Orthohantaviruses in Misiones Province, Northeastern Argentina.

Few cases of hantavirus pulmonary syndrome have been reported in northeastern Argentina. However, neighboring areas show a higher incidence, suggesting underreporting. We evaluated the presence of antibodies against orthohantavirus in small rodents throughout Misiones province. Infected Akodon affinis montensis and Oligoryzomys nigripes native rodents were found in protected areas of Misiones.

Hydrocortisone cardioprotection in ischaemia/reperfusion injury involves antioxidant mechanisms.

BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids. AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress. MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis. RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI. CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.

Corneal stromal localization of TGF beta isoforms in spontaneous persistent epithelial defects after PRK in rabbits.

The purpose of this study was to evaluate transforming growth factor beta (TGFß) isoform localization in rabbit corneas with spontaneous persistent epithelial defects (PEDs) after photorefractive keratectomy (PRK). Four cryofixed corneas from a previously reported series of PEDs in rabbits that had PRK were evaluated with triplex immunohistochemistry (IHC) for TGFß3, myofibroblast marker alpha-smooth muscle actin (α-SMA) and mesenchymal marker vimentin. One cornea had sufficient remaining tissue for triplex IHC for TGFß1, TGFß2, or TGFß3 (each with α-SMA and vimentin) using isoform-specific antibodies. All three TGFß isoforms were detected in the subepithelial stroma at and surrounding the PED. Some of each TGFß isoform co-localized with α-SMA of myofibroblasts, which could be TGFß isoform autocrine production by myofibroblasts or TGFß-1, -2, and -3 binding to these myofibroblasts.

Chronic postsurgical pain: A European survey.

BACKGROUND: Chronic postsurgical pain (CPSP) is a clinical problem, and large prospective studies are needed to determine its incidence, characteristics, and risk factors. OBJECTIVE: To find predictive factors for CPSP in an international survey. DESIGN: Observational study. SETTING: Multicentre European prospective observational trial. PATIENTS: Patients undergoing breast cancer surgery, sternotomy, endometriosis surgery, or total knee arthroplasty (TKA). METHOD: Standardised questionnaires were completed by the patients at 1, 3, and 7 days, and at 1, 3, and 6 months after surgery, with follow-up via E-mail, telephone, or interview. MAIN OUTCOME MEASURE: The primary goal of NIT-1 was to propose a scoring system to predict those patient likely to have CPSP at 6 months after surgery. RESULTS: A total of 3297 patients were included from 18 hospitals across Europe and 2494 patients were followed-up for 6 months. The mean incidence of CPSP at 6 months was 10.5%, with variations depending on the type of surgery: sternotomy 6.9%, breast surgery 7.4%, TKA 12.9%, endometriosis 16.2%. At 6 months, neuropathic characteristics were frequent for all types of surgery: sternotomy 33.3%, breast surgery 67.6%, TKA 42.4%, endometriosis 41.4%. One-third of patients experienced CPSP at both 3 and 6 months. Pre-operative pain was frequent for TKA (leg pain) and endometriosis (abdomen) and its frequency and intensity were reduced after surgery. Severe CPSP and a neuropathic pain component decreased psychological and functional wellbeing as well as quality of life. No overarching CPSP risk factors were identified. CONCLUSION: Unfortunately, our findings do not offer a new CPSP predictive score. However, we present reliable new data on the incidence, characteristics, and consequences of CPSP from a large European survey. Interesting new data on the time course of CPSP, its neuropathic pain component, and CPSP after endometriosis surgery generate new hypotheses but need to be confirmed by further research. TRIAL REGISTRATION: clinicaltrials.gov ID: NCT03834922.

Envenomation by Eyelash Viper Bothriechis schlegelii (Berthold, 1846) in Southwestern Colombia.

INTRODUCTION: Bothriechis schlegelii is a Crotaline viperid species of Central America and Northern South America. The characteristics of its envenomation have not been well established. We present clinical characteristics of human cases evaluated and treated in a hospital in southwestern Colombia. METHODS: We evaluated data from patients who suffered Bothriechis schlegelii envenomation and were seen at Fundación Valle del Lili Hospital, Cali, Colombia between 2011 and 2022. RESULTS: Eight patients were included, with a median age of 24 years. Snakebites occurred in rural areas. Six (75%) patients were bitten on the upper extremities in relation to the arboreal habits of this animal. The most common symptoms were pain and edema (N = 8, 100%), ecchymoses (N = 2, 25%), and paresthesia (N = 2, 25%). The most common systemic findings were hypofibrinogenemia (N = 8, 100%) and prolonged prothrombin time in five patients (N = 5, 62.5%). All were treated with polyvalent antivenom for Colombian snakes, with a good response and outcome. CONCLUSIONS: Most bite sites from B. schlegelii were on the upper limbs. All patients had both local manifestations, including edema, pain, and systemic effects with hypofibrinogenemia, but none had systemic bleeding. Every patient received antivenom and had favorable outcomes.

"Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina.

BACKGROUND: From November 2018 through February 2019, person-to-person transmission of Andes virus (ANDV) hantavirus pulmonary syndrome occurred in Chubut Province, Argentina, and resulted in 34 confirmed infections and 11 deaths. Understanding the genomic, epidemiologic, and clinical characteristics of person-to-person transmission of ANDV is crucial to designing effective interventions. METHODS: Clinical and epidemiologic information was obtained by means of patient report and from public health centers. Serologic testing, contact-tracing, and next-generation sequencing were used to identify ANDV infection as the cause of this outbreak of hantavirus pulmonary syndrome and to reconstruct person-to-person transmission events. RESULTS: After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events. After 18 cases were confirmed, public health officials enforced isolation of persons with confirmed cases and self-quarantine of possible contacts; these measures most likely curtailed further spread. The median reproductive number (the number of secondary cases caused by an infected person during the infectious period) was 2.12 before the control measures were enforced and decreased to 0.96 after the measures were implemented. Full genome sequencing of the ANDV strain involved in this outbreak was performed with specimens from 27 patients and showed that the strain that was present (Epuyén/18-19) was similar to the causative strain (Epilink/96) in the first known person-to-person transmission of hantavirus pulmonary syndrome caused by ANDV, which occurred in El Bolsón, Argentina, in 1996. Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection. Disease severity, genomic diversity, age, and time spent in the hospital had no clear association with secondary transmission. CONCLUSIONS: Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission. (Funded by the Ministerio de Salud y Desarrollo Social de la Nación Argentina and others.).

Hantavirus infection-induced B cell activation elevates free light chains levels in circulation.

In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients' peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings.

Transforming growth factor beta-3 localization in the corneal response to epithelial-stromal injury and effects on corneal fibroblast transition to myofibroblasts.

The purpose of this study was to evaluate the localization of TGF beta-3 in situ in unwounded rabbit corneas and corneas that had epithelial-stromal injuries produced by photorefractive keratectomy (PRK) in rabbits and to evaluate the in vitro effects of TGF beta-3 compared to TGF beta-1 on alpha-smooth muscle actin (α-SMA) protein expression and myofibroblast development in corneal fibroblasts. Forty-eight New Zealand white rabbits underwent either -3 diopter (D) or -9D PRK and were studied from one to eight weeks (four corneas in each group at each time point) after surgery with immunohistochemistry for TGF beta-3, laminin alpha-5, and alpha-smooth muscle actin (α-SMA). Rabbit corneal fibroblasts were treated with activated TGF beta-1 and/or TGF beta-3 at different concentrations and duration of exposure and studied with immunocytochemistry for myofibroblast development and the expression of α-SMA using Jess automated Western blotting. TGF beta-3 was detected at high levels in the stroma of unwounded corneas and corneas at one to eight weeks after -3D or -9D PRK, as well as in the epithelium and epithelial basement membrane (EBM). No difference was noted between corneas that healed with and without myofibroblast-mediated fibrosis, although TGF beta-3 was commonly associated with myofibroblasts. TGF beta-3 effects on corneal fibroblasts in vitro were similar to TGF beta-1 in stimulating transition to α-SMA-positive myofibroblasts and promoting α-SMA protein expression. The corneal stromal localization pattern of TGF beta-3 protein in unwounded corneas and corneas after epithelial-stromal injury was found to be higher and different from TGF beta-1 and TGF beta-2 reported in previous studies. TGF beta-3 had similar effects to TGF beta-1 in driving myofibroblast development and α-SMA expression in corneal fibroblasts cultured in medium with 1% fetal bovine serum.

Standardization of corneal alkali burn methodology in rabbits.

