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3D bioprinters present techniques that have various applications in the food industry. For this reason, this work aims to compile and review various research works focused on the utilities and advantages of this type of machinery. Where we first mention the basis of these bioprinting techniques and then proceed to highlight the bioethical issues that surround their application in the food industry, analyze the current advantages and disadvantages, the user that has been given in the production of food for astronauts, and also mention some of the research that has been taking place in Latin America and the world. The greatest advantage of 3D bioprinting of food is the speed of production compared to traditional manufacturing methods, allowing one to obtain food with various geometric shapes; it allows control of the nutritional value, and the texture of the product, reduces environmental pollution and has the advantage of being able to take advantage of the greater performance of the materials required for production. Additionally, this technology is considered an alternative production technique that will be used to solve the problem of feeding in places of scarce resources such as space and areas not suitable for animal husbandry.

Desert locust plagues have threatened food security in northern African countries for centuries. To prevent their effects, current early warning systems in arid environments need to be improved using the latest and most advanced modelling techniques and Earth observation datasets. Previous studies have analysed certain environmental predictors such as NDVI or soil moisture individually in an effort to detect suitable areas. However, we introduce new variables (Surface Temperature, LAI and Soil Moisture Root Zone) from the SMAP satellite and apply different machine learning methods in our species distribution model in order to identify desert locust presence. We obtain highly satisfactory model results (KAPPA & TSS = 0.901 and ROC = 0.986) to detect the probability of presence and, hence, likely breeding areas based on environmental factors. The most relevant variables were surface temperature, NDVI and soil moisture at root zone under different time scenarios. This study also confirms the potential of the SMAP satellite to retrieve critical temperatures due to its time pass, in addition to reinforcing the NDVI product from MODIS as a reliable environmental predictor. These results demonstrate the validity of this new approach based on machine learning methods to identify favourable breeding areas in Mauritania.

Setting Tuberculosis spondylodiscitis (TS), or Pott's disease, an extra-pulmonary form of tuberculosis (TB), is rare and difficult to diagnose in children. Some cases of severe TB in children were recently explained by inborn errors of immunity affecting the interleukin-12/interferon-gamma (IL-12/IFN-γ) axis. Objective To analyse clinical data on Moroccan children with TS, and to perform immunological and genetic explorations of the IL-12/IFN-γ axis. Design We studied nine children with TS diagnosed between 2012 and 2014. We investigated the IL-12/IFN-γ circuit by both whole-blood assays and sequencing of the coding regions of 14 core genes of this pathway. Results A diagnosis of TS was based on a combination of clinical, biological, histological and radiological data. QuantiFERON(®)-TB Gold In-Tube results were positive in 75% of patients. Whole-blood assays showed normal IL-12 and IFN-γ production in all but one patient, who displayed impaired decreased response to IL-12. No candidate disease-causing mutations were detected in the exonic regions of the 14 genes. Conclusions TS diagnosis in children remains challenging, and is based largely on imaging. Further investigations of TS in children are required to determine the role of genetic defects in pathways that may or may not be related to the IL-12/IFN-γ axis.

Interleukin-12 (IL-12) plays an important role in the production of interferon gamma from T cells and natural killer cells and is essential for protection against intra-macrophagic pathogens such as Mycobacterium and Salmonella. Here, we describe a 16-year-old girl with homozygous mutation in exon 12 of the IL12RB1 gene, which causes complete IL-12Rβ1 deficiency in association with heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase gene. She presented with disseminated Mycobacterium tuberculosis complex infection, retroperitoneal fungal abscess and also thrombosis in the superior mesenteric-portal vein junction. This is the first case report of a primary immunodeficiency associated with a genetically determined venous thrombosis.

Resume Differents types de deficits immunitaires constitutionnels exposent au risque d’infections fongiques severes. Ces infections peuvent etre revelatrices du deficit. Le type de micro-organismes impliques, la presentation clinique, la reaction immune observee autour du germe peuvent alors orienter le diagnostic etiologique. Comme souvent dans le domaine des deficits immunitaires, les avancees dans leur physiopathologie apportent des informations capitales sur les mecanismes de defense naturelle contre ces micro-organismes. Les progres therapeutiques ont considerablement ameliore le pronostic de ces infections potentiellement graves, chroniques et invalidantes.

