"Is everyone as tired as I am?" The CMA's physician survey results, 1999.
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Burnout, Professional↗
Biomedical subjects
S Martin
Publications and source records attributed to S Martin.
Phospholipase C binds to the receptor-like GPR1 protein and controls pseudohyphal differentiation in Saccharomyces cerevisiae.
The hormone receptor-like protein Gpr1p physically interacts with phosphatidylinositol-specific phospholipase C (Plc1p) and with the Galpha protein Gpa2p, as shown by two-hybrid assays and co-immune precipitation of epitope-tagged proteins. Plc1p binds to Gpr1p in either the presence or absence of Gpa2, whereas the Gpr1p/Gpa2p association depends on the presence of Plc1p. Genetic interactions between the null mutations plc1Delta, gpr1Delta, gpa2Delta, and ras2Delta suggest that Plc1p acts together with Gpr1p and Gpa2p in a growth control pathway operating in parallel to the Ras2p function. Diploid cells lacking Gpr1p, Plc1p, or Gpa2p fail to form pseudohyphae upon nitrogen depletion, and the filamentation defect of gpr1Delta and plc1Delta strains is rescued by activating a mitogen-activated protein kinase pathway via STE11-4 or by activating a cAMP pathway via overexpressed Tpk2p. Plc1p is also required for efficient expression of the FG(TyA)::lacZ reporter gene under nitrogen depletion. In conclusion, we have identified two physically interacting proteins, Gpr1p and Plc1p, as novel components of a nitrogen signaling pathway controlling the developmental switch from yeast-like to pseudohyphal growth. Our data suggest that phospholipase C modulates the interaction of the putative nutrient sensor Gpr1p with the Galpha protein Gpa2p as a downstream effector of filamentation control.
Base Sequence↗
Significance of capacitative Ca2+ entry in the regulation of phosphatidylserine expression at the surface of stimulated cells.
The transverse redistribution of plasma membrane phosphatidylserine is one of the hallmarks of cells undergoing apoptosis and also occurs in cells fulfilling a more specialized function, such as platelets after appropriate activation. Although an increase in intracellular Ca2+ is required to trigger the remodeling of the plasma membrane, little information regarding intracellular signals leading to phosphatidylserine externalization has been provided. Scott syndrome is an extremely rare inherited disorder of the migration of phosphatidylserine toward the exoplasmic leaflet of the plasma membrane of stimulated blood cells. We have studied here the intracellular Ca2+ mobilization and Ca2+ entry involved in tyrosine phosphorylation in Epstein Barr virus (EBV)-infected B cells derived from a patient with Scott syndrome, her daughter, and control subjects. An alteration of Ca2+ entry through the plasma membrane and subsequent tyrosine phosphorylation induced by Ca2+ were observed in Scott EBV-B cells, but the release of Ca2+ from intracellular stores was normal. Furthermore, phosphatidylserine externalization at the surface of stimulated cells does not depend on tyrosine kinases. These results suggest that the defect of phosphatidylserine exposure in Scott syndrome cells is related to the alteration of a particular way of Ca2+ entry, referred to as capacitative Ca2+ entry, although some differences may be related to the cell type. Hence, this genetic mutant testifies to the prime significance of Ca2+ signaling in the regulation of phosphatidylserine expression at the surface of stimulated cells.
Aged↗
Vaccine delivery to animals.
For many years vaccination of animals has been practiced to prevent infectious diseases using inactivated organisms or modified live organisms. The live vaccines were effective but lacked safety. The vaccines made with inactivated organisms required an adjuvant to induce an immune response that was not as effective as either the clinical disease or live vaccines. An 'ideal' vaccine would induce effective immunity specific for the type of infection, have long duration, require minimal or no boosters, have impeccable safety, would not induce adverse reactions, and be easy to administer. The desire to meet these criteria, and especially safety, has resulted in the development of vaccines that do not depend on the use of the viable disease agent. The emphasis on subunit or inactivated vaccines that meet the desired criteria of a perfect vaccine has resulted in a critical need for better adjuvants and delivery systems. This has resulted in a technological innovation revolution with development of a wide array of different technologies to generate effective vaccines. This review will describe the historical relevance of adjuvants used for parenterally administered inactivated/subunit vaccines as well as describe some of the exciting technological advances including adjuvants (ISCOMS), delivery systems (recombinant vectors, microparticles), and novel approaches (transgenic plants, naked DNA) that are currently being, or will be used in the future, in the search for better, more effective vaccines that meet the current and future needs of veterinary medicine.
