G-protein-coupled receptor heteromers: function and ligand pharmacology

Almost all existing models for G-protein-coupled receptors (GPCRs) are based on the occurrence of monomers. Recent studies show that many GPCRs are dimers. Therefore for some receptors dimers and not monomers are the main species interacting with hormones/neurotransmitters/drugs. There are reasons for equivocal interpretations of the data fitting to receptor dimers assuming they are monomers. Fitting data using a dimer-based model gives not only the equilibrium dissociation constants for high and low affinity binding to receptor dimers but also a 'cooperativity index' that reflects the molecular communication between monomers within the dimer. The dimer cooperativity index (D(C)) is a valuable tool that enables to interpret and quantify, for instance, the effect of allosteric regulators. For different receptors heteromerization confers a specific functional property for the receptor heteromer that can be considered as a 'dimer fingerprint'. The occurrence of heteromers with different pharmacological and signalling properties opens a complete new field to search for novel drug targets useful to combat a variety of diseases and potentially with fewer side effects. Antagonists, which are quite common marketed drugs targeting GPCRs, display variable affinities when a given receptor is expressed with different heteromeric partners. This fact should be taken into account in the development of new drugs.     

Lack of cytotoxic and genotoxic effects of Minthostachys verticillata essential oil: Studies in vitro and in vivo

Minthostachys verticillata (peperina) is an aromatic and medicinal plant with several uses and ethnobotanical properties. Numerous studies have demonstrated that its essential oil (Mv-EO) presents antimicrobial capacity and shows immunomodulating and anti-allergic properties in human cell lines. Thus, the goal of this study was to investigate the main chemical composition, analyzed by GC–FID, and the cyto-genotoxic effects of Mv-EO, using Vero cells, human PBMCs and mice bone marrow cells. The Mv-EO was rich in pulegone 60.5% and menthone 18.2%. Our results clearly show that Mv-EO is not cyto-genotoxic in vitro nor in vivo. It not induced cytotoxic effects, as indicated by trypan blue dye exclusion and NRU assays both in Vero cells and human PBMCs. In addition, Mv-EO (100–1000 μg/mL) not induced apoptotic effects on human PBMCs, as indicated by Hoechst staining and DNA fragmentation analysis by agarose gel electrophoresis. The in vivo assay showed that Mv-EO (25–500 mg/kg) not increased the frequency of micronucleus in bone marrow cells of mice. Further, the ratio of polychromatic/normochromatic erythrocytes was not modified. These findings suggest that Mv-EO appears to be safe as a therapeutic agent.     

The 1711 rinderpest in Bernardino Ramazzini’s XIII Oration and the COVID-19 public health emergency: facts and common aspects

Although Bernardino Ramazzini is usually regarded only as the father of occupational medicine, his approach to fight the devastating rinderpest epidemic in 1711 is worth mentioning in the light of the public health emergency represented by Coronavirus Disease-2019 (COVID-19). This commentary (i) focuses on Ramazzini‘s XIII oration describing that event, (ii) analyses the approach suggested to fight the cattle epidemic and economic threats, (iii) highlights some similar aspects between the 1711 rinderpest epidemic and the current COVID-19 pandemic (team expertise, contagion transmissibility, drug treatment, preventive measures, decision timeliness).Key words: Bernardino Ramazzini, rinderpest, COVID-19     

In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix metalloproteinases secretion by macrophages

Plaque rupture and thromboembolism play a major role in atherosclerotic acute syndrome. Experimental studies have demonstrated the potential direct anti-atherosclerotic effects of calcium antagonists. We investigated the in vitro effect of lercanidipine (REC 15/2375), a third-generation, highly lipophilic calcium antagonist on cholesterol metabolism and matrix metalloproteinases secretion in macrophages, two functions that predispose plaques to rupture. Lercanidipine (10(-6)-10(-5) M) inhibited cholesterol esterification in macrophages and reduced cellular free and esterified cholesterol accumulation from acetylated LDL (63%, 62% of control P < 0.05, respectively). In addition, lercanidipine inhibited the release of metalloproteinases in the extracellular medium (50% and 95% inhibition at 10(-5) M for MMP-9 and MMP-2, respectively). Experiments performed with lercanidipine enantiomers or other dihydropyridine derivatives, endowed with different lipophilicity and affinity for calcium channels, indicated that the above effects could be related to the lipophilic, but not to the calcium channel blocking properties of these molecules. When cells, after exposure to the drug, were allowed to equilibrate, lercanidipine inhibitory action could be observed at initial concentrations as low as 10(-9) M, which is the actual concentration range observed in plasma in clinical settings. In conclusion, our data indicate that lercanidipine may exert potent anti-atherosclerotic effects by inhibiting macrophage functions involved in plaque stability.     

The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases

Background  

Following World Health Assembly resolutions 50.36 in 1997 and 56.7 in 2003, the World Health Organization (WHO) committed itself to supporting human African trypanosomiasis (HAT)-endemic countries in their efforts to remove the disease as a public health problem. Mapping the distribution of HAT in time and space has a pivotal role to play if this objective is to be met. For this reason WHO launched the HAT Atlas initiative, jointly implemented with the Food and Agriculture Organization of the United Nations, in the framework of the Programme Against African Trypanosomosis.     

