RNA and condensates: Disease implications and therapeutic opportunities.

Biomolecular condensates are dynamic membraneless organelles that compartmentalize proteins and RNA molecules to regulate key cellular processes. Diverse RNA species exert their effects on the cell by their roles in condensate formation and function. RNA abnormalities such as overexpression, modification, and mislocalization can lead to pathological condensate behaviors that drive various diseases, including cancer, neurological disorders, and infections. Here, we review RNA's role in condensate biology, describe the mechanisms of RNA-induced condensate dysregulation, note the implications for disease pathogenesis, and discuss novel therapeutic strategies. Emerging approaches to targeting RNA within condensates, including small molecules and RNA-based therapies that leverage the unique properties of condensates, may revolutionize treatment for complex diseases.

A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development.

Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/ß-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/ß-catenin signaling and cell type commitment in somatic development.

A multi-iron enzyme installs copper-binding oxazolone/thioamide pairs on a nontypeable Haemophilus influenzae virulence factor.

The multinuclear nonheme iron-dependent oxidases (MNIOs) are a rapidly growing family of enzymes involved in the biosynthesis of ribosomally synthesized, posttranslationally modified peptide natural products (RiPPs). Recently, a secreted virulence factor from nontypeable Haemophilus influenzae (NTHi) was found to be expressed from an operon, which we designate the hvf operon, that also encodes an MNIO. Here, we show by Mössbauer spectroscopy that the MNIO HvfB contains a triiron cofactor. We demonstrate that HvfB works together with HvfC [a RiPP recognition element (RRE)-containing partner protein] to perform six posttranslational modifications of cysteine residues on the virulence factor precursor peptide HvfA. Structural characterization by tandem mass spectrometry and NMR shows that these six cysteine residues are converted to oxazolone and thioamide pairs, similar to those found in the RiPP methanobactin. Like methanobactin, the mature virulence factor, which we name oxazolin, uses these modified residues to coordinate Cu(I) ions. Considering the necessity of oxazolin for host cell invasion by NTHi, these findings point to a key role for copper during NTHi infection. Furthermore, oxazolin and its biosynthetic pathway represent a potential therapeutic target for NTHi.

Synthesis of Structural ADP-Ribose Analogues as Inhibitors for SARS-CoV-2 Macrodomain 1.

Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, a prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, a relatively underexplored angle in design pertains to the synthesis of structural substrate mimics. Here, we present the synthesis and biophysical activity of novel adenosine diphosphate ribose (ADPr) analogues as SARS-CoV-2 NSP3 Mac1 inhibitors.

Lung Cancer Screening Before and After a Multifaceted Electronic Health Record Intervention: A Nonrandomized Controlled Trial.

Importance: Lung cancer is the deadliest cancer in the US. Early-stage lung cancer detection with lung cancer screening (LCS) through low-dose computed tomography (LDCT) improves outcomes. Objective: To assess the association of a multifaceted clinical decision support intervention with rates of identification and completion of recommended LCS-related services. Design, Setting, and Participants: This nonrandomized controlled trial used an interrupted time series design, including 3 study periods from August 24, 2019, to April 27, 2022: baseline (12 months), period 1 (11 months), and period 2 (9 months). Outcome changes were reported as shifts in the outcome level at the beginning of each period and changes in monthly trend (ie, slope). The study was conducted at primary care and pulmonary clinics at a health care system headquartered in Salt Lake City, Utah, among patients aged 55 to 80 years who had smoked 30 pack-years or more and were current smokers or had quit smoking in the past 15 years. Data were analyzed from September 2023 through February 2024. Interventions: Interventions in period 1 included clinician-facing preventive care reminders, an electronic health record-integrated shared decision-making tool, and narrative LCS guidance provided in the LDCT ordering screen. Interventions in period 2 included the same clinician-facing interventions and patient-facing reminders for LCS discussion and LCS. Main Outcome and Measure: The primary outcome was LCS care gap closure, defined as the identification and completion of recommended care services. LCS care gap closure could be achieved through LDCT completion, other chest CT completion, or LCS shared decision-making. Results: The study included 1865 patients (median [IQR] age, 64 [60-70] years; 759 female [40.7%]). The clinician-facing intervention (period 1) was not associated with changes in level but was associated with an increase in slope of 2.6 percentage points (95% CI, 2.4-2.7 percentage points) per month in care gap closure through any means and 1.6 percentage points (95% CI, 1.4-1.8 percentage points) per month in closure through LDCT. In period 2, introduction of patient-facing reminders was associated with an immediate increase in care gap closure (2.3 percentage points; 95% CI, 1.0-3.6 percentage points) and closure through LDCT (2.4 percentage points; 95% CI, 0.9-3.9 percentage points) but was not associated with an increase in slope. The overall care gap closure rate was 175 of 1104 patients (15.9%) at the end of the baseline period vs 588 of 1255 patients (46.9%) at the end of period 2. Conclusions and Relevance: In this study, a multifaceted intervention was associated with an improvement in LCS care gap closure. Trial Registration: ClinicalTrials.gov Identifier: NCT04498052.

