Heteroleptic (S

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [Au(dpta)Cl2, Au(dpta)(mrdtc), and Au(dpta)(dedtc)] or thiophosphonamide [Au(bpta)(dedtc)] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity.

Antiviral activity of immunosuppressors alone and in combination against human adenovirus and cytomegalovirus.

Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC50) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC50=0.05 µM and 0.3 µM, respectively) and HCMV (IC50=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI50) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI50=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI50=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human Cmax values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.

Acidic Urine pH and Clinical Outcome of Lower Urinary Tract Infection in Kidney Transplant Recipients Treated with Ciprofloxacin and Fosfomycin.

Different factors, including antimicrobial resistance, may diminish the effectiveness of antibiotic therapy, challenging the management of post-transplant urinary tract infection (UTI). The association of acidic urine pH with microbiological and clinical outcomes was evaluated after fosfomycin or ciprofloxacin therapy in 184 kidney transplant recipients (KTRs) with UTI episodes by Escherichia coli (N = 115) and Klebsiella pneumoniae (N = 69). Initial urine pH, antimicrobial therapy, and clinical and microbiological outcomes, and one- and six-month follow-up were assessed. Fosfomycin was prescribed in 88 (76.5%) E. coli and 46 (66.7%) K. pneumoniae UTI episodes in the total cohort. When the urine pH ≤ 6, fosfomycin was prescribed in 60 (52.2%) E. coli and 29 (42.0%) K. pneumoniae. Initial urine pH ≤ 6 in E. coli UTI was associated with symptomatic episodes (8/60 vs. 0/55, p = 0.04) at one-month follow-up, with a similar trend in those patients receiving fosfomycin (7/47 vs. 0/41, p = 0.09). Acidic urine pH was not associated with microbiological or clinical cure in K. pneumoniae UTI. At pH 5, the ciprofloxacin MIC90 increased from 8 to >8 mg/L in E. coli and from 4 to >8 mg/L in K. pneumoniae. At pH 5, the fosfomycin MIC90 decreased from 8 to 4 mg/L in E. coli and from 512 to 128 mg/L in K. pneumoniae. Acidic urine is not associated with the microbiological efficacy of fosfomycin and ciprofloxacin in KTRs with UTI, but it is associated with symptomatic UTI episodes at one-month follow-up in E. coli episodes.

In Vitro and In Vivo Virulence Study of Listeria monocytogenes Isolated from the Andalusian Outbreak in 2019.

In 2019, the biggest listeriosis outbreak by Listeria monocytogenes (Lm) in the South of Spain was reported, resulting in the death of three patients from 207 confirmed cases. One strain, belonging to clonal complex 388 (Lm CC388), has been isolated. We aimed to determine the Lm CC388 virulence in comparison with other highly virulent clones such as Lm CC1 and Lm CC4, in vitro and in vivo. Four L. monocytogenes strains (Lm CC388, Lm CC1, Lm CC4 and ATCC 19115) were used. Attachment to human lung epithelial cells (A549 cells) by these strains was characterized by adherence and invasion assays. Their cytotoxicities to A549 cells were evaluated by determining the cells viability. Their hemolysis activity was determined also. A murine intravenous infection model using these was performed to determine the concentration of bacteria in tissues and blood. Lm CC388 interaction with A549 cells is non-significantly higher than that of ATCC 19115 and Lm CC1, and lower than that of Lm CC4. Lm CC388 cytotoxicity is higher than that of ATCC 19115 and Lm CC1, and lower than that of Lm CC4. Moreover, Lm CC388 hemolysis activity is lower than that of the Lm CC4 strain, and higher than that of Lm CC1. Finally, in the murine intravenous infection model by Lm CC388, higher bacterial loads in tissues and at similar levels of Lm CC4 were observed. Although a lower rate of mortality of patients during the listeriosis outbreak in Spain in 2019 has been reported, the Lm CC388 strain has shown a greater or similar pathogenicity level in vitro and in an animal model, like Lm CC1 and Lm CC4.

IgM-enriched immunoglobulin improves colistin efficacy in a pneumonia model by Pseudomonas aeruginosa.

