Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.

Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment. A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease. The elicited antibodies showed high specificity toward S100A9 without cross-reactivity toward S100A8, another member of the S100A family. When tested in metastatic mouse models of breast cancer and melanoma, the vaccines significantly reduced lung tumor nodules after intravenous challenge or postsurgical removal of the primary tumor. Mechanistically, the vaccines reduce the levels of S100A9 within the lungs and sera, thereby increasing the expression of immunostimulatory cytokines with antitumor function [(interleukin) IL-12 and interferonγ] while reducing levels of immunosuppressive cytokines (IL-10 and transforming growth factorß). This also correlated with decreased myeloid-derived suppressor cell populations within the lungs. This work has wide-ranging impact, as S100A9 is overexpressed in multiple cancers and linked with poor prognosis in cancer patients. The data presented lay the foundation for the development of therapies and vaccines targeting S100A9 to prevent metastasis.

SUMO modifies GßL and mediates mTOR signaling.

The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications; however, underlying mechanisms remain unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GßL (G protein ß-subunit-like protein, also known as mLST8), is modified by SUMO1, 2, and 3 isoforms. Using mutagenesis and mass spectrometry, we identified that GßL is SUMOylated at lysine sites K86, K215, K245, K261, and K305. We found that SUMO depletion reduces mTOR-Raptor (regulatory protein associated with mTOR) and mTOR-Rictor (rapamycin-insensitive companion of mTOR) complex formation and diminishes nutrient-induced mTOR signaling. Reconstitution with WT GßL but not SUMOylation-defective KR mutant GßL promotes mTOR signaling in GßL-depleted cells. Taken together, we report for the very first time that SUMO modifies GßL, influences the assembly of mTOR protein complexes, and regulates mTOR activity.

Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression.

Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting "cross-SUMOylation" of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9). Nevertheless, the identity of the SUMO substrates of Rhes remains largely unknown. Here, by combining high throughput interactome and SUMO proteomics, we report that Rhes regulates the SUMOylation of nuclear proteins that are involved in the regulation of gene expression. Rhes increased the SUMOylation of histone deacetylase 1 (HDAC1) and histone 2B, while decreasing SUMOylation of heterogeneous nuclear ribonucleoprotein M (HNRNPM), protein polybromo-1 (PBRM1) and E3 SUMO-protein ligase (PIASy). We also found that Rhes itself is SUMOylated at 6 different lysine residues (K32, K110, K114, K120, K124, and K245). Furthermore, Rhes regulated the expression of genes involved in cellular morphogenesis and differentiation in the striatum, in a SUMO-dependent manner. Our findings thus provide evidence for a previously undescribed role for Rhes in regulating the SUMOylation of nuclear targets and in orchestrating striatal gene expression via SUMOylation.

Rickettsial Disease Outbreak, Mexico, 2022.

Beginning in 2022, Nuevo Leon, Mexico, experienced an outbreak of rickettsioses that is still ongoing despite multidisciplinary control efforts. A total of 57 cases have been confirmed, particularly affecting children. We report a high mortality rate among hospitalized persons in Nuevo Leon. Continuing efforts are required to control the outbreak.

Characterization of gut microbiota associated with metabolic syndrome and type-2 diabetes mellitus in Mexican pediatric subjects.