Gravedad y complicaciones en lactantes con infección por el virus respiratorio sincitial posterior a la pandemia por SARS-CoV-2 / Severity and complications in infants with respiratory syncytial virus infection after the SARS-CoV-2 pandemic

Resumen Introducción: Posterior a la pandemia por SARS-CoV-2 se ha observado un incremento en la hospitalización por virus respiratorio sincitial (VRS), con mayores complicaciones. Se han encontrado alteraciones extrapulmonares asociadas, disfunción biventricular y lesión renal aguda, entre otras. El objetivo de este estudio fue analizar la evolución y las complicaciones en niños hospitalizados con enfermedad respiratoria de vías bajas secundaria a infección por VRS tras la pandemia de COVID-19. Métodos: Se incluyeron todos los menores de 2 años que ingresaron al servicio de urgencias con infección por VRS. Se analizaron las características clínicas, la necesidad de oxígeno suplementario, el uso de aminas, el índice de angina renal y el requerimiento de terapia de sustitución renal. Se realizó ecografía pulmonar al ingreso. En el análisis estadístico, para las variables cuantitativas se determinaron la media y la desviación estándar, y para las variables cualitativas la frecuencia y el porcentaje. Se evaluaron las diferencias de la distribución con la prueba exacta de Fisher. Resultados: Hubo 45 pacientes con infección por VRS. El 26.7% requirieron ventilación mecánica invasiva y el 11.1% diálisis peritoneal. La letalidad fue de cuatro casos, tres de ellos menores de 12 meses con puntuación de LUS > 7; esto contrasta con el 90.2% de los sobrevivientes con puntaje < 7 (p = 0.0004). Conclusiones: Se observó un aumento en la incidencia de bronquiolitis tras la pandemia, en más de la mitad de los casos con cuadros de moderados a graves, y todos requirieron oxígeno suplementario al ingreso. La lesión renal aguda fue la manifestación extrapulmonar más frecuente.

Abstract Background: After the SARS-CoV-2 pandemic, there has been an increase in hospitalization for lower respiratory infection secondary to respiratory syncytial virus (RSV), with greater complications. Associated extrapulmonary alterations, biventricular dysfunction, acute kidney injury, among others, have been found. The objective of this study was to analize the evolution and complications in hospitalized children with lower respiratory infection secondary to RSV after COVID-19 pandemic. Methods: All pediatric patients under 2 years of age admitted to the emergency department with RSV infection were included. Clinical characteristics, need for supplemental oxygen, use of amines, renal angina index, and requirement for renal replacement therapy were analyzed. Lung ultrasound was performed upon admission. Statistical analysis was carried out for the quantitative variables by means of mean and standard deviation, and qualitative variables by frequency and percentage. Differences in the distribution were evaluated with Fisher’s exact distribution. Results: 45 patients with RSV infection were identified, 26.7% required invasive mechanical ventilation and 11.1% requiered peritoneal dialysis. Fatality was observed in four cases, three of these younger than 12 months with a LUS score > 7; contrasts with 90.2% of survivors with a score < 7 (p = 0.0004). Conclusions: An increase in the incidence of bronchiolitis after pandemic was observed, with more than half having moderate to severe symptoms and requiring supplemental oxygen support in all patients upon admission. Acute kidney injury is the most common extrapulmonary manifestation.

Diphenyl Diselenide Through Reduction of Inflammation, Oxidative Injury and Caspase-3 Activation Abates Doxorubicin-Induced Neurotoxicity in Rats.

