Thymic atrophy induced by Plasmodium berghei ANKA and Plasmodium yoelii 17XL infection.

The thymus is the anatomical site where T cells undergo a complex process of differentiation, proliferation, selection, and elimination of autorreactive cells which involves molecular signals in different intrathymic environment. However, the immunological functions of the thymus can be compromised upon exposure to different infections, affecting thymocyte populations. In this work, we investigated the impact of malaria parasites on the thymus by using C57BL/6 mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL; these lethal infection models represent the most severe complications, cerebral malaria, and anemia respectively. Data showed a reduction in the thymic weight and cellularity involving different T cell maturation stages, mainly CD4-CD8- and CD4+CD8+ thymocytes, as well as an increased presence of apoptotic cells, leading to significant thymic cortex reduction. Thymus atrophy showed no association with elevated serum cytokines levels, although increased glucocorticoid levels did. The severity of thymic damage in both models reached the same extend although it occurs at different stages of infection, showing that thymic atrophy does not depend on parasitemia level but on the specific host-parasite interaction.

The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System.

The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-ß-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.

Monocyte Locomotion Inhibitory Factor confers neuroprotection and prevents the development of murine cerebral malaria.

Cerebral malaria (CM) is a neurological complication derived from the Plasmodium falciparum infection in humans. The mechanisms involved in the disease progression are still not fully understood, but both the sequestration of infected red blood cells (iRBC) and leukocytes and an exacerbated host inflammatory immune response are significant factors. In this study, we investigated the effect of Monocyte Locomotion Inhibitory Factor (MLIF), an anti-inflammatory peptide, in a well-characterized murine model of CM. Our data showed that the administration of MLIF increased the survival and avoided the neurological signs of CM in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. MLIF administration down-regulated systemic inflammatory mediators such as IFN-γ, TNF-α, IL-6, CXCL2, and CCL2, as well as the in situ expression of TNF-α in the brain. In the same way, MLIF reduced the expression of CD31, CD36, CD54, and CD106 in the cerebral endothelium of infected animals and prevented the sequestration of iRBC and leucocytes in the brain microvasculature. Furthermore, MLIF inhibited the activation of astrocytes and microglia and preserved the integrity of the blood-brain barrier (BBB). In conclusion, our results demonstrated that the administration of MLIF increased survival and conferred neuroprotection by decreasing neuroinflammation in murine CM.

In vitro and in silico studies of terpenes, terpenoids and related compounds with larvicidal and pupaecidal activity against Culex quinquefasciatus Say (Diptera: Culicidae).

BACKGROUND: In order to develop new larvicidal agents derived from phytochemicals, the larvicidal activity of fifty molecules that are constituent of essential oils was evaluated against Culex quinquefasciatus Say. Terpenes, terpenoids and phenylpropanoids molecules were included in the in vitro evaluation, and QSAR models using genetic algorithms were built to identify molecular and structural properties of biological interest. Further, to obtain structural details on the possible mechanism of action, selected compounds were submitted to docking studies on sterol carrier protein-2 (SCP-2) as possible target. RESULTS: Results showed high larvicidal activity of carvacrol and thymol on the third and fourth larval stage with a median lethal concentration (LC50) of 5.5 and 11.1 µg/mL respectively. Myrcene and carvacrol were highly toxic for pupae, with LC50 values of 31.8 and 53.2 µg/mL. Structure-activity models showed that the structural property π-bonds is the largest contributor of larvicidal activity while ketone groups should be avoided. Similarly, property-activity models attributed to the molecular descriptor LogP the most contribution to larvicidal activity, followed by the absolute total charge (Qtot) and molar refractivity (AMR). The models were statistically significant; thus the information contributes to the design of new larvicidal agents. Docking studies show that all molecules tested have the ability to interact with the SCP-2 protein, wherein α-humulene and ß-caryophyllene were the compounds with higher binding energy. CONCLUSIONS: The description of the molecular properties and the structural characteristics responsible for larvicidal activity of the tested compounds were used for the development of mathematical models of structure-activity relationship. The identification of molecular and structural descriptors, as well as studies of molecular docking on the SCP-2 protein, provide insight on the mechanism of action of the active molecules, and the information can be used for the design of new structures for synthesis as potential new larvicidal agents.

Microsurgical reconstruction in limb salvage due to a giant cell tumor of the distal radius. Case report.

The giant cell tumor of bone is one of the most controversial neoplasms due to growth patterns that may present. The case reported shows a very aggressive tumor in a classic location, but key to hand function. Rather than treat with radical surgery, was planned and performed a wide resection with an ulnar-carpus arthrodesis and microsurgical reconstruction of the defect throught an anterolateral thigh flap. The multidisciplinary approach of bone neoplasms produce a positive impact on patients.

