Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

Surveillance and epidemiology of syphilis,gonorrhoea and chlamydia in the non-European Union countries of the World Health Organization European Region, 2015 to 2020

BackgroundEpidemics of sexually transmitted infections (STI) are a major public health challenge in the World Health Organization (WHO) European Region.AimWe aimed to provide an overview of case reporting and other surveillance data for syphilis, gonorrhoea and chlamydia for the non-European Union (EU)/European Economic Area (EEA) countries of the Centre and East part of the WHO European Region as per classification used by the WHO Regional Office for Europe (WHO/Europe) and the European Centre for Disease Prevention and Control.MethodsData were provided by the surveillance agencies of the Member States for the period 2015 to 2019 through the WHO/Europe Communicable Diseases Annual Reporting Form. We analysed reported cases, explored data reported to the WHO Gonococcal Antimicrobial Surveillance Programme (GASP) and performed a review of publications on antimicrobial resistance (AMR) in gonorrhoea in the period 2015 to 2020 using systematic methodology.ResultsFrom 2015 to 2019, in most of the countries with three or more data points, there was a pattern of decrease in reported syphilis, gonorrhoea and chlamydia cases, which is in contrast to the EU/EEA. The number of reported cases per 100,000 population was 0.4–26.5 for syphilis, 0–18.5 for gonorrhoea and 0–43.3 for chlamydia. Four countries reported recent data on AMR in gonorrhoea to GASP, and we identified further publications from Georgia, Russia and Ukraine.ConclusionWe found wide heterogeneity in reported rates of STI. There is a strong need to improve availability and quality of STI surveillance data in the non-EU/EEA countries.     

COAT platelets

PURPOSE OF REVIEW: COAT platelets are a recently described subpopulation of cells resulting from simultaneous activation with collagen and thrombin. The complete process by which COAT platelets are produced is still not clear, although significant recent progress has been made. RECENT FINDINGS: COAT platelets retain several procoagulant proteins on their surface by a previously unrecognized mechanism involving transglutaminase mediated conjugation of serotonin to released alpha-granule proteins. Fibrinogen and thrombospondin have been found to bind serotonin-conjugated proteins and thereby provide the requisite link for stabilization of serotonin-derivatized, procoagulant proteins on COAT platelets. SUMMARY: Multivalent interactions, resulting from traditional receptor interactions and binding of conjugated serotonin by fibrinogen and thrombospondin, result in exceptionally strong retention of procoagulant alpha-granule proteins on the surface of COAT platelets. The physiologic significance of this new subclass of platelets remains to be determined.     

Neuropharmacological evaluation of diethylether extract and xanthones of Gentiana kochiana

Diethylether extract of aerial parts of Gentiana kochiana mostly consists of two tetraoxygenated xanthones: gentiacaulein (1,7-dihidroxy-3,8-dimethoxyxanthone; 76.1%) and gentiakochianin (1,7,8-trihidroxy-3-methoxyxanthone; 14.2%). The extract and these xanthones were evaluated for the CNS pharmacological activity in rodents. In vitro assays on rat brain preparations revealed insignificant interaction of the compounds with the specific dopamine and serotonin receptors or synaptosomal uptake of serotonin. However, the extract and gentiacaulein strongly inhibited rat microsomal MAO A (IC50=0.22 microg/ml and 0.49 microM, respectively). Their effects on MAO B and a gentiakochianin blocking potential on both MAO enzymes were moderate. Behavioral examinations on mice showed that 10 day s.c. administration of the extract (20 mg/kg) significantly decreased immobility score in a forced swimming test and strongly inhibited ambulation and stereotypy in an open-field test. These effects resembled those induced by 10 mg/kg imipramine. The ex vivo MAO A activity in crude brain mitochondrial fraction of mice treated with 20 mg/kg of the extract was significantly elevated, whilst that outside brain nerve terminals was declined. This study suggests some antidepressant therapeutic potential of G. kochiana, particularly of gentiacaulein, with an ambiguity whether pharmacological mechanism could be related only to the central inhibition of MAO A.     

Structural encoding of body and face in human infants and adults

Most studies on visual perception of human beings have focused on perception of faces. However, bodies are another important visual element, which help us to identify a member of our species in the visual scene. In order to study whether similar configural information processing is used in body and face perception, we recorded high-density even-related potentials (ERPs) to normal and distorted faces and bodies in adults and 3-month-old infants. In adults, the N1 responses evoked by bodies and faces were similar in amplitude but differed slightly in latency. The voltage topography of N1 also differed in concordance with fMRI data showing that two distinct areas are involved in face and body perception. Distortion affected ERPs to faces and bodies similarly from N1 on, although the effect was significant earlier for bodies than for faces. These results suggest that fast processing of configural information is not specific to faces but it also occurs for bodies. In 3-month-old infants, distortion decreased the amplitude of P400 around 450 msec, showing no interaction with image category. This result demonstrates that infants are not only able to recognize the normal configuration of faces, but also that of bodies. This could either be related to an innate knowledge of this particular type of biological object, or to fast learning through intense exposure during the first months of life.     

Reactions after pneumococcal vaccine alone or in combination with influenza vaccine

We studied adverse reactions to immunisation in 541 individuals receiving simultaneous pneumococcal and influenza vaccination, and in 320 recipients of pneumococcal vaccine alone. Five days after immunisation, the participants completed a questionnaire covering systemic and local reactions to vaccination. Adverse effects were rated as mild if they did not interfere with the participant's daily activities, and moderate or serious if they moderately or markedly restricted these activities. There were no differences between the groups regarding general malaise, headache, myalgias and elevated body temperature. Redness at the injection site, but not soreness or swelling, occurred more frequently in individuals immunised simultaneously with both vaccines. Except for fever and local swelling, adverse reactions were significantly more frequent in women than in men in study groups. The rate of adverse reactions was higher in individuals less then 65 years of age than in older participants. Local reactions were reported by 358 (41.6%) participants, but they were mild and soon subsided. No serious reactions were reported. pneumococcal and influenza vaccine can be safely administered simultaneously.