BACKGROUND: Childhood obesity is a serious public health concern that confers a greater risk of developing important comorbidities such as MetS and T2DM. Recent studies evidence that gut microbiota may be a contributing factor; however, only few studies exist in school-age children. Understanding the potential role of gut microbiota in MetS and T2DM pathophysiology from early stages of life might contribute to innovative gut microbiome-based interventions that may improve public health. The main objective of the present study was to characterize and compare gut bacteria of T2DM and MetS children against control subjects and determine which microorganisms might be potentially related with cardiometabolic risk factors to propose gut microbial biomarkers that characterize these conditions for future development of pre-diagnostic tools. RESULTS: Stool samples from 21 children with T2DM, 25 with MetS, and 20 controls (n = 66) were collected and processed to conduct 16S rDNA gene sequencing. α- and ß-diversity were studied to detect microbial differences among studied groups. Spearman correlation was used to analyze possible associations between gut microbiota and cardiometabolic risk factors, and linear discriminant analyses (LDA) were conducted to determine potential gut bacterial biomarkers. T2DM and MetS showed significant changes in their gut microbiota at genus and family level. Read relative abundance of Faecalibacterium and Oscillospora was significantly higher in MetS and an increasing trend of Prevotella and Dorea was observed from the control group towards T2DM. Positive correlations were found between Prevotella, Dorea, Faecalibacterium, and Lactobacillus with hypertension, abdominal obesity, high glucose levels, and high triglyceride levels. LDA demonstrated the relevance of studying least abundant microbial communities to find specific microbial communities that were characteristic of each studied health condition. CONCLUSIONS: Gut microbiota was different at family and genus taxonomic levels among controls, MetS, and T2DM study groups within children from 7 to 17 years old, and some communities seemed to be correlated with relevant subjects' metadata. LDA helped to find potential microbial biomarkers, providing new insights regarding pediatric gut microbiota and its possible use in the future development of gut microbiome-based predictive algorithms.

A novel sulindac derivative protects against oxidative damage by a cyclooxygenase-independent mechanism.

Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a cyclooxygenase (COX) inhibitor and FDA approved anti-inflammatory drug, has chemoprotective activity in cells and intact organs by initiating a pharmacological preconditioning response, similar to ischemic preconditioning (IPC). The mechanism is independent of its COX inhibitory activity as suggested by studies on the protection of the heart against oxidative damage from ischemia/reperfusion and retinal pigmented endothelial (RPE) cells against chemical oxidative and UV damage . Unfortunately, sulindac is not recommended for long-term use due to toxicities resulting from its COX inhibitory activity. To develop a safer and more efficacious derivative of sulindac, we screened a library of indenes and identified a lead compound, MCI-100, that lacked significant COX inhibitory activity but displayed greater potency than sulindac to protect RPE cells against oxidative damage. MCI-100 also protected the intact rat heart against ischemia/reperfusion damage following oral administration. The chemoprotective activity of MCI-100 involves a preconditioning response similar to sulindac, which is supported by RNA sequencing data showing common genes that are induced or repressed by sulindac or MCI-100 treatment. Both sulindac and MCI-100 protection against oxidative damage may involve modulation of Wnt/ß-catenin signaling resulting in proliferation while inhibiting TGFb signaling leading to apoptosis. In summary MCI-100, is more active than sulindac in protecting cells against oxidative damage, but without significant NSAID activity, and could have therapeutic potential in treatment of diseases that involve oxidative damage. Significance Statement In this study, we describe a novel sulindac derivative, MCI-100, that lacks significant COX inhibitory activity, but is appreciably more potent than sulindac in protecting retinal pigmented epithelial (RPE) cells against oxidative damage. Oral administration of MCI-100 markedly protected the rat heart against ischemia/reperfusion damage. MCI-100 has potential therapeutic value as a drug candidate for age-related diseases by protecting cells against oxidative damage and preventing organ failure.

Type I Interferon acts as a major barrier to the establishment of infectious bursal disease virus (IBDV) persistent infections.

