Endothelial deletion of Wt1 disrupts coronary angiogenesis and myocardium development.

Wt1 encodes a zinc finger protein that is crucial for epicardium development. Although WT1 is also expressed in coronary endothelial cells (ECs), the abnormal heart development observed in Wt1 knockout mice is mainly attributed to its functions in the epicardium. Here, we have generated an inducible endothelial-specific Wt1 knockout mouse model (Wt1KOΔEC). Deletion of Wt1 in ECs during coronary plexus formation impaired coronary blood vessels and myocardium development. RNA-Seq analysis of coronary ECs from Wt1KOΔEC mice demonstrated that deletion of Wt1 exerted a major impact on the molecular signature of coronary ECs and modified the expression of several genes that are dynamically modulated over the course of coronary EC development. Many of these differentially expressed genes are involved in cell proliferation, migration and differentiation of coronary ECs; consequently, the aforementioned processes were affected in Wt1KOΔEC mice. The requirement of WT1 in coronary ECs goes beyond the initial formation of the coronary plexus, as its later deletion results in defects in coronary artery formation. Through the characterization of these Wt1KOΔEC mouse models, we show that the deletion of Wt1 in ECs disrupts physiological blood vessel formation.

Deletion of Wt1 during early gonadogenesis leads to differences of sex development in male and female adult mice.

Assessing the role of the WT1 transcription factor (WT1) during early gonad differentiation and its impact on adult sex development has been difficult due to the complete gonadal agenesis and embryonic lethality exhibited by Wt1KO mouse models. Here, we generated Wt1LoxP/GFP;Wt1Cre mice, the first Wt1KO mouse model that reaches adulthood with a dramatically reduced Wt1 expression during early gonadogenesis. Wt1LoxP/GFP;Wt1Cre mice lacked mature gonads and displayed genital tracts containing both male and female genital structures and ambiguous genitalia. We found that WT1 is necessary for the activation of both male and female sex-determining pathways, as embryonic mutant gonads failed to upregulate the expression of the genes specific for each genetic programme. The gonads of Wt1LoxP/GFP;Wt1Cre mice showed a lack of production of Sertoli and pre-granulosa cells and a reduced number of germ cells. NR5A1 and the steroidogenic genes expression was modulated differently in XY and XX Wt1LoxP/GFP;Wt1Cre gonads, explaining the mutant phenotypes. Further studies of the XX Wt1LoxP/GFP;Wt1Cre gonads revealed that deletion of WT1 at an early stage impaired the differentiation of several cell types including somatic cells and the ovarian epithelium. Through the characterisation of this Wt1KO mouse model, we show that the deletion of Wt1 during early gonadogenesis produces dramatic defects in adult sex development.

Tetraspanin32 (TSPAN32) is downregulated in rheumatoid arthritis: Evidence from animal models and patients.

This study aimed to investigate the role of TSPAN32, a member of the tetraspanin family, in rheumatoid arthritis (RA). The objective was to assess the expression levels of TSPAN32 in experimental RA models and in RA patient immune cells, exploring its potential as a regulatory factor in RA pathogenesis. The study employed adjuvant-induced arthritis in rats and collagen-induced arthritis (CIA) in mice as experimental models. Ex vivo analyses included evaluating TSPAN32 expression in immune cells at different stages of the disease. In silico data analysis involved examining transcriptomic datasets from drug-naïve and treated RA patients to correlate TSPAN32 expression with clinical parameters. TSPAN32 overexpression experiments in splenocytes from CIA mice aimed to demonstrate its functional impact on antigen-specific immune responses. The animal models revealed a significant downregulation of TSPAN32, particularly in synovial-infiltrating T cells. Also, TSPAN32 overexpression inhibited pro-inflammatory cytokine production in splenocytes. In RA patients, TSPAN32 was consistently downregulated in circulating and synovial-infiltrating T cells, as well as in CD8+ T cells, B cells and NK cells. Drug treatment did not significantly alter TSPAN32 levels. Negative correlations were observed between TSPAN32 expression and inflammatory markers (CRP, ESR) and clinical scores (SDAI) in RA patients. This study suggests that reduced TSPAN32 expression characterizes pathogenic T-cell populations in RA, highlighting its potential as biomarker for inflammation and disease activity. TSPAN32 may play a crucial role in shaping adaptive immune responses in RA, opening avenues for novel therapeutic strategies targeting this tetraspanin family member.

