The potential role of necroptosis in clinical diseases (Review).

As an important type of programmed cell death in addition to apoptosis, necroptosis occurs in a variety of pathophysiological processes, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors. It can be triggered by a variety of factors, such as tumor necrosis factor receptor and Toll­like receptor families, intracellular DNA and RNA sensors, and interferon, and is mainly mediated by receptor­interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain­like protein. A better understanding of the mechanism of necroptosis may be useful in the development of novel drugs for necroptosis­related diseases. In this review, the focus is on the molecular mechanisms of necroptosis, exploring the role of necroptosis in different pathologies, discussing their potential as a novel therapeutic target for disease therapy, and providing suggestions for further study in this area.

Kaposi's sarcoma-associated herpesvirus seropositivity is associated with parasite infections in Ugandan fishing communities on Lake Victoria islands.

We investigated the impact of helminths and malaria infection on Kaposi's sarcoma associated herpesvirus (KSHV) seropositivity, using samples and data collected from a cluster-randomised trial of intensive versus standard anthelminthic treatment. The trial was carried out in 2012 to 2016 among fishing communities on Lake Victoria islands in Uganda. Plasma samples from 2881 participants from two household surveys, the baseline (1310 participants) and the final (1571 participants) surveys were tested for KSHV IgG antibody responses to K8.1 and ORF73 recombinant proteins using ELISA. The baseline survey was carried out before the trial intervention while the final survey was carried out after three years of the trial intervention. Additionally, a subset sample of 372 participants from the final survey was tested for IgE, IgG and IgG4 antibody concentrations to S. mansoni adults worm antigen (SWA) and S. mansoni egg antigen (SEA) using ELISA. Infection by helminths (S. mansoni, N. americanus, T. trichiura and S. stercoralis) was diagnosed using real-time PCR, urine circulating cathodic antigen (CCA) and stool microscopy (Kato-Katz method) while malaria infection was diagnosed using microscopy. We analysed the relationship between helminth and malaria infections and KSHV seropositivity using regression modelling, allowing for survey design. At baseline, 56% of the participants were male while 48% of the participants were male in the final survey. The most prevalent helminth infection was S. mansoni (at baseline 52% and 34% in the final survey by microscopy, 86% by CCA and 50% by PCR in the final survey). KSHV seropositivity was 66% (baseline) and 56% (final survey) among those 1-12 years and >80% in those 13+ years in both surveys; malaria parasitaemia prevalence was 7% (baseline) and 4% (final survey). At baseline, individuals infected with S. mansoni (detected by microscopy) were more likely to be KSHV seropositive (aOR = 1.86 (1.16, 2.99) p = 0.012) and had higher anti-K8.1 antibody levels (acoefficient = 0.03 (0.01, 0.06) p = 0.02). In the final survey, S. mansoni (by microscopy, adjusted Odds Ratio (aOR = 1.43 (1.04-1.95), p = 0.028) and malaria parasitaemia (aOR = 3.49 (1.08-11.28), p = 0.038) were positively associated with KSHV seropositivity. Additionally, KSHV seropositive participants had higher S. mansoni-specific IgE and IgG antibody concentrations in plasma. Furthermore, HIV infected individuals on cART were less likely to be KSHV seropositive compared to HIV negative individuals (aOR = 0.46 (0.30, 0.71) p = 0.002). Schistosoma species skew the immune response towards Th2 and regulatory responses, which could impact on KSHV reactivation if co-infected with both organisms.

Response to comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation".

According to the literature review, CO2 insufflation on parasitic myoma implantation is not well studied, and we concur that our study is related to "Morcellation-induced parasitic myomas." We did not compare CO2 insufflation to non-insufflation in our study. The reason is the efficacy of gasless laparoscopic myomectomy and morcellation is not well established and this modality is seldom performed. Moreover, the effects of pneumoperitoneum on mesothelial cells and the role of the entire peritoneal cavity as a cofactor in adhesion formation have become well established, the role of CO2 insufflation in the establishment of parasitic myomas has not yet been studied. As such, more in-depth and well-designed studies for the role of CO2 insufflation are needed.

Cancer and life-history traits: lessons from host-parasite interactions.

