Pathogenic diversification of the gut commensal Providencia alcalifaciens via acquisition of a second type III secretion system.

Providencia alcalifaciens is a Gram-negative bacterium found in various water and land environments and organisms, including insects and mammals. Some P. alcalifaciens strains encode gene homologs of virulence factors found in pathogenic Enterobacterales members, such as Salmonella enterica serovar Typhimurium and Shigella flexneri. Whether these genes are pathogenic determinants in P. alcalifaciens is not known. In this study, we investigated P. alcalifaciens-host interactions at the cellular level, focusing on the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS1b is widespread in Providencia spp. and encoded on the chromosome. A large plasmid that is present in a subset of P. alcalifaciens strains, primarily isolated from diarrheal patients, encodes for T3SS1a. We show that P. alcalifaciens 205/92 is internalized into eukaryotic cells, lyses its internalization vacuole, and proliferates in the cytosol. This triggers caspase-4-dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS1a in entry, vacuole lysis, and cytosolic proliferation is host cell type-specific, playing a more prominent role in intestinal epithelial cells than in macrophages or insect cells. In a bovine ligated intestinal loop model, P. alcalifaciens colonizes the intestinal mucosa and induces mild epithelial damage with negligible fluid accumulation in a T3SS1a- and T3SS1b-independent manner. However, T3SS1b was required for the rapid killing of Drosophila melanogaster. We propose that the acquisition of two T3SS has allowed P. alcalifaciens to diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.

Association Between Systemic Levels of Vascular Endothelial Growth Factor and Optical Coherence Tomography Biomarkers in a Non-Neovascular Age-Related Macular Degeneration Cohort.

BACKGROUND AND OBJECTIVE: Investigate associations between systemic vascular endothelial growth factor (VEGF) and optical coherence tomography (OCT) biomarkers in eyes with complete retinal pigment epithelium and outer retina atrophy (cRORA) secondary to non-neovascular age-related macular degeneration. PATIENTS AND METHODS: Cross-sectional study of patients with cRORA. OCT images and blood samples were collected at study enrollment. OCT images were evaluated for biomarkers. Systemic VEGF levels were measured using a standard multiplex assay. RESULTS: Study included 187 eyes from 96 patients. Lower levels of systemic VEGF were significantly associated with retinal pseudocysts (RPs) and subretinal hyper-reflective material (SHRM), a median of 7.7 pg/mL and 6.1 pg/mL for patients with the imaging biomarkers compared to those without (10.3 pg/mL [P = 0.004] and 9.3 pg/mL [P = 0.02], respectively). CONCLUSION: This novel study shows that lower systemic VEGF levels were associated with SHRM and RP, which was shown to correspond to an intermediate stage of the atrophic process in age-related macular degeneration. Systemic VEGF could be a useful biomarker and therapeutic target for eyes with cRORA. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Differential effects of 40S ribosome recycling factors on reinitiation at regulatory uORFs in GCN4 mRNA are not dictated by their roles in bulk 40S recycling.

Recycling of 40S ribosomal subunits following translation termination, entailing release of deacylated tRNA and dissociation of the empty 40S from mRNA, involves yeast Tma20/Tma22 heterodimer and Tma64, counterparts of mammalian MCTS1/DENR and eIF2D. MCTS1/DENR enhance reinitiation (REI) at short upstream open reading frames (uORFs) harboring penultimate codons that confer heightened dependence on these factors in bulk 40S recycling. Tma factors, by contrast, inhibited REI at particular uORFs in extracts; however, their roles at regulatory uORFs in vivo were unknown. We examined effects of eliminating Tma proteins on REI at regulatory uORFs mediating translational control of GCN4 optimized for either promoting (uORF1) or preventing (uORF4) REI. We found that the Tma proteins generally impede REI at native uORF4 and its variants equipped with various penultimate codons regardless of their Tma-dependence in bulk recycling. The Tma factors have no effect on REI at native uORF1 and equipping it with Tma-hyperdependent penultimate codons generally did not confer Tma-dependent REI; nor did converting the uORFs to AUG-stop elements. Thus, effects of the Tma proteins vary depending on the REI potential of the uORF and penultimate codon, but unlike in mammals, are not principally dictated by the Tma-dependence of the codon in bulk 40S recycling.

