Thoracic impedance pneumography in propofol-sedated patients undergoing percutaneous endoscopic gastrostomy (PEG) placement in gastrointestinal endoscopy: A prospective, randomized trial.

STUDY OBJECTIVE: To assess the efficacy of an ECG-based method called thoracic impedance pneumography to reduce hypoxic events in endoscopy. DESIGN: This was a single center, 1:1 randomized controlled trial. SETTING: The trial was conducted during the placement of percutaneous endoscopic gastrostomy (PEG). PATIENTS: 173 patients who underwent PEG placement were enrolled in the present trial. Indication was oncological in most patients (89%). 58% of patients were ASA class II and 42% of patients ASA class III. INTERVENTIONS: Patients were randomized in the standard monitoring group (SM) with pulse oximetry and automatic blood pressure measurement or in the intervention group with additional thoracic impedance pneumography (TIM). Sedation was performed with propofol by gastroenterologists or trained nurses. MEASUREMENTS: Hypoxic episodes defined as SpO2 < 90% for >15 s were the primary endpoint. Secondary endpoints were minimal SpO2, apnea >10s/>30s and incurred costs. MAIN RESULTS: Additional use of thoracic impedance pneumography reduced hypoxic episodes (TIM: 31% vs SM: 49%; p = 0.016; OR 0.47; NNT 5.6) and elevated minimal SpO2 per procedure (TIM: 90.0% ± 8.9; SM: 84.0% ± 17.6; p = 0.007) significantly. Apnea events >10s and > 30s were significantly more often detected in TIM (43%; 7%) compared to SM (1%; 0%; p < 0.001; p = 0.014) resulting in a time advantage of 17 s before the occurrence of hypoxic events. As a result, adjustments of oxygen flow were significantly more often necessary in SM than in TIM (p = 0.034) and assisted ventilation was less often needed in TIM (2%) compared with SM (9%; p = 0.053). Calculated costs for the additional use of thoracic impedance pneumography were 0.13$ (0.12 €/0.11 £) per procedure. CONCLUSIONS: Additional thoracic impedance pneumography reduced the quantity and extent of hypoxic events with less need of assisted ventilation. Supplemental costs per procedure were negligible. KEY WORDS: thoracic impedance pneumography, capnography, sedation, monitoring, gastrointestinal endoscopy, percutaneous endoscopic gastrostomy.

Hepatitis C viral dynamics during ribavirin priming differ according to prior treatment response and HCV type.

The mode of action of ribavirin is not completely understood. Ribavirin monotherapy has a measurable antiviral effect, which shows great variability. It might lead to an earlier steady state of plasma concentration and therefore enhance the effect of following combination treatment. The aim of this study was to evaluate the antiviral effect of ribavirin priming and its influence on sustained virologic response after combination treatment in a group of patients with different hepatitis C virus (HCV) types with or without prior treatment experience. Retrospective analysis of 75 patients (37 treatment naïve, 20 prior relapse, 16 prior nonresponse, genotype 1 present in 60 patients) from five centres who received ribavirin priming as part of an individual strategy in order to improve treatment outcome. All patients received ribavirin monotherapy with a mean dose of 14.5 mg kg-1 body weight for a mean of 28 days. After ribavirin priming, dual combination treatment with pegylated interferon alfa and ribavirin was started. The mean HCV RNA decline after ribavirin priming was 0.6 log10  IU mL-1 (P<.001). The initial viral decline depended on HCV type and previous treatment status being highest among prior relapsers (0.8 log10  IU mL-1 ; P=.002) and HCV type 2/3 (1.2 log10  IU mL-1 ; P=.05) and lowest among those with prior nonresponse (0.3 log10  IU mL-1 , P=.01). IFNL4 (formerly IL28B) genotype for rs12979860 and IFNL3 genotype rs8099917 did not influence the initial viral decline. The study demonstrates a significant variability in the viral dynamics and antiviral efficacy of ribavirin monotherapy, which is mainly influenced by prior treatment status. The fact that the lowest response pattern was observed in prior nonresponder patients to pegylated interferon alfa plus ribavirin combination therapy can be taken as a hint that not only the individual interferon, but also the ribavirin sensitivity contributes significantly to the nonresponsive state.

Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection.

Ribavirin amplifies the interferon-alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)-IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy on viral kinetics, on-treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty-eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG-IFN2a (PEG-IFN2a arm) for 6 weeks prior to 12 weeks of PEG-IFN2a/ribavirin combination therapy within a double-blind, placebo-controlled trial. Then, standard PEG-IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG-IFN2a at a dose of 180 µg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of -0.58 log10  IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG-IFN2a-induced first- or second-phase viral decline (P values >0.100) nor on-treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG-IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG-IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy did neither increase the first- or second-phase viral decline nor on-treatment response or SVR.

