Health-economic analysis of real-time continuous glucose monitoring in people with Type 1 diabetes.

AIM: To evaluate the clinical benefits and cost-effectiveness of the sensor-augmented pump compared with self-monitoring of plasma glucose plus continuous subcutaneous insulin infusion in people with Type 1 diabetes. METHODS: The CORE Diabetes Model was used to simulate disease progression in a cohort of people with baseline characteristics taken from a published meta-analysis. Direct and indirect costs for 2010-2011 were calculated from a societal payer perspective, with cost-effectiveness calculated over the patient's lifetime. Discount rates of 3% per annum were applied to the costs and the clinical outcomes. RESULTS: Use of the sensor-augmented pump was associated with an increase in mean discounted, quality-adjusted life expectancy of 0.76 quality-adjusted life years compared with continuous subcutaneous insulin infusion (13.05 ± 0.12 quality-adjusted life years vs 12.29 ± 0.12 quality-adjusted life years, respectively). Undiscounted life expectancy increased by 1.03 years for the sensor-augmented pump compared with continuous subcutaneous insulin infusion. In addition, the onset of complications was delayed (by a mean of 1.15 years) with use of the sensor-augmented pump. This analysis resulted in an incremental cost-effectiveness ratio of 367,571 SEK per quality-adjusted life year gained with the sensor-augmented pump. The additional treatment costs related to the use of the sensor-augmented pump were partially offset by the savings attributable to the reduction in diabetes-related complications and the lower frequency of self-monitoring of plasma glucose. CONCLUSIONS: Analysis using the CORE Diabetes Model showed that improvements in glycaemic control associated with sensor-augmented pump use led to a reduced incidence of diabetes-related complications and a longer life expectancy. Use of the sensor-augmented pump was associated with an incremental cost-effectiveness ratio of 367,571 SEK per quality-adjusted life year gained, which is likely to represent good value for money in the treatment of Type 1 diabetes in Sweden.

Health care costs for the treatment of breast cancer recurrent events: estimates from a UK-based patient-level analysis.

Cost pressures and the need to demonstrate cost-effectiveness of new interventions require consideration of the costs of treating disease. This study presents analyses of resource use data covering 199 postmenopausal women who experienced a breast cancer recurrent event between 1991 and 2004 and were treated at the Western General Hospital, Edinburgh. Aggregate (5-year) treatment costs for alternative recurrent events were estimated, as well as the annual costs incurred by patients experiencing contralateral, locoregional, or distant recurrence, who remained alive without further recurrence for a year. The 95% confidence intervals for the 5-year costs of recurrence ranged from pounds 10,000 to pounds 37,000 for locoregional recurrence, and pounds 14,500- pounds 20,000 for distant recurrence. No evidence of significant variations in these costs across time periods between 1991 and 2004 was identified. Annual costs for patients remaining in the same health state showed high initial costs for contralateral and locoregional recurrence, with low costs in subsequent years, while costs associated with distant recurrence declined at a slower rate and plateaued at 4-5 years post-diagnosis. The cost estimates presented in this paper not only inform the magnitude of the resource consequences of breast cancer recurrences, but they are also better suited to informing cost-effectiveness analyses, which have a far greater role in allocating health-care resources.

Host defense peptides as new weapons in cancer treatment.

In the last decade intensive research has been conducted to determine the role of innate immunity host defense peptides (also termed antimicrobial peptides) in the killing of prokaryotic and eukaryotic cells. Many antimicrobial peptides damage the cellular membrane as part of their killing mechanism. However, it is not clear what makes cancer cells more susceptible to some of these peptides, and what the molecular mechanisms underlying these activities are. Two general mechanisms were suggested: (i) plasma membrane disruption via micellization or pore formation, and (ii) induction of apoptosis via mitochondrial membrane disruption. To be clinically used, these peptides need to combine high and specific anticancer activity with stability in serum. Although so far very limited, new studies have paved the way for promising anticancer host defense peptides with a new mode of action and with a broad spectrum of anticancer activity.

In vitro activity and mode of action of diastereomeric antimicrobial peptides against bacterial clinical isolates.

