Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes-gender imbalance and splenic marginal zone B-cell lymphoma-emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer-deficient animals.

An ultrasound-based referential of body height-adjusted normal liver organometry in school children from Bokito in rural Cameroon.

The grading system for ultrasonographic assessment of Schistosoma mansoni morbidity is crucial for evaluation of control programs. This requires prior definition of normal liver organometric ranges in the population from the endemic area. A cross-sectional study was conducted in a S. mansoni endemic area in rural Cameroon. 1002 Participants were screened and 234 of them, free from all common liver-affecting diseases in the area (schistosomiasis, malaria, hepatitis B and C) and with no ultrasonographic signs of liver disease were selected and their liver parameters measured by ultrasonography. All statistics were considered significant for p-values < 0.05. Normal dimensions of livers lobe sizes, portal vein wall thickness and portal vein diameters are reported. The liver organometric data are presented for the entire study population as a whole and separately for males and females as prediction plots, with observed values and fitted regression line with 95% confidence. Reference ranges for liver parameters (size, portal vein thickness and diameter) adjusted for body height established in the current study are novel for Cameroon. The prediction plots generated should improve the accuracy of the assessment of liver morbidity by ultrasonography in the region.

Pathological roles of MRP14 in anemia and splenomegaly during experimental visceral leishmaniasis.

Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL.

Comparison Between Immuno-Clinicopathological Features of Experimental and Human Visceral Leishmaniasis by Leishmania donovani.

BACKGROUND: Current understanding of visceral leishmaniasis (VL) depends upon the experimental model. Different species of mouse and hamster have been used as model for VL. It is already evident that the mouse model of VL is not a true reflection of the pathology of human visceral leishmaniasis (HuVL). On the other hand, hamster is reported to be a better model of VL to study the progressive as well as chronic pathology of the disease. OBJECTIVE: To compare immuno-clinicopathological features of experimental VL (ExVL) and HuVL by Leishmania donovani. METHODS: Hamsters were infected (15 and 60 days) and their immunological, clinical and biochemical parameters were compared with the cases of HuVL. RESULTS: Splenomegaly and hepatomegaly were observed in infected hamster post-infection, which are hallmarks of symptomatic HuVL cases. Clinical, biochemical and pathological manifestations of infected hamsters were consistent with that of HuVL cases, except parameters such as body weight, uric acid, alkaline phosphatase and random glucose. The absence of clear dichotomy between pro- and anti-inflammatory cytokines was also observed after infection at different sites of infection. CONCLUSION: Our results suggest that the golden hamster (Mesocricetus auratus), infected via the intracardiac route, constitutes a very good model for the study of experimental Leishmania donovani infections. However, certain differences in clinical presentations of infected hamsters (via intracardiac route) with HuVL suggest further optimization of this animal model like route of infection such as intradermal, which is more close to natural infection.

Splenic findings in patients with acute babesiosis.

PURPOSE: To identify the imaging manifestations of splenic involvement in babesiosis, a potentially fatal tick-borne zoonosis with multi-organ involvement. METHODS: In our single center HIPAA compliant IRB-approved study, we performed a retrospective search of the electronic medical record at our institution to identify all patients with known or suspected acute babesiosis from 2000 to 2017. We then reviewed all abdominal imaging of patients with confirmed disease to identify incidence and characteristics of splenic involvement. Splenomegaly was determined using a height- and gender-adjusted reference. RESULTS: After exclusions, 63 patients with a confirmed diagnosis of babesiosis and contemporaneous imaging of the spleen were included in the final cohort. Within this cohort, 56 (89%) had splenomegaly at a minimum and 13 had splenic infarcts. Splenic rupture was present in eight patients with three having a pseudoaneurysm. In 14 patients with follow-up imaging, the spleen subsequently diminished in size. One additional patient with ruptured spleen underwent emergency splenectomy prior to imaging. CONCLUSION: Although the literature suggests splenic involvement is a rare finding, acute parasitemia with babesiosis commonly affects the spleen. Recognition of this association can aid radiologists diagnosing splenic involvement in babesiosis and can lead to appropriate intervention in the minority with splenic hemorrhage.

A man in his 80s with arthritis and persistent fever. / En mann i 80-årene med leddgikt og vedvarende feber.