We evaluated the efficacy of ceftazidime or colistin in combination with polyclonal IgM-enriched immunoglobulin (IgM-IG), in an experimental pneumonia model (C57BL/6J male mice) using two multidrug-resistant Pseudomonas aeruginosa strains, both ceftazidime-susceptible and one colistin-resistant. Pharmacodynamically optimised antimicrobials were administered for 72 h, and intravenous IgM-IG was given as a single dose. Bacterial tissues count and the mortality were analysed. Ceftazidime was more effective than colistin for both strains. In mice infected with the colistin-susceptible strain, ceftazidime reduced the bacterial concentration in the lungs and blood (-2.42 and -3.87 log10 CFU/ml) compared with colistin (-0.55 and -1.23 log10 CFU/ml, respectively) and with the controls. Colistin plus IgM-IG reduced the bacterial lung concentrations of both colistin-susceptible and resistant strains (-2.91 and -1.73 log10 CFU/g, respectively) and the bacteraemia rate of the colistin-resistant strain (-44%). These results suggest that IgM-IG might be useful as an adjuvant to colistin in the treatment of pneumonia caused by multidrug-resistant P. aeruginosa.

Repurposing of the Tamoxifen Metabolites to Treat Methicillin-Resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococcus faecalis Infections.

Repurposing drugs provides a new approach to the fight against multidrug-resistant (MDR) bacteria. We have reported that three major tamoxifen metabolites, N-desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM), and endoxifen (ENDX), presented bactericidal activity against Acinetobacter baumannii and Escherichia coli. Here, we aimed to analyze the activity of a mixture of the three tamoxifen metabolites against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus species. MRSE (n = 17) and Enterococcus species (Enterococcus faecalis n = 8 and Enterococcus faecium n = 10) strains were used. MIC of the mixture of DTAM, HTAM, and ENDX and that of vancomycin were determined by microdilution assay. The bactericidal activity of the three metabolites together and of vancomycin against MRSE (SE385 and SE742) and vancomycin-resistant E. faecalis (EVR1 and EVR2) strains was determined by time-kill curve assays. Finally, changes in membrane permeability of SE742 and EVR1 strains were analyzed using fluorescence assays. MIC90 of tamoxifen metabolites was 1 mg/liter for MRSE strains and 2 mg/liter for E. faecalis and E. faecium strains. In the time-killing assays, tamoxifen metabolites mixture showed bactericidal activity at 4× MIC for MRSE (SE385 and SE742) and at 2× MIC and 4× MIC for E. faecalis (EVR1 and EVR2) strains, respectively. SE385 and EVR2 strains treated with the tamoxifen metabolites mixture presented higher membrane permeabilization. Altogether, these results showed that tamoxifen metabolites presented antibacterial activity against MRSE and vancomycin-resistant E. faecalis, suggesting that tamoxifen metabolites might increase the arsenal of drug treatments against these bacterial pathogens. IMPORTANCE The development of new antimicrobial therapeutic strategies requires immediate attention to avoid the tens of millions of deaths predicted to occur by 2050 as a result of MDR bacterial infections. In this study, we assessed the antibacterial activity of three major tamoxifen metabolites, N-desmethyltamoxifen (DTAM), 4-hydroxytamoxifen (HTAM), and endoxifen (ENDX), against methicillin-resistant Staphylococcus epidermidis (MRSE) and Enterococcus spp. (E. faecalis and E. faecium). We found that the tamoxifen metabolites have antibacterial activity against MRSE, E. faecalis, and E. faecium strains by presenting MIC90 between 1 and 2 mg/liter and bactericidal activity over 24 h. In addition, this antibacterial activity is paralleled by an increased membrane permeability of these strains. Our results showed that tamoxifen metabolites might be potentially used as a therapeutic alternative when treating MRSE and E. faecalis strains in an animal model of infection.

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients.

Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome.

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome.

Design, synthesis and in vitro biological evaluation of a novel class of anti-adenovirus agents based on 3-amino-1,2-propanediol.

Nowadays there is not an effective drug for the treatment of infections caused by human adenovirus (HAdV) which supposes a clinical challenge, especially for paediatric and immunosuppressed patients. Here, we describe the design, synthesis and biological evaluation as anti-adenovirus agents of a new library (57 compounds) of diester, monoester and triazole derivatives based on 3-amino-1,2-propanediol skeleton. Seven compounds (17, 20, 26, 34, 44, 60 and 66) were selected based on their high anti-HAdV activity at low micromolar concentration (IC50 from 2.47 to 5.75 µM) and low cytotoxicity (CC50 from 28.70 to >200 µM). In addition, our mechanistic assays revealed that compounds 20 and 44 might be targeting specifically the HAdV DNA replication process, and compound 66 would be targeting HAdV E1A mRNA transcription. For compounds 17, 20, 34 and 60, the mechanism of action seems to be associated with later steps after HAdV DNA replication.