During the second half of the month of June 1997, a massive catch of red tuna (Thunnus thynnus) took place off the coast of Babarte (Spain), in contrast to the first half of that month when there was hardly any presence of this species. The aim of this paper was to examine the relation between the high fishing productivity and the meteorological conditions under which the oceanic events to which the tuna fisheries were attracted took place. This was carried out through the analysis of Advanced Very High Resolution Radiometer (AVHRR) sensor data and the data from the Tiros-N Operational Vertical Sounder (TOVS) probe of the NOAA-14 satellite from 10 to 24 June 1997. Results show that the formation of the fishing front was caused by an ocean-atmosphere energetic exchange, which was localized and described through the data transmitted from the NOAA satellites.

Unter den Begriff leukozytar-mykobakterizide Defekte fallen verschiedene partielle oder komplette Storungen, die den Interferon-γ-Rezeptor, den Interleukin-12-Rezeptor oder Interleukin 12 selbst betreffen. Die Patienten werden durch disseminierte Infektionen mit nichttuberkulosen Mykobakterien oder auch BCG sowie Non-Typhus-Salmonellen-Infektionen auffallig. Die Histologie zeigt Granulome in den betroffenen Organen. Die einzige kurative Therapie bei homozygoten Interferon-γ-Rezeptor-1- oder -2-Defekten stellt die bei dieser Indikation wenig erprobte Stammzelltransplantation dar. Infektionen, die durch partielle Interferon-γ-Rezeptor-1- oder -2-Defekte verursacht werden, werden antibiotisch, evtl. mit zusatzlicher Gabe von Interferon, behandelt. Die Kasuistik beschreibt die erfolgreiche medikamentose Therapie einer chronisch multifokalen Mycobacterium-avium-Osteomyelitis aufgrund eines erstmalig beschriebenen homozygoten Interferon-γ-Rezeptor-2-Defekts bei einem jetzt 8 Jahre alten Knaben. Bei der nun seit 30 Monaten etablierten antibiotischen Therapie konnte bis jetzt eine Remission erzielt werden.

The classic primary immunodeficiencies confer predisposition to multiple infectious diseases. However since ten years severe pediatric infections which were idiopathic have now molecular explanation. Indeed, defects in several genes confer a predisposition to infection with specific pathogenes in otherwise healthy individuals. These children present a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition of others patients with "classic" primary immunodeficiency.

The aim of this work is to show an automatic method of cloud classification for direct application in civil aviation. We start from the premise of an acceptable trade‐off between calculation speed and accuracy in the output data. For this reason, visible and infrared channels of the Meteosat satellite were used alongside data provided by the A/TOVS (Advanced/Tiros‐N Operational Vertical Sounder) probe onboard NOAA (National Oceanic and Atmospheric Administration) polar satellites. A historical database of mean temperatures at ground level was also used. The analysis of different significant synoptic and mesoscale situations highlighted the efficacy of this method in the representation of the different cloud structures that normally appear in these situations. Considering the results of the study and given its speed and accuracy, it can be concluded that the method is appropriate for monitoring cloud systems in real time.

Resume Depuis une dizaine d'annees, des infections pediatriques severes qui etaient ⪡ idiopathiques ⪢ ont ete comprises au plan moleculaire, puisque les nouveaux deficits immunitaires en cause ont ete identifies. Les enfants presentant ces nouveaux types de deficit immunitaire hereditaire ont en commun de faire des infections severes et/ou recurrentes a une famille de microbes sans autre infection, ce en quoi ils different de la plupart des patients ayant un deficit immunitaire primaire ⪡ classique ⪢ Les explorations immunologiques de ⪡ routine ⪢, telles que la numeration-formule sanguine, le phenotypage lymphocytaire T et B, les proliferations lymphocytaires T, les serologies specifiques, le dosage ponderal des immunoglobulines et du complement, sont normales. Pourtant, les enfants presentent une vulnerabilite parfois mortelle a certaines infections. L' objectif de cette revue est de faire le point sur 3 nouveaux syndromes de predisposition genetique: les deficits de l'axe IL-12-IFNγ (syndrome de predisposition mendelienne aux infections mycobacteriennes), le deficit en STAT1 (predisposition aux infections virales) et les deficits en NEMO et IRAK-4 (predisposition aux infections par les bacteries pyogenes).