Journal Article↗
Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia.
CONTEXT: Infertile men with obstructive azoospermia may have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of which are rare in classic cystic fibrosis and not evaluated in most routine mutation screening. OBJECTIVE: To assess how often CFTR mutations or sequence alterations undetected by routine screening are detected with more extensive screening in obstructive azoospermia. DESIGN: Routine screening for the 31 most common CFTR mutations associated with the CF phenotype in white populations, testing for the 5-thymidine variant of the polythymidine tract of intron 8 (IVS8-5T) by allele-specific oligonucleotide hybridization, and screening of all exons through multiplex heteroduplex shift analysis followed by direct DNA sequencing. SETTING: Male infertility clinic of a Canadian university-affiliated hospital. SUBJECTS: Of 198 men with obstructive (n = 149) or nonobstructive (n = 49; control group) azoospermia, 64 had congenital bilateral absence of the vas deferens (CBAVD), 10 had congenital unilateral absence of the vas deferens (CUAVD), and 75 had epididymal obstruction (56/75 were idiopathic). MAIN OUTCOME MEASURE: Frequency of mutations found by routine and nonroutine tests in men with obstructive vs nonobstructive azoospermia. RESULTS: Frequency of mutations and the IVS8-5T variant in the nonobstructive azoospermia group (controls) (2% and 5.1% allele frequency, respectively) did not differ significantly from that in the general population (2% and 5.2%, respectively). In the CBAVD group, 72 mutations were found by DNA sequencing and IVS8-5T testing (47 and 25, respectively; P<.001 and P = .002 vs controls) vs 39 by the routine panel (P<.001 vs controls). In the idiopathic epididymal obstruction group, 24 mutations were found by DNA sequencing and IVS8-5T testing (12 each; P=.01 and P=.14 vs controls) vs 5 by the routine panel (P=.33 vs controls). In the CUAVD group, 2 mutations were found by routine testing (P=.07 vs controls) vs 4 (2 each, respectively; P=.07 and P=.40 vs controls) by DNA sequencing and IVS8-5T testing. The routine panel did not identify 33 (46%) of 72, 2 (50%) of 4, and 19 (79%) of 24 detectable CFTR mutations and IVS8-5T in the CBAVD, CUAVD, and idiopathic epididymal obstruction groups, respectively. CONCLUSIONS: Routine testing for CFTR mutations may miss mild or rare gene alterations. The barrier to conception for men with obstructive infertility has been overcome by assisted reproductive technologies, thus raising the concern of iatrogenically transmitting pathogenic CFTR mutations to the progeny.
Adult↗
Lipid-lowering drugs and homocysteine.
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Fenofibrate↗
Outbreak of Yersinia pseudotuberculosis in British Columbia--November 1998.
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Adolescent↗
Porcine guanylin and uroguanylin: cDNA sequences, deduced amino acid sequences, and biological activity of the chemically synthesized peptides.
Guanylin and uroguanylin are structurally related intestinal peptide hormones which were purified from a limited number of mammals and are capable of activating the particulate guanylate cyclase-C. Although the biological functions of guanylin and uroguanylin are not yet clarified in detail, they are involved in the regulation of the intestinal water and electrolyte balance. In order to verify the general importance of this hormone system in mammals, we cloned the corresponding cDNAs from pig. Here, we present the nucleotide sequences and the deduced amino acid sequences representing porcine guanylin and uroguanylin. The expression patterns of the corresponding genes, as shown by Northern hybridization and RT-PCR analysis, resemble those of the human homologues. Further, we demonstrate the bioactivity of both porcine peptide hormones by inducing the intracellular cGMP production in human T84 cells and by ion transport experiments using porcine intestinal mucosa in the Ussing chamber.
Amino Acid Sequence↗
Oral vaccination of animals with antigens encapsulated in alginate microspheres.