Treatment patterns and persistence on disease modifying therapies for multiple sclerosis and its associated factors.

BACKGROUND: Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing treatment in people with MS, especially in low prevalence populations, are unknown. OBJECTIVES: To describe the persistence, reasons of DMT switches and prescription patterns in a cohort of Colombian people with MS. METHODS: We conducted a retrospective observational study including patients with confirmed MS with at least one visit at our centre. We estimated the overall incidence rate of medication changes and assessed the persistence on medication with Kaplan-Meier survival estimates for individual medications and according to efficacy and mode of administration. The factors associated with changing medications were assessed using adjusted Cox proportional-hazards models. The reasons for switching medication changes were described, and the prescription patterns were assessed using network analysis, with measures of centrality. RESULTS: Seven hundred one patients with MS were included. Mean age was 44.3 years, and 67.9% were female. Mean disease duration was 11.3 years and 84.5% had relapsing MS at onset, with median EDSS of 1.0. Treatment was started in 659 (94%) of the patients after a mean of 3 years after MS symptom onset. Among them, 39.5% maintained their initial DMT, 29.9% experienced a single DMT change, while 18.7% went through two, and 11.9% had three or more DMT changes until the final follow-up. The total number of treatment modifications reached 720, resulting in an incidence rate of 1.09 (95% confidence interval: 1.01-1.17) per patient per year The median time to change after the first DMT was 3.75 years, and was not different according to the mode of administration or efficacy classification. The main reasons for changing DMT were MS activity (relapses, 56.7%; MRI activity, 18.6%), followed by non-serious adverse events (15.3%) and disability (11.1%). Younger age at MS onset, care under our centre and insurer status were the main determinants of treatment change. Network analysis showed that interferons and fingolimod were the most influential DMTs. CONCLUSIONS: A majority of patients switch medications, mostly due to disease activity, and in association with age and insurer status.

Myxoinflammatory fibroblastic sarcoma: ultrastructural study of 7 cases.

Since first described, several studies about Myxoinflammatory fibroblastic sarcomas (MIFS) have been published stating the clinicopathological, morphological and immunohistochemical features. However, the ultrastructural findings of these MIFS are limited. Thus, the objective of the present paper is to describe the ultrastructural characteristics of these type of tumors by utilizing tissue that was embedded in paraffin and submitted for immunohistochemistry.The tissue of seven different cases was obtained for ultrastructural study with automatized staining devices, that were later observed by using transmission electron microscopy. Histologically all cases displayed conventional structures of Myxoinflammatory fibroblastic sarcoma (Reed-Sternberg like cells, pseudolipoblasts and emperipolesis). Conversely, two of them exhibited high-grade components, one rich in osteoclastic type giant cells and hypercellular areas, and another one rich in inflammation (Hodgkin-like).After immunohistochemistry, all the samples revealed positivity for CD68 with six cases CD163 and five being positive to CD34, Cyclin-D1, and D2-40. Ultrastructural findings indicated rough endoplasmic reticulum with dilatation of the cisterns that indented the nuclei ("soccer ball" cells), abundant lysosomes, phagolysosomes, and intermediate filaments evidencing this entity as a morphologic continuum that exhibited modified fibroblastic phenotype and variable proportion of macrophagic differentiation.

Exploring the Role of PD-1 in the Autoimmune Response: Insights into Its Implication in Systemic Lupus Erythematosus.

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4+ T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE.

Beyond Tumors: Gastric Syphilis Emulating a Gastric Neoplasia.

We present the case of a 35-year-old male with a first-degree family history of gastric cancer (his father was diagnosed at the age of 45), who was presumed to have gastric cancer himself when evaluating the features of his upper endoscopy performed after hematemesis. Surprisingly, no cancer cells were found in the biopsies. Thanks to a different diagnostic suspicion subsequent to performing a full clinical history, a more favorable diagnosis was reached: gastric syphilis.

