Impact of Antifibrotic Treatment on the Course of Schistosoma mansoni Infection in Murine Model

Administration of an antifibrotic agent as an adjunct to antihelmintic treatment with the objective of morbidity reduction was investigated in the murine schistosomiasis mansoni model. Antifibrotic, ß-aminopropionitrile treatment has a profound effect on the cellular matrix composition of the liver granuloma of Schistosoma mansoni infected mice when given alone, resulting in increase macrophage infiltration. These macrophages, in response to stimulation with soluble egg antigen or lipopolysaccharide produced elevated levels of nitric oxide but low levels of tumor necrosis factor alpha compared to untreated infected mice. This also correlated with reduced liver granuloma size. In spite of low numbers of eggs in the liver, mice receiving a combine treatment had a high level of resistance to a challenge infection compared with mice receiving only praziquantel. Those mice also exhibited a reduced lymphocyte proliferative response, similar to that of infected untreated mice. Antifibrotic treatment has an impact on the dynamic of the cellular nature of granulomas and impacts on the host immunity to infection

Immunological system and Schistosoma mansoni: co-evolutionary immunobiology. What is the eosinophil role in parasite-host relationship?

Schistosomes, ancestors and recent species, have pervaded many hosts and several phylogenetic levels of immunity, causing an evolutionary pressure to eosinophil lineage expression and response. Schistosoma mansoni adult worms have capitalized on the apparent adversity of living within the mesenteric veins, using the dispersion of eggs and antigens to other tissues besides intestines to set a systemic activation of several haematopoietic lineages, specially eosinophils and monocytes/macrophages. This activation occurs in bone marrow, spleen, liver, lymph nodes, omental and mesenteric milky spots (activation of the old or primordial and recent or new lymphomyeloid tissue), increasing and making easy the migration of eosinophils, monocytes and other cells to the intestinal periovular granulomas. The exudative perigranulomatous stage of the periovular reaction, which present hystolitic characteristics, is then exploited by the parasites, to release the eggs into the intestinal lumen. The authors hypothesize here that eosinophils, which have a long phylogenic story, could participate in the parasite - host co-evolution, specially with S. mansoni, operating together with monocytes/ macrophages, upon parasite transmission.

The role of the eosinophil-selective chemokine, eotaxin, in allergic and non-allergic airways inflammation

Blood eosinophilia and tissue infiltration by eosinophils are frequently observed in allergic inflammation and parasitic infections. This selective accumulation of eosinophils suggested the existence of endogenous eosinophil-selective chemoattractants. We have recently discovered a novel eosinophil-selective chemoattractant which we called eotaxin in an animal model of allergic airways disease. Eotaxin is generated in both allergic and non-allergic bronchopulmonary inflammation. The early increase in eotaxin paralled eosinophil infiltration in the lung tissue in both models. An antibody to IL-5 suppressed lung eosinophilia, correlating with an inhibition of eosinophil release from bone marrow, without affecting eotaxin generation. This suggests that endogenous IL-5 is important for eosinophil migration but does not appear to be a stimulus for eotaxin production. Constitutive levels of eotaxin observed in guinea-pig lung may be responsible for the basal lung eosinophilia observed in this species. Allergen-induced eotaxin was present mainly in the epithelium and alveolar macrophages, as detected by immunostaining. In contrast there was no upregulation of eotaxin by the epithelial cells following the injection of Sephadex beads and the alveolar macrophage and mononuclear cells surrounding the granuloma were the predominant positive staining cells. Eotaxin and related chemokines acting through the CCR3 receptor may play a major role in eosinophil recruitment in allergic inflammation and parasitic diseases and thus offer an attractive target for therapeutic intervention.