Most infectious diseases begin at a mucosal surface. Prevention of infection must therefore consider ways to enhance local immunity to prevent the attachment and invasion of microbes. Despite this understanding, most vaccines depend on parenterally administered vaccines that induce a circulating immune response that often does not cross to mucosal sites. Administration of vaccines to mucosal sites induces local immunity. To be effective requires that antigen be administered often. This is not always practical depending on the site where protection is needed, nor comfortable to the patient. Not all mucosal sites have inductive lymphoid tissue present as well. Oral administration is easy to do, is well accepted by humans and animals and targets the largest inductive lymphoid tissue in the body in the intestine. Oral administration of antigen requires protection of antigen from the enzymes and pH of the stomach. Polymeric delivery systems are under investigation to deliver vaccines to the intestine while protecting them from adverse conditions that could adversely affect the antigens. They also can enhance delivery of antigen specifically to the inductive lymphoid tissue. Sodium alginate is a readily available, inexpensive polymer that can be used to encapsulate a wide variety of antigens under mild conditions. Orally administered alginate microspheres containing antigen have successfully induced immunity in mice to enteric (rotavirus) pathogens and in the respiratory tract in cattle with a model antigen (ovalbumin). This delivery system offers a safe, effective means of orally vaccinating large numbers of animals (and perhaps humans) to a variety of infectious agents.
Administration, Oral↗
Effect of neutron-gamma radiation on dopamine and serotonin metabolism in the rat brain: a regional analysis.
The concentrations of dopamine (DA) and its metabolites and the levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin, were determined in discrete cerebral areas of rats 3 hr after (neutron-gamma) irradiation at 4 and 7 Gy. After the 7 Gy irradiation, no significant effect was observed. After the 4 Gy exposure, the most marked difference between irradiated and control rats was in the levels of DA and its metabolites in the striatum. We observed a decrease of DA, HVA, and DOPAC levels in the striatum and an opposite pattern in the substantia nigra. Whatever the brain area observed, an increase of 5-HIAA levels was noted.
3,4-Dihydroxyphenylacetic Acid↗
Lithiated Clusters from Primary Silylphosphanes and Silylarsanes: Spherical Bodies with and without Li(2)O Filling.
Molecular clusters with archimedean and platonic shape, which in order to build a closed polyhedron, spontaneously eliminate H(2) or voluntarily encapsulate Li(2)O as a "cluster nucleus", result from the dilithiation of primary silylphosphanes and silylarsanes with BuLi. Thus, the first mixed-valent, decameric P(10)Li(16) cluster 1 was obtained from iPr(3)SiPH(2) and tBuLi (molar ratio 1:2) with strict exclusion of LiOH and Li(2)O, whereas partial metalation in the presence of LiOH initially leads to a dodecameric, Li(2)O-containing cluster 2, from which the three-shell cluster 3 with a [Li(6)O](4+) core is obtained.
Journal Article↗
Rimantadine for treatment of hepatitis C infection in liver transplant recipients.
Hepatitis C recurrence after liver transplantation is a serious problem, leading to increased graft loss and morbidity in some individuals. Treatment with interferon and other agents is controversial and not highly efficacious. The use of an effective antiviral agent to reduce or eliminate viral burden is desirable. To this end, we performed an open-label pilot trial to determine if rimantadine would show antiviral activity against hepatitis C virus (HCV) in the posttransplantation setting. Eleven patients with recurrent post-liver transplantation disease, characterized by transaminase level abnormality and HCV RNA in serum and liver biopsy specimens consistent with HCV infection were offered enrollment onto the study. Patients were treated for 12 weeks with rimantadine, 100 mg orally twice daily, and followed up after treatment for up to 8 additional weeks. Serum was collected at 2-week intervals to assess transaminase and HCV RNA levels. Nine patients completed the planned course of therapy. There was no significant change in serum alanine aminotransferase levels during treatment. No patients cleared HCV RNA from the serum, and fluctuations in the viral titer were not clearly associated with the initiation and completion of the active-treatment phase. Rimantadine was well tolerated, with only one patient who stopped therapy for perceived side effects. We conclude that rimantadine monotherapy has no role in the management of recurrent hepatitis C after liver transplantation.
Adult↗
GLUT4 trafficking in insulin-sensitive cells. A morphological review.
In recent years, there have been major advances in the understanding of both the cell biology of vesicle trafficking between intracellular compartments and the molecular targeting signals intrinsic to the trafficking proteins themselves. One system to which these advances have been profitably applied is the regulation of the trafficking of a glucose transporter, GLUT4, from intracellular compartment(s) to the cell surface in response to insulin. The unique nature of the trafficking of GLUT4 and its expression in highly differentiated cells makes this a question of considerable interest to cell biologists. Unraveling the tangled web of molecular events coordinating GLUT4 trafficking will eventually lead to a greater understanding of mammalian glucose metabolism, as well as fundamental cell biological principles related to organelle biogenesis and protein trafficking.