BACKGROUND: Febrile illness is a common clinical problem and frequently caused by bacterial and viral infections. When blood cultures are negative and symptoms persist despite empirical antibiotic treatment, clinicians must consider other differential diagnoses including malignancy, rheumatologic disease and parasitic infections. CASE PRESENTATION: A Norwegian male in his eighties experienced febrile illness during a stay in Southern Spain. Upon return to Norway, he was hospitalized with fever, weight-loss, enlarged spleen, pancytopenia and hypergammaglobulinemia. After failing to respond to broad-spectrum antibiotics and antifungals, he was diagnosed with visceral leishmaniasis and Leishmania infantum was confirmed by PCR and sequencing of spleen biopsy and blood. INTERPRETATION: With increasing migration and tourism, doctors in non-endemic countries should be familiar with visceral leishmaniasis.

Case Report: Hyperreactive Malarial Splenomegaly Syndrome Diagnosed with Loop-Mediated Isothermal Amplification and Treated with Artemisinin-Based Combination Therapy.

Hyperreactive malarial splenomegaly syndrome (HMSS) is a rare cause of splenomegaly in the Western world. Hyperreactive malarial splenomegaly syndrome is caused by an aberrant immunological response to chronic malaria exposure in endemic areas. Revised Fakunle's criteria may be helpful for diagnosis: persistent splenomegaly (> 10 cm below the costal margin), increased anti-Plasmodium antibodies, increased IgM levels, exclusion of other causes of splenomegaly or malignancy, and a favorable response to antimalarial treatment. We describe the case of a 16-year-old patient, who recently arrived in Belgium from Guinea with a history of splenomegaly and B symptoms in whom HMSS diagnosis was achieved, thanks to the loop-mediated isothermal amplification method. To our knowledge, this is also the first described case treated by dihydroartemisinin/piperaquine.

IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. donovani Infected Mice.

Persistent Leishmania donovani infection is characterized by chronic inflammation, immune suppression, and splenomegaly. We have previously reported that the transcription factor interferon regulatory factor 5 (IRF-5) is largely responsible for inducing the inflammatory response and maintaining protective Th1 cells following L. donovani inoculation in mice. However, the cellular source responsible for these effects is yet unknown. In this study, we investigated the role of IRF-5 in myeloid cells during experimental visceral leishmaniasis (VL). First, we show that the LysM-Cre mouse model is not suited for investigating gene expression in splenic myeloid cells during experimental VL. Using the Cd11c-Cre mouse model, we demonstrate that Irf5 expression in CD11c+ cells (monocytes, dendritic cells, activated macrophages) is essential for inducing splenomegaly and for recruiting myeloid cells to the spleen, but it is not required for the development or maintenance of parasite-specific IFNγ-producing CD4 T cells. CD11c-specific Irf5-/- mice are more resistant to L. donovani infection, suggesting that the induction of splenomegaly is detrimental to the host.

Limited parasite acquisition by non-native Lepomis gibbosus (Actinopterygii: Centrarchidae) at two ponds in the Upper Rhine basin, Germany.

Metazoan parasite communities of Lepomis gibbosus (Centrarchidae), one of the most successfully introduced fish species in Europe, were studied at two isolated ponds (Knielingen, Tropfen) along the Upper Rhine in Germany. Nine parasite taxa were observed, including North American species co-introduced to Europe (ancyrocephalid monogeneans, diplostomid trematodes), circumpolar species infecting L. gibbosus in both their native and non-native ranges (bothriocephalid cestodes) and locally acquired parasitic nematodes. Both parasite communities consisted predominantly of North American species. Acquisition of local parasites was not observed at Tropfen, where the fish community comprised just two species, with L. gibbosus dominant. Low prevalence and abundance of acquired parasites was found at Knielingen, which supported a diverse fish community. At Tropfen, a high abundance of the North American parasite Posthodiplostomum centrarchi probably contributed to the lower condition index, hepatomegaly and splenomegaly observed. Due to low local parasite competency, L. gibbosus appears to have no significant impact on parasite dynamics in affected habitats.

Correlation between the values of circulating blood elements with the size of spleen in the presence of schistosomal splenomegaly

Abstract Purpose: To evaluate a possible relationship between the size of the spleen and values of circulating blood elements in patients with schistosomatic splenomegaly. Methods: ixty one patients with hepatosplenic schistosomiasis mansoni underwent a clinical exam and peripheral venous blood was collected for a hemogram. The erythrocyte, hemoglobin, hematocrit, leukocyte, and platelet values were determined. All patients underwent abdominal ultrasound to measure the spleen. The hematological test results were compared to the size of the spleen. Results: The size of the spleen varied from 14.0 to 28.4 (19.9 ± 3.7) cm according to the ultrasound image. Thrombocytopenia was observed 58 (95%) patients, leukopenia in 55 (90%) patients, and anemia in 32 (52.4%) patients. Leukopenia was proportional to splenomegaly. Conclusion: Schistosomal splenomegaly leads to leukopenia in direct proportion to the size of the spleen.

