Cost-of-illness analysis and regression modeling in cystic fibrosis: a retrospective prevalence-based study

Background

Economic data pertaining to cystic fibrosis (CF), is limited in Europe generally, and completely lacking in Central and Eastern Europe. We performed an analysis of all direct costs associated with CF relative to key disease features and laboratory examinations.

Methods

A retrospective prevalence-based cost-of-illness (COI) study was performed in a representative cohort of 242 CF patients in the Czech Republic, which represents about 65 % of all Czech CF patients. Medical records and invoices to health insurance companies for reference year 2010 were analyzed.

Results

The mean total health care costs were €14,486 per patient, with the majority of the costs going towards medicinal products and devices (€10,321). Medical procedures (€2676) and inpatient care (€1829) represented a much smaller percentage of costs. A generalized linear model showed that the strongest cost drivers, for all cost categories, were associated with patient age and lung disease severity (assessed using the FEV1 spirometric parameter), when compounded by chronic Pseudomonas aeruginosa airway infections. Specifically, maximum total costs are around the age 16 years; a FEV1 increase of 1 % point represented a cost decrease of: 0.9 % (medicinal products), 1.7 % (total costs), 2.8 % (procedures) and 7.0 % (inpatient care).

Conclusions

COI analysis and regression modeling using the most recent data available can provide a better understanding of the overall economic CF burden. A comparison of our results with other methodologically similar studies demonstrates that although overall costs may differ, FEV1 can nonetheless be utilized as a generally transferrable indicator of the relative economic impact of CF.

     

Toxic and heavy metals as a cause of crayfish mass mortality from acidified headwater streams

Mining activities are responsible for high concentrations of metals in river networks in many parts of the world. Mining activities and the resulting high loads of heavy metals interact with intensive acid rain, and often have great consequences for biodiversity. However, considering the frequently episodic nature of these heavy acid rains, there is little detailed evidence of direct impacts. In 2011 we observed a massive mortality of noble crayfish and stone crayfish in Padr?sko Special Area of Conservation (SAC) in the Brdy Mountain region of the Czech Republic. Based on concentrations of metals (Al, Fe, As, Cd, Pb, Cu, Zn and Hg) in various tissues (gills, hepatopancreas, muscle) of both dead and live crayfish in this locality compared to reference populations, these crayfish had experienced long-term exposure to increased levels of these metals. Here we give detailed documentation of crayfish mortality associated with high metal concentrations in the gills and other tissues of these endangered invertebrates.     

Methylenetetrahydrofolate reductase (MTHFR): a novel target for cancer therapy

Tumor cells have an enhanced requirement for glucose, amino acids and DNA precursors. Since folates are required for the synthesis of thymidine and purines, the metabolism of folate has been exploited as an anti-cancer target for over 6 decades, with emphasis on the inhibition of DNA synthesis. However, folate is also used to generate methionine, which is essential for proliferation by virtue of its role in protein synthesis, polyamine synthesis and transmethylation reactions. Tumor-derived cell lines and human tumor xenografts have been shown to be methionine dependent i.e., they are unable to survive without methionine and are unable to efficiently utilize homocysteine, the immediate metabolic precursor of methionine. Since non-transformed cells are methionine-independent, the targeting of methionine metabolism presents an opportunity to selectively disrupt the unique metabolic networks in cancer cells. This chapter provides an overview of the critical role of folate and methionine metabolism in tumor cells and summarizes the current anti-folate and anti-methionine strategies to inhibit growth of transformed lines and tumors. We also present our work on the development of a novel anti-cancer target, methylenetetrahydrofolate reductase (MTHFR), a key enzyme of both folate and methionine metabolism. Our data demonstrate that antisense-mediated inhibition of MTHFR is associated with increased cytotoxicity in vitro and with decreased growth of tumors in vivo. These findings warrant further investigation of this enzyme and the methionine biosynthetic pathway in exploring new strategies for cancer chemotherapy.     

JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes

SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.     

Cortico-spinal excitability and hand motor recovery in stroke: a longitudinal study

Objective

To describe the relationship between changes of cortico-spinal excitability and motor recovery of the affected hand after stroke.

Methods

Eighteen hemiparetic stroke patients with a severe-to-mild upper limb motor impairment were randomized. Cortico-spinal excitability measures (resting motor thresholds and motor evoked potentials) obtained from a distal (abductor pollicis brevis) and proximal (biceps brachii) upper limb muscle were assessed for both hemispheres. Motor function of the affected hand was tested by the Wolf Motor Function and Action Research Arm tests. The evaluations were performed at baseline and weekly over 7 weeks of in-patient neurological rehabilitation.

Results

Severe hand dysfunction was associated with a strong suppression of ipsilesional cortico-spinal excitability and a shift of excitability towards the contralesional hemisphere. Mild hand impairment was associated with a shift of cortico-spinal excitability towards the ipsilesional hemisphere. Favorable motor recovery correlated with an increase of ipsilesional cortico-spinal excitability.

     

The influence of pre-emptive analgesia on postoperative analgesia and its objective evaluation

Introduction

The evaluation of pain intensity is still a subject of research. Mostly psychological evaluations are used. We started to conduct biochemical evaluation in animal experiments. Now we present biochemical evaluation in postoperative pain in man.

Material and methods

In 67 patients herniotomy was done. For pre-emptive analgesia morphine and pethidine were used and the following indicators were measured: visual analogue scale (VAS), measurement of lipid spectra, saccharides and proteins, thioredoxin, super-oxide dismutase (SOD), glutathione peroxidase (GPx) and NAD(P)H-oxidase (NOX), and free radicals using electron paramagnetic resonance (EPR). Blood samples were taken and tested: before pre-medication and intervention, 4 h after and 24 h after intervention.

Results

Free radicals (FR) increased in individual samples during the postoperative course in pethidine and without pre-medication. After application of morphine the FR were insignificantly reduced. Statistically significant differences were found in albumin, prealbumin, apolipoprotein A, total cholesterol, atherosclerotic index, CRP, glucose, and thioredoxin (p ≤ 0.001). A greater difference was seen in VAS values between morphine and pethidine premedications (p ≤ 0.001).

Conclusions

It was proved that the biochemical markers of lipid, protein and saccharide metabolisms and free radicals as well as singlet oxygen can serve as very good indicators of the intensity of pain and nociception. In patients it was proved that pre-emptive analgesia plays an important role in reducing the intensity of postoperative pain. From the three modalities of pre-emptive analgesia morphine represents the best solution.