OBJECTIVES: Increasing resistance of pathogenic bacteria to antibiotics is a severe problem in health care and has intensified the search for novel drugs. Cationic antibacterial peptides are the most abundant antibiotics in nature and have been frequently proposed as new anti-infective agents. Here, a group of diastereomeric (containing d- and l-amino acids) peptides is studied regarding their potency against multiply resistant clinical isolates and their modes of action against Gram-positive cocci. METHODS: MIC determinations and chequerboard titrations followed established procedures. Mode of action studies included killing kinetics and a series of experiments designed to characterize the impact of the diastereomeric peptides on bacterial membranes. RESULTS: The tested diastereomers displayed high antimicrobial and broad spectrum activity with amphipathic-2D being the most active peptide. Synergic activities were observed with individual strains. Mode of action studies clearly demonstrated that the cytoplasmic membrane is a primary target for the peptides and that membrane disruption constitutes a significant bactericidal activity for the major fraction of a bacterial population. However, depending on the indicator strain, the results also suggest that additional molecular events contribute to the overall activity.

Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system--active chiral valproylamide.

The purpose of this study was to evaluate the anticonvulsant activity and pharmacokinetics (PK) of a novel chiral CNS-active 2-hydroxypropyl valpromide (HP-VPD), a derivative of valproic acid (VPA). The individual enantiomers, R, S, and racemic (R,S)-HP-VPD were synthesized and evaluated for their pharmacokinetics and pharmacodynamics in a stereoselective manner. A stereoselective gas chromatography (GC) assay for simultaneous quantification of HP-VPD enantiomers in plasma and urine was developed and used to investigate the pharmacokinetics of HP-VPD in dogs. Pharmacodynamic analysis in rats showed that (S)-HP-VPD was 2.5 times more potent as an anticonvulsant in the maximal electroshock seizure (MES) test than its enantiomer and approximately 10 times more potent than VPA. No significant differences were observed in major PK parameters (clearance, volume of distribution, and half-life) between S and (R)-HP-VPD, and this suggested that pharmacodynamic differences could be attributed to the intrinsic pharmacodynamics of each enantiomer rather than to a preferable pharmacokinetic profile. The pharmacokinetic (metabolic) analysis showed that the fraction metabolized to HP-VPD-glucuronide ranged from 5% to 7% and no biotransformation of HP-VPD to VPA and 2-ketopropyl valpromide was observed. This is the first report of significant stereoselectivity in the anticonvulsant activity of a valproylamide with a chiral carbon situated on the alkyl chain of the amine moiety.

Calcium supplements interact significantly with long-term diet while suppressing rectal epithelial proliferation of adenoma patients.

BACKGROUND: Calcium supplements to the western-style diet may reduce the risk for colorectal neoplasia. Using rectal epithelial proliferation (REP) measurements as a biomarker of response to intervention, the authors evaluated the effects of 1-year calcium supplementation in adenoma patients and its possible interactions with the patients' dietary and lifestyle habits. METHODS: Consenting adenoma patients, without a family history of colorectal neoplasia, were randomly selected to receive 3.75 g calcium carbonate (1.5 g Ca2+) daily or to receive no treatment. All had their long-term dietary and lifestyle habits assessed and their REP labeling index (LI) evaluated before and at end of follow-up. The change in LI was compared between groups, and statistical associations were examined between mean nutrient consumption and treatment effect and between lifestyle and treatment effect. RESULTS: Fifty-two adenoma patients (33 treated and 19 untreated) completed intervention and follow-up. There were no significant differences between study groups in age, weight, cigarette smoking, or medication use. The LI decreased in 58% of calcium-intervened patients and in only 26% of nonintervened patients (P = 0.04); the mean LI x 100 (+/- standard deviation) of the former fell from 5.04 +/- 1.93 to 4.54 +/- 1.58, and rose from 4.32 +/- 1.58 to 4.93 +/- 1.58 in the latter (P = 0.04). A lower fat, a higher carbohydrate, fiber, or fluid intake each interacted with the calcium supplementation to decrease the LI (P = 0.02, 0.001, 0.02, and 0.08, respectively). CONCLUSIONS: Long-term calcium supplements significantly suppressed REP in adenoma patients, and long-term dietary habits contributed to this effect. Patient diet should be assessed when researchers use REP as a biomarker in calcium chemoprevention studies. Study results indicated that relevant dietary counseling may be useful in addition to calcium supplements in persons at increased risk for colorectal neoplasia.

