Predicting solute partitioning in lipid bilayers: Free energies and partition coefficients from molecular dynamics simulations and COSMOmic.

Quantitative predictions of biomembrane/water partition coefficients are important, as they are a key property in pharmaceutical applications and toxicological studies. Molecular dynamics (MD) simulations are used to calculate free energy profiles for different solutes in lipid bilayers. How to calculate partition coefficients from these profiles is discussed in detail and different definitions of partition coefficients are compared. Importantly, it is shown that the calculated coefficients are in quantitative agreement with experimental results. Furthermore, we compare free energy profiles from MD simulations to profiles obtained by the recent method COSMOmic, which is an extension of the conductor-like screening model for realistic solvation to micelles and biomembranes. The free energy profiles from these molecular methods are in good agreement. Additionally, solute orientations calculated with MD and COSMOmic are compared and again a good agreement is found. Four different solutes are investigated in detail: 4-ethylphenol, propanol, 5-phenylvaleric acid, and dibenz[a,h]anthracene, whereby the latter belongs to the class of polycyclic aromatic hydrocarbons. The convergence of the free energy profiles from biased MD simulations is discussed and the results are shown to be comparable to equilibrium MD simulations. For 5-phenylvaleric acid the influence of the carboxyl group dihedral angle on free energy profiles is analyzed with MD simulations.

Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

[Bilateral medial rectus recession with posterior fixation suture for large infantile esotropia]. / Beidseitige Medialis-Rücklagerung mit Fadenoperation bei großer frühkindlicher Esotropie.

BACKGROUND: Surgery for infantile large angle esotropia is not uniform. Bilateral medial rectus recession (BMR), combined recess-resect procedure, also combined with simultaneous contralateral medial rectus recession or secondary other procedures are common. Alternatively, bilateral medial rectus recession with posterior fixation suture (BMRF) has been used. We analysed the effect of BMRF for this specific indication. PATIENTS AND METHODS: We undertook a retrospective evaluation of squint angles in simultaneous (S) and alternating (A) prism cover test before and 3 months after BMRF with and without additional oblique muscle surgery as primary surgery for esotropia ≥ 20° performed at our department between 1997 and 2009, as well as the rate of second procedures. RESULTS: Sixty-one children (0.5 % of all patients who received eye muscle surgery during the same time interval) were included. Medians (10 % and 90 % quantiles) were: age at surgery 48.4 months (23.6; 76.0), refraction (spherical equivalent)2.25 dpt (0.25; 5.50), posterior fixation 5.5 mm + 13.0 mm (12.5; 13.0) from limbus, recession 5.0 mm (4.0; 5.0), inferior oblique recession in 29 children (27 bilateral), preoperative squint angles at 5 m S/A 29° (20; 40), at 0.3 m S/A 35° (24; 45), postoperative at 5 m S 0° (-6; 10), A 2° (-6; 11), at 0.3 m S 1° (-5; 12), A 3.5° (-5; 13), S ≤ 5° in 70.2 % at 5 m and 60.3 % at 0.3 m, consecutive exotropia 6-10° and > 10° in 7.0 and 3.5 % at 5 m and 8.6 and 1.7 % at 0.3 m, residual esotropia 6-10° and > 10° in 10.5 and 8.8 % at 5 m and 13.8 and 15.5 % at 0.3 m. Seven children (11.5 %) were re-operated for esotropia, four for exotropia (6.6 %). CONCLUSION: Bilateral medial rectus recession with retroequatorial myopexy (Cüppers procedure) is an effective one-step procedure for large infantile esotropia. In roughly two-thirds of the cases, the squint angle was corrected within ±â€Š5° with one surgery, which is similar to reported success rates of BMR.

The use of echocardiography as a health assessment tool in green sea turtles (Chelonia mydas).