This study presents the methodology followed in the land use mapping at scale 1:50,000 for the Functional Area of Segovia, Spain. The study is included in the regional planning directives for Segovia, and makes a comprehensive use of the remote sensing techniques developed during the second half of the 1990s. The methodological precedents in this respect are analyzed, mainly the CORINE land cover project, together with the data sources and the techniques that were used to obtain the thematic information searched for. The less known methods are described and a complete methodological sequence of the work is offered. The main characteristics of the methodology are the high degree of automation, objectivity, possibility of direct contrasting and its capacity for quick updating. Diverse data sources have been used, such as cartographic vector information and satellite imagery. LANDSAT-TM and IRS-1D Pan were used as well as aerial oblique photography. All information was integrated into a Geographic Information System (GIS; named SIGIM-TD). Data fusion methods were also widely used to improve the spatial resolution of the images. A neural network was generated to provide an appropriate classification method. Results of the neural network-based classification are shown and a classification-fieldwork correlation of 0.887 was obtained, in contrast with coefficients of 0.334, 0.432, 0.234 and 0.678 achieved through other techniques. Graphic results of the work are presented together with the data sources used for the map elaboration. Finally, a discussion on the advances that these techniques represent is done.

Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFNgamma production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNgamma (Fig. 9). At one pole of this spectrum, represented by the complete IFNgammaR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNgammaR1/2, complete IL-12p40 and complete IL-12Rbeta1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFNgamma responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited.

This study focuses on multiple fire phenomena in Valencia, Spain. The monitoring of fire recurrence was conducted by means of smoke visualization, mapping the burned area and fire detection, and took place for the whole of the fire period from 21 May to 13 July 1994. The temporal and spatial evolution of the fire was addressed on a daily basis, by means of approaches for mapping burned areas, fire detection, and integrated fire evolution monitoring system.

This work offers a new algorithm for the fusion of images for improving the spatial resolution of multispectral images, using the concepts of entropy of information and a priori probability. The algorithm is based on Jaynes' maximum entropy method and starts from a previous modelling of the fusion of data as an operation in which a series of probabilities are designated at a micro-scale in terms of average statistical values at a macro-scale, which are those recorded by the image with the lowest spatial resolution. The theoretical base of the model is presented, its practical implementation is explained, a complete description allowing reproduction of the analysis is offered and the results of fusing Landsat Thematic Mapper (TM) images with IRS-1D Pan are shown.

Nontuberculous mycobacterial infections are rare in immunocompetent children, and usually present as adenitis. We report a case of a 6-year-old girl with a multifocal chronic osteomyelitis and pulmonary localisation due to Mycobacterium intracellulare associated with an autosomal dominant mutation of interferon gamma receptor 1 gene (INFGR1) leading to a syndrome of mendelian predisposition to mycobacteria infections by partial deficiency of intracellular signalisation of gamma interferon. This child has been cured with anti-mycobacteria drugs and gamma interferon. This report focus on the importance of looking for a susceptibility of the host to infectious diseases, which can lead to a specific treatment. As far as we know, this is the first case described in a tropical area.

Resume L'isolement d'une souche de Bacillus cereus dans un liquide cephalorachidien est le plus souvent du a une contamination du prelevement ou de sa mise en culture. Il a cependant ete decrit quelques cas, dont six en pediatrie, de meningites a ce germe. Observation Nous presentons le cas d'un nourrisson âge de 2,5 mois ayant developpe une meningite a B cereus , 3 jours apres son entree a l'hopital pour un bilan metabolique dans le cadre du suivi d'un syndrome de Reye. L'identification du germe a ete confirmee par sequencage de l'ARN 16S. Le traitement antibiotique precoce par l'association imipeneme-amikacine et corticoides a permis une evolution favorable de l'infection. Aucun facteur de risque evident n'a pu etre montre; notamment, le bilan immunitaire effectue etait normal et il n'y a pas eu de manœuvre invasive profonde. Conclusion Bien que souvent en rapport avec une contamination, l'isolement repete d'une souche de B cereus doit faire evoquer la possibilite d'une reelle infection a ce germe.

