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The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection.To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773.The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg).Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ).The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.

A latitudinal frequency cline observed for the two alleles B 1 and B 2 at the IDH- B enzyme locus in European silver fir suggested the existence of a correlation between the associated north-south temperature gradient and the thermostability of the two alloenzymes. B 1 prevailed in the northern and B 2 in the southern populations. Thermostability of an enzyme is defined by the length of time the enzyme can endure a given temperature without suffering damage (denaturation) that reduces its catalytic efficiency below a specified threshold; the threshold is specified by the visibility of activity in the zymogram. Using extracts from endosperms of homozygous trees incubated under various temperatures and followed by electrophoresis, it turned out that the B2 distinctly exceeds the B1 alloenzyme in thermostability in trees from both extremes of the fir transect. Supported by observations made in other species, it is concluded that catalytic activity and thermostability are negatively correlated for this enzyme locus. Based on this relationship, the observed IDH polymorphism is argued to be the result of adaptation to high temperature regimes.

The photoadmittance of a two-step charge transfer sequence with chemisorbed intermediate on semiconductor electrodes has been treated, taking explicitly into account the nonlinear adsorption kinetics. A prominent example of this reaction type is the hydrogen evolution reaction. A significantly different partial charge transfer of m -type in the consecutive steps of the hydrogen reaction has been evaluated, in three independent ways. A numerical simulation of the two-step photoadmittance provides estimates of rate coefficients and adsorption parameters. Admittance phenomena in dark reactions are briefly considered.

This paper reviews results of studies on genetic variation in various European coniferous and angiosperm tree species, with emphasis on Picea abies and Pinus sylvestris, Abies alba, Fagus sylvatica, and Castanea sativa. Most of the studies employ enzyme gene markers, but terpenes and other markers are also used. The comparison of data is complicated due to the variety of measures of genetic variation that are reported. Nevertheless, substantial differences in intra- and interpopulational genetic variation can be observed among and also within species. Causes for such heterogeneity are briefly discussed. The necessity for monitoring genetic variation and for standardizing measurement of genetic variation is emphasized.

We compared, in a cross-over study, the toxicity of 300 mg enteric-coated aspirin with regular aspirin used for the prevention of cardiovascular events. In terms of endoscopic haemorrhagic lesions, enteric-coated aspirin is less gastrotoxic than regular aspirin.

The sickle cell trait-asymptomatic carriage is frequent in people originating from sub-Saharan Africa. Several host factors (including sickle cell anemia) have been previously reported to act upon the course of HIV disease. We studied the progression of infection in a cohort of African patients heterozygous for the sickle hemoglobin gene and harboring normal hemoglobin genes. No significant difference was evidenced between the two groups from this preliminary study.

AIM: Aripiprazole (ABILIFY ® ) is an effective antipsychotic used in a dose range from 10 to 30 mg, administered once daily. Soon after its approval in Germany for treatment of schizophrenia, a 12-month post-marketing surveillance study was initiated that included 1 096 patients cared for by 408 office-based psychiatrists and/or neurologists in private practice. The aim was to gain further insights into safety and efficacy of aripiprazole in an outpatient real-life setting focusing on general health, well-being and psychosocial functioning. PATIENTS AND METHODS: Efficacy was rated by using standard CGI, SF-12 ® and SIWM-PsySo ® instruments for severity of disease, physical and mental health outcomes and psychosocial state, respectively. Safety was evaluated according to the reports of adverse events. Mean total daily dose of aripiprazole increased from 15.4 mg at the visit after 1 month to 17.6 mg at the visits after 6 to 12 months, the most frequently administered maintenance dose being 15 mg. RESULTS AND DISCUSSION: Within the observation period significant improvements of CGI, SF-12 ® and SIWM-PsySo ® scores over time versus baseline values were observed (p