Computational modeling of social decision-making.

Social decision-making is guided by a complex set of social norms. Computational modeling can play a significant role in enriching our understanding of these norms and how precisely they direct social choices. Here, we highlight three major advantages to using computational modeling, particularly models derived from Utility Theory, in the study of social norms. We illustrate how such models can help generate detailed processes of decision-making, enforce theoretical precision by delineating abstract concepts, and unpack when, and why, people adhere to specific social norms. For each benefit, we discuss a recent study which has employed modeling in the service of assessing the role of norms in decision-making, collectively revealing how computational modeling enables better prediction, description, and explanation of important social choices.

INTRAVITREAL 0.18-mg FLUOCINOLONE ACETONIDE IMPLANT FOR PEDIATRIC UVEITIS.

PURPOSE: This study reports the outcomes of the 0.18-mg intravitreal fluocinolone acetonide implant in the treatment of pediatric noninfectious uveitis. METHODS: A retrospective cohort study was performed on patients under 18 years old who received fluocinolone acetonide implant between June 1, 2020 and March 1, 2023. Data collected included demographics, uveitis diagnosis, use of anti-inflammatory therapy, visual acuity, intraocular pressure, and grading of uveitis activity. Uveitis recurrence was defined as increased inflammation that required additional anti-inflammatory therapy. RESULTS: Eleven eyes from seven patients were included in this study. One patient (one eye) had a diagnosis of immune recovery uveitis and the remaining six patients (10 eyes) had pars planitis. The rate of remaining recurrence-free was 82% at 6 months, 60% at 12 months, and 60% at 24 months. Two of the six phakic eyes at baseline required cataract extraction during follow-up. Two of the four eyes that did not have intraocular pressure-lowering surgery before implantation required surgery in follow-up. CONCLUSION: The 0.18-mg fluocinolone acetonide implant has a similar efficacy for the treatment of pediatric uveitis, particularly pars planitis, as in the adult population, although with higher rates of ocular hypertension requiring intervention.

Decapping activators Edc3 and Scd6 act redundantly with Dhh1 in post-transcriptional repression of starvation-induced pathways.

Degradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts also are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 act redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.

Association between non-injection drug use and hepatitis C infection among HIV-negative men who have sex with men.

BACKGROUND: Prior research predominantly examined the association between HIV-positive men who have sex with men (MSM) or those using injection drugs and hepatitis C virus (HCV) infection. However, limited attention has been given to understanding the association among HIV-negative MSM who do not inject drugs. This gap leaves apportion of the population unexamined, potentially overlooking important factor that may contribute to the transmission and prevalence of HCV. This study aims to investigate the relationship between non-injection drug use and HCV infection in this population. METHODS: In this cross-sectional study, we analyzed data on 118 MSM who reported use of non-injection drugs. The participants were recruited from two inner-city communities in Houston, TX, between 2004 and 2007 and were negative for both HIV and hepatitis B virus infection. Latent class analysis (LCA) was used to identify drug use latent classes. Multinomial logistic regression analysis was used to evaluate the association between drug use latent class and HCV infection. RESULTS: Four distinct latent classes of drug use were identified: class 1, persons ≥ 42 years of age who used only crack cocaine; class 2, persons approximately 42 years of age who used > 2 drugs; class 3, persons < 42 years of age who used > 5 drugs; and class 4, persons ≥ 42 years of age who used > 6 drugs. Class 4 was significantly associated with HCV infection. The odds of HCV infection in members of class 4 was 17 times higher than in class 2 members (adjusted odds ratio [aOR] = 16.9, 95% confidence interval [CI]: 1.4-205.4) and almost 22 times higher than in class 3 members (aOR = 21.8, 95% CI: 1.5-322.8). CONCLUSIONS: Among MSM with non-injection drug use, the subgroup of individuals who were ≥ 42 years of age and used multiple drugs (including heroin, speedball, methamphetamine, crack cocaine, and marijuana) had a high probability of HCV infection. Public health and education programs, as well as drug treatment and rehabilitation programs, should be developed for this high-risk subgroup of individuals to prevent HCV acquisition and transmission.