Human interferon γ receptor ligand binding chain (IFNγR1) deficiency is an autosomal recessive inherited disorder. Affected children show severe, profound and apparently selective susceptibility to weakly pathogenic mycobacteria, such as bacillus Calmette-Guerin (BCG) and non-tuberculous mycobacteria. This article reviews the evidence supporting a causative relationship between the genotype (IFNgR1 mutations) and the phenotype (mycobacterial infections) of these children.

IL-12 receptor β1 deficiency (IL-12Rβ1) predisposes patients to mycobacteria and Salmonella infections. We report a case of IL-12Rβ1 deficiency with a fatal multi-resistant Salmonella enteritidis infection. This boy was born after from a consanguineous marriage, and diagnosed as having a IL-12Rβ1 deficiency since the age of 3 months. He presented with recurrent Salmonella enteritidis essentially digestive localization, complicated by purulent pericarditis at the same germ at the age of two and a half years. At the age of 3, a colonic infiltration due to a Salmonella enteritidis resistant to antibiotics, was complicated by acute intussusception, and the child died. The IL-12Rβ1 deficiency is considered as having a good prognosis, in contrast to what happened in our patient. We review therapeutic issues in these patients.

La tuberculose, causée par Mycobacterium tuberculosis, demeure un problème majeur de santé publique avec plus de 8,7 millions de nouveaux cas et 1,4 millions de décès par an. Après exposition, la plupart des individus, mais pas la totalité, deviennent infectés par le bacille. Parmi les sujets infectés, seule une minorité (environ 10%) développera une tuberculose clinique, qui est typiquement soit une tuberculose primaire, extra-pulmonaire, chez l’enfant, soit une tuberculose de réactivation, pulmonaire, chez l’adulte. Il existe de très nombreuses observations montrant que cette variabilité dépend pour une large part de facteurs génétiques de l’hôte. Dans la tuberculose pulmonaire, des études d’association avec de multiples gènes candidats ont été réalisées mais avec des résultats peu convaincants. Les récentes études d’association génome entier n’ont retrouvé qu’un rôle très modeste de deux variants intergéniques. Néanmoins, un premier locus majeur de prédisposition à la tuberculose pulmonaire a été identifié dans la région du chromosome 8q12–q13 par analyse de liaison génétique dans une population marocaine. En utilisant cette même stratégie d’analyse de liaison, deux autres gènes majeurs contrôlant l’infection tuberculeuse (en particulier la résistance à l’infection) ont été identifiés. Alors que l’identification précise de ces gènes est en cours, l’autre observation fascinante de ces dernières années a été la découverte que la tuberculose pouvait également relever d’une prédisposition mendélienne, en particulier liée à un défaut complet d’un des récepteurs de l’IL-12, IL12Rβ1. Au total, l’ensemble de ces études fournissent la preuve du concept d’un spectre continu de prédisposition génétique à la tuberculose, allant d’un contrôle monogénique simple à une hérédité polygénique complexe en passant par des effets intermédiaires de gène majeur. L’identification des facteurs génétiques prédisposant à la tuberculose est fondamentale pour comprendre la physiopathologie de cette maladie et permettre ainsi le développement de nouvelles stratégies vaccinales et thérapeutiques.

Different types of hereditary immune deficiencies are at risk of severe fungal infections. Such infections can reveal the deficit. The type of micro-organisms involved, the clinical presentation, the immune reaction observed around the germ can then guide the etiological diagnosis. As often in the field of immunodeficiencies, advances in the pathophysiology provide crucial informations on the natural defense mechanisms against these organisms. Therapeutic advances have dramatically improved the prognosis of these potentially serious and disabling infections.