Neurotoxicity associated with chemotherapy is a debilitating side effect of cancer management in humans which reportedly involves inflammatory and oxidative stress responses. Diphenyl diselenide (DPDS) is an organoselenium compound which exhibits its anti-tumoral, anti-oxidant, anti-inflammatory and anti-mutagenic effects. Nevertheless, its possible effect on chemotherapy-induced neurotoxicity is not known. Using rat model, we probed the behavioral and biochemical effects accompanying administration of antineoplastic agent doxorubicin (7.5 mg/kg) and DPDS (5 and 10 mg/kg). Anxiogenic-like behavior, motor and locomotor insufficiencies associated with doxorubicin were considerably abated by both DPDS doses with concomitant enhancement in exploratory behavior as demonstrated by reduced heat maps intensity and enhanced track plot densities. Moreover, with exception of cerebral glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, biochemical data demonstrated reversal of doxorubicin-mediated decline in cerebral and cerebellar antioxidant status indices and the increase in acetylcholinesterase (AChE) activity by both doses of DPDS. Also, cerebellar and cerebral lipid peroxidation, hydrogen peroxide as well as reactive oxygen and nitrogen species levels were considerably diminished in rats administered doxorubicin and DPDS. In addition, DPDS administration abated myeloperoxidase activity, tumour necrosis factor alpha and nitric oxide levels along with caspase-3 activity in doxorubicin-administered rats. Chemoprotection of doxorubicin-associated neurotoxicity by DPDS was further validated by histomorphometry and histochemical staining. Taken together, DPDS through offsetting of oxido-inflammatory stress and caspase-3 activation elicited neuroprotection in doxorubicin-treated rats.

Adaptive immune cells are necessary for SARS-CoV-2-induced pathology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the ongoing global pandemic associated with morbidity and mortality in humans. Although disease severity correlates with immune dysregulation, the cellular mechanisms of inflammation and pathogenesis of COVID-19 remain relatively poorly understood. Here, we used mouse-adapted SARS-CoV-2 strain MA10 to investigate the role of adaptive immune cells in disease. We found that while infected wild-type mice lost ~10% weight by 3 to 4 days postinfection, rag-/- mice lacking B and T lymphocytes did not lose weight. Infected lungs at peak weight loss revealed lower pathology scores, fewer neutrophils, and lower interleukin-6 and tumor necrosis factor-α in rag-/- mice. Mice lacking αß T cells also had less severe weight loss, but adoptive transfer of T and B cells into rag-/- mice did not significantly change the response. Collectively, these findings suggest that while adaptive immune cells are important for clearing SARS-CoV-2 infection, this comes at the expense of increased inflammation and pathology.

Barriers and enablers of active surveillance for prostate cancer: a qualitive study of clinicians.

OBJECTIVES: To identify and explore barriers to, and enablers of, active surveillance (AS) in men with low-risk prostate cancer (LRPCa), as perceived by PCa clinicians. PATIENTS AND METHODS: Urologists and radiation oncologists in Australia and New Zealand were purposively sampled for a cross-section on gender and practice setting (metropolitan/regional; public/private). Using a grounded theory approach, semi-structed interviews were conducted with participants. Interviews were coded independently by two researchers using open, axial, and selective coding. A constant comparative approach was used to analyse data as it was collected. Thematic saturation was reached after 18 interviews, and a detailed model of barriers to, and enablers of, AS for LRPCa, as perceived by clinicians was developed. RESULTS: A model explaining what affects clinician decision making regarding AS in LRPCa emerged. It was underpinned by three broad themes: (i) clinician perception of patients' barriers and enablers; (ii) clinician perception of their own barriers and enablers; and (iii) engagement with healthcare team and resource availability. CONCLUSIONS: Clinicians unanimously agree that AS is an evidence-based approach for managing LRPCa. Despite this many men do not undergo AS for LRPCa, which is due to the interplay of patient and clinician factors, and their interaction with the wider healthcare system. This study identifies strategies to mitigate barriers and enhance enablers, which could increase access to AS by patients with LRPCa.

Effect of ultra-violet light radiation on Scenedesmus vacuolatus growth kinetics, metabolic performance, and preliminary biodegradation study.

