Predominance of a rare type of HIV-1 in Estonia

An earlier study has indicated that a complex recombinant HIV-1 strain dominates the epidemic in Estonia. The objective of this study was to further investigate the molecular epidemiology and genetic structure of HIV-1 in Estonia. Most of the investigated individuals became infected after August 2000 when HIV-1 started to spread rapidly among Estonian intravenous drug users (IDUs). Two viral DNA regions, gag/pol and gp41, were sequenced and subtyped from peripheral blood mononuclear cells or plasma from 141 individuals. Phylogenetic analysis in the gp41 region revealed that the most frequent type of the virus among IDUs was a circulating recombinant form, CRF06_cpx, whereas a few samples showed highest sequence similarity to a subtype A strain circulating in Ukraine and Russia. Likewise, in the gag/pol region, most of the samples were classified as CRF06_cpx, with a few classified as subtype A. In this region, however, 16% of the sequences turned out to be mosaic unique recombinant forms consisting of CRF06_cpx and subtype A. At least 9 mosaic forms were identified, each with distinct patterns of multiple crossover. To characterize Estonian CRF06_cpx as well as recombinant isolates in more detail, 4 near-full-length HIV-1 genomes were sequenced.     

Cytokine removal in septic patients with continuous venovenous hemofiltration

Despite the progress that has been made in intensive care medicine, multiple organ failure is still associated with high mortality. Apart from the prevention of infectious complications, numerous efforts are being made to improve the treatment of sepsis through adequate antibiotic therapy, the development of new respirator therapies, better control of the hemodynamic situation, and adequate renal replacement therapy. Some authors advocate continuous renal replacement therapy not only for acute renal failure but also for the elimination of inflammatory molecules such as cytokines. Continuous renal replacement therapy improves the cardiovascular hemodynamics in patients with multiple organ failure. Therapeutic options such as volume control, clearance of uremic toxins, correction of acid base disturbances and temperature control are improved. Suitable renal replacement therapy improves not only cardiovascular hemodynamics but also patient survival. In current practice, continuous renal replacement therapy is not used to eliminate mediators such as cytokines. In patients with multiple organ failure and compromised cardiovascular hemodynamics, renal replacement therapy should be carried out as early as possible. In the following review, experimental and clinical findings concerning mediator elimination by continuous and intermittent renal replacement therapy are summarized.     

Dopamin in „Nierendosis“ beim akuten Nierenversagen – Wirksamkeit eindeutig widerlegt

Ohne Zusammenfassung     

Antidepressant-like effect of agmatine is not mediated by serotonin

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light-dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.     

Determinanten zirkulierender Nitrat (NO3)-Plasmaspiegel bei septischen Patienten: Parenterale Ern?hrung, Nierenfunktion und kontinuierlich venoven?se H?mofiltration (CVVH)

Hintergrund Im tierexperimentellen Modell der Sepsis kann über den NO₃-Plasmaspiegel die sepsis-assoziierte Induktion der NO-Synthase (iNOS) nachgewiesen werden. Bei Menschen liegen darüber bisher uneinheitliche Ergebnisse vor, da die Nitrat (NO₃)-Konzentration im Plasma beim Menschen durch eine Vielzahl iNOS-unabh?ngiger Einflussfaktoren determiniert wird. Untersuchungen über den quantitativen Einfluss dieser einzelnen Faktoren lagen bisher nicht vor. Methoden In einer prospektiven Studie mit 424 Patienten unserer Intensivstation mit insgesamt 2274 Beobachtungstagen wurde der Einfluss der Ern?hrungsform, der renalen Funktion und der Einfluss einer kontinuierlich venoven?sen H?mofiltration auf den NO₃-Plasmaspiegel untersucht. Alle Patienten, die in dem Beobachtungszeitraum von acht Monaten auf unserer internistischen Intensivstation aufgenommen wurden, wurden prospektiv in die Studie aufgenommen. Entsprechend der qualitativen und quantitativen Auspr?gung der zu untersuchenden Parameter, wurden die Patienten bestimmten Subkollektiven zugeordnet. Jeder Patient wurde t?glich mittels eines Sepsis-Score auf das Vorhandensein und den Schweregrad eines septischen Schocks bewertet, die Ern?hrungsform und die Durchführung einer kontinuierlich venoven?sen H?mofiltration wurden t?glich dokumentiert und es wurden t?glich die Serumkreatininwerte und die NO₃-Plasmakonzentration der Patienten bestimmt. Ergebnisse Bei konstantem Sepsis-Score führte die alleinige Umstellung der Ern?hrungsform von oral auf parenteral bei 29 Patienten zu einem signifikanten Abfall der NO₃-Plasmaspiegel um 36%, von 62±9μmol/L auf 40±7μmol/L. Umgekehrt zeigte eine Umstellung von parenteral auf oral bei 96 Patienten einen signifikanten Anstieg der Nitratkonzentration um 30%, von 37±6μmol/L auf 53±8μmol/L. Eine Korrelation der Kreatininwerte der Patienten (p=159, n=318) mit den entsprechenden NO₃-Plasmaspiegeln ergab eine signifikante Abh?ngigkeit (r=0,71; p<0,0001). Bei Einleitung einer kontinuierlich venoven?sen H?mofiltration (CVVH) fielen die NO₃-Spiegel unter CVVH signifikant um 44% ab. Schlussfolgerung Die NO₃-Plasmaspiegel beim Intensivpatienten werden ganz entscheidend zum einen über die Ern?hrungsform und zum anderen über die Nierenfunktion determiniert. Dieses sollte bei der Wertung einer ?nderung des Plasmaspiegels von Nitrat als m?glicher Index einer Induktion der NO-Synthese bei Sepsis-Patienten Berücksichtigung finden.     