Adhesion and Co-stimulatory Molecules in the Pathogenesis of Hepatic and Intestinal Schistosomiasis Mansoni

Infection of a susceptible host with the blood fluke Schistosoma mansoni results in the formation of periovular granulomas and subsequent fibrosis in the target organs. Granulomogenesis and fibrogenesis are mediated by immunological events which require cell-cell and cell-matrix interactions. In this review, the role of adhesion and co-stimulatory molecules in the genesis of the schistosomal pathology (granulomogenesis and fibrogenesis) is outlined. These molecules provide essential immunological interactions not only for the initiation of granuloma formation but also for the maintenance and modulation of the schistosomal granuloma during chronic infection. Furthermore, the role of secreted soluble adhesion molecules in the different clinical forms and in the modulation of the schistosomal granuloma is discussed. Recent new insights into the role of adhesion molecules for the induction of pathology by other developmental stages of the parasite (other than eggs) will be presented.

Role of cytokines in the formation and downregulation of hepatic circumoval granulomas and hepatic fibrosis in Schistosoma mansoni-infected mice

Schistosoma mansoni infections are associated with a strong Th2 cytokine response. Treatment of mice with IL-12 or anti-IL-2 or anti-IL-4 before i.v. injection of eggs increased IFN-gamma production and downregulated Th2 responses and pulmonary granuloma size. Conversely, anti-IFN-gamma antibody treatment increased Th2 responses and granuloma size. Similar manipulation produced less dramatic results in infected mice. However, sensitization of mice with eggs + IL-12 before infection augmented the Th1 response and decreased Th2 cytokines, granuloma size and fibrosis. Antisera to IFN-gamma, TNF-alpha or IL-12 during IL-12-egg immunization partly restored granuloma size and fibrosis following infection. Variations in the size of granulomas in acute (8 week) infections may be influenced primarily by the number and state of activation of T cells. In chronic (12-16 week) infections immunologic downmodulation proceeded normally in mice without functional CD8+ cells and in IFN-gamma KO mice but not in B cell KO (muMT) mice or in mice deficient in FcR expression in spite of the fact that these mice downregulated their T cell and cytokine responses. It is evident that the participation of cytokines in granuloma formation and regulation is complicated and that the mechanisms controlling both these phenomena are likely to involve both T cells and antibody/FcR interactions.

Immunization with PIII, a fraction of Schistosoma mansoni soluble adult worm antigenic preparation, affects nitric oxide production by murine spleen cells

Nitric oxide (NO) is an important effector molecule involved in immune regulation and defense. NO produced by cytokine-activated macrophages was reported to be cytotoxic against the helminth Schistosoma mansoni. Identification and characterization of S. mansoni antigens that can provide protective immunity is crucial for understanding the complex immunoregulatory events that modulate the immune response in schistosomiasis. It is, then, essential to have available defined, purified parasite antigens. Previous work by our laboratory identified a fraction of S. mansoni soluble adult worm antigenic preparation (SWAP), named PIII, able to elicit significant in vitro cell proliferation and at the same time lower in vitro and in vivo granuloma formation when compared either to SEA (soluble egg antigen) or to SWAP. In the present work we report the effect of different in vivo trials with mice on their spleen cells ability to produce NO. We demonstrate that PIII-immunization is able to significantly increase NO production by spleen cells after in vitro stimulation with LPS. These data suggest a possible role for NO on the protective immunity induced by PIII.

Penetration Sites and Migratory Routes of Angiostrongylus costaricensis in the Experimental Intermediate Host (Sarasinula marginata)

The intermediate hosts of Angiostrongylus costaricensis are terrestrian molluscs, mostly of the family Veronicellidae. The present work aimed at clarifying more accurately the sites of penetration and the migratory routes of A. costaricensis in the tissue slugs and at verifying the pattern of the perilarval reaction at different times of infection. Slugs were individually infected with 5,000 L1, and killed from 30 min to 30 days after infection. From 30 min up to 2 hr after infection, L1 were found within the lumen of different segments of the digestive tube having their number diminished in more advanced times after exposition until complete disappearance. After 30 min of exposition, percutaneous infection occurred, simultaneously to oral infection. Perilarval reaction was observed from 2 hr of infection around larvae in fibromuscular layer, appearing later (after 6 hr) around larvae located in the viscera. A pre-granulomatous reaction was characterized by gradative concentration of amebocytes around larvae, evolving two well-organized granulomas. In this work we confirmed the simultaneous occurrence of oral and percutaneous infections. Perilarval reaction, when very well developed, defined typical granulomatous structure, including epithelioid cell transformation. The infection also caused a systemic mobilization of amebocytes and provoked amebocyte-endothelium interactions.