Despite important differences between infectious diseases and cancers, tumour development (neoplasia) can nonetheless be closely compared to infectious disease because of the similarity of their effects on the body. On this basis, we predict that many of the life-history (LH) responses observed in the context of host-parasite interactions should also be relevant in the context of cancer. Parasites are thought to affect LH traits of their hosts because of strong selective pressures like direct and indirect mortality effects favouring, for example, early maturation and reproduction. Cancer can similarly also affect LH traits by imposing direct costs and/or indirectly by triggering plastic adjustments and evolutionary responses. Here, we discuss how and why a LH focus is a potentially productive but under-exploited research direction for cancer research, by focusing our attention on similarities between infectious disease and cancer with respect to their effects on LH traits and their evolution. We raise the possibility that LH adjustments can occur in response to cancer via maternal/paternal effects and that these changes can be heritable to (adaptively) modify the LH traits of their offspring. We conclude that LH adjustments can potentially influence the transgenerational persistence of inherited oncogenic mutations in populations.

Situación de la hidatidosis humana en la provincia de Santiago del Estero, República Argentina

La Hidatidosis Humana es una enfermedad grave, de evolución crónica, causadda por el estadio larval del echinococcus granulosus que en su ciclo biológico convierte al ser humano en un huésped intermediario, causando estragos en la salud de quien la padecen por las secuelas orgánicas y psicológicas ocasionadas por la implantación del tumores originados por dicho parásito, en diversos órganos de la economía.

Human Hydatidosis is a serious disease of chronic evolution caused by the larval stage of the Echinococcosis Granulosis. During its biological cycle it turns the human being into an intermediate host. It still causes havoc to the health of those who suffer from it because of the organic and psychological sequels caused by the implantation of tumors originate by such parasite.

Diagnóstico parasitológico e molecular de enteroparasitos entre crianças residentes e funcionários de uma institução beneficente para menores no município de Niterói-RJ, Brasil / Parasitological and molecular diagnosis of enteroparasites among resident children and employees of a child care institution at Niterói city, RJ, Brazil

Os enteroparasitos são causa importante de agravos à saúde humana e podem interferir de forma significativa no desenvolvimento infantil. Embora as formas de transmissão sejam bemdocumentadas, a desinformação e as precárias condições socioeconômicas de alguns segmentos da população ainda são fatores que contribuem para a manutenção de parasitos no País, viabilizando a transmissão. Este estudo foi realizado entre crianças residentes e funcionários de uma instituiçãofilantrópica religiosa, situada na cidade de Niterói, Rio de Janeiro, consistindo em um ciclo de palestras educativas, seguido da coleta de amostras fecais para diagnóstico coproparasitológico.Foram coletadas 68 amostras fecais frescas e encontrados enteroparasitos em 41 delas (60 por cento),sendo o Blastocystis hominis o parasito mais prevalente (44 por cento). Adicionalmente, sete amostrasforam positivas para o complexo Entamoeba histolytica/E. dispar, sendo uma confirmada como E. histolytica pelo ELISA para pesquisa de coproantígeno. Em 37 amostras de fezes foi pesquisadaa presença de E. histolytica e E. dispar pela técnica de Nested-PCR. Entre essas, 12 (32 por cento) amplificaram um fragmento de 195 pb quando utilizados primers específicos para E. dispar, não havendo amplificação de qualquer produto com os primers de E. histolytica. Estudo feito no entornoda instituição revelou acúmulo de lixo e a presença de saídas de esgoto no peridomicílio, as quais desembocavam nas proximidades da área de lazer das crianças. É possível que esses pontos sejam responsáveis pela contaminação do solo e mesmo incriminados como uma das possíveis fontes deinfestação para as crianças.

Intestinal parasites are important agents of human diseases, besides being responsible for impairingchildhood development. Although transmission is well known, lack of information and precarioussocial and economic conditions are risk factors that allow maintenance of parasite cycles, favoringtransmission. This study was carried out among resident children and employees of a Catholic Institution, located in Niterói, Rio de Janeiro, and consisted of delivering lectures and collectingfresh stool samples, which were processed through the Willis and Hoffman, Pons and Janermethods. Enteroparasites were found in 41 samples (60 percent) and Blastocystis hominis was the mostprevalent (44 percent). Additionally, in seven samples where microscopic examination was positive forthe E. histolytica/E. dispar complex an ELISA was employed to detect E. histolytica and only onereacted positively in the immunoassay. In 37 samples a Nested-PCR was carried out for detectionof E. histolytica and E. dispar and in 12 samples (32 percent) a product with 195 bp was observed usingE. dispar primers, while there was no amplification product with E. histolytica specific primers. As the Institution has a good pattern of hygiene not related with the results, a superficial analysis of its peripheral area was carried out and showed lots of garbage in the neighborhood and sewage outflowinto the play area of the Institution. We concluded that these points may be responsible for the soil contamination and could be incriminated as one of the sources of infection in the children.