Bei ca. 5% aller Schwangeren entwickeln sich nach der 20. SSWo Zeichen der Praeklampsie. Hypertonie und Proteinurie sind nur 2 Symptome einer Multiorgankrankheit, die weltweit eine Hauptursache mutterlicher Morbiditat und Mortalitat darstellt. Eine Vielzahl pradisponierender Faktoren ist bekannt. Hierzu zahlt die erworbene Thrombophilie bedingt durch Antiphospholipid Antikorper/Lupusantikoagulanz. Diese lassen sich bei ca. 20% der betroffenen Frauen, die vor der 34. SSWo eine Praeklampsie entwickeln nachweisen. Ob auch die hereditaren Risikofaktoren, z.B. FV-Leiden- und Prothrombinmutation, eine klinische Relevanz bei dieser Fragestellung haben, ist umstritten, da diese Gene nicht in allen Populationen gleich verteilt sind. Es existiert eine Vielzahl von Theorien zum Pathomechansimus der Erkrankung. Im Vordergrund steht die endotheliale Dysfunktion mit Schadigung und Freisetzung von gerinnungsaktiven Substanzen aus dem Endothel sowie der Thrombozytenaktivierung mit der konsekutiven Ausbildung von Mikrothromben. Es kommt zur Imbalance zwischen Prostaglandinen zur Vasodilatation und Vasokonstriktion durch ein Thromboxan-Uberangebot. An diesem Punkt setzt die Wirkung von Azetylsalicylsaure ein, durch die Hemmung der Thromboxansynthese in den Thrombozyten. Im Verlauf der Schwangerschaft kann eine Vielzahl von Veranderungen, die physiologisch im Gerinnungssystem auftreten, gemessen werden. Aus einem isolierten Wert den Ubergang zu einer pathologischen Gerinnungsaktivierung abzuleiten, ist bisher nicht sicher moglich. Wichtig ware es hier Parameter zu haben, die Wochen vor dem Auftreten der klinischen Zeichen einer Praeklampsie bereits pathologisch verandert sind, so dass ein fruhzeitiges Erkennen gefahrdeter Frauen moglich ist, oder die zur Abschatzung eines Wiederholungsrisikos beitragen konnen. Seit wenigen Jahren wird uber vasoaktive Cytokine berichtet, die auch die plazentare Gefasentwicklung steuern. PLGF (placental growth factor) konnte ein entsprechender Marker sein. Dargestellt wird, welche (Gerinnungs-)analytik zu welchem Zeitpunkt sinnvoll durchgefuhrt werden kann.

Routinedaten in der Psychiatrie sind im Bereich der ambulanten vertragsarztlichen Versorgung rar gesat. Dies hat unter anderem etwas zu tun mit der Sektorisierung in der ambulanten psychiatrisch-psychotherapeutischen Versorgung die der Tabelle 1.3 zu entnehmen ist.

The genetic implications of plus-tree selection were studied in Norway spruce (Picea abies) with the aid of isozyme gene markers. For this purpose, 45 phenotypically selected seed orchard clones and 60 randomly chosen trees from the same Bavarian forest districts were compared with respect to their genetic structure, gene diversity and heterozygosity at eight enzyme gene loci. In general, the gene frequency distributions, the gene multiplicity and the gene diversity did not significantly differ between the selected clone (plus-tree) collection and the random tree sample; however, the average degree of heterozygosity and the distribution of individual heterozygosity clearly differed between the two collections. The most significant differences in heterozygosity between the two collections were observed in the case of three loci controlling enzymes involved in the pentose phosphate cycle. The implications of these results for tree improvement procedures, establishment of seed orchards and programmes in gene conservation are discussed.

The role of the hypothalamus (HTH) in the pathogenesis of genetic hypertension was studied in spontaneously hypertensive rats (SHR). It is currently believed that, in this strain, the genetic defect manifests itself mainly in the HTH. We examined this hypothesis by grafting HTH neurons from embryos of SHR or control Wistar Kyoto (WKY) rats into the HTH of adult normotensive WKY rats. Changes in host systolic blood pressure (SBP) were monitored, and alterations in vasoactive intestinal polypeptide (VIP) gene expression of the host brain were studied. In rats grafted with HTH tissue from SHR embryos (G- SHR), the blood pressure rose by 31% as compared with that in the grafted control group. The blood pressure climbed gradually over a period of 6 weeks to its highest level, which was maintained for at least 3 months following grafting. Along with the elevated blood pressure, the heart weight increased by 80% compared to controls. Behavioral changes were also evident in the G-SHR rats, and these were similar to those of the native SHR strain. In situ hybridization histochemistry showed a 40% elevation in VIP transcripts in the suprachiasmatic nucleus of the host G-SHR brain compared to controls. These studies demonstrate that transplantation of embryonic SHR HTH tissue into brains of adult normotensive rats results in the development of hypertensive characteristics in the host. It thus appears that the HTH is a prime candidate for the source of changes leading to spontaneous hypertension in mammals.

The p-nitrophenylethylsulfonyl and methoxycarbonylethylsulfonyl group are alternative 2′-OH protecting groups in oligoribonucleotide synthesis. The corresponding, more reactive 3′-0-(B-cyanoethyl, N, N-diethy1)phosphoramidites have to be applied in solid-phase synthesis to achieve high yields and short coupling times.

