Search Results (54)

Background: PP-007 (SANGUINATE^®, PEGylated carboxyhemoglobin, bovine) is under development to treat conditions of ischemia/hypoxia. Hemorrhagic/hypovolemic shock (H/HVS) becomes a life-threatening comorbidity due in part to hypotension and hypoxia. Blood transfusions are indicated, but supply and compatibility issues may limit subject access or when blood is not an option due to religious restriction or concern for clinical complications. PP-007 is universally compatible with an effective hydrodynamic radius and colloidal osmotic pressure facilitating perfusion without promoting extravasation. Methods: A review of previous clinical trials was performed and revealed an Open-Label Phase 1 safety study of acute severe anemia (hemoglobin ≤ 5 g/dL) in adult (≥18 y) patients unable to receive red blood cell transfusion (NCT02754999). Primary outcomes included safety events with secondary efficacy measures of organ function and survival at 1, 14, and 28 days. Additionally, a retrospective review of published, peer-reviewed case reports was performed, evaluating the administration of Sanguinate for Expanded Access in those patient populations where blood was not an option over the past 12 years. Results: A total of 103 subjects were enrolled in the Phase I safety study with significant co-morbidities that most commonly included hypertension (n = 43), acute and chronic kidney disease (n = 38), diabetes mellitus (n = 29), gastrointestinal bleeds (n = 18), and sickle cell disease (n = 13). Enrollment characteristics included decreased hemoglobin and severe anemia (mean baseline hemoglobin of 4.2 g/dL). Treatments included an average of three infusions [range 1–17]. Secondary efficacy measures were mean Hb levels, respiratory support, and vasopressor requirements, all demonstrating clinically relevant improvements. Fourteen additional cases were identified in the literature. Though one patient died due to pre-treatment conditions, all patients but one were discharged home in stable condition. Conclusion: Collectively, these observations are encouraging and provide support for the continued evaluation of PP-007 in advanced clinical trials in severe anemia including H/HVS. The review of published case reports underscored the potential of Sanguinate to reduce early mortality. Adverse effects included transient hypertension, lethargy, dizziness, and troponin elevation. These findings highlight the need for continued research and funding of blood alternatives to improve outcomes when standard blood transfusions are unavailable or contraindicated. Full article

Background and Clinical Significance: Congenital myasthenic syndrome-4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency is an autosomal recessive defect of the motor endplate caused by homozygous or compound heterozygous mutations in the CHRNE gene on chromosome 17p13. Case Presentation: The authors present a familial case of CMS4C with three affected children in a consanguineous Romani family. Muscle weakness, fatigue, and ocular muscle impairment were present in all cases; two of the three siblings had delayed motor milestones, highly arched palates, and facial weakness. None of the children expressed bulbar symptoms. One child expressed a severe form, with recurrent respiratory infections, and multiple hospitalizations, while the other siblings expressed a mild phenotype, without hospital admissions. Repetitive nerve stimulation showed a myasthenic-type decrement greater than 10% of several muscles. A pathogenic frameshift variant (NM_000080.4: c.1327del) in the CHRNE gene was found in a homozygous status in all the affected children and in both parents. After 6 months of Pyridostigmine and Salbutamol treatment, the evolution of the case was good, with the improvement of most of the signs and no need for hospitalization. Conclusions: Early genetic diagnosis and appropriate therapy in the context of a multidisciplinary approach is mandatory for an optimal long-term prognosis. Community-wide carrier screening through comprehensive genetic testing is imperative to ensure accurate genetic counseling in genetic isolates. The authors report this case due to the increased number of affected children in a consanguine family from a small Romani community. Full article

Dengue virus is an enveloped virus with an icosahedral assembly of envelope proteins (E). The E proteins are arranged as a head-to-tail homodimer, and domain III (EDIII) is placed at the edge of the dimer, converging to a pentamer interface. For a structure-based approach, cholera toxin B (CTB) was harnessed as a structural scaffold for the five-fold symmetry of EDIII. Pivoted by an RNA-mediated chaperone for the protein folding and assembly, CTB-EDIII of dengue serotype 1 (DV1) was successfully produced as soluble pentamers in an E. coli host with a high yield of about 28 mg/L. Immunization of mice with CTB-DV1EDIII elicited increased levels of neutralizing antibodies against infectious viruses compared to the control group immunized with DV1EDIII without CTB fusion. IgG isotype switching into a balanced Th1/Th2 response was also observed, probably triggered by the intrinsic adjuvant activity of CTB. Confirming the immune-enhancing potential of CTB in stabilizing the pentamer assembly of EDIII, this study introduces a low-cost bacterial production platform designed to augment the soluble production of subunit vaccine candidates, particularly those targeting flaviviruses. Full article