The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.

The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.

Leptin, a tool of parasites?

One common physiological phenomenon that is involved both in infectious and in malignant processes is the reduction in appetite: disease anorexia. An increase in plasma levels of leptin with inflammation is thought to be involved in this process. However, from an evolutionary perspective, in certain cases, it would be more adaptive for an internal parasite to stimulate the appetite of the host instead of causing its suppression. We tested whether a parasitic infection with the larvae of the helminth parasite Taenia taeniaformis affects the levels of appetite-regulating proteins, such as leptin, ghrelin and neuropeptide-Y (NPY) in wild yellow-necked mouse (Apodemus flavicollis). We found that infected mice had lower plasma levels of leptin and increased levels of NPY than the uninfected subjects. Ghrelin levels were not associated with the occurrence of the parasites; however, these levels strongly correlated with the levels of NPY. This study suggests a possible manipulation by parasitic larvae of appetite regulation in infected subjects.

Hypereosinophilic syndrome, Churg-Strauss syndrome and parasitic diseases: possible links between eosinophilia and thrombosis.

Throughout the past decade, a possible role of eosinophils in blood coagulation and thrombosis has been suggested. We conducted a Pubmed (MEDLINE) search of case and series referring to any kind of thrombotic events described in three conditions characterised by persistent blood eosinophilia, i.e. the hypereosinophilic syndrome (HES), the Churg Strauss syndrome (CSS), and parasitic infestations from 1966 to date. One hundred and ninety-two articles were found regarding thrombotic events in HES and CSS, and 209 cases of thrombosis were extracted. One hundred and seventy- seven articles dealing with parasitic diseases and thrombosis were found, but only 15 manuscripts reporting thrombosis of unknown origin in 22 patients were selected. In HES, arterial thromboses were more frequent than in CSS (p=0.006), representing almost half of the cases (45%), while venous and mixed artero-venous thrombosis were respectively 28% and 27%. In contrast, in CSS there was a predominance of venous thrombosis (56%, p=0.006), with arterial thrombosis representing 38% of total thrombotic events, and mixed thrombosis being the least frequent (4%). The higher incidence of arterial thrombosis in HES patients can be explained by the common cardiac involvement (64% of patients). In the 22 patients with parasitoses and thrombosis, 15 had arterial thrombosis (68%) and 7 had venous thrombosis (32 %). Literature analysis shows that there are numerous reports of thrombotic events in patients with eosinophil-related disorders supporting a role for eosinophils in thrombosis. This observation raises the problem of prevention and treatment of thromboembolism particularly in HES and CSS patients.

Primer reporte de pseudomiasis intestinal humana por Eristalis tenax (Diptera, Syrphidae) en zona semiárida urbana del estado Falcón, Venezuela / First report of human intestinal pseudomiasis by Eristalis tenax (Diptera, Syrphidae) in urban semiarid area from Falcon state, Venezuela

Pseudomiasis es el término empleado cuando se considera que las larvas y/o huevos de moscas se adquieren accidentalmente per os y atraviesan con inmediatez a lo largo del tracto digestivo. Se documenta un caso de una pseudomiasis intestinal por larvas de Eristalis tenax (Diptera: Syrphidae) en una paciente femenina de 39 años de edad, proveniente de un sector periférico de la ciudad de Coro, estado Falcón, Venezuela. La paciente observó inmediatamente la presencia de la larva viva en sus heces. Aunque refirió sufrir eventualmente de cólicos, al examen físico se presentó normal. La paciente aparentemente no sufre de trastornos mentales, y posee un nivel socioeconómico bajo. El presente trabajo constituye el primer reporte documentado de una pseudomiasis entérica por E. tenax en la zona semiárida del estado Falcón, en la región nor-occidental de Venezuela.

Pseudomyiasis is the term used for the accidental entrapment of swallowed fly maggots and/or eggs immediately passing through the digestive tract. We report a case of intestinal pseudomyasis caused by the larvae of the cosmopolitan drone fly Eristalis tenax (Diptera: Syrphidae) in a 39 year old woman, resident in a suburban sector from Coro city, Falcon state, Venezuela. The patient immediately noticed a living larva in her stool. Although patient referred eventually became colic, her physical examination was normal, with no mental disturbance. She was in a low socioeconomic level. This is the first report of an enteric pseudomyasis by E. tenax in the semiarid zone of Falcon state, in the northwestern region of Venezuela.

