Identification of RIP140 as a nuclear receptor cofactor with a role in female reproduction.
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Adaptor Proteins, Signal Transducing↗
Biomedical subjects
S Milligan
Publications and source records attributed to S Milligan.
Handlebar hernia masquerading as an inguinal haematoma.
We report a child who sustained a traumatic hernia of the lower abdominal wall after being thrown forward against the handlebar of his bicycle. This is a rare injury in children, and the clinical features mimic an inguinal haematoma. Suspicion should be raised by the immediate appearance of a mass above the inguinal canal following groin injury, particularly if the swelling then disappears with the patient supine.
Abdominal Injuries↗
Oestrogenic activity of the hop phyto-oestrogen, 8-prenylnaringenin.
The female flowers of the hop plant (hop cones) are used as a preservative and as a flavouring agent in beer. A novel phyto-oestrogen, 8-prenylnaringenin, was recently identified in hops and this study was undertaken to characterize the oestrogenic activity of this compound using a combination of in vitro and in vivo assays. Natural and semi-synthetic 8-prenylnaringenin showed similar bioactivities both in a yeast screen transfected with the human oestrogen receptor and in oestrogen-responsive human Ishikawa Var-I cells. 8-Prenylnaringenin showed comparable binding activity to both oestrogen receptor isoforms (ER alpha and ER beta). 8-Prenylnaringenin extracted from hops contains similar amounts of both (R)- and (S)- enantiomers, indicating that the compound is normally formed non-enzymatically. Both enantiomers showed similar bioactivity in vitro and similar binding characteristics to ER alpha and ER beta. The oestrogenic activity of 8-prenyl-naringenin in vitro was greater than that of established phyto-oestrogens such as coumestrol, genistein and daidzein. The high oestrogenic activity was confirmed in an acute in vivo test using uterine vascular permeability as an end point. When the compound was given to ovariectomized mice in their drinking water, oestrogenic stimulation of the vaginal epithelium required concentrations of 100 mug ml(-1) (about 500-fold greater than can be found in any beer).
Animals↗
Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis.
Infection of mice by murine gammaherpesvirus 68 (MHV-68) is an excellent small-animal model of gammaherpesvirus pathogenesis in a natural host. We have carried out comparative studies of another herpesvirus, murine herpesvirus 76 (MHV-76), which was isolated at the same time as MHV-68 but from a different murid host, the yellow-necked mouse (Apodemus flavicollis). Molecular analyses revealed that the MHV-76 genome is essentially identical to that of MHV-68, except for deletion of 9,538 bp at the left end of the unique region. MHV-76 is therefore a deletion mutant that lacks four genes unique to MHV-68 (M1, M2, M3, and M4) as well as the eight viral tRNA-like genes. Replication of MHV-76 in cell culture was identical to that of MHV-68. However, following infection of mice, MHV-76 was cleared more rapidly from the lungs. In line with this, there was an increased inflammatory response in lungs with MHV-76. Splenomegaly was also significantly reduced following MHV-76 infection, and much less latent MHV-76 was detected in the spleen. Nevertheless, MHV-76 maintained long-term latency in the lungs and spleen. We utilized a cosmid containing the left end of the MHV-68 genome to reinsert the deleted sequence into MHV-76 by recombination in infected cells, and we isolated a rescuant virus designated MHV-76(cA8+)4 which was ostensibly genetically identical to MHV-68. The growth properties of the rescuant in infected mice were identical to those of MHV-68. These results demonstrate that genetic elements at the left end of the unique region of the MHV-68 genome play vital roles in host evasion and are critical to the development of splenic pathology.
Animals↗
In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease.
Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and individual monoterpenoid constituents have been shown to inhibit the enzyme acetylcholinesterase in-vitro and in-vivo. This activity is relevant to the treatment of Alzheimer's disease, since anticholinesterase drugs are currently the only drugs available to treat Alzheimer's disease. Other activities relevant to Alzheimer's disease include antioxidant, anti-inflammatory and estrogenic effects. Results of in-vitro tests for these activities are reported here for S. lavandulaefolia extracts, the essential oil and its major constituents. Antioxidant activity (inhibition of bovine brain liposome peroxidation) was found in the EtOH extract of the dried herb (5 mg mL(-1)) and the monoterpenoids (0.1 M) alpha- and beta-pinene and 1,8-cineole. Thujone and geraniol had lower antioxidant effects, while camphor had no antioxidant effects. Possible anti-inflammatory activity (eicosanoid inhibition in rat leucocytes) was found in the EtOH extract (50 microg mL(-1)) and was shown by the monoterpenoids alpha-pinene and geraniol (0.2 mM), but not 1,8-cineole, thujone or camphor. Possible estrogenic activity (via induction of beta-galactosidase activity in yeast cells) was found in the essential oil (0.01 mg mL(-1)) and the monoterpenoid geraniol (0.1-2 mM). 1,8-Cineole, alpha- and beta-pinene and thujone did not exhibit estrogenic activity in this analysis. These results demonstrate that S. lavandulaefolia, its essential oil and some chemical constituents have properties relevant to the treatment of Alzheimer's disease and provide further data supporting the value of carrying out clinical studies in patients with Alzheimer's disease using this plant species.
