The lipid interaction capacity of Sin a 2 and Ara h 1, major mustard and peanut allergens of the cupin superfamily, endorses allergenicity.

BACKGROUND: Sin a 2 (11S globulin) and Ara h 1 (7S globulin) are major allergens from yellow mustard seeds and peanut, respectively. The ability of these two allergens to interact with lipid components remains unknown. OBJECTIVE: To study the capacity of Sin a 2 and Ara h 1 to interact with lipid components and the potential effects of such interaction in their allergenic capacity. METHODS: Spectroscopic and SDS-PAGE binding assays of Sin a 2 and Ara h 1 with different phospholipid vesicles and gastrointestinal and endolysosomal digestions in the presence or absence of lipids were performed. The capacity of human monocyte-derived dendritic cells (hmoDCs) to capture food allergens in the presence or absence of lipids, the induced cytokine signature, and the effect of allergens and lipids to regulate TLR2-L-induced NF-kB/AP-1 activation in THP1 cells were analyzed. RESULTS: Sin a 2 and Ara h 1 bind phosphatidylglycerol (PG) acid but not phosphatidylcholine (PC) vesicles in a pH-dependent manner. The interaction of these two allergens with lipid components confers resistance to gastrointestinal digestion, reduces their uptake by hmoDCs, and enhances their stability to microsomal degradation. Mustard and peanut lipids favor a proinflammatory environment by increasing the IL-4/IL-10 ratio and IL-1ß production by hmoDCs. The presence of mustard lipids and PG vesicles inhibits TLR2-L-induced NF-kB/AP-1 activation in THP1 cells. CONCLUSION: Sin a 2 and Ara h 1 interact with lipid components, which might well contribute to explain the potent allergenic capacity of these two clinically relevant allergens belonging to the cupin superfamily.

Discovering the meaning of monoclonal gammopathy of undetermined significance: current knowledge, future challenges.

Monoclonal gammopathy of undetermined significance (MGUS) is a non malignant plasma cell disorder with a relatively low risk of progression to Multiple Myeloma (MM) and to related Plasma cells disordes (lymphoplasmacellular neoplasms, Waldenstrom Macroglobulinemia or light chain amyloidosis). It is a quite common finding, especially in the population above the age of 50 and it can also present in association with many non malignant conditions. Differential diagnosis of symptomatic and asymptomatic forms is the determinant for starting therapy. Over the last few years many advances in the understanding of the biology of MGUS, together with large epidemiological studies, allowed to define risk models to estimate the risk of progression to MM according to MGUS isotype and, more recently, to peculiar flow cytometry findings. The goal of many recent studies aims at evaluating individual patients and their overall risk of progression, the detection of early signs of progression and the development of timely treatment strategies.

Characteristics and circumstances of falls in hip fractures.

Osteoporosis is a chronic disease characterized by a loss of bone mass and deterioration of bone microstructure that lead to a greater risk of fragility fractures. Fall is generally the main cause of fractures. Hip fractures are the most common ones and are usually correlated to a greater morbidity and mortality. The aim of our observational study was to evaluate, among patients with hip fragility fracture, characteristics and circumstances of falls. We conducted a national epidemiological survey, involving 80 physiatrists. They were asked to collect data on patients over 55 years of age who underwent a fragility fracture in the 12 months prior to recruitment. For each patient they had to fill a form including questions on different aspects of patients' medical history: age, gender, reason for the visit, type of fracture, number of falls in the last year and the year before the fall. Among 419 patients who sustained hip fracture, 70 had experienced a fall, while 119 were incurred in more falls in the 12 months before the fracture. In most people of our cohort, hip fracture was caused by a fall that occurred on the side during the morning.

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients.

