Search Results (351)

An increase in invasive group A streptococcal (iGAS) infections among children under 15 years of age was reported in several countries between late 2022 and early 2023. This retrospective study aims to describe the epidemiology and clinical features of iGAS infections in children in Cyprus during the same period. Medical records of patients under 16 years old admitted with iGAS infection to the Archbishop Makarios Hospital, the only tertiary paediatric referral centre in Cyprus, between 1 January 2021 and 30 June 2024, were reviewed. Twenty-two cases were identified, of which twenty were classified as confirmed and two as probable. Half of the cases occurred in children aged 0–4 years, and 59% were recorded between December 2022 and April 2023. Scarlet fever was diagnosed in six children, five of whom developed pneumonia and empyema. Streptococcal toxic shock syndrome (STSS) was observed in five patients, resulting in two deaths and one case requiring prolonged extracorporeal membrane oxygenation (ECMO). The overall case fatality rate was 9.1%. Emm 1, belonging to the M1UK clone, was the predominant strain (66.6%). The findings underscore the severity of iGAS infections, particularly in younger children, and highlight the importance of timely diagnosis, appropriate management and continued epidemiological surveillance. Full article

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article

Staphylococcus spp. skin colonization is involved in the pathogenesis of atopic dermatitis (AD). While coagulase-positive Staphylococcus aureus strains are known to worsen symptoms, the role of coagulase-negative staphylococci (CoNS) remains controversial. Further research is needed to clarify the pathogenicity of CoNS in AD patients. A study involving 329 children with AD (mean age: 4.89 years) assessed the frequency of staphylococcal colonization on affected skin, along with the toxin-producing properties and antibiotic resistance of isolated strains. Mild AD: Predominantly colonized by CoNS (especially S. epidermidis). Moderate/Severe AD: Showed a significant increase in S. aureus colonization. CoNS (including S. epidermidis) could produce enterotoxins (A, B, C) and toxic shock syndrome toxin-1 (TSST-1), though less frequently than S. aureus strains. In severe AD, the number of toxin-producing CoNS strains (especially enterotoxin A producers) was higher than in mild AD, and the number of non-toxin-producing strains was lower. CoNS exhibited higher resistance rates than S. aureus. Methicillin-resistant S. epidermidis (MRSE): 23.4%. Methicillin-resistant S. aureus (MRSA): 1.27%. CoNS may contribute to AD pathogenesis through toxin production (exacerbating inflammation) and antibiotic resistance (limiting treatment options). Severe AD may involve a synergistic effect between S. aureus and toxin-producing CoNS. Full article

Clostridium sordellii, which has recently been reclassified as Paeniclostridium sordellii and subsequently as Paraclostridium sordellii, is a rare human pathogen linked to infections of high morbidity and mortality, often presenting as fulminant toxic shock syndrome. Although most documented cases involve individuals with pre-existing health issues, such as immunosuppression and cancer, or those who have undergone specific gynecological procedures, there are few instances reported in otherwise healthy individuals. In this report, we present a case of fatality associated with P. sordellii infection in a young individual with a history of drug abuse, following post-mortem examinations. Additionally, we provide an updated review of the latest literature on this topic. Full article

Introduction: Methadone, a synthetic opioid used for opioid substitution therapy (OST), is typically associated with arrhythmias rather than direct myocardial depression. Neurological complications, especially with concurrent antipsychotic use, have also been reported. Acute left ventricular failure in young adults is uncommon and often linked to genetic or infectious causes. We present a rare case of reversible cardiogenic shock and cerebellar insult due to methadone toxicity. Case Presentation: A 37-year-old man with a history of drug abuse on OST with methadone (130 mg/day) was admitted to the ICU with hemodynamic instability, seizures, and focal neurological deficits. Diagnostic workup revealed low cardiac output syndrome and a right cerebellar insult, attributed to methadone toxicity. The patient received individualized catecholamine support. After 10 days in the ICU, he was transferred to a general ward for ongoing cardiac and neurological rehabilitation and discharged in stable condition seven days later. Conclusions: Methadone-induced reversible left ventricular failure, particularly when accompanied by cerebellar insult, is rare but potentially life-threatening. Early recognition and multidisciplinary management are essential for full recovery in such complex toxicological presentations. Full article

