Objective frequency-specific hearing thresholds definition for medicolegal purposes in case of occupational NIHL: ASSR outperforms CERA.

Audiological use of the 40 Hz-ASSR (auditory steady state responses) could be valuable for objectively estimating the frequency-specific threshold in adults undergoing an expertise examination for medicolegal and/or compensation purposes. The present prospective study was set up to clarify the relationship between the thresholds obtained by cortical evoked response audiometry (CERA) and by 40 Hz-ASSR, in the same ears, within a large homogeneous sample of 164 subjects (328 ears) with NIHL and well documented exposure to noise. All these subjects claimed financial compensation for occupational NIHL, and there was a suspicion of exaggeration of the reported NIHLs. ASSR thresholds show a good correlation with the CERA thresholds. However, a systematic shift is noticed, ASSR thresholds being on average (1-2 - 3 kHz) 4.38 dB lower (i.e. showing less hearing loss) than CERA thresholds. Moreover, the binaural multiple ASSR technique allows a considerable time gain when compared to the CERA.

[Clinical outcomes of total hip arthroplasty after previous hip arthrodesis]. / Klinische uitkomsten van totale heupprothese na eerdere artrodese van de heup.

OBJECTIVE: To describe the clinical results of conversion of an arthrodesis of the hip to a total hip arthroplasty (THA) at the Erasmus MC, Rotterdam, the Netherlands. DESIGN: Retrospective study. METHOD: Data were collected from the case notes of patients who had undergone conversion ofarthrodesis of the hip to a total hip prosthesis between 1 January 1985 and 31December 2003. This was a total of 13 patients, 1 of whom had died and 2 of whom were excluded because of dementia and severe psychiatric disorder respectively. The remaining 10 patients (5 men and 5 women) were sent the Short form-36 quality-of-life questionnaire and asked, if, in hindsight, they would undergo the operation again. Their hip function was assessed using the Harris Hip Score (HHS) and the weakness of the gluteus muscles using Trendelenburg's test. The preoperative and most recent postoperative X-rays of the pelvis were evaluated. RESULTS: Median age at the time ofTHA was 45 years (range: 21-62). THA was done median 15 years (range: 2-50) after arthrodesis. Follow-up was done median 5 years (range: 0-18) after THA. The main reasons for conversion were ipsilateral knee pain and low back pain, which both improved after conversion. The median HHS was 75.0 (range: 44.7-99.4) and the Trendelenburg test was positive in 5 patients. 6 patients had heterotopic ossification without limitation in joint range. 9 patients confirmed they would undergo the operation again. CONCLUSION: Arthrodesis ofthe hip was a reasonable treatment option for young patients with monoarticular hip disease.

Technical note: dimensionless ray transference.

The ray transference matrix completely characterises the first-order optical nature of an optical system including the eye. It is in terms of the transference that quantitative analyses (for example, calculation of an average eye) can be performed. However, the fact that the entries of the transference do not have the same physical dimensions precludes the calculation of the usual scalar value (a Frobenius norm for example) for a change or difference between two optical systems. The purpose of this note is to show how to use the wavelength of the light as a natural unit of length to define a dimensionless transference and so make it possible to calculate a meaningful norm. In most practical applications, some components of the dimensionless transference may dominate unreasonably in the resulting norm in which case suitably weighted norms may be more appropriate. In an appendix, some of the issues are illustrated by application to a lens.

Relation between anterior and posterior converter systems.

A corrected or uncorrected human eye may be astigmatic and noncoaxial. The first-order (i.e., paraxial) character of arbitrary astigmatic and noncoaxial optical systems can be compared quantitatively in terms of the ray transference of either an anterior or a posterior converter system. This article derives equations that give the relationships between the transferences of the anterior and posterior converter systems.

The cost of treating systemic fungal infections.

The increasing incidence of systemic fungal infections and rising medical costs have highlighted the need for an economic appraisal of antifungal agents to determine the most cost-effective therapeutic option. Cost savings derived from the prophylactic or empirical use of antifungal agents have been difficult to estimate because of the lack of information on the costs of systemic fungal infections. Fluconazole is effective in prophylaxis and represents a direct cost saving compared with polyenes. However, itraconazole oral solution, an effective and widely used antifungal prophylactic agent, has not been analysed for cost effectiveness. In empirical therapy, the development of new formulations of existing agents has prompted a number of cost comparisons. In particular, the cost of treatment with conventional amphotericin-B has been compared with the costs of the new lipid-associated formulations of amphotericin-B or the new intravenous (IV) formulation of itraconazole. The acquisition costs of lipid-associated amphotericin-B and IV itraconazole are higher than the cost of conventional amphotericin-B; however, these costs appear to be offset by reductions with both these agents in the cost for increased length of hospital stay and treating adverse events seen with conventional amphotericin-B. In neutropenic patients and bone marrow transplant recipients, IV itraconazole may be the most cost-effective option for empirical therapy.

