RESUMO
Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of Escherichia coli UTI, C3H/HeN mice develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by a reduction of neutrophil function within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenic E. coli (UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101-). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced function in vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Furthermore, aged immature neutrophils manifested little phagocytic activity within intratubular UPEC communities in vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens is attributable, at least in part, to local impairment of neutrophil maturation in the urinary tract (largely via cell-intrinsic AR signaling) and a kidney-specific reduction in neutrophil antimicrobial capacity.IMPORTANCEAlthough urinary tract infections (UTIs) predominantly occur in women, male UTIs carry an increased risk of morbidity and mortality. Pyelonephritis in androgen-exposed mice features robust neutrophil recruitment and abscess formation, while bacterial load remains consistently high. Here, we demonstrate that during UTI, neutrophils infiltrating the urinary tract of androgen-exposed mice exhibit reduced maturation, and those that have infiltrated the kidney have reduced phagocytic and degranulation functions, limiting their ability to effectively control infection. This work helps to elucidate mechanisms by which androgens enhance UTI susceptibility and severity, illuminating why male patients may be predisposed to severe outcomes of pyelonephritis.
Assuntos
Infecções por Escherichia coli , Pielonefrite , Infecções Urinárias , Escherichia coli Uropatogênica , Feminino , Humanos , Masculino , Animais , Camundongos , Idoso , Androgênios , Neutrófilos/patologia , Escherichia coli , Abscesso/patologia , Infecções por Escherichia coli/microbiologia , Camundongos Endogâmicos C3H , Rim/microbiologia , Infecções Urinárias/microbiologia , Pielonefrite/microbiologia , Escherichia coli Uropatogênica/genéticaRESUMO
Recent advances in preclinical modeling of urinary tract infections (UTIs) have enabled the identification of key facets of the host response that influence pathogen clearance and tissue damage. Here, we review new insights into the functions of neutrophils, macrophages, and antimicrobial peptides in innate control of uropathogens and in mammalian infection-related tissue injury and repair. We also discuss novel functions for renal epithelial cells in innate antimicrobial defense. In addition, epigenetic modifications during bacterial cystitis have been implicated in bladder remodeling, conveying susceptibility to recurrent UTI. In total, contemporary work in this arena has better defined host processes that shape UTI susceptibility and severity and might inform the development of novel preventive and therapeutic approaches for acute and recurrent UTI.
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Sistema Urinário , Animais , Humanos , Epigênese Genética , Células Epiteliais , Cinética , Macrófagos , MamíferosRESUMO
Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.
Assuntos
Neoplasias da Bexiga Urinária , Infecções Urinárias , Sistema Urinário , Feminino , Hormônios Esteroides Gonadais , Humanos , Masculino , Caracteres Sexuais , Infecções Urinárias/epidemiologiaAssuntos
Contorno Corporal , Lipectomia , Contorno Corporal/efeitos adversos , Estética , Humanos , Fenômenos Magnéticos , Músculos , Projetos PilotoRESUMO
BACKGROUND AND OBJECTIVES: To understand patterns of care and circumstances surrounding end of life in patients with intracranial gliomas. METHODS: We retrospectively analyzed end-of-life circumstances in patients with intracranial high-grade gliomas at Columbia University Irving Medical Center who died from January 2014 to February 2019, including cause of death, location of death, and implementation of comfort measures and resuscitative efforts. RESULTS: There were 152 patients (95 men, 57 women; median age at death 61.5 years, range 24-87 years) who died from January 2014 to February 2019 with adequate data surrounding end-of-life circumstances. Clinical tumor progression (n = 117, 77.0%) was the most common cause of death, with all patients transitioned to comfort measures. Other causes included, but were not limited to, infection (19, 12.5%); intratumoral hemorrhage (5, 3.3%); seizures (8, 5.3%); cerebral edema (4, 2.6%); pulmonary embolism (4, 2.6%); autonomic failure (2, 1.3%); and hemorrhagic shock (2, 1.3%). Multiple mortal events were identified in 10 (8.5%). Seventy-three patients (48.0%) died at home with hospice. Other locations were inpatient hospice (40, 26.3%); acute care hospital (34, 22.4%), including 27 (17.8%) with and 7 (4.6%) without comfort measures; skilled nursing facility (4, 3.3%), including 3 (2.0%) with and 1 (0.7%) without comfort measures; or religious facility (1, 0.7%) with comfort measures. Acute cardiac or pulmonary resuscitation was performed in 20 patients (13.2%). DISCUSSION: Clinical tumor progression was the most common (77.0%) cause of death, followed by infection (12.5%). Hospice or comfort measures were ultimately implemented in 94.7% of patients, although resuscitation was performed in 13.2%. Improved understanding of circumstances surrounding death, frequency of use of hospice services, and frequency of resuscitative efforts in patients with gliomas may allow physicians to more accurately discuss end-of-life expectations with patients and caregivers, facilitating informed care planning.
