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Biomedical subjects

R Francis

Publications and source records attributed to R Francis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Immunomagnetic separation for enrichment and sensitive detection of disseminated tumour cells in patients with head and neck SCC.

Screening for malignant cells in the blood and bone marrow was introduced as a strategy for the improved detection of tumour spread and may predict the development of distant metastases. The sensitivity of these approaches depends on several factors, including the choice of antibody for immunocytochemistry (ICC) and the number of cells examined. In this study criteria have been defined for scoring cells reactive with a pan-cytokeratin antibody as tumour, by comparing immunostained cells in clinical samples obtained from head and neck cancer patients and a control group without epithelial malignancy. When leucocyte subfractions are prepared by density gradient separation (DGS) from central venous blood obtained from patients with advanced head and neck squamous cell carcinoma (SCC) and screened by ICC, epithelial tumour cells sediment preferentially with the mononuclear cells but may also be detected in the granulocyte (GC) fraction. Some cases were found to have more tumour cells in the GC fraction. Similar results were seen in model experiments. To increase the sensitivity of the ICC approach, the efficiency of positive immunomagnetic selection (IMS) using Dynabeads coated with an antibody recognizing the Ber-EP4 epitope has been compared with negative IMS using anti-CD45 Dynabeads. Tumour cells were recovered from bone marrow aspirates for 2/17 cases using the positive enrichment technique and for 11/17 patients following negative IMS. These findings justify prospective studies incorporating negative IMS to establish the prognostic significance of these disseminated tumour cells for this group of patients.

Antigens, Neoplasm↗
PubMed1997

Immediate early gene expression to examine neuronal activity following acute and chronic stressors in rat pups: examination of neurophysiological alterations underlying behavioral consequences of prenatal cocaine exposure.

Altered behavioral responses to stressors have been observed in animals exposed to cocaine prenatally. In the present study, both behavioral and physiological responses to repeated and single stressor exposure were measured in animals prenatally exposed to cocaine. Offspring were derived from 3 prenatal treatment groups: dams that were administered 40 mg/kg cocaine from gestational day 8-20 (C40); dams that were pair-fed and -watered to weight-matched C40 dams (PF); and untreated dams (LCC). Starting on postnatal day 16-17 (P16-17), offspring from the 3 prenatal treatment groups were exposed to either footshock or isolation daily for 5 days. Two days after the last day of stressor exposure (P21-22), subjects were given 1 final exposure to the stressor to which they were previously exposed. In addition, at P21-22, littermates of animals given repeated exposure to stressors were exposed to either footshock or isolation for the first and only time. During all footshock sessions, the duration of freezing behavior was recorded. Plasma adrenocorticotrophin (ACTH) and corticosterone levels were determined from blood samples taken immediately following the final stressor session and brains were processed for C-FOS immunoreactivity (FOS-IR). Plasma corticosterone was increased following either single or repeated exposure to either stressor compared to homecage control animals. Plasma ACTH was increased by exposure to both repeated and single footshock exposure, but the increase was not as great following repeated footshock exposure, suggesting adaptation to repeated exposure to this stressor. Following both single and repeated footshock exposure, FOS-IR was increased relative to baseline levels in the paraventricular nucleus of the hypothalamus (PVN) and in the supraoptic nucleus (SON), but not the locus coeruleus (LC). Repeatedly footshocked animals exhibited more time freezing than animals given a single footshock session. Prenatal exposure to cocaine resulted in more time spent freezing in C40 than LCC animals during the chronic footshock exposure period; however, no differences were seen in any of the physiological measures taken from these 2 groups on the final test day. The implications of these findings are discussed in the context of other research examining the effects of prenatal cocaine exposure on stress responses.

Animals↗
PubMed1997

Gender difference in cocaine-induced HPA axis activation.