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article

Group A Streptococcus (GAS) imposes a significant global health burden across all age groups, annually causing over 600 million cases of pharyngitis and more than 18 million severe invasive infections or sequelae. The resurgence of scarlet fever globally and streptococcal toxic shock syndrome (STSS) outbreaks in Japan have brought GAS infections back into the spotlight as a pressing global health concern. Unfortunately, no licensed vaccine against GAS is yet available for clinical use. Our comprehensive review examines the developmental history of GAS vaccines, outlining the research trajectory from early inactivated vaccines to contemporary multivalent, conjugate, multi-antigen, and mRNA-based vaccine platforms. It systematically analyzes clinical trial outcomes of GAS vaccines, highlighting recent advances in both M protein-based and non-M protein vaccine candidates while summarizing promising target antigens. The review concludes with critical strategies to accelerate vaccine commercialization, including enhanced investment in research and development, expanded collaborations, leveraging advanced vaccine technologies, streamlined clinical trials, and strengthened public health advocacy. This review critically evaluates the current evidence and future prospects in GAS vaccine development, emphasizing innovative strategies and engaging broader stakeholders to accelerate GAS vaccine development. Full article

Assisted reproduction technology (ART) has advanced significantly over the past four decades, leading to improved pregnancy outcomes and a reduction in complications, particularly those associated with multiple pregnancies. These improvements largely stem from advances in understanding embryonic physiology, which has enabled better culture conditions. As a result, embryologists can now efficiently culture embryos to the blastocyst stage and successfully cryopreserve them for future use. However, while incubators aim to replicate the maternal environment of the oviduct and uterus, embryos in vitro are cultured in static conditions, unlike the dynamic, constantly changing environment they experience in vivo. Key factors such as pH, temperature, osmolality, and gas concentrations are crucial for establishing optimal embryo development and implantation potential. Moreover, the vitrification procedure for gametes or embryos can introduce oxidative stress, as well as osmotic shock and cryoprotectant toxicity, which may affect embryo viability and increase the risk of birth defects. Since the first successful ART birth in 1978, over 10 million babies have been conceived through these techniques. Although most of these children are healthy, concerns exist about potential birth defects or changes linked to the handling of gametes and embryos. The preimplantation period is marked by significant epigenetic reprogramming, which can be influenced by ART procedures such as ovarian stimulation, in vitro fertilization, embryo culture, and cryopreservation. However, the long-term health implications for offspring remain uncertain. Epigenetic reprogramming during early embryogenesis is essential for proper embryo development and can be changed by ART-related conditions. These concerns have raised questions about the possible connection between ART and a higher risk of birth defects or other changes in children born through these methods. Therefore, we conducted a scoping review following PRISMA-ScR guidelines to map evidence on ART-related risks, including epigenetic and birth defect outcomes. Full article

The recirculating aquaculture system (RAS) has been rapidly adopted worldwide in recent years due to its high productivity, good stability, and good environmental controllability (and therefore friendliness to environment and ecology). Nevertheless, the effluent from seawater RAS contains a high level of ammonia nitrogen which is toxic to fish, so it is necessary to overcome the salinity conditions to achieve rapid and efficient nitrification for recycling. The moving bed biofilm reactor (MBBR) has been widely applied often by using PE fillers for efficient wastewater treatment. However, the start-up of MBBR in seawater environments has remained a challenge due to salinity stress and harsh inoculation conditions. This study investigated a new PE-filler surface modification method towards the enhanced start-up of mariculture MBBR by combining liquid-phase oxidation and maifanstone powder. The aim was to obtain a higher porous surface and roughness and a strong adsorption and alkalinity adjustment for the MBBR PE filler. The hydrophilic properties, surface morphology, and chemical structure of a raw polyethylene filler (an unmodified PE filler), liquid-phase oxidation modified filler (LO-PE), and liquid-phase oxidation combined with a coating of a maifanstone-powder-surface-modified filler (LO-SCPE) were first investigated and compared. The results showed that the contact angle was reduced to 45.5° after the optimal liquid-phase oxidation modification for LO-PE, 49.8% lower than that before modification, while SEM showed increased roughness and surface area by modification. Moreover, EDS presented the relative content of carbon (22.75%) and oxygen (42.36%) on the LO-SCPE surface with an O/C ratio of 186.10%, which is 177.7% higher than that of the unmodified filler. The start-up experiment on MBBRs treating simulated marine RAS wastewater (HRT = 24 h) showed that the start-up period was shortened by 10 days for LO-SCPE compared to the PE reactor, with better ammonia nitrogen removal observed for LO-SCPE (95.8%) than the PE reactor (91.7%). Meanwhile, the bacterial community composition showed that the LO-SCPE reactor had a more diverse and abundant AOB and NOB. The Nitrospira has a more significant impact on nitrification because it would directly oxidize NH₄⁺-N to NO₃⁻-N (comammox pathway) as mediated by AOB and NOB. Further, the LO-SCPE reactor showed a higher NH₄⁺-N removal rate (>99%), less NO₂⁻-N accumulation, and a shorter adaption period than the PE reactor. Eventually, the NH₄⁺-N concentrations of the three reactors (R1, R2, and R3) reached <0.1 mg/L within 3 days, and their NH₄⁺-N removal efficiencies achieved 99.53%, 99.61%, and 99.69%, respectively, under ammonia shock load. Hence, the LO-SCPE media have a higher marine wastewater treatment efficiency. Full article

