Allergen-induced cytokine secretion in atopic and non-atopic asthmatic children

Atopic asthma is characterized by excessive T helper 2 (Th2)-like immunity to allergens in the bronchial mucosa. The Th2-cytokine interleukin (IL)-4 induces IgE production, while the Th2-cytokine IL-5 promotes eosinophilic inflammation in the airways of asthmatics. Most asthmatics are atopic, but a subgroup is non-atopic. We hypothesize that allergen-induced Th2, particularly IL-5, responses can be observed in peripheral blood in both atopic and non-atopic asthmatic children but not in healthy control children. The aim of the present study was to determine IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-γ secretion induced from peripheral blood mononuclear cells (PBMC) by a broad panel of inhalant allergens (timothy, cat, birch, dog and house dust mite) in asthmatic children with and without sensitization. The study included 13 atopic asthmatic, 5 non-atopic asthmatic, and 12 non-atopic non-asthmatic children. PBMC were stimulated with allergens and cytokine production was measured with enzyme-linked immunosorbent assay (ELISA). Higher levels of cat and dog antigen-induced IL-5 release were more commonly observed in both atopic and non-atopic asthmatics than in controls. Children with atopic, but not non-atopic, asthma produced higher levels of allergen-induced IL-4 and IL-9 than controls. Non-atopic asthmatics produced more IL-10 than atopic asthmatics after cat stimulation. High levels of eosinophilia-associated IL-5 responses are induced by cat and dog allergen in both atopic and non-atopic asthmatic children. The Th2 cytokines IL-4 and IL-9 were associated only with atopic asthma, probably due to their IgE-inducing properties.     

Individuals with an increased risk of colorectal cancer: perceived benefits and psychological aspects of surveillance by means of regular colonoscopies.

PURPOSE: To evaluate the psychological consequences of genetic counseling followed by a surveillance program using colonoscopy among individuals with increased risk of colorectal cancer. PATIENTS AND METHODS: Two hundred sixty-five individuals, participating in a surveillance program with colonoscopy, were mailed a survey questionnaire that assessed their experience of the surveillance program and their perception of the risk of colorectal cancer. The Hospital Anxiety and Depression scale and the Swedish Short Form-36 Health Survey was also included. RESULTS: Two hundred forty individuals completed the questionnaire and were divided into the following risk groups: risk group 1, an individual with a mutation in hMLH1 or hMSH2 and a lifetime colorectal cancer risk of 80% (n = 28); risk group 2, a lifetime colorectal cancer risk of 40% (n = 129); and risk group 3, a lifetime colorectal cancer risk of 20% (n = 83). Among all individuals, the mean for perceived benefit was 8.0, and the perception of discomfort was 3.3 on the visual analog scale (1-10). In risk group 1, 61% underestimated personal risks as being 40% or less. Approximately 50% of the subjects in risk groups 2 and 3 either under- or overestimated their lifetime risk. According to the Swedish Short Form-36 Health Survey and the Hospital Anxiety and Depression scale, the study sample resembled the reference population. CONCLUSION: A majority of the study sample understood why they were under surveillance, and regular colonoscopies were well-tolerated. The wide range of risk perception as well as low-risk perception in mutation positive subjects is acceptable, as long as these individuals adhere to surveillance programs and do not demonstrate increased levels of anxiety or depression.     

The effect of the preoperative bone quality on the fixation of the tibial component in total knee arthroplasty

