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Background: Hemophagocytic lymphohistiocytosis (HLH) is considered a rare disease with high morbidity and mortality risks. Most research on this disease is conducted in pediatric settings. Therefore, this study aimed to describe the clinical characteristics, laboratory findings, and outcomes related to HLH in people living with human immunodeficiency virus (HIV)/AIDS) and disseminated histoplasmosis., Methods: A retrospective and descriptive study was conducted in a tertiary hospital in México City from January 2018 to December 2022, including people living with HIV who had disseminated histoplasmosis confirmed through direct microbiological or immunological methods with an HScore ≥169 or who met 5 of the 8 HLH-2004 criteria., Results: HLH occurred in 36.1% (n = 26) of patients with HIV and disseminated histoplasmosis; the majority were men (84.9%), and their mean age (standard deviation) was 30.19 (5.6) years. The most frequent clinical manifestations were hepatomegaly (100%), fever (96.2%), and dyspnea (84.6%). The most common biochemical changes were hyperferritinemia (100%), elevated lactate dehydrogenase (100%), and bicytopenia (61.5%). Partial thromboplastin time ( P = .012) and prothrombin time ( P = .004) were associated with the 30-day mortality rate, and the 30-day survival rate was 65.4%., Conclusions: We detected a high frequency of HLH; therefore, we encourage physicians to use diagnostic prediction tools (HLH-2004 and HScore criteria) in each reassessment for timely detection., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Expanding the chemical diversity of aptamers remains an important thrust in the field in order to increase their functional potential. Previously, our group developed LOOPER, which enables the incorporation of up to 16 unique modifications throughout a ssDNA sequence, and applied it to the in vitro evolution of thrombin binders. As LOOPER-derived highly modified nucleic acids polymers are governed by two interrelated evolutionary variables, namely, functional modifications and sequence, the evolution of this polymer contrasts with that of canonical DNA. Herein we provide in-depth analysis of the evolution, including structure-activity relationships, mapping of evolutionary pressures on the library, and analysis of plausible evolutionary pathways that resulted in the first LOOPER-derived aptamer, TBL1. A detailed picture of how TBL1 interacts with thrombin and how it may mimic known peptide binders of thrombin is also proposed. Structural modeling and folding studies afford insights into how the aptamer displays critical modifications and also how modifications enhance the structural stability of the aptamer. A discussion of benefits and potential limitations of LOOPER during in vitro evolution is provided, which will serve to guide future evolutions of this highly modified class of aptamers.

Competing Interests: There are no conflicts of interest.

Competing Interests: There are no conflicts of interest.

Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor 10 Panx1. Sampling was performed 1, 3, 6, 24 and 48 h after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant readouts, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was paralleled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10 Panx1-treated mice. Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced hepatotoxicity.

Background and Aims: Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity., Methods: C57BL/6 mice were overdosed with 300mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione., Results: It was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts., Conclusion: These results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.

Unlabelled: Background and goal of study: there is evidence that perioperative intravenous ketamine and lidocaine reduce postoperative pain, postoperative opioids consumption, shortens hospital stay and accelerates intestinal function recovery. However, it has not been studied the beneficial effects in the intraoperative period. The aim of this study was to evaluate the effect of a single dose of lidocaine and ketamine on intraoperative opioids requirements in patients undergoing elective gynecological laparotomies under general anesthesia., Materials and Methods: we performed a single-centre, prospective, randomized, double-blinded, placebo-controlled study. We included 33 patients (11 in the ketamine group, 11 in the lidocaine group and 11 in the placebo group). Postoperative analgesia was accomplished by patient-controlled morphine. Patients were randomly assigned to receive either a 1.5 mg/kg of 2% lidocaine, 0.5 mg/kg of 5% ketamine or 0.9% saline bolus. The primary outcome was the opioids consumption during surgery. The secondary outcomes included: emergence time, pain scores, opioids consumption within 24 h after surgery and side effects., Results: decreased intraoperative opioids requirements were noted in the experimental groups (ketamine: 402.3 } 106.3 and lidocaine: 397.7 } 107.5, compared with saline: 561.4 } 97.1); p = 0.001. We found a positive correlation between intraoperative opioids consumption and emergence time (r = 0.864, p < 0.001). There was no significant difference between the groups in VAS pain scores at rest within the first 24 postoperative hours. Total morphine consumption within 24 h after surgery did not differ significantly among the groups (placebo: 27.54 } 11.75; ketamine: 30.95 } 7.88; lidocaine 34.77 } 4510.25; p = 0.26). Postoperative nausea and vomiting were more common in placebo group (it was observed in 3 subjects in ketamine group, in 5 subjects in lidocaine group and in 9 subjects in placebo group; p = 0.027)., Conclusion: our results do not support the use of intraoperative single dose of lidocaine or ketamine to reduce postoperative pain and postoperative opioids consumption after open gynecological surgery. However, they seem to decrease intraoperative opioids requirements and shorten emergence time. Nevertheless, these findings should be validating in further studies with large sample size., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Introduction: In vitro antibiotic combination testing would guide therapy selection in patients severely affected by multi-drug resistant Pseudomonas., Objectives: In vitro, a two-antibiotic combination susceptible against multi-drug resistant Pseudomonas isolated at the Laboratorio Clínico of the Hospital de Oncología, Centro Médico Nacional Siglo XXI in Mexico City were analyzed to determine which antibiotic combination showed the best bactericidal activity., Material and Methods: During 10 months, 30 multi-drug resistant Pseudomonas strains were tested. An automated method was used, including a diluting solution with a well-known concentration of a second antibiotic. Quality controls recommended by the NCCLS were used. Pseudomonas aeruginosa ATCC 27853; Escherichia coli ATCC 25922; and Escherichia coli ATCC 35218. Combinations were betalactamics-aminoglycosides; carbapenemis-amikacin; fluoroquinolones-cefepime; and ciprofloxacin-ampicillin., Results: Ampicillin-ciprofloxacin combination was bactericidal against 100% of the isolates. Cefazolin, cefixime and ticarcillin with amikacin: <50%; aztreonam, cefoxilin, cefuroxime, cefotaxime, ceftazidime and piperacillin with amikacin: 50-60%; cefepime with gentamicin: 76%; cefepime with amikacin: 86%; imipenem and meropenem with amikacin: 70% and 76%; cefepime with ciprofloxacin: 83%; cefepime with levofloxacin: 73%., Conclusions: In vitro antibiotic combination susceptibilities against multi-drug resistant bacteria would be the only way to guide clinicians to select the best therapy in severe infections. We found that the ampicillin-ciprofloxacin combination showed the best in vitro effect against multi-drug resistant Pseudomonas.