Retained hemothorax (RH) is a commonly encountered and potentially severe complication of intrapleural bleeding that can organize with lung restriction. Early surgical intervention and intrapleural fibrinolytic therapy have been advocated. However, the lack of a reliable, cost-effective model amenable to interventional testing has hampered our understanding of the role of pharmacological interventions in RH management. Here, we report the development of a new RH model in rabbits. RH was induced by sequential administration of up to three doses of recalcified citrated homologous rabbit donor blood plus thrombin via a chest tube. RH at 4, 7, and 10 days post-induction (RH4, RH7, and RH10, respectively) was characterized by clot retention, intrapleural organization, and increased pleural rind, similar to that of clinical RH. Clinical imaging techniques such as ultrasonography and computed tomography (CT) revealed the dynamic formation and resorption of intrapleural clots over time and the resulting lung restriction. RH7 and RH10 were evaluated in young (3 mo) animals of both sexes. The RH7 recapitulated the most clinically relevant RH attributes; therefore, we used this model further to evaluate the effect of age on RH development. Sanguineous pleural fluids (PFs) in the model were generally small and variably detected among different models. The rabbit model PFs exhibited a proinflammatory response reminiscent of human hemothorax PFs. Overall, RH7 results in the consistent formation of durable intrapleural clots, pleural adhesions, pleural thickening, and lung restriction. Protracted chest tube placement over 7 d was achieved, enabling direct intrapleural access for sampling and treatment. The model, particularly RH7, is amenable to testing new intrapleural pharmacologic interventions, including iterations of currently used empirically dosed agents or new candidates designed to safely and more effectively clear RH. Full article

Plasmodium vivax malaria affects 14 million people each year. Its invasion requires interactions between the parasitic Duffy-binding protein (PvDBP) and the N-terminal extracellular domain (ECD1) of the host’s Duffy antigen/receptor for chemokines (DARC). ECD1 is highly flexible and intrinsically disordered, therefore it can adopt different conformations. We computationally modeled the challenging ECD1 local structure. With T-REMD simulations, we sampled its dynamic behavior and collected its most representative conformations. Our results suggest that most of the DARC ECD1 domain remains in a disordered state during the simulated time. Globular local conformations are found in the analyzed local free-energy minima. These globular conformations share an α-helix spanning residues Ser18 to Ser29 and in many cases they comprise an antiparallel β-sheet, whose β-strands are formed around residues Leu10 and Ala49. The formation of a parallel β-sheet is almost negligible. So far, progress in understanding the mechanisms forming the basis of the P. vivax malaria infection of reticulocytes has been hampered by experimental difficulties, along with a lack of DARC structural information. Our collection of the most probable ECD1 structural conformations will help to advance modeling of the DARC structure and to explore DARC–ECD1 interactions with a range of physiological and pathological ligands. Full article

Rice bran, a by-product of rice milling, is abundant in bioactive molecules and is highly recognized for its health-promoting properties, particularly in improving metabolic conditions. Building on this knowledge, we aimed to optimize the extraction conditions to maximize the functional efficacy of rice bran extract (RBE) and further validate its impact on lipid metabolism. We found that the optimized RBE (ORBE) significantly suppressed high-fat diet-induced weight gain, hyperlipidemia, and hepatosteatosis in mouse models. ORBE treatment not only suppressed lipid uptake in vivo, but also reduced lipid accumulation in HepG2 cells. Importantly, we discovered that ORBE administration resulted in activation of AMPK and inhibition of STAT3, which are both crucial players in lipid metabolism in the liver. Collectively, ORBE potentially offers promise as a dietary intervention strategy against hyperlipidemia and hepatosteatosis. This study underlines the value of optimized extraction conditions in enhancing the functional efficacy of rice bran. Full article