Effect of ribavirin on the frequency of RNase L cleavage sites within the hepatitis C viral genome.

The mechanisms of synergy in antiviral activity of interferon-alpha and ribavirin in treating chronic hepatitis C virus (HCV) infection are still unknown. Interferon-alpha indirectly induces cleavage of viral RNA by RNase L at UU/UA dinucleotides. There is evidence that HCV genomes with a higher number of UU/UA dinucleotides are more sensitive to interferon-alpha. As a guanosine analogue, ribavirin exerts a mutagenic effect promoting G-to-A and C-to-U transitions. This study investigates whether ribavirin-induced mutagenesis causes a higher frequency of UU/UA dinucleotides in the viral progeny sequences. Increased mutational frequencies in favour of G-to-A and C-to-U transitions during ribavirin treatment was reported by Hofmann et al. (Gastroenterology 2007;132:921-930). Overall, 937 nucleotide sequences from that publication were reanalysed for RNase L cleavage sites. These included HCV NS3 quasispecies from three patients with ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone (n = 7) or in combination with interferon-alpha (n = 7) at baseline and during treatment; NS5B quasispecies from a subgenomic HCV replicon system after 24, 48 and 72 h of cultivation with or without ribavirin or with levovirin. For NS3 quasispecies during ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone or in combination with interferon-alpha, analysis of RNase L cleavage sites did not reveal changes during treatment or differences between treatment regimes. Similarly, RNaseL cleavage sites from NS5B quasispecies of the HCV replicon did not differ significantly between time points or treatments. In conclusion, Ribavirin-induced mutagenesis did not increase RNase L cleavage sites (UU/UA dinucleotides) within the HCV NS3 or NS5B encoding regions.

Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon alpha and ribavirin therapy.

The importance of osteoporosis as a complication of end-stage liver disease is well known. However, significant osteopenia may occur in earlier stages of chronic hepatitis C (CHC). Furthermore, antiviral therapy may influence bone metabolism. Thirty patients with CHC genotype 1 infection and without established cirrhosis were treated with peginterferon-alfa and ribavirin. Dual-energy x-ray absorptiometry was performed at baseline, after 48 weeks of therapy, and by the end of a 24-week follow-up period. Bone mineral density (BMD), T-scores, and Z-scores were assessed. Serum C-terminal propeptide of type I collagen (CICP) and osteocalcin levels were measured. Thirteen patients had osteopenia (43%) and osteoporosis was present in four patients (13%). Antiviral therapy led to significant on-treatment increases of lumbar spine and hip BMD (P < or = 0.05) as well as T-scores (P < or = 0.05) and Z-scores (P < or = 0.01) irrespective of subsequent treatment response. Further analyses showed that in patients with sustained virological response (n = 19) most parameters remained highly above baseline values by the end of the 24-week follow-up period, while patients with virological relapse (n = 11) had decreases of BMD, T-scores and Z-scores thereafter that did not differ from baseline. Serum CICP and osteocalcin levels decreased during therapy. Osteocalcin levels remained below baseline in sustained responder, but showed an increase in relapsers by the end of the 24-week follow-up (P < or = 0.05). Osteopenia is detectable in a substantial proportion of CHC patients without established cirrhosis. Antiviral therapy leads to an on-treatment increase of BMD, which may last in those patients who achieve a sustained virological response.

Somatic hypermutation and mRNA expression levels of the BCL-6 gene in patients with hepatitis C virus-associated lymphoproliferative diseases.

Chronic hepatitis C virus (HCV) infection leads to mixed cryoglobulinaemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Aberrant somatic hypermutation and deregulation of the oncogene BCL-6 is associated with lymphomagenesis. Recently, HCV was shown to induce BCL-6 mutations in vitro. The BCL-6 gene (area B) was cloned and sequenced from peripheral blood mononuclear cells (PBMC) of 21 chronically HCV-infected patients with or without MC and B-NHL, and six healthy controls. Mutational frequencies, genetic complexity and diversity were calculated. BCL-6 mRNA from PBMC was quantified by real-time polymerase chain reaction, and additional sustained virologic responders to antiviral therapy and HBV patients served as controls. The overall/recurrent mutational frequencies tended to be lower in MC and B-NHL patients when compared with controls (P = 0.15 and 0.06, respectively). Genetic complexity was significantly lower in MC and B-NHL patients (P = 0.025). BCL-6 mRNA concentration was decreased in all HCV patients when compared with healthy controls, sustained virologic responder and HBV patients (P = 0.005). Although HCV can induce BCL-6 mutations in vitro, lower mutational frequencies and decreased BCL-6 mRNA expression in vivo suggest no major role of aberrant somatic hypermutation in HCV-associated MC and B-NHL.