Assuntos
Glioma , Cuidados Paliativos na Terminalidade da Vida , Assistência Terminal , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Feminino , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Pseudomonas aeruginosa has four Na+/H+ antiporters that interconvert and balance Na+ and H+ gradients across the membrane. These gradients are important for bioenergetics and ionic homeostasis. To understand these transporters, we constructed four strains, each of which has only one antiporter, i.e., NhaB, NhaP, NhaP2, and Mrp. We also constructed a quadruple deletion mutant that has no Na+/H+ antiporters. Although the antiporters of P. aeruginosa have been studied previously, the strains constructed here present the opportunity to characterize their kinetic properties in their native membranes and their roles in the physiology of P. aeruginosa. The strains expressing only NhaB or Mrp, the two electrogenic antiporters, were able to grow essentially like the wild-type strain across a range of Na+ concentrations and pH values. Strains with only NhaP or NhaP2, which are electroneutral, grew more poorly at increasing Na+ concentrations, especially at high pH values, with the strain expressing NhaP being more sensitive. The strain with no Na+/H+ antiporters was extremely sensitive to the Na+ concentration and showed essentially no Na+(Li+)/H+ antiporter activity, but it retained most K+/H+ antiporter activity of the wild-type strain at pH 7.5 and approximately one-half at pH 8.5. We also used the four strains that each express one of the four antiporters to characterize the kinetic properties of each transporter. Transcriptome sequencing analysis of the quadruple deletion strain showed widespread changes, including changes in pyocyanin synthesis, biofilm formation, and nitrate and glycerol metabolism. Thus, the strains constructed for this study will open a new door to understanding the physiological roles of these proteins and their activities in P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa has four Na+/H+ antiporters that connect and interconvert its Na+ and H+ gradients. We have constructed four deletion mutants, each of which has only one of the four Na+/H+ antiporters. These strains made it possible to study the properties and physiological roles of each antiporter independently in its native membrane. Mrp and NhaB are each able to sustain growth over a wide range of pH values and Na+ concentrations, whereas the two electroneutral antiporters, NhaP and NhaP2, are most effective at low pH values. We also constructed a quadruple mutant lacking all four antiporters, in which the H+ and Na+ gradients are disconnected. This will make it possible to study the role of the two gradients independently.
Assuntos
Antiporters/genética , Antiporters/metabolismo , Proteínas de Bactérias/genética , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Sódio/metabolismo , Antiporters/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Perfilação da Expressão Gênica , Concentração de Íons de Hidrogênio , Cinética , Pseudomonas aeruginosa/química , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismoRESUMO
Platelet-like and cylindrical nanostructures from sugar-based polymers are designed to mimic the aspect ratio of bacteria and achieve uroepithelial cell binding and internalization, thereby improving their potential for local treatment of recurrent urinary tract infections. Polymer nanostructures, derived from amphiphilic block polymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline poly(l-lactide) segments, were constructed with morphologies that could be tuned to enhance uroepithelial cell binding. These nanoparticles exhibited negligible cytotoxicity, immunotoxicity, and cytokine adsorption, while also offering substantial silver cation loading capacity, extended release, and in vitro antimicrobial activity (as effective as free silver cations) against uropathogenic Escherichia coli. In comparison to spherical analogues, cylindrical and platelet-like nanostructures engaged in significantly higher association with uroepithelial cells, as measured by flow cytometry; despite their larger size, platelet-like nanostructures maintained the capacity for cell internalization. This work establishes initial evidence of degradable platelet-shaped nanostructures as versatile therapeutic carriers for treatment of epithelial infections.