Objective: Anti-HBs antibodies are elicited upon hepatitis B vaccination, and concentrations above 10 mIU/mL are considered protective. Our aim was to assess the relationship between IU/mL of anti-HBs and neutralization activity. Methods: Immunoglobulins G (IgGs) were purified from individuals who received a serum-derived vaccine (Group 1), a recombinant vaccine, Genevac-B or Engerix-B (Group 2), or who recovered from acute infection (Group 3). IgGs were tested for anti-HBs, anti-preS1, and anti-preS2 antibodies and for their neutralizing activity in an in vitro infection assay. Results: Anti-HBs IUs/mL value did not strictly correlate with neutralization activity. The Group 1 antibodies demonstrated a greater neutralizing activity than those of Group 2. Anti-preS1 antibodies were detected in Groups 1 and 3, and anti-preS2 in Group 1 and Group 2/Genhevac-B, but the contribution of anti-preS antibodies to neutralization could not be demonstrated. Virions bearing immune escape HBsAg variants were less susceptible to neutralization than wild-type virions. Conclusion. The level of anti-HBs antibodies in IUs is not sufficient to assess neutralizing activity. Consequently, (i) an in vitro neutralization assay should be included in the quality control procedures of antibody preparations intended for HB prophylaxis or immunotherapy, and (ii) a greater emphasis should be placed on ensuring that vaccine genotype/subtype matches with that of the circulating HBV. Full article

The pursuit for blood a substitute has spanned over a century, but a majority of the efforts have been disappointing. As of today, there is no widely accepted product used as an alternative to human blood in clinical settings with severe anemic condition(s). Blood substitutes are currently also termed oxygen therapeutics. There are two major categories of oxygen therapeutics, hemoglobin-based and perfluorocarbon-based products. In this article, we reviewed the most developed but failed products and products still in active clinical research in the category of hemoglobin-based oxygen carriers. Among all of the discussed hemoglobin-based oxygen therapeutics, HemAssist, PolyHeme, Hemolink, Hemospan, and Hemoximer were discontinued. Hemopure is in clinical use in South Africa and Russia. Oxyglobin, the sister product of Hemopure, has been approved for veterinary use in the European Union and the United States. HemO2life has recently been approved for organ preservation in organ transplantation in the European Union. OxyVita and Sanguinate are still undergoing active clinical studies. The field of oxygen therapeutics seems to be entering a phase of rapid growth in the coming 10–20 years. Full article

In Mali, hepatocellular carcinoma (HCC) is the third and sixth most common cancer in men and women, respectively. Mali comprises several distinct climato-ecological zones. Most studies to date have been conducted in the sub-Sahelian zone of southern Mali, including the capital city Bamako. In this part of the country, the main risk factors for HCC are chronic hepatitis B virus (HBV) carriage and dietary exposure to aflatoxins, a well-known hepatocarcinogen. Data are scarce for other ecological zones, but our preliminary data from 721 blood donors in the area of Timbuktu, presented in this study, suggest that chronic HBV carriage is also endemic in the northern Saharan zone of Mali. For further study, 29 healthy HBV chronic carrier volunteers were recruited from the blood transfusion center in Timbuktu. Successful viral genotyping in 20 volunteers revealed HBV genotype E in 13 cases and D in 7 cases, suggesting that this geographical and anthropological transition zone may also represent a transition zone between HBV genotypes that dominate sub-Saharan and northern Africa, respectively. Sequencing of circulating cell-free plasma DNA (cfDNA) from donors did not reveal the presence of the TP53 R249S mutation in these donors, a marker of dietary exposure to aflatoxins in sub-Saharan Africa. These results suggest that the geo-epidemiological distribution of the risk factors for HCC is not uniform across Mali, but is dependent upon climatic, socioeconomic and anthropological factors that might have an impact on patterns of chronic liver disease and cancer. Full article