Racial, ethnic, and socioeconomic disparities in rates of stage IV prostate cancer after USPSTF category "D" recommendation against prostate-specific antigen screening: a retrospective cohort study.

Background: In 2012 the United States Preventative Services Task Force (USPSTF) changed its prostate-specific antigen (PSA) screening recommendation to a category "D". The purpose of this study is to examine racial, ethnic, and socioeconomic differences in risk of presentation with metastatic prostate cancer (mPCa) at time of diagnosis before and after the 2012 USPSTF category "D" recommendation. Methods: This is a population-based cohort study. We identified patients with mPCa at diagnosis within the National Cancer Database from 2004-2017. Logistic regression models were used to examine associations of mPCa with age, race, ethnicity, geographic location, education level, income, and insurance status. Linear regression models assuming underlying binomial distribution were fitted to annual percentage of mPCa at diagnosis for years 2012-2017 to evaluate the post category "D" recommendation era. Results: From 2004 to 2017, 88,987 patients presented with mPCa. A higher percentage of mPCa was noted post-USPSTF category "D" recommendation, with a disproportionately greater increase observed among Hispanics and non-Hispanic Blacks [Δslope/year: Hispanics (0.0092), non-Hispanic Blacks (0.0073) and non-Hispanic Whites (0.0070)]. Insurance status impacts race/ethnicity differently: uninsured Hispanics were 3.66 times more likely to present with mPCa than insured Hispanics, while uninsured non-Hispanic Blacks were 2.62 times more likely to present with mPCa than insured non-Hispanic Blacks. Household income appears to be associated with differences in mPCa, particularly among non-Hispanic Blacks. Those earning <$30,000 were more likely to present with mPCa compared to higher income brackets. Conclusions: Since the USPSTF grade "D" recommendation against PSA screening, the percentage of mPCa at diagnosis has increased, with a higher rate of increase among Hispanic and non-Hispanic Blacks compared to non-Hispanic Whites.

Phytoremediation Potential of Azolla filiculoides: Uptake and Toxicity of Seven Per- and Polyfluoroalkyl Substances (PFAS) at Environmentally Relevant Water Concentrations.

Environmental contamination of aquatic systems by per- and polyfluoroalkyl substances (PFAS) has generated significant health concerns. Remediation of contaminated sites such as the fire-fighting emergency training grounds that use aqueous film-forming foams is a high priority. Phytoremediation may help play a part in removing PFAS from such contaminated waters. We investigated the potential of the water fern Azolla filiculoides, which is used for phytoremediation of a wide range of contaminants, to uptake seven common PFAS (perfluorobutanoic acid [PFBA], perfluorobutane sulfonic acid [PFBS], perfluoroheptanoic acid [PFHpA], perfluorohexanoic acid [PFHxA], perfluorohexane sulfonic acid [PFHxS], perfluorooctanoic acid [PFOA], and perfluoropentanoic acid [PFPeA]), during a 12-day exposure to environmentally relevant concentrations delivered as equimolar mixtures: low (∑PFAS = 0.0123 ± 1.89 µmol L-1), medium (∑PFAS = 0.123 ± 2.88 µmol L-1), and high (∑PFAS = 1.39 µmol L-1) treatments, equivalent to approximately 5, 50, and 500 µg L-1 total PFAS, respectively. The possible phytotoxic effects of PFAS were measured at 3-day intervals using chlorophyll a content, photosystem II efficiency (Fv/Fm), performance index, and specific growth rate. The PFAS concentrations in plant tissue and water were also measured every 3 days using ultra-high-performance liquid chromatography-tandem mass spectrometry. Treatments with PFAS did not lead to any detectable phytotoxic effects. All seven PFAS were detected in plant tissue, with the greatest uptake occurring during the first 6 days of exposure. After 12 days of exposure, a maximum bioconcentration factor was recorded for PFBA of 1.30 and a minimum of 0.192 for PFBS. Consequently, the application of Azolla spp. as a stand-alone system for phytoremediation of PFAS in aquatic environments is not sufficient to substantially reduce PFAS concentrations. Environ Toxicol Chem 2024;00:1-12. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.

