Costs and where to find them: identifying unit costs for health economic evaluations of diabetes in France, Germany and Italy.

BACKGROUND: Health economic evaluations require cost data as key inputs. Many countries do not have standardized reference costs so costs used often vary between studies, thereby reducing transparency and transferability. The present review provided a comprehensive overview of cost sources and suggested unit costs for France, Germany and Italy, to support health economic evaluations in these countries, particularly in the field of diabetes. METHODS: A literature review was conducted across multiple databases to identify published unit costs and cost data sources for resource items commonly used in health economic evaluations of antidiabetic therapies. The quality of unit cost reporting was assessed with regard to comprehensiveness of cost reporting and referencing as well as accessibility of cost sources from published cost-effectiveness analyses (CEA) of antidiabetic medications. RESULTS: An overview of cost sources, including tariff and fee schedules as well as published estimates, was developed for France, Germany and Italy, covering primary and specialist outpatient care, emergency care, hospital treatment, pharmacy costs and lost productivity. Based on these sources, unit cost datasets were suggested for each country. The assessment of unit cost reporting showed that only 60% and 40% of CEAs reported unit costs and referenced them for all pharmacy items, respectively. Less than 20% of CEAs obtained all pharmacy costs from publicly available sources. CONCLUSIONS: This review provides a comprehensive account of available costs and cost sources in France, Germany and Italy to support health economists and increase transparency in health economic evaluations in diabetes.

How Ponto-Caspian invaders affect local parasite communities of native fish.

Invasive species are a major threat to ecosystems worldwide. Their effects are versatile and mostly well studied. However, not much is known about the impact of invasion on native parasite communities, although parasites are usually important response variables for ecosystem health. To improve the knowledge on how native fish parasite communities and their dynamics are affected by invasive species and how these processes change local host-parasite interactions over time, we studied different host-parasite systems in four German rivers. Three of these rivers (Rhine, Ems, and Elbe) are heavily invaded by different Ponto-Caspian species such as the amphipod Dikerogammarus villosus and various gobiids such as Neogobius melanostomus and Ponticola kessleri that serve as potential hosts for different local parasite species, while the fourth river (Schwentine) was free of any Ponto-Caspian invaders. Due to the lack of additional uninvaded river systems, literature data on parasite communities before invasion were compared with the post invasion status for the rivers Rhine and Elbe. The results showed differences among the parasite communities of different host species from the three invaded rivers when compared to the Schwentine River. Among the local internal parasite communities, especially the acanthocephalan Pomphorhynchus laevis and the nematode Raphidascaris acus have to be considered as key species associated with invasions from the Ponto-Caspian region. As the examined invasive Ponto-Caspian fish species serves as suitable host for both parasite species, the increases in their infection rates in native fish species are examples of parasite spill back (R. acus) and spill over (P. laevis, at least in the river Rhine). These results were further supported by the analysis of literature data on parasite communities of the past 20 years. Consequences for local parasite communities range from decreased prevalence of native parasites towards an extinction of entire parasite species.

Fipronil and two of its transformation products in water and European eel from the river Elbe.

Fipronil is an insecticide which, based on its mode of action, is intended to be predominantly toxic towards insects. Fipronil bioaccumulates and some of its transformation products were reported to be similar or even more stable in the environment and to show an enhanced toxicity against non-target organisms compared to the parent compound. The current study investigated the occurrence of Fipronil and two of its transformation products, Fipronil-desulfinyl and Fipronil-sulfone, in water as well as muscle and liver samples of eels from the river Elbe (Germany). In water samples total concentrations of FIP, FIP-d and FIP-s ranged between 0.5-1.6ngL(-1) with FIP being the main component in all water samples followed by FIP-s and FIP-d. In contrast, FIP-s was the main component in muscle and liver tissues of eels with concentrations of 4.05±3.73ngg(-1) ww and 19.91±9.96ngg(-1) ww, respectively. Using a physiologically based toxicokinetic (PBTK) model for moderately hydrophobic organic chemicals, the different distributions of FIP, FIP-d and FIP-s in water and related tissue samples could be attributed to metabolic processes of eels. The measured concentrations in water of all analytes and their fractional distribution did not reflect the assumed seasonal application of FIP and it seems that the water was constantly contaminated with FIP, FIP-d and FIP-s.