Hepatitis B virus (HBV) infection is the most frequent viral infection found in blood donors (BDs) in France. We analyzed the epidemiological and sero-molecular data on HBV infection gathered over the past two decades by the French haemovigilance surveillance network, blood screening laboratories, and the national reference center for transfusion infectious risks (NRC). Between 2000 and 2020, 6149 of the 58,160,984 donations (1.06/10,000) tested HBV positive, 98% of them from first-time blood donors (FTBDs). In addition, 2212 (0.0071%) of the 30,977,753 donations screened for HBV DNA tested DNA positive, of which 25 (1.1%) were positive only for this marker. HBV prevalence decreased by 2.8-fold and the residual risk for transfusion-transmitted HBV infection decreased 13-fold and was divided by 13. The major risk factor for HBV infection was the origin of donors (endemic country, 66.5%), followed by parenteral exposure (10.7%). In the whole HBV-positive BD population, genotype D was predominant (41.8%), followed by genotypes A (26.2%) and E (20.4%), reflecting the geographical origin of donors. The low and decreasing prevalence and incidence of HBV infection in French BDs, coupled with a screening strategy using three HBV markers (HBsAg, anti-HBc and DNA), ensures a high level of blood safety, further reinforced by the implementation of pathogen-reduction measures. Full article

Usutu virus (USUV) and West Nile virus (WNV) are phylogenetically closely related arboviruses. These viruses mainly follow an enzootic cycle involving mosquitoes and birds, but they occasionally infect humans and other mammals, inducing neurotropic disorders. Since the discovery of USUV, only two human cases have been reported in Africa, including one in Burkina Faso in 2004. Since then, no studies have been conducted to measure the extent of the circulation of this virus in Burkina Faso, and no study regarding the circulation of WNV has been conducted. Our study aimed to determine the seroprevalence of USUV and WNV in blood donations and in animals (horses, dogs, chickens and pigeons) and to perform molecular screening in patients with febrile fever and in Culex quinquefasciatus and Aedes aegypti mosquitoes. The prevalence of USUV and WNV was studied by serological (ELISA and microneutralization tests) and molecular analyses (RT-qPCR) of mosquito, dog, domestic bird, horse, and human samples in Burkina Faso between 2019 and 2021. We detected a very active transmission of both viruses in Burkina Faso. WNV and USUV seroprevalence is particularly high in humans (19.16% and 14.17%, respectively) and horses (17.28% and 6.17%). Molecular screening did not detect WNV or USUV in the mosquito or human samples tested. Our study shows an active spread of USUV and WNV in Burkina Faso, especially for WNV. This study highlights the value of developing surveillance programs to better prevent, detect, and alert people to USUV and WNV circulation in both primary and incidental hosts. Full article

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by hyperactivated immune reactions in the skin. AD is a prevalent health concern in developing countries, with a particularly high incidence among children. Despite ongoing research on AD, prevention and treatment strategies for patients remain inadequate. In this study, the inhibitory effects of Cornus walteri on AD were investigated. C. walteri (Cornaceae), commonly known as “Walter’s dogwood,” is a deciduous shrub used as a traditional medicine to treat dermatologic inflammation caused by lacquer poisoning. However, the role of C. walteri in AD remains largely unknown. To evaluate its anti-AD potential, we investigated the anti-inflammatory activity of the MeOH extract of C. walteri stems (CWS) using the HaCaT human keratinocyte cell line. CWS reduced the secretion of AD-related chemokines, eotaxin-3/CCL26 and thymus and activation-regulated chemokine (TARC/CCL17). In addition, CWS also inhibited the mRNA expression of macrophage-derived chemokine (MDC/CCL22) and upregulated filaggrin, which plays an essential role in skin barrier functions. To identify the bioactive constituents of CWS, phytochemical investigation of CWS led to the isolation of potential bioactive constituents (1–6), including four triterpenoids, one steroid and one diterpene analog, the structures of which were identified as lupeol (1), betulinic acid (2), 5α-stigmast-3,6-dione (3), 3-O-acetylbetulin (4), betulinic acid methyl ester (5) and norphytan (6) through nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography (LC)–mass spectrometry (MS) analysis. The isolated compounds (1–6) were evaluated for their inhibitory activities against eotaxin-3 expression. Compounds 1, 2 and 3 significantly reduced the levels of eotaxin-3. These findings provided experimental evidence that CWS, particularly active compounds 1, 2 and 3, could be further utilized as potential therapeutic agents to treat AD. Full article