Common antibiotics, azithromycin and amoxicillin, affect gut metagenomics within a household.

BACKGROUND: The microbiome of the human gut serves a role in a number of physiological processes, but can be altered through effects of age, diet, and disturbances such as antibiotics. Several studies have demonstrated that commonly used antibiotics can have sustained impacts on the diversity and the composition of the gut microbiome. The impact of the two most overused antibiotics, azithromycin, and amoxicillin, in the human microbiome has not been thoroughly described. In this study, we recruited a group of individuals and unrelated controls to decipher the effects of the commonly used antibiotics amoxicillin and azithromycin on their gut microbiomes. RESULTS: We characterized the gut microbiomes by metagenomic sequencing followed by characterization of the resulting microbial communities. We found that there were clear and sustained effects of the antibiotics on the gut microbial community with significant alterations in the representations of Bifidobacterium species in response to azithromycin (macrolide antibiotic). These results were supported by significant increases identified in putative antibiotic resistance genes associated with macrolide resistance. Importantly, we did not identify these trends in the unrelated control individuals. There were no significant changes observed in other members of the microbial community. CONCLUSIONS: As we continue to focus on the role that the gut microbiome plays and how disturbances induced by antibiotics might affect our overall health, elucidating members of the community most affected by their use is of critical importance to understanding the impacts of common antibiotics on those who take them. Clinical Trial Registration Number NCT05169255. This trial was retrospectively registered on 23-12-2021.

No seasonality in the risk of multiple sclerosis in an equatorial country: A case-control ecological study.

BACKGROUND: Multiple sclerosis risk has been shown to have seasonal variations that are more pronounced in higher latitudes. However, this phenomenon has not been adequately studied near the Equator. OBJECTIVE: To explore the risk of multiple sclerosis associated with month, season of birth, and sunlight exposure variables in Colombia. METHODS: In this case-control study, 668 multiple sclerosis cases were matched to 2672 controls by sex and age. Association of multiple sclerosis with each month/season of birth and sunlight exposure variables was estimated with multilevel mixed-effects logistic regression and ecological regression models, respectively. Seasonality in the births of multiple sclerosis was assessed with a non-parametric seasonality test. RESULTS: We found a higher probability of multiple sclerosis in September (0.25; 95% confidence interval (CI) = 0.21-0.31) and lower in March (0.15; 95% CI = 0.10-0.18), which turned non-significant after a multiple comparisons test. Sunlight exposure variables had no significant effect on the risk of MS, and the tests of seasonality in the births of MS did not show significant results. CONCLUSION: Our results show no seasonality in the risk of multiple sclerosis near the Equator, supporting the hypothesis that this phenomenon is latitude dependent.

BAFFR expression in circulating T follicular helper (CD4+CXCR5+PD-1+) and T peripheral helper (CD4+CXCR5-PD-1+) cells in systemic lupus erythematosus.

BACKGROUND: Circulating T follicular helper (cTfh) and T peripheral helper (Tph) subpopulations are shown to be higher in systemic lupus erythematosus (SLE) patients and have been involved in promoting extrafollicular B cell responses. However, a possible association with the B cell activating factor (BAFF), a cytokine mainly related to B cell responses and disease activity in SLE, has not been investigated. Therefore, this study aimed to evaluate the association of cTfh and Tph subpopulations with the BAFF system expression and clinical activity in SLE patients. METHODS: This study included 43 SLE patients and 12 healthy subjects (HS). The identification of cTfh (CD4+CXCR5+PD-1+), Tph (CD4+CXCR5-PD-1+) cells, expression of membrane-bound BAFF (mBAFF), BAFFR, TACI, BCMA, and intracellular IL-21 was performed by flow cytometry. Serum levels of IL-21, CXCL13, and BAFF were analyzed using ELISA. The SLEDAI-2K score was used to evaluate disease activity in SLE patients. RESULTS: Compared with HS, SLE patients showed a significantly increased percentage of cTfh and Tph cells, higher in patients with clearly active disease. SLE patients had markedly higher IL-21-producing cTfh and Tph cells than HS. Both subpopulations were positively correlated with the disease activity in SLE patients. Tph cells were negatively correlated with CD19+CXCR5+ B cells and positively correlated with CD19+CXCR5- B cells. A low expression of mBAFF and their receptors TACI and BCMA was found on cTfh and Tph cells in SLE patients and HS. However, SLE patients with clearly active disease showed decreased expression of BAFFR on cTfh and Tph subpopulations than patients with mildly active/nonactive disease. Serum IL-21, CXCL13, and BAFF levels were higher in SLE patients than in HS. Levels of CXCL13 were correlated with disease activity. Non-significant correlations were observed among T cell subpopulations and IL-21, CXCL13, and BAFF levels. CONCLUSIONS: This study emphasizes the importance of cTfh and Tph cells in SLE pathogenesis. Besides the importance of IL-21, our results suggest that BAFFR could play a role in cTfh and Tph subpopulations in the autoimmunity context.