Co-infection: the outcome of Plasmodium infection differs according to the time of pre-existing helminth infection.

Although helminth-Plasmodium coinfections are common in tropical regions, the implications of this co-existence for the host immune response are poorly understood. In order to understand the effect of helminth infection at different times of coinfection on the immune response against Plasmodium infection, BALB/c mice were intraperitoneally infected with Taenia crassiceps (Tc). At 2 (Tc2) or 8 (Tc8) weeks post-infection, mice were intravenously infected with 1 × 103 Plasmodium yoelii (Py) 17XL-parasitized red blood cells. Py 17XL-single-infected mice developed cachexia, splenomegaly, and anemia, and died at 11 days post-infection. Importantly, Tc2 + Py-coinfected mice showed increased survival of 58% on day 11, but developed pathology (cachexia and splenomegaly) and succumbed on day 18 post-coinfection, this latter associated with high levels of IL-1ß and IL-12, and reduced IFN-γ in serum compared with Py 17XL-single-infected mice. Interestingly, Tc8 + Py-coinfected mice showed increased survival up to 80% on day 11 and succumbed on day 30 post-coinfection. This increased survival rate conferred by chronic helminth infection was associated with a decreased pathology and mixed inflammatory-type 1/anti-inflammatory-type 2 immune profile as evidenced by the production of high levels of IL-12 and IL-10, and reduced TNF-α from macrophages, high levels of IL-4 and IL-10, and low levels of IFN-γ from spleen cells. Also high serum levels of IL-1ß, TNF-α, IL-12, IL-4, and IL-10, but a significant reduction of IFN-γ were observed. Together, these data indicate that polarization of the cell-mediated response modulated by a pre-existing helminth infection differentially impacts on the host immune response to Py 17XL in a time-dependent manner.

[Clinical characteristics of 16 newly discovered advanced schistosomiasis patients in Dongpo District, Meishan City, Sichuan Province].

OBJECTIVE: To understand the clinical characteristics of newly discovered advanced schistosomiasis patients in Dongpo District, Meishan City, Sichuan Province, so as to provide the reference for enhancing the clinicians' awareness for diagnosis and treatment of this disease and improving the therapeutic effect. METHODS: The data of medical records and schedule of case survey of 16 newly discovered advanced schistosomiasis patients in Dongpo District, Meishan City, Sichuan Province were collected and analyzed. RESULTS: The mean age of the 16 newly discovered advanced schistosomiasis patients was 63 years, and there were 10 cases at ages of over 60 years. The 16 cases included 8 men and 8 women, and 10 cases were detected in the historical hyper-endemic areas. There were 11 cases with an ascitic type of advanced schistosomiasis, 4 cases with a megalosplenia type, and one case with a colon proliferation type. The primary initial symptoms mainly included ascites, splenomegaly, hypersplenism and portal hypertension. Following inpatient treatments, 15 cases achieved clinical improvments. CONCLUSIONS: It is necessary to enhance the prevention and control of advanced schistosomiasis. If the patients with portal hypertension, hepatosplenomegaly, upper gastrointestinal hemorrhage visit a doctor, the clinicians should pay much attention to advanced schistosomiasis and they need to comprehensively analyze the clinical data in combination with the epidemiological information, clinical features and laboratory examinations, and make a correct diagnosis and give treatments timely.

Visceral leishmaniasis from a non-endemic Himalayan region of Nepal.

Visceral leishmaniasis (VL) is endemic to the southern plains of Nepal. Here, we report the first case of VL from a non-endemic Himalayan region of Nepal. The patient presented with a history of high-grade fever, splenomegaly, and anemia but had not traveled to a VL-endemic region. Visceral leishmaniasis was diagnosed following microscopic detection of the Leishmania species amastigote in a bone marrow aspirate, positive result for the rK39 test, and further validation by nested polymerase chain reaction (PCR). The patient was treated with 5 mg/kg liposomal amphotericin B and was clinically improved upon discharge. Our result suggests that VL is expanding towards non-endemic regions of Nepal, and it should therefore be considered that VL surveillance systems be strengthened, particularly for non-program districts and VL be included as a differential diagnosis in febrile illnesses.