This study presents the effect of ultra-violet (UV) light radiation on the process kinetics, metabolic performance, and biodegradation capability of Scenedesmus vacuolatus. The impact of the UV radiation on S. vacuolatus morphology, chlorophyll, carotenoid, carbohydrates, proteins, lipid accumulation, growth rate, substrate affinity and substrate versatility were evaluated. Thereafter, a preliminary biodegradative potential of UV-exposed S. vacuolatus on spent coolant waste (SCW) was carried out based on dehydrogenase activity (DHA) and total petroleum hydrocarbon degradation (TPH). Pronounced structural changes were observed in S. vacuolatus exposed to UV radiation for 24 h compared to the 2, 4, 6, 12 and 48 h UV exposure. Exposure of S. vacuolatus to UV radiation improved cellular chlorophyll (chla = 1.89-fold, chlb = 2.02-fold), carotenoid (1.24-fold), carbohydrates (4.62-fold), proteins (1.44-fold) and lipid accumulations (1.40-fold). In addition, the 24 h UV exposed S. vacuolatus showed a significant increase in substrate affinity (1/Ks) (0.959), specific growth rate (µ) (0.024 h-1) and biomass accumulation (0.513 g/L) by 1.50, 2 and 1.9-fold respectively. Moreover, enhanced DHA (55%) and TPH (100%) degradation efficiency were observed in UV-exposed S. vacuolatus. These findings provided major insights into the use of UV radiation to enhance S. vacuolatus biodegradative performance towards sustainable green environment negating the use of expensive chemicals and other unfriendly environmental practices.

The Association Between Frailty and Visual Field Loss in US Adults.

PURPOSE: To describe the association between visual field loss and frailty in a nationally representative cohort of US adults. DESIGN: Retrospective cross-sectional study. METHODS: The cohort included adults 40 years or older with complete eye examination data from the 2005-2006 and 2007-2008 National Health and Nutrition Examination Surveys (NHANES). Visual field loss (VFL) was determined by frequency doubling technology and a 2-2-1 algorithm. A 36-item deficit accumulation-based frailty index was used to divide subjects into 4 categories of increasing frailty severity. RESULTS: Of the 4897 participants, 4402 (93.2%) had no VFL, 301 (4.1%) had unilateral VFL, and 194 (2.73%) had bilateral VFL. Within the sample, 2 subjects197 (53.1%) were categorized as non-frail, 1659 (31.3%) as vulnerable, 732 (11.3%) as mildly frail, and 312 (4.3%) as most frail. In multivariable models adjusted for demographics, visual acuity, and history of cataract surgery, subjects with unilateral VFL had higher adjusted odds of being in a more frail category (adjusted odds ratio [aOR], 2.07; 95% CI, 1.42-3.02) than subjects without VFL. Subjects with bilateral VFL also had higher odds of a more frail category compared to subjects without VFL (aOR, 1.74; 95% CI, 1.20-2.52). CONCLUSIONS: In the 2005-2008 NHANES adult population, VFL is associated with higher odds of frailty, independent of central visual acuity loss. Frail individuals may be more susceptible to diseases that can cause VFL, and/or VFL may predispose to frailty. Additional studies are needed to determine the directionality of this relationship and to assess potential interventions.

Usefulness of lung ultrasound in the evaluation of children with lower respiratory tract infection in the emergency room / Utilidad de ecografía pulmonar en la valoración de niños con infección respiratoria baja en urgencias

Abstract Background: Lung ultrasound is a bedside tool that allows the evaluation of pulmonary parenchymal involvement in pediatric patients through the lung ultrasound score (LUS). We aimed to evaluate a group of patients under 3 years of age with lower respiratory tract infections using LUS at the Hospital Infantil del Estado de Sonora. Methods: We included patients younger than 3 years admitted to the emergency department with lower respiratory tract infections. A lung ultrasound was performed within the first 24 h of admission to the emergency department and evaluated using LUS. We analyzed age, sex, etiology of infection, days of stay, use of mechanical ventilation, Downes scale, failure of mechanical ventilation on admission, and mortality. Descriptive analysis was performed with frequencies and percentages for qualitative variables and medians and interquartile intervals for quantitative variables. Differences in the distribution of LUS variables were evaluated with the Fishers´ exact test and Student´s t-test. Results: We included a total of 19 patients with lower respiratory tract infections, 73.7% with bronchiolitis. Fifty percent of the cases scored 7 on the LUS, 91.7% were admitted to the pediatric intensive care unit, and 53.8% required invasive mechanical ventilation. Conclusions: The use of LUS in lower respiratory tract infections can predict the need for PICU admission, the use of invasive ventilatory support, and prolonged hospital stay.