Focusing ethical dilemmas of evidence-based practice in SMF-exposed MRI-workers: a qualitative analysis

Purpose  

To analyze ethical dilemmas for occupational health physicians and other stakeholders involved in the implementation of a surveillance program in workers exposed to static magnetic fields (SMF) used in magnetic resonance imaging.     

Reducción de los niveles de estrés y ansiedad en médicos de Atención Primaria mediante la aplicación de un programa de entrenamiento en conciencia plena (mindfulness)

PurposeTo check the effectiveness of a mindfulness development meditation technique on stress and anxiety in a group of primary-care physicians.DesignQuasi-experimental with pretest/posttest/follow-up measurements in a control group and an experimental group.SiteUniversity of Almeria.Participants38 primary-care physicians enrolled in a Teaching Aptitude Course (CAP).InterventionAn experimental group and a control group were formed with 19 participants in each. The experimental group took a psycho-educational meditation program for training and practice in mindfulness.MeasurementThe Perceived Stress Scale (PSS), the Strain Questionnaire and the State-Trait Anxiety Questionnaire were used to measure stress and anxiety levels.ResultsA comparative statistical analysis was performed using the Mann-Whitney non-parametric U test, finding a significant reduction in all the primary-care physician stress and anxiety variables in the experimental group compared to the control group in pretest-posttest and follow-up tests.ConclusionsThe results of this study support the effectiveness of mindfulness development meditation techniques in decreasing stress and anxiety in primary-care physicians. Nevertheless, the study shows various limitations that would have to be corrected in successive studies to bring more validity to the results.     

Herbal medicinal products for inflammatory bowel disease: A focus on those assessed in double‐blind randomised controlled trials

Inflammatory bowel disease patients frequently use herbal products as complementary or alternative medicines to current pharmacotherapies and obtain information on them mainly from the internet, social media, or unlicensed practitioners. Clinicians should therefore take a more active role and become knowledgeable of the mechanisms of action and potential drug interactions of herbal medicines for which evidence of efficacy is available. The therapeutic efficacy and safety of several herbal medicines have been studied in double‐blind randomised controlled trials (RCTs). Evidence of efficacy is available for Andrographis paniculata extract; curcumin; a combination of myrrh, extract of chamomile flower, and coffee charcoal; and the Chinese herbal medicines Fufangkushen colon‐coated capsule and Xilei san in patients with ulcerative colitis; and Artemisia absinthium extract and Boswellia serrata resin extract in patients with Crohn's disease. However, most of this evidence comes from single small RCTs with short follow‐up, and the long‐term effects and safety of their use have not yet been established. Thus, our findings indicate that further appropriately sized RCTs are necessary prior to the recommended use of these herbal medicines in therapy. In the meantime, increasing awareness of their use, and potential drug interactions among physicians may help to reduce unwanted effects and adverse disease outcomes.     

Serology of paracoccidioidomycosis. II. Correlation between class-specific antibodies and clinical forms of the disease

Untreated and previously treated patients with paracoccidioidomycosis were studied for: (i) serum levels of total IgG, IgM and IgA immunoglobulins, by radial immunodiffusion and Paracoccidioides brasiliensis (Pb) antibodies, by indirect immunofluorescence; (ii) correlation between their levels with the clinical forms of the disease; (iii) correlation between the serum titres obtained by tube precipitin with those of anti-Pb IgG, IgM and IgA.In the untreated group, serum IgG levels were significantly increased in patients with the more systemic forms of the disease, especially the acute progressive form. Serum IgA levels were significantly increased in all patients with no statistical difference between clinical forms. Serum IgM levels were normal in all patients. Anti-Pb IgG, IgA and IgM were detected in 97·5%, 32·5% and 45·0% of all cases, respectively. There was a sharp tendency towards higher levels of anti-Pb IgG among those with the acute progressive form (83·4%) in relation to the chronic, more localized forms, mixed form (68·0%) and isolated organic form (55·5%). In the untreated and previously treated group sera, there was positive correlation between the level of anti-Pb IgG and positivity for the tube precipitin test, suggesting that the precipitin-type antibodies are of the IgG class.Broadly, the present data demonstrate a polyclonal activation of the humoral immune system in paracoccidioidomycosis, with a positive relationship between serological results and severity of the disease.     

Hepatitis B and Delta virus infection among heterosexuals,homosexuals and bisexual men

The hepatitis B virus (HBV) and hepatitis Delta virus (HDV) infection rates were estimated in patients attending a venereal disease outpatient clinic: 759 heterosexuals and 154 homosexual-bisexual men. The anti-HBC prevalence was higher in homo-bisexual men (68.8 per 100) than in heterosexuals (41.8 per 100), whereas HBsAg was roughly the same in the two groups (about 6 per 100). The anti-HBc prevalence rate among heterosexuals was higher than that estimated in hospital personnel from the same geographical area. A positive association between anti-HBc prevalence and present or past sexually transmitted diseases (STD) was found among homo-bisexual men. Anti-HBc was also positively associated with herpes simplex type 2 antibodies in both heterosexuals and homo-bisexual men. These data are consistent with the hypothesis that sexual behavior also plays a role in the spread of infection among heterosexuals. Ten of the 46 HBsAg-positive subjects were anti-HDV positive: 6 of the 36 heterosexuals and 4 of the 10 homosexuals. All HDV-positive subjects had present or past STDs. These findings suggest sexual transmission of HDV infection.