The relationship between the preoperative level of bone mineral density (BMD) in the proximal tibia and the migration of the tibial component 2 years after total knee arthroplasty was investigated in 28 knees with osteoarthrosis (10 men, 18 women; mean age, 71). Sixteen components were inserted uncemented and 12 were cemented. Mean average BMD measured 10 mm below the joint level was 0.81 g/cm2 (range, 0.15-1.33 g/cm2) and was not influenced by gender, age, weight, or preoperative alignment. Local BMD measured in the medial and lateral condyles was influenced by the preoperative alignment. In knees with uncemented fixation, most of the tibial component migration (ie, subsidence and lift-off) occurred within the first months, and thereafter the implants seemed to stabilize. In the uncemented implants, there was a significant relationship between average BMD and migration (regression analysis with curve-fit estimation). The least migration was seen when average BMD was 0.6 to 1.0 g/cm2. Beyond this range, increased subsidence and lift-off was seen. There was no relationship between BMD and the change in maximum migration between 1 and 2 years postoperatively, however. In knees with cemented fixation, subsidence was initially small but continuously increasing. There were no relationships between BMD and subsidence, lift-off, and maximum migration, indicating that bone-cement can compensate for variations in bone quality, at least in the early period after operation.     

Laminin-5 γ2-chain expression and DNA ploidy as predictors of prognosis in endometrial carcinoma

Expression of the laminin-5 γ2-chain in carcinoma cells has been implicated in tumor invasion. The aim was to investigate the expression and prognostic significance of the In-5 γ2-chain compared with clinicopathological factors and tumor cell DNA ploidy in endometrial carcinoma. Histological specimens from 80 endometrial carcinomas were examined with respect to immunohistochemical In-5 γ2-chain expression and correlated to the clinicopathological characteristics, DNA ploidy, and survival. Sixty-eight of 80 investigated cases were judged to be positive for the In-5 γ2-chain. Ln-5 γ2-chain did not show any correlation to stage, histopathological subtype, grade, and DNA ploidy. In univariate analyses, advanced stage (p<0.001), nonendometrioid carcinoma (p=0.030), low grade (p<0.001), aneuploid tumors (p<0.001), and In-5 γ2-chain expression (p=0.017) were highly associated with poor survival. Aneuploid tumors in combination with strong In-5 γ2-chain expression were significant predictors (p<0.001) of poor prognosis. In multivariate analyses including stage, histopathological subgroup, grade, DNA ploidy, and In-5 γ2-chain expression, all lost their significant prognostic information except for stage (p<0.001) and grade (p<0.05). Ln-5 γ2-chain expression and DNA ploidy both as a single parameter and in combination were demonstrated to be significant prognostic factors in univariate analysis. However, stage and grade provided more useful clinical information beyond histopathological subgroup, DNA ploidy, and In-5 γ2-chain expression. The results also indicate that In-5 γ2-chain expression is upregulated during the progression of endometrial carcinoma.     

Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes

Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated inflammatory reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.     

Cholecystectomy: costs and health-related quality of life: a comparison of two techniques.

BACKGROUND: Outcomes of previous health economic evaluations comparing minilaparotomy cholecystectomy and laparoscopic cholecystectomy have been inconsistent. OBJECTIVE: To compare costs for minilaparotomy cholecystectomy and laparoscopic cholecystectomy and to study changes in quality of life induced by these operations. DESIGN: Single-blind, randomized controlled trial, run from 1 March 1997 to 30 April 1999. SETTING: One university hospital and four non-university hospitals in Sweden. MAIN MEASURE: : Cost and perceived health estimation according to the global quality of life instrument EuroQol-5D. RESULTS: Of 1719 cholecystectomy patients at five centres, 724 entered the trial and were treated with minilaparotomy cholecystectomy or laparoscopic cholecystectomy, 362 in each group. Total health care costs were less for minilaparotomy cholecystectomy than for laparoscopic cholecystectomy (median values US$2428 for minilaparotomy cholecystectomy versus US$2613 or US$3006 for laparoscopic cholecystectomy with 100 operations per year and reusable trocars or 50 operations per year and disposable trocars, respectively). There was no significant difference in total costs (including costs due to loss of production) between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with 100 operations per year and reusable trocars in laparoscopic cholecystectomy (US$3731 versus US$3649, respectively). However, in calculations assuming 50 operations per year and disposable trocars in laparoscopic cholecystectomy, this technique was more expensive than minilaparotomy cholecystectomy (US$4042 versus US$3731). Health-related quality of life was slightly but significantly lower for the minilaparotomy cholecystectomy group 1 week after surgery. One month and 1 year postoperatively no difference between the randomized groups was found. CONCLUSION: Total costs did not differ between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with high-volume surgery and disposable trocars, whereas laparoscopic cholecystectomy was more expensive with fewer operations and disposable trocars. The gain in health-related quality of life with laparoscopic cholecystectomy compared with minilaparotomy cholecystectomy was small and of limited duration.     

