Interleukin-18 Antagonism Improved Histopathological Conditions of Malaria Infection in Mice

Background: Interleukin 18 (IL-18) exerts pleiotropic roles in many inflammatory-related diseases including parasitic infection. Previous studies have demonstrated the promising therapeutic potential of modulating IL-18 bioactivity in various pathological conditions. However, its involvement during malaria infection has yet to be established. In this study, we demonstrated the effect of modulating IL-18 on the histopathological conditions of malaria infected mice. Methods: Plasmodium berghei ANKA infection in male ICR mice was used as a model for malaria infection. Modulation of IL-18 release was carried out by treatment of malarial mice with recombinant mouse IL-18 (rmIL-18) and recombinant mouse IL-18 Fc chimera (rmIL-18Fc) intravenously. Histopathological study and analysis were performed on major organs including brain, liver, spleen, lungs and kidney. Results: Treatment with rmIL-18Fc resulted in significant improvements on the histopathological conditions of the organs in malaria-infected mice. Conclusion: IL-18 is an important mediator of malaria pathogenesis and targeting IL-18 could prove beneficial in malaria-infected host.Key Words: Malaria, Interleukin-18, Plasmodium berghei, Histopathology     

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis

Clinical Rheumatology - Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare...     

Exploring the fuzzy border between senolytics and senomorphics with chemoinformatics and systems pharmacology

Biogerontology - Senescent cells accumulate within tissues during aging and secrete an array of pro-inflammatory molecules known as senescent-associated secretory phenotype (SASP), which contribute...     

HCV serotypes in Brazilian patients.

OBJECTIVE: To investigate the prevalence of the different types of hepatitis C virus (HCV) in a population of chronic HCV carriers using the Murex HCV serotyping 1-6 assay. METHODS: All serum samples from these patients had a positive nested PCR HCV reaction. The sera were submitted to ELISA, modified, for the identification of antibodies against HCV serotypes 1, 2, 3, 4, 5 and 6 (Murex HCV serotyping 1-6 assay). RESULTS: The viral serotype was identified in 166 (75.8%) of the 219 patients, 108 (65.11%) males and 58 (34.9%) females. Patient age ranged from 12 to 73 years, with a mean of 41.1 years. The form of acquisition of the disease most frequently reported was blood transfusion. The results showed a predominance of type 1 (70.0%), followed by type 3 (22.3%) and type 2 (4.2%). CONCLUSION: Samples presenting low and very close optical density readings may lead to discrepant diagnoses concerning HCV serotypes and should be confirmed by genotyping. The serotyping can be useful in clinical practice and can be of help in establishing the prognosis of the disease, also favoring epidemiologic studies independently of the technology required for genotyping tests.     

Step‐down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

Objective

To evaluate the feasibility and outcome of the step‐down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA).

Methods

Fifty‐seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single‐agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated.

Results

When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (± SEM) of survival on treatment was 0.273 ± 0.09 for CSA and 0.852 ± 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups.

Conclusion

Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step‐up approach) may be more appropriate in early RA.

     

Leukocyte and platelet activation in patients with giant cell arteritis and polymyalgia rheumatica: A clue to thromboembolic risks?

Ischemia is a leading causes of morbidity in giant cell arteritis (GCA). We studied circulating platelets and leukocytes in patients with GCA and with polymyalgia rheumatica. Normal healthy donors (>60 a) served as controls. Patients had a significantly greater fraction of platelets expressing P-selectin, of platelet–Nph and platelet–Mo aggregates, and of Nph and Mo expressing tissue factor. These differences were correlated with the percentage of platelets expressing P-selectin and were not influenced by clinical features or by systemic inflammation. Activated circulating leukocytes and platelets could contribute to indolent vessel inflammation and possibly to thromboembolic events in patients with systemic large vessel vasculitis.     