Assuntos
Nanopartículas , Polímeros , Antibacterianos/farmacologia , Prata , AçúcaresRESUMO
Autologous fat grafting, first described in the 1890s, has since undergone many modifications to optimize safety and efficacy. These changes have resulted in the technique that we now consider standard of care, one that is applied to reconstruction and cosmetic enhancement of the breast and the face both independently and in conjunction with surgical treatment. There is a growing body of evidence that this application has positive outcomes for patient satisfaction, surgeon satisfaction, and overall aesthetic appearance. This article summarizes the body of literature regarding these outcomes, reviews complications of fat grafting in the face and breast, and discusses controversies including radiologic imaging changes and longevity of grafting. Level of Evidence: 4.
Assuntos
Mamoplastia , Tecido Adiposo , Autoenxertos , Mama , Humanos , Mamoplastia/efeitos adversos , Transplante Autólogo , Resultado do TratamentoRESUMO
INTRODUCTION: Clinical data on body contouring with injectable poly-L-lactic acid are sparsely reported in published literature. This study describes the lead author's clinical experience using injectable poly-L-lactic acid for body contouring in various anatomic locations. METHODS: Twenty consecutive patients undergoing body contouring treatments with poly-L-lactic acid were prospectively followed. All treatments were performed at a single clinic between February 2017 and February 2019. Treatment details such as reconstitution, injection volume and dosage were documented. Treatment response was assessed independently by patients and the treating physician. Adverse events were recorded. RESULTS: Twenty patients (85% women) received injectable poly-L-lactic acid for body contouring treatments such as buttocks volumization, cellulite and skin quality treatment. In most patients (65%), poly-L-lactic acid was administered to correct postsurgical soft tissue deformities. Overall, patients had a mean of 5.1 treatment sessions in a mean of 1.4 anatomic locations. The most commonly treated anatomic locations were buttocks (58% of treatment sessions), thighs (20%) and abdomen (9%). Dosage and injection volume varied between patients depending on anatomic location and desired outcome. Most treatment sessions (86%) resulted in improvement of the treated area. Adverse events included bruising, oedema, numbness and tenderness. Nodule formation was recorded for one patient (5%). CONCLUSION: According to the lead author's clinical experience, poly-L-lactic acid injection is well tolerated and can achieve good aesthetic outcomes when used for body contouring in appropriate patients. Preliminary data suggest that poly-L-lactic acid injection may be a viable nonsurgical technique for correcting postsurgical soft tissue deformities.
Assuntos
Contorno Corporal , Técnicas Cosméticas , Envelhecimento da Pele , Feminino , Humanos , Ácido Láctico , Masculino , Poliésteres , PolímerosRESUMO
Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen which relies on a highly adaptable metabolism to achieve broad pathogenesis. In one example of this flexibility, to catalyze the NADH:quinone oxidoreductase step of the respiratory chain, P. aeruginosa has three different enzymes: NUO, NQR and NDH2, all of which carry out the same redox function but have different energy conservation and ion transport properties. In order to better understand the roles of these enzymes, we constructed two series of mutants: (i) three single deletion mutants, each of which lacks one NADH dehydrogenase and (ii) three double deletion mutants, each of which retains only one of the three enzymes. All of the mutants grew approximately as well as wild type, when tested in rich and minimal medium and in a range of pH and [Na+] conditions, except that the strain with only NUO (ΔnqrFΔndh) has an extended lag phase. During exponential phase, the NADH dehydrogenases contribute to total wild-type activity in the following order: NQR > NDH2 > NUO. Some mutants, including the strain without NQR (ΔnqrF) had increased biofilm formation, pyocyanin production, and killed more efficiently in both macrophage and mouse infection models. Consistent with this, ΔnqrF showed increased transcription of genes involved in pyocyanin production.
Assuntos
Proteínas de Bactérias/metabolismo , Metabolismo Energético/fisiologia , NADH Desidrogenase/metabolismo , Pseudomonas aeruginosa/metabolismo , Proteínas de Bactérias/genética , NADH Desidrogenase/genética , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidade , VirulênciaRESUMO
Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis.