Evaluación de un nuevo método de sutura para la cirugía endoscopica transluminal a través de orificios naturales en un modelo animal

Natural Orifice Transluminal Endoscopic Surgery (NOTES) is a novel, potentially less invasive alternative to laparoscopic surgery. However, the problems of transluminal access and closure represent significant obstacles to its successful introduction in humans. Objective: to evaluate the feasibility and safety of a novel device designed for transluminal access and closure in a survival porcine model. Subjects: Four adult female Yorkshire pigs were used in the study. Interventions: While under general anesthesia, the animals were prepared with multiple tap water enemas followed by instillation of an antibiotic suspension and povidone-iodine lavage. At a distance of 15 to 20 cm from the anus, the prototype device (LSI Solutions, Victor, NY, USA) deployed a circumscribing purse-string suture around the planned incision site and subsequently used a blade mechanism to create a 2.5-cm linear incision. The transcolonic incision was then closed by cinching and securing the purse-string suture with a titanium knot by use of a separate hand-activated suture-locking device. Main Outcome Measurements: The animals were monitored daily for signs of peritonitis and sepsis and were survived for 14 days. The peritoneal cavity was examined for peritonitis, and the colonic incision site was examined for wound dehiscence, pericolic abscess formation, and gross adhesions. Tissue samples from both incisional and random peritoneal sites were obtained for histologic examination. Results: Transcolonic incision and closure were successful in all 4 animals. The device performed in a rapid and reproducible fashion. All animals recovered without septic complications. At necropsy, there was no evidence of peritonitis, abscesses, or wound dehiscence. Salpingocolonic and colovesicular adhesions were noted in 3 of 4 animals. Histologic examination revealed microabscesses at the incision site in all animals. Conclusions: The prototype incision and closure device represents a promising solution to the problems of transluminal access for NOTES. The presence of incision-related adhesions and microabscesses signal the need for further refinement in aseptic technique. 

Sedimentary record of the northward flight of India and its collision with Eurasia (Ladakh Himalaya, India)

Stratigraphic and petrographic analysis of the Cretaceous to Eocene Tibetan sedimentary succession has allowed us to reinterpret in detail the sequence of events which led to closure of Neotethys and continental collision in the NW Himalaya. During the Early Cretaceous, the Indian passive margin recorded basaltic magmatic activity. Albian volcanic arenites, probably related to a major extensional tectonic event, are unconformably overlain by an Upper Cretaceous to Paleocene carbonate sequence, with a major quartzarenite episode triggered by the global eustatic sea-level fall at the Cretaceous/Tertiary boundary. At the same time, Neotethyan oceanic crust was being subducted beneath Asia, as testified by calc-alkalic volcanism and forearc basin sedimentation in the Transhimalayan belt. Onset of collision and obduction of the Asian accretionary wedge onto the Indian continental rise was recorded by shoaling of the outer shelf at the Paleocene/Eocene boundary, related to flexural uplift of the passive margin. A few My later, foreland basin volcanic arenites derived from the uplifted Asian subduction complex onlapped onto the Indian continental terrace. All along the Himalaya, marine facies were rapidly replaced by continental redbeds in collisional basins on both sides of the ophiolitic suture. Next, foreland basin sedimentation was interrupted by fold-thrust deformation and final ophiolite emplacement. The observed sequence of events compares favourably with theoretical models of rifted margin to overthrust belt transition and shows that initial phases of continental collision and obduction were completed within 10 to 15 My, with formation of a proto-Himalayan chain by the end of the middle Eocene.