Infectious bursal disease virus (IBDV), the best characterized member of the Birnaviridae family, is a highly relevant avian pathogen causing both acute and persistent infections in different avian hosts. Here, we describe the establishment of clonal, long-term, productive persistent IBDV infections in DF-1 chicken embryonic fibroblasts. Although virus yields in persistently-infected cells are exceedingly lower than those detected in acutely infected cells, the replication fitness of viruses isolated from persistently-infected cells is higher than that of the parental virus. Persistently-infected DF-1 and IBDV-cured cell lines derived from them do not respond to type I interferon (IFN). High-throughput genome sequencing revealed that this defect is due to mutations affecting the IFNα/ß receptor subunit 2 (IFNAR2) gene resulting in the expression of IFNAR2 polypeptides harbouring large C-terminal deletions that abolish the signalling capacity of IFNα/ß receptor complex. Ectopic expression of a recombinant chicken IFNAR2 gene efficiently rescues IFNα responsiveness. IBDV-cured cell lines derived from persistently infected cells exhibit a drastically enhanced susceptibility to establishing new persistent IBDV infections. Additionally, experiments carried out with human HeLa cells lacking the IFNAR2 gene fully recapitulate results obtained with DF-1 cells, exhibiting a highly enhanced capacity to both survive the acute IBDV infection phase and to support the establishment of persistent IBDV infections. Results presented here show that the inactivation of the JAK-STAT signalling pathway significantly reduces the apoptotic response induced by the infection, hence facilitating the establishment and maintenance of IBDV persistent infections.IMPORTANCE Members of the Birnaviridae family, including infectious bursal disease virus (IBDV), exhibit a dual behaviour, causing acute infections that are often followed by the establishment of life-long persistent asymptomatic infections. Indeed, persistently infected specimens might act as efficient virus reservoirs, hence potentially contributing to virus dissemination. Despite the key importance of this biological trait, information about mechanisms triggering IBDV persistency is negligible. Our report evidences the capacity of IBDV, a highly relevant avian pathogen, to establishing long-term, productive, persistent infections in both avian and human cell lines. Data presented here provide novel and direct evidence about the crucial role of type I IFNs on the fate of IBDV-infected cells and their contribution to controlling the establishment of IBDV persistent infections. The use of cell lines unable to respond to type I IFNs opens a promising venue to unveiling additional factors contributing to IBDV persistency.

Multivalent Display of ApoAI Peptides on the Surface of Tobacco Mosaic Virus Nanotubes Improves Cholesterol Efflux.

Atherosclerosis is a progressive cardiovascular disease in which cholesterol-rich plaques build up within arteries, increasing the risk of thrombosis, myocardial infarction, and stroke. One promising therapeutic approach is the use of high-density lipoprotein (HDL) biomimetic formulations based on ApoAI peptides that promote cholesterol efflux from plaques, ultimately leading to cholesterol excretion. Here, we describe the multivalent display of ApoAI peptides on the surface of protein nanotubes derived from the plant virus tobacco mosaic virus (TMV) and protein nanoparticles using virus-like particles from bacteriophage Qß. Bioconjugation yielded ApoAI conjugates varying in size and morphology. We tested ABCA1-mediated cholesterol efflux using macrophage foam cells, the mitigation of reactive oxygen species in endothelial cells, and wound healing in endothelial cells. We found that the multivalent ApoAI platform, in particular the TMV-based nanotube, significantly improved the efficacy of cholesterol efflux compared to free peptides, Qß nanoparticle formulations, and traditional HDL therapy. Finally, to better understand the mechanistic basis of enhanced cholesterol efflux, we used confocal microscopy to show that while native TMV was taken up by cells, TMV-ApoAI remained at the exterior of foam cell membranes and efflux was documented using fluorescent cholesterol. Together, these data highlight that high aspect ratio materials with multivalent display of ApoAI peptides offer unique capabilities promoting efficient cholesterol efflux and may find applications in cardiovascular therapy.

Injectable Slow-Release Hydrogel Formulation of a Plant Virus-Based COVID-19 Vaccine Candidate.