Review article: predicting response in hepatitis C virus therapy.

The introduction of combination therapy with ribavirin and of pegylated interferons has improved treatment results in patients with chronic hepatitis C. However, overall rates of sustained virologic response following antiviral therapy of chronic hepatitis C still do not exceed 54-63%. Because of several virus- and patient-related factors, treatment is even less successful in some patient subpopulations. The major viral factors associated with impaired response are hepatitis C virus genotype 1 infection and a high viral load. Among patient-related factors cirrhosis is of special importance. Baseline predictive factors for sustained virologic response become less important for prediction of treatment outcome when quantifications of hepatitis C virus RNA during early therapy are taken into account. This article provides a summary of virus- and patient-related parameters, which are prognostic for response to antiviral therapy in chronic hepatitis C and focuses on the prediction of treatment response by quantification of hepatitis C virus RNA concentration during therapy.

Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C.

In patients with chronic hepatitis C, alanine aminotransferase (ALT) levels do not accurately reflect the extent of liver inflammation. The discrepancy between ALT level and liver damage could be related to the mode of cell death. In the present study, we quantified serum levels of apoptotic cytokeratin 18 (CK-18) neoepitopes that are generated by activated caspases during apoptosis. Apoptotic CK-18 neoepitopes were quantified by enzyme linked immunosorbent assay in sera from patients with chronic hepatitis C and elevated ALT levels (n = 72), patients with chronic hepatitis C and persistently normal ALT levels (n = 27) and healthy controls (n = 19). Serum CK-18 neoepitope levels were strongly correlated with ALT (r = 0.659, P < 0.0001) and the histology activity index (r = 0.374, P < 0.001). Patients with chronic hepatitis C and persistently normal ALT levels had higher apoptotic CK-18 neoepitope levels than healthy controls (P = 0.03) but lower levels than patients with chronic hepatitis C and elevated ALT levels (P < 0.001). Highest serum CK-18 neoepitope levels were observed in patients with cirrhosis (P = 0.002). Hence apoptotic CK-18 neoepitopes in serum of patients with chronic hepatitis C are associated with ALT level and histological liver damage. Serum apoptotic CK-18 neoepitope levels are elevated both in patients with chronic hepatitis C and elevated ALT levels as well as in patients with normal ALT levels indicating that also patients with chronic hepatitis C and normal ALT have an increased hepatocyte loss by apoptosis.

Response predictors and results of a long-term treatment with lamivudine in patients with chronic hepatitis B.

INTRODUCTION: European data on outcome and follow-up of long-term lamivudine treatment are sparse. Moreover, little is known about predictors for sustained virologic response and for development of drug resistance in patients with lamivudine monotherapy. Patients and methods : 39 patients (17 HBeAg+, 22 HBeAg-) were treated with lamivudine for a median duration of 2.5 years (range: 0.5-4). Outcome to therapy and predictors for response and drug resistance were analyzed retrospectively. RESULTS: None of the patients lost HBsAg. In 14 of 17 initially HBeAg positive patients the HBeAg status was available at the end of treatment. Loss of HBeAg was observed in 8 patients and 7 of these 8 patients seroconverted to anti-HBe. Five of 6 patients with HBeAg seroconversion and a post-treatment follow-up period showed sustained HBeAg seroconversion. In HBeAg negative patients virologic response (serum HBV DNA< or =1 x 10(5) copies/ml) was observed in 12 of 22 patients after a median treatment period of 2.5 years. Post-treatment follow-up data were available in only 2 patients, one of which remained below 1 x 10(5) HBV DNA copies/ml for one year. Resistance emerged in 15 of 36 patients with available serum HBV DNA data after a median treatment period of 2 years. CONCLUSION: The present retrospective study confirms international data for lamivudine treatment in a central European setting. Lamivudine therapy achieved disease control in more than 50 % of patients treated for chronic hepatitis B. Baseline predictors could neither be identified for sustained virologic response nor for the development of drug resistance.

Proton MR spectroscopy of neurometabolites in hepatic encephalopathy during L-ornithine-L-aspartate treatment--results of a pilot study.

