The effect of socioeconomic status on access to primary care: an audit study.

BACKGROUND: Health care office staff and providers may discriminate against people of low socioeconomic status, even in the absence of economic incentives to do so. We sought to determine whether socioeconomic status affects the response a patient receives when seeking a primary care appointment. METHODS: In a single unannounced telephone call to a random sample of family physicians and general practices (n = 375) in Toronto, Ontario, a male and a female researcher each played the role of a patient seeking a primary care physician. Callers followed a script suggesting either high (i.e., bank employee transferred to the city) or low (i.e., recipient of social assistance) socioeconomic status, and either the presence or absence of chronic health conditions (diabetes and low back pain). We randomized the characteristics of the caller for each office. Our primary outcome was whether the caller was offered an appointment. RESULTS: The proportion of calls resulting in an appointment being offered was significantly higher when the callers presented themselves as having high socioeconomic status than when they presented as having low socioeconomic status (22.6% v.14.3%, p = 0.04) and when the callers stated the presence of chronic health conditions than when they did not (23.5% v. 12.8%, p = 0.008). In a model adjusted for all independent variables significant at a p value of 0.10 or less (presence of chronic health conditions, time since graduation from medical school and membership in the College of Family Physicians of Canada), high socioeconomic status was associated with an odds ratio of 1.78 (95% confidence interval 1.02-3.08) for the offer of an appointment. Socioeconomic status and chronic health conditions had independent effects on the likelihood of obtaining an appointment. INTERPRETATION: Within a universal health insurance system in which physician reimbursement is unaffected by patients' socioeconomic status, people presenting themselves as having high socioeconomic status received preferential access to primary care over those presenting themselves as having low socioeconomic status.

Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells.

Folylpolyglutamyl synthase (FPGS) converts intracellular folates and antifolates to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one-carbon transfer. FPGS modulation affects the chemosensitivity of cancer cells to antifolates, such as methotrexate, and 5-fluorouracil (5FU) by altering polyglutamylation of antifolates and specific target intracellular folate cofactors. However, this effect may be counterbalanced by FPGS modulation-induced changes in polyglutamylation of other intracellular folate cofactors and total intracellular folate pools. We generated an in vitro model of FPGS overexpression and inhibition in breast cancer cells by stably transfecting human MDA-MB-435 breast cancer cells with the sense FPGS cDNA or FPGS-targeted small interfering RNA, respectively, and investigated the effects of FPGS modulation on chemosensitivity to 5FU and methotrexate. FPGS modulation-induced changes in polyglutamylation of both antifolates and folate cofactors and in intracellular folate pools affected chemosensitivity of breast cancer cells to pemetrexed and trimetrexate whose cytotoxic effects do or do not depend on polyglutamylation, respectively, in a predictable manner. However, the effects of FPGS modulation on the chemosensitivity of breast cancer cells to 5FU and methotrexate seem to be highly complex and depend not only on polyglutamylation of a specific target intracellular folate cofactor or methotrexate, respectively, but also on total intracellular folate pools and polyglutamylation of other intracellular folate cofactors. Whether or not FPGS modulation may be an important clinical determinant of chemosensitivity of breast cancer cells to 5FU and methotrexate-based chemotherapy needs further exploration.

Targeting of voltage-gated K+ and Ca2+ channels and soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins to cholesterol-rich lipid rafts in pancreatic alpha-cells: effects on glucagon stimulus-secretion coupling.

Pancreatic alpha-cells secrete glucagon in response to low glucose to counter insulin actions, thereby maintaining glucose homeostasis. The molecular basis of alpha-cell stimulus-secretion coupling has not been fully elucidated. We investigated the expression of voltage-gated K(+) (K(V)) and Ca(2+) (Ca(V)) channels, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in pancreatic alpha-cells and examined their targeting to specialized cholesterol-rich lipid rafts. In alpha-cells, we detected the expression of K(V)4.1/4.3 (A-type current), K(V)3.2/3.3 (delayed rectifier current), Ca(V)1.2 (L-type current), Ca(V)2.2 (N-type current), and the SNARE (synaptosomal-associated protein of 25 kDa, syntaxin 1A, and vesicle-associated membrane protein 2) and SNARE-associated proteins (Munc-13-1 and Munc-18a). We also detected caveolin-2, a structural protein of cholesterol-rich lipid rafts. Of these proteins, caveolin-2, K(V)4.1/4.3, Ca(V)1.2, and SNARE proteins (syntaxin 1A, synaptosomal-associated protein of 25 kDa, and vesicle-associated membrane protein 2) target to lipid raft domains on alpha-cell plasma membranes. Disruption of lipid rafts by depletion of membrane cholesterol with methyl-beta-cyclodextrin decreased the association of K(V)4.1/4.3, Ca(V)1.2, and SNARE proteins with lipid rafts. This resulted in inhibition of A-type K(V) currents and enhancement of glucagon secretion from alpha-cells. Consistently, capacitance measurements of exocytosis of single alpha-cells showed enhanced exocytosis after membrane cholesterol depletion. Taken together, our results demonstrate the association of K(V)4, Ca(V)1.2, and SNARE proteins with lipid rafts in pancreatic alpha-cells. Glucagon secretion from alpha-cells is regulated by lipid rafts, and the dissociation of SNARE proteins from cholesterol-rich lipid raft domains enhances glucagon secretion.