Quantifying malaria endemicity in Ethiopia through combined application of classical methods and enzyme-linked immunosorbent assay: an initial step for countries with low transmission initiating elimination programme.

BACKGROUND: In the context of reduced transmission of malaria, it is essential to re-evaluate and determine the level of transmission as it guides re-orientation of control measures which is appropriate to local disease epidemiology. However, little is known about level of malaria transmission in Ethiopia. The present study aimed to investigate the level of malaria transmission through combined application of classical methods and enzyme-linked immunosorbent assay (EIA) in low transmission settings of Ethiopia. METHODS: This study was conducted in June 2016 on 763 apparently healthy children 2-9 years of age. Children were recruited from ten sites representing different malaria transmission settings in Ethiopia. Splenomegaly rate, infection rate and EIA antibody test were used to determine endemicity. The data were analysed using SPSS 21.0 and Stata 12.0. RESULTS: The overall prevalence of malaria parasitaemia was 2.49% (95% CI 1.38-3.59) and 2.36% (95% CI 1.28-3.44) as detected using rapid diagnostic test and microscopy, respectively. Plasmodium falciparum accounted for 62.63% of the infections. The prevalence of parasitaemia significantly varied by altitude and localities; the highest (5.8%) in areas below 1500 m above sea level. Overall, splenomegaly rate was 1.70% (95% CI 0.78-0.2.66%), making the overall malaria transmission hypoendemic. Infection rate was higher among males (2.7%), but rate of splenomegaly was higher in females. Incongruent with spleen rate and parasitaemia, EIA showed a higher level of cumulative exposure to malaria with spatially localized and highly heterogeneous transmission. Overall, 126 (18.75%, 95% CI 15.79-21.71) of the children were positive for total malaria antibodies with significant variations with altitude, age and sex; the higher in areas of < 1500 m asl (25.8%), children ≥ 5 years (22.1%) and among males (20.9%). CONCLUSIONS: Splenomegaly and parasitaemia are not good measures to show variations in the levels of malaria transmission in reduced and/or low endemic settings. The malaria antibody (i.e. serological) test seems to be a good measure of malaria endemicity showing greater degree of heterogeneity and localized risk of transmission. Thus, malaria elimination efforts need to be supported with serological indicators to identify patterns of foci of transmission to set priorities for interventions.

Hepatic schistosomiasis with massive splenomegaly: a case report and literature review.

Schistosomiasis is a parasitic disease caused by Schistosoma species. Intestinal and hepatic schistosomiases are the most common forms of chronic disease. We describe a case of a 26-year old patient from Eritrea who was referred to our hospital with abdominal pain and diarrhea. The diagnosis of hepatosplenic schistosomiasis was made by liver biopsy and the patient was treated with praziquantel. Hepatic schistosomiasis is characterised by deposition of schistosomal eggs in the liver which results in a host cell immune response and leads to granuloma formation and neoangiogenesis. This is hallmarked by different grades of periportal fibrosis with portal hypertension leading to splenomegaly. Normal liver architecture is preserved and periportal fibrosis can be reversible if treated adequately and timely. With a recent native schistosomiasis cluster report from France and the expected influx to Europe of persons from regions endemic for schistosomiasis, increased awareness of this disease in healthcare practitioners is needed. We review the epidemiology, pathogenesis, clinical presentation and treatment of schistosomiasis.

HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis.

Inflammation, although responsible for controlling infection, is often associated with the pathogenesis of chronic diseases. Leishmania donovani, the causative agent of visceral leishmaniasis, induces a strong inflammatory response that leads to splenomegaly and ultimately immune suppression. Inflamed tissues are typically characterized by low levels of oxygen, a microenvironment that triggers the hypoxia-inducible transcription factor 1α (HIF-1α). Although HIF-1α plays an integral role in dendritic cell function, its involvement in the generation of protective Th1 responses against Leishmania has not yet been studied. Here we demonstrate that HIF-1α inhibits IL-12 production in dendritic cells, limiting therefore Th1 cell development. Indeed, depletion of HIF-1α in CD11c+ cells resulted in higher and sustained expression of IL-12 and complete abrogation of IL-10. Moreover, CD11c-specific HIF-1α-deficient mice showed higher frequencies of IFN-γ-producing CD4 T cells in the spleen and bone marrow and, consequently, a significantly reduced parasite burden in both organs. Taken together, our results suggest that HIF-1α expression in dendritic cells largely contributes to the establishment of persistent Leishmania infection and may therefore represent a possible therapeutic target.

