Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellowperoba, coffee-peroba andmatiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium bergheiin mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.

OBJECTIVE: Connective tissue diseases (CTDs) are associated with several interstitial lung diseases. The aim of this study was to describe the recently individualized syndrome of combined pulmonary fibrosis and emphysema (CPFE) in a population of patients with CTD. METHODS: In this multicenter study, we retrospectively investigated data from patients with CTD who also have CPFE. The demographic characteristics of the patients, the results of pulmonary function testing, high-resolution computed tomography, lung biopsy, and treatment, and the outcomes of the patients were analyzed. RESULTS: Data from 34 patients with CTD who were followed up for a mean±SD duration of 8.3±7.0 years were analyzed. Eighteen of the patients had rheumatoid arthritis (RA), 10 had systemic sclerosis (SSc), 4 had mixed or overlap CTD, and 2 had other CTDs. The mean±SD age of the patients was 57±11 years, 23 were men, and 30 were current or former smokers. High-resolution computed tomography revealed emphysema of the upper lung zones and pulmonary fibrosis of the lower zones in all patients, and all patients exhibited dyspnea during exercise. Moderately impaired pulmonary function test results and markedly reduced carbon monoxide transfer capacity were observed. Five patients with SSc exhibited pulmonary hypertension. Four patients died during followup. Patients with CTD and CPFE were significantly younger than an historical control group of patients with idiopathic CPFE and more frequently were female. In addition, patients with CTD and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures, and more frequently were male than those with CTD and lung fibrosis without emphysema. CONCLUSION: CPFE warrants inclusion as a novel, distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases in smokers or former smokers, especially in patients with RA or SSc.

Nouvelles thérapies en rhumatologie pédiatrique [New therapies in pediatric rheumatology].

Biotherapies are recent treatments, which target molecules implicated in the pathogenesis of inflammatory diseases. In pediatric rheumatology, we use anti-TNF-alpha and abatacept in JIA patients with polyarticular involvement, whereas anti-IL-6 and anti-IL-1 blockers are efficacious in the systemic form of JIA and other auto-inflammatory conditions. These new treatments have significantly improved the control of articular and systemic inflammation and the prognosis of rheumatic diseases. Their effect and their safety on the long-term need to be assessed on large cohorts of patients. Due to the impact of these chronic illnesses on the young patient and its family, and the required specific knowledge, the care of these children should be provided by a multidisciplinary team linked to a centre of competence.

Medicine and Science in a New Medical-surgical Context: The Royal College of Surgery of Barcelona (1760–1843)

Taking the Royal College of Barcelona (1760 -1843) as a case study this paper shows the development of modern surgery in Spain initiated by Bourbon Monarchy founding new kinds of institutions through their academic activities of spreading scientific knowledge. Antoni Gimbernat was the most famousinternationally recognised Spanish surgeon. He was trained as a surgeon at the Royal College of Surgery in Cadiz and was later appointed as professor of theAnatomy in the College of Barcelona. He then became Royal Surgeon of King Carlos IV and with that esteemed position in Madrid he worked resiliently to improve the quality of the Royal colleges in Spain. Learning human bodystructure by performing hands-on dissections in the anatomical theatre has become a fundamental element of modern medical education. Gimbernat favoured the study of natural sciences, the new chemistry of Lavoisier and experimental physics in the academic programs of surgery. According to the study of a very relevant set of documents preserved in the library, the so-called “juntas literarias”, among the main subjects debated in the clinical sessions was the concept of human beings and diseases in relation to the development of the new experimental sciences. These documents showed that chemistry andexperimental physics were considered crucial tools to understand the unexplained processes that occurred in the diseased and healthy human bodyand in a medico-surgical context. It is important to stress that through these manuscripts we can examine the role and the reception of the new sciences applied to healing arts.

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.

Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.

