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Biomedical subjects

G Robinson

Publications and source records attributed to G Robinson.

At least 73 records · Page 4Linked to original sources
PubMed1997

A mouse histone H1 variant, H1b, binds preferentially to a regulatory sequence within a mouse H3.2 replication-dependent histone gene.

H1 histones, found in all multicellular eukaryotes, associate with linker DNA between adjacent nucleosomes, presumably to keep the chromatin in a compact, helical state. The identification of multiple histone H1 subtypes in vertebrates suggests these proteins have specialized roles in chromatin organization and thus influence the regulation of gene expression in the multicellular organism. The mechanism by which the association of H1 with nucleosomal DNA is regulated is not completely understood, but affinity for different DNA sequences may play a role. Here we report that a specific H1 subtype in the mouse, namely H1b, selectively binds to a regulatory element within the protein-encoding sequence of a replication-dependent mouse H3.2 gene. We have previously shown that this coding region element, Omega, is the target of very specific interactions in vitro with another nuclear factor called the Omega factor. This element is required for normal gene expression in stably transfected rodent cells. The mouse H1b protein interacts poorly (100-fold lower affinity) with the comparable "Omega" sequence of a replication-independent mouse H3.3 gene. This H3.3 sequence differs at only 4 out of 22 nucleotide positions from the H3.2 sequence. Our findings raise the possibility that this H1b protein plays a specific role in regulation of expression of the replication-dependent histone gene family.

Amino Acid Sequence↗
PubMed1997

Guidelines for the diagnosis and management of migraine in clinical practice. Canadian Headache Society.

OBJECTIVE: To provide physicians and allied health care professionals with guidelines for the diagnosis and management of migraine in clinical practice. OPTIONS: The full range and quality of diagnostic and therapeutic methods available for the management of migraine. OUTCOMES: Improvement in the diagnosis and treatment of migraine, which will lead to a reduction in suffering, increased productivity and decreased economic burden. EVIDENCE AND VALUES: The creation of the guidelines followed a needs assessment by members of the Canadian Headache Society and included a statement of objectives; development of guidelines by multidisciplinary working groups using information from literature reviews and other resources; comparison of alternative clinical pathways and description of how published data were analysed; definition of the level of evidence for data in each case; evaluation and revision of the guidelines at a consensus conference held in Ottawa on Oct. 27-29, 1995; redrafting and insertion of tables showing key variables and data from various studies and tables of data with recommendations; and reassessment by all conference participants. BENEFITS, HARMS AND COSTS: Accuracy in diagnosis is a major factor in improving therapeutic effectiveness. Improvement in the precise diagnosis of migraine, coupled with a rational plan for the treatment of acute attacks and for prophylactic therapy, is likely to lead to substantial benefits in both human and economic terms. RECOMMENDATIONS: The diagnosis of migraine can be improved by using modified criteria of the International Headache Society as well as a semistructured patient interview technique. Appropriate treatment of symptoms should take into account the severity of the migraine attack, since most patients will have attacks of differing severity and can learn to use medication appropriate for each attack. When headaches are frequent or particularly severe, prophylactic therapy should be considered. Both the avoidance of migraine trigger factors and the application of nonpharmacological therapies play important roles in overall migraine management and will be addressed at a later date. VALIDATION: The guidelines are based on consensus of Canadian experts in neurology, emergency medicine, psychiatry, psychology, family medicine and pharmacology, and consumers. Previous guidelines did not exist. Field testing of the guidelines is in progress.

Adrenergic beta-Antagonists↗
PubMed1997

Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution.

Programmed cell death (PCD) of mammary alveolar cells during involution commences within hours of the end of suckling. Locally, milk accumulates within alveolar lumens; systemically, levels of lactogenic hormones fall. Four experimental models were used to define the role of local factors as compared with systemic hormones during the first and second stages of involution. In three models, milk release was disrupted in the presence of systemic lactogenic hormones: (i) sealing of the teats, (ii) mammary gland transplants that cannot release milk due to the absence of a teat connection, and (iii) inactivation of the oxytocin gene. The ability of systemic hormones to preserve lobular-alveolar structure without blocking PCD was illustrated using a fourth transgenic model of lactation failure. During the first stage of involution, local signals were sufficient to induce alveolar PCD even in the presence of systemic lactogenic hormones. PCD coincided with bax induction, decreased expression of milk proteins, block of prolactin signal transduction through Stat5a and 5b, and activation of Stat3. The two stages of mammary gland involution are regulated by progressive gain of death signals and loss of survival factors. This study demonstrates that genetic events that occur during the first reversible stage are controlled by local factors. These mammary-derived death signals are dominant over protective effects related to systemic hormone stimulation.