BACKGROUND: We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV-1. METHODS: A multicentre retrospective study of 23 multidrug-resistant paediatric patients (five children and 18 adolescents) enrolled in the study from 1 September 2007 to 28 February 2010 was carried out. We performed a longitudinal analysis of immunological, virological and clinical data. RESULTS: The median age of the patients was 14.2 years [interquartile range (IQR) 12.5-15.8 years]. At baseline, the median HIV-1 RNA was 29 000 (4.5 log(10) ) HIV-1 RNA copies/mL (range 4300-83 000 copies/mL), the median CD4 T-cell count was 445 cells/µL (range 221-655 cells/µL) and the median CD4 percentage was 19.6% (IQR 13.0-31.0). Remarkably, 16 of 23 patients (70%) harboured one or more etravirine-associated resistance mutations. The backbone regimen included at least two fully active drugs in 91% of patients. After etravirine-based therapy, 20 patients (87%) achieved HIV-1 RNA<400 copies/mL and 18 of 23 (78%) achieved HIV-1 RNA<50 copies/mL: three (13%) within the first month, seven (30%) within the first 4 months, and six (26%) between the 5th and 8th months. CD4 T-cell recovery was observed in 19 patients (83%). The median follow-up time was 48.4 weeks (IQR 35.7-63.4 weeks); four patients (17%) were exposed to etravirine for >120 weeks. Three mild/short-term and two moderate skin rashes were observed in the adolescents. Laboratory abnormalities included hypercholesterolaemia (11 of 23 patients), hypertriglyceridaemia (eight of 23 patients), and reduced high-density lipoprotein cholesterol (10 of 23 patients). Adherence was complete in seven patients (30%). No patients showed complete resistance to etravirine after follow-up. However, three of 21 patients (14%) who initially showed intermediate resistance interrupted etravirine treatment because of virological failure. CONCLUSIONS: We observed a sustained antiviral response and improved immunological parameters in multidrug-resistant paediatric patients, most of whom had received etravirine as part of salvage regimens with at least two fully active drugs.

Análisis ecológico y perfil materno de la transmisión vertical del virus de la inmunodeficiencia humana en la Comunidad de Madrid desde 1980 hasta 2008 / An ecological analysis and the maternal profile of vertical HIV transmission in the Community of Madrid from 1980 until 2008

La pandemia del sida sigue siendo uno de los principales problemas que afectan al desarrollo y la seguridad en todo el mundo. En España, y más específicamente en la Comunidad de Madrid (CM), los primeros afectados fueron hombres homosexual eso bisexuales, seguidos de adictos a drogas por vía parenteral (ADVP) y la vía heterosexual; esta última afectaba principalmente a las mujeres, y la transmisión vertical (TV). La TV es la prioritaria en los niños (95,3%). A 31 de diciembre de 2008, la cohorte de niños infectados por TV de la CM estaba constituida por 261 pacientes, de los que 48 se habían quedado huérfanos de madre; estos niños vivieron el deterioro de la madre a causa de la enfermedad, con las graves repercusiones en la calidad de vida que este hecho implica, y afectando de manera significativa a su desarrollo. Además, se observó un cambio en la vía de transmisión de las madres a partir de 2002 (la principal vía era la heterosexual frente a ADVP), debido al aumento de la población inmigrante y a una modificación en el paradigma socioambiental, ya que estas madres no pertenecían a grupos con prácticas de riesgo, aunque sí mantuvieron contactos de riesgo. En cuanto a la TV, existe una asociación significativa entre el descenso de infecciones por el virus de la inmunodeficiencia humana (VIH) tipo 1 y los tratamientos antirretrovirales recibidos como profilaxis en el embarazo y el parto. Sin embargo, no puede decirse que la TV esté erradicada, por lo que sigue siendo un problema de salud pública relevante (AU)