Rectal epithelial proliferation in persons with or without a history of adenoma and its association with diet and lifestyle habits.

BACKGROUND: Rectal epithelial proliferation (REP) measurements are used as a biomarker of risk for colorectal neoplasia and response to chemoprevention. The authors evaluated REP in screenees with and without a history of adenoma and its association with demographic and adenoma characteristics, diet, and other lifestyle habits. METHODS: Long term lifestyle habits were evaluated and proliferation assessed by in vitro bromodeoxyuridine labeling of rectal biopsies in 223 screenees, 132 of whom had adenomas removed > 3 years previously. Analyses included the total population, screenees with a previous history of adenomas and adenoma free screenees separately, and a subgroup of 55 matched adenoma cases and controls. RESULTS: Crypt proliferation measurements were not elevated in screenees with a history of adenomas compared with adenoma free screenees (mean total labeling index [LI] of 4.8% and 4.9%, respectively). This was confirmed by the case-control analysis, in which the LI of the most superficial crypt compartment was lower in the adenoma cases (P=0.05). Moreover, their total LI correlated negatively with the number of adenomas removed previously (P < 0.01). Proliferation was more frequent in the most superficial crypt compartments of female adenoma free screenees than in female screenees with a history of adenomas (P=0.02), and in men age > 65 years compared with younger men (P=0.06). In the total population, negative Spearman rank correlations were found between total LI and long term dietary intake of calcium (correlation coefficient [r]=-0.15; P=0.02), LI of the two most superficial crypt compartments and intake of fiber (r=-0.18; P=0.01), water (r=-0.12; P=0.08), and carbohydrates (not significant). A positive correlation was found between LI of the most superficial crypt compartment and cigarette smoking (r=0.4; P=0.02). CONCLUSIONS: REP measurements did not discriminate between screenees with a history of adenomas and adenoma free screenees. Long-term lifestyle habits, gender, and age were associated with REP levels and need to be considered when evaluating human intervention studies.

Evaluation and comparison of an immunochemical and a guaiac faecal occult blood screening test for colorectal neoplasia.

Guaiac tests for faecal occult blood are used for colorectal neoplasia screening. Specificity may be improved by using an immunochemical test for human blood. We evaluated and compared, within an endoscopic study, an immunochemical test for human stool albumin, BM-Test Colon Albumin, with the guaiac test, Hemoccult SENSA. Both tests were given to 527 screenees who had had a low-peroxidase diet before and during the tests. All had a colonoscopic (59%) or flexible sigmoidoscopic (41%) examination. Both tests were easy to perform and develop. They were of similar sensitivity (35-30%) for adenomas > or = 1.0 cm in diameter or cancers, but Colon Albumin had a higher specificity (90%) than Hemoccult (85%; P < 0.05). The latter, however, had a higher sensitivity for neoplasia of all sizes (25% vs 20%; NS) but lower specificity (85% vs 90%; P < 0.05). Colon Albumin was positive in 11.2%, while Hemoccult SENSA was positive in 16.7% and appears very sensitive to dietary peroxidases. Positivity was reduced to 7% by changing the methodology protocol. Overall, the guaiac test is more sensitive but less specific than the immunochemical test for colorectal neoplasia. However, the technical and diagnostic limitations of these tests must be appreciated, and because of their high positivity rate neither is suitable for mass screening. A more specific test for neoplasia is needed.

Induction of gamma-glutamyl transferase by dexamethasone in cultured fetal rat hepatocytes.

Hepatocytes isolated as a relatively pure population from normal fetal rats were maintained in primary monolayer culture for 4-10 days. Hepatocytes exhibited a small increase in basal gamma-glutamyl transferase (GGT) activity over time. Exposure to dexamethasone (10(-6) mol/l) elicited a rise in GGT activity after a lag of 24 h. The presence of the steroid was necessary to maintain induction, and its removal resulted in reversal of induction. The maximal response was 2- to 3-fold, 72 h after exposure to the steroid. After this maximal response, a gradual decay in enzyme activity occurred, despite the continuous presence of the hormone. Actinomycin D or cycloheximide given prior to/or simultaneously with the steroid prevented the induction, thus suggesting that both RNA and protein biosynthesis are necessary for induction to occur.