Hepatic encephalopathy (HE) is associated with typical changes in neurometabolites most likely being caused by an elevated systemic ammonia level. Blood ammonia is a valid over-all biomarker of HE and thus is regularly determined in clinical trials. The neurometabolites affected in HE can be assessed in vivo by proton magnetic spectroscopy. The aim of this study was to show the effect of the ammonia lowering drug L-ornithine-L-aspartate (OA) on the cerebral glutamate+glutamine/creatine (Glu+GLN/Cr) ratio. In an open clinical trial (pilot study), 15 patients with stable HE were treated with an infusion of 40 g OA over 8 h (5 g/h). Immediately before and 6-8 (mean 6.8) h after start of the infusion, spectroscopy of the parietal white matter was performed and arterial blood ammonia quantified. Glu+GLN/Cr-ratios correlated significantly with ammonia data (Spearman's correlation coefficient rs = 0.72, p < 0.001). Likewise, the OA induced changes (versus baseline before infusion) in blood ammonia level and in Glu+GLN/Cr-ratios correlated significantly rs = 0.54, p = 0.0375). Magnetic resonance (MR) spectroscopy assesses the neurometabolite variation present in HE. OA induced changes in cerebral Glu+GLN/ Cr-ratio were significantly correlated with the drug effects on arterial blood ammonia. These pilot data indicate that MR spectroscopy detects a specific biomarker of HE that may reflect the extent of the cerebral alterations associated with the disease.

[Studies to investigate the ecological importance of the mass development of Hydrodictyon reticulatum in infiltration basins for drinking water. III. Identification of the active components by the use of spectroscopic methods and gas chromatography (author's transl)]. / Untersuchungen zur ökologischen Bedeutung der Massenentwicklung von Hydrodictyon reticulatum in Trinkwasserinfiltrationsbecken. III. Identifizierung der Wirkstoffe durch spektroskopische Methoden in Verbindung mit Gaschromatographie.

Antibacterial substances from H. reticulatum, that was harvested from its natural habitat or grown under culture conditions, could be isolated by extraction with ethanol or by steam destillation from cells as well as from culture filtrate. The active substances were tested by gas chromatography, infrared spectroscopy and mass spectrometry and characterized as a fraction of saturated fatty acids. Its composition seems to depend on external circumstances or culture conditions, respectively, because it differed from experiment to experiment even in samples, harvested at the same day. The most effective acids, active, however, only against grampositive strains are the long chain unsaturated ones with 16 or 18 C-atoms, as shown by bioassay detection (Fig. 3). The C16 = 3-acid was only found in the strain LB236-1b.

[Studies to investigate the ecological importance of the mass development of Hydrodicyton reticulatum in infiltration basins for drinking water. II. Localization of the active components with the aid of thin-layer chromatography and bioassay detection (author's transl)]. / Untersuchungen zur ökologischen Bedeutung der Massenentwicklung von Hydrodictyon reticulatum in Trinkwasserinfiltrationsbecken. II. Eingrenzung der Wirkstoffe mit Hilfe von Dünnschicht-chromatographie und Bioautographie.

Thin-layer chromatogramms made from ethanol extracts of the green fresh-water alga H. reticulatum were tested by bioassay detection against several strains of Bac. subtilis. The chromatogramms were overlayed with agar, seeded with the test strains. The production of two growth-inhibiting zones could be demonstrated (Fig. 1). One of them seems to be correlated with chlorophyll derivatives. The second zone--larger than the first one--was formed by a fatty acid fraction which was more active in cells harvested in 1973, than in those harvested in 1974. Only a very small cell free zone was found in bioassays of water extracts of H74, presumably caused by chlorophyll derivatives, but there was an area of weak inhibition in H73 as well as in H74.

[Influence of atmospheric aerosol materials on microorganisms (author's transl)]. / Zur Wirkung des atmosphärischen Aerosols auf Mikroorganismen.

The concentration of microorganisms showed variations over a wide range. As factors influencing their viability meteorological parameters as relative humidity and temperature were recognized. Furthermore there are other antimicrobial compounds in the air. For their demonstration the aerosol was collected on air filters and then extracted in aqueous solutions. Their examinations showed that there are geographic and seasonal dependences of the antimicrobial activity of the aerosol.

[A simple climatic chamber for testing air filters 2. Communication: adjustment of relative humidity (author's transl)]. / Eine einfache Klimakammer zur Untersuchung von Luftfiltern 2. Mitteilung: Regulierung der relativen Luftfeuchte

A climatic chamber for laboratory use is constructed using unexpensive materials. The relative humidity is to be adjusted between 20% and nearly 100% by regulation of the water temperature in the humidifier. The temperature range is 20-40 degrees C. As there are to be done experiments with air filter samples under practical conditions the system is enabled to work up 75 m3 of fresh air per hour. In comparison to commercially available apparatus the system described may be easily modified to fit the geometrical and experimental conditions.