[Urinary symptoms and urodynamic findings in argentinian patients with advanced pelvic organ prolapse (POP).] / Características clínicas urinarias y hallazgos urodinámicos en pacientes argentinas con prolapso de órganos pelvianos (POP) en estadío avanzado.

OBJECTIVE: To describe urinary symptoms and urodynamic findings in patients with advanced pelvic organ prolapse. MATERIAL AND METHODS: A descriptive and retrospective evaluation with advanced POP referred for urodynamic test before surgical repair between 2015 and 2017 were included. All patients under went a urogynexam, physical examination, uroflow and urodynamics exam. Clinical features (filling and emptying symptoms, stress incontinence questionnaire (ISIQ-SF) and urodynamics (sensitivity, capacity and hyperactive detrusor, internal sphincter deficiency and voiding symptoms). RESULTS: A total of 170 patients with advanced PRP were evaluated. The most prevalent symptoms were urgency (63%), urinary stream disturbance (64%), incomplete voiding (63%). Mixt urinary incontinence wasthe most commonly reported (30%). Only 11% had anormal urodynamics exam. 36% had a hidden stress incontinence. 47% had voiding symptoms related to infravesical obstruction (30%). CONCLUSIONS: Patients with advanced POP havea wide variety of urinary symptoms such as urgency, voiding dysfunction and mixt urinary incontinence. Urodynamics studies provide relevant information regardingat the bladder dysfunction that may decrease surgical outcomes.

OBJETIVO: Describir las características clínicas urinarias y los hallazgos urodinámicos en pacientes con Prolapso de Órganos Pelvianos (POP) deestadio III-IV. MATERIAL Y MÉTODOS: Realizamos un estudio descriptivo y retrospectivo evaluando a todas las pacientes con POP avanzado (estadío 3-4) derivadas para estudio urodinámico previo a tratamiento quirúrgico entre 2015 y 2017. A todas las pacientes se les realizó un interrogatorio uroginecológico, examen físico, uroflujometría yurodinamia completa. Se evaluaron características clínicas (síntomas de llenado y de vaciado, IOE con cuestionario ISIQ-SF) y urodinámicas (sensibilidad, capacidad, presencia de detrusor hiperactivo, presencia de DEI y disfunción de vaciado). RESULTADOS: Se evaluaron 170 pacientes con POP avanzado (estadio 3-4). Los síntomas más prevalentes fueron urgencia miccional (63,5%), alteración en el chorro miccional (64,7%) y sensación de vaciado incompleto (63,5%). Entre las formas de incontinencia urinaria, la IOM fue la más evidenciada (30%). Solo 11,3% tenían estudio urodinámico normal. Se evidenció 36,5% de IOE oculta y 47,6% de disfunción de vaciado principalmente asociado a obstrucción infravesical (30%). CONCLUSIONES: Los pacientes con POP avanzado presentan una gran variedad de síntomas urinarios principalmente urgencia miccional, trastornos de vaciado e IOM. El estudio urodinámico brinda información importante en la evaluación de la disfunción vesical que puede comprometer los resultados quirúrgicos.

Características clínicas urinarias y hallazgos urodinámicos en pacientes argentinas con prolapso de órganos pelvianos (pop) en estadío avanzado / Urinary clinical characteristics and urodynamic findings in Argentine patients with advanced stage pelvic organ prolapse (POP)