The study investigates the influence of gender on the activation of the hypothalamo-pituitary-adrenal (HPA) axis by cocaine and other monamine uptake inhibitors. Drug-induced secretion of adrenocorticotrophic hormone (ACTH) was used to pursue this question. Cocaine produced a dose-related rise in serum ACTH levels in both male and female rats, but the rise was significantly greater in females than in males. Females also showed enhanced HPA axis activation following administration of the dopamine uptake inhibitor GBR 12909, the serotonin uptake inhibitor fluoxetine, and the norepinephrine uptake inhibitor desipramine. No gender difference in HPA axis activation was observed in a dose-response study of cocaine-induced HPA activation in 10 day old rats. Ovariectomy of females decreased the ACTH response to cocaine, but castration did not affect the response of males. To evaluate the role of the pituitary in this gender difference, ACTH levels were determined after corticotropin-releasing factor (CRF) administration. Females showed greater ACTH responses to CRF than males. These studies demonstrate that female rats show exaggerated HPA responses to monoamine uptake inhibitors and that enhanced pituitary responsivity to CRF contributes to this gender difference.

Adrenocorticotropic Hormone↗
PubMed1996

GLD-1, a cytoplasmic protein essential for oocyte differentiation, shows stage- and sex-specific expression during Caenorhabditis elegans germline development.

GLD-1, a putative RNA binding protein, is essential for oocyte development in Caenorhabditis elegans. A gld-1 null mutation abolishes hermaphrodite oogenesis and confers a tumorous germline phenotype in which presumptive female germ cells exit the meiotic pathway and return to the mitotic cell cycle. Here we demonstrate that gld-1(null) germ lines express female-specific, but not male-specific, molecular markers, indicating that gld-1 acts downstream of sexual fate specification to regulate oocyte differentiation. Immunolocalization studies identify GLD-1 as a cytoplasmic germline protein that displays differential accumulation during germline development. First, germ cells that are in the mitotic cell cycle contain low levels of GLD-1 that likely reflect a nonessential gld-1 function (negative regulation of proliferation in the mitotic germ line) revealed in previous genetic studies. Second, entry of presumptive oocytes into the meiotic pathway is accompanied by a strong increase in GLD-1 expression/accumulation. GLD-1 levels are high through the pachytene stage but fall to background as germ cells exit pachytene and complete oogenesis. The meiotic prophase accumulation pattern is consistent with GLD-1's essential role in oocyte differentiation, which may be to repress the translation of a subset of maternal RNAs synthesized during early oogenesis until late oogenesis when GLD-1 is absent.

Animals↗
PubMed1996

emo-1, a Caenorhabditis elegans Sec61p gamma homologue, is required for oocyte development and ovulation.

emo-1(oz1) is a member of a class of hermaphrodite sterile mutations in Caenorhabditis elegans that produce endomitotic oocytes in the gonad arm. Oocytes in emo-1(oz1) mutants exhibit multiple defects during oogenesis. After meiotic maturation, ovulation fails, trapping oocytes in the gonad arm where they become endomitotic. emo-1 encodes a homologue of the Sec61p gamma subunit, a protein necessary for translocation of secretory and transmembrane proteins into the endoplasmic reticulum of yeast and mammalian cells. A putative emo-1 null mutation, oz151, displays embryonic lethality. The oz1 sterile mutation is a transposable element insertion into the emo-1 3' untranslated region that almost completely eliminates germline mRNA accumulation. Genetic mosaic analysis using the oz1 allele indicates that emo-1(+) expression in germ cells is required for fertility. The J67 monoclonal antibody, which recognizes an oocyte surface antigen (Strome, S. 1986. In Gametogenesis and the Early Embryo. J.G. Gall, editor. Alan R. Liss, Inc., New York. 77-95.), does not stain oz1 oocytes, a finding consistent with defective protein transport in the mutant. We propose that the emo-1 gene product acts in the transport of secreted and transmembrane proteins in C. elegans oocytes, and is necessary for both oogenesis and the coupling of ovulation with meiotic maturation.

Amino Acid Sequence↗
PubMed1995

Elective ventilation of potential organ donors.