Animals↗
PubMed1997

The feasibility of assessing women's perceptions of the risks and benefits of fertility drug therapy in relation to ovarian cancer risk.

OBJECTIVE: To determine the feasibility of asking women undergoing fertility treatment the maximum increased risk of ovarian cancer they would be willing to tolerate in order to take ovulation-induction drugs. DESIGN: A prospective pilot study of women attending fertility clinics over a 2-month period. SETTING: Two tertiary care fertility clinics in Toronto. PATIENT(S): Sixty-one English-speaking women were approached and 85% (n = 52) were enrolled. INTERVENTION(S): A self-administered questionnaire with fertility-specific questions. Thirty-eight women also were asked to complete standardized scales of anxiety and optimism. MAIN OUTCOME MEASURE(S): Women's report of the maximum level of lifetime risk of ovarian cancer they were willing to tolerate in order to undergo fertility treatment. RESULT(S): Seventy-nine percent were willing to accept an increased risk of ovarian cancer. Only 24% understood that treatment for ovarian cancer usually was not curative. CONCLUSION(S): A majority of patients were willing to tolerate a modest increase in their lifetime risk of ovarian cancer because of fertility treatment, most basing their estimate of acceptable risk on limited awareness of the issue.

Adult↗
PubMed1997

Assessment of pfmdr 1 gene copy number by tandem competitive polymerase chain reaction.

The pfmdr 1 gene encodes a Plasmodium falciparum homologue of the human P-glycoprotein expressed on the surface of the parasite food vacuole. Variation in copy number and specific codon mutations of pfmdr 1 have been implicated in the development of parasite resistance to antimalarial drugs. We describe here the technique of Tandem-Competitive Polymerase Chain Reaction (TC-PCR), which allows accurate measurement of pfmdr 1 copy number in parasite DNA obtained directly from small quantities (100 microliters) of red blood cells. We reliably quantified pfmdr1 in previously well characterised strains of Plasmodium falciparum with differing pfmdr1 gene copy numbers using starting amounts of between 3,000 and 40,000 gene copies. We then used TC-PCR to determine pfmdr1 gene copy number in field specimens of venous blood taken from 10 patients with malaria contracted along the Thai-Burmese border. In this region of high grade parasite resistance to mefloquine greater than 70% of samples had a copy number greater than 1 of pfmdr1 determined with a repeatability coefficient of 0.58.

ATP-Binding Cassette Transporters↗
PubMed1997

The effect of pulsatile gonadotropin-releasing hormone and estradiol administration on luteinizing hormone and follicle-stimulating hormone concentrations in pituitary stalk-sectioned ovariectomized pony mares.

Hourly pulses of gonadotropin-releasing hormone (GnRH) or bi-daily injections of estradiol (E2) can increase luteinizing hormone (LH) secretion in ovariectomized, anestrous pony mares. However, the site (pituitary versus hypothalamus) of positive feedback of estradiol on gonadotropin secretion has not been described in mares. Thus, one of our objectives involved investigating the feedback of estradiol on the pituitary. The second objective consisted of determining if hourly pulses of GnRH could re-establish physiological LH and FSH concentrations after pituitary stalk-section (PSS), and the third objective was to describe the declining time trends of LH and FSH secretion after PSS. During summer months, ovariectomized pony mares were divided into three groups: Group 1 (control, n = 2), Group 2 (pulsatile GnRH (25 micrograms/hr), n = 3), and Group 3 (estradiol (5 mg/12 hr), n = 3). All mares were stalk-sectioned and treatment begun immediately after stalk-section. Blood samples were collected every 30 min for 8 h on the day before surgery (D0) and 5 d post surgery (D5) to facilitate the comparison of gonadotropin levels before and after pituitary stalk-section. Additionally, jugular blood samples were collected every 12 hr beginning the evening of surgery, allowing for evaluation of the gonadotropin secretory time trends over the 10 d of treatment. On Day 10, animals were euthanized to confirm pituitary stalk-section and to submit tissue for messenger RNA analysis (parallel study). Plasma samples were assayed for LH and FSH by RIA. Mean LH secretion decreased from Day 0 to Day 5 in Groups 1 and 3, whereas LH secretion tended (P < 0.08) to decrease in Group 2 mares. On Day 5, LH was higher (P < 0.01) in Group 2 (17.26 +/- 3.68 ng/ml: LSMEANS = SEM), than either Group 1 (2.65 +/- 4.64 ng/ml) or Group 3 (4.28 +/- 3.68 ng/ml). Group 1 did not differ from Group 3 on Day 5 (P < 0.40). Similarly, mean FSH levels decreased in all groups after surgery, yet Group 2 mares had significantly (P < 0.001) higher FSH concentrations (17.66 +/- 1.53 ng/ml) than Group 1 or Group 3 (8.34 +/- 1.84 and 7.69 +/- 1.63 ng/ml, respectively). Regression analysis of bi-daily LH and FSH levels indicated that the time trends were not parallel. These findings indicate: 1) Pituitary stalk-section lowered LH and FSH to undetectable levels within 5 d after surgery. 2) pulsatile administration of GnRH (25 micrograms/hr) maintained LH and FSH secretion, although concentrations tended to be lower than on Day 0, and 3) E2 did not stimulate LH or FSH secretion.