Primary immunodeficiencies (PIDs) are often recognized in adults, either because of delayed diagnosis of a paediatric illness, or increasingly because of the recognition of adult onset forms of these diseases. Moreover, a growing fraction of children diagnosed with PIDs reach adulthood. It has become clear that many of these conditions affect various organs and therefore will be referred to professionals from various fields of internal medicine. It is well known that infectious diseases, allergy, auto-immunity and cancer may result from PIDs. Surprisingly, other clinical manifestations were recently found to reflect inborn errors of immunity. Ground-breaking discoveries suggest that atypical haemolytic uraemic syndrome, Crohn's disease, and alveolar proteinosis may actually be manifestations of novel PIDs.

The spatial resolution of sensors is a concept frequently described in an inappropriate way, usually identified by the sampling distance in the image capturing process. The shape of the modulation transfer function (MTF) has no influence on the results in applications based on homogeneous distribution of radiance. However, in the case of high-temperature events (HTEs), the spatial location of the burning area inside the pixel is a key issue to solve, in order to quantify the radiance. The point spread function (PSF) should be considered both in fire detection-oriented algorithms and in the application of bispectral processes. This paper analyses the impact of the PSF of the Meteosat Second Generation Spinning Enhanced Visible and Infrared Imager (MSG-SEVIRI) sensor on the determination of thermal fire parameters. The PSF influence on the brightness temperature (BT), in the mid-infrared (MIR) 3.9 μm spectral band, on detection algorithms is analysed. Errors in the fire temperature retrieved by the bispectral technique, due to non-coincidence in the PSF involved, are also analysed. The results obtained show a difference of around 20 K in the BT in the 3.9 μm spectral band, depending on the fire location inside the pixel. Finally, the probability detection of the minimal size of the burning area was analysed, and revealed that there is a 90% probability of detecting a fire with a burning area of 10 ha whereas an area of 4 ha is detected with a probability of 50%. © 2009 Taylor & Francis.

The detection of fires in an operative way is not a finished task in remote sensing. This work present approaches for fire detection and fire monitoring. The described rare detection algorithm exploits a physical radiative transfer model based on a sub-pixel description of the remote sensing data. This model allows refining the detection capabilities in order to perform early detection by exploiting geostationary sensors which have a low spatial resolution but high temporal resolution. Polar sensors are used to supply updated parameters to the physical model. The described fire monitoring approaches allows estimating fire parameters and defining the evolution of the fire, using different spatial resolutions, in order to complete and refine the analysis performed by the detection algorithm.

[1] Detection and parameterization of forest fires is a task traditionally performed by polar-orbiting sensors, mainly advanced very high resolution radiometer (AVHRR) advanced along track scanning radiometer (AATSR), bispectral infrared detection (BIRD), and Moderate Resolution Imaging Spectroradiometer (MODIS). However, their time resolution is a problem to operate in real time. New geostationary sensors have proven their capacity for Earth observation. GOES, MSG, and MTSAT are already operative with time resolutions below 30 min. The international community feels that a real-time global observation network may become a reality, which is the aim of the Global Observations of Forest Cover and Land Cover Dynamics (GOFC/GOLD) FIRE Mapping and Monitoring program, focusing internationally on decision-making concerning research into global change. This paper shows the operation in real time by the MSG SEVIRI sensor over the Iberian Peninsula. For fire detection, a temporal gradient of temperature 3.9 μm is used, which is more efficient at eliminating incoming false alarms from solar reflection. Capacity to detect hot forest fires below 0.3 ha in Mediterranean latitudes has been analyzed along with the conditions in which it is possible to apply the MODIS methodology to establish the fire radiative energy (FRE) by means of experimental relation. We found that in this case, fire size can introduce maximum differences of 40% in FRE for small-scale fires. The capacity of this sensor is shown in different cases that have greatly impacted Spain and Portugal because of the loss of human life.

The classic primary immunodeficiencies confer predisposition to multiple infectious diseases. However since ten years severe pediatric infections which were idiopathic have now molecular explanation. Indeed, defects in several genes confer a predisposition to infection with specific pathogenes in otherwise healthy individuals. These children present a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition of others patients with "classic" primary immunodeficiency.