There are limited techniques available to assess the health of sea turtles as physical examination has little correlation to clinical findings, and blood reference intervals are broad and provide limited prognostic significance. Advances in the portability of ultrasound machines allow echocardiography to be increasingly used in the health assessments of wild animals. This study performed blood analysis and echocardiograms on 11 green sea turtles upon admission to a rehabilitation clinic and six animals before release. Significant differences were seen between groups, with admission animals having significantly smaller diameters of the cavum arteriosum at systole and diastole, smaller E-waves and an increased fractional shortening. Pre-release animals displayed significant increases in the maximum blood velocities of both the pulmonary artery and the left aorta. Significant negative correlations were seen between fractional shortening and uric acid and between the velocity time integral of the pulmonary artery and urea. The pulmonary artery velocity time integral was also significantly correlated to the E wave. Furthermore, there was asynchrony between the cavum arteriosum and the cavum pulmonale and the detection of a parasitic granuloma in the ventricular outflow tract of one animal. Overall, the results suggest that cardiac function in stranded green sea turtles is significantly impaired and that echocardiography has applications in the health assessments of green sea turtles.

Effect of antiviral therapy on circulating cytokeratin-18 fragments in patients with chronic hepatitis C.

Hepatocellular apoptosis plays a major role in the pathogenesis of chronic hepatitis C. It can be measured noninvasively by determining the circulating levels of cytokeratin-18 fragments. We hypothesized that the effect of antiviral therapy on this parameter will be different in patients with a sustained virological response, relapse (REL) and nonresponse (NR). We quantified cytokeratin-18 fragments in plasma of patients participating in the Swiss Hepatitis C cohort, who received antiviral therapy without stopping because of sides effects. A total of 315 patients were included, 183 with a sustained response, 64 with NR and 68 who relapsed. Mean levels ±SD of circulating cytokeratin-18 fragments before therapy were 174 ± 172 U/L for responsders, 188 ± 145 for nonresponders and 269 ± 158 U/L for patients who relapsed. The values were significantly higher in the REL group (ANOVA P < 0.006). A sustained response was associated with a significant improvement of the plasma levels (94 ± 92 U/L, paired test P < 0.000001), whereas there was no improvement in the nonresponder group (183 ± 158 U/L) and in the relapser group (158 ± 148 U/L). There was a weak correlation between alanine aminotransferase (ALT) and cytokeratin-18 fragment levels (r² = 0.35, P < 0.000001) before therapy but not after therapy and none with hepatitis C virus (HCV) viremia. Successful antiviral therapy results in a significant decrease in circulating levels of cytokeratin-18 fragments arguing for a reduction in hepatocellular apoptosis after clearance of the HCV. Baseline cytokeratin-18 fragment levels are higher in relapsers. Correlations with ALT are weak, suggesting that these two tests measure different but related processes.

Magmatic vapor source for sulfur dioxide released during volcanic eruptions: evidence from mount pinatubo.

Sulfur dioxide (SO(2)) released by the explosive eruption of Mount Pinatubo on 15 June 1991 had an impact on climate and stratospheric ozone. The total mass of SO(2) released was much greater than the amount dissolved in the magma before the eruption, and thus an additional source for the excess SO(2) is required. Infrared spectroscopic analyses of dissolved water and carbon dioxide in glass inclusions from quartz phenocrysts demonstrate that before eruption the magma contained a separate, SO(2)-bearing vapor phase. Data for gas emissions from other volcanoes in subduction-related arcs suggest that preeruptive magmatic vapor is a major source of the SO(2) that is released during many volcanic eruptions.

Gas emissions and the eruptions of mount st. Helens through 1982.

The monitoring of gas emissions from Mount St. Helens includes daily airborne measurements of sulfur dioxide in the volcanic plume and monthly sampling of gases from crater fumaroles. The composition of the fumarolic gases has changed slightly since 1980: the water content increased from 90 to 98 percent, and the carbon dioxide concentrations decreased from about 10 to 1 percent. The emission rates of sulfur dioxide and carbon dioxide were at their peak during July and August 1980, decreased rapidly in late 1980, and have remained low and decreased slightly through 1981 and 1982. These patterns suggest steady outgassing of a single batch of magma (with a volume of not less than 0.3 cubic kilometer) to which no significant new magma has been added since mid-1980. The gas data were useful in predicting eruptions in August 1980 and June 1981.

13C-methacetin breath test as a quantitative liver function test in patients with chronic hepatitis C infection: continuous automatic molecular correlation spectroscopy compared to isotopic ratio mass spectrometry.