Animals↗
PubMed1997

Comparative study between pony mares and ewes evaluating gonadotrophic response to administration of gonadotrophin-releasing hormone.

This study compared equine and ovine LH secretory responses to GnRH treatment. Dioestrous mares and ewes were challenged with continuous GnRH for 15 h. Mares that received constant GnRH (110 micrograms h-1) had sustained LH secretion (P < 0.01), whereas LH concentrations in ewes treated with continuous GnRH (25 micrograms h-1) initially increased, then declined and remained low, suggesting GnRH receptor desensitization or downregulation. In addition, progesterone-primed, ovariectomized mares and ewes were challenged with pulsatile or continuous GnRH for 5 days. Plasma LH concentrations were increased by day 5 in mares treated with pulsatile (25 micrograms pulse-1 h-1) and continuous (110 micrograms h-1) GnRH (P < 0.01). Furthermore, mean LH concentrations and time-response curves were not different. In contrast, ewes treated with continuous GnRH (2.5 micrograms h-1) demonstrated LH secretory patterns indicative of GnRH receptor downregulation on day 1 of treatment. LH concentrations in ewes treated with pulsatile GnRH (250 ng pulse-1 h-1) did not differ from controls. In conclusion, pony mares responded continuously to GnRH treatment (pulsatile and continuous), whereas ewes treated with continuous GnRH experienced reduced LH secretion. These findings suggest a unique hypothalamic-pituitary axis in pony mares.

Animals↗
PubMed1996

Gay, lesbian and bisexual health care issues and medical curricula.

The authors respond to Nancy Robb's account of the inadequacy of medical school curricula in addressing health care issues relevant to gay, lesbian and bisexual people (see page 765 of this issue) by proposing a framework for curriculum reform. This framework supports the development of knowledge, attitudes and skills necessary to the provision of sensitive and comprehensive care for these patient groups through four types of learning experiences: didactic instruction, small-group discussions, simulated patient encounters, and supervised encounters with real patients. Equally important is the attitudinal context in which learning takes place. Without fostering a supportive and accepting environment for education about gay, lesbian and bisexual health care issues, medical schools cannot ensure that future physicians will be equipped to provide appropriate care for all members of society.

Bisexuality↗
PubMed1996

Pravastatin and risk factor modification in patients with moderate primary hypercholesterolaemia.

AIM: To evaluate the efficacy and safety of pravastatin 20mg at night, versus placebo, in combination with dietary, smoking cessation, and other lifestyle advice in general practice. METHODS: This was a multicentre, randomised double blind placebo controlled trial carried out in thirty general practices in three New Zealand centres. Patients with moderate primary hypercholesterolaemia (5.2-6.7 mmol/L) and two or more risk factors for coronary heart disease were enrolled. After a minimum of 6 weeks lifestyle changes, 95 patients (aged 18-70 years) were randomised to active or placebo therapy. They continued to receive advice and encouragement in maintaining dietary, exercise or smoking cessation changes. RESULTS: Seventy eight patients, pravastatin (n = 39) and placebo (n = 39), completed the treatment phase of the study. After 6 weeks on 20 mg pravastatin, total cholesterol decreased by 18% (0.9 mmol/L, p < 0.0001), triglycerides decreased by 6% (0.1 mmol/L ns), LDL-cholesterol decreased by 23% (1.1 mmol/L, p < 0.0001), and HDL-cholesterol increased by 8% (0.1 mmol/L, ns). A similar effect was also observed after 26 weeks of therapy. These effects were also significant when compared with the placebo group. In 61% of patients treated with pravastatin there was a reduction in cholesterol to less than 5.2 mmol/L, and no real change in lipid levels in patients receiving placebo. No significant differences were observed between the active and placebo groups with regard to patient withdrawal, compliance, or adverse reactions. CONCLUSIONS: In general practice pravastatin is a well tolerated and safe drug that induces a favourable effect on lipid profile in patients with primary moderate hypercholesterolaemia and two or more other risk factors for coronary artery disease.

Adolescent↗
PubMed1996

Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis.