Cowpea mosaic virus (CPMV) is a potent immunogenic adjuvant and epitope display platform for the development of vaccines against cancers and infectious diseases, including coronavirus disease 2019. However, the proteinaceous CPMV nanoparticles are rapidly degraded in vivo. Multiple doses are therefore required to ensure long-lasting immunity, which is not ideal for global mass vaccination campaigns. Therefore, we formulated CPMV nanoparticles in injectable hydrogels to achieve slow particle release and prolonged immunostimulation. Liquid formulations were prepared from chitosan and glycerophosphate (GP) before homogenization with CPMV particles at room temperature. The formulations containing high-molecular-weight chitosan and 0-4.5 mg mL-1 CPMV gelled rapidly at 37 °C (5-8 min) and slowly released cyanine 5-CPMV particles in vitro and in vivo. Importantly, when a hydrogel containing CPMV displaying severe acute respiratory syndrome coronavirus 2 spike protein epitope 826 (amino acid 809-826) was administered to mice as a single subcutaneous injection, it elicited an antibody response that was sustained over 20 weeks, with an associated shift from Th1 to Th2 bias. Antibody titers were improved at later time points (weeks 16 and 20) comparing the hydrogel versus soluble vaccine candidates; furthermore, the soluble vaccine candidates retained Th1 bias. We conclude that CPMV nanoparticles can be formulated effectively in chitosan/GP hydrogels and are released as intact particles for several months with conserved immunotherapeutic efficacy. The injectable hydrogel containing epitope-labeled CPMV offers a promising single-dose vaccine platform for the prevention of future pandemics as well as a strategy to develop long-lasting plant virus-based nanomedicines.

Dissolving Microneedle Delivery of a Prophylactic HPV Vaccine.

Prophylactic vaccines capable of preventing human papillomavirus (HPV) infections are still inaccessible to a vast majority of the global population due to their high cost and challenges related to multiple administrations performed in a medical setting. In an effort to improve distribution and administration, we have developed dissolvable microneedles loaded with a thermally stable HPV vaccine candidate consisting of Qß virus-like particles (VLPs) displaying a highly conserved epitope from the L2 protein of HPV (Qß-HPV). Polymeric microneedle delivery of Qß-HPV produces similar amounts of anti-HPV16 L2 IgG antibodies compared to traditional subcutaneous injection while delivering a much smaller amount of intradermal dose. However, a dose sparing effect was found. Furthermore, immunization yielded neutralizing antibody responses in a HPV pseudovirus assay. The vaccine candidate was confirmed to be stable at room temperature after storage for several months, potentially mitigating many of the challenges associated with cold-chain distribution. The ease of self-administration and minimal invasiveness of such microneedle patch vaccines may enable wide-scale distribution of the HPV vaccine and lead to higher patient compliance. The Qß VLP and its delivery technology is a plug-and-play system that could serve as a universal platform with a broad range of applications. Qß VLPs may be stockpiled for conjugation to a wide range of epitopes, which are then packaged and delivered directly to the patient via noninvasive microneedle patches. Such a system paves the way for rapid distribution and self-administration of vaccines.

Photothermal immunotherapy of melanoma using TLR-7 agonist laden tobacco mosaic virus with polydopamine coat.

Photothermal therapy (PTT) is a promising cancer treatment that debulks tumors locally while priming immune responses. However, PTT as a standalone treatment approach often has limited systemic efficacy, motivating the development of synergistic combination approaches. Toward this goal, herein, the tobacco mosaic virus (TMV) was loaded with a small molecule immunomodulator, toll-like receptor 7 agonist (1V209), and its surface was coated with photothermal biopolymer polydopamine (PDA). The resulting 1V209-laden and PDA-coated TMV was used to treat B16F10 dermal melanoma in C57BL/6 mice. 1V209-TMV-PDA was intratumorally injected and irradiated using an 808-nm near infrared laser. 60 % of the mice receiving PTT with intratumoral 1V209-TMV-PDA + laser remained alive at the end point - in contrast to only 20 % survivors were observed in the control group. Immunological analysis indicates systemic anti-tumor immunity being induced by the combination therapy with a greater number of tumor-specific T cells (as determined by a splenocyte assay). This study highlights the potential of TMV versatility as a multifunctional nano-platform for combined PTT-immunotherapy.

Rhes, a striatal-enriched protein, promotes mitophagy via Nix.

Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here, we find that striatal-enriched protein, Rhes, is a critical regulator of mitophagy and striatal vulnerability in brain. In vivo interactome and density fractionation reveal that Rhes coimmunoprecipitates and cosediments with mitochondrial and lysosomal proteins. Live-cell imaging of cultured striatal neuronal cell line shows Rhes surrounds globular mitochondria, recruits lysosomes, and ultimately degrades mitochondria. In the presence of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, Rhes disrupts mitochondrial membrane potential (ΔΨ m ) and promotes excessive mitophagy and cell death. Ultrastructural analysis reveals that systemic injection of 3-NP in mice promotes globular mitochondria, accumulation of mitophagosomes, and striatal lesion only in the wild-type (WT), but not in the Rhes knockout (KO), striatum, suggesting that Rhes is critical for mitophagy and neuronal death in vivo. Mechanistically, Rhes requires Nix (BNIP3L), a known receptor of mitophagy, to disrupt ΔΨ m and promote mitophagy and cell death. Rhes interacts with Nix via SUMO E3-ligase domain, and Nix depletion totally abrogates Rhes-mediated mitophagy and cell death in the cultured striatal neuronal cell line. Finally, we find that Rhes, which travels from cell to cell via tunneling nanotube (TNT)-like cellular protrusions, interacts with dysfunctional mitochondria in the neighboring cell in a Nix-dependent manner. Collectively, Rhes is a major regulator of mitophagy via Nix, which may determine striatal vulnerability in the brain.

Trivalent Subunit Vaccine Candidates for COVID-19 and Their Delivery Devices.

The COVID-19 pandemic highlights the need for platform technologies enabling rapid development of vaccines for emerging viral diseases. The current vaccines target the SARS-CoV-2 spike (S) protein and thus far have shown tremendous efficacy. However, the need for cold-chain distribution, a prime-boost administration schedule, and the emergence of variants of concern (VOCs) call for diligence in novel SARS-CoV-2 vaccine approaches. We studied 13 peptide epitopes from SARS-CoV-2 and identified three neutralizing epitopes that are highly conserved among the VOCs. Monovalent and trivalent COVID-19 vaccine candidates were formulated by chemical conjugation of the peptide epitopes to cowpea mosaic virus (CPMV) nanoparticles and virus-like particles (VLPs) derived from bacteriophage Qß. Efficacy of this approach was validated first using soluble vaccine candidates as solo or trivalent mixtures and subcutaneous prime-boost injection. The high thermal stability of our vaccine candidates allowed for formulation into single-dose injectable slow-release polymer implants, manufactured by melt extrusion, as well as microneedle (MN) patches, obtained through casting into micromolds, for prime-boost self-administration. Immunization of mice yielded high titers of antibodies against the target epitope and S protein, and data confirms that antibodies block receptor binding and neutralize SARS-CoV and SARS-CoV-2 against infection of human cells. We present a nanotechnology vaccine platform that is stable outside the cold-chain and can be formulated into delivery devices enabling single administration or self-administration. CPMV or Qß VLPs could be stockpiled, and epitopes exchanged to target new mutants or emergent diseases as the need arises.

Association between Irisin, hs-CRP, and Metabolic Status in Children and Adolescents with Type 2 Diabetes Mellitus.

Proinflammatory cytokines and the novel myokine irisin, a cleavage product of FNDC5, have been found to play a role in obesity and type 2 diabetes mellitus (T2DM). Irisin has been shown to increase browning of adipose tissue, thermogenesis, energy expenditure, and insulin sensitivity, yet its association with inflammatory markers is still limited. Circulating irisin has been found to be increased in obesity, while in adult subjects with T2DM decreased levels have been found. However, data establishing the association of circulating irisin in children and adolescents with T2DM has not been described in the literature. The objective of this study was to determine irisin plasma concentration and its association with metabolic and adiposity markers and with hs-CRP, a surrogate marker of inflammation used in clinical practice, in a pediatric population with T2DM. A cross-sample of 40 Mexican children and adolescents aged 7-17 were recruited, 20 diagnosed with T2DM and 20 healthy controls. Plasma irisin levels were found to be lower in the T2DM group compared with controls, which could be attributed to a reduced PGC-1α activity in muscle tissue with a consequent decrease in FNDC5 and irisin expression. Irisin concentration was found to be positively correlated with HDL-c, LDL-c, and total cholesterol, while negatively correlated with BMI, waist circumference, and triglycerides. However, after multiple regression analysis, only HDL-c correlation remained significant. hs-CRP was higher in the T2DM group and positively associated with adiposity markers, unfavorable lipid profile, insulin levels, and HOMA-IR, but no association with irisin was found. Given the favorable metabolic effects attributed to irisin, the low plasma levels found in children and adolescents with T2DM could exacerbate the inflammatory and metabolic imbalances and the intrinsic cardiovascular risk of this disease. We propose an "irisin-proinflammatory/anti-inflammatory axis" to explain the role of irisin as a metabolic regulator in obesity and T2DM.

Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs.

Bisphenol A (BPA) and diethylstilbestrol (DES) are xenoestrogens, which have been associated with altered effects on reproduction. We hypothesized that neonatal xenoestrogen exposure affects the ovarian functionality in lambs. Thus, we evaluated the ovarian response to exogenous ovine FSH (oFSH) administered from postnatal day 30 (PND30) to PND32 in female lambs previously exposed to low doses of DES or BPA (BPA50: 50 µg/kg per day, BPA0.5: 0.5 µg/kg per day) from PND1 to PND14. We determined: i) follicular growth, ii) circulating levels of 17ß-estradiol (E2), iii) steroid receptors (estrogen receptor alpha, estrogen receptor beta, and androgen receptor (AR)) and atresia, and iv) mRNA expression levels of the ovarian bone morphogenetic protein (BMPs) system (BMP6, BMP15, BMPR1B, and GDF9) and FSH receptor (FSHR). Lambs neonatally exposed to DES or BPA showed an impaired ovarian response to oFSH with a lower number of follicles ≥2 mm in diameter together with a lower number of atretic follicles and no increase in E2 serum levels in response to oFSH treatment. In addition, AR induction by oFSH was disrupted in granulosa and theca cells of lambs exposed to DES or BPA. An increase in GDF9 mRNA expression levels was observed in oFSH-primed lambs previously treated with DES or BPA50. In contrast, a decrease in BMPR1B was observed in BPA0.5-postnatally exposed lambs. The modifications in AR, GDF9, and BMPR1B may be associated with the altered ovarian function due to neonatal xenoestrogen exposure in response to an exogenous gonadotropin stimulus. These alterations may be the pathophysiological basis of subfertility syndrome in adulthood.

[Increase S/D ratio in uterine artery as a predictor for preeclampsia in adolescent patients]. / Aumento del índice S/D en la arteria uterina como predictor de preeclampsia en adolescentes.

BACKGROUND: Pregnancy during adolescence has been rising in the past years, and it is well known that preeclampsia affects teenagers, because maternal age and primigravida are risk factors. There are different ways and methods to predict preeclampsia, for example doppler velocimetry. OBJECTIVE: Determine S/D ratio of uterine artery in pregnant teenagers between 24-28 weeks and correlation with preeclampsia. MATERIAL AND METHOD: Observational study in 50 pregnant teenagers (14-19 years) obtaining uterine artery waveform at 24-28 weeks gestation recording S/D ratio. RESULTS: Sensitivity and specificity of 90% with a positive predictive value of 69.23% and negative predictive value of 97.3%. 13 patients had S/D ratio greater than 2.6, of which 5 had gestational hypertension, 3 with preeclampsia, 1 with Fetal Growth Restriction, 4 with normal pregnancy. Relative Risk was 25.62 (3.58-183.13) with odds ratio of 81.00 (6.83-2260.88) and p value 0.00002. CONCLUSION: analysis of uterine artery flow velocity waveforms is a method to predict preeclampsia.

[Ultrasonographic evaluation of the diameter of the optic nerve sheath for medication of intracranial pressure: a case report]. / Evaluación ultrasonográfica del diámetro de la vaina del nervio óptico (DVNO) para la medición de la presión intracraneana (PIC): a propósito de un caso.

The main complication associated with acute brain injury is the elevation of intracranial pressure (ICP) and it is associated with high morbidity and mortality. In these patients, multimodal neurological monitoring has emerged as a fundamental tool in the intensive care unit, with the minimally invasive trend seen in recent years. We report the case of a patient in which ICP monitoring was based on the measurement of the diameter of the optic nerve sheath (DONS), a procedure that has shown a good correlation with the ICP, as well as a high specificity, sensitivity, and low cost.