Assuntos
Adesinas de Escherichia coli/metabolismo , Desmogleína 2/metabolismo , Infecções por Escherichia coli/microbiologia , Escherichia coli/patogenicidade , Proteínas de Fímbrias/metabolismo , Pielonefrite/microbiologia , Adesinas de Escherichia coli/genética , Animais , Desmogleína 2/genética , Epitélio/microbiologia , Escherichia coli/genética , Feminino , Proteínas de Fímbrias/genética , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Bexiga Urinária/microbiologia , VirulênciaRESUMO
Urinary tract infections (UTIs) are generally considered a disease of women. However, UTIs affect females throughout the lifespan, and certain male populations (including infants and elderly men) are also susceptible. Epidemiologically, pyelonephritis is more common in women but carries increased morbidity when it does occur in men. Among children, high-grade vesicoureteral reflux is a primary risk factor for upper-tract UTI in both sexes. However, among young infants with UTI, girls are outnumbered by boys; risk factors include posterior urethral valves and lack of circumcision. Recent advances in mouse models of UTI reveal sex differences in innate responses to UTI, which vary somewhat depending on the system used. Moreover, male mice and androgenized female mice suffer worse outcomes in experimental pyelonephritis; evidence suggests that androgen exposure may suppress innate control of infection in the urinary tract, but additional androgen effects, as well as non-hormonal sex effects, may yet be specified. Among other intriguing directions, recent experiments raise the hypothesis that the postnatal testosterone surge that occurs in male infants may represent an additional factor driving the higher incidence of UTI in males under 6 months of age. Ongoing work in contemporary models will further illuminate sex- and sex-hormone-specific effects on UTI pathogenesis and immune responses.
Assuntos
Pielonefrite , Animais , Feminino , Humanos , Masculino , Pielonefrite/epidemiologia , Fatores de Risco , Testosterona , Infecções Urinárias/epidemiologia , Refluxo VesicoureteralRESUMO
Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ~250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization.
Assuntos
Ativinas/metabolismo , Androgênios/toxicidade , Infecções por Escherichia coli/metabolismo , Rim/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Pielonefrite/metabolismo , Testosterona/análogos & derivados , Infecções Urinárias/metabolismo , Animais , Carga Bacteriana , Citocinas/metabolismo , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Fibrose , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/microbiologia , Rim/patologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Pielonefrite/microbiologia , Pielonefrite/patologia , Testosterona/toxicidade , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia , Escherichia coli Uropatogênica/patogenicidadeRESUMO
Renal scarring after pyelonephritis is linked to long-term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti-androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post-infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFß1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)-like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFß1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non-androgenized female mice. Pharmacologic inhibition of TGFß1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFß1 signaling cascade, leading to increases in cortical populations of MSC-like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.
Assuntos
Androgênios/metabolismo , Pielonefrite/metabolismo , Pielonefrite/patologia , Fator de Crescimento Transformador beta/metabolismo , Infecções Urinárias/metabolismo , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/metabolismo , Animais , Feminino , Fibrose/metabolismo , Fibrose/microbiologia , Rim/metabolismo , Rim/microbiologia , Rim/patologia , Camundongos Endogâmicos C57BL , Pielonefrite/microbiologia , Transdução de Sinais , Testosterona/administração & dosagem , Testosterona/análogos & derivadosRESUMO
The Balance for Better campaign theme of the 2019 International Women's Day prompted a closer look at diversity within the plastic surgery specialty. Gender balance in the United States has improved through many organizational efforts and enactment of laws. Unfortunately, despite these endeavors, statistics show that men still enjoy greater financial and career success. Within the field of medicine, a similar trend has been observed. Although women constitute 50% of medical school graduates, the majority still enter fields outside of surgical subspecialties. In comparison to other surgical subspecialties, women are most represented in plastic surgery. Unfortunately, significant gender discrepancies remain in postgraduate practice including academic practice rank, societal board membership, invited speaker opportunities, and compensation, to name a few. The "leaky pipeline" of women describes the precipitous decline in the numbers of women at each step up the professional ladder. We explore the multifaceted nature of this phenomenon and highlight factors that contribute to limiting female growth within the plastic surgery profession. We also emphasize the continued growth of female plastic surgeon presence in all sectors despite these existing obstacles. We submit that continued leadership, mentorship, and sponsorship provided by both male and female physicians in the field will facilitate future leadership, advance gender parity, and cultivate a sense of belonging within the plastic surgery community, allowing brilliant minds to flourish and the profession to thrive.