Resumen Introducción: El ultrasonido pulmonar es una herramienta a pie de cama que permite evaluar la afectación del parénquima pulmonar en pacientes pediátricos por medio de la escala de LUS (lung ultrasound score, por sus siglas en inglés). El objetivo del estudio fue evaluar a niños menores de 3 años con infección respiratoria baja mediante la escala de LUS, en el Hospital Infantil del Estado de Sonora. Métodos: Se incluyeron pacientes menores de 3 años que ingresaron al Servicio de Urgencias con infección respiratoria baja. Se realizó ecografía pulmonar en las primeras 24 horas de ingreso a urgencias y se evaluó mediante la escala de LUS. Se analizó, edad, sexo, etiología de la infección, días de estancia, uso de terapia ventilatoria, escala de Downes, fracaso a la terapia ventilatoria de ingreso y mortalidad. Se realizó un análisis descriptivo por medio de frecuencia y porcentaje para las variables cualitativas y para las cuantitativas con mediana e intervalo intercuartil. Las diferencias en la distribución de las variables por la escala de LUS con la prueba exacta de Fisher y la t de Student. Resultados: Se identificaron 19 pacientes con infección pulmonar aguda, de los cuales el 73.7% presentó bronquiolitis. El 50% de los casos obtuvo 7 puntos de la escala de LUS, el 91.7% ingresó a UCIP y el 53.8% requirió ventilación mecánica asistida. Conclusiones: El uso de la escala LUS en infección respiratoria baja puede predecir la necesidad de ingreso a Unidad de Cuidados Intensivos Pediátricos, así como la utilización de soporte ventilatorio invasivo y una estancia hospitalaria prolongada.

Perfluorooctanoic acid induces behavioral impairment and oxidative injury in Nauphoeta cinerea nymphs.

Perfluorooctanoic acid (PFOA) is a persistent organic contaminant with potential health threats to both animals and humans. However, the impact of PFOA on insects, which play significant roles in ecosystems, is understudied. We evaluated the toxicological impact of ecologically relevant concentrations of PFOA (0, 25, 50, 100, and 200 µg L-1) on Nauphoeta cinerea nymphs following exposure for 42 consecutive days. We analyzed the behavior of the insects with automated video-tracking software and processed the head, midgut, and fat body for biochemical assays. PFOA-exposed insects exhibited significant reductions in locomotory abilities and an increase in freezing time. Furthermore, PFOA exposure reduced acetylcholinesterase activity in the insect head. PFOA exposure increased the activities of superoxide dismutase, glutathione peroxidase, and catalase in the head and midgut, but decreased them in the fat body. PFOA also significantly increased glutathione-S transferase activity, while decreasing glutathione levels in the head, midgut, and fat body. Additionally, PFOA exposure increased reactive oxygen and nitrogen species, nitric oxide, lipid peroxidation, and protein carbonyl contents in the head, midgut, and fat body of the insects. In conclusion, our findings indicate that PFOA exposure poses an ecological risk to Nauphoeta cinerea.

Short-term assays for mesenchymal stromal cell immunosuppression of T-lymphocytes.