The AIDS pandemic continues to be one of the main problems affecting development and safety throughout the world, in Spain and more specifically in the Community of Madrid(CM). The first to be affected were homosexual/bisexual men, followed by intravenous drug users and infection through heterosexual transmission, a route which affected women, and vertical transmission (VT). VT dominates in children (95.3%). At 31 December 2008, the cohort of children infected via VT in the CM was made up of 261 children. Of those children, 48 had lost their mothers after witnessing their deterioration due to the disease, which had serious repercussions on the children’s quality of life and substantially affected their development. Moreover, a change was seen in the route of transmission in mothers as of 2002, with the main route being heterosexual contact versus intravenous drug use. That change was brought about by the increase in the immigrant population and by a change in the socio-environmental paradigm since these mothers did not belong to groups with risk practices, but their sexual practices did involve contact that put them at risk. With regard to VT, there is a significant association between the decrease in HIV-1 infections and the taking of antiretroviral treatments like prophylaxis during pregnancy and birth. Nevertheless, VT has not yet been eradicated, which means it continues to be a relevant public health problem (AU)

Análisis socioeconómico y demográfico de la prevalencia en niños infectados por el virus de la inmunodeficiencia humana por transmisión vertical en la Comunidad de Madrid / A socio-economic and demographic analysis of the prevalence of paediatric HIV due to vertical transmission in the Community of Madrid

España sigue siendo uno de los países con tasas más altas deincidencia del virus de la inmunodeficiencia humana (VIH)/sidaen Europa occidental. La Comunidad de Madrid es la zona másafectada por la infección, con un total de 17.667 casos de sidahasta diciembre de 2008, lo que representa el 23,9% de loscasos registrados en toda España. En dicha comunidad se identificaroncomo áreas básicas de transmisión los distritos delsur y del norte-este, especialmente Usera, Puente de Vallecas,San Blas y Hortaleza, con una mayor prevalencia en el númerode casos de transmisión vertical. También se observó un cambiorespecto al flujo migratorio en los diferentes distritos de laciudad, coincidiendo los distritos con mayor censo de inmigrantescon un registro superior de las tasas de prevalencia de lainfección por el VIH por transmisión vertical. La prevalencia decasos de VIH por transmisión vertical se correlacionó significativamentecon el porcentaje de los inmigrantes (p= –0,544; p=0,011), personas sin estudios (p= 0,487; p= 0,025), mujeres desempleadas(p= 0,477; p= 0,029) y población con una renta percápita baja (p= –0,508; p= 0,019). Por otra parte, cabe pensarque estas zonas sur y norte-este, a su vez, pueden ser franjasimportantes para la propagación de otras enfermedades infecciosas,por lo que la presente memoria podría contribuir aldesarrollo de estrategias efectivas para la educación sobre elVIH, en cuanto a la prevención de situaciones de riesgo(AU)

Spain continues to be one of the countries with the highest HIV/AIDS incidence rates in Western Europe. The Community of Madrid is the area most affected by the infection, with a total of 17,667 cases of AIDS until December 2008, accounting for 23.9% of the cases recorded on a nation level. The south and north-eastern districts of the aforementioned Community, and especially Usera, Puente de Vallecas, San Blas and Hortaleza, were identified as basic transmission areas with a higher prevalence of cases of vertical transmission. A change was also observed with regard to the migration flow in the different districts of the city, with the districts with the highest numbers of immigrants coinciding with those with the highest recorded prevalence rates of cases of vertically transmitted HIV. The prevalence of cases of vertically transmitted HIV was significantly correlated with the percentage of migrants (p= –0.544; p=0.011), people without degrees (p= 0.487; p= 0.025), un employed women (p= 0.477; p= 0.029) and populations with a low per capitain come (p= –0.508; p= 0.019). Moreover, this leads to the thought that these south and north-eastern districts may also be important areas for the spread of other infectious diseases and, therefore, this report may contribute to the development of effective strategies for HIV education as regards the prevention of risk situations (AU)

Short communication: evaluation of the effect of enfuvirtide in 11 HIV-1 vertically infected pediatric patients outside clinical trials.

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Genetic complexity and gametocyte production of Plasmodium falciparum in Fulani and Mossi communities in Burkina Faso.