Necrotizing soft tissue infections (NSTIs) are serious and aggressive infections which can result in significant morbidity and mortality. Both prompt surgical intervention and early antibiotics can decrease patient mortality. Based on microbiology, NSTIs can be categorized into four different types. Type I is polymicrobial, caused by a mix of both anaerobic and aerobic bacteria. Type II is monomicrobial, usually caused by either Streptococcus or Staphylococcus. Type III infections are caused by Gram-negative bacteria, often marine-related organisms, such as Vibrio. Lastly, Type IV infections are caused by fungi, and they are often associated with trauma. Despite the possibility of all these different pathogens in NSTI, early therapy often consists of a broad Gram-positive antimicrobial such as linezolid or vancomycin, and a broad Gram-negative agent such as piperacillin/tazobactam. Multiple factors including patient comorbidities, environmental exposures, and clinical presentation must also be considered when choosing antimicrobial agents and dosing. Adjunct medical therapies such as intravenous immunoglobulin (IVIG) and the antibiotics clindamycin and linezolid that are aimed at toxin suppression may be utilized to improve outcomes. Microbiological data are critical for optimizing the antimicrobial regimen. Full article

Staphylococcus aureus is a significant pathogen responsible for various infections, with its production of toxic shock syndrome toxin-1 (TSST-1) being a central factor in the pathogenesis of toxic shock syndrome (TSS). This study investigates the prevalence, molecular mechanisms, and public health implications of TSST-1-producing S. aureus. This study reviews methods for detecting TSST-1, focusing on PCR-based molecular techniques and immunological methods like ELISA, as well as the challenges in accurately diagnosing TSST-1 due to antibiotic resistance and strain variability. The findings reveal that TSST-1 is widely distributed across clinical, foodborne, and zoonotic sources, with significant prevalence in both healthcare and agricultural settings. This study also discusses the regulatory networks controlling TSST-1 production, including the agr system and other environmental cues like glucose, iron, and pH levels, which influence toxin expression. The results underline the need for improved surveillance and diagnostic approaches, as well as the development of targeted therapies to mitigate the impact of TSST-1 in both hospital and community settings. The conclusions highlight the importance of understanding TSST-1’s molecular mechanisms for developing effective public health strategies to control its spread. Full article

With the rapid development of the livestock farming industry, the treatment of livestock farming wastewater has become increasingly important. The microbial-algal biofilm method has gained widespread attention for cattle wastewater treatment owing to its non-toxic nature, resistance to shock loading, and high treatment efficiency. In this study, three types of substrates—polyurethane sponge, ceramic material, and moving bed biofilm reactor media—were evaluated. The formation of biofilms was assessed through variations in chlorophyll content, microscopic observations, and measurements of biofilm dry weight and attachment rate. Biofilm characterization on the different substrates was conducted via Fourier transform infrared spectroscopy, confocal laser scanning microscopy, and scanning electron microscopy. The results demonstrated that polyurethane sponge was the most effective substrate. Furthermore, a single-factor experiment was conducted to optimize the cultivation conditions for the microbial-algal biofilms and identify the optimal parameters based on the ability of the biofilm to remove COD, TN, TP, and NH₄⁺-N. The optimal conditions were as follows: an illumination intensity of 8000 lux, red light, a temperature of 20 °C, a pH of 7, and an aeration intensity of 8 L/min. Under these conditions, the pollutant removal rates were exceptionally high: ~73.4% for COD, 51.8% for TP, 57.0% for TN, and 75.1% for NH₄⁺-N. Full article

