Few studies have assessed the burden of Chagas disease in non-endemic countries and most of them are based on prevalence estimates from Latin American (LA) countries that likely differ from the ...prevalence in migrants living in Europe. The aim of this study was to systematically review the existing data informing current understanding of the prevalence of Chagas disease in LA migrants living in European countries.
We conducted a systematic review and meta-analysis of studies reporting prevalence of Chagas disease in European countries belonging to the European Union (EU) before 2004 in accordance with the MOOSE guidelines and based on the database sources MEDLINE and Global Health. No restrictions were placed on study date, study design or language of publication. The pooled prevalence was estimated using random effect models based on DerSimonian & Laird method.
We identified 18 studies conducted in five European countries. The random effect pooled prevalence was 4.2% (95%CI:2.2-6.7%); and the heterogeneity of Chagas disease prevalence among studies was high (I2 = 97%,p<0.001). Migrants from Bolivia had the highest prevalence of Chagas disease (18.1%, 95%CI:13.9-22.7%).
Prevalence of Chagas in LA migrants living in Europe is high, particularly in migrants from Bolivia and Paraguay. Data are highly heterogeneous dependent upon country of origin and within studies of migrants from the same country of origin. Country-specific prevalence differs from the estimates available from LA countries. Our meta-analysis provides prevalence estimates of Chagas disease that should be used to estimate the burden of disease in European countries.
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Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on ...RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set. Expression of wild-type, but not mutant, ADAR1 enhances Alu-dependent editing and transcriptional activity of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist, and promotes immunomodulatory drug resistance in vitro. Finally, ADAR1 knockdown reduces regeneration of high-risk MM in serially transplantable patient-derived xenografts. These data demonstrate that ADAR1 promotes malignant regeneration of MM and if selectively inhibited may obviate progression and relapse.
Thromboembolic events were described in patients with Chagas disease without cardiomyopathy. We aim to confirm if there is a hypercoagulable state in these patients and to determine if there is an ...early normalization of hemostasis factors after antiparasitic treatment. Ninety-nine individuals from Chagas disease-endemic areas were classified in two groups: G1, with T.cruzi infection (n = 56); G2, healthy individuals (n = 43). Twenty-four hemostasis factors were measured at baseline. G1 patients treated with benznidazole were followed for 36 months, recording clinical parameters and performance of conventional serology, chemiluminescent enzyme-linked immunosorbent assay (trypomastigote-derived glycosylphosphatidylinositol-anchored mucins), quantitative polymerase chain reaction, and hemostasis tests every 6-month visits. Prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were abnormally expressed in 77% and 50% of infected patients at baseline but returned to and remained at normal levels shortly after treatment in 76% and 96% of cases, respectively. Plasmin-antiplasmin complexes (PAP) were altered before treatment in 32% of G1 patients but normalized in 94% of cases several months after treatment. None of the patients with normal F1+2 values during follow-up had a positive qRT-PCR result, but 3/24 patients (13%) with normal ETP values did. In a percentage of chronic T. cruzi infected patients treated with benznidazole, altered coagulation markers returned into normal levels. F1+2, ETP and PAP could be useful markers for assessing sustained response to benznidazole.
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Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, ...infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.
Summary Background Skin infections with ulceration are a major health problem in countries of the south Pacific region. Yaws, caused by Treponema pallidum subspecies pertenue and diagnosed by the ...presence of skin ulcers and a reactive syphilis serology, is one major cause, but this infection can be confused clinically with ulcers due to other causative agents. We investigated T pallidum pertenue and another bacterium known to cause skin infections in the Pacific islands— Haemophilus ducreyi —as causes of skin ulceration in a yaws-endemic region. Additionally, we identified specific signs and symptoms associated with these causative agents of cutaneous ulcers and compared these findings with laboratory-based diagnoses. Methods We did a prospective cohort study of five yaws-endemic villages (total population 3117 people) during a yaws elimination campaign in Papua New Guinea in April, 2013. We enrolled all consenting patients with chronic moist or exudative skin ulcers. We undertook a detailed dermatological assessment, syphilis serology, and PCR on lesional swabs to detect the presence of T pallidum pertenue and H ducreyi . Patients with PCR-confirmed bacterial infections were included in a comparative analysis of demographics and clinical features. Findings Full outcome data were available for 90 people with skin ulcers. Of these patients, 17 (19%) had negative results in all molecular tests and were therefore excluded from the comparative analyses. A bacterial cause was identified in 73 (81%) participants—either H ducreyi (n=42), T pallidum pertenue (yaws; n=19), or coinfection with both organisms (dual infection; n=12). The demographic characteristics of the patients infected with yaws and with H ducreyi were similar. Skin lesions in patients with yaws and in those with dual infection were larger than those in patients infected with H ducreyi (p=0·071). The lesions in patients with yaws and dual infection were more circular in shape (79% and 67%) than in those infected with H ducreyi (21%; p<0·0001); more likely to have central granulating tissue (90% and 67% vs 14%; p<0·0001); and more likely to have indurated edges (74% and 83% vs 31%; p=0·0003). The prevalence of reactive combined serology (positive T pallidum haemagglutination test and rapid plasmin reagin titre of ≥1:8) was higher in cases of yaws (63%) and dual infections (92%) than in H ducreyi infections (29%; p<0·0001). Interpretation In this yaws-endemic community, H ducreyi is an important and previously unrecognised cause of chronic skin ulceration. Reactive syphilis serology caused by latent yaws can occur in ulcers with the presence of H ducreyi alone. The introduction of PCR for ulcer surveillance could improve the accuracy of diagnosis in countries with yaws eradication campaigns. Funding Newcrest Mining Company.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with the bone marrow (BM) microenvironment. Myeloma cells ...educate BM cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the reprogramming of BM stromal cells. In this work we demonstrate,
and by using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resistance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine system CXCR4/SDF1α. Myeloma cell-derived Jagged ligands trigger Notch activity in BM stromal cells. These, in turn, secrete higher levels of SDF1α in the BM microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the augmented pharmacological resistance, SDF1α boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with BM stromal cells and, conceivably, improve patients' response to standard-of-care therapies.