[Colorimetric cleck of the working dilutions of disinfectants on an aldehyde and phenol basis (author's transl)]. / Kolorimetrische Kontrolle der Gebrauchsverdünnungen von Desinfektionsmitteln auf Aldehyd- und Phenolbasis

The applicability of 2 colour reactions were tested for the monitoring of the working concentration of disinfectant solutions containing aldehyde or phenol. The red coloration of Schiff's acid solution (Schiff's reagent to aldehydes) can be used with limitations. The formation of a red dye by the reaction of phenols with 1-phenyl-2,3-dimethyl-4-amino-pyrazolone-(5) in the p-esence of alkali and potassium hexacyano-ferrate (III) is unequivocal and is not influenced by contaminations in the water. Evaluation is made in either case by comparison with standard dilutions of the respective commercially available preparation. The samplest procedure for this a visual colour comparison in test tubes with calibration spectrum. Pyrazolone dye can be analysed photometrically. Thus this colour reaction can be regarded as an analytic method of satisfactory accuracy. A frequent monitoring of the disinfectant concentrations by means of simple chemical procedures is expected to help limit the improper use of disinfectants and to check hospital infections.

[Heavy metal content in sediment samples taken from drinking-water reservoir (author's transl)]. / Untersuchungen über den Schwermetallgehalt im Sediment einer Trinkwassertalsperre

Sediment samples were taken from the small preliminary catchment basin of the Wahnbachtal reservoir at Siegburg, extracted under mild conditions with nitric acid and hydrogen peroxide and analysed for their content of heavy metals. The sediment sample of the most recent date showed the highest concentrations of metal, that of older date revealed lower values, but by far the lowest metal content was found in the clay of the former valley. The high metal contents in the sediment are not only to be attributed to human influence but are primarily caused by the lead and zinc ores in the catchment area. The hygienic significance of these results is to be seen in the remobilization processes which could lead to an undesirable increase of metal concentrations in the raw water fed to the drinking water treatment plant.

[Glass fibre HEPA filters. II. Communication: Microbiological and physico-chemical researchs on used and unusued, hydrophilic and hydrophobic filter materials in an air conditioning plant (author's transl)]. / Glasfaser-HEPA-Filter. II. Mitteilung: Mikrobiologische und physikalisch-chemische Untersuchungen an gebrauchtem und ungebrauchtem, hydrophilem und hydrophobem Filtermaterial in einer Klimaanlage

Hydrophobic and hydrophilic, used and unused HEPA filters from various manufacturers, inoculated with vegetative bacteria, bacterial and fungal spores, were exposed to clean outside air for up to 17 weeks in an air conditioning plant. With relative humidities up to 60%, an increase in germ count could not be found. The rate of killing the micro-organisms inoculated were different and were generally higher on used filters. The low water content of the filter material was apparently not sufficient for microbial growth. In addition, the increase in electric conductivity and reduction of pH value resulting from deposition of substances from the outside air with an acid reaction ascertained in the aqueous filter extracts had a negative effect on the living conditions of the microorganisms.

[Glass fibre HEPA filters. I. Communication: Microbiological and physico-chemical researchs on used and unused, hydrophobic and hydrophilic filter materials at relative humidities up to 98% in the climatic test chamber (author's transl)]. / Glasfaser-HEPA-Filter. I. Mitteilung: Mikrobiologische und physikalisch-chemische Untersuchungen an gebrauchtem und ungebrauchtem, hydrophobem und hydrophilem Filtermaterial bei relativen Feuchen bis zu 98% in der Klimakammer

1. At high humidities up to 98%, an increase in bacteria cannot be detected. This applies to all HEPA filters investigated from the various manufacturers, independent of whether they are hydrophilic or hydrophobic, used or unused. 2. Fungal growth can only be obtained when large amounts of nutrient material (e.g. bacterial cultures) are present. In these cases a streaky growth appears . Under normal conditions of use, however, such intense contamination is not to be expected because of the prefiltration. Penetration only occurs with fungi. 3. Limitation of supply air humidity to 90% or less seems therefore to be unjustified on the basis of these investigations, if prefiltration and a satisfactory intermixing section can be guaranteed technically, and condensation is avoided. 4. HEPA filters of Grade S from various manufacturers and with different behaviour with respect to water do not allow bacterial growth even in the presence of nutrients. Additional measures for the killing of bacteria are therefore not considered necessary.