Introduction: Trauma patients are susceptible to coagulopathy and dysfunctional immune responses. Mesenchymal stromal cells (MSCs) are at the forefront of the cellular therapy revolution with profound immunomodulatory, regenerative, and therapeutic potential. Routine assays to assess immunomodulation activity examine MSC effects on proliferation of peripheral blood mononuclear cells (PBMCs) and take 3-7 days. Assays that could be done in a shorter period of time would be beneficial to allow more rapid comparison of different MSC donors. The studies presented here focused on assays for MSC suppression of mitogen-stimulated PBMC activation in time frames of 24 h or less. Methods: Three potential assays were examined-assays of apoptosis focusing on caspase activation, assays of phosphatidyl serine externalization (PS+) on PBMCs, and measurement of tumor necrosis factor alpha (TNFα) levels using rapid ELISA methods. All assays used the same initial experimental conditions: cryopreserved PBMCs from 8 to 10 pooled donors, co-culture with and without MSCs in 96-well plates, and PBMC stimulation with mitogen for 2-72 h. Results: Suppression of caspase activity in activated PBMCs by incubation with MSCs was not robust and was only significant at times after 24 h. Monitoring PS+ of live CD3+ or live CD4+/CD3+ mitogen-activated PBMCs was dose dependent, reproducible, robust, and evident at the earliest time point taken, 2 h, although no increase in the percentage of PS+ cells was seen with time. The ability of MSC in co-culture to suppress PBMC PS+ externalization compared favorably to two concomitant assays for MSC co-culture suppression of PBMC proliferation, at 72 h by ATP assay, or at 96 h by fluorescently labeled protein signal dilution. TNFα release by mitogen-activated PBMCs was dose dependent, reproducible, robust, and evident at the earliest time point taken, with accumulating signal over time. However, suppression levels with MSC co-culture was reliably seen only after 24 h. Discussion: Takeaways from these studies are as follows: (1) while early measures of PBMC activation is evident at 2-6 h, immunosuppression was only reliably detected at 24 h; (2) PS externalization at 24 h is a surrogate assay for MSC immunomodulation; and (3) rapid ELISA assay detection of TNFα release by PBMCs is a robust and sensitive assay for MSC immunomodulation at 24 h.

Neurotoxicity of ochratoxin A: Molecular mechanisms and neurotherapeutic strategies.

Data from epidemiological and experimental studies have evidenced that some chemical contaminants in food elicit their harmful effects by targeting the central nervous system. Ochratoxin A is a foodborne mycotoxin produced by Aspergillus and Penicillium species. Research on neurotoxicity associated with ochratoxin A exposure has increased greatly in recent years. The present review accrued substantial evidence on the neurotoxicity associated with ochratoxin A exposure as well as discussed notable susceptible targets of noxious ochratoxin A at molecular, cellular and genetic levels. Specifically, the neurotoxic mechanisms associated with ochratoxin A exposure were unequivocally unraveled in vitro using human neuroblastoma SH-SY5Y cells, mouse hippocampal HT22 cells, human astrocyte (NHA-SV40LT) cells and microglia cells as well as in vivo using mammalian and non-mammalian models. Data from human biomonitoring studies on plasma ochratoxin A levels in patients with neurodegenerative diseases with some age- and sex-related responses were also highlighted. Moreover, the neurotherapeutic mechanisms of some naturally occurring bioactive compounds against ochratoxin A neurotoxicity are reviewed. Collectively, accumulated data from literature demonstrate that ochratoxin A is a neurotoxin with potential pathological involvement in neurological disorders. Cutting edge original translational research on the development of neurotherapeutics for neurotoxicity associated with foodborne toxicants including ochratoxin A is indispensable.

A Case of Visceral Leishmaniasis in a 4-Year-Old Child Living in Nonendemic Area Located in Suburbs of Dakar, Senegal.

Visceral leishmaniasis (VL) is an infectious disease caused by protozoa of the genus Leishmania. Sporadic cases are observed in nonendemic areas and often associated with limited foci; therefore, the disease is easily overlooked. In addition, other diseases have similar clinical symptoms, which make it difficult for clinicians to make an accurate diagnosis and to provide effective treatment. We identified visceral leishmaniasis in a 4-year-old child in Pikine, Senegal. The patient was admitted to the Pikine National Teaching Hospital for haemorrhagic, tumoral, and infectious syndromes. At admission, the patient presented with epistaxis and gingivorrhagia, a severe anaemic syndrome poorly tolerated, a systemic inflammatory response syndrome with fever at 39.5°C, a tumoral syndrome with 11 cm of hepatomegaly and 12 cm of type IV splenomegaly, and noninflammatory macropoly adenopathies. A spinal cord puncture was performed, and direct microscopy examination of the sample after GIEMSA staining revealed amastigote forms of Leishmania. The PCR amplification of extracted DNA from the bone marrow aspiration using specific primers for VL (forward and reverse) confirmed that VL was responsible for the infection. A treatment with meglumine antimoniate (Glucantime) was given and it gave a successful outcome with remission of clinical symptoms and favourable evolution with 3 months hindsight. Conclusion. This visceral leishmaniasis case diagnosis in Senegal has shown that, apart from haematological malignancies, this disease must be considered in combination with a tumor syndrome, haemorrhagic syndrome, and infectious syndrome.