The clinical diagnosis of ocular toxoplasmosis is based on clinical features and biological tests: polymerase chain reaction (PCR) and the determination of intraocular specific antibody secretion (Goldmann-Witmer coefficient) on aqueous humor. Older patients may have a higher prevalence of ocular involvement and more severe ocular disease during the acute phase of recently acquired systemic infection because of altered cell-mediated immunity. Moreover, the genotype of the infecting parasite (particularly involving neotropical Type I Toxoplasma gondii strain), appears to be an important determinant of disease severity.

The diagnosis of antiphospholipid syndrome is based on clinical symptoms and is verified by laboratory testing. The spectrum of clinical symptoms includes not only arterial or venous thrombosis, a variety of neurological manifestations as well as pregnancy associated complications have been defined as relevant for the diagnosis. This article discusses the complexity of laboratory testing, problems of its standardisation and interpretation of test results. Progress and limitations of laboratory analysis are compared and the clinician will learn to read lab results with caution.

To move from a chemical entity to a real drug, preclinical trials have to be followed by phase I human studies to evaluate human toxicity, phase II studies to demonstrate the pharmacological activity in healthy volunteers and patients, followed by phase III studies to evaluate the real therapeutic efficacy. Then new drug authorization is granted for a product that shows good pharmaceutical quality and a positive risk-benefit ratio. However, full knowledge of a new drug is available only after several years of clinical use.

Die Abrechnungsmoglichkeiten nach dem Einheitlichen Bewertungsmasstab (EBM) und der Gebuhrenordnung fur Arzte (GOA) folgen einer unterschiedlichen Systematik. Im EBM sind besondere Komplexziffern zu berucksichtigen, um kein Geld zu verschenken. Eine praxisspezifische Liste mit den eigenen Abrechnungsziffern schafft uberblick.

The quality of a therapeutic trial depends on several parameters. The ideal trial in prostate cancer should be a high-quality trial on a well-defined and significant population. The method used to calculate the number of subjects necessary should appear in the study. There should be a single and significant evaluation criterion and follow-up should be long given the natural history of the disease. Intention to treat is also a quality terion. Finally, the therapeutic class effect does not exist; therefore, the efficacy of inoma any new drug must be proven.

The new treatments of orphan diseases must be assessed according to the methodologic rules of therapeutic trials, in order to ensure clinically and statistically significant evaluations: randomized controled trials, single primary end-point, statistically significant and clinically relevant efficience. Although these rules may be relaxed in orphan diseases, they have to maintain the standard of therapeutic efficiency.

The distribution of genetic variation at nine enzyme gene loci in the European range of silver fir is studied with the aim to characterize the genetic basis of this species' adaptive potentials. For this purpose, the basic notions of physiological and evolutionary adaptive potential are briefly discussed in connection with operating and latent genetic potentials of populations. A measure for the quantification of latent genetic potential is introduced together with a procedure that evaluates the detective power of the samples taken. The results obtained from application of this measure are in striking accordance with earlier suggestions based chiefly on ecophysiological traits, and which assume both low physiological and evolutionary adaptive potential in the central and northeastern European populations of silver fir. Moreover, careful consideration of the structural and functional characteristics of the enzymes used in the present study support the assumption that they are not selectively neutral, and in one case it can indeed be demonstrated that the two alleles at a locus are very likely to be under selection for temperature differences between central and southern European populations.

Atrial fibrillation (AF) is the most frequent sustained arrhythmia. After restoration of normal sinus rhythm, the recurrence rate of AF is high. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear.To determine, in patients who recovered sinus rhythm after AF, the effect of long-term treatment with antiarrhythmic drugs on death, stroke and embolism, adverse effects, pro-arrhythmia and recurrence of AF. If several antiarrhythmics were effective our secondary aim was to compare them.The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Libary (Issue 2, 2005), MEDLINE (1950 to May 2005) and EMBASE (1966 to May 2005) were searched. The reference lists of retrieved articles, recent reviews and meta-analyses were checked. No language restrictions were applied.Two independent reviewers selected randomised controlled trials comparing any antiarrhythmic with a control (no treatment, placebo or drugs for rate control) or with another antiarrhythmic, in adults who had AF and in whom sinus rhythm was restored. Post-operative AF was excluded.Two reviewers independently assessed quality and extracted data, on an intention-to-treat basis. Disagreements were resolved by discussion. Studies were pooled, if appropriate, using Peto odds ratio (OR).45 studies met inclusion criteria, comprising 12,559 patients. All results were calculated at 1 year of follow-up. Class IA drugs (disopyramide, quinidine) were associated with increased mortality compared with controls (OR 2.39, 95% confidence interval (CI) 1.03 to 5.59, P = 0.04, number needed to harm (NNH) 109, 95% CI 34 to 4985). Other antiarrhythmics did not modify mortality. Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of AF (OR 0.19 to 0.60, number needed to treat 2 to 9), but all increased withdrawals due to adverse affects (NNH 17 to 36) and all but amiodarone and propafenone increased pro-arrhythmia (NNH 17 to 119).Several class IA, IC and III drugs are effective in maintaining sinus rhythm but increase adverse events, including pro-arrhythmia, and disopyramide and quinidine are associated with increased mortality. Any benefit on clinically relevant outcomes (embolisms, heart failure, mortality) remains to be established.