Demonstrating drug treatment efficacies by monitoring superoxide dynamics in human lung cancer cells with time-lapse fluorescence microscopy.

Metformin hydrochloride, an antihyperglycemic agent, and sulindac, a nonsteroidal anti-inflammatory drug, are FDA-approved drugs known to exert anticancer effects. Previous studies demonstrated sulindac and metformin's anticancer properties through mitochondrial dysfunction and inhibition of mitochondrial electron transport chain complex I and key signaling pathways. In this study, various drugs were administered to A549 lung cancer cells, and results revealed that a combination of sulindac and metformin enhanced cell death compared to the administration of the drugs separately. To measure superoxide production over time, we employed a time-lapse fluorescence imaging technique using mitochondrial-targeted hydroethidine. Fluorescence microscopy data showed the most significant increases in superoxide production in the combination treatment of metformin and sulindac. Results showed significant differences between the combined drug treatment and control groups and between the positive control and control groups. This approach can be utilized to quantify the anticancer efficacy of drugs, creating possibilities for additional therapeutic options.

Altered ovarian reserve in Ewe lambs exposed to a glyphosate-based herbicide.

Glyphosate-based herbicides (GBHs) are considered endocrine disruptors that affect the female reproductive tract of rats and ewe lambs. The present study aimed to investigate the impact of neonatal exposure to a low dose of a GBH on the ovarian follicular reserve of ewe lambs and the response to a gonadotropic stimulus with porcine FSH (pFSH). To this end, ewe lambs were orally exposed to an environmentally relevant GBH dose (1 mg/kg/day) or vehicle (Control) from postnatal day (PND) 1 to PND14, and then some received pFSH (50 mg/day) between PND41 and 43. The ovaries were dissected, and follicular types and gene expression were assessed via RT-PCR. The treatments did not affect the body weight of animals, but pFSH increased ovarian weight, not observed in GBH-exposed lambs. GBH-exposed lambs showed decreased Estrogen receptor-alpha (56%), Progesterone receptor (75%), Activin receptor II (ACVRII) (85%), and Bone morphogenetic protein 15 (BMP15) (88%) mRNA levels. Control lambs treated with pFSH exhibited downregulation of Follistatin (81%), ACVRII (77%), BMP15 (93%), and FSH receptor (FSHr) (72%). GBH-exposed lambs treated with pFSH displayed reduced ACVRII (68%), BMP15 (81%), and FSHr (50%). GBH-exposed lambs also exhibited decreased Anti-Müllerian hormone expression in primordial and antral follicles (27%) and (54%) respectively) and reduced Bone morphogenetic protein 4 (31%) expression in primordial follicles. Results suggest that GBH disrupts key follicular development molecules and interferes with pFSH action in ovarian receptors, decreasing the ovarian reserve. Future studies should explore whether this decreased ovarian reserve impairs adult ovarian function and its response to superovulation stimuli.

Congenital mixed hiatal hernia: A case report of an atypical cause of neonatal vomiting.

Congenital mixed hiatal hernia is a disorder that combines features of both sliding and paraoesophageal hernias. The precise incidence of congenital mixed hiatal hernia during the pediatric and neonatal period remains uncertain, making diagnosis challenging within this age cohort. This case presents a 15-day-old female with an 8% postnatal weight loss and apost-feeding vomiting. An upper gastrointestinal series, computer tomography, and upper endoscopy revealed a mixed hiatal hernia. The patient underwent a laparoscopic herniorrhaphy and Nissen fundoplication achieving successful resumption of complete oral feeding before discharge. Diagnosis and management of this condition in neonates remain challenging due to its rarity and variable clinical presentations. This report emphasizes the importance of early recognition, accurate diagnosis, and tailored management strategies in the neonatal period. Further research, with a collaborative effort between pediatricians and surgeons, is needed to refine diagnostic criteria, establish evidence-based management approaches, and improve outcomes for affected children.