Elective ventilation describes the procedure of transferring selected patients dying from rapidly progressive intracranial haemorrhage from general medical wards to intensive care units for a brief period of ventilation before confirmation of brain stem death and harvesting of organs. This approach in Exeter has led to a rate of kidney retrieval and transplant higher than has been achieved elsewhere in the United Kingdom, with a stabilisation of numbers on patients on dialysis. Recently doubt has been cast on the legality of our practice of elective ventilation on the grounds that relatives are not permitted to consent to treatment of an incompetent person when that treatment is not in the patient's best interests. We are thus faced with the dilemma of a protocol that is ethical, practical, and operates for the greater good but which may be illegal. This article explores various objections to the protocol and calls for public, medical, and legal debate on the issues.

Brain Death↗
PubMed1995

Effect of four vehicles on the pH of calcium hydroxide and the release of calcium ion.

Nonsetting calcium hydroxide pastes are commonly used in endodontic practice. The desired therapeutic effect of such a paste is in part dependent on the dissociation of calcium hydroxide into hydroxy ion and calcium ion. This in turn is influenced by the vehicle used to make the paste. This investigation attempts to quantitatively estimate the release of hydroxyl ion and calcium ion from pastes made by using distilled water, normal saline solution, camphorated monochlorophenol and also an experimental vehicle, propylene glycol. The results of this study indicate that propylene glycol induces the most favorable release characteristics of the two ionic species.

Calcium↗
PubMed1995

gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans.

We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1 (null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1 (null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells.

Animals↗
PubMed1995

Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway.

The Caenorhabditis elegans gene gld-1 is essential for oocyte development; in gld-1 (null) hermaphrodites, a tumor forms where oogenesis would normally occur. We use genetic epistasis analysis to demonstrate that tumor formation is dependent on the sexual fate of the germline. When the germline sex determination pathway is set in the female mode (terminal fem/fog genes inactive), gld-1 (null) germ cells exit meiotic prophase and proliferate to form a tumor, but when the pathway is set in the male mode, they develop into sperm. We conclude that the gld-1 (null) phenotype is cell-type specific and that gld-1(+) acts at the end of the cascade to direct oogenesis. We also use cell ablation and epistasis analysis to examine the dependence of tumor formation on the glp-1 signaling pathway. Although glp-1 activity promotes tumor growth, it is not essential for tumor formation by gld-1 (null) germ cells. These data also reveal that gld-1(+) plays a nonessential (and sex nonspecific) role in regulating germ cell proliferation before their entry into meiosis. Thus gld-1(+) may negatively regulate proliferation at two distinct points in germ cell development: before entry into meiotic prophase in both sexes (nonessential premeiotic gld-1 function) and during meiotic prophase when the sex determination pathway is set in the female mode (essential meiotic gld-1 function).

Animals↗
PubMed1995

Cocaine sensitization in periadolescent and adult rats.

Periadolescent rats have been reported to be affected differentially by catecholaminergic agents when compared with younger or adult animals. The present study evaluated the behavioral responsivity of periadolescent (34- to 39-day-old) and adult (60- to 70-day-old) Sprague-Dawley rats of both sexes to i.p. cocaine (Coc) administration (0, 10 or 20 mg/kg, once daily for 4 days). All animals received injections of both saline and Coc every day paired with a different context, with one-half of the animals receiving the drug in the home cage (Coc-Home) and the other half in the testing chamber (Coc-Test). Forty-eight hours after the last drug injection, all animals were challenged with 10 mg/kg i.p. of Coc, and their behavior in the test chamber was scored. As expected, acute Coc induced a prominent increase in a number of behaviors, and this response profile was less marked in periadolescent relative to adult animals. In contrast, Coc-Test animals of both ages showed a clear behavioral sensitization relative to the chronic saline group. No evidence of carry-over effects was found in Coc-Home animals. Females were in general more sensitive than males to acute Coc effects. The development of behavioral sensitization to Coc was a function of age-specific alterations in sensitivity to psychostimulants. Periadolescent rats of both sexes showed sensitization to the locomotor activating effects (matrix crossings) of Coc, whereas a consistent sensitization profile for both stereotyped head scanning and focused sniffing activities were found in adults but not in periadolescents. Chronic Coc reduced body weight and food consumption, particularly in adult males, whereas it did not affect periadolescent patterns. No evidence of sensitization to Coc was found in the hormonal parameters considered.