Comparing optical systems, and the concept of the converter system.

The purpose of this article was to present a complete and general method for comparing the first-order optical character of optical systems. The method provides a common basis for quantifying the difference between systems of all kinds including thin lenses, ophthalmic prisms, eyes before and after accommodation, eyes before and after refractive surgery, etc. Systems may be astigmatic or stigmatic, coaxial or noncoaxial. In special cases, the method reduces to being equivalent in essence to ostensibly incommensurate comparisons implicit or explicit in current optometric and ophthalmological usage (difference in power for refractions, corneas, and thin lenses, difference in prismatic power for prisms, ratio of magnifications for afocal telescopes, etc.). The method uses the concept of a converter system that when placed in front of or behind one system, converts its first-order optical character to the equivalent of a second system. Equations are presented for the ray transferences of the anterior and posterior converter systems for pair-wise comparisons in general. For any two systems, the transferences of the converter systems always exist and are unique. Numerical examples are presented; they illustrate converter systems that may be thin in special cases but thick otherwise. The transference of a converter system embodies and quantifies the optical difference between systems or characterizes the change from one state of a system (presurgical or preaccommodative, for example) to another (postsurgical or postaccommodative). The method provides a rational and uniform methodology for research and clinical applications in many areas of optometry and ophthalmology.

Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes.

The role of multidrug resistance protein 1 (MRP1) in the maintenance of transbilayer lipid asymmetry in the erythrocyte membrane was investigated. The transbilayer distribution of endogenous phospholipids and [(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl (NBD)-labelled lipid analogues was compared in the absence and the presence of inhibitors of MRP1. At equilibrium the transbilayer distribution of the NBD analogues (in the absence of MRP1 inhibitors) was very similar to that of the endogenous lipids. Inhibition of MRP1 by verapamil or indomethacin resulted in a shift in the amount of probe that was internalized: approx. 50% of NBD-labelled phosphatidylcholine (PtdCho) and 9% of NBD-sphingomyelin (NBD-Spm) were no longer extractable by BSA in cells treated with inhibitor, in comparison with 25% and 3% for control cells respectively. To verify whether inhibition of MRP1 also affected the distribution of the endogenous phospholipids, phospholipase A2 and sphingomyelinase were used to assess the amount of each of the various lipid classes present in the membrane outer leaflet. No shift in phospholipid distribution was observed after 5 h of incubation with verapamil or indomethacin. However, after 48 h of incubation with these inhibitors, significantly smaller amounts of PtdCho and Spm were present in the outer membrane leaflet. No appreciable change was observed in the distribution of phosphatidylethanolamine or phosphatidylserine. Decreased hydrolysis of PtdCho and Spm was not due to endovesicle formation, as revealed by electron microscopy. This is the first report to show that MRP1 has a role in the maintenance of the outwards orientation of endogenous choline-containing phospholipids in the erythrocyte membrane.

Refractive variation under accommodative demand: curvital and scaled torsional variances and covariance across the meridians of the eye.

Autorefractor measurements were taken on the right eye of 10 students with an external target at vergences -1.00 and -3.00 D. The refractive errors in the form of sphere, cylinder, and axis were converted to vectors h and variance-covariance matrices calculated for different reference meridians. Scatter plots are drawn in symmetric dioptric power space. The profiles of curvital and scaled torsional variances, the scaled torsional fraction, and the scaled torsional-curvital correlation are shown using a polar representation. This form of representation provides a meridional pattern of variation under accommodative demand. The profile for scaled torsional variance is characteristically in the form of a pair of rabbit ears. At both target vergences curvital variance is larger than scaled torsional variance in all the meridians of the eye: the relative magnitudes are quantified by the scaled torsional fraction. An increase in accommodative demand generally results in an increase in variance. The rabbit ears usually become larger but less well divided. The correlation between curvital and torsional powers is usually positive in the first quadrant and negative in the second quadrant. Typical, atypical, and mean typical responses are discussed.

Population analysis of the non linear red blood cell partitioning and the concentration-effect relationship of draflazine following various infusion rates.

AIMS: To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition (ABI). METHODS: Draflazine was administered to healthy volunteers as a 15-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity-limited specific binding of draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach. RESULTS: The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax) was 0.385 (3.5) ng ml-1 plasma and 158 (2.1) ng ml-1 RBC, respectively. The non-specific binding was low. The specific binding to the erythrocytes was a source of non-linearity in the pharmacokinetics of draflazine. The total plasma clearance of draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml-1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml-1 and 4.47 (5.5), respectively. The RBC occupancy of draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes. CONCLUSIONS: The findings of this study show that the occupancy of the nucleoside transporter by draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting.