Protein kinase Gcn2 attenuates protein synthesis in response to amino acid starvation while stimulating translation of a transcriptional activator of amino acid biosynthesis. Gcn2 activation requires a domain related to histidyl-tRNA synthetase (HisRS), the enzyme that aminoacylates tRNAHis. While evidence suggests that deacylated tRNA binds the HisRS domain for kinase activation, ribosomal P-stalk proteins have been implicated as alternative activating ligands on stalled ribosomes. We report crystal structures of the HisRS domain of Chaetomium thermophilum Gcn2 that reveal structural mimicry of both catalytic (CD) and anticodon-binding (ABD) domains, which in authentic HisRS bind the acceptor stem and anticodon loop of tRNAHis. Elements for forming histidyl adenylate and aminoacylation are lacking, suggesting that Gcn2HisRS was repurposed for kinase activation, consistent with mutations in the CD that dysregulate yeast Gcn2 function. Substituting conserved ABD residues well positioned to contact the anticodon loop or that form a conserved ABD-CD interface impairs Gcn2 function in starved cells. Mimicry in Gcn2HisRS of two highly conserved structural domains for binding both ends of tRNA-each crucial for Gcn2 function-supports that deacylated tRNAs activate Gcn2 and exemplifies how a metabolic enzyme is repurposed to host new local structures and sequences that confer a novel regulatory function.

Using Low-cost Videoscopes to Obtain Accurate Video "Oral Selfies" as Screening for HPV-associated Oropharyngeal Cancer: A New Screening Technology?

Human papillomavirus (HPV)-related oropharyngeal cancers associated with sexual contact are increasing, with high rates in men who have sex with men. HPV-related cancers have the advantage of being frequently detectable through oropharyngeal visual examination and having much higher survival rates than classic oropharyngeal cancers. It has been demonstrated that gay and bisexual men can take smartphone oropharyngeal "selfies" of sufficient quality for screening. However, there is an issue with the inability to move the tongue to allow a clear view of the palatine tonsils, where a majority of oropharyngeal cancer cases occur. We attempted to investigate the feasibility of using commercially available videoscopes to visualize the oropharynx. Fourteen healthy volunteers used a provided low-cost commercial endoscope to video their oropharynx. Participants used the videoscope connected to a laptop and could visualize the oropharynx on the screen. Attempts were observed, and the process was noted. A focus group of participants was carried out immediately afterwards to ascertain barriers and facilitators to using the videoscopes. All participants were able to use the videoscope and obtain videos of sufficient clarity to note major oropharyngeal landmarks. The palatine tonsils were initially difficult to visualize because the tongue could not be sufficiently controlled. Participants were given time to practice using visual cues to control the position of the tongue, which helped in obtaining good videos. Videoscopes can be used effectively with minimal instruction and provide a better view than still images, as they illuminate and magnify the site. Low-cost commercially available videoscopes may be an improvement over smartphone "selfies".

Self-collected versus clinician-collected anal swabs for anal cancer screening: A systematic review and meta-analysis.

Anal squamous cell carcinoma (ASCC) incidence is increasing globally. International consensus guidelines published in 2024 include HPV and/or cytology testing of anal swabs in those at greatest risk of ASCC. Self-collected anal swabs may be important for increasing screening uptake, but evidence is needed as to their equivalence to clinician-collected swabs. We searched Medline, Embase, Cochrane Library, and CINAHL databases for publications to 13 June 2023. Studies were included if reporting data on HPV testing, cytology testing, or acceptability, for both self- and clinician-collected anal swabs. Risk of bias was assessed using the QUADAS-2 assessment tool. The primary outcome was HPV and cytology sampling adequacy. Secondary outcomes were HPV and cytology results, and acceptability of collection methods. Thirteen papers describing 10 studies were eligible. Sample adequacy was comparable between self- and clinician-collected swabs for HPV testing (meta-adequacy ratio: 1.01 [95% CI 0.97-1.05]) but slightly lower for cytology by self-collection (meta-adequacy ratio: 0.91 [95% CI 0.88-0.95]). There was no significant difference in prevalence (meta-prevalence ratio: 0.83 (95% CI 0.65-1.07) for any HR-HPV, 0.98 (95% CI 0.84-1.14) for any HPV, and 0.68 (95% CI 0.33-1.37) for HPV16), or any cytological abnormality (meta-prevalence ratio 1.01 [95% CI 0.86-1.18]). Only three papers reported acceptability results. Findings indicate self-collection gives equivalent sample adequacy for HPV testing and ~ 10% inferior adequacy for cytological testing. Meta-prevalence was similar for HPV and cytology, but confidence intervals were wide. Larger studies are required to definitively assess use of self-collected swabs in anal cancer screening programs, including acceptability.