To evaluate the ability of two graphologists and two practising internists not trained in graphology to differentiate letters written by subjects who have attempted to commit suicide by self-poisoning and healthy volunteers, we performed a maximal blind controlled study vs. healthy volunteers. Forty fully recovered patients who had attempted to commit suicide and 40 healthy volunteers wrote and signed a short letter or story not related to the parasuicide or their mental health status. The evaluators classified the 80 letters as 'suicide' or 'no suicide' in an intention-to-treat analysis. Letters expressing sadness were subsequently excluded for a per-protocol analysis. Correct diagnosis of suicide and of healthy controls was made in, respectively, 32 of 40 and 33 of 40 letters by the graphologists and in 27 of 40 and 34 of 40 letters by the internists. After the exclusion of 12 letters expressing sadness, the sensitivity, specificity, positive predictive value and negative predictive value were, respectively, 73, 88, 81 and 82% for the graphologists and 53, 89, 80 and 71% for the internists. Both classified the letters with significantly more effectiveness than chance (p0.001) with no statistically significant difference between the two groups of evaluators. We concluded that graphological analysis is able to differentiate letters written by patients who attempt suicide from those written by healthy controls. This technique shows an acceptable degree of accuracy and could therefore become an additional discharge or decision-making tool in Psychiatry or Internal Medicine.

Troponin is now the gold standard for the diagnosis of myocardial infarction. Aiming at improving the management of a patient suspect of an acute coronary syndrome, this article will point the interpretation of troponin dosages according to the clinical presentation and concomitant diseases.First, the interest of troponin dosage as compared with other markers of myocardial ischemia will be underlined. Then, the literature available about troponin in cardiovascular diseases but also in extracardiac diseases will be analysed. Finally, the difficulties of assay will be discussed.The availability of a sensitive and specific marker such as troponin is definitively a progress in the management of patients with an acute coronary syndromes. But it remains a biological contribution to the global management of the patient. It is important to know the causes susceptible to increase the levels of troponin to avoid a wrong interpretation of the dosage, leading to diagnostic but also therapeutic mistakes.

In the outpatient treatment of depression, the potential of diagnostic and therapeutic methods is seldom exhausted resulting in variable quality of treatment and partly insufficient cost effectiveness. Implementation of a guideline-oriented reimbursement system seems to be an option to improve quality of treatment. Corresponding incentive systems have been outlined and evaluated for the health care of somatic diseases such as diabetes. Acting on these experiences, an attempt was made to utilize them for the area of psychiatric disorders. Taking depression as an example, a model for a quality-oriented, guideline-based reimbursement system for general and specialist practice is presented.

Disruptions of glutamate- and Ca2+-dependent signal cascades are critical steps underlying “excitotoxic” cell damage in different forms of neurodegenerative disease, including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis (ALS). Recent investigations have provided increasing evidence that a highly interactive network of proteins and organelles precisely controls the spatio-temporal profile of [Ca2+]i and — accordingly — the activation pattern of “downstream” excitotoxic cascades. This network displays a substantial cell-to-cell variability, which might partially explain the profound heterogeneity in neuronal damage induced by a given insult. The cellular basis of this “selective neuronal vulnerability” has been studied in great detail in mouse models of ALS, which are characterized by a highly selective degeneration of motoneurons in the brain stem and spinal cord. Comparative studies between vulnerable and resistant cells demonstrated the critical importance of Ca2+ buffering, diffusion and uptake for neuronal vulnerability. As more detailed information becomes available, it might become feasible to develop novel neuroprotective strategies based on a targeted “stabilisation” of Ca2+ homeostasis in selectively vulnerable systems. The future potential of such strategies will be discussed.

Today we have certain knowledge about a number of hereditary factors which change the hemostatic balance of their carriers towards a tendency to develop venous thrombo-embolism. Typically the first Manifestation occurs frequently without any recognizable cause at a young age and in the Majority of cases as thrombotic occlusion of the deep veins of the lower extremities. Pulmonary embolizations as life-threatening complications May be observed in young patients. Furthermore a Marked tendency to recurrent thrombotic events exists.