Novel bacterial acetyl coenzyme A carboxylase inhibitors with antibiotic efficacy in vivo.

The pseudopeptide pyrrolidinedione antibiotics, such as moiramide B, have recently been discovered to target the multisubunit acetyl coenzyme A (acetyl-CoA) carboxylases of bacteria. In this paper, we describe synthetic variations of each moiety of the modularly composed pyrrolidinediones, providing insight into structure-activity relationships of biochemical target activity, in vitro potency, and in vivo efficacy. The novel derivatives showed highly improved activities against gram-positive bacteria compared to those of previously reported variants. The compounds exhibited a MIC(90) value of 0.1 microg/ml against a broad spectrum of Staphylococcus aureus clinical isolates. No cross-resistance to antibiotics currently used in clinical practice was observed. Resistance mutations induced by pyrrolidinediones are exclusively located in the carboxyltransferase subunits of the bacterial acetyl-CoA carboxylase, indicating the identical mechanisms of action of all derivatives tested. Improvement of the physicochemical profile was achieved by salt formation, leading to aqueous solubilities of up to 5 g/liter. For the first time, the in vitro activity of this compound class was compared with its in vivo efficacy, demonstrating a path from compounds weakly active in vivo to agents with significant efficacy. In a murine model of S. aureus sepsis, the 100% effective dose of the best compound reported was 25 mg/kg of body weight, only fourfold higher than that of the comparator molecule linezolid. The obvious improvements achieved by chemical derivatization reflect the potential of this novel antibiotic compound class for future therapy.

In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor.

BAY 59-7939 is an oral, direct Factor Xa (FXa) inhibitor in development for the prevention and treatment of arterial and venous thrombosis. BAY 59-7939 competitively inhibits human FXa (K(i) 0.4 nm) with > 10 000-fold greater selectivity than for other serine proteases; it also inhibited prothrombinase activity (IC(50) 2.1 nm). BAY 59-7939 inhibited endogenous FXa more potently in human and rabbit plasma (IC(50) 21 nm) than rat plasma (IC(50) 290 nm). It demonstrated anticoagulant effects in human plasma, doubling prothrombin time (PT) and activated partial thromboplastin time at 0.23 and 0.69 microm, respectively. In vivo, BAY 59-7939 reduced venous thrombosis (fibrin-rich, platelet-poor thrombi) dose dependently (ED(50) 0.1 mg kg(-1) i.v.) in a rat venous stasis model. BAY 59-7939 reduced arterial (fibrin- and platelet-rich) thrombus formation in an arteriovenous (AV) shunt in rats (ED(50) 5.0 mg kg(-1) p.o.) and rabbits (ED(50) 0.6 mg kg(-1) p.o.). Slight inhibition of FXa (32% at ED(50)) reduced thrombus formation in the venous model; to affect arterial thrombosis in the rat and rabbit, stronger inhibition of FXa (74%, 92% at ED(50)) was required. Calculated plasma levels in rabbits at the ED(50) were 14-fold lower than in the rat AV shunt model, correlating with the 14-fold lower IC(50) of FXa inhibition in rabbit compared with rat plasma; this may suggest a correlation between FXa inhibition and antithrombotic activity. Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses (3 mg kg(-1) p.o., AV shunt). Based on these results, BAY 59-7939 was selected for clinical development.

New aminoacyl-tRNA synthetase inhibitors as antibacterial agents.

Increasing rates of bacterial resistance to known classes of antibiotics present a severe global challenge. As a consequence, the search for new chemical entities that address novel bacterial targets remains ongoing. Aminoacyl-tRNA synthetases (aa-RS) are essential enzymes for protein biosynthesis and emerged as an interesting target class in antibacterial research. These enzymes are present in all living organisms, and they are indispensable for the highly specific translation of the messenger-RNA (mRNA) template into protein via specific transfer-RNAs (tRNAs) as adapter molecules. When one aa-RS is inhibited, the corresponding tRNA is not charged and is therefore unavailable for translation. This leads to protein synthesis inhibition, which, in turn, causes cell growth arrest. Consequently, each compound that inhibits any of the aa-RS is a potential antibacterial agent. The clinical utility of this principle is proven by the natural product Ile-RS inhibitor pseudomonic acid, which is currently marketed as an antibacterial agent for topical application. Various chemical structures that inhibit aa-RS have been identified. These inhibitors have either been isolated from natural sources or have been generated synthetically. The synthetic inhibitors are modifications of natural inhibitors, derivatives of the natural synthetase substrates and reaction intermediates, or have been identified by screening of compound libraries. The recent progress achieved with these different classes of aa-RS inhibitors and their antibacterial potential in vitro and in vivo is discussed in this review.