Alkali burns are one of the most common injuries used in corneal wound healing studies. Investigators have used different conditions to produce corneal alkali injuries that have varied in sodium hydroxide concentration, application methods, and duration of exposure. A critical factor in the subsequent corneal healing responses, including myofibroblast generation and fibrosis localization, is whether, or not, Descemet's membrane and the endothelium are injured during the initial exposure. After exposures that produce injuries confined to the epithelium and stroma, anterior stromal myofibroblasts and fibrosis are typical, with sparing of the posterior stroma. However, if there is also injury to Descemet's membrane and the endothelium, then myofibroblast generation and fibrosis is noted full corneal thickness, with predilection to the most anterior and most posterior stroma and a tendency for relative sparring of the central stroma that is likely related to the availability of TGF beta from the tears, epithelium, and the aqueous humor. A method is described where a 5 mm diameter circle of Whatman #1 filter paper wetted with only 30 µL of alkali solution is applied for 15 s prior to profuse irrigation in rabbit corneas. When 0.6N, or lower, NaOH is used, then the injury, myofibroblasts, and fibrosis generation are limited to the epithelium and stroma. Use of 0.75N NaOH triggers injury to Descemet's membrane and the corneal endothelium with fibrosis throughout the stroma, but rare corneal neovascularization (CNV) and persistent epithelial defects (PED). Use of 1N NaOH with this method produces greater stromal fibrosis and increased likelihood that CNV and PED will occur in individual corneas.

Functional Distinction between Human and Mouse Sodium-Coupled Citrate Transporters and Its Biologic Significance: An Attempt for Structural Basis Using a Homology Modeling Approach.

NaCT (SLC13A5; mINDY), a sodium-coupled citrate transporter, is the mammalian ortholog of Drosophila INDY. Loss-of-function mutations in human NaCT cause severe complications with neonatal epilepsy and encephalopathy (EIEE25). Surprisingly, mice lacking this transporter do not have this detrimental brain phenotype. The marked differences in transport kinetics between mouse and human NaCTs provide at least a partial explanation for this conundrum, but a structural basis for the differences is lacking. Neither human nor mouse NaCT has been crystallized, and any information known on their structures is based entirely on what was inferred from the structure of VcINDY, a related transporter in bacteria. Here, we highlight the functional features of human and mouse NaCTs and provide a plausible molecular basis for the differences based on a full-length homology modeling approach. The transport characteristics of human NaCT markedly differ from those of VcINDY. Therefore, the modeling with VcINDY as the template is flawed, but this is the best available option at this time. With the newly deduced model, we determined the likely locations of the disease-causing mutations and propose a new classification for the mutations based on their location and potential impact on transport function. This new information should pave the way for future design and development of novel therapeutics to restore the lost function of the mutant transporters as a treatment strategy for patients with EIEE25.

Modeling potential risk areas of Orthohantavirus transmission in Northwestern Argentina using an ecological niche approach.

BACKGROUND: Hantavirus Pulmonary Syndrome (HPS) is a rodent-borne zoonosis in the Americas, with up to 50% mortality rates. In Argentina, the Northwestern endemic area presents half of the annually notified HPS cases in the country, transmitted by at least three rodent species recognized as reservoirs of Orthohantavirus. The potential distribution of reservoir species based on ecological niche models (ENM) can be a useful tool to establish risk areas for zoonotic diseases. Our main aim was to generate an Orthohantavirus risk transmission map based on ENM of the reservoir species in northwest Argentina (NWA), to compare this map with the distribution of HPS cases; and to explore the possible effect of climatic and environmental variables on the spatial variation of the infection risk. METHODS: Using the reservoir geographic occurrence data, climatic/environmental variables, and the maximum entropy method, we created models of potential geographic distribution for each reservoir in NWA. We explored the overlap of the HPS cases with the reservoir-based risk map and a deforestation map. Then, we calculated the human population at risk using a census radius layer and a comparison of the environmental variables' latitudinal variation with the distribution of HPS risk. RESULTS: We obtained a single best model for each reservoir. The temperature, rainfall, and vegetation cover contributed the most to the models. In total, 945 HPS cases were recorded, of which 97,85% were in the highest risk areas. We estimated that 18% of the NWA population was at risk and 78% of the cases occurred less than 10 km from deforestation. The highest niche overlap was between Calomys fecundus and Oligoryzomys chacoensis. CONCLUSIONS: This study identifies potential risk areas for HPS transmission based on climatic and environmental factors that determine the distribution of the reservoirs and Orthohantavirus transmission in NWA. This can be used by public health authorities as a tool to generate preventive and control measures for HPS in NWA.

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis.

Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.

Assessing Spanish Health Literacy and Cervical Cancer Knowledge, Attitudes, and Behaviors in a Student-Run Free Clinic.

