[Hemophagocytic lymphohistiocytosis in critically ill patients]. / Die hämophagozytische Lymphohistiozytose bei kritisch kranken Patienten.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome. In adults, secondary HLH is mostly observed. HLH is often triggered by infections, malignancies or autoimmune disorders. However, HLH cases in association with immunotherapies have been described recently. HLH in critically ill patients is often difficult to differentiate from sepsis. Both conditions can also be present at the same time. Early diagnosis and timely initiation of an adequate immunosuppressive therapy are essential for the further course and the prognosis of HLH. Therefore, HLH should represent a differential diagnosis in critically ill patients with persistent fever and additional symptoms (e.g. enlarged spleen, neurologic symptoms) or laboratory parameters (e.g. hyperferritinemia, cytopenia, increased transaminases) compatible with HLH. The diagnosis of HLH is made using the HLH-2004 criteria. The probability of the presence of HLH can be calculated using the HScore. High-dose corticosteroids represent the cornerstone of HLH treatment. Etoposide, immunoglobulins, anakinra or other drugs are added depending on the trigger. The course of HLH is influenced by the time of treatment initiation, the underlying trigger and the response to treatment. Generally, the prognosis of critically ill HLH patients is poor.

Personalized risk prediction of postoperative cognitive impairment - rationale for the EU-funded BioCog project.

Postoperative cognitive impairment is among the most common medical complications associated with surgical interventions - particularly in elderly patients. In our aging society, it is an urgent medical need to determine preoperative individual risk prediction to allow more accurate cost-benefit decisions prior to elective surgeries. So far, risk prediction is mainly based on clinical parameters. However, these parameters only give a rough estimate of the individual risk. At present, there are no molecular or neuroimaging biomarkers available to improve risk prediction and little is known about the etiology and pathophysiology of this clinical condition. In this short review, we summarize the current state of knowledge and briefly present the recently started BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), which is funded by the European Union. It is the goal of this research and development (R&D) project, which involves academic and industry partners throughout Europe, to deliver a multivariate algorithm based on clinical assessments as well as molecular and neuroimaging biomarkers to overcome the currently unsatisfying situation.

[Hemophagocytic lymphohistiocytosis : A diagnostic challenge on the ICU]. / Hämophagozytische Lymphohistiozytose : Diagnostische Herausforderung auf der ITS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T­cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease. Missed or late diagnosis is believed to be a major cause of the high mortality. OBJECTIVES: To describe the current knowledge on HLH and to raise awareness. MATERIALS AND METHODS: Analysis of case reports, current studies, and expert recommendations. RESULTS: Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with a clinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. A promising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. CONCLUSIONS: Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.

A dual-channel gas chromatography method for the quantitation of low and high concentrations of NF3 and CF4 to study membrane separation of the two compounds.

A dual-channel gas chromatographic method is described in this paper that can be conveniently used for quantitation of NF3/CF4 mixtures with a thermal conductivity detector (TCD) on one channel for the quantitation of high-concentrations, and a pulsed discharge helium ionization detector (PDHID) on a second channel for the quantitation of low concentrations. It is shown that adequate separation is achieved on both channels with this dual single-column setup in which column switching as used for NF3/CF4 analysis in industrial chromatographic methods are not required, thus yielding an effective analysis method for laboratory-scale investigations. In addition, the use of packed columns with purified divinylbenzene-styrene co-polymers as the sole stationary phase yields satisfactory resolution between NF3 and CF4 at isothermal conditions of 30°C, with elution times of less than 8min on the TCD channel and less than 4min on the PDHID channel. Consequently, this method allows for reliable, straight-forward quantitation of NF3/CF4 mixtures, which is necessary when studying the commercially important problem of NF3 and CF4 separation by different methods. Therefore, the applicability of the method to studying membrane separation of NF3 and CF4 is briefly discussed and illustrated, for which the dual-channel setup is especially beneficial.

Sodium iron (III) ethylenediaminetetraacetic acid synthesis to reduce iron deficiency globally.

Despite major interest in sodium iron (III) ethylenediaminetetraacetic acid's (EDTA) potential use in food fortification programs in potentially curbing the global problem of iron deficiency and its anemia, synthesis methods of stable isotope-labeled sodium iron (III) EDTA for use in human bioavailability studies are incomplete, incorrect or totally lacking. Owing to a number of clinical research groups requiring this compound in bioavailability studies, in both developing and already developed countries, we simplified and optimized the synthesis of sodium iron (III) EDTA from a block of isotopically enriched iron metal, in order that it be easily reproduced, cheaply, using simple basic laboratory apparatus. The resulting product is of high purity (>99.0%), and may be used for human stable isotope bioavailability studies. The simplicity of this method allows for the many research groups, currently doing such studies, to perform their own syntheses. Additionally, more uniformity in this synthesis will reduce the variation observed between such studies.

[The pharmacokinetics of the S35 labeled labeled garlic constituents alliin, allicin and vinyldithiine]. / Untersuchungen zur Pharmakokinetik der mit 35S markierten Knoblauchinhaltsstoffe Alliin, Allicin und Vinyldithiine.