The identification and characterization of new immunogenic egg components: implications for evaluation and control of the immunopathogenic T cell response in schistosomiasis

In schistosomiasis, granuloma formation to parasite eggs signals the beginning of a chronic and potentially life-threatening disease. Granulomas are strictly mediated by CD4+ T helper (Th) cells specific for egg antigens; however, the number and identity of these T cell-sensitizing molecules are largely unknown. We have used monoclonal T cell reagents derived from egg-sensitized individuals as probes to track down, isolate and positively identify several egg antigens; this approach implicitly assures that the molecules of interest are T cell immunogens and, hence, potentially pathogenic. The best studied and most abundant egg component is the Sm-p40 antigen. Sm-p40 and its peptide 234-246 elicit a strikingly immunodominant Th-1-polarized response in C3H and CBA mice, which are H-2k strains characterized by severe egg-induced immunopathology. Two additional recently described T cell-sensitizing egg antigens are Schistosoma mansoni phosphoenolpyruvate carboxykinase (Sm-PEPCK) and thioredoxin peroxidase-1 (Sm-TPx-1). In contrast to Sm-p40, both of these molecules induce a more balanced Th-1/Th-2 response, and are relatively stronger antigens in C57BL/6 mice, which develop smaller egg granulomas. Importantly, Sm-p40 and Sm-PEPCK have demonstrated immunogenicity in humans. The findings in the murine model introduce the important notion that egg antigens can vary significantly in immunogenicity according to the host's genetic background. A better knowledge of the principal immunogenic egg components is necessary to determine whether the immune responses to certain antigens can serve as indicators or predictors of the form and severity of clinical disease, and to ascertain whether such responses can be manipulated for the purpose of reducing pathology.

Quantitave and qualitative interferences of pentoxifillyne on hepatic Schistosoma mansoni granulomas: effects on extracellular matrix and eosinophil population

Mast cells and eosinophils actively participate in tissue repair and are prominent components of Schistosoma mansoni granulomas. Since pentoxifillyne (PTX) is an immunomodulatory and antifibrotic substance, we aimed to characterize, by morphological techniques, the effect of this drug on fibrosis developed inside murine hepatic schistosomal granulomatous reaction, beyond the quantification of eosinophil and mast cell populations. The drug (1 mg/100 g animal weight) was administrated from 35 to 90 days post-infection, when the animals were killed. The intragranulomatous interstitial collagen network was analyzed by confocal laser scanning microscopy, the number of eosinophils and mast cells was quantified and the results were validated by t-student test. Treatment did not interfere on the granuloma evolution but caused a significant decrease in the total and involutive number of hepatic granulomas (p = 0.01 and 0.001, respectivelly), and in the intragranulomatous accumulation of eosinophils (p = 0.0001). Otherwise, the number of mast cells was not significantly altered (p = 0.9); however, it was positively correlated with the number of granulomatous structures (r = 0.955). In conclusion, PTX does not affect development and collagen deposition in S. mansoni murine granuloma, but decreases the intragranulomatous eosinophil accumulation possibly due to its immunomodulatory capability, interfering in cellular recruitment and/or differentiation.

Systematized stenting of Baerveldt shunts: techniques to reduce early post-operative hypotony

Purpose: To investigate the effect of the systematized use of intraluminal stents in Baerveldt shunts (BS) on early postoperative IOP control and complication rates. Methods: One hundred and twenty eyes with medically uncontrolled glaucoma were prospectively recruited to undergo BS implantation at Jules Gonin Eye Hospital, Switzerland. Baerveldt shunts were stented (full-length of the intraluminal tube) using a Supramid® 3.0 suture. A minority of shunts (37%) were also ligated intraoperatively and laser suture lysis performed postoperatively. Stent removals, either partial (retraction of 5mm) or complete, were carried out according to a predetermined protocol. Surgery was considered a success when IOP was ≤ 21mmHg and a minimum of 20% reduction from baseline was achieved with/without glaucoma medication (GMs). Hypotony related complications were defined as: choroidal effusions, shallow AC, hypotonous maculopathy or IOP≤5mmHg for over 2 weeks. Results: Mean age was 61.8 years (± standard deviation; ±21.5). Mean follow-up was 17.1 (±7.9) months. Mean preoperative IOP was 26.9 mmHg; mean IOP on the last visit 13.2 mmHg (p<0.001). At year one, the success rate was 87%. In 90% of eyes, IOP was ≤18 mmHg at last visit. Mean number of preoperatively GMs was 3.1; postoperatively 1.4 (p<0.001). Stent removals were performed in 87% of eyes (24% partial; 61% complete). 13% of eyes required no stent removal to reach target IOP. Complications were minor and infrequent (16%) and only 7% were hypotony related. Conclusions: Systematized use of intraluminal stents with Baerveldt aqueous shunts resulted in gradual and controlled IOP lowering with minimal hypotony-related complications. This may have important implications on clinical practice, given the rising rates of aqueous shunt implantation.