Objetivo: Describir las característicasclínicas urinarias y los hallazgos urodinámicos en pacientes con Prolapso de Órganos Pelvianos (POP) deestadio III-IV.Material y métodos: Realizamos un estudio descriptivo y retrospectivo evaluando a todas las pacientes conPOP avanzado (estadío 3-4) derivadas para estudiourodinámico previo a tratamiento quirúrgico entre 2015y 2017. A todas las pacientes se les realizó un interrogatorio uroginecológico, examen físico, uroflujometría yurodinamia completa. Se evaluaron características clínicas (síntomas de llenado y de vaciado, IOE con cuestionario ISIQ-SF) y urodinámicas (sensibilidad, capacidad,presencia de detrusor hiperactivo, presencia de DEI ydisfunción de vaciado).Resultados: Se evaluaron 170 pacientes con POPavanzado (estadio 3-4). Los síntomas más prevalentesfueron urgencia miccional (63,5%), alteración en el chorro miccional (64,7%) y sensación de vaciado incompleto (63,5%). Entre las formas de incontinencia urinaria, laIOM fue la más evidenciada (30%). Solo 11,3% teníanestudio urodinámico normal. Se evidenció 36,5% deIOE oculta y 47,6% de disfunción de vaciado principalmente asociado a obstrucción infravesical (30%).Conclusiones: Los pacientes con POP avanzadopresentan una gran variedad de síntomas urinarios principalmente urgencia miccional, trastornos de vaciadoe IOM. El estudio urodinámico brinda información importante en la evaluación de la disfunción vesical quepuede comprometer los resultados quirúrgicos.(AU)

Objetive: To describe urinary symptoms and urodynamic findings in patients with advancedpelvic organ prolapse.Mmaterial and methods: A descriptive and retrospective evaluation with advanced POP referred for urodynamic test before surgical repair between 2015 and2017 were included. All patients underwent a urogynexam, physical examination, uroflow and urodynamicsexam. Clinical features (filling and emptying symptoms, stress incontinence questionnaire (ISIQ-SF) and urodynamics (sensitivity, capacity and hyperactive detrusor,internal sphincter deficiency and voiding symptoms).Results: A total of 170 patients with advanced PRPwere evaluated. The most prevalent symptoms wereurgency (63%), urinary stream disturbance (64%), incomplete voiding (63%). Mixt urinary incontinence wasthe most commonly reported (30%). Only 11% had anormal urodynamics exam. 36% had a hidden stressincontinence. 47% had voiding symptoms related to infravesical obstruction (30%).Conclusions: Patients with advanced POP havea wide variety of urinary symptoms such as urgency,voiding dysfunction and mixt urinary incontinence. Urodynamics studies provide relevant information regardingat the bladder dysfunction that may decrease surgicaloutcomes.(AU)

Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome.

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

Serinol-Based Benzoic Acid Esters as New Scaffolds for the Development of Adenovirus Infection Inhibitors: Design, Synthesis, and In Vitro Biological Evaluation.

Over the years, human adenovirus (HAdV) has progressively been recognized as a significant viral pathogen. Traditionally associated with self-limited respiratory, gastrointestinal, and conjunctival infections, mainly in immunocompromised patients, HAdV is currently considered to be a pathogen presenting significant morbidity and mortality in both immunosuppressed and otherwise healthy individuals. Currently available therapeutic options are limited because of their lack of effectivity and related side effects. In this context, there is an urgent need to develop effective anti-HAdV drugs with suitable therapeutic indexes. In this work, we identified new serinol-derived benzoic acid esters as novel scaffolds for the inhibition of HAdV infections. A set of 38 compounds were designed and synthesized, and their antiviral activity and cytotoxicity were evaluated. Four compounds (13, 14, 27, and 32) inhibited HAdV infection at low micromolar concentrations (2.82-5.35 µM). Their half maximal inhibitory concentration (IC50) values were lower compared to that of cidofovir, the current drug of choice. All compounds significantly reduced the HAdV DNA replication process, while they did not block any step of the viral entry. Our results showed that compounds 13, 14, and 32 seem to be targeting the expression of the E1A early gene. Moreover, all four derivatives demonstrated a significant inhibition of human cytomegalovirus (HCMV) DNA replication. This new scaffold may represent a potential tool useful for the development of effective anti-HAdV drugs.

Vaginal Sacrospinous Ligament Fixation Using Tissue Anchoring System Versus a Traditional Technique for Women With Apical Vaginal Prolapse: A Randomized Controlled Trial.