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.

Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

Post-acute sequelae of COVID-19 in solid organ transplant recipients.

BACKGROUND: Post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC), defined as prolonged symptoms following an episode of COVID-19, is not well-characterized in solid organ transplant recipients (SOTR). In this study, we aimed to assess the prevalence of PASC in SOTR, its descriptive characteristics, and associated risk factors. METHODS: We retrospectively identified SOTRs with acute COVID-19 between June 1, 2020 and April 15, 2022, and abstracted demographic and medical history, characteristics of acute COVID-19 illness, and COVID-19 vaccination status. We defined PASC as ongoing/new symptoms present at 6 weeks or longer following acute COVID-19 diagnosis. RESULTS: Among 208 SOTRs with acute COVID-19, 72 (35%) developed PASC. Common symptoms were respiratory symptoms (67%), headache (40%), and difficulty concentrating (10%). Severe acute COVID-19 disease and presence of respiratory symptoms were associated with higher odds of PASC in multivariable analyses, while receipt of at least one COVID-19 vaccination prior to transplantation was protective. CONCLUSION: We found that PASC occurs in about a third of SOTRs with acute COVID-19 and has similar symptoms as described previously in immunocompetent hosts. Pre-transplant vaccination may be protective. Further prospective multicenter studies are needed.

Ultrasound findings in painful spastic hip. Muscle thickness in children with cerebral palsy.

BACKGROUND: In cerebral palsy (CP), spasticity is the dominant symptom and hip pain is one of the most common secondary conditions. Aetiology is not clear. Musculoskeletal ultrasound (MSUS) is a low-cost, non-invasive imaging technique that allows assessment of structural status, dynamic imaging, and quick contralateral comparison. OBJECTIVE: A retrospective case-matched-control study. To investigate associated factors with painful spastic hip and to compare ultrasound findings (focusing on muscle thickness) in children with CP vs. typically developing (TD) peers. SETTING: Paediatric Rehabilitation Hospital in Mexico City, from August to November 2018. PARTICIPANTS: 21 children (13 male, 7 + 4.26 years) with CP, in Gross Motor Function Classification System (GMFCS) levels IV to V, with spastic hip diagnosis (cases) and 21 children age- and sex-matched (7 + 4.28 years) TD peers (controls). CHARACTERISTICALLY DATA: Sociodemographic data, CP topography, degree of spasticity, mobility arch, contractures, Visual Analog Scale (VAS), GMFCS, measurements of the volumes of eight major muscles of the hip joint and MSUS findings of both hips. RESULTS: All children with CP group reported chronic hip pain. Associated factors for hip pain (high VAS hip pain score) were degree of hip displacement (percentage of migration), Ashworth Level, GMFCS level V. No synovitis, bursitis or tendinopathy was found. Significant differences (p < 0.05) were found in muscle volumes in all hip muscles (right and left) except in the right and left adductor longus. CONCLUSION: Though possibly the most important issue with diminished muscle growth in CP children is the influence on their long-term function, it is likely that training routines that build muscle size may also increase muscle strength and improve function in this population. To improve the choice of treatments in this group and maintain muscle mass, longitudinal investigations of the natural history of muscular deficits in CP as well as the impact of intervention are needed.