Measuring fitness of Kenyan children with polyparasitic infections using the 20-meter shuttle run test as a morbidity metric.

BACKGROUND: To date, there has been no standardized approach to the assessment of aerobic fitness among children who harbor parasites. In quantifying the disability associated with individual or multiple chronic infections, accurate measures of physical fitness are important metrics. This is because exercise intolerance, as seen with anemia and many other chronic disorders, reflects the body's inability to maintain adequate oxygen supply (VO(2) max) to the motor tissues, which is frequently linked to reduced quality-of-life in terms of physical and job performance. The objective of our study was to examine the associations between polyparasitism, anemia, and reduced fitness in a high risk Kenyan population using novel implementation of the 20-meter shuttle run test (20mSRT), a well-standardized, low-technology physical fitness test. METHODOLOGY/PRINCIPAL FINDINGS: Four villages in coastal Kenya were surveyed during 2009-2010. Children 5-18 years were tested for infection with Schistosoma haematobium (Sh), malaria, filaria, and geohelminth infections by standard methods. After anthropometric and hemoglobin testing, fitness was assessed with the 20 mSRT. The 20 mSRT proved easy to perform, requiring only minimal staff training. Parasitology revealed high prevalence of single and multiple parasitic infections in all villages, with Sh being the most common (25-62%). Anemia prevalence was 45-58%. Using multiply-adjusted linear modeling that accounted for household clustering, decreased aerobic capacity was significantly associated with anemia, stunting, and wasting, with some gender differences. CONCLUSIONS/SIGNIFICANCE: The 20 mSRT, which has excellent correlation with VO(2), is a highly feasible fitness test for low-resource settings. Our results indicate impaired fitness is common in areas endemic for parasites, where, at least in part, low fitness scores are likely to result from anemia and stunting associated with chronic infection. The 20 mSRT should be used as a common metric to quantify physical fitness and compare sub-clinical disability across many different disorders and community settings.

Immunoendocrine mechanisms associated with resistance or susceptibility to parasitic diseases during pregnancy.

During pregnancy, the mammalian endocrine system plays a leading role in maintaining the fetus, characterized by an increase in the level of hormones such as progesterone, oestradiol and some gonadotropic hormones. The immune system participates during pregnancy by self-regulating to prevent fetus rejection. The distinctive type of immunity during gestation is characterized by an increase in levels of Th2 type cytokines IL-4, IL-6 and IL-10, concomitant with a decrease in IL-2, INF-gamma and TNF-alpha levels. Along pregnancy, sex steroids and factors associated with them regulate the immune response. In this way, endocrine and immunologic factors have an impact on the pregnant female's susceptibility or resistance to parasitic diseases. There are three main mechanisms proposed to explain this susceptibility or resistance: (1) sex steroids influence the host's immune system; (2) hormones acting directly on the parasites inhibit or promote their reproduction, or (3) the two effects can occur simultaneously within a network of immuno-endocrine host-parasite interactions, mediated by hormones, cytokines, antibodies and other factors interacting directly and bidirectionally. The present work reviews recent literature concerning the most frequent parasitic infections during pregnancy and discusses the mechanisms implied in the establishment, growth, reproduction or elimination of the parasite.

Ceramide-enriched membrane domains in infectious biology and development.

Ceramide has been shown to be critically involved in multiple biological processes, for instance induction of apoptosis after ligation of death receptors or application of gamma-irradiation or UV-A light, respectively, regulation of cell differentiation, control of tumor cell growth, infection of mammalian cells with pathogenic bacteria and viruses or the control of embryo and organ development to name a few examples. Ceramide molecules form distinct large domains in the cell membrane, which may serve to re-organize cellular receptors and signalling molecules. Thus, in many conditions, ceramide may be involved in the spatial and temporal organisation of specific signalling pathways explaining the pleiotrophic effects of this lipid. Here, we focus on the role of ceramide and ceramide-enriched membrane domains, respectively, in bacterial infections, in particular of the lung, and sepsis. We describe the role of ceramide for infections with Neisseriae gonorhoeae, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, we discuss newly emerging aspects of the cellular function of ceramide, i.e. its role in germ line and embryo development.

The clinical spectrum of lymphatic disease.