Detection of a recurring mutation in the human growth hormone-releasing hormone receptor gene

OBJECTIVE: Mutations in the gene encoding for the GH-releasing hormone receptor (GHRHR) have been recently described in patients with familial isolated GH deficiency (IGHD) type IB. To date, all reported mutations have been found in kindreds sharing common ancestors. The only exception is a T to A transversion which causes a substitution of histidine for leucine in codon 144 (L144H) and creates a DraIII restriction site. This mutation was described in two families with different ethnic background residing in two different continents (Europe and North America). DESIGN: We searched for GHRHR mutations in a new family with IGHD from a third continent (South America) and found the affected individuals to be homozygous for the same L144H change. We performed linkage analysis with intra- and para-genic polymorphisms to determine if the three families carrying the L144H allele are related. RESULTS: Linkage analysis studies demonstrated that one of the three families does not share the same para- and intragenic GHRHR polymorphisms with the other two. CONCLUSIONS: The L144H mutation has arisen at least twice and should be considered for initial genetic analysis in patients with familial IGHD in whom the a GHRHR mutation is suspected.     

Evidence of Hantavirus Infection among Bats in Brazil

Hantaviruses are zoonotic viruses harbored by rodents, bats, and shrews. At present, only rodent-borne hantaviruses are associated with severe illness in humans. New species of hantaviruses have been recently identified in bats and shrews greatly expanding the potential reservoirs and ranges of these viruses. Brazil has one of the highest incidences of hantavirus cardiopulmonary syndrome in South America, hence it is critical to know what is the prevalence of hantaviruses in Brazil. Although much is known about rodent reservoirs, little is known regarding bats. We captured 270 bats from February 2012 to April 2014. Serum was screened for the presence of antibodies against a recombinant nucleoprotein (rN) of Araraquara virus (ARAQV). The prevalence of antibody to hantavirus was 9/53 with an overall seroprevalence of 17%. Previous studies have shown only insectivorous bats to harbor hantavirus; however, in our study, of the nine seropositive bats, five were frugivorous, one was carnivorous, and three were sanguivorous phyllostomid bats.Hantaviruses (family Bunyaviridae) are present throughout the globe in rodents, bats, and shrews.¹ Humans exposed to rodent excreta from hantaviral reservoirs may develop life-threatening diseases. However, none of the other reservoirs are associated with human illness presently.^1,2 Bats (order Chiroptera) are known to harbor a broad diversity of emerging zoonotic pathogens.² Their ability to fly and social behavior favors maintenance, evolution, and spread of pathogens.^1,2 The prevailing hypothesis has been that hantaviruses have coevolved with their rodent reservoirs over millions of years.^1,3 With the recognition of new species of hantavirus in bats in Africa and Asia,⁴ Guo and others⁵ hypothesized that hantaviruses originated primarily in bats and then spilled over into rodents and shrews, but it seems that shrews are the original hosts from which the viruses jumped into both rodents and bats.³ To determine if New World bats in Brazil may harbor hantaviruses, we screened bat sera for antibodies that react against the recombinant nucleoprotein (rN) of Araraquara hantavirus (ARAQV).Bats were collected at five ecologically distinct sites in the northeast region of São Paulo state (sites 1–3) and north region of Minas Gerais state (sites 4 and 5), southeastern Brazil (Figure 1 and 9 and one specimen per species by trap-night was anesthetized to collect blood by cardiac puncture; blood samples were stored in cryovials and flash-frozen in liquid nitrogen. At sites 4 and 5, five specimens per trap-night were randomly selected for blood collection. All bats were handled and sampled according to Sikes and others¹⁰ guidelines. This research project, along with its procedures and protocols, is in accordance with Brazilian environment and wildlife protection laws and regulations, and have been approved by the Chico Mendes Institute of Biodiversity Conservation (Ministry of Environment, Brasília, Distrito Federal, Brazil.), protocols nos. 19838-1 and 41709-3. It has also been approved by the Ethics Committee for Animal Research of University of São Paulo and Federal University of Minas Gerais (nos. 020/2011 and 333/2013, respectively). From 270 captured bats, 53 were bled for detection of immunoglobulin G (IgG) antibodies to rN-ARAQV by indirect enzyme-linked immunosorbent assay (ELISA) using anti-bat (Bethyl Laboratories, Inc., Montgomery, TX) secondary antibody. This ELISA, as previously described, showed 97.2% sensitivity, 100% specificity, 100% positive predictive value, and 98.1% negative predictive value when compared with an IgG-ELISA using rN antigen of Andes virus, which is the serological test for hantavirus most used in South America.^11,12Open in a separate windowFigure 1.Study areas, highlighting the states of São Paulo and Minas Gerais in southeastern Brazil. The map shows cities where bats have been captured.

Table 1

Trap sites general features⁶