Effects of vasoactive intestinal polypeptide (VIP) on intraocular pressure, facility of outflow and formation of aqueous humor in the monkey

Stimulation of the facial nerve causes a non-cholinergic vasodilation in the uvea and a rise in the intraocular pressure in rabbits, cats and monkeys. Vasoactive intestinal polypeptide (VIP) has been suggested as the neurotransmitter mediating these effects. In the present investigation, the effects of VIP on aqueous humor dynamics were studied in cynomolgus monkeys. After intracameral injection of 1 microgram VIP, the outflow facility was higher in the experimental eye than in the control; 0.42 +/- 0.46 compared with 0.33 +/- 0.03 microliter cm H20-1 min-1, difference 0.09 +/- 0.04 microliter cm H2O-1 min-1. Intravenous infusion of VIP, 160 ng min-1, increased aqueous humor flow from 1.12 +/- 0.07 to 1.65 +/- 0.09 microliter min-1. Almost the same effect, a 50% increase in aqueous humor flow, was found after intracameral administration of 90 micrograms VIP. This dose of VIP caused a significant increase in intraocular pressure (IOP) in the experimental eye. The maximal difference in IOP between the experimental eye and the control eye was 7.5 +/- 0.4 cm H2O. A lower dose of VIP, 30 micrograms intracamerally, increased aqueous humor flow by about 20%, but had no consistent effect on IOP. The effect of VIP on aqueous humor flow was not affected by pretreatment with indomethacin. The results suggest that most of the rise in IOP caused by intracameral VIP administration is due to a rise in the pressure in the veins into which the aqueous humor is drained. Enhanced formation of aqueous humor plays a smaller role. The effects of VIP on aqueous humor formation and outflow facility suggest that the facial nerve may be involved in nervous control of aqueous humor dynamics, as VIP is most probably released in the eye by stimulation of the facial nerve.     

Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man

Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491 mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 ± 0.045 (sd) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 ± 11%) and pivampicillin (92± 18%) was significantly greater than that of ampicillin (62 ± 17%); however, the difference between the esters was not statistically significant. The absorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The absorption rate was highest for bacampicillin (0.89 ± 0.39% of dose absorbed per minute), followed by pivampicillin (0.64 ± 0.19) and ampicillin (0.58 ± 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 ± 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.This work was supported by the Swedish Medical Research Council, Project No. 522 (L. O. B.).     

Reducing uncertainty in health-care resource allocation

A key task for health policymakers is to optimise the outcome of health care interventions. The pricing of a new generation of cancer drugs, in combination with limited health care resources, has highlighted the need for improved methodology to estimate outcomes of different treatment options. Here we introduce new general methodology, which for the first time employs continuous hazard functions for analysis of survival data. Access to continuous hazard functions allows more precise estimations of survival outcomes for different treatment options. We illustrate the methodology by calculating outcomes for adjuvant treatment of gastrointestinal stromal tumours with imatinib mesylate, which selectively inhibits the activity of a cancer-causing enzyme and is a hallmark representative for the new generation of cancer drugs. The calculations reveal that optimal drug pricing can generate all win situations that improve drug availability to patients, make the most of public expenditure on drugs and increase pharmaceutical company gross profits. The use of continuous hazard functions for analysis of survival data may reduce uncertainty in health care resource allocation, and the methodology can be used for drug price negotiations and to investigate health care intervention thresholds. Health policy makers, pharmaceutical industry, reimbursement authorities and insurance companies, as well as clinicians and patient organisations, should find the methodology useful.