BACKGROUND: The (13)C-methacetin breath test (MBT) has been proposed for the non-invasive evaluation of hepatic microsomal activity. AIM: To test a new continuous breath analysis system (BreathID) in comparison with gold-standard isotopic ratio mass spectrometry (IRMS) in patients with chronic hepatitis C infection and to assess the diagnostic performance of these validation data compared with liver biopsy for the quantification of liver fibrosis. METHODS: Fifty patients at different METAVIR stages received 75 mg of (13)C-methacetin. Breath isotopic ratio was analysed over 90 min by BreathID (one sample/3 min; BreathID) and IRMS (one sample/10 min). Results were expressed as delta over baseline [DOB (%)] at each time interval and maximal DOB [DOB(max)(%)]. RESULTS: A high linear association between both methods was observed (R(2) = 0.95, P < 0.001). For all DOB and DOB(max), the limits of agreement by Bland-Altman analysis were within the predefined maximal width of s.d. <2.5%. MBT parameters in patients with high-grade fibrosis were different from patients with low-grade fibrosis (P < 0.001). CONCLUSION: The MBT obtained by an easy to operate, automated BreathID provides results comparable with standard IRMS and differentiates fibrosis grades in patients with chronic hepatitis C infection.

Solute Partitioning in Micelles: Combining Molecular Dynamics Simulations, COSMOmic, and Experiments.

The partition equilibria of solutes between micelles and an aqueous phase is a key factor in many applications. Depending on the task, many micelle-solute combinations are possible. Therefore, theoretical methods to predict the partition behavior in micellar systems are needed. Here, two predictive methods are evaluated and compared. First, it is shown how molecular dynamics simulations (MD) with the umbrella sampling method can be used to calculate free energy profiles in micellar systems. The second applied method is an extension of the COSMO-RS theory to anisotropic systems termed COSMOmic. Both methods are compared by means of free energy profiles and experimental micelle/water partition coefficients. A particular focus is on the partitioning of ionized solutes. As experimental data for partitioning in micelles especially for charged solutes is rare, partition coefficients were also determined experimentally. To get a general understanding of micelles examples of all micelle classes (classified by headgroup charge) are studied: nonionic Triton X-114 (TX114), zwitterionic miltefosine (HePC), anionic sodium dodecyl sulfate (SDS), and cationic cetyltrimethylammonium bromid (CTAB). The free energy profiles of neutral solutes obtained from MD simulations and COSMOmic are in an overall good agreement, and partition coefficients from both methods are in good agreement with experimental data. Depending on the system, the results for charged solutes show some deviations between the methods and experimental data.

The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C.

Since the discovery of hepatitis C virus it has become clear that chronic hepatitis C is a major health problem throughout the world. Because antiviral agents are of limited value in the treatment of chronic hepatitis C, research has focused on the antiviral immune response for the development of both a protective vaccine and effective immunotherapies for established chronic infection. Antiviral antibodies are present in almost all patients with chronic hepatitis C but do not seem to be virus neutralizing, probably due to the high mutational rate of viral envelope proteins. Studies on the antiviral T cell response have revealed the presence of virus-specific CD4+ helper and CD8+ cytotoxic T cells in a substantial proportion of patients with chronic hepatitis C. Recent studies describe an association between strong CD4+ T helper cell activity to certain hepatitis C virus antigens and a self-limited course of acute hepatitis C and possibly also a sustained response to treatment with interferon-alpha. Therapeutic manipulation of the virus-specific T cell response may thus develop into a new approach for prevention and treatment of hepatitis C virus infection.

Vitamin A in parenteral nutrition: uptake and distribution of retinyl esters after intravenous application.

Short-term parenteral application of vitamin A was examined in rats. Retinyl margarinate, which is chemically similar to physiological retinyl esters, was used in vitamin A-depleted rats to study uptake, distribution, and storage of retinyl esters in tissues. Vitamin A-depleted and Vitamin A-sufficient rats were infused with a micellar suspension of retinyl margarinate for 7 h and then killed at different times. Retinyl margarinate was directly taken up by all tissues examined. It appears that infusion of retinyl esters in micellar form provides a direct way to supply vitamin A to peripheral, vitamin A-dependent tissues. Therefore, a short-term infusion of retinyl esters with an emulsifier may be an effective means of preventing development of vitamin A-deficiency during long-term application of TPN, particularly in cases of liver dysfunction.

Regulation of seasonal reproductive activity in the stallion, ram and hamster.