Population analysis of the non-linear red blood cell partitioning of draflazine following various infusion durations.

OBJECTIVE: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22-55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg.h-1) and variable duration (2-24 h). METHODS: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. RESULTS: The population typical value for the dissociation constant Kd (%CV) was 0.648 (12) ng.ml-1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng.ml-1 RBC. The interindividual variability (%CV) was moderate for Kd (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2 beta averaged 11.0-30.5 h and the mean CL from the plasma was 327 to 465 ml.min-1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2 beta was 30.2 to 42.2 h and the blood CL averaged 17.4-35.6 ml.min-1. CONCLUSION: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg.h-1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.

The implications of non-linear red blood cell partitioning for the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine.

1. Draflazine, a nucleoside transport inhibitor, was administered as a 15 min i.v. infusion of 2.5 mg to eight healthy male subjects. Plasma and whole blood concentrations were measured up to 32 h post-dose, and were related to adenosine breakdown inhibition (ABI) measured ex vivo, which served as a pharmacodynamic endpoint. 2. The red blood cell/plasma distribution of draflazine was non-linear and characterized as a capacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant Kd was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164 ng ml-1 RBC, which corresponds to about 14,000 specific binding sites per erythrocyte. Non-specific binding amounted to less than 15% of the total binding. 3. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model. The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml mm-1, volume of distribution at steady-state 39.8 +/- 4.7 l and terminal half-life 24.0 +/- 9.4 h. Concentrations in plasma were much lower, and could only be determined accurately in pooled plasma samples with a red blood cell binding assay. The pharmacokinetic parameters in pooled plasma were: clearance 551 ml min-1, volume of distribution at steady-state 349 l and terminal half-life 10.7 h. 4. A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex vivo. This relationship was characterized by the sigmoidal Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax 100%, IC50 10.5 ng ml-1 and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean +/- s.d.) Emax 92.4 +/- 5.6%, IC50 76.0 +/- 15.3 ng ml-1 and Hill factor 3.5 +/- 0.9. 5. Binding to the nucleoside transporter on red blood cells is an important determinant of the pharmacokinetics of draflazine and a high degree of occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo. It is suggested that red blood cell nucleoside transporter occupancy may serve as a useful pharmacodynamic endpoint in dose ranging studies with draflazine.

Unstimulated platelets evoke calcium responses in human umbilical vein endothelial cells.

Interactions between human platelets and human umbilical vein endothelial cells (HUVEC) were studied by monitoring changes in cytosolic [Ca2+]i in both cell types. Confluent monolayers of Fura-2-loaded HUVEC, grown on gelatin-coated coverslips, responded to repeated addition of a suspension of unstimulated platelets by transient increases in cytosolic [Ca2+]i. These platelet-evoked Ca2+ responses were not caused by products secreted from the platelets and were insensitive to inhibitors of platelet activation and/or platelet aggregation. The platelet-evoked rises in [Ca2+]i in endothelial cells, similarly as the thrombin-evoked rises, were blocked by preincubation of HUVEC with the phospholipase C inhibitor U73122 or the Ca2+ influx blocker Ni2+. In contrast, treatment with the protein tyrosine kinase inhibitor genistein was without effect. Video imaging experiments, in which the fluorescence signal was analysed from the individual cells of an endothelial monolayer, showed that only 2-20% of the cells, scattered over the monolayer, responded to the addition of platelets by a transient increase in [Ca2+]i, whereas most of the cells responded to thrombin. This leads to the conclusion that unstimulated platelets can activate HUVEC putatively by mechanical interaction with individual endothelial cells in the monolayer.

Differential tissue expression of Annexin VIII in human.

The expression of Annexins V and VIII by human lung, liver, kidney, skin, heart, uterus, spleen and skeletal muscle was investigated by ELISA. All investigated tissues contained Annexin V. Its level varied with the tissue from around 5 microgram (skin) to approximately 120 micrograms (spleen) per g of wet tissue. Contradistinctionally Annexin VIII expression was less ubiquitous and less abundant. Only lung, skin, liver, and kidney expressed Annexin VIII. Its levels were approximately 100-fold less then the Annexin V levels. Immunohistochemical analysis of lung sections revealed Annexin VIII presence exclusively in the endothelia. Annexin V and VIII levels of cultured human umbilical vein endothelial cells, human arterial smooth muscle cells, human lung fibroblasts and HeLa cells were measured by ELISA. All cell types expressed Annexin V whereas only HeLa cells had detectable levels of Annexin VIII. The results indicate a tissue specific expression of Annexin VIII by lung endothelium, suggesting a highly specialised function.