Frontal sinus size in South African Later Stone Age Holocene Khoe-San.

Frontal size variation is comparatively poorly sampled among sub-Saharan African populations. This study assessed frontal sinus size in a sample of Khoe-San skeletal remains from South African Later Stone Age contexts. Volumes were determined from CT scans of 102 adult crania; individual sex could be estimated in 82 cases. Sinus volume is not sexually dimorphic in this sample. The lack of frontal sinus aplasia is concordant with the low incidences recorded for other sub-Saharan African and most other global populations save those that inhabit high latitudes. There is considerable variation in frontal sinus size among global populations, and the Khoe-San possess among the smallest. The Khoe-San have rather diminutive sinuses compared to sub-Saharan Bantu-speaking populations but resemble a northern African (Sudanese) population. Genetic studies indicate the earliest population divergence within Homo sapiens to have been between the Khoe-San and all other living groups, and that this likely occurred in Africa during the span of Marine Isotope Stages 8-6. There is scant information on frontal sinus development among Late Quaternary African fossils that are likely either closely related or attributable to Homo sapiens. Among these, the MIS 3 cranium from Hofmeyr, South Africa, exhibits distinct Khoe-San cranial affinities and despite its large size has a very small frontal sinus. This raises the possibility that the small frontal sinuses of the Holocene South African Khoe-San might be a feature retained from an earlier MIS 3 population.

Cytomegalovirus Retinitis in the Modern Era of Solid Organ Transplantation.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined. METHODS: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR. RESULTS: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type. CONCLUSION: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia.

Clinical evidence for high-risk CE-marked medical devices for glucose management: A systematic review and meta-analysis.

AIMS: To conduct a systematic review and meta-analysis, within the Coordinating Research and Evidence for Medical Devices (CORE-MD) project, evaluating CE-marked high-risk devices for glucose management. MATERIALS AND METHODS: We identified interventional and observational studies evaluating the efficacy and safety of eight automated insulin delivery (AID) systems, two implantable insulin pumps, and three implantable continuous glucose monitoring (CGM) devices. We meta-analysed randomized controlled trials (RCTs) comparing AID systems with other treatments. RESULTS: A total of 182 studies published between 2009 and 2024 were included, comprising 166 studies on AID systems, six on insulin pumps, and 10 on CGM devices; 26% reported industry funding; 18% were pre-market; 37% had a comparator group. Of the studies identified, 29% were RCTs, 24% were non-randomized trials, and 47% were observational studies. The median (interquartile range) sample size was 48 (28-102), age 34.8 (14-44.2) years, and study duration 17.5 (12-26) weeks. AID systems lowered glycated haemoglobin by 0.5 percentage points (absolute mean difference [MD] = -0.5; 21 RCTs; I2 = 86%) and increased time in target range for sensor glucose level by 13.4 percentage points (MD = 13.4; 14 RCTs; I2 = 90%). At least one safety outcome was assessed in 71% of studies. CONCLUSIONS: High-risk devices for glucose monitoring or insulin dosing, in particular AID systems, improve glucose control safely, but evidence on diabetes-related end-organ damage is lacking due to short study durations. Methodological heterogeneity highlights the need for developing standards for future pre- and post-market investigations of diabetes-specific high-risk medical devices.

