Chemokine production by human vascular smooth muscle cells: modulation by IL-13

1. The production of chemokines by vascular smooth muscle cells (SMC) is implicated in the pathogenesis of atherosclerosis, although the factors regulating chemokine production by these cells are incompletely characterized.
2. We describe the differential stimulation of interleukin-(IL)-8, monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) synthesis following treatment of human vascular SMC with IL-1α or tumour necrosis factor α (TNFα). Under basal conditions, cultured SMC release very low amounts of IL-8, MCP-1 and RANTES as assessed by specific ELISA. Concentration-response studies with IL-1α or TNFα revealed that each stimulus induced a similar amount of MCP-1. In contrast approximately three fold more IL-8 was induced by IL-1α than by TNFα whereas significant RANTES production was induced only by TNFα. These findings point to a divergence in the regulation of synthesis of the different chemokines in response to IL-1α or TNFα stimulation.
3. The T-cell derived cytokines IL-10 and IL-13 were also found to have differential effects on chemokine production by SMC. IL-13, but not IL-10, significantly enhanced IL-8 and MCP-1 release in response to IL-1α or TNFα. This increase in chemokine release appeared to be accounted for by increased mRNA expression.
4. These findings provide support for the concept that smooth muscle cells can have an active role in a local immune response via the production of chemokines which can be selectively modulated by T-cell derived cytokines.

     

To Stay or Not to Stay: Issues in Rural Primary Care Physician Retention in Eastern Kentucky

An important aspect of primary care physician availability is the retention of physicians once they have located. While retention has been under-researched compared to recruitment, it is especially important in rural areas where physician shortages already exist. This study reports the results of a retention survey completed by 132 primary care physicians in rural eastern Kentucky. The survey sets up an objective, hypothetical retention scenario and asks physicians to respond to structured questions and to an open-ended question about factors not appearing in the survey. In response to the structured portion of the survey, physicians indicate that relief coverage is the most important factor in rural physician retention. A content analysis of 75 open-ended responses reveals that besides the other factors in the survey, "sociocultural integration" is the pre-eminent retention issue for rural practitioners. This article concludes that the role of the local rural community may be more important in retention than in recruitment. Finally, it is suggested that additional in-depth qualitative research be conducted within the local contexts to enhance the understanding of rural physician retention processes.     

Antigen presenting cell function in HIV-1 infected patients

Antigen presenting cell (APC) function is central to the activation of anti-viral cytotoxic T-cells and antibody production. In previous studies we have evaluated APC function in HIV-1 infected patients as the capacity to present peptide to a well defined panel of CD4 T-cell clones. We found that APC from HIV-1 infected patients were defective in the capacity to present peptide to CD4 T-cell clones. The APC defect uncovered by this method was present early in infection and worsened with increasing viral load, suggesting that it was an important determinant of progression and anti-viral efficacy. The CD4 T-cell clones were, however, found to vary in their susceptibility to the APC defect. CD4 T-cell clones that failed to respond to peptide presented by HIV + APC were 1000-fold more readily inhibited by anti-CD4 antibody than T-cell clones which consistently responded to APC from patients infected with HIV-1 (HIV + APC). An intermediate group of T-cell clones were also identified that only responded to peptide and HIV + APC from asymptomatic patients. These results suggested that the underlying mechanism for the APC defect was binding of T-cell CD4 by APC-associated gp120. In this paper we discuss the evidence to support this hypothesis.     