Monitoring the HIV epidemic in a defined population is critical for planning treatment and preventive strategies. This is especially important in sub-Saharan Africa, which harbours the highest burden ...of the disease.
To estimate HIV incidence in adults aged 18-47 years old and to investigate spatial variations of HIV prevalence in Manhiça, a semi-rural area of southern Mozambique.
Two cross-sectional community-based surveys were conducted in 2010 and 2012 to determine HIV prevalence. Individual participants were randomly selected from the demographic surveillance system in place in the area and voluntary HIV counselling and testing was offered at the household level. HIV incidence was calculated using prevalence estimates from the two sero-surveys. Each participant's household was geocoded using a global information system. The Spatial Scan Statistics programme was used to identify areas with disproportionate excess in HIV prevalence.
A total of 1511 adults were tested. The estimated HIV prevalence in the community was 39.9% in 2010 and 39.7% in 2012. The overall HIV incidence was 3.6 new infections per 100 person-years at risk (PYAR) 95CI 1.56; 7.88, assuming stable epidemic conditions, and tended to be higher in women (4.9/100 PYAR 95CI 1.74; 11.85) than in men (3.2/PYAR 95CI 1.36; 9.92). One cluster with significant excess HIV prevalence was identified at the same geographic location in both surveys. This cluster had an HIV prevalence of 79.0% in 2010 and 52.3% in 2012.
The findings of these first individually-randomised community-HIV sero-surveys conducted in Mozambique reinforce the need to combine HIV incidence estimates and research on micro geographical infection patterns to guide and consolidate effective prevention strategies.
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Summary Background Yaws—an endemic treponematosis and, as such, a neglected tropical disease—is re-emerging in children in rural, tropical areas. Oral azithromycin is effective for syphilis. We ...assessed the efficacy of azithromycin compared with intramuscular long-acting penicillin to treat patients with yaws. Methods We did an open-label, non-inferiority, randomised trial at Lihir Medical Centre, Papua New Guinea, between Sept 1, 2010, and Feb 1, 2011. Children aged 6 months to 15 years with a serologically confirmed diagnosis of yaws were randomly allocated, by a computer-generated randomisation sequence, to receive either one 30 mg/kg oral dose of azithromycin or an intramuscular injection of 50 000 units per kg benzathine benzylpenicillin. Investigators were masked to group assignment. The primary endpoint was treatment efficacy, with cure rate defined serologically as a decrease in rapid plasma reagin titre of at least two dilutions by 6 months after treatment, and, in participants with primary ulcers, also by epithelialisation of lesions within 2 weeks. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10%. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov , number NCT01382004. Findings We allocated 124 patients to the azithromycin group and 126 to the benzathine benzylpenicillin group. In the per-protocol analysis, after 6 months of follow-up, 106 (96%) of 110 patients in the azithromycin group were cured, compared with 105 (93%) of 113 in the benzathine benzylpenicillin group (treatment difference −3·4%; 95% CI −9·3 to 2·4), thus meeting prespecified criteria for non-inferiority. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (ten 8% in the azithromycin group vs eight 7% in the benzathine benzylpenicillin group). Interpretation A single oral dose of azithromycin is non-inferior to benzathine benzylpenicillin and avoids the need for injection equipment and medically trained personnel. A change to the simpler azithromycin treatment regimen could enable yaws elimination through mass drug administration programmes. Funding International SOS and Newcrest Mining.
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The definition of natural background levels (NBLs) for potentially toxic elements (PTEs) in groundwater from mining environments is a real challenge, as anthropogenic activities boost water–rock ...interactions, further increasing the naturally high concentrations. This study illustrates the procedure followed to derive PTE concentration values that can be adopted as NBLs for the former Balangero asbestos mine, a “Contaminated Site of National Interest”. A full hydrogeochemical characterisation allowed for defining the dominant Mg-HCO3 facies, tending towards the Mg-SO4 facies with increasing mineralisation. PTE concentrations are high, and often exceed the groundwater quality thresholds for Cr VI, Ni, Mn and Fe (5, 20, 50 and 200 µg/L, respectively). The Italian guidelines for NBL assessment recommend using the median as a representative concentration for each monitoring station. However, this involves discarding half of the measurements and in particular the higher concentrations, thus resulting in too conservative estimates. Using instead all the available measurements and the recommended statistical evaluation, the derived NBLs were: Cr = 39.3, Cr VI = 38.1, Ni = 84, Mn = 71.36, Fe = 58.4, Zn = 232.2 µg/L. These values are compared to literature data from similar hydrogeochemical settings, to support the conclusion on their natural origin. Results highlight the need for a partial rethink of the guidelines for the assessment of NBLs in naturally enriched environmental settings.
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment ...resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients' bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients' overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.
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