Alzheimer Disease↗
Oral care for people with advanced cancer: an evidence-based protocol.
Poor oral health is an extremely common problem in patients with advanced cancer and, because of its impact on quality of life, promoting oral care should be regarded as a priority by every hospice and palliative care team. At Accord Hospice, Paisley, UK, a protocol for oral care has been developed which is simple, inexpensive and evidence-based. Evaluation of the protocol has shown that it can lead to significant and consistent improvements in oral health and comfort. A survey of mouth-care practices in other Scottish hospice units reveals that although much agreement exists, certain practices that are unsupported by research evidence are still undertaken.
Adult↗
The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility.
Ovulatory dysfunction is the commonest cause of female infertility. Here we show that the co-repressor nuclear-receptor-interacting protein 1 (Nrip1; encoded by the gene Nrip1) is essential for ovulation. Mice null for this protein are viable, but female mice are infertile because of complete failure of mature follicles to release the oocyte at ovulation. In contrast, luteinization proceeds normally, resulting in a phenotype closely resembling that of luteinized unruptured follicle syndrome, often associated with infertility in women. Therefore, whereas the pre-ovulatory surge of luteinizing hormone induces both ovulation and luteinization, the ability to suppress the action of nuclear receptors is essential for the coordinated control of ovarian function with the essential process of oocyte release dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40).
Adaptor Proteins, Signal Transducing↗
How significant are environmental estrogens to women?
Women are exposed to xenobiotic estrogens at least to the same extent as men. These estrogenic chemicals are either from plant material in the diet (phytoestrogens) or from industrial sources. Mainly industrially derived environmental estrogens may accumulate within the food chain and persist in human adipose tissue. In contrast, phytoestrogens do not bioaccumulate and are rapidly excreted in urine. The phytoestrogens probably represent the source of most extensive exposure for humans. Epidemiological evidence suggests that diets rich in phytoestrogens are associated with reduced incidences of cardiovascular disease, breast cancer, prostate cancer and osteoporosis. The numerous bioactivities (other than just estrogenicity) of phytoestrogens and related dietary compounds make it difficult to single out the mechanisms mediating such protective effects. The possibility that the newly discovered estrogen receptor beta may be an important modulator of phytoestrogen action is opening up new lines of research. While the evidence suggests that phytoestrogens may be of positive relevance to postmenopausal women, indications that exposure of women to industrially derived xenobiotic estrogens provides risks to health remain unproven. Further work is necessary to clarify the relative importance of 'xenobiotic' estrogens to human health, but it must be emphasized that the estrogenic potency of all the xenobiotic estrogens is very low compared with that of endogenous estrogens.
Breast Neoplasms↗
Mammalian homolog of Drosophila retinal degeneration B rescues the mutant fly phenotype.
Mutations in the Drosophila rdgB gene, which encodes a transmembrane phosphatidylinositol transfer protein (PITP), cause a light-enhanced retinal degeneration. Cloning of mammalian rdgB orthologs (mrdgB) reveal predicted proteins that are 39% identical to rdgB, with highest homology in the N-terminal PITP domain (62%) and in a region near the C terminus (65%). The human mrdgB gene spans approximately 12 kb and maps to 11q13.1, a locus where several retinal diseases have also been mapped. Murine mrdgB maps to a syntenic region on the proximal region of chromosome 19. MrdgB is specifically expressed in the retina and brain. In the retina, MrdgB protein is localized to photoreceptor inner segments and the outer and inner plexiform layers. Expression of murine mrdgB in mutant flies fully rescues both the rdgB-dependent retinal degeneration and abnormal electroretinogram. These results suggest the existence of similarities between the invertebrate and mammalian retina that were not previously appreciated and also identify mrdgB as a candidate gene for retinal diseases that map to 11q13.1.