We have examined Plasmodium falciparum gametocyte prevalence, density and their genetic complexity among children of 2 sympatric ethnic groups (Mossi and Fulani) in villages in Burkina Faso. The 2 groups are known to have distinct differences in their susceptibility and immune responses to malaria. We used RT-PCR and sequence-specific probes to detect and type RNA of the gametocyte-specific protein Pfs48/45. There were no differences in detection rates of asexual forms and gametocytes among the 2 groups, using PCR and RT-PCR, respectively. However, there were significant differences in densities of asexual forms and gametocytes, which were both higher among Mossi than Fulani. Both asexual forms and gametocyte densities were influenced by age and ethnicity. Multiple-clone infections with more than 1 gametocyte genotype were equally prevalent among Fulani and Mossi. These differences can most probably be attributed to genetic differences in malaria susceptibility in the 2 ethnic groups.

Activation of matrix-metalloproteinase-2 and membrane-type-1-matrix-metalloproteinase in endothelial cells and induction of vascular permeability in vivo by human immunodeficiency virus-1 Tat protein and basic fibroblast growth factor.

Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV-uninfected individuals with classic KS, indicating that these mechanisms are operative in AIDS-KS. This suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.

Mechanism of paclitaxel activity in Kaposi's sarcoma.

Kaposi's sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-shaped cells predominantly of endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. At least in early stage, KS behaves as a reactive lesion sustained by the action of inflammatory cytokines and growth factors, has a polyclonal nature, and can regress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increased expression of antiapoptotic oncogenes. We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spindle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatment of certain neoplasms, has recently been found to be active also in patients with advanced HIV-associated KS. In this report we investigated the mechanism(s) of paclitaxel activity in KS. By using a model of experimental KS induced by the inoculation of KS-derived spindle cells in nude mice and primary cultures of KS spindle cells, we found that paclitaxel promotes regression of KS lesions in vivo and that it blocks the growth, migration, and invasion of KS cells in vitro. Furthermore, paclitaxel treatment promoted apoptosis and down-regulated Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. Our results suggest that paclitaxel interferes with KS by down-regulating Bcl-2 antiapoptotic effect.

Inflammatory cytokines synergize with the HIV-1 Tat protein to promote angiogenesis and Kaposi's sarcoma via induction of basic fibroblast growth factor and the alpha v beta 3 integrin.

The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi's sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1 beta, TNF-alpha, and IFN-gamma, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the alpha v beta 3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat. In contrast, no correlation is observed with the expression of alpha v beta 5, which is promoted by VEGF and binds Tat basic region. Finally, KS lesion formation induced by bFGF and Tat in nude mice is blocked by antagonists of RGD-binding integrins. Because alpha v beta 3 is an RGD-binding integrin that is highly expressed in primary KS lesions, where it colocalizes with extracellular Tat on vessels and spindle cells, these results suggest that alpha v beta 3 competitors may represent a new strategy for the treatment of AIDS-KS.

Virological and molecular parameters of HIV-1 infection of human embryonic astrocytes.

Two different strains of HIV-1, the lymphotropic HIV-IIIB and the monocytotropic HIV-Ba-L, were able to infect tertiary cultures of astrocytes established from the human embryonic brain. The infection did not require contact with infected cells, as astrocytes were exposed to infectious cell-free supernatants. Except for an early transient peak of p24 consistently observed after infection with HIV-Ba-L, the infection of astrocytes appeared to be nonproductive. However, viral production was always observed when infected astrocytes were cocultured with permissive cells (CEM-SS or monocytes). To exclude the possibility that undetectable levels of virus are chronically produced by astrocytes, we exposed permissive cells to p24 negative supernatants taken from infected cultures. In such conditions permissive cells were never infected. Infection of astrocytes by HIV-1 was further supported by the finding that provirus persisted in these cells. Indeed, by a nested PCR, we detected HIV-1 DNA even one month after infection. Moreover, at the transcriptional level we observed expression of the multiply spliced RNA (tat and nef primers). Noteworthy, this pattern of HIV-1 expression did not change appreciably when astrocytes were pretreated and cultivated in the presence of IL-1 beta. Altogether, our data support the concept that astrocytes may play a role in the spread of HIV-1 infection within the brain and in the pathogenesis of neuro-AIDS.