TNFSF13B rs9514828 gene polymorphism and soluble B cell activating factor levels: Association with apical periodontitis.

AIM: The aim of this case-control study was to evaluate the association between the TNFSF13B rs9514828 (-871 C > T) polymorphism and soluble BAFF (sBAFF) in apical periodontitis (AP) patients. METHODOLOGY: Two hundred and sixty one healthy subjects (HS) and 158 patients with AP classified as: 46 acute apical abscess (AAA), 81 primary AP (pAP) and 31 secondary AP (sAP) patients were included. Genomic DNA (gDNA) was extracted from peripheral blood cells according to the salting out method. The TNFSF13B rs9514828 (NC_000013.11:g.108269025C > T) were identified using polymerase chain reaction (PCR) followed by restriction fragment length polymorphisms (RFLP). Serum sBAFF levels were measured by ELISA test. The chi-squared or Fisher's exact test was performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the risk of AP associated with the rs9514828. The Mann-Whitney U test and Kruskal-Wallis analysis were used for non-normally distributed data. Differences were considered significant with a p-value <.05. RESULTS: No differences in the genotype/allele frequencies were shown between HS and patients with AAA. However, the TT genotype (OR = 2.68, 95% CI: 1.10-6.53; p = .025) and T allele (OR = 1.46, 95% CI: 1.00-2.12; p = .045) were associated with increased risk of pAP. In contrast, the minor allele T significantly decreased the risk of sAP (OR = 0.49, 95% CI: 0.024-0.99; p = .043). sBAFF serum levels were increased in AAA and pAP compared with HS (p < .01 and p = .021, respectively). The AAA patients had higher sBAFF serum levels than pAP (p = .034) and sAP (p < .01). CONCLUSIONS: These results suggest that the TNFSF13B rs9514828 (-871 C > T) polymorphism is associated with pAP susceptibility and that BAFF is a cytokine that might be involved in acute and chronic AP. The future exploration of the rs9514828 polymorphism in other AP cohorts is recommended.

Synaptic Activity Regulates Mitochondrial Iron Metabolism to Enhance Neuronal Bioenergetics.

Synaptic activity is the main energy-consuming process in the central nervous system. We are beginning to understand how energy is supplied and used during synaptic activity by neurons. However, the long-term metabolic adaptations associated with a previous episode of synaptic activity are not well understood. Herein, we show that an episode of synaptic activity increases mitochondrial bioenergetics beyond the duration of the synaptic activity by transcriptionally inducing the expression of iron metabolism genes with the consequent enhancement of cellular and mitochondrial iron uptake. Iron is a necessary component of the electron transport chain complexes, and its chelation or knockdown of mitochondrial iron transporter Mfrn1 blocks the activity-mediated bioenergetics boost. We found that Mfrn1 expression is regulated by the well-known regulator of synaptic plasticity CREB, suggesting the coordinated expression of synaptic plasticity programs with those required to meet the associated increase in energetic demands.

Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer.

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.

Effects of Different Irrigation Regimes, Nitrogen Levels and Storage Conditions on Volatiles of 'Gala' Apple.

With a characteristic flavour and aroma, "Maçã de Alcobaça" are apples produced in the western region of the mainland of Portugal. Given the known influence of pre-harvest cultural techniques and post-harvest conservation methods on fruit quality, this work evaluated the effect of cultural factors and conservation methods on the volatile profile of 'Gala' apples. Tests were carried out during four seasons (2018 to 2021) in two 'Gala' apple orchards (F and S) maintained with different irrigation rates and nitrogen fertilisation [normal irrigation and normal nitrogen (Control, NINN), normal irrigation and excess nitrogen (NIEN), excess irrigation and normal nitrogen (EINN), excess irrigation and excess nitrogen (EIEN)], and under three storage conditions [Controlled Atmosphere + 1-methylcyclopropene (CA+1-MCP), Dynamic Controlled Atmosphere (DCA) and DCA+1-MCP]. The intact fruit volatiles were isolated by headspace solid-phase microextraction (HS-SPME) and analysed by Gas Chromatography with Flame Ionisation Detection and Gas Chromatography-Mass Spectrometry at harvest (T0) and after 8 months of storage (T8). HS-SPME volatiles from 'Gala' apples, obtained at T0 in control conditions, were characterised by trans,trans-α-farnesene dominance (36-69%), followed by hexyl acetate (5-23%) and hexyl hexanoate (3-9%). The four irrigation and nitrogen treatments did not evidence main changes in the apple volatile profile. Instead, storage conditions changed the ratio between compounds; previously undetected compounds attained high percentages and decreased the intensity of the dominant compounds in the control conditions. Although all storage conditions tested changed the volatile profile and emanation intensity, the effect was more accentuated in storage for 8 months with DCA+1-MCP.