OBJECTIVE: The aim of the study was to compare the efficacy and safety of the tissue anchoring system (TAS) kit versus the traditional technique for sacrospinous ligament fixation (SSLF) to treat apical vaginal wall prolapse. METHODS: A prospective randomized controlled multicenter study of noninferiority involving women with apical prolapse (C-point≥+1). Primary outcome is surgical success as C-point≤-4 at the 1-year follow-up. Secondary outcomes are success according to the composite criteria as C-point≤-4, Ba-point ≤0, and Bp-point ≤0; POP-Q measures of the vaginal compartments; intraoperative findings, complications; reoperation rate; hospital stay; and quality of life and sexual functioning (PISQ-12). It was estimated that 50 individuals per group would yield an 80% power for a noninferiority margin of 15%. RESULTS: Ninety-nine women were randomized: TAS (n = 55) and traditional SSLF (n = 44). The groups' preoperative data were similar. Drop-out rate was 11% for 12-month follow-up. Success rates were 90% for TAS and 80% for traditional SSLF (P = 0.0006; absolute difference, 9.8%; 90% confidence interval, -5.2 to 24.8) with the sensivity analyses per-protocol considering only the subjects that completed the 12-month follow-up and 80% versus 73%, respectively (P = 0.0048; absolute difference, 7.3%; 90% confidence interval, -9.6 to 24.2) by sensivity analyses considering the total number of participants randomized and treated with drop-out cases as failure. We detected shorter intraoperative time to dissect and reach the SSL, shorter length of hospitalization, lower rates of urinary tract infection, and lower pain scores in the first 30 days postoperative in the TAS compared with the traditional SSLF groups (P < 0.05). There was an improvement in women's quality of life that did not differ between groups. CONCLUSIONS: The modified technique of SSLF using the TAS kit is noninferior to the traditional technique for the treatment of apical compartment in 12-month follow-up.

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors.

An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC50 = 0.27 µM), significantly decreased cytotoxicity (CC50 = 156.8 µM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.

Voiding dynamics in women with urinary incontinence but without voiding symptoms.

AIMS: To describe the voiding pattern (VP) of women with urinary incontinence but without voiding symptoms and compare their clinical and urodynamic features between those voiding with and without a measurable detrusor contraction (DET-cont). METHODS: Retrospective analysis of a prospectively built database of female urodynamic studies (UDS). Women with voiding symptoms and having medical history of different factors that could alter the lower urinary tract function were excluded. All UDS were performed following the ICS guidelines. DET-cont and abdominal straining (ABD-strain) were defined as an increase ≥10 cm H2 O over the baseline for pdet and pabd at Qmax , respectively. RESULTS: A total of 186 women were included in the analysis. Mean age was 58 ± 10.7 years (24-83). Most women showed a VP with DET-cont (77.4%), with or without ABD-strain. When compared to women voiding without DET-cont, those with DET-cont were younger (P = .004), more likely to have detrusor overactivity (P = .035) and better urinary sphincter competency in the UDS (P = .018). On multivariate analysis, the presence of DET-cont was associated with age ≤50 years (P = .004) and the absence of urodynamic stress urinary incontinence (SUI) or SUI with abdominal leak point pressure ≥100 cm H2 O (P = .008). CONCLUSIONS: Most women without voiding symptoms show a VP characterized by a measurable detrusor contraction, with or without ABD-strain. The results suggest that the VP may vary independently with aging and with changes in the state of the urinary sphincter, emphasizing that for the interpretation of micturition in women different aspects must be considered.

Exploration of piperazine-derived thioureas as antibacterial and anti-inflammatory agents. In vitro evaluation against clinical isolates of colistin-resistant Acinetobacter baumannii.

A. baumannii is one of the most important multidrug-resistant microorganisms in hospital units. It is resistant to many classes of antibiotics and the development of new therapeutic strategies is necessary. The aim of this study was to evaluate the antibacterial activity of a set of piperazine-derived thioureas against 13 clinical strains of colistin-resistant A. baumannii. Six derivatives were identified to inhibit bacterial growth of 46% of the A. baumannii strains at low micromolar concentrations (Minimum Inhibitory Concentration from 1.56 to 6.25 µM). A common structural feature in most active compounds was the presence of a 3,5-bis-trifluoromethyl phenyl ring at the thiourea function. In addition, the ability of the compounds to inhibit production of nitric oxide (NO) was examined in RAW 264.7 murine macrophages, highlighting the potential of piperazine-derived thioureas as promising scaffolds for the design of new combined anti-bacterial/anti-inflammatory agents.