyperplasia, but it is not known whether prolactin plays an essential role in these processes in the prostate. To address this question, we investigated prostate development, gene expression, and simian virus 40 (SV40)T-induced prostate carcinogenesis in prolactin receptor knockout mice. These animals showed a small increase in dorsolateral and ventral prostate weight but no change in the weight of the anterior prostate. The dorsal but not ventral or lateral lobes showed a 12% loss of epithelial cells; all other morphological parameters were normal. The area of SV40T-induced prostate intraepithelial neoplasia was reduced by 28% in the ventral lobe but not the dorsal lobe, and no tumors were seen in 20 prolactin receptor knockout animals, compared with 1 of 11 detected in wild-type and 4 of 21 found in heterozygous animals. Oligonucleotide microarrays were used to identify essential transcriptional roles of prolactin and revealed a small set of genes with decreased expression involved in sperm/oocyte interaction and copulatory plug formation. Infertility or reduced fertility was apparent in these animals. These findings establish essential though subtle roles for prolactin in the regulation of prostate morphology, gene expression, SV40T-induced neoplasia, and reproductive function.

Androgens↗
PubMed2003

Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice.

Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR), and various members of the receptor's signaling pathway. This allowed an in vivo genetic analysis of the role of PRL in target organ function. In PRLKO and PRLRKO mice, mammary ductal side branching was absent, terminal end bud (TEB)-like structures persisted at the ductal termini well into maturity, and no alveolar buds formed along the ductal tree. Transplants of recombined mammary glands formed from stromal and epithelial elements with and without PRLR showed normal development, while supplementation of progesterone levels in PRLKO animals restored ductal side branching. During pregnancy, PRLR heterozygous animals initially showed normal ductal and alveolar development. However, alveolar development stalled during late pregnancy, preventing successful lactation. This defect could be rescued by the loss of a single allele of the suppressor of cytokine signaling (SOCS) 1 gene. Transplants of recombined glands containing PRLRKO epithelium and wild-type (WT) stroma formed alveolar buds during pregnancy but showed no lobuloalveolar development. Recombinations of WT epithelium and PRLRKO stroma showed normal development, demonstrating that a direct action of the lactogenic hormones is confined to the epithelium, to promote lobuloalveolar development. Transcript profiling of epithelial transplants expressing or not expressing PRLR was used during early pregnancy to investigate the transcriptional response to lactogens underlying this defect. Such profiling has identified a number of genes with well-characterized roles in mammary development, in addition to a number of novel transcripts.

Animals↗
PubMed2002

Local insulin-like growth factor-II mediates prolactin-induced mammary gland development.

Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II. During sexual maturity and in early pregnancy, the level of IGF-II mRNA in the mammary gland was increased concurrent with increased PRL receptor expression. The level of IGF-II mRNA was reduced in mammary tissue from PRL receptor-/- mice during early pregnancy, and explants of mouse mammary gland and HC11 mammary epithelial cells both increased their expression of IGF-II after exposure to PRL in vitro. These findings coincided with the demonstration that IGF-II stimulated alveolar development in mammary glands in whole organ culture. PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro. Insight into the mechanism by which PRL induced IGF-II expression was provided by the fact that it was blocked by the Jak2 inhibitor AG490 and the MAPK inhibitor PD98059. Finally, induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors. Together, these data demonstrate a role for IGF-II as a mediator of PRL action in the mouse mammary gland during ductal branching and alveolar development.

Animals↗
PubMedDate not supplied

Smoking cessation and associated factors during pregnancy.

OBJECTIVE: To examine smoking habits before and during pregnancy, as well as factors associated with smoking cessation, in three European settings. METHODS: Women seeking antenatal care in Ashford (UK), Minorca and Barcelona (Spain) were recruited to the Asthma Multicenter Infant Cohort Study (AMICS). Questionnaires inquiring into the smoking habits of each woman and her partner, demographic data, occupation, educational level, number of previous children, breast feeding, alcohol intake, and history of asthma and of other allergic diseases were completed during pregnancy and in the first year after delivery. RESULTS: A total of 1,572 pregnant women were included in the three cohorts. Smoking prior to pregnancy was more common in Barcelona (46.2%) than in Minorca (39.8%) or Ashford (31.6%). Cessation rates during pregnancy also differed: 18% of women in Ashford, 20.4% in Minorca and 31.9% in Barcelona were still smoking during the first trimester. In a multivariate regression model, the factors showing a significant (negative) association with smoking cessation during pregnancy were having older children, having a partner who smoked and starting smoking at a young age. CONCLUSIONS: Baseline smoking habits and changes in smoking habits during pregnancy significantly differed between the three communities studied. Women pregnant with their first child, those who had started smoking at a later age and those whose partners were non-smokers were more likely to stop smoking when pregnant.

Adult↗