Treatment of experimental osteomyelitis with antibiotic-impregnated bone graft substitute

The model of Norden was used to induce osteomyelitis in the left tibia of New Zealand White rabbits. Twenty-one days following inoculation, the animals had primary debridement and then were randomized into one of three treatment groups. Group I received no additional treatment; in Group II, plain hydroxyapatite beads were packed into the defect; and in Group III, gentamicin crobefat-loaded hydroxyapatite beads were packed into the defect. The animals were observed for 40 days after the primary debridement and then were killed. The intensity of infection was determined by swab cultures and quantitative bacterial cultures of the debrided material. At primary debridement, all of the animals in each group were equally infected. At the time of secondary debridement, only the animals in Group III had a statistically significant reduction in infection (p < 0.001). In this study, we demonstrated that an antibiotic-loaded osteoinductive ceramic bead can effectively eliminate bacteria from an osteomyelitic cavity.     

Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

A series of potent and highly selective time-dependent monocyclic beta-lactam inhibitors of human polymorphonuclear leukocyte elastase (PMNE, EC 3.4.21.37) is described. The intrinsic potency of these compounds, as exemplified by L-680,833 (k(inactivation)/K(i) of 622,000 M-1.s-1), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product A alpha-(1-21) from the A alpha chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC50 of 0.06 microM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of A alpha-(1-21) and PMNE-alpha 1-proteinase inhibitor complex formation with IC50 values of 9 microM. Pharmacokinetic studies indicate that after oral dosing L-680,833 is bioavailable in rats and rhesus monkeys. This oral bioavailability is reflected by the inhibition (i) of tissue damage elicited in hamster lungs by intratracheal instillation of human PMNE and (ii) enzyme released from human PMN stimulated after their transfer into the pleural cavity of mice. The properties of L-680,833 allow it to effectively supplement the activity of natural inhibitors of PMNE in vivo, suggesting that this type of low-molecular-weight synthetic inhibitor could have therapeutic value in diseases where PMNE damages tissue.     

Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery

High molecular weight biomolecules are becoming more and more important in the development of new therapeutic drugs. However, the hydrophilic nature of such molecules creates a major limitation for their application--poor penetration through biological membranes. In 1994, a new class of peptides--cell-penetrating peptides (CPPs)--was discovered. CPPs seem to greatly facilitate the delivery of hydrophilic macromolecules over the plasma membrane, both in vitro and in vivo, and show promise for therapeutic purposes. One such example--suppressor of cytokine signalling 3 protein--was shown to act as an effective inhibitor of acute inflammation in vivo owing to its successful delivery by CPPs.     

Distribution and fate of 2-C14-glucose in the liver fluke,Fasciola hepatica L., after short in vitro incubation

Summary Adult stages of Fasciola hepatica L. were incubated in 2-C¹⁴-glucose for 10 minutes. The distribution and fate of C¹⁴ was followed by microautoradiography and paper electrophoresis and paper chromatography in combination with autoradiography. It was found that C¹⁴ accumulated predominately in the parenchyme and in the suckers. Within the fluke C¹⁴ was found in high molecular weight compounds like glycogen and in acids belonging to the citric acid cycle. These acids were not observed in the incubation medium. Labelled compounds behaving like amino acids were found both in the fluke and in the incubation medium.

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Zusammenfassung Erwachsene Stadien von Fasciola hepatica L. wurden in 2-C¹⁴-Glucose 10 min lang inkubiert. Verteilung und Schicksal des C¹⁴ wurden mittels Microautoradiographie und Papierelektrophorese und Papierchromatographie kombiniert mit Autoradiographie studiert. C¹⁴ wurde insbesondere im Parenchym und in den Saugnäpfen angereichert. C¹⁴ fand sich in hoch molekularen Verbindungen wie Glykogen und in Säuren des Citronensäurezyklus. Diese Säuren wurden nicht in dem Inkubationsmedium gefunden. Markierte Verbindungen mit Eigenschaften wie Aminosäuren wurden sowohl in dem Leberegel wie in dem Inkubationsmedium nachgewiesen.

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Supported by a grant A 1460/B 1110 from Jordbrukets Forskningsr»d.