Social construction of risk and prevention practices related to Aedes mosquito-borne disease in an endemic municipality in Colombia.

INTRODUCTION: This article analyzes risk discourses around dengue, zika and chikungunya constructed by lay people, community leaders and disease control experts from the fields of medical anthropology, medical sociology, and public health. METHODS: A qualitative ethnographic study was conducted in a municipality in Colombia (December 2016 and January 2018) with semistructured and open-ended interviews, informal dialogues, and fieldwork journal observations. RESULTS: This study found a mismatch in risk discourse about vector-borne diseases among health officials, lay people, and community leaders. These discourses are linked to the sociocultural contexts in which people live, and offer particular ways of giving meaning and acting in the face of disease prevention. CONCLUSION: The findings show a multisituated risk that refers to the inside and outside of homes; and the prevention practices mentioned by different actors, in which a continuity of tensions between lay people, leaders and government officials can be observed.

Antimicrobial-Resistant Shigella spp. in San Diego, California, USA, 2017-2020.

Annually, Shigella spp. cause ≈188 million cases of diarrheal disease globally, including 500,000 cases in the United States; rates of antimicrobial resistance are increasing. To determine antimicrobial resistance and risk factors in San Diego, California, USA, we retrospectively reviewed cases of diarrheal disease caused by Shigella flexneri and S. sonnei diagnosed during 2017-2020. Of 128 evaluable cases, S. flexneri was slightly more common than S. sonnei; most cases were in persons who were gay or bisexual cisgender men, were living with HIV, were unhoused, or used methamphetamines. Overall, rates of resistance to azithromycin, fluoroquinolones, ampicillin, and trimethoprim/sulfamethoxazole (TMP/SMX) were comparable to the most recent national data reported from the Centers for Disease Control and Prevention; 55% of isolates were resistant to azithromycin, 23% to fluoroquinolones, 70% to ampicillin, and 83% to TMP/SMX. The rates that we found for TMP/SMX were slightly higher than those in national data.

ICOS Gene Polymorphisms (IVS1 + 173 T/C and c. 1624 C/T) in Primary Sjögren's Syndrome Patients: Analysis of ICOS Expression.

Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, which affects exocrine glands. T cell activation is a trigger mechanism in the immune response. Hyperreactivity of T cells and antibody production are features in pSS. ICOS can be critical in the pathogenesis of pSS. Methods: A total of 134 pSS patients and 134 control subjects (CS) were included. Genotyping was performed by PCR-RFLP. ICOS mRNA expression was quantified by real-time PCR, and CD4+ ICOS+ T cells were determined by flow cytometry. Results: The ICOS IVS1 + 173 T>C polymorphisms were not associated with susceptibility to pSS (p = 0.393, CI = 0.503−1.311). However, the c.1624 C>T polymorphism was associated with a reduction in the risk of development of pSS (p = 0.015, CI = 0.294−0.884). An increase in ICOS mRNA expression in patients was observed (3.7-fold). Furthermore, pSS patients showed an increase in membranal-ICOS expression (mICOS). High expression of mICOS (MFI) was associated with lymphocytic infiltration. Conclusions: The IVS1 + 173 polymorphism is not a genetic marker for the development of pSS, while c.1624 T allele was associated with a low risk. However, elevated mICOS expression in pSS patients with high lymphocytic infiltration was found. ICOS may have an important role in the immunopathogenesis of pSS and should be analyzed in T cell subsets in pSS patients as a possible disease marker.