Lymphatic disease is quite prevalent, and often not well clinically characterized. Beyond lymphedema, there is a broad array of human disease that directly or indirectly alters lymphatic structure and function. The symptomatic and objective presentation of these patients can be quite diverse. In this review, we have attempted to provide a systematic overview of the subjective and objective spectrum of lymphatic disease, with consideration of all of the categories of disease that primarily or secondarily impair the functional integrity of the lymphatic system. Lymphedema is discussed, along with chromosomal disorders, lymphangioma, infectious diseases, lymphangioleiomyomatosis, lipedema, heritable genetic disorders, complex vascular malformations, protein-losing enteropathy, and intestinal lymphangiectasia.

Exploring the non-viral infectious causes of cancer.

This article discusses the contribution made by non-viral infections to the global burden of cancer and describes the bacterial, protozoan and fungal organisms that are believed to cause cancer, either directly or indirectly.

Infectious muscle disease.

Infectious muscle diseases have very different aetiologies. The viral myositides are proved by clinical and laboratory evidences in various etiologic settings (Influenza A and B, Coxsackie and HIV). The bacterial myositis was considered in the near past a tropical disease, but in our days with migration of people from South to North and the endemia of AIDS it became a problem of the "civilized" world. On the other hand, tuberculous endemia in Central-Eastern Europe, including Romania, results in quite high incidence of osteoarticular tuberculosis. In this section the authors take into consideration some clinical entities, such as psoas abscess, postanginal sepsis, beta-haemolytic streptococcus infection and that caused by Koch bacillus. Other rare musculoskeletal infections such as gas gangrene and non-clostridial anaerobic myonecrosis are also reviewed. Immune depression caused by underlying diseases, therapies, alcoholism or old age is often encountered. The parasitic aetiologies include infestations with Trichinella spiralis, Cysticercus cellulosae, Toxoplasma and Amoeba. The contribution of imagistic methods to diagnosis is emphasised. Ultrasonography associated with CT imaging are usually used, while MRI should be reserved for cases in which axial skeleton is involved. The management is based on appropriate antibiotic therapy and surgery.

Olfactory-mediated parasite recognition and avoidance: linking genes to behavior.

A major cost of social behavior is the increased risk of exposure to parasites and infection. Animals utilize social information, including chemical signals, to recognize and avoid conspecifics infected with either endoparasites or ectoparasites. Here, we briefly discuss the relations among odors, parasite recognition, and avoidance, and consider some of the associated hormonal, neural, and genomic mechanisms. In rodents, odor cues mediate sexual and competitive interactions and are of major importance in individual recognition and mate detection and choice. Female mice distinguish between infected and uninfected males by urinary odors, displaying aversive response to, and avoidance of, the odors of infected individuals. This reduces both the likelihood of the transmission of parasites to themselves and allows females to select for parasite-free males. This set of olfactory and mate choice responses can be further modulated by social factors such as previous experience and exposure to infected males and the mate choices of other females. Male mice, who also face the threat of infection, similarly distinguish and avoid parasitized individuals by odor, thus reducing their likelihood of infection. This recognition and avoidance of the odors of infected individuals involves genes for the neuropeptide, oxytocin (OT), and estrogenic mechanisms. Mice with deletions of the oxytocin gene [OT knockout mice (OTKO)] and mice whose genes for estrogen receptor (ER)-alpha or ER-beta have been disrupted [ER knockout mice (ERKO), alpha-ERKO and beta-ERKO] are specifically impaired in their recognition of, aversion to, and memory of the odors of infected individuals. These findings reveal some of the genes involved in the mediation of social recognition in the ecologically relevant context of parasite recognition and avoidance.

Infection and the gut.

Gastrointestinal symptoms, including vomiting, are caused by a variety of infective organisms in children, many of which are self-limiting and resolve within a week, but others are potentially much more serious in their consequences. Diarrhea, vomiting and abdominal pain are common but nonspecific symptoms. Investigation is dictated by the likely causative organism, given the age and presentation of the child. The role of bacteria in the pathogenesis of necrotizing enterocolitis, recognition that Yersinia, Campylobacter and Salmonella may produce symptoms difficult to distinguish clinically from appendicitis, the viral causes of idiopathic intussusception, the occurrence of intussusception after administration of rotavirus vaccine, and the evidence incriminating mycobacterium avium subspecies paratuberculosis in the aetiology of Crohn disease are discussed.

Infecções por helmintos do gênero Echinococcus / Helminths infections of Echinococcus

Neste artigo são revisados os aspectos mais importantes das infecções por Echinococcus spp., com ênfase nos aspectos epidemiológicos, etiológicos, imunopatogênicos, clínicos e terapêuticos, como forma de delinear a situação atual.