While the incidence of cervical cancer continues to decrease, there is a significant discrepancy in incidence rates and screening behaviors among Hispanic and non-Hispanic white patients in the USA. This project examines the relationship between Spanish health literacy and cervical cancer screening knowledge, attitudes, and practices among native Spanish-speaking patients at risk for cervical cancer at the USF BRIDGE Healthcare Clinic, a student-run free clinic in Tampa, FL. Spanish-speaking patients ≥21 years (n = 34) participated in a quality improvement project that included an assessment of Spanish health literacy and a written survey on cervical cancer knowledge. Chi-squared tests were performed to assess potential relationships between health literacy and cervical cancer knowledge, attitudes, health behaviors, and demographics. Seven participants (20.6%) scored between 0 and 14 on the SAHL-S, indicating inadequate health literacy. A significant difference in cervical cancer health knowledge was found between patients with adequate health literacy compared to patients with inadequate health literacy (p = 0.002). There is a potential association between low Spanish health literacy and subsequent poorer understanding of cervical cancer in BRIDGE patients. This implies that patients of low health literacy may have poorer comprehension of other aspects of their care beyond cervical cancer screening. Strategies are discussed to improve communication with BRIDGE patients of low Spanish health literacy that may be applicable to other patient populations.

Chronic pain after posterolateral and axillary approaches to lung surgery: a monocentric observational study.

PURPOSE: Post-thoracotomy pain syndrome (PTPS) and chronic postsurgical neuropathic pain (CPNP) were evaluated 4 months after thoracic surgery whether the approach was a posterolateral (PL) incision or the less invasive axillary (AX) one. METHODS: Patients, 79 in each group, undergoing a thoracotomy between July 2014 and November 2015 were analyzed 4 months after surgery in this prospective monocentric cohort study. RESULTS: More PL patients suffered PTPS (60.8% vs. 40.5%; p = 0.017) but CPNP was equally present (45.8% and 46.9% in the PL and AX groups). Patients with PTPS have more limited daily activities (p < 0.001) but a similar psychological disability (i.e., catastrophism). Patients with CPNP have an even greater limitation of daily activities (p = 0.007) and more catastrophism (p = 0.0002). Intensity of pain during mobilization of the homolateral shoulder at postoperative day 6 (OR = 1.40, CI 95% [1.13-1.75], p = 0.002); age (OR = 0.97 [0.94-1.00], p = 0.022), and presence of pain before surgery (OR = 2.22 [1.00-4.92], p = 0.049) are related to the occurrence of PTPS; while, height of hypoesthesia area on the breast line measured 6 days after surgery is the only factor related to that of CPNP (OR = 1.14 [1.01-1.30], p = 0.036). CONCLUSION: Minimally invasive surgery was associated with less frequent PTPS, but with equal risk of CPNP. Pain before surgery and its postoperative intensity are associated with PTPS. This must lead to a more aggressive care of pain patients before surgery and of a better management of postoperative pain. CPNP can be forecasted according to the early postoperative height of hypoesthesia area on the breast line.

Hantavirus Pulmonary Syndrome in a COVID-19 Patient, Argentina, 2020.

We describe a patient in Argentina with severe acute respiratory syndrome coronavirus 2 infection and hantavirus pulmonary syndrome (HPS). Although both coronavirus disease and HPS can be fatal when not diagnosed and treated promptly, HPS is much more lethal. This case report may contribute to improved detection of co-infections in HPS-endemic regions.

Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype.

Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.

A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects.

NaCT (SLC13A5) is a Na+-coupled transporter for citrate, which is expressed in the liver, brain, testes, and bone. It is the mammalian homolog of Drosophila INDY, a cation-independent transporter for citrate, whose partial loss extends lifespan in the organism. In humans, loss-of-function mutations in NaCT cause a disease with severe neurological dysfunction, characterized by neonatal epilepsy and delayed brain development. In contrast with humans, deletion of NaCT in mice results in a beneficial metabolic phenotype with protection against diet-induced obesity and metabolic syndrome; the brain dysfunction is not readily noticeable. The disease-causing mutations are located in different regions of human NaCT protein, suggesting that different mutations might have different mechanisms for the loss of function. The beneficial effects of NaCT loss in the liver versus the detrimental effects of NaCT loss in the brain provide an opportunity to design high-affinity inhibitors for the transporter that do not cross the blood-brain barrier so that only the beneficial effects could be harnessed. To realize these goals, we need a detailed knowledge of the 3D structure of human NaCT. The recent report by Sauer et al. in Nature describing the cryo-EM structure of human NaCT represents such a milestone, paving the way for a better understanding of the structure-function relationship for this interesting and clinically important transporter.