El tumor óseo de células gigantes es una de las neoplasias más controversiales debido a los patrones de crecimiento que pueden presentar. El caso reportado muestra un tumor muy agresivo en una localización clásica, pero clave para la función de la mano. En lugar de tratarla mediante cirugía radical, se planeó y realizó una resección amplia con artrodesis cúbito-carpiana y la reconstrucción microquirúrgica del defecto mediante un colgajo anterolateral de muslo. El abordaje multidisciplinario de las neoplasias óseas repercute positivamente en los pacientes.

[Origin of surgical metastatic bone disease]. / Origen de la enfermedad ósea metastática quirúrgica.

BACKGROUND: Metastatic bone disease should be considered as a public health problem. The alterations it may cause include pain that is refractory to medical treatment, metabolic instability, pathologic fractures and spinal disorders. MATERIAL AND METHODS: The primary tumor site that led to the need for surgery was investigated in a series of patients with a diagnosis of metastatic bone disease. The bone involved and the histology of the lesions were also studied. RESULTS: Kidney cancer was the one that most frequently required a surgical procedure; it was followed by breast and prostate cancer. The primary tumor was not found in 6.36% of cases. The bones affected by the lesions studied were as follows in order of occurrence: femur, spine, humerus and pelvis. Adenocarcinoma was the most frequent histological diagnosis. DISCUSSION: The diagnosis of metastatic bone disease should always be considered in patients over forty years of age with skeletal lesions, preferably lytic. CONCLUSIONS: In this study, kidney cancer, the proximal limbs and adenocarcinomas were the variables that most frequently produced metastatic bone lesions that warranted a surgical procedure.

[The art of diagnosing bone tumors]. / El arte de diagnosticar tumores oseos.

Bone tumors are infrequent and at times difficult to diagnose, especially when the medical team is not familiar enough with this type of pathology. A close relationship between the surgeon, the radiologist and the pathologist is necessary to diagnose bone neoplasias. A thorough case history and physical exam are mandatory to get the first clinical impression. After the former aspects, conventional radiology offers a powerful tool for the characterization and differential diagnosis of bone tumors and seudotumor lesions. Patient age and radiologic findings are very important to reach a diagnosis. Supplementary studies contribute to stage the lesion and guide the biopsy and they are necessary to plan the definitive surgery. Biopsy is a very important procedure that should be performed at the hospital by the surgeon who will later perform the definitive surgery. When the pathologist gets the tissue specimen, regardless of the type of biopsy, the entire patient history should be considered before making the final diagnosis.

[Massive allograft and wrist arthrodesis for a giant cell tumor of the distal radius. Report of two cases and literature review]. / Aloinjerto masivo y artrodesis de la muñieca para un tumor de células gigantes del radio distal. Reporte de dos casos y revisión de la literatura.

INTRODUCTION: The giant cell tumor represents 5% of all the primary bone tumors and 20% of the benign bone neoplasias. The most common locations are the distal femur and the proximal tibia (50%) as well as the distal radius (10%). Treatment methods include the intralesional resection of the latent and active tumors, and broad resection for the aggressive lesions. The wrist reconstruction after broad resection of the distal radius represents a challenge for the orthopedic surgeon. OBJECTIVE: To present 2 clinical cases of patients diagnosed with giant cell tumor of the distal radius who were treated with broad resection and placement of a massive allograft with wrist arthrodesis. To perform a bibliographic review and the analysis of the different treatment methods described. MATERIAL AND METHODS: Description of the treatment and course of each case, as well as a bibliographic review and the analysis of the treatments found. RESULTS: Radiologic data of the allograft integration at 11 months and a functionality which was compatible with all the activities of daily living. DISCUSSION: The massive allograft of the distal radius with wrist arthrodesis represents a very safe and appropriate option for the reconstruction of this anatomic segment after broad resection.

[Complications of oncologic hemipelvectomy]. / Complicaciones en hemipelvectomía oncológica.

INTRODUCTION: The treatment of bone pelvic tumors is associated with high compli cation rates. The surgeon usually has to decide between external and internal hemipelvectomy. OBJECTIVE: To describe the frequency of infectious and wound-related complications in a group of patients undergoing hemipelvectomy for different types of musculoskeletal tumors. MATERIAL AND METHODS: This is an observational, descriptive, retrospective study with a single measurement. We observed the complications that occurred in eight patients treated with different modalities of hemipelvectomy without reconstruction. Infectious and wound-related complications were described as follows: a) no complications, b) seroma, c) hematoma, d) mild infectious process, e) moderate infectious process, f) severe infectious process, and g) flap necrosis. Internal hemipelvectomies were classified usin Enneking and Dunham's criteria. RESULTS: Eight patients were assessed. Five patients underwent external hemipelvectomy and three internal hemipelvectomy. Two patients had no complications (25%), three had seromas (37.5%), one patient wa treated for a mild infectious process (12.5%) and two for severe infectious processes (25%). 75% of the patients had complications. No cases of flap necrosis were observed. DISCUSSION: The surgeon decides which the best procedure in each case is. Different types of complications of hemipelvectomy have been reported; the most common ones are infectious processes and flap necrosis, and our results are similar to those reported by other authors. CONCLUSIONS: Pelvic bone tumors are usually large masses that hinder the achievement of tumor-free surgical margins. There is a high likelihood of postoperative wound complications.