Three groups of 3 rats received oral doses (8 mg/kg) of garlic constituents (alliin, allicin and vinyldithiines (2-vinyl-[4H]-1,3-dithiine and 3-vinyl-[4H]-1,2-dithiine)) in the form of an oil macerate of the 35S-labeled substance. The measured activity was referred to 35S-alliin (35S-alliin equivalents). The blood activity levels in each group were monitored for 72 h. For 35S-allicin and the labeled vinyldithiines the excretion with the urine, feces, and exhaled air was also measured. The distribution among the organs (whole-body autoradiography) and the urinary metabolite pattern (thin-layer chromatography) were also determined. For 35S-alliin the blood activity profile differed considerably from those of 35S-allicin and the labeled vinyldithiines: both the absorption and the elimination of the radioactivity were distinctly faster than for the other garlic constituents, maximum blood levels being reached within the first 10 min and elimination from the blood being almost complete after 6 h. For the other garlic constituents the maximum blood levels were not reached until 30-60 min (35S-allicin) or 120 min (vinyldithiines) p.a. and blood levels > 1000 ng-Eq/ml were still present at the end of the study after 72 h. The mean total urinary and fecal excretion after 72 h was 85.5% (35S-allicin) or 92.3% (labeled vinyldithiines) of the dose. The urinary excretion indicates a minimum absorption rate of 65% (35S-allicin) or 73% (vinyldithiines). It is uncertain whether the 19-21% recovered in the feces was unabsorbed substance or had been excreted via the bile or intestinal mucosa. The exhaled air showed only traces of activity although the whole-body autoradiographs, after fairly long exposure (96 h), showed distinct enrichment of activity in the mucosa of the airways and pharynx. The activity is deposite mainly in the cartilage of the vertebral column and ribs. There was no detectable difference in organ distribution between 35S-allicin and the labeled vinyldithiines. All that could be established from the urinary metabolite pattern was that unchanged 35S-allicin and unchanged labeled vinyldithiines are absent. There is therefore extensive metabolization. The metabolites must have a very polar structure with acid functional groups since satisfactory separation was achievable only with acid solvent systems. Conjugates with sulfuric or glucuronic acid were not detectable. These results reveal no differences in pharmacokinetic behavior between 35S-allicin and the labeled vinyldithiines. A final verdict as to whether the metabolites, which may be pharmacologically active, are identical must await further studies designed to identify the metabolites.

Absorption, tissue distribution and excretion of radiolabelled compounds in rats after administration of [14C]-L-alpha-glycerylphosphorylcholine.

The kinetics and metabolism of L-alpha-glycerylphosphoryl-choline (alpha-GPC) were investigated in male and female rats after i.v. (10 mg/kg) and oral doses (100-300 mg/kg). alpha-GPC was labelled with [14C]-glycerol ([14G]-GPC) or [14C]-choline ([14C]-GPC). Different kinetic and metabolic profiles were observed after i.v. and oral administration. It is assumed that alpha-GPC is hydrolyzed by phosphodiesterases in the gut mucosa. The different labelled metabolites have different kinetic properties of absorption, distribution and clearance, leading to different blood concentration-time curves of total radioactivity. Both labelled compounds gave a wide distribution of radioactivity, particularly concentrated in the liver, kidney, lung and spleen compared to blood. Brain concentrations of [14C]-GPC were comparable to ([14G]-GPC) or lower than ([14C]-GPC) total blood radioactivity. The metabolite profile in the perfused brain showed a small amount of choline and two unknown metabolites, probably the same as in blood. In addition, choline was incorporated into brain phospholipids in increasing amounts within 24 h of dosing. In all cases renal and fecal excretion of radioactivity was low and comparable for [14G]-GPC and [14C]-GPC. Mostly the administered radioactivity was exhaled as 14CO2, this degradation being faster and more pronounced for the glycerol-labelled metabolites than for the choline-labelled metabolites for both routes of administration. In all cases the results were the same for male and female rats.

[Methodical studies of transmucosal oxygen partial pressure measurement in the calf and dog]. / Methodische Untersuchungen zur transmukösen Sauerstoffpartialdruckmessung an Kalb und Hund.

Transcutaneous PO2-measurement has been thought being non practicable in veterinary medicine. Consequently, the measuring method has been slightly modified. PO2 was taken from the mucous membrane of the lower surface of tongue. This has been practised in 6 dogs and 10 calves. We achieved a significant correlation between transmucosal and arterial PO2, taken simultaneously in each animal. Considering these results the use of transmucosal measurement may be recommended for a trend-measuring in anesthesized animals. Nevertheless, there has to be pointed out that transmucosal PO2 has to be interpreted regarding its complexity.

Pharmacokinetics and metabolism of 14C-oxaceprol in beagle dogs after intramuscular and oral administration.