Animals↗
Appointment attendance, pill counts, and achievement of goal blood pressure in the African American Study of Kidney Disease and Hypertension Pilot Study.
The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study evaluated the feasibility of conducting a 7-year clinical trial to assess the effect of two levels of blood pressure control based on mean arterial pressure (MAP) (low goal < or = 92 mm Hg or usual goal of 102-107 mm Hg) and three antihypertensive drug regimens (atenolol, amlodipine, or enalapril) as initial therapy in slowing the decline of renal function in African Americans with clinically diagnosed hypertensive nephrosclerosis. Ninety-four African American men and women between 18 and 70 years of age were randomized and followed for an average of 4.6 months. On average participants attended 87.5% of the scheduled monthly follow-up visits and achieved an acceptable level of medication adherence (80%-100% of prescribed doses by pill count) at 65.4% of those visits Blood pressure levels within goal were observed in 17.5% and 25.6% of the participants in the low- and usual MAP goal groups, respectively. Neither attendance nor medication adherence by pill count was associated with attainment of goal blood pressure. Although AASK Pilot Study participants maintained excellent attendance, their pill counts were lower than previously reported among clinical trial participants and goal blood pressure levels were difficult to achieve during the short period of follow-up.
Adult↗
Effect of blood pressure control and antihypertensive drug regimen on quality of life: the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study.
The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study evaluated the feasibility of carrying out a randomized, multicenter, 7-year clinical trial to determine the effects of two goal levels of blood pressure control and three antihypertensive drug regimens on decline in glomerular filtration rate in African Americans with clinically diagnosed hypertensive nephrosclerosis. Participants were randomized to either a usual mean arterial blood pressure (MAP) goal group (102-107 mm Hg) or a low-MAP goal group (< or = 92 mm Hg) and to a drug regimen (initial therapy with either atenolol, amlodipine, or enalapril). Quality of life was assessed by the Medical Outcomes Short-Form 36 (MOS SF-36) at baseline and the last follow-up visit for 84 of the 94 participants of the AASK Pilot Study. Symptoms were assessed at baseline and throughout the course of therapy by participant self-report. Mean SF-36 scores increased significantly on physical functioning (9.2), role limitations (physical) (19.0), social functioning (9.0), and vitality dimensions (5.6) from baseline to the last follow-up visit in the usual MAP goal group. Scores for the eight health dimensions assessed by the MOS SF-36 did not change significantly during the same time period either in the low-MAP goal group or in any of the drug regimens. The mean score for general health perception was significantly lower at the last follow-up visit in the enalapril drug regimen (49.9) compared to drug regimens with atenolol (65.4) or amlodipine (63.9). Physical functioning, role limitations (emotional), social functioning, mental health, vitality, and general health perception scores were negatively correlated with self-reported symptoms during treatment. We conclude that selected dimensions of quality of life improved during the AASK Pilot Study only in participants randomized to the usual MAP goal group. Significant differences between MAP goal groups and drug regimens at the end of follow-up were observed for only a few health dimensions.
Adult↗
Participant satisfaction in the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study.
Seventy-one of the 94 eligible participants of the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study completed a self-administered questionnaire at the end of the study to determine their satisfaction with the study, difficulties encountered during participation, and willingness to join a similar study in the future. Nearly all of the participants (97%) believed that they would directly benefit from the study; treatment and information from physicians (94%), and more knowledge (92%) and closer monitoring (90%) of their physical condition were often cited as the ways in which the AASK Pilot Study helped. The two most commonly reported problems in the study were side effects from antihypertensive drugs (27%) and travel to and from the clinic (25%). Eighty-two percent of those who completed the survey indicated that they would volunteer for a similar study in the future. We conclude that AASK Pilot Study participants believed that they would benefit directly from the trial and that medical aspects of the trial were of major importance. Side effects from antihypertensive drugs and difficulties in travel to and from the clinic were commonly encountered problems and may hinder long-term participation in the AASK Full-Scale Trial.
Adult↗
Nitric oxide synthase in circulating vs. extravasated polymorphonuclear leukocytes.