Extracellular fluid and its proteins: dehydration, shock, and recovery

This review highlights characteristics of extracellular fluid (ECF) that are often overlooked. ECF has, in addition to plasma and interstitial fluid (ISF) surrounding cells, a third large compartment, the ISF of skin and connective tissue. This acts as a reservoir that gives up ECF to plasma volume (PV) in order to sustain circulation in the event of either shock or dehydration. While Starling forces drive filtration, ECF is returned to PV more by lymph and less by Starling forces than previously appreciated. Lymph return to PV is dependent on physical activity and muscle contraction to overcome gravity. Regional change in metabolic rate alters the need for oxygen and nutrients that is met by a regional increase in capillary blood flow. Blood flow is controlled by vasoactive compounds released in response to a drop in PO₂; these relax capillary smooth muscle to increase blood flow and delivery of oxygen and nutrients. Plasma proteins, including albumin, are filtered into the interstitium through larger pores than those filtering ECF. The rate of protein filtration is set by size and charge of these larger endothelial pores and by size and charge of proteins. Charge of these pores, hence albumin permeability, is regulated by many of the same vasoactive compounds that control capillary flow. As a consequence, in response to gravitational stress and other forms of shock that reduce effective circulation, albumin as well as ECF is rapidly shifted from plasma and sequestered in ISF. When this has occurred, as in burn shock, restoration is better effected by generous expansion of ECF with Ringer’s solution alone, rather than with Ringer’s solution supplemented with human serum albumin or other colloid. Restoring both PV and ISF volume restores lymph circulation and returns sequestered albumin to PV. Received: 12 November 1998 / Revised: 30 March 1999 / Accepted: 2 April 1999     

Platinum distribution in malignant glioma following intraoperative intravenous infusion of carboplatin

The objective of this paper was to determine the time course and extent of platinum uptake into human malignant glioma tissue. An intraoperative, intravenous infusion of carboplatin was given to nine patients (seven glioblastoma and two anaplastic glioma) undergoing tumour excision. Carboplatin dosage was calculated individually to achieve a target systemic free carboplatin exposure. Tumour and peritumoural tissue was harvested at timed intervals following carboplatin administration. Plasma and tumour platinum concentrations were measured by graphite furnace flameless atomic absorption spectrophotometry. Histological examination was also performed on a piece of each tissue sample. The mean carboplatin dose administered was 783, SEM 56 mg (range 485-903). Plasma pharmacokinetics showed a typical elimination curve. The mean peak plasma platinum concentration was 44, SEM 5 micrograms/ml (range 27-74). The mean total elemental plasma platinum area under the curve (AUC) was 9.0, SEM 1.4 mg/ml/min. Platinum was detected in 61 tumour samples, the mean peak concentration being 13 SEM 2 micrograms/g (range 5-21). Platinum was also detected in peritumoural brain and necrotic tumour. No correlation was apparent between the degree of necrosis in each tumour specimen and tumour platinum concentration. Platinum concentrations achieved in tumour were similar to levels that would be cytotoxic for glioma cells in vitro. The results of this study have implications for future studies using capillary permeability modifying agents as adjuncts to brain tumour chemotherapy.     

The influences of age and caffeine on psychomotor and cognitive function

Rationale: The response to caffeine is affected by a number of factors, including age. Older subjects may be more sensitive to the objective effects than younger but report fewer subjective effects. Objective: This study assessed the influence of age on the effects of caffeine on a variety of psychomotor, cognitive and subjective tests. Methods: Forty-eight healthy subjects, male and female, were recruited, 24 in the age range 20–25 and 24 in the range 50–65 years. All subjects were regular moderate caffeine drinkers and were not withdrawn from caffeine before entry to the study. A double-blind parallel group design was used with two groups of 12 subjects in each age range. One group in each age range received placebo and the other 250 mg caffeine B.P. A range of tests was used to assess psychomotor, cognitive and subjective functioning before and 1 h post-treatment. Results: Before treatment, young subjects generally performed better than older on psychomotor and cognitive tests. On the subjective tests, however, older subjects rated themselves as more alert and less tired than the younger ones. After placebo, performance and alertness improved in the younger group but declined in the older. After caffeine there were improvements in psychomotor performance and cognitive functioning in both groups, particularly in offsetting declining performance over time in the older subjects. It also produced subjective improvements in alertness. One factor to emerge was that on most assessments older subjects were better earlier in the day whereas in younger subjects performance did not show the same magnitude of decline throughout the day. Conclusions: Caffeine induced small but significant improvements in vigilance and psychomotor performance. Received: 27 October 1998/Final version: 15 February 1999