A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Postpartum depression without delivering a child?

OBJECTIVE: Depression in people related to delivering women is documented in their mates, but only anecdotal in other family members. We describe a case of depression in a woman who had previously experienced postpartum depression after the birth of her nephew. METHOD: A clinical description of the case. RESULTS: A 53-year-old woman, hysterectomized at age 47 years, was admitted for attempted suicide. She developed major depressive episode 1 month after her daughter had delivered a son. She had a past history of two postpartum depressive episodes clinically identical to the current episode. The episode resolved after 5 weeks. At 1-year follow-up, the patient is still asymptomatic. CONCLUSION: Psychological and cultural factors were at play in this case more than hormonal and biopsychosocial ones.

Remission of mood disorder with psychotic features after treatment with mirtazapine.

The antidepressant mirtazapine enhances both noradrenergic and serotonergic transmission by blocking α2-adrenergic presynaptic auto- and heteroreceptors, respectively. We here report on three patients with mood disorders with psychotic features (two cases with depressive and one with bipolar disorder). Treatment with mirtazapine significantly improved not only their depression, but also their delusions. Depressive symptoms were only partially responsive and delusions unresponsive in all three patients to previous antidepressive and/or antipsychotic treatment, and only mirtazapine induced persistent improvement. These clinical cases suggest that mirtazapine can be a valid alternative for patients with depression with psychotic features and partial treatment-resistance.

Correlation between high intake of glycyrrhizin and myolysis of the papillary muscles: an experimental in vivo study.

The ingestion of large quantities of glycyrrhizin, whether as a drug or a sweetener, is known, in susceptible subjects, to induce a syndrome similar to hypermineralcorticoidism, with bouts of hypertension, hypokaliaemia and rabdomyolysis, sometimes associated with severe renal failure and hypokaliaemia-induced arrythmias. Glycyrrhizin is also known to isomerize into the glycyrrhetic (or glycyrrhetinic) acids 18alpha- and 18beta-. In previous works, we reported that these metabolites cause bouts of hypertension and reduction in diuresis at low doses in the rat. In particular, the alpha isomer causes significant elimination of the calcium ion in the urine. The present findings confirm that 18alpha-glycyrrhetic acid is more toxic than either glycyrrhizin or the beta isomer. Histopathological study of tissue samples taken from rats treated with the alpha isomer also reveal selective damage to the myocardium with oedema, myolysis, apoptosis and blistering of the sarcoplasm. These effects begin to appear in the course of subchronic treatment, they manifest themselves in acute treatment and correlate closely with the electrocardiographic changes recorded in rats acutely treated with 18alpha-glycyrrhetic acid.

In-vitro studies of two 5-nitroimidazole derivatives.

This paper reports the findings obtained using two new compounds belonging to the 5-nitroimidazole family: sulphuridazole (V1) and sulphonidazole (V2). We first assessed their antimicrobial activity on Clostridia spp. and then extended the study to Gram-positive and Gram-negative aerobic microorganisms and to Candida albicans. Their MICs were compared with those of metronidazole. The findings show that the antibacterial and antimycotic activity of sulphonidazole is greater than that of sulphuridazole, while metronidazole is not active against any aerobic organism. It also emerges that the NO2 group is indispensable for all the microorganisms assayed and that sulphuridazole and sulphonidazole are the first two 5-nitroimidazoles active against C. albicans. The redox potentials of the 5-nitroimidozoles studied suggest that their action mechanism is mainly based on redox processes.

Immunomagnetic separation and conventional culture procedure for detection of naturally occurring Salmonella in raw pork sausages and chicken meat.

The aim of the study was to compare immunomagnetic separation (IMS) and conventional selective enrichment procedures using selenite cystine broth (SC) and Rappaport-Vassiliadis broth (RV) in 137 naturally contaminated food samples (69 raw pork sausages and 68 chicken meat). The utilization of SC or IMS appeared to be the most appropriate enrichment procedure: 15 out of 18 Salmonella-positive samples (83.3%) were detected by SC and 12 (66.7%) by IMS; RV yielded only seven positive isolations (38.9%). However, RV yielded the highest count of Salmonella colonies per plate and the lowest interference by competing organisms. IMS could become a reliable alternative to standard enrichment procedures and a combined IMS and selective enrichment broth could increase the chance of Salmonella recovery.

Role of chemotherapeutic antagonism in opportunistic infections.

The most widely-known anti-tumor drugs often induce marked immunosuppression which can give rise to one or more sepses. Anti-infection measures immediately applied can sometimes prove largely ineffective or even useless, the patient dying not as a result of the spread of the tumour but as a direct consequence of opportunistic infection. We postulate that antagonism between anti-tumour and antimicrobial drugs may also play an important part in this. By way of illustration of this hypothesis, we have studied the action of a number of known inhibitors of peptidoglycan synthesis and of DNA-gyrases on certain strains of Gram-positive and Gram-negative microorganisms cultured in medium containing various concentrations of some of the best-known anti-tumour antimetabolites. The experimental data show that antimicrobial and anti-tumour drugs can sometimes induce synergic or indifferent chemotherapeutic interactions with many bacteria, while in others the effect is antagonistic. In practice, the action of the drugs could lead to bacterial selectivity, which, in conjunction with immunosuppression and the presence of resistant strains, could favour the evolution of opportunistic infection.

Influence of antimalarials chloroquine, quinine, primaquine and mepacrine on the evolution of Ehrlich ascites tumour.