New approaches for the prevention of airway infection in ventilated patients. Lessons learned from laboratory animal studies at the National Institutes of Health.

Despite early diagnosis and appropriate antibiotic therapy, ventilator-associated pneumonia (VAP) remains the leading cause of death from hospital-acquired infection in ventilator-dependent patients. Strategies to prevent bacterial colonization of the trachea and lungs are the key to decrease mortality, hospital length of stay, and cost. It is well established that the VAP can result from entry of infected oropharyngeal/gastric secretions into the lower airways. Aspiration may occur during 1) intubation, 2) mechanical ventilation through leakage around the tracheal tube cuff, 3) suctioning of the tracheal tube when bacteria can detach from the biofilm within the tube, or 4) areosolization of bacterial biofilm during mechanical ventilation through the tracheal tube or the ventilator circuit biofilm. From experimental studies in sheep, we drew 3 relevant conclusions: 1) The tracheal tube and neck should be oriented horizontal/below horizontal to prevent aspiration of colonized secretions and subsequent bacterial colonization of the lower respiratory tract. 2) Continuous aspiration of subglottic secretions (CASS) can lower bacterial colonization of the respiratory tract, but at the price of severe tracheal mucosal damage at the level of the suction port. 3) Coating the interior of the tracheal tube with bactericidal agents can prevent bacterial colonization of the tube surface and of the entire respiratory circuit, during 24 hours of mechanical ventilation.

[Aortoesophageal fistula. A rare cause of hematemesis]. / Aortoøsofageal fistel. En sjoelden arsag til haematemese.

A case of aorto-oesophageal fistula (AEF) resulting from a foreign body is presented. High mortality accompanies this rare complication and only a few survivors have been reported previously. AEF should be suspected in any patient with midthoracic pain or dysphagia that heralds upper gastrointestinal haemorrhage. We report the salvage of a 64 year-old man with AEF resulting from a denture.

[Sports fitness of active handball and soccer players with anterior instability of the knee joint]. / Sportfähigkeit von aktiven Handball- und Fussballspielern mit einer vorderen Instabilität des Kniegelenkes.

Based on an epidemiological study of 582 active handball and soccer players the abilities and limitations were analysed for sports activities of 24 athletes with an ACL-deficient knee. 22 of the 24 athletes suffered from a straight anterior instability. 50% attempted to avoid cutting mechanisms. The level of motivation was better than in the whole population. Handball players could continue their sports better and longer than soccer players. However, 19 athletes had to be classified as "knee-abusers" because they continued their sports inspite of having complaints. If athletic participation following ligament injuries of the knee should be rated, an accurate quantification and qualification is imperative.

[The knee arthrometer KT-1000: value of instrumental measurement in diagnosis of complex anterior knee instability]. / Knie-Arthrometer KT-1000: Stellenwert der instrumentellen Messung bei der Diagnose einer komplexen vorderen Knieinstabilität.

Clinical examination is the most accurate means of determining cruciate ligament integrity in the initial evaluation. In the case of a rupture of the anterior cruciate ligament the Lachman test has a high diagnostic accuracy, especially if the end point is absent. The Knee Arthrometer KT-1000 is a useful tool, as it is easy and fast to handle by an experienced examiner. Supplementary to noninvasive diagnostical methods it improves the confidence in clinical diagnosis. However, the importance of instrumental measurement should not be overrated even though reproducible results can be obtained. To compare the results of different studies the design has to be very similar. Although the examination conditions in this study were very homogeneous, a systematic mistake was produced. The average value of tibial displacement was significantly higher for the left knee. Data, obtained retrospectively in clinical practice, should not be used to scientifically document the results of therapeutic procedures.

Environmental induction of differentiation-specific keratins in malignant mouse keratinocyte lines.