Nontuberculous mycobacterial infections are rare in immunocompetent children, and usually present as adenitis. We report a case of a 6-year-old girl with a multifocal chronic osteomyelitis and pulmonary localisation due to Mycobacterium intracellulare associated with an autosomal dominant mutation of interferon gamma receptor 1 gene (INFGR1) leading to a syndrome of mendelian predisposition to mycobacteria infections by partial deficiency of intracellular signalisation of gamma interferon. This child has been cured with anti-mycobacteria drugs and gamma interferon. This report focus on the importance of looking for a susceptibility of the host to infectious diseases, which can lead to a specific treatment. As far as we know, this is the first case described in a tropical area.

Environmental non tuberculous mycobacteria and Bacillus Calmette-Guerin vaccines are weakly virulent mycobacteria. Nevertheless they may cause severe diseases in otherwise healthy children with no overt immunodeficiency. Parental consanguinity and familial forms are frequently observed among these patients, therefore this syndrome was named "Mendelian Susceptibility to Mycobacterial Disease".In the last nine years, fife genes have been found to be mutated in patients with this syndrome: IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1. Allelic heterogeneity accounts for ten distinct genetic disorders. Clinical phenotype differs between patients. The spectrum of disease extends from early-onset overwhelming mycobacterial infection to adult-onset localized disease and tuberculosis. Impaired IFN-gamma-mediated immunity is the common mechanism of the disease, outlining its major role in mycobacterial immunity.Better understanding of these disorders reveals an expanding clinical phenotype which justifies studying adult patients with pulmonary non tuberculous mycobacterial infection without known risk factors, severe BCGitis and recurrent tuberculosis. Molecular diagnosis makes it possible to introduce a specific regimen based on physiopathology.

Tuberculosis, caused by Mycobacterium tuberculosis, is the most common mycobacterial disease in the world and remains a leading public health problem. Numerous other mycobacterial species are present in the environment and are most often termed atypical or nontuberculous mycobacteria. Like the attenuated vaccine Bacille Calmette-Guérin (BCG) they are generally poorly virulent, even so they can be at the origin of severe infections if the host immune response is impaired. It has been clearly demonstrated that the intrinsic virulence of a mycobacterial species is not the only factor determining disease severity, which is illustrated by the observation that the majority of individuals infected with M. tuberculosis do not develop clinical disease. Numerous arguments suggest that disease severity depends largely on susceptibility/resistance determined by the host genetic make up. In the following review we will discuss the studies on the genes implicated in complex predisposition to tuberculosis and Mendelian predisposition to disease caused by less virulent mycobacteria, proposing a continuous spectrum between those two types of predisposition.

Since ten years severe pediatric infections which were idiopathic have now molecular explanation, defined new primary immunodeficiencies. These children presented a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one micro-organisms family. Some of these children have mycobacterial infections. Standard immunologic explorations were normal. However, they presented a vulnerability, sometimes lethal caused by Mycobacteria. The goal of this article is to describe the IL-12-IFNgamma axis deficiency (mendelian susceptibility to mycobacterial disease).

Since 10 years severe pediatric infections which were idiopathic have now molecular explanation, because new primary immunodeficiencies responsible of these severe infections were identified. These children presented a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition to other patients with "classic" primary immunodeficiency. Standard immunologic explorations for example white blood counts, lymphocyte counts, vaccine serology, immunoglobulin levels and complement were normal. However, these children presented a vulnerability, sometimes lethal, caused by one type of microorganism. The aim of this review is to describe 3 new syndromes with a genetic predisposition of infectious diseases: IL-12-IFN gamma axis deficiency (Mendelian susceptibility to mycobacterial disease), STAT1 deficiency (predisposition to viral disease) and NEMO and IRAK-4 deficiencies (predisposition to infections caused by pyogenic bacteria).

Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFNgamma production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNgamma (Fig. 9). At one pole of this spectrum, represented by the complete IFNgammaR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNgammaR1/2, complete IL-12p40 and complete IL-12Rbeta1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFNgamma responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited.

Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.

Despite significant progress in intensive care medicine, the mortality of septic shock has not changed in recent years. Early recognition of subtle signs in favor of meningococcal sepsis, early antibiotic treatment, and aggressive hemodynamic support remains the cornerstone of therapy of severe meningococcal shock in children. Recent work has emphasized the role of genetic polymorphisms in various systems to explain the most severe cases: anti-inflammatory cytokine profile IL-10/TNF-alpha, elevated levels of plasminogen activator inhibitor type-1, variants of the gene for mannose-binding lectin complement pathway. This may explain the disillusionment of pediatric intensivists, and the general failure of immunotherapy for sepsis. Reasonable hope lies upon new meningococcal vaccines.

We prospectively validated the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative lymph nodes.In a retrospective study of 66 patients we demonstrated the predictive value of the association of local tumor stage and grade for occult micrometastasis, identifying 3 risk groups. A therapy strategy was designed according to these risk groups. A total of 37 consecutive patients were included in a prospective study in which the same criteria for risk group allocation and the same therapeutic recommendations were used as in the retrospective study.In the prospective study we noted positive lymph nodes in 11% of stage T1, 63% of stages T2-3, 15% of grade 1, 67% of grade 2 and 75% of grade 3 cases. The incidence of positive nodes was 0% in the low, 83.3% in the high and 33.3% in the intermediate risk group. These rates were similar to those in the retrospective study with no significant difference.The predictive value of the association of local tumor stage and grade for occult lymph node micrometastasis was validated in a prospective study. This factor allows the differentiation of 3 risk groups of patients with high reliability in the low and high risk groups. However, other prognostic factors are needed in the intermediate risk group to improve the prediction of lymph node involvement.

Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon gamma receptor ligand-binding chain (IFNgR1), interferon gamma receptor signalling chain (IFNgR2), interleukin 12 p40 subunit (IL-12p40), and interleukin 12 receptor beta 1 chain (IL-12Rb1) genes have been identified in a number of patients with disseminated BCG or NTM infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man.

A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in immunology.

Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impaired IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN gamma. Different types of mutation define two types of complete and two types of partial IFNgammaR1 deficiency. Complete and partial IFNgammaR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-gamma. Patients with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFNgammaR1, IFNgammaR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-gamma. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with mild, intermediate, or severe disease). This correlation suggests that IFN-gamma-mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.

Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), bas long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon gamma receptor ligand-binding chain (IFN gamma R1), interferon gamma receptor signalling chain (IFN gamma R2), interleukin 12 p40 subunit (IL-12 p40), and interleukin 12 receptor beta 1 chain (IL-12R beta 1) genes have been identified in a number of patients with disseminated BCG or NTM infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man.