Zika virus (ZIKV) and dengue virus (DENV) are two closely related members of the Flaviviridae family, both transmitted by mosquitoes of the genus Aedes, and are among the arboviruses most at risk to human health. Burkina Faso has been facing an upsurge in DENV outbreaks since 2013. Unlike DENV, there is no serological evidence of ZIKV circulation in humans in Burkina Faso. The main objective of our study was to determine the seroprevalence of ZIKV and DENV in blood donors in Burkina Faso. A total of 501 donor samples collected in the two major cities of the country in 2020 were first tested by a competitive enzyme-linked immunosorbent assay to detect flavivirus antibodies. Positive sera were then tested using Luminex to detect ZIKV and DENV antibodies and virus-specific microneutralization tests against ZIKV were performed. The ZIKV seroprevalence was 22.75% in the donor samples and we found seropositivity for all DENV-serotypes ranging from 19.56% for DENV-1 to 48.86% for DENV-2. Molecular analyses performed on samples from febrile patients and Aedes aegypti mosquitoes between 2019 and 2021 were negative. Our study showed the important circulation of ZIKV and DENV detected by serology although molecular evidence of the circulation of ZIKV could not be demonstrated. It is essential to strengthen existing arbovirus surveillance in Burkina Faso and more broadly in West Africa by focusing on fevers of unknown origin and integrating vector surveillance to assess the extent of ZIKV circulation and identify the circulating strain. Further studies are needed to better understand the epidemiology of this virus in order to define appropriate prevention and response methods. Full article

The anti-oxidant properties of vitamin C and of phenolic compounds of citrus fruits are well established. However, the evaluation of the anti-inflammatory and antithrombotic potential of both vitamin C and of the more amphiphilic and lipophilic components of citrus fruits needs further attention. In this study, the anti-inflammatory and antithrombotic properties of vitamin C and of freshly squeezed juices and their lipid bioactives from the Navalina and Sanguine orange varieties and the Clementine variety of mandarins, as well as from their remaining by-products, were evaluated against the inflammatory and thrombotic pathways of the platelet-activating factor (PAF) and thrombin in platelets, as well as against PAF-biosynthesis in leukocytes. The non-oxidized juices of these citrus fruits and a vitamin C supplement showed stronger anti-PAF and antithrombin effects than their oxidized versions through their general anti-oxidant effect in platelets. The total lipids (TLs) and the HPLC-derived fractions of phenolic compounds and of polar lipid bioactives from both juices and their peels’ by-products showed a more specific stronger inhibitory effect against the inflammatory and thrombotic pathways of PAF and thrombin in platelets, while these bioactives strongly inhibited also the specific enzyme activities of the main biosynthetic enzymes of PAF in leukocytes. The stronger bioactivity of the dietary bioactives found in the juices of these citrus fruits against specific biochemical pathways of inflammation and thrombosis seems to act with synergy with the anti-oxidant potential of their vitamin C content, which further supports the notion that these juices are functional foods with anti-inflammatory protective health benefits. In addition, the presence of these dietary bioactive phenolic compounds and polar lipid bioactives in the remaining peels’ wastes further enhance the valorization of such food industry by-products as potential sources of anti-inflammatory bioactives to be used as ingredients for novel functional products. Full article

Current anti-hepatitis B virus (HBV) drugs are suppressive but not curative for HBV infection, so there is considerable demand for the development of new anti-HBV agents. In this study, we found that fungus-derived exophillic acid inhibits HBV infection with a 50% maximal inhibitory concentration (IC₅₀) of 1.1 µM and a 50% cytotoxic concentration (CC₅₀) of >30 µM in primary human hepatocytes. Exophillic acid inhibited preS1-mediated viral attachment to cells but did not affect intracellular HBV replication. Exophillic acid appears to target the host cells to reduce their susceptibility to viral attachment rather than acting on the viral particles. We found that exophillic acid interacted with the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP). Exophillic acid impaired the uptake of bile acid, the original function of NTCP. Consistent with our hypothesis that it affects NTCP, exophillic acid inhibited infection with HBV and hepatitis D virus (HDV), but not that of hepatitis C virus. Moreover, exophillic acid showed a pan-genotypic anti-HBV effect. We thus identified the anti-HBV/HDV activity of exophillic acid and revealed its mode of action. Exophillic acid is expected to be a potential new lead compound for the development of antiviral agents. Full article