Training the Next Generation of Transplant Surgeons With a 3-Dimensional Trainer: A Pilot Study.

Background: In the United States, no published guidelines promote exposure to technical variants (ie, living donor or split liver) during transplant fellowship. Simulation with hands-on liver models may improve training in transplantation. This pilot study addressed 3 overall goals (material and model creation tools, recruitment rates and assessment of workload, and protocol adherence). Methods: A patient-specific hands-on liver model was constructed from clinical imaging, and it needed to be resilient and realistic. Multiple types of materials were tested between January 2020 and August 2022. Participants were recruited stepwise. A left lateral segmentectomy simulation was conducted between August 2022 and December 2022 to assess protocol adherence. Results: Digital anatomy 3-dimensional printing was considered the best option for the hands-on liver model. The recruitment rate was 100% and 47% for junior attendings and surgical residents, respectively. Ten participants were included and completed all the required surveys. Seven (70%) and 6 (60%) participants "agreed" that the overall quality of the model and the material were acceptable for surgical simulation. Five participants (50%) "agreed" that the training improved their surgical skills. Nine participants (90%) "strongly agreed" that similar sessions should be included in surgical training programs. Conclusions: Three-dimensional hands-on liver models have the advantage of tactile feedback and were rated favorably as a potential training tool. Study enrollment for further studies is possible with the support of leadership. Rigorous multicenter designs should be developed to measure the actual impact of 3-dimensional hands-on liver models on surgical training.

Safety and efficacy assessment of a synthetic porcine recombinant corticotrophin for the ACTH stimulation test in healthy cats.

Porcine adrenocorticotrophic hormone (ACTH) has been considered valid for the ACTH stimulation test (ACTHST) in humans and dogs; however, its safety and efficacy for use in cats are unknown. Also, the equivalence between 5 µg/kg and 125 µg/cat dose of synthetic corticotropin (1-24 ACTH - cosyntropin/tetracosactide) is assumed for ACTHST in cats. This study evaluated the safety and effectiveness of different porcine recombinant ACTH doses for the ACTHST in healthy cats and its equivalence with tetracosactide. The study was divided into two arms. The first evaluated safety and equivalence of intravenous 1 µg/kg, 5 µg/kg, or 125 µg/cat porcine ACTH in seven healthy cats for the ACTHST evaluating basal and post-ACTH androstenedione, aldosterone, cortisol, and progesterone concentrations. In the second arm, the equivalence of the 125 µg/cat porcine ACTH dose was evaluated compared to results obtained using 125 µg/cat of tetracosactide in ten healthy cats regarding cortisol responses. In all tests, several cat-friendly strategies were adopted, and the ACTHST protocol involved basal and 60-minute post-ACTH blood sampling and intravenous ACTH injection. No adverse reactions were documented, and no tested cat showed any complications during the study. No porcine ACTH tested dose significantly increased androstenedione secretion. In contrast, all tested doses were able to increase progesterone concentration significantly (P < 0.05), and Δ-progesterone in response to 5 µg/kg or 125 µg/cat was considered equivalent (P > 0.99). The 125 µg/cat dose promoted greater responses for both cortisol and aldosterone, characterized by Δ-cortisol (P = 0.009) and Δ-aldosterone (P = 0.004). Despite equivalent Δ-cortisol results in response to 5 µg/kg or 125 µg/cat (P = 0.18); post-ACTH results of cortisol in response to 5 µg/kg only approximate statistical significance when compared with basal (P = 0.07). Porcine ACTH and tetracosactide significantly increased post-ACTH cortisol concentration (P < 0.0001) while the Δ-cortisol was slightly greater in response to the porcine ACTH (P = 0.006). These results suggest porcine ACTH could be an alternative source of corticotropin for the ACTHST in cats; however, maximum corticoadrenal stimulation seemed more reliable in response to a 125 µg/cat regarding cortisol and aldosterone.

Intraperitoneal Administration of 17-DMAG as an Effective Treatment against Leishmania braziliensis Infection in BALB/c Mice: A Preclinical Study.