Four spontaneously transformed keratinocyte lines (HELP I-IV) were raised from primary cultures of mouse epidermal cells grown on gas-permeable (Petriperm) dishes. Although tumorigenic, these cell lines still expressed the differentiated phenotype under mesenchymal influence in vivo in a fashion similar to normal cells and in contrast to previous observations on other transformed cell lines. Initially, after transplantation onto adult mice, HELP cells generally formed well organized ortho-keratinizing epithelia closely resembling those of normal epidermal cells. Later, dysplastic epithelia and papilloma-like structures developed and cells invaded subcutaneous host tissue. When injected subcutaneously into newborn syngeneic mice, all four cell lines gave rise to differentiated carcinomas at high frequency. Keratinized metastases were detected in the lung with HELP I, albeit at low frequency. Although the four HELP cell lines differed morphologically and biochemically in their degree of ortho-keratinization, no inverse relationship to their malignant potential was evident. In contrast to cell cultures, HELP transplants and tumors expressed epidermis-type "suprabasal" keratins. Metabolic labeling and electrophoresis on one and two-dimensional gels revealed both the basic 67 kilodaltons (kDa) and acidic 58 kDa components, including presumptive derivatives analogous to those observed in epidermal stratum corneum. However, associated with alterations in tissue architecture, the spatial control of keratin expression was gradually lost in papilloma-like and invading transplants and tumors, as demonstrated by indirect immunofluorescence microscopy (IIF). Thus, while cell differentiation appeared virtually normal, the progressive disturbances in tissue differentiation indicate important changes in the responsiveness of these malignant keratinocytes to environmental conditions.

Simplified detection of quaternary ammonium compounds by gas chromatography.

An analytical method for the measurement of quaternary ammonium compounds in biological fluids has been developed. Samples are prepared by forming the corresponding iodides, which are extracted and isolated. The residue is taken into n-hexane or into water and part of the solution obtained is injected onto the gas chromatograph where thermal degradation takes place. The methyl iodide released is measured by a 63Ni electron capture detector. This method is quite sensitive and detects with good reliability and reproducibility as little as 10(-14) mole quaternary ammonium compound.

The pharmacokinetics of pyridostigmine.

A simplified gas chromatographic method for measuring quaternary ammonium compounds has been developed and used to measure the serum concentration of pyridostigmine in human beings. Pyridostigmine is present in the serum within 1 hour after oral administration and reaches a peak at 2 hours. Results in several patients suggest that the serum concentration achieved is related to the size of the dose and that there is a relationship between serum concentration and clinical response.

[Population equilibrium in tetraploid dioecists]. / Populationsgleichgewicht bei tetraploiden Diöcisten.

Based on certain defined assumptions a general model for tetraploid populations with heterosomes is presented. With respect to their heterosomes, an equilibrium is attained in all populations, so that the frequencies of genotypes are dependent on the distribution of sexes in relation to the genotypes (z) and the degree of heterosomy (h). As the equilibrium is reached in only a few generations, natural populations ought to be in a balanced state.

A Multivariate Analysis of Selected Class Characteristic and Student Rating of Instruction.

This study examined the relationship between selected class characteristics and student ratings of instructors. A large number of classes (N = 1247)and students (over 33,000) a t a large Midwestern University provided the data for this study. The results indicated that the class characteristics that had the strongest influence on the results of instructor ratings were the grades expected by students and the percentage of students in the class taking the course as an elective.

[Cucurbitacins as stathmokinetic agents]. / Cucurbitacine als stathmokinetische Wirkstoffe.

A synergism of colchicine and different cucurbitacins has been shown, to be a cause in the formation of ball-metaphases in Bryonia species. The bitter principles cucurbitacin L and I, dihydrocucurbitacin B, and tetrahydrocucurbitacin I, which were examined more closely with respect to their karyological effects, were shown to give rise to C-metaphases in Hordeum and Vicia at concentrations of about 0.016 per cent. On the one hand the number of mitotic stages is reduced, and on the other hand there is an increase of metaphase stages. Higher concentrations lead to pycnotic degenerations of nuclei and are toxic. When colchicine is applied together with cucurbitacins, ball-metaphases result. This could be demonstrated in plants lacking colchicine and cucurbitacins (Hordeum) when both substances were applied at the same time. Ball-metaphases also appear in plants containing cucurbitacins (Bryonia alba, B. dioica, Citrullus colocythis, Iberis amara) when they are treated with colchicine.