Insertional mutation of the Int3 gene, a member of the Notch gene family, is frequently associated with primary mouse mammary tumors induced by the mouse mammary tumor virus (MMTV). A major consequence of these mutations is the production of a shortened 2.4-kb tumor specific Int3 RNA transcript that encodes the entire intracellular domain of the Int3 protein. Previous studies have demonstrated that mammary gland development and function was severely impaired in transgenic mice expressing the truncated Int3 gene product from the MMTV viral promoter. Both mammary ductal growth and secretory lobule development were curtailed in these mice. These results were attributed to a gain of function modification of the Int3 gene, which led to a restriction of cell fate selection in the affected mammary epithelial cells. To confirm and extend these findings, truncated Int3 was expressed from the whey acidic protein (WAP) promoter, the activity of which, unlike that of the MMTV long terminal repeat, is restricted to the secretory mammary epithelial population. In transgenic mice carrying the WAP/Int3 construct, mammary ductal growth was unaffected in virgin females, but growth and differentiation of secretory lobules during gestation was profoundly inhibited. Coincidental with the block in lobular secretory differentiation, mammary dysplasia and tumorigenesis occurred in all breeding females by 25 weeks of age. In nonbreeding WAP/Int3 females, mammary tumor incidence also reached 100%, but only after 70 weeks. The WAP/Int3 mammary tumors were highly malignant, and most tumor-bearing females, irrespective of breeding history, developed metastatic lung lesions. These results suggest that WAP promotor-targeted Int3 function is associated with mammary secretory cell differentiation and maintenance in this transgenic model. Consistent with the conclusion that WAP-driven truncated Int3 expression influenced only lobular differentiation and not ductal growth and extension during mammary gland development, transplants of WAP/Int3 gland into nontransgenic mammary fat pads produced complete mammary ductal outgrowths in virgin FVB/N mice but failed to develop secretory lobules when the females were impregnated.

Animals↗
PubMed1996

Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer.

The effect of gastrin neutralization was evaluated on the in vivo growth of the rat colon line, DHDK12, which expressed cholecystokinin B/gastrin receptors and secreted glycine-extended gastrin-17 (G17). Gastrin neutralization was achieved by administration of the immunogen, Gastrimmune, which is composed of the amino terminal portion of G17 linked to a diphtheria toxoid. A rat-specific version of Gastrimmune was used to preimmunize rats, with control animals receiving diphtheria toxoid only. The antibodies raised neutralized both carboxy-amidated and glycine-extended G17. The tumor was implanted into the muscle layer of the abdominal wall, and rats immunized with Gastrimmune had significantly reduced median cross-sectional tumor areas (70.2% reduction; P = 0.005) and weights (56.5% reduction; P = 0.0078)) when compared to control rats. Histological analysis revealed that the tumors had an enhanced degree of necrosis, with the area of viable tumor in the Gastrimmune-immunized rat reduced to 40.3% compared to 58.6% in the control rats (P = 0.003). Immunization with Gastrimmune raised antibodies that inhibited the growth of a rat colon tumor. This could have been mediated by neutralization of both serum G17 and cell-associated precursor gastrin molecules.

Amino Acid Sequence↗
PubMed1996

Macrophages are the major target cell for HIV infection in long-term marrow culture and demonstrate dual susceptibility to lymphocytotropic and monocytotropic strains of HIV-1.

Haematological abnormalities are often seen in patients infected with HIV. A number of mechanisms are thought to contribute to this bone marrow suppression, including impaired stromal function and direct infection of progenitor cells. Evidence suggests that both bone marrow progenitor cells and perhaps stromal cells are open to infection by HIV, which raises the possibility that bone marrow stromal cells may serve as a reservoir for HIV. This study investigated the cellular targets and kinetics of in vitro infection of stroma in long-term bone marrow culture (LTBMC) using both mono- and lymphocytotropic strains of HIV-1. p24 ELISA and reverse transcriptase (RT) assay demonstrated that stroma could be infected with HIV and release infectious virions. The target cells for infection were shown to be macrophages by immunohistochemistry (APAAP), dual immunofluorescence staining (using CD68 and p24) and electron microscopy. The data show that it was possible to infect stroma in LTBMC with HIV and that such infection was productive. The main target for infection was bone marrow macrophages. In contrast to peripheral blood derived macrophages, these cells were susceptible to both lymphocytotropic and monocytotropic strains of HIV-1. The data suggests that these bone marrow macrophages may act as a reservoir for HIV, Infection of bone marrow macrophages may affect haemopoiesis either by transmission of HIV infection to developing progenitor cells through direct cell-to-cell contact or by altering the ability of the stroma to support normal development.

Bone Marrow↗