Praziquantel Targets M1 Macrophages and Ameliorates Splenomegaly in Chronic Schistosomiasis.

Splenomegaly is a common feature of many infectious diseases, including schistosomiasis japonica. However, the immunopathogenesis and the treatment of splenomegaly due to schistosomiasis have been largely neglected. Praziquantel (PZQ), a classical schistosomicide, has been demonstrated by us and others to have antifibrotic and anti-inflammatory activities against schistosomiasis. In this study, we investigated the effect of PZQ on alleviating the splenomegaly caused by Schistosoma japonicum infection in mice. The results showed that the number of macrophages, especially the number of M1 macrophages, was significantly increased in the enlarged spleens of infected mice (P < 0.001). After PZQ treatment for 4 weeks, the number of splenic macrophages, especially the number of M1 macrophages, was significantly reduced (P < 0.001) by the way of apoptosis, and another schistosomicide, mefloquine, had no effect either on the splenomegaly or on reducing the number of macrophages. Furthermore, by using the murine macrophage line RAW 264.7, we found that PZQ could inhibit the formation of the NLRP3 inflammasome and attenuate phagocytic activity in M1 macrophages. Thus, our studies suggest that PZQ plays a powerful role in ameliorating the splenomegaly caused by S. japonicum infection, which presents a new strategy for the therapy of splenomegaly resulting from other pathological conditions.

Correlation between the values of circulating blood elements with the size of spleen in the presence of schistosomal splenomegaly.

PURPOSE: To evaluate a possible relationship between the size of the spleen and values of circulating blood elements in patients with schistosomatic splenomegaly. METHODS: ixty one patients with hepatosplenic schistosomiasis mansoni underwent a clinical exam and peripheral venous blood was collected for a hemogram. The erythrocyte, hemoglobin, hematocrit, leukocyte, and platelet values were determined. All patients underwent abdominal ultrasound to measure the spleen. The hematological test results were compared to the size of the spleen. RESULTS: The size of the spleen varied from 14.0 to 28.4 (19.9 ± 3.7) cm according to the ultrasound image. Thrombocytopenia was observed 58 (95%) patients, leukopenia in 55 (90%) patients, and anemia in 32 (52.4%) patients. Leukopenia was proportional to splenomegaly. CONCLUSION: Schistosomal splenomegaly leads to leukopenia in direct proportion to the size of the spleen.

The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry.

Schistosomiasis is a neglected parasitic disease that affects millions of people worldwide and is caused by helminth parasites from the genus Schistosoma. When caused by S. mansoni, it is associated with the development of a hepatosplenic disease caused by an intense immune response to the important antigenic contribution of adult worms and to the presence of eggs trapped in liver tissue. Although the importance of the spleen for the establishment of immune pathology is widely accepted, it has received little attention in terms of the molecular mechanisms operating in response to the infection. Here, we interrogated the spleen proteome using a label-free shotgun approach for the potential discovery of molecular mechanisms associated to the peak of the acute phase of inflammation and the development of splenomegaly in the murine model. Over fifteen hundred proteins were identified in both infected and control individuals and 325 of those proteins were differentially expressed. Two hundred and forty-two proteins were found upregulated in infected individuals while 83 were downregulated. Functional enrichment analyses for differentially expressed proteins showed that most of them were categorized within pathways of innate and adaptive immunity, DNA replication, vesicle transport and catabolic metabolism. There was an important contribution of granulocyte proteins and antigen processing and presentation pathways were augmented, with the increased expression of MHC class II molecules but the negative regulation of cysteine and serine proteases. Several proteins related to RNA processing were upregulated, including splicing factors. We also found indications of metabolic reprogramming in spleen cells with downregulation of proteins related to mitochondrial metabolism. Ex-vivo imunophenotyping of spleen cells allowed us to attribute the higher abundance of MHC II detected by mass spectrometry to increased number of macrophages (F4/80+/MHC II+ cells) in the infected condition. We believe these findings add novel insights for the understanding of the immune mechanisms associated with the establishment of schistosomiasis and the processes of immune modulation implied in the host-parasite interactions.