Provider and User Acceptability of Integrated Treatment for the Control of Malaria and Helminths in Saraya, South-Eastern Senegal.

Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria and neglected tropical diseases (NTD) by 2030. This qualitative study was conducted within the context of a randomized controlled trial to explore the perceptions and views of parents/caregivers of at-risk children and healthcare providers to determine their acceptability of the integrated malaria-helminth treatment approach. Randomly selected parents/caregivers of children enrolled in the trial, healthcare providers, trial staff, malaria, and NTD program managers were interviewed using purpose-designed topic guides. Transcripts obtained from the interviews were coded and common themes identified using content analysis were triangulated. Fifty-seven study participants comprising 26 parents/caregivers, 10 study children aged ≥ 10 years, 15 trial staff, four healthcare providers, and two managers from the Senegal Ministry of Health were interviewed. Thirty-eight of the participants (66.7%) were males, and their ages ranged from 10 to 65 years. Overall, the integrated malaria-helminth treatment approach was considered acceptable, but the study participants expressed concerns about the taste, smell, and side effects associated with amodiaquine and praziquantel in the combination package. Reluctance to accept the medications was also observed among children aged 10 to 14 years due to peer influence and gender-sensitive cultural beliefs. Addressing concerns about the taste and smell of amodiaquine and praziquantel is needed to optimize the uptake of the integrated treatment program. Also, culturally appropriate strategies need to be put in place to cater for the inclusion of children aged 10 to 14 years in this approach.

Cellular and molecular mechanisms of aflatoxin B1-mediated neurotoxicity: The therapeutic role of natural bioactive compounds.

Aflatoxin B1 (AFB1), a dietary toxin from the mold Aspergillus species, is well acknowledged to elicit extra-hepatic toxicity in both animals and humans. The neurotoxicity of AFB1 has become a global public health concern. Contemporary research on how AFB1 enters the brain to elicit neuronal dysregulation leading to noxious neurological outcomes has increased greatly in recent years. The current review discusses several neurotoxic outcomes and susceptible targets of AFB1 toxicity at cellular, molecular and genetic levels. Specifically, neurotoxicity studies involving the use of brain homogenates, neuroblastoma cell line IMR-32, human brain microvascular endothelial cells, microglial cells, and astrocytes, as well as mammalian and non-mammalian models to unravel the mechanisms associated with AFB1 exposure are highlighted. Further, some naturally occurring bioactive compounds with compelling therapeutic effects on AFB1-induced neurotoxicity are reviewed. In conclusion, available data from literature highlight AFB1 as a neurotoxin and its possible pathological contribution to neurological disorders. Further mechanistic studies aimed at discovering and developing effective therapeutics for AFB1 neurotoxicity is warranted.

Metoprolol elicits neurobehavioral insufficiency and oxidative damage in nontarget Nauphoeta cinerea nymphs.

Metoprolol, a drug for hypertension and cardiovascular diseases, has become a contaminant of emerging concern because of its frequent detection in various environmental matrices globally. The dwindling in the biodiversity of useful insects owing to increasing presence of environmental chemicals is currently a great interest to the scientific community. In the current research, the toxicological impact of ecologically relevant concentrations of metoprolol at 0, 0.05, 0.1, 0.25, and 0.5 µg/L on Nauphoeta cinerea nymphs following exposure for 42 consecutive days was evaluated. The insects' behavior was analyzed with automated video-tracking software (ANY-maze, Stoelting Co, USA) while biochemical assays were done using the midgut, head and fat body. Metoprolol-exposed nymphs exhibited significant diminutions in the path efficiency, mobility time, distance traveled, body rotation, maximum speed and turn angle cum more episodes, and time of freezing. In addition, the heat maps and track plots confirmed the metoprolol-mediated wane in the exploratory and locomotor fitness of the insects. Compared with control, metoprolol exposure decreased acetylcholinesterase activity in insects head. Antioxidant enzymes activities and glutathione level were markedly decreased whereas indices of inflammation and oxidative injury to proteins and lipids were significantly increased in head, midgut and fat body of metoprolol-exposed insects. Taken together, metoprolol exposure induces neurobehavioral insufficiency and oxido-inflammatory injury in N. cinerea nymphs. These findings suggest the potential health effects of environmental contamination with metoprolol on ecologically and economically important nontarget insects.