3T3 Cells↗
Adjuvant high-dose therapy with peripheral blood stem cell support for patients with high-risk breast cancer.
We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 107 patients with high-risk stage II/III breast cancer. There were 90 patients with more than 9 tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7,500 mg/m(2)) and epirubicin (120 mg/m(2)) was given, and PBSC were harvested during granulocyte colony-stimulating factor (G-CSF)-supported leukocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose 12,000 mg/m(2)), carboplatin (900 mg/m(2)) and epirubicin (180 mg/m(2)). Patients were autografted with a median number of 4.1 x 10(6) CD34+ cells/kg (range 1.9-26.5 x 10(6)), resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-nine patients (27.1% of all patients) relapsed between 3 and 46 months following the last cycle of high-dose therapy (median 15 months). The probability of disease-free and overall survival at 3 years was 56% and 83%, respectively. A multivariate analysis showed that patients with stage II disease had a significantly better probability of disease-free survival (71%) in comparison with patients with stage III disease (30%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (62%) compared with patients with receptor-negative ones (40%). In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy including the addition of non-cross-resistant drugs or immunological approaches may be envisaged for patients with stage III disease and hormone receptor-negative tumours.
Adult↗
Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia.
The aim of this study was to develop a mutation screening protocol for familial hypercholesterolaemia (FH) patients and to assess genotype/phenotype effects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possible (120) or definite (38) FH were studied using a tiered screening protocol. Mutations were identified in 52 families, 44 families showing 23 different LDLR gene defects and eight families showing the common Apo B100 gene defect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor homology domain (exons 7-14). The most common mutations were D461N(7), C210X(5), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with nonsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diagnosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22/120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthomata were present in only 58% (30/52) of genetically defined FH families, thus limiting its use as a strict diagnostic criteria. Families with low density lipoprotein receptor (LDLR) defects present with higher total and LDL cholesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe presentation.
Electrophoresis, Agar Gel↗
Use of interleukin 12 to enhance the cellular immune response of swine to an inactivated herpesvirus vaccine.
Vaccination is the single most successful medical measure against infectious disease. However, the major barrier for achieving the full protective effect or immunization is how to render attenuated, killed, or subunit vaccines as immunogenic as the fully infectious versions of these microbes (Hughes and Babiuk, 1995; Rabinovich et al., 1994). In the case of PrV, infection with wild-type virus induces an immune response superior to vaccination with a live modified vaccine. After primary intranasal infection with wild-type PrV, the replication of a homologous secondary virus challenge is completely inhibited, and the much sought "sterile immunity" is generated (Kimman et al., 1994). In contrast, the immune response of pigs similarly exposed to PrV mutants, which have been attenuated by removal of the thymidine kinase (TK) and the envelope glycoprotein gE gene (McGregor et al., 1985; Zuckermann et al., 1988), is insufficient for preventing the replication of a homologous wild-type virus challenge (Kimman et al., 1994). Furthermore, inactivated PrV vaccines are even less effective at inducing protective immunity than are live modified PrV vaccines (de Leeuw and Van Orischot, 1985; Stellman et al., 1989; Vannier, 1985). The importance of inactivated and subunit vaccines resides in their stability and safety, since no infectious microbe is being introduced into the animal. However, because of the recognized lower effectiveness of inactivated vaccine types, they usually fall in disfavor when a modified live vaccine alternative is available. There is a critical need to develop strategies to enhance the immunogenicity of live, inactivated, and sub-unit vaccines for human and veterinary use (Hughes and Babiuk, 1995; Rabinovich et al., 1994). Although the inoculation of an animal with a virulent microbe is obviously not the desired method to produce sterile immunity, the immune response generated to infection with wild-type PrV clearly demonstrates that this type of immunity is possible. Research directed at devising strategies to increase the immunogenicity of different types of vaccines is necessary. Because of the wealth of information available on PrV immunity (reviewed by Chinsakchai and Molitor, 1994; Nauwynck, 1997), on PrV vaccines (Kimman et al., 1992, 1994; Mettenleiter, 1991; Scherba and Zuckermann, 1996) and increasingly on the porcine immune system (Lunney, 1993; Lunney et al., 1996; Saalmüller, 1995), the swine herpesvirus model is ideal for investigating the development of vaccine formulations with enhanced immunogenicity. Among the strategies currently being examined for the enhancement of the immunogenicity of inactivated and subunit vaccines is the use of recombinant cytokines administered together with antigen (Hughes and Babiuk, 1995; Rabinovich et al., 1994). The ability to regulate the development of an immune response by cytokines such as IL-12 provides the theoretical basis to use these cytokines as adjuvants to immunopotentiate the response to an inactivated vaccine. More importantly, it provides a model to investigate the mechanisms behind the induction of protective immunity and the components of a vaccine necessary for stimulating such a response. By providing cytokines such as IL-12 or IFN-gamma in combination with the vaccine inoculum, it is reasonable to expect that they will be able to direct the differentiation of T cells during the primary immune response. Modulation, in a predictable and desired manner of the quality and quantity of the induced protective immunity, should be achievable. The ability to manipulate a vaccine-induced immune response in the direction of a predominantly cellular response (Th1-like) instead of a predominantly humoral one (Th2-like) is perhaps best illustrated by the need to develop an effective vaccine against the porcine reproductive and respiratory syndrome (PRRS) virus, whose infectivity can be significantly enhanced in vitro and in vivo by antibody induced by vaccination
Animals↗
Benzyl alcohol as an alternative local anesthetic.