BACKGROUND: Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. OBJECTIVE: This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutaneous leishmaniasis through in vitro and in vivo approaches. MATERIALS AND METHODS: We assessed 17-DMAG's cytotoxic effect on bone marrow-derived macrophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction in lesion size and the decrease in parasite load in the ears and lymph nodes of infected animals. RESULTS: 17-DMAG showed selective toxicity [selective index = 432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and resulted in parasite clearance from ears and lymph nodes. It also diminished inflammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-γ, TNF) and the regulatory cytokine IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. CONCLUSIONS: Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

Effects of methyl jasmonate seed treatments on adult oviposition preference and larval performance of seed corn maggot (Delia platura) in corn (Zea mays).

BACKGROUND: Eliciting host plant resistance using plant hormones such as jasmonates has the potential to protect seeds and seedlings against insect pests; however, several hurdles exist for adapting it for pest management. This includes determining a dose that promotes resistance without limiting plant growth, an application method that growers could use, and ensuring the plants are responsive in the abiotic conditions when the pest occurs. In laboratory and field assays, we tested if treating corn seeds with multiple concentrations of methyl jasmonate would reduce the preference of ovipositing seed corn maggot adults and the performance of larvae feeding on seeds. RESULTS: We found that corn seeds soaked in aqueous 0.2 mM methyl jasmonate solution showed marginally lower seedling growth, but the adult oviposition preference was ~60% lower on these seeds compared to control water-soaked seeds. Seeds that were treated with methyl jasmonate using a conventional polymer-based seed coating showed no effect on seedling growth but reduced adult oviposition preference. In no-choice bioassays with adult flies, we found reduced oviposition on seeds soaked with aqueous methyl jasmonate compared to controls. Larval survival to pupation was also lower in methyl jasmonate-treated seeds. Lastly, the methyl jasmonate-induced resistance also occurred at the lower temperatures typical of the spring soil conditions when this fly is most damaging. CONCLUSION: Methyl jasmonate seed treatment in aqueous solution or using conventional polymer-based technology, has the potential to deter adult oviposition and reduce maggot performance in spring temperature conditions with minor effects on seed germination and growth. © 2024 Society of Chemical Industry.

Outcomes of Micropulse Transscleral Cyclophotocoagulation in Uveitic Glaucoma.

PURPOSE: To report a case series of patients with uveitic glaucoma who were treated with micropulse transscleral cyclophotocoagulation (mpCPC). METHODS: This retrospective case series consists of patients from the University of Colorado Sue Anschutz-Rodgers Eye Center from 2015 to 2020 who were diagnosed with uveitic glaucoma. Information collected includes demographic data, type of uveitis, glaucoma severity, and prior glaucoma surgeries. Pre- and postoperative best corrected visual acuity, intraocular pressure (IOP), glaucoma medications, degree of inflammation, and uveitis therapies were included up to 36 months postoperatively. Surgical success was defined as an IOP reduction of 30% with achievement of IOP goal using the same number of glaucoma medications or less at 6 months or 1 year. Uveitis success was defined as the absence of persistent anterior uveitis at 3 months. RESULTS: Six patients and seven eyes with uveitic glaucoma underwent mpCPC. Types of uveitis included idiopathic anterior uveitis, HLA-B27-associated anterior uveitis, varicella zoster virus anterior uveitis, juvenile idiopathic arthritis-associated chronic anterior uveitis, lichen planus-associated intermediate uveitis, and sarcoidosis-associated panuveitis. Two of six eyes (33.3%) at 6 months and three of five eyes (60%) at 1 year achieved surgical success. Around 6 months postoperatively, two out of seven eyes (28.6%) required Ahmed glaucoma valve placement (n = 1) or repeat mpCPC (n = 1). One eye (14.3%) required phacoemulsification with goniotomy followed by an Ahmed glaucoma valve 18 months after mpCPC. There were no cases of persistent anterior uveitis, hypotony, or phthisis after mpCPC in this cohort. CONCLUSIONS: Micropulse transscleral cyclophotocoagulation may safely reduce intraocular pressure in some patients with uveitic glaucoma without exacerbation of intraocular inflammation. Multiple treatments may be required to achieve longer-term success.