Adrenocorticotropic Hormone↗
PubMed1994

Recombinant human erythropoietin shortens the bleeding time and corrects the abnormal platelet aggregation in hemodialysis patients.

Uremia may be associated with abnormal hemostasis characterized by a prolonged bleeding time and abnormal in-vitro platelet aggregation. The mechanisms underlying these derangements are not fully elucidated. The present study examined the effect of correction of anemia by recombinant human erythropoietin (r-HuEPO) on these abnormalities in eight dialysis patients. Prior to r-HuEPO therapy the patients had low hematocrits (Hct) (20% +/- 0.7), abnormal bleeding times (23 +/- 1.2 minutes), and marked impairment in platelet aggregation induced by adenosine diphosphate (ADP), epinephrine (Epi), thrombin (Th) and collagen. After correction of the anemia to a Hct of 32% +/- 0.9 over 5 +/- 0.9 months, there were a) significant shortening of the bleeding time (from 23 +/- 1.2 to 10.6 +/- 2.4 minutes, p < 0.01), b) an inverse correlation between the Hct and the bleeding time (r = -0.89, p < 0.001) and c) significant improvement, or normalization of platelet aggregation in response to both concentrations of epinephrine [Epi2 (5.4 x 10(-6) M), 45% +/- 10.5 vs 73.5% +/- 7.3, p < 0.01, and Epi1 (5.4 x 10(-5) M), 49% +/- 10.6 vs 64% +/- 6.6, p < 0.05)], both concentrations of ADP [ADPC'(2 x 10(-6) M), 31% +/- 5.9 vs 60% +/- 9.3, p < 0.05, and ADPB (2 x 10-5), 69.5% +/- 7.6 vs 99% +/- 4.8, p < 0.01], and both concentrations of thrombin [ThC (0.22 u/ml) 28.6% +/- 8.9 vs 80.4% +/- 8.3, p < 0.01, and TH50/50 (0.44 u/ml), 57.8% +/- 6.7 vs 83.3% +/- 9.2, p < 0.01)].(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1993

Epidemic meningococcemia and purpura fulminans with induced protein C deficiency.

Patients with epidemic infections caused by Neisseria meningitidis serogroup C were studied to assess the relationship of abnormal coagulation parameters to prognosis. Patients were categorized into stages within the first hour of observation according to severity of illness. During the epidemic years 1986 through 1991, 113 patients with bacteriologically proven N. meningitidis infection were observed, 15 of whom died. Purpura fulminans was seen in 28 patients, of whom 14 (50%) died. Among the 14 surviving patients who had purpura fulminans, 10 suffered gangrene with deforming autoamputation secondary to the dermal microvascular thrombosis and hemorrhagic necrosis. Evaluation of the induced diffuse intravascular coagulation in 59 patients included studies of the naturally occurring anticoagulants, focusing on protein C and protein S. The magnitude of the declining levels of protein C, the degree of thrombocytopenia, and the presence of fibrin split products are directly related to the clinical severity of the illness (P = .0053). Thus, in individuals with severe disease expression, the risk of purpura fulminans with death or deformity was significantly increased when the platelet count was < 50,000 cells/mm3 (P = .0001) and protein C levels were low (P = .0158). The immaturity of the protein C system in children who are < 4 years of age may contribute to the rapid and more frequent pathogenesis of purpura fulminans. Therapy directed at replacement of the naturally occurring anticoagulants, such as protein C, may ultimately improve the prognosis for individuals with purpura fulminans.

Adolescent↗