Expanded distribution of orthohantavirus Pergamino genotype: First record in Entre Rios province, Argentina.

Hantavirus Pulmonary Syndrome (HPS) is an emerging infectious disease of the Americas. Eight native rodent species have been identified as HPS virus reservoirs in Argentina. The aim of this work was to detect the orthohantavirus genotypes present in a rodent community that inhabits a zone where a fatal HPS case occurred within an endemic locality of Central Argentina. We captured 27 rodents with a trapping effort of 723 trap nights. We detected 14.3% of infected Akodon azarae with the Pergamino genotype. This result expands the known distribution of this orthohantavirus. Although the Pergamino genotype has not been associated with human cases, the information about its distribution is relevant for risk assessment against potential changes in the virus infectivity.

Systemic erythematosus lupus and pregnancy outcomes in a Colombian cohort.

OBJECTIVE: Pregnant women with SLE have higher probabilities of maternal complications. SLE during pregnancy has alternating patterns of remission and flare-ups; however, most pregnant SLE patients tend to worsen with associated poor obstetric and perinatal outcomes. This study aimed to describe obstetric outcomes in pregnant women with SLE. METHODS: This retrospective study was performed between 2011 and 2020 at a highly complex referral health center in Cali, Colombia. Pregnant women with a diagnosis of SLE were included. Demographic, clinical, and laboratory features and obstetric and fetal outcomes, including intensive care unit (ICU) characteristics, were evaluated. RESULTS: Forty-eight pregnant women with SLE were included. The median age was 29 (25-33.7) years. The SLE diagnosis was made before pregnancy in 38 (79.1%) patients, with a median disease duration of 46 (12-84) months. Thirteen (27.1%) patients had lupus nephritis. Preterm labor (34, 70.8%), preeclampsia (25, 52%), and preterm rupture of membranes (10, 20.8%) were the most common obstetric complications. A relationship between a greater systemic lupus erythematosus pregnancy disease activity index (SLEPDAI) and the development of hypertensive disorders during pregnancy was established (preeclampsia = p < 0.0366; eclampsia = p < 0.0153). A relationship was identified between lupus nephritis (LN) and eclampsia (p < 0.01), preterm labor (p < 0.045), and placental abruption (p < 0.01). Seventeen (35.4%) patients required ICU admission; 52.9% of them were due to AID activity, 17.6% for cardiovascular damage, 11.7% for septic shock, and 5.8% for acute kidney failure. Fetal survival was 89.5% (N = 43/48). Among the live births, two (4.2%) newborns were diagnosed with neonatal lupus, and two (4.2%) were diagnosed with congenital heart block. One maternal death was registered due to preeclampsia and intraventricular hemorrhage. CONCLUSIONS: This study is the first to describe SLE during pregnancy in Colombia. SLE was the most prevalent AID in this cohort, and complications included preterm labor, preeclampsia, and postpartum hemorrhage. A higher SLEPDAI and lupus nephritis predicted adverse maternal outcomes.

Functional analysis of a species-specific inhibitor selective for human Na+-coupled citrate transporter (NaCT/SLC13A5/mINDY).

The Na+-coupled citrate transporter (NaCT/SLC13A5/mINDY) in the liver delivers citrate from the blood into hepatocytes. As citrate is a key metabolite and regulator of multiple biochemical pathways, deletion of Slc13a5 in mice protects against diet-induced obesity, diabetes, and metabolic syndrome. Silencing the transporter suppresses hepatocellular carcinoma. Therefore, selective blockers of NaCT hold the potential to treat various diseases. Here we report on the characteristics of one such inhibitor, BI01383298. It is known that BI01383298 is a high-affinity inhibitor selective for human NaCT with no effect on mouse NaCT. Here we show that this compound is an irreversible and non-competitive inhibitor of human NaCT, thus describing the first irreversible inhibitor for this transporter. The mouse NaCT is not affected by this compound. The inhibition of human NaCT by BI01383298 is evident for the constitutively expressed transporter in HepG2 cells and for the ectopically expressed human NaCT in HEK293 cells. The IC50 is ∼100 nM, representing the highest potency among the NaCT inhibitors known to date. Exposure of HepG2 cells to this inhibitor results in decreased cell proliferation. We performed molecular modeling of the 3D-structures of human and mouse NaCTs using the crystal structure of a humanized variant of VcINDY as the template, and docking studies to identify the amino acid residues involved in the binding of citrate and BI01383298. These studies provide insight into the probable bases for the differential effects of the inhibitor on human NaCT versus mouse NaCT as well as for the marked species-specific difference in citrate affinity.