Study of the proteolytic activity of the paracaspase MALT1 in T cell activation

Summary : Several signalling cascades are initiated through the triggering of the T cell receptor (TCR) by an antigenic peptide expressed at the surface of an antigen presenting cell. These pathways lead to morphological changes controlling T cell adhesiveness and migration to the site of infection, and to the activation of transcription factors that regulate key genes for the proper development of the immune response. Amongst them, the nuclear factor xB (NF-κB) is the subject of intense research since more than twenty years because deregulated NF-κB signalling in lymphocytes can lead to immunodeficiency, autoimmunity or lymphomas. Therefore, the understanding of the molecular mechanisms regulating NF-κB activation is important for the development of new therapeutics aimed at treating various diseases. In T lymphocytes, a complex composed of CARMAI, BCL10 and MALT1 relays signals from TCR proximal events to NF-κB activation. Gene translocations of the BCL10 or MALTI genes or oncogenic mutations affecting CARNA 1 result in constitutive NF-κB activation and are related to the development of certain forms of lymphomas. MALT1 contains acaspase-like domain, but it is unknown whether this domain is proteolytically active. In this study, we found that MALT1 has arginine-directed proteolytic activity. We showed that the proteolytic activity of MALT 1 is key to TCR-induced NF-κB activation and production of interleukin 2. We identified BCL 10 as a MALT 1 substrate, and we showed that its cleavage regulates T cell adhesion to the extracellular matrix protein fibronectin. Furthermore, we identified caspase 10 as another substrate of MALT1. caspase 10 is a close homologue of caspase 8 and is known to be involved in the induction of apoptosis upon Fast or TRAIL stimulation. We showed that caspase 10 is important for TCR-induced NF-κB activation and interleukin 2 production, identifying for the first time a non apoptotic function for caspase 10. These data provide evidence for previously uncharacterized roles of MALT 1 and BCL 10 in the regulation of T cell adhesion and of caspase 10 in the activation of lymphocytes, and allow a better understanding of the molecular mechanisms of T lymphocyte activation. Since the proteolytic activity of MALT1 is essential to T cell activation, it suggests that the targeting of this activity may be relevant for the development of immunomodulatory or anticancer drugs. Résumé : De nombreuses voies de signalisation sont initiées via la stimulation des récepteurs des cellules T (TCR) par un peptide antigénique exprimé à la surface d'une cellule présentatrice d'antigènes. Ces cascades de signalisation produisent des changements morphologiques qui contrôlent l'adhésion des cellules T et leur migration vers le site d'infection. Elles contrôlent également l'activation de facteurs de transcription qui régulent la transcription de gènes importants pour la réponse immunitaire. Parmi ces derniers, le facteur nucléaire KB (NF-κB) joue un rôle essentiel, puisqu'une régulation aberrante de son activité dans les lymphocytes peut causer des immunodéficiences, des maladies autoimmunes ou des lymphomes. C'est pour cela que la compréhension des mécanismes moléculaires qui contrôlent l'activation de NF-κB est donc importante pour le développement de nouvelles thérapies. Un complexe contenant les protéines CAIZMAI, BCL10 et MALT1 transmet, dans les lymphocytes T, le signal du TCR vers l'activation de NF-κB. Des translocations des gènes qui codent pour BCL10 et MALTI et des mutations affectant la fonction de CARNAI ont été liées au développement de certaines formes de lymphomes. MALTI contient un domaine qui ressemble au domaine catalytique présent dans les caspases, mais il n'est pas connu si ce domaine a une activité protéolytique. Dans cette étude, nous avons découvert que MALTI est une protéase qui a une spécificité pour les acides aminés basiques comme l'arginine. Nous montrons que l'activité protéolytique de MALTI est importante pour l'activation de NF-κB et la production d'interleukine 2 après stimulation du TCR. Nous avons observé que BCL10 est clivé par MALTI pendant l'activation des lymphocytes T, et que ce clivage est impliqué dans la régulation de l'adhésion des lymphocytes T à la fibronectin, une protéine de la matrice extracellulaire. De plus, nous avons identifié que la caspase 10, qui a une grande homologie avec la caspase 8 et qui jusqu'à maintenant est connue pour son rôle dans l'induction de la mort cellulaire en réponse à une stimulation par Fast ou par TRAIL, est également un substrat de MALT 1. En montrant que la caspase 10 est nécessaire à l' activation de NF-icB et à la production de l'interleukine 2 après stimulation du TCR, nous décrivons pour la première fois une fonction non apoptotique de la caspase 10. Ces résultats décrivent de nouveaux rôles pour MALT1 et BCL10 dans le contrôle de l'adhésion des lymphocytes T et de la caspase 10 pour l'activation des lymphocytes T. Puisque l'activité protéolytique de MALT1 est essentielle pour l'activation des lymphocytes T, nous suggérons que cibler cette activité protéolytique de MALT 1 pourrait amener de nouvelles possibilités de traitement de maladies où une activation aberrante des lymphocytes est impliquée.

Rhumatologie. Une nouvelle option thérapeutique dans la prise en charge de l'inflammation chronique en rhumatologie: les inhibiteurs des janus kinases [A new therapeutical option for chronic inflammation in rheumatology: janus kinases inhibitors (JAK)].

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Maternal side-effects after multiple courses of antenatal corticosteroids (MACS): the three-month follow-up of women in the randomized controlled trial of MACS for preterm birth study.