Following infection with intracellular pathogens like mycobacteria, listeria, toxoplasma and leishmania, mononuclear phagocytes and related antigen-presenting cells (APC), i.e. dendritic cells, secrete the heterodimeric cytokine IL-12. IL-12 comprises two disulphide-linked subunits, p40 and p35, which together form the biologically active p70 hetrodimer molecule (reviewed in [1,2]). IL-12 production by macrophages and dendritic cells can also be enhanced by a T cell-dependent pathway through interaction of CD40 on the surface of the APC with CD40-ligand expressed on activated T cells. The IL-12 receptor (IL-12R), which is expressed by both natural killer (NK) cells at certain stages of development and by activated T cells, is made up of two chains called IL-12Rβ1 and IL-12Rβ2, respectively. Both receptor chains have extracellular, transmembrane and intracellular segments. Each of these receptor proteins can only bind to IL-12 with low affinity, but when co-expressed can bind IL-12 with high affinity, initiating a physiological response to this cytokine [3]. A schematic representation of the IL-12 receptor-mediated intracellular signalling pathway is illustrated in Fig. 1. Fig. 1 Binding of IL-12 to the IL-12Rβ1 and β2 chains induces phosphorylation of the kinases Tyk2 and Jak2, which associate with the cytoplasmic tails of the β1 and β2 chains, respectively. Subsequently the signal transducing ... Binding of IL-12 to activated CD4 T cells partitions them to develop and differentiate along the so-called Th1 pathway, crucially important for cell-mediated immunity against intracellular pathogens. Furthermore, acting at picomolar and subpicomolar levels on T cells and NK cells, IL-12 induces high-level production of the cytokine IFN-γ[2]. IFN-γ plays a central role in the resistance of mammalian hosts to pathogens, particularly bacteria and parasites capable of intramacrophage survival (reviewed in [4,5]). The main cells producing IFN-γ are activated Th1 cells, activated CD8 cytotoxic cells of the TC1 phenotype, and activated NK cells. Biologically active IFN-γ is a homodimer, which has a range of pleiotropic effects on a number of cell types, with the ability to modulate the function of over 200 genes. It is one of the principal macrophage-activating cytokines, and mice with disrupted IFN-γ or IFN-γ receptor (IFN-γR) genes show increased susceptibility to intracellular pathogens including Leishmania major, Listeria monocytogenes, mycobacteria and certain viruses, e.g. vaccinia virus. IFN-γ interacts with a specific cell surface receptor, which is widely expressed on most nucleated cells. The IFN-γR consists of two transmembrane proteins, namely IFN-γR1 which is a ligand-binding chain, and IFN-γR2, which is required for signal transduction. A schematic representation of the IFN-γ receptor-mediated intracellular signalling pathway is shown in Fig. 2. Fig. 2 A schematic representation of the IFN-γ receptor-mediated intracellular signalling pathways (modified from [4,5]). Two IFN-γR1 chains dimerize on binding the IFN-γ homodimer and subsequently associate with two IFN-γR2 chains. ... Key actions of IFN-γ include increased expression of MHC class I and class II proteins which enhance antigen processing and presentation, activation of mononuclear phagocytes through a multiplicity of effects, influencing IgG heavy-chain switching and modulating the production of cytokines such as IL-12, tumour necrosis factor-alpha (TNF-α) and IFN-γ itself. Following IFN-γR ligation the receptor–ligand complexes recycle into an acidified subcellular compartment, where they dissociate. Free IFN-γ is then degraded by lysosomal enzymes. The uncoupled IFN-γR1 receptors eventually relocate to the cell surface via an intracellular pool. An amino acid motif present on the intracellular domain of the IFN-γR1 close to the Jak1 association site is required for normal recycling of this receptor (Fig. 2). The above background information helps in the understanding of the clinical, pathological and immunological features of defects in the IL-12-dependent, high-output IFN-γ pathway and the laboratory methods required for identifying these defects.

We describe the history of a girl with interferon-gamma-receptor (IFNgammaR1) deficiency and studies performed to identify the molecular and clinical characteristics of this recently discovered disorder. This is the first report of a child from Northern Europe with IFNgammaR1 deficiency. The patient, now 7 years old, first presented with swelling and reddening at the Bacille Calmette-Guerin (BCG) vaccination site, swelling of lymph nodes, hepatomegaly, and an unusually severe varicella rash at the age of 4 months. At that time, she was diagnosed with BCG histiocytosis without typical granuloma formation and was treated with antituberculous agents. During the clinical course of her illness, several different types of atypical mycobacteria and (for the first time in an IFNgammaR1-deficient patient) Listeria monocytogenes were detected. Flow cytometric analysis showed that the patient's monocytes could not bind a monoclonal antibody specific for the IFNgamma-receptor. Our analysis of mRNA derived from the alpha-chain (IFNgammaR1) gene of this receptor revealed deletions of 173 bp and 4 bp in cDNA sequences originating from individual alleles. The 173 bp deletion was located between nucleotide positions 200 and 372, exactly matching those of exon 3, and the 4 bp deletion was located between nucleotide positions 561 and 564 of the coding region of the cDNA. Analysis of genomic DNA revealed the presence of a G to T transition at the 5'end of the splice consensus sequence of intron 3, which explains the absence of exon 3. The other allele carried the 4-base-pair deletion (ACTC) at nucleotide positions 15-18 of exon 5. Twelve months after an allo\geneic bone marrow transplantation, the patient had clinically improved.