This review considers seasonal reproduction in male animals with emphasis on the stallion, ram and hamster. The pineal hormone melatonin is the common link between photoperiod and reproduction. An increase in the daily diurnal period of melatonin secretion is associated with a decrease in GnRH release in long-day breeders, but an increase in GnRH release in short-day breeders. Melatonin influences GnRH release within or close to the mediobasal hypothalamus in rams; whereas melatonin receptors have not been found in the hypothalamus of horses. Prolactin release is positively correlated with daylength. Prolactin concentrations are consequently low during the breeding season of sheep and high during the breeding season of horses and hamsters. Prolactin stimulates testicular function in rams. Seasonal changes in GnRH release in the horse are regulated by changes in a GnRH-inhibitory opioidergic tone. Opioids are at least, in part, responsible for the decrease in testicular function during winter. An opioidergic inhibition of LH release is present during the breeding season in rams; but dopaminergic pathways inhibit LH release during long daylight hours. A dopaminergic inhibition of LH release does not exist in stallions.

Characterization of the neuraminidase of the H1N1/09 pandemic influenza virus.

In this study, we compared properties of the neuraminidase (NA) of the H1N1/2009 pandemic virus (H1N1pdm) and N1 NAs of other influenza viruses. The H1N1pdm NA was more active than NAs of seasonal H1N1 viruses, hydrolyzed Neu5Acα2-3Gal linkage as efficiently as did avian viruses and cleaved Neu5Acα2-6Gal linkage as efficiently as classical swine viruses. To assess the functional balance between heterologous NAs and pandemic virus HA, we generated four recombinant viruses that shared seven genes of A/Hamburg/5/09 and contained the NA gene from representative avian, swine and human viruses. The viruses harboring NA from avian, Eurasian avian-like swine and seasonal human viruses eluted more slowly from red blood cells, were more sensitive to neutralization by human airway mucins, and replicated less efficiently in differentiated human tracheo-bronchial epithelial cultures as compared with the viruses containing the NA of H1N1pdm and the NA of the North American classical swine virus lineage. Our data suggest that functional properties of the NA of H1N1pdm could be closer to those of classical swine viruses than to those of avian, avian-like swine and seasonal human viruses.

Treatment outcome in relation to alcohol consumption during hepatitis C therapy: an analysis of the Swiss Hepatitis C Cohort Study.

BACKGROUND: Adherence to hepatitis C treatment is influenced by alcohol as is the action of interferon; yet the clinical significance of the latter remains unclear. The aim of our study was to investigate the influence of ongoing alcohol intake on sustained viral response (SVR) rates in adherent patients receiving hepatitis C treatment. METHODS: A retrospective analysis of patients treated with antiviral therapy for hepatitis C infection who were enrolled in the Swiss Hepatitis C Cohort Study was completed. Patients were eligible for the study if they had their HCV RNA tested 6 months following treatment completion and at least one cohort follow-up visit during HCV therapy, documenting the consumed amount of alcohol. They were assigned to three groups according to the amount of alcohol consumption: group A without alcohol consumption, group B < or =24 g/d alcohol and group C >24 g/d alcohol. RESULTS: 554 patients were included. Patients with at least 80% of the scheduled cumulative dose and duration did not significantly differ between the three groups. SVR rates according to alcohol consumption were 60% for non-drinkers (group A), 57% in group B and 50% in group C. No significant negative influence from alcohol consumption during therapy was observed in the multiple regression analysis for treatment success. CONCLUSION: In this evaluation, we demonstrated comparable SVR rates in non-drinkers and in patients with daily amounts of alcohol intake up to 24 g during hepatitis C therapy.

Concepts for the treatment of adolescent patients with missing permanent teeth.

INTRODUCTION: Missing permanent teeth is observed with syndromes or is frequently hereditarily propagated in families. The treatment of these patients is a multi-task of specialists of oral surgery, orthodontics and prosthodontics. DISCUSSION: Despite functional and aesthetic considerations, the main problem of all treatment is that it had to be performed in a growing child. This article discusses the conventional and implant-driven concepts to treat patients from childhood to adolescence with selective or multiple missing permanent teeth.

Metabolism and secretion of retinol transport complex in acute renal failure.