Blood and plasma levels and renal and faecal excretion of 14C-oxaceprol (N-acetyl-4-hydroxyproline, AHP 200) were measured after p.o. and after i.m. administration to 3 male Beagle dogs each. In addition, the concentration of 14C-oxaceprol equivalents in synovia was determined at tmax and at tmax + t1/2(elim.). The pattern of metabolites was investigated for plasma, synovia, and urine samples. Peak plasma levels were obtained for the individual animals between 20 and 30 min after i.m. administration and between 2 and 2.5 h after p.o. administration, respectively. The concentrations of 14C-oxaceprol equivalents in synovia 2.5 and 3.5 h after oral administration and 1.3 h after i.m. administration were comparable to the respective plasma levels at the same time. After oral administration the amount of absorbed oxaceprol varied between 43 and 79% of the dose. Oxaceprol was exclusively eliminated via the kidneys. Excretion was complete within 72 h p.a. for both administration routes. Elimination half-lives were 44 +/- 9 min. or 68 +/- 14 min. (means +/- S.D.) after i.m. and p.o. administration, respectively. Oxaceprol was not metabolized.

High-performance liquid chromatographic determination of ibuprofen, its metabolites and enantiomers in biological fluids.

An isocratic high-performance liquid chromatographic method to determine racemic ibuprofen (assay I) and its major metabolites (assay II) in biological fluids (plasma, urine, bile) using a conventional reversed-phase column is described. A third assay using beta-cyclodextrin as stationary phase (Cyclobond I) for the separation of the ibuprofen enantiomers is also described. A wavelength of 220 nm was used to monitor the substances. The sensitivity of the method was 0.1 microgram/ml for all three assays. The method was demonstrated to be suitable for stereoselective pharmacokinetic studies of ibuprofen in humans and animals.

[The acid-base status of venous blood and erythrocyte hemolysate in the dog]. / Untersuchungen zum Säure-Basen-Status im venösen Blut und Erythrozytenhämolysat beim Hund.

Determination of intracellular acid-base status is reported in this paper by the example of erythrocytic haemolysate in dog. The difference between intracellular and extracellular acid-base ratios is highly significant and is of clinical relevance. Differences between species and the need for further experimental verification of the method are discussed in some detail. Reference values are suggested for orientation, on the basis of 20 experimental dogs.

[Comparative studies of the acid-base status in venous, capillary and mixed blood from the ear of the dog]. / Vergleichende Untersuchungen zum Säure-Basen-Status im venösen, kapillären und gemischten Blut aus dem Ohr des Hundes.

Ten experimental dogs were tested in twelve experimental arrangements, with a view to finding out the extent to which results of acid-base determination or blood gas analysis could be significantly affected by induced hyperaemia of the ear or by the choice of a site for blood collection, including puncture of an ear vein. No difference was secured. Hence, ear vein puncture may be used to collect so-called capillary blood. Reference is made to the author's own values for use as criteria.

[The fat mobilization syndrome in guinea pigs (Cavia porcellus L.)]. / Untersuchungen zum Fettmobilisationssyndrom am Meerschweinchen (Cavia porcellus L.).

Feeding experiments were applied to 82 guinea pigs, different by age, sex, and stage of reproduction, and showed that high-energy feeding and subsequent feed withdrawal could trigger off with high probability a fat mobilising syndrome with clinically manifest ketosis in animals in gravidity and lactation or subclinical ketosis in all non-gravid individuals. High-energy or restrictive feeding alone did not cause in guinea pigs any disease along the lines of gravidity toxicosis. Aspects relating to aetiological and pathogenetic comparability with ruminants are discussed in some detail.

Temperature-dependent structural rearrangement of apotryptophanase in potassium phosphate.

Apotryptophanase (L-tryptophan indole-lyase, EC 4.1.99.1) from Escherichia coli B/1t7A shows, in the presence of potassium phosphate, a temperature-dependent structural rearrangement which is not observed in the presence of sodium phosphate or imidazole plus KC1. This rearrangement can be described by a two-state equilibrium between two forms of the apoenzyme. The midpoint temperature of the rearrangement (TM) and the van't Hoff enthalpy (delta H) at different potassium phosphate concentrations and pH values, respectively, were determined by measuring the temperature-dependence of the ultraviolet absorbance of apotryptophanase. Increasing the potassium phosphate concentration at pH 7.8 causes a simultaneous increase in total absorbance and the delta H value, whereas the TM increases between pH 7.0 and 7.8 but starts to decrease at pH values above 7.8. In 0.1 M potassium phosphate at the pH optimum of the enzyme (7.8) TM and delta H were found to be 293.1 K and 167 kJ X mol-1, respectively. Moreover, the tyrosine residues of apotryptophanase dissociate in potassium phosphate and in imidazole plus KCl with pK values of 8.6 and 9.8, respectively, indicating that potassium phosphate favors the formation of tyrosinate. The rearrangement might be interpreted as the formation of specific hydrogen bonds between tyrosine and potassium phosphate which are ruptured at higher temperature. Such hydrogen bonds cannot be formed at all or only to a small extent in the presence of imidazole plus KCl or sodium phosphate. Those hydrogen bonds stabilize the structure of apotryptophanase. In contrast, holotryptophanase requires only K+ for enzymatic activity.