Parasitaemia levels in Plasmodium chabaudi infected-mice modify IFN-gamma and IL-10 expression after a homologous or heterologous challenge.

CB6F1 mice infected with the nonlethal Plasmodium chabaudi chabaudi AS suffer parasitaemia levels up to 40% (full parasitaemia, FP) and develop both homologous and heterologous (against the lethal Plasmodium yoelii 17XL) protective immunity. However, if mice are treated with anti-malarial drug when parasitaemia is below 10% (low parasitaemia, LP), they only develop homologous immunity. For the better understanding of this interesting dissociation related to the degree of parasitaemia, in this work, we studied the genetic expression of some cytokines. We found that during primary parasitaemia both FP and LP mice showed at first a TNF-alpha, IL-2 and IFN-gamma response which is followed by an IL-4 and IL-10 response. When FP and LP mice were challenged with either the homologous (FP + AS and LP + AS mice) or the heterologous parasite (FP + 17XL and LP + 17XL mice), we observed that LP + 17XL mice, which failed to develop heterologous immunity and succumbed to the challenge, showed a stronger IFN-gamma and a weaker IL-10 expression than FP + 17XL mice, which developed heterologous immunity and survived the challenge. The importance and the possible implications of these findings are discussed.

Perezone and its isomer isoperezone induce caspase-dependent and caspase-independent cell death.

In this study, we investigated the cytotoxic effect of perezone, a constituent isolated from the roots of Perezia spp. and of its synthetic isomer isoperezone on the K562 human leukemia cell line. Perezone showed greater cytotoxic effect than isoperezone but both compounds were found to induce cytotoxicity trough a caspase-dependent and a caspase-independent mechanisms; important changes in their light scattering properties, phosphatidylserine translocation and mitochondrial membrane potential disruption were detected by cytometry. The mechanism of death induction of each compound showed interesting concentration-dependent differences. Neither compound induced the apoptosis inducing factor.

Apoptosis in lymph nodes and changes in lymphocyte subpopulations in peripheral blood of pigs infected with porcine rubulavirus.

In a first experiment, five pigs were inoculated intranasally with porcine rubulavirus (PoRV) at 5 days of age and killed 7 days post-infection (pi). In a second experiment, four pigs were infected with the same virus at 17 days of age and killed at 9 or 15 days pi. Control piglets in each experiment received uninfected cell culture supernate. All PoRV-infected pigs developed respiratory and nervous signs, and histological lesions of non-suppurative encephalitis and interstitial pneumonia. All control pigs remained clinically normal and did not have histological lesions. Significantly increased numbers of apoptotic cells were detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) in tonsil and lymph nodes of the pigs infected at 7 days of age and killed at 7 days pi. Significantly increased percentages of CD2(+) and CD8(+) T lymphocytes were also found in peripheral blood of these animals at this time, while the percentages of CD4(+) and MHC class II lymphocytes were significantly reduced. Significantly increased numbers of apoptotic cells were detected in lymphoid tissues of the pigs infected at 17 days of age and killed at 9 days pi. The percentages of CD2(+), CD8(+) and MHC class II lymphocytes in peripheral blood were also significantly increased at this time; the percentage of MHC class II lymphocytes remained elevated at 15 days pi. These results indicate that induction of apoptosis is an important mechanism in the pathogenesis of PoRV infection in young pigs, and that this virus induces changes in lymphocyte subpopulations in peripheral blood.

Mouse splenic CD4+ and CD8+ T cells undergo extensive apoptosis during a Plasmodium chabaudi chabaudi AS infection.

The presence and phenotype of apoptotic lymphocytes was studied in spleen cell suspensions taken from CB6F1 mice infected with Plasmodium chabaudi chabaudi AS. High levels of apoptotic cells were found, associated with high parasitaemias and splenomegaly. This was also accompanied by expansion and disarray of spleen white pulp. Apoptosis levels lowered when parasitaemia was cleared, but were still higher than in normal mice. At this time, the spleen was diminishing in size and the white pulp was contracting and rearranging. When parasitaemia was patent, the cells most affected by apoptosis were CD4+ T cells followed by CD8+ T cells, and to a lesser extent B220+ B cells. When parasitaemia was cleared, CD8+ T cells and B220+ B cells returned to basal levels of apoptosis, while CD4+ T cells still had higher apoptosis levels than normal mice. A similar pattern of lymphocyte subpopulation apoptosis was found in infected BALB/c mice, despite the fact that, for this mouse model, it has been reported that B cells are the cells that are most affected by apoptosis. We consider that the high levels of apoptosis in CD4+ T cells when parasitaemias are still high are not easily explained by a normal mechanism of down regulation of the immune response.