Tissue uptake and distribution of retinol from circulatory vitamin A transport complex was studied in order to determine the origin of the increased serum retinol in rats with short-term acute renal failure. In rats with acute renal failure, serum retinol increased 37-70% within 2 h after surgery. After an injection of donor plasma containing 1.8 muCi of [3H]retinol in retinol transport complex, in rats with renal failure the ability to clear radioactivity was decreased 36% by 0.5 h and 57% by 2 h, as compared to sham-operated rats. The uptake and distribution of radioactivity by nonrenal tissues was similar in rats with acute renal failure and with intact kidneys. The lack of renal function did not alter hepatic cycling of [3H]retinol from the circulation and thus could not account for the increased serum retinol in renal failure. When hepatic release of retinol-retinol binding protein was blocked by colchicine, the up-regulation of serum retinol, normally observed in rats with acute renal failure, was abolished. Our studies provide strong evidence that kidney has an important role in maintaining serum retinol homeostasis by influencing the release of retinol-retinol binding protein from liver into circulation. Peripheral tissue uptake of circulatory retinol and hepatic cycling of nonutilized retinol are not directly influenced by the kidney.

Effect of retinoic acid and apo-RBP on serum retinol concentration in acute renal failure.

We recently demonstrated a rapid up-regulation of serum retinol-retinol binding protein-transthyretin concentration in rats with short-term acute renal failure. We examine the effect of retinoic acid and apo-retinol binding protein (apo-RBP) on the up-regulation of serum retinol in renal failure. Injection of retinoic acid (10 micrograms) into rats with acute renal failure or sham-operated rats increased circulatory retinoic acid concentration 29-fold within 2 h but did not influence serum retinol concentration in either group. Injection of a large dose of retinoic acid (100 micrograms) decreased serum retinol concentration in rats with acute renal failure (19%) and sham-operated rats (29%). These results suggest that changes in serum retinoic acid concentration within the near-physiological range have no effect on regulation of hepatic retinol release. Injection of a large dose of retinoic acid may depress serum retinol indirectly via a retinol sparing effect in target tissues. In rats with renal failure the serum retinol concentration, elevated 44-52% above that of sham-operated controls, was also increased to 70-164% above controls by the injection of 52-63 micrograms of apo-RBP. This suggests that circulatory apo-RBP can up-regulate serum retinol. Circulatory apo-RBP may be a positive physiological feedback signal from peripheral tissues for hepatic release of retinol.

Upregulation of serum retinol in experimental acute renal failure.

Serum vitamin A homeostasis was studied in rats with nonfiltering kidneys prepared by ligation of renal arteries. Within 1-2 h of acute renal failure, the serum retinol level increased by 11-73% and was maintained for at least 4 h. More than 90% of the increase in serum retinol was associated with retinol in the retinol binding protein-transthyretin (RBP-TTR) complex. The activities of acyl-CoA:retinol acyltransferase and retinyl-palmitate hydrolase were not altered by short-term acute renal failure. Oral administration of 3H-labeled retinol 3 h before surgery resulted in 350% more tritium in the serum retinol-RBP-TTR complex of rats with acute renal failure as compared to sham-operated rats; this increase represented the fraction of retinol in RBP-TTR contributed by hepatic retinol from newly absorbed 3H-labeled retinol. Total retinol in the retinol-RBP-TTR complex was increased by only 60%. We conclude that short-term acute renal failure causes rapid upregulation of serum retinol-RBP-TTR; the extent of the increase depends on the magnitude of hepatic vitamin A stores, particularly the retinol pools. We hypothesize that kidney modulates the regulation of hepatic release of retinol-RBP from the pool of newly acquired retinol.

[Serum vitamin A determinations and their value in determining vitamin A status]. / Serum-Vitamin-A-Bestimmungen und ihre Aussagekraft zum Vitamin-A-Status.

As demonstrated in the literature on vitamin A metabolism and homeostasis of retinol in serum, the concentration of retinol in serum is regulated very exactly if the liver stores are within the physiological range (20-300 micrograms/g liver). Therefore, the serum level indicates the status of vitamin A storage only if there is an extreme depletion or overconsumption of vitamin A. At marginal depletion, however, there is damage to peripheral tissue before changes in the vitamin A level in serum occur. At the beginning of hypervitaminosis A, changes in the level of vitamin A in serum also occur later. Therefore, the determination of vitamin A in serum gives no information on the adequacy of liver reserves for judging the necessity of a substitution.