OBJECTIVE: A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Multiple Courses of Antenatal Corticosteroids Study (MACS), a study involving 1858 women, was a multicentre randomized placebo-controlled trial of multiple courses of ACS, given every 14 days until 33+6 weeks or birth, whichever came first. The primary outcome of the study, a composite of neonatal mortality and morbidity, was similar for the multiple ACS and placebo groups (12.9% vs. 12.5%), but infants exposed to multiple courses of ACS weighed less, were shorter, and had smaller head circumferences. Thus for women who remain at increased risk of preterm birth, multiple courses of ACS (every 14 days) are not recommended. Chronic use of corticosteroids is associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to ascertain if multiple courses of ACS were associated with maternal side effects. METHODS: Three months postpartum, women who participated in MACS were asked to complete a structured questionnaire that asked about maternal side effects of corticosteroid use during MACS and included the Edinburgh Postnatal Depression Scale. Women were also asked to evaluate their study participation. RESULTS: Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. There were no significant differences in the risk of maternal side effects between the two groups. Large numbers of women met the criteria for postpartum depression (14.1% in the ACS vs. 16.0% in the placebo group). Most women (94.1%) responded that they would participate in the trial again. CONCLUSION: In pregnancy, corticosteroids are given to women for fetal lung maturation and for the treatment of various maternal diseases. In this international multicentre randomized controlled trial, multiple courses of ACS (every 14 days) were not associated with maternal side effects, and the majority of women responded that they would participate in such a study again.

Spatially-resolved eigenmode decomposition of red blood cells membrane fluctuations questions the role of ATP in flickering.

Red blood cells (RBCs) present unique reversible shape deformability, essential for both function and survival, resulting notably in cell membrane fluctuations (CMF). These CMF have been subject of many studies in order to obtain a better understanding of these remarkable biomechanical membrane properties altered in some pathological states including blood diseases. In particular the discussion over the thermal or metabolic origin of the CMF has led in the past to a large number of investigations and modeling. However, the origin of the CMF is still debated. In this article, we present an analysis of the CMF of RBCs by combining digital holographic microscopy (DHM) with an orthogonal subspace decomposition of the imaging data. These subspace components can be reliably identified and quantified as the eigenmode basis of CMF that minimizes the deformation energy of the RBC structure. By fitting the observed fluctuation modes with a theoretical dynamic model, we find that the CMF are mainly governed by the bending elasticity of the membrane and that shear and tension elasticities have only a marginal influence on the membrane fluctations of the discocyte RBC. Further, our experiments show that the role of ATP as a driving force of CMF is questionable. ATP, however, seems to be required to maintain the unique biomechanical properties of the RBC membrane that lead to thermally excited CMF.

Quoi de neuf en medecine des voyages? [What's new in travel medicine?]

Les menaces pour la santé des voyageurs proviennent souvent de l'émergence ou de la réémergence d'anciennes et de nouvelles maladies infectieuses. En Amérique du Sud c'est une augmentation des cas de fièvre jaune qui a fait du bruit. A Bornéo, une nouvelle espèce de Plasmodium pathogène pour l'humain a été mise en évidence. Après l'épidémie sur les îles de l'océan Indien, le virus du Chikungunya a causé de nouveaux foyers et ceci même en Europe. La première journée mondiale de la rage a rappelé que cette maladie continue à tuer un nombre important de personnes dans les pays aux ressources limitées. La rage affecte également des personnes de nos pays comme l'illustre deux situations récentes. Finalement, le nouveau Règlement sanitaire international permettra à l'OMS de mieux répondre aux urgences de santé publique de portée internationale. The threats for the health of travellers come often from the emergence or the re-emergence of old and new infectious diseases. In South America an important increase of the number of cases of yellow fever was reported. On the island of Borneo a new species of Plasmodium pathogenic for humans has been identified. After the Chikungunya epidemic that affected the islands of the Indian Ocean, the virus has caused new epidemic foci and this even in Europe. The first World Rabies Day reminded us that this disease still kills a large number of persons in countries with limited resources. Rabies can also affect persons from our countries, as it was illustrated by two recent situations. Finally the new International Health Regulation will allow the WHO to better respond to public health emergencies of international concern

Distribution of hospital admissions in a middle-income country of the African region