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic avenue by leveraging the ubiquitin–proteasome system to selectively degrade essential parasite proteins. This review introduces the conceptual framework of “TrypPROTACs” as a prospective strategy for T. cruzi, integrating a comprehensive analysis of druggable targets across critical biological pathways, including ergosterol biosynthesis, redox metabolism, glycolysis, nucleotide synthesis, protein kinases, molecular chaperones such as heat shock protein 90 (Hsp90), and epigenetic regulators such as T. cruzi bromodomain factor 3 (TcBDF3). It is important to note that no TrypPROTAC compound has yet been synthesized or experimentally validated in T. cruzi; the approach discussed herein remains theoretical and forward-looking. Representative inhibitors for each target class are compiled, highlighting potency, selectivity, and structural features relevant to ligand design. We also examine the parasite’s ubiquitination machinery and compare it to the human system to identify putative E3 ubiquitin ligases. Key aspects of linker engineering and ternary complex stabilization are discussed, alongside potential validation techniques such as the cellular thermal shift assay (CETSA) and bioluminescence resonance energy transfer (NanoBRET). Collectively, these insights outline a roadmap for the rational design of TrypPROTACs and support the feasibility of expanding targeted protein degradation strategies to neglected tropical diseases. Full article

Background: Severe poisoning can lead to catastrophic cardiovascular collapse, often progressing to multiorgan failure and death. While intensive supportive care and pharmacological intervention remain the cornerstone of management, cases of refractory cardiogenic shock, particularly those caused by membrane stabilizing agents and calcium channel blockers, pose a significant therapeutic challenge. Extracorporeal membrane oxygenation (ECMO) has emerged as a potential life-saving intervention in critically ill patients. This review examines the feasibility, clinical outcomes, and optimal indications for ECMO in the management of drug-induced cardiogenic shock. Methods: A systematic narrative review was conducted to evaluate the current evidence of ECMO use in poisoning-related cardiovascular failure, with a particular focus on patient selection criteria and the prognostic determinants of therapeutic resistance. Results: Extracorporeal membrane oxygenation may serve as a crucial hemodynamic support strategy in drug-induced circulatory collapse. Most reported cases involve peripheral ECMO, demonstrating variable but promising survival outcomes. Conclusions: Despite its potential to rescue patients from otherwise fatal toxic cardiomyopathy, the role of ECMO remains incompletely defined. Further prospective studies are essential to refine patient selection criteria and identify the toxicant-specific predictors of therapeutic failure. A deeper understanding of these factors may enhance clinical decision making and improve survival rates in severe poisoning cases. Full article

Inflammation plays a central role in various pathological conditions, necessitating the search for safer and more effective anti-inflammatory agents. This study investigates the anti-inflammatory activity of caulerpin, a bisindolic alkaloid isolated from Caulerpa racemosa. In vitro assays demonstrated that caulerpin significantly reduced nitric oxide, TNF-α, IL-6, and IL-12 levels in macrophages stimulated with LPS + IFN-γ, without affecting cell viability. In silico toxicity predictions using Protox 3.0 reinforce a favorable safety profile of caulerpin. Molecular docking and molecular dynamics simulations revealed its high-affinity binding to the glucocorticoid receptor ligand-binding domain (GR-LBD), suggesting a mechanism of action similar to dexamethasone. The involvement of the glucocorticoid receptor was confirmed by the partial reversal of caulerpin’s effects upon RU486 treatment. In vivo, caulerpin exhibited a favorable safety profile, with no signs of acute toxicity at an oral dose of 100 mg/kg. Moreover, in a mouse model of endotoxic shock, caulerpin administration significantly improved survival rates in a dose-dependent manner, providing complete protection at 4 mg/kg. These findings highlight caulerpin as a promising candidate for the development of novel anti-inflammatory therapies. Further studies are warranted to explore its pharmacokinetics, optimize its structure, and evaluate its efficacy in chronic inflammatory diseases. Full article