An alternative plate tectonic model for the Palaeozoic-Early Mesozoic Palaeotethyan evolution of Southeast Asia (northern Thailand-Myanmar)

An alternative model for the geodynamic evolution of Southeast Asia is proposed and inserted in a modern plate tectonic model. The reconstruction methodology is based on dynamic plate boundaries, constrained by data such as spreading rates and subduction velocities; in this way it differs from classical continental drift models proposed so far. The different interpretations about the location of the Palaeotethys suture in Thailand are revised, the Tertiary Mae Yuam fault is seen as the emplacement of the suture. East of the suture we identify an Indochina derived terrane for which we keep the name Shan-Thai, formerly used to identify the Cimmerian block present in Southeast Asia, now called Sibumasu. This nomenclatural choice was made on the basis of the geographic location of the terrane (Eastern Shan States in Burma and Central Thailand) and in order not to introduce new confusing terminology. The closure of the Eastern Palaeotethys is related to a southward subduction of the ocean, that triggered the Eastern Neotethys to open as a back-arc, due to the presence of Late Carboniferous-Early Permian arc magmatism in Mergui (Burma) and in the Lhasa block (South Tibet), and to the absence of arc magmatism of the same age East of the suture. In order to explain the presence of Carboniferous-Early Permian and Permo-Triassic volcanic arcs in Cambodia, Upper Triassic magmatism in Eastern Vietnam and Lower Permian-Middle Permian arc volcanites in Western Sumatra, we introduce the Orang Laut terranes concept. These terranes were detached from Indochina and South China during back-arc opening of the Poko-Song Ma system, due to the westward subduction of the Palaeopacific. This also explains the location of the Cathaysian West Sumatra block to the West of the Cimmerian Sibumasu block.

Osteoid osteoma and osteoid osteoma-mimicking lesions: biopsy findings, distinctive MDCT features and treatment by radiofrequency ablation.

OBJECTIVE: To report the biopsy findings of osteoid osteoma (OO) and OO-mimicking lesions, assess their distinctive multidetector computed tomography (MDCT) features and evaluate treatment by radiofrequency ablation (RFA). METHODS: In this multicentric retrospective study, 80 patients (54 male, 26 female, mean age 24.1 years, range 5-48) with presumed (clinical and MDCT features) OO were treated by percutaneous RFA between May 2002 and June 2009. Per-procedural biopsies were always performed. The following MDCT features were assessed: skeletal distribution and location within the bone, size, central calcification, surrounding osteosclerosis and periosteal reaction. Clinical success of RFA was evaluated. RESULTS: Histopathological diagnoses were: 54 inconclusive biopsies, 16 OO, 10 OO-mimicking lesions (5 chronic osteomyelitis, 3 chondroblastoma, 1 eosinophilic granuloma, 1 fibrous dysplasia). OO-mimicking lesions were significantly greater in size (p = 0.001) and presented non-significant trends towards medullary location (p = 0.246), moderate surrounding osteosclerosis (p = 0.189) and less periosteal reaction (p = 0.197), compared with OO. Primary success for ablation of OO-mimicking lesions was 100% at 1 month, 85.7% at 6 and 12 months, and 66.7% at 24 months. Secondary success was 100%. CONCLUSION: Larger size, medullary location, less surrounding osteosclerosis and periosteal reaction on MDCT may help differentiate OO-mimicking lesions from OO. OO-mimicking lesions are safely and successfully treated by RFA.