Introduction: Few studies have reported the distribution of all hospital admissions at the entire country level in low and middle-income countries (LMICs). We examined this question in Seychelles, a rapidly developing small island state in the Africa region, in which access to health care is provided free of charge to all inhabitants through a national health system and all hospital admissions are routinely registered. Methods: Based on all admissions to all hospitals in Seychelles in 2005-2008, we calculated the distribution of hospital admissions, age at admission, length of stay and bed occupancy (i.e. cumulated number of patients * number of days spent in all hospitals) according to both hospital departments and broad causes of diseases (using codes of the ICD-10 classification of diseases). Results: Bed occupancy was largest in the surgical wards (36.7% of all days spent in all hospitals), followed by the medical wards (24.3%), gynecology/obstetrics wards (18.4%), pediatric wards (11.2%), and psychiatric wards (7.2%). According to broad causes of diseases/conditions, bed occupancy was highest for obstetrics/gynecology conditions (19.9% of all days spent at hospital), mental diseases (8.6%), cardiovascular diseases (8.1%), upper aerodigestive/pulmonary diseases (8%), infectious/parasitic diseases (8%), gastrointestinal diseases (7.2%), and urogenital diseases (6.7%). Adjusted to 100'000 population, 153 hospital beds are needed every day, including 31 for obstetrics/gynecologic conditions, 13 for mental diseases, 12 for cardiovascular diseases, 12 for upper aerodigestive diseases, 12 for infectious/parasitic diseases, and 11 for gastrointestinal diseases. Conclusion: Our findings give a good indication of the overall distribution of admissions according to both hospital departments and broad causes of diseases in a middle-income country. These findings provide important information for health care planning at the national level

Assessement of Malaria Transmission in an Area with Very Low Mosquito Density

The increase in world travel in recent years, especially to and from areas where vector-borne diseases are endemic, has resulted in a substantial rise in imported cases of those diseases. In particular, malaria is a cause of concern. In those countries at the edge of its distribution, it can be difficult to distinguish between autochthonous and imported cases. However, distinguishing between the two is important because of the different allocation of resources to combat the disease that each requires. In general, observation of the various stages of parasite development in wild-caught female mosquitoes is considered evidence of autochthonous transmission. Observation of oocysts in the mosquito mid-gut testifies that mosquitoes are susceptible to infection but conclusions cannot be reached about their ability to complete the transmission cycle. Perhaps the best indication of autochthonous transmission is microscopic observation of sporozoites in mosquito salivary glands, since this detects parasites ready to be inoculated (BELER et al., 1990). Detection of circumsporozoite protein (CSP)(BURKOT, WILLIAMS & SCHNEIDER, 1984) in dry mosquito thoraxes, by Enzyme Linked Immunosorbent Assay (ELISA) is also widely used to determine transmission, especially when large numbers of mosquitoes need to be processed. Such assays provide information about the parasite species infecting the mosquito (BURKOT & WIRTZ, 1986; WIRTZ et al., 1987; BELER et al., 1990).

The expression and impact of antifungal grooming in ants.

Parasites can cause extensive damage to animal societies in which many related individuals frequently interact. In response, social animals have evolved diverse individual and collective defences. Here, we measured the expression and efficiency of self-grooming and allo-grooming when workers of the ant Formica selysi were contaminated with spores of the fungal entomopathogen Metarhizium anisopliae. The amount of self-grooming increased in the presence of fungal spores, which shows that the ants are able to detect the risk of infection. In contrast, the amount of allo-grooming did not depend on fungal contamination. Workers groomed all nestmate workers that were re-introduced into their groups. The amount of allo-grooming towards noncontaminated individuals was higher when the group had been previously exposed to the pathogen. Allo-grooming decreased the number of fungal spores on the surface of contaminated workers, but did not prevent infection in the conditions tested (high dose of spores and late allo-grooming). The rate of disease transmission to groomers and other nestmates was extremely low. The systematic allo-grooming of all individuals returning to the colony, be they contaminated or not, is probably a simple but robust prophylactic defence preventing the spread of fungal diseases in insect societies.

Genome-wide association study of major recurrent depression in the U.K. population.

OBJECTIVE: Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. METHOD: Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. RESULTS: Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. CONCLUSIONS: This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

The three horsemen of riches: Plague, war and urbanization in early modern Europe

How did Europe escape the "Iron Law of Wages?" We construct a simple Malthusian model withtwo sectors and multiple steady states, and use it to explain why European per capita incomes andurbanization rates increased during the period 1350-1700. Productivity growth can only explain a smallfraction of the rise in output per capita. Population dynamics changes of the birth and death schedules were far more important determinants of steady states. We show how a major shock to population cantrigger a transition to a new steady state with higher per-capita income. The Black Death was such ashock, raising wages substantially. Because of Engel's Law, demand for urban products increased, andurban centers grew in size. European cities were unhealthy, and rising urbanization pushed up aggregatedeath rates. This effect was reinforced by diseases spread through war, financed by higher tax revenues.In addition, rising trade also spread diseases. In this way higher wages themselves reduced populationpressure. We show in a calibration exercise that our model can account for the sustained rise in Europeanurbanization as well as permanently higher per capita incomes in 1700, without technological change.Wars contributed importantly to the "Rise of Europe", even if they had negative short-run effects. We thustrace Europe s precocious rise to economic riches to interactions of the plague shock with the belligerentpolitical environment and the nature of cities.