It is becoming increasingly apparent that certain forms of acute and chronic inflammation are associated with enhanced production of nitric oxide (NO). Although substantial information has been obtained describing the regulation of NO synthase (NOS) in macrophages, little information is available regarding the biochemistry and molecular biology of NOS in circulating vs. extravasated polymorphonuclear leukocytes (PMNs). The objective of this study was to characterize the molecular and biochemical properties of the inducible NO synthase (iNOS) in circulating vs. extravasated rat and human PMNs. Circulating rat and human PMNs were purified from peripheral blood and extravasated PMNs were elicited in rats by intraperitoneal injection of 1% oyster glycogen or in humans by peritoneal dialysis of patients with peritonitis. Inducible NOS mRNA from circulating and elicited PMNs was quantified using slot blot hybridization analysis with a cDNA probe specific for iNOS. iNOS protein was identified using Western immunoblot analysis, and NOS activity was quantified by measuring the NG-monomethyl-L-arginine (L-NMMA)-inhibitable conversion of 14C-labeled L-arginine to L-[14C]citrulline. In a separate series of experiments, circulating or extravasated PMNs were cultured for 4 h and the accumulation of L-NMMA-inhibitable nitrite (NO2-) in the supernatant was determined and used as a measure of NO production in vitro. We found that circulating PMNs (rat or human) contained no iNOS mRNA, protein, or enzymatic activity. Furthermore, circulating rat or human PMNs (2 x 10(6) cells/well) were unable to generate significant amounts of NO2- when cultured for 4 h in vitro. In contrast, iNOS mRNA levels in 4- and 6-h elicited rat PMNs increased 21- and 42-fold, respectively, when compared with circulating cells. Western blot analysis revealed the presence of iNOS protein in the elicited rat PMNs and iNOS enzymatic activity increased from normally undetectable levels in circulating rat PMNs to 81 and 285 pmol/min/mg for the 4- and 6-h elicited rat PMNs, respectively. Approximately 20-30% of the total iNOS activity was Ca(2+)-dependent. Nitrite formation by elicited rat PMNs in the absence of any exogenous stimuli increased from normally undetectable amounts for circulating PMNs to approximately 8 and 11 microM/10(6) cells for the 4- and 6-h elicited PMNs, respectively. Highly enriched preparations of extravasated human PMNs contained neither message, protein nor iNOS enzymatic activity. Taken together our data demonstrate that inflammation-induced extravasation of rat PMNs upregulates the transcription and translation of iNOS in a time-dependent fashion and that 20-30% of the total inducible NOS is Ca(2+)-dependent. In contrast, neither circulating nor extravasated human PMNs contained iNOS message, protein, or enzymatic activity. These data suggest that the human PMN iNOS gene is under very different regulation than is the rat gene.
Animals↗
Therapist-driven protocols: the state of the art.
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Clinical Protocols↗
Localization of Drosophila retinal degeneration B, a membrane-associated phosphatidylinositol transfer protein.
The Drosophila retinal degeneration B (rdgB) mutation causes abnormal photoreceptor response and light-enhanced retinal degeneration. Immunoblots using polyclonal anti-rdgB serum showed that rdgB is a 160-kD membrane protein. The antiserum localized the rdgB protein in photoreceptors, antennae, and regions of the Drosophila brain, indicating that the rdgB protein functions in many sensory and neuronal cells. In photoreceptors, the protein localized adjacent to the rhabdomeres, in the vicinity of the subrhabdomeric cisternae. The rdgB protein's amino-terminal 281 residues are > 40% identical to the rat brain phosphatidylinositol transfer protein (PI-TP). A truncated rdgB protein, which contains only this amino-terminal domain, possesses a phosphatidylinositol transfer activity in vitro. The remaining 773 carboxyl terminal amino acids have additional functional domains. Nitrocellulose overlay experiments reveal that an acidic amino acid domain, adjacent to the PI transfer domain, binds 45Ca+2. Six hydrophobic segments are found in the middle of the putative translation product and likely function as membrane spanning domains. These results suggest that the rdgB protein, unlike the small soluble PI-TPs, is a membrane-associated PI-TP, which may be directly regulated by light-induced changes in intracellular calcium.
Alleles↗
Ethnicity, self-care, and use of medical care among the elderly with joint symptoms.
Elderly individuals with self-reported joint symptoms representing three ethnic groups (i.e., blacks [n = 105], Hispanics [n = 100], and whites of Eastern European origin [n = 112] answered questions about their use of self-care and medical care for these symptoms. Ethnic groups differed in both self-care practices and their use of medical care for joint symptoms. Multiple regression analyses demonstrated that arthritis-specific and general health status were better predictors than ethnicity of the tendency to rely on self-care and medical care. There was no evidence that self-care served as a substitute for medical care.
Aged↗
An end to patchwork reform of health care.
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Delivery of Health Care↗