STUDY OBJECTIVES: Benzyl alcohol has been used as a local anesthetic for brief superficial skin procedures; however, its efficacy for long-term cutaneous anesthesia has not been established. We sought to compare the cutaneous anesthetic effects of benzyl alcohol with epinephrine with the effects of lidocaine with epinephrine and with placebo. METHODS: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial of 30 healthy paid adult volunteers. Subjects received 1-mL intradermal injections of benzyl alcohol.9% with 1:100,000 epinephrine, lidocaine 1% with 1:100,000 epinephrine, and physiologic saline solution without benzyl alcohol as placebo in a randomized, double-blind fashion. Pain on injection and degree of anesthesia at 5, 15, 30, and 45 minutes was assessed with a 10-cm graded visual analog scale (VAS). Statistical significance was determined by repeated measures ANOVA between groups with a Neuman-Keuls test for post hoc comparison of means and Student's t test for paired means. RESULTS: Benzyl alcohol was 48% less painful on injection than placebo (P <.008) and 42% less painful on injection than lidocaine with epinephrine (P <.05). Lidocaine with epinephrine and placebo were equally painful on injection. After the 5-minute measurement, benzyl alcohol provided significantly better anesthesia than placebo during the remaining observation period (VAS score 48%, 49%, and 51% decreased from baseline at 15, 30, and 45 minutes, respectively, all P <.02 versus placebo). However, benzyl alcohol provided less effective anesthesia than lidocaine with epinephrine (VAS score 72%, 76%, 84%, and 88% decreased from baseline at 5, 15, 30, and 45 minutes, respectively, all P <.001 versus placebo) throughout most of the observation period. CONCLUSION: Benzyl alcohol with epinephrine provides prolonged cutaneous anesthesia, although it is not as effective as lidocaine with epinephrine. However, benzyl alcohol is significantly less painful on injection than lidocaine with epinephrine, and it may offer an alternative for local anesthesia.
Adult↗
Stage III and oestrogen receptor negativity are associated with poor prognosis after adjuvant high-dose therapy in high-risk breast cancer.
We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 85 patients with high-risk stage II/III breast cancer. There were 71 patients with more than nine tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7.5 g m(-2)) and epirubicin (120 mg m(-2)) was given, and PBSC were harvested during G-CSF-supported leucocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose, 12,000 mg m(-2)), carboplatin (900 mg m(-2)) and epirubicin (180 mg m(-2)). Patients were autografted with a median number of 3.7 x 10(6) CD34+ cells kg(-1) (range, 1.9-26.5 x 10(6)) resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-one patients relapsed between 3 and 30 months following the last cycle of high-dose therapy (median, 11 months). The probability of disease-free and overall survival at 4 years were 60% and 83%, respectively. According to a multivariate analysis, patients with stage II disease had a significantly better probability of disease-free survival (74%) in comparison to patients with stage III disease (36%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (70%) compared to patients with receptor-negative ones (40%). Bone marrow samples collected from 52 patients after high-dose therapy were examined to evaluate the prognostic relevance of isolated tumour cells. The proportion of patients presenting with tumour cell-positive samples did not change in comparison to that observed before high-dose therapy (65% vs 71%), but a decrease in the incidence and concentration of tumour cells was observed over time after high-dose therapy. This finding was true for patients with relapse and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone receptor-negative tumours.
Adult↗