Substances like imidazoles, benzimidazoles and also quinolines, whose chemical structure includes a heterocyclic nitrogen, are known to interfere with the microsomal oxidation and, in some cases, with the metabolism of drugs. Since chloroquine and primaquine exert this effect in vivo and in vitro, we studied the influence of other antimalarials (quinine and mepacrine) in mice with induced Ehrlich ascites tumour (EAT) to find out whether variations in oxygen consumption affected the course of the disease. In vitro data, obtained by a polarographic technique, indicate that primaquine and, in particular, mepacrine increase EAT-cell oxygen consumption, while in vivo data, obtained in mice injected with an inoculum of about 1 x 10(6) tumour cells per mouse, show that both drugs, but notably mepacrine, accelerate tumour growth, as monitored by Cox's statistical method for body weight, and lead to earlier death. In cases of existing neoplasia, therefore, the potentially toxic effects of certain antimalarials must be borne in mind.

Prevalence of Helicobacter-like organisms in porcine gastric mucosa: a study of swine slaughtered in Italy.

Recent reports described some cases of gastritis in man caused by an uncultured gram-negative spiral bacterium morphologically identical to organisms observed in the stomachs of mammalians (e.g. cats, dogs, pigs). The aim of the present study is to confirm the presence of these bacteria in Italian swine. Tightly spiralled organisms (Gastrospirillum suis) were found in the stomach of eight (9.4%) out of 85 pigs examined. The bacteria were always associated with macroscopic lesions indicative of gastritis. Attempts to culture H. pylori or Helicobacter-like organisms were unsuccessful. The possibility that Gastrospirillum may be a zoonotic pathogen, with transmission occurring from pigs to humans, is discussed.

In vitro activity of trimethoprim in association with sulfimidazole against aerobic gram-negative and gram-positive microorganisms and Clostridia.

The in vitro activity of a chemotherapeutic agent, sulfimidazole (SIZ), obtained by combining two molecules belonging to groups of extremely different antibacterial drugs, p-aminobenzene sulfonamide and a derivative with a 5-nitroimidazole ring, was studied. In association with trimethoprim, SIZ induces an intense synergistic antibacterial effect on gram-negative and gram-positive aerobic microorganisms and Clostridia. The results show that, in SIZ, the activity of each starting molecule remains unchanged providing that its structure-action relationship is kept intact.

Influence of glycyrrhizin on the evolution and respiration of Ehrlich ascites tumour cells.

It has been demonstrated that 18 alpha-glycyrrhetinic acid, 18 beta-glycyrrhetinic acid and glycyrrhizin effectively inhibit the inception and growth of skin tumours. Moreover, glycyrrhizin and its aglycone act on the growth and differentiation of mouse melanoma cells in culture. In this study we investigated the effect of glycyrrhizin, 18 alpha- and 18 beta-glycyrrhetinic acids on the evolution of Ehrlich ascites tumour in mice. A prolonged glycyrrhizin treatment proved to be effective in modifying the animals' survival pattern.

In situ mapping of urease-positive areas in porcine gastric mucosa.

Urease activity is a feature of gastric helicobacters, and its abundant production provides an indirect means of detecting their colonization. A method for mapping urease-positive areas directly on the gastric mucosa was developed, and 57.8% of pigs had evidence of Helicobacter colonization based on urease assay. Moreover, 89.2% of urease-positive pigs had gastritis, confirming that the known association found in man between Helicobacter and gastritis was found also in pigs. The proposed urease assay allowed detection of all urease-positive areas on the gastric mucosa, thus overcoming the biopsy sampling problems derived from the patchy distribution of helicobacters. In this way, gastric mucosa specimens from urease-positive areas could be usefully utilized for culture attempts and for microscopic examination.

Glycyrrhizin and 18 beta-glycyrrhetinic acid: a comparative study of the pharmacological effects induced in the rat after prolonged oral treatment.

Recent clinical and toxicological studies have investigated the mineralcorticoid-like and hypertensive effects of liquorice, and we therefore set out to identify the active component responsible for these effects. We conducted a 30-day comparative analysis of glycyrrhizin and 18 beta-glycyrrhetinic acid and found that the latter causes significant variations both in systolic blood pressure and in the excretion in the urine of Ca++. The effects were fully reversible on suspension of treatment.

In vitro activity of sulphimidazole alone and in association with trimethoprim against enteric pathogens.

Sulphimidazole is a new sulphonamide belonging to the class of intestinal sulphonamides and characterized by the fact that it is active even in vitro. It has the heterocyclic ring of 5-nitroimidazoles on amidic nitrogen. Its antibacterial activity is similar to that of the classical sulphonamides but differs in that it also combats certain anaerobic bacteria such as Clostridium botulinum. This effect is completely absent in the case of sulphadiazine and sulphamethoxazole. Also, since p-amino-benzene-sulphonamide is present in the molecule, the drug acts in synergism with trimethoprim against certain aerobic or facultative strains of enteric pathogens.

[Projective identification, mimesis and the analytical situation. Preliminary observations]. / Identificazione proiettiva, mimesis e situazione analitica. Riflessioni preliminari.

In an attempt to underline the need to refer to an imaginary setting, in which the analytical relationship is acted out, the Authors have considered the possible relations between the concept of projective identification, as defined by Klein and further developed by Bion, and the idea of "Mimesis", which is inevitably involved in every story, and which confronts the imaginary at the very moment in which it is produced. The "fusion" between subject and object, which may occur in a more or less partial manner, is defined as a phenomenal demonstration of the participation of the two poles of the relationship in a "super-individual" experience which embraces them both. The mythical image of the hunter. Anyone is, in our opinion, a paradigmatic clement in this from of "meeting" which takes place within an impersonal and illusionary dimension.