Assuntos
Médicas , Procedimentos de Cirurgia Plástica , Cirurgiões , Cirurgia Plástica , Feminino , Humanos , Liderança , Masculino , Estados UnidosRESUMO
Urinary tract infections (UTIs) are among the most common microbial infections in humans and represent a substantial burden on the health care system. UTIs can be uncomplicated, as when affecting healthy individuals, or complicated, when affecting individuals with compromised urodynamics and/or host defenses, such as those with a urinary catheter. There are clear differences between uncomplicated UTI and catheter-associated UTI (CAUTI) in clinical manifestations, causative organisms, and pathophysiology. Therefore, uncomplicated UTI and CAUTI cannot be approached similarly, or the risk of complications and treatment failure may increase. It is imperative to understand the key aspects of each condition to develop successful treatment options and improve patient outcomes. Here, we will review the epidemiology, pathogen prevalence, differential mechanisms used by uropathogens, and treatment and prevention of uncomplicated UTI and CAUTI.
Assuntos
Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controle , Antibacterianos/uso terapêutico , Humanos , Imunoterapia , Imunoterapia AtivaRESUMO
Females across their lifespan and certain male populations are susceptible to urinary tract infections (UTI). The influence of female vs. male sex on UTI is incompletely understood, in part because preclinical modeling has been performed almost exclusively in female mice. Here, we employed established and new mouse models of UTI with uropathogenic Escherichia coli (UPEC) to investigate androgen influence on UTI pathogenesis. Susceptibility to UPEC UTI in both male and female hosts was potentiated with 5α-dihydrotestosterone, while males with androgen receptor deficiency and androgenized females treated with the androgen receptor antagonist enzalutamide were protected from severe pyelonephritis. In androgenized females and in males, UPEC formed dense intratubular, biofilm-like communities, some of which were sheltered from infiltrating leukocytes by the tubular epithelium and by peritubular fibrosis. Abscesses were nucleated by small intratubular collections of UPEC first visualized at five days postinfection and briskly expanded over the subsequent 24 hours. Male mice deficient in Toll-like receptor 4, which fail to contain UPEC within abscesses, were susceptible to lethal dissemination. Thus, androgen receptor activation imparts susceptibility to severe upper-tract UTI in both female and male murine hosts. Visualization of intratubular UPEC communities illuminates early renal abscess pathogenesis and the role of abscess formation in preventing dissemination of infection. Additionally, our study suggests that androgen modulation may represent a novel therapeutic route to combat recalcitrant or recurrent UTI in a range of patient populations.
Assuntos
Abscesso/patologia , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/farmacologia , Túbulos Renais/patologia , Pielonefrite/patologia , Receptores Androgênicos/metabolismo , Abscesso/microbiologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Benzamidas , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/microbiologia , Suscetibilidade a Doenças/patologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Fatores Sexuais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia , Escherichia coli Uropatogênica/patogenicidadeRESUMO
AIM: A Phase II trial of bevacizumab plus tandutinib. METHODS: We enrolled 41 recurrent, bevacizumab-naive glioblastoma patients for a trial of bevacizumab plus tandutinib. Median age was 55 and 71% were male. Treatment consisted of tandutinib 500 mg two-times a day (b.i.d.) and bevacizumab 10 mg/kg every 2 weeks starting day 15. Of 37 (90%) evaluable, nine (24%) had partial response. RESULTS & CONCLUSION: Median overall and progression-free survival was 11 and 4.1 months; progression-free survival at 6 months was 23%. All patients suffered treatment-related toxicities; common grade ≥3 toxicities were hypertension (17.1%), muscle weakness (17.1%), lymphopenia (14.6%) and hypophosphatemia (9.8%). Four of six with grade ≥3 tandutinib-related myasthenic-like muscle weakness had electromyography-proven neuromuscular junction pathology. Tandutinib with bevacizumab was as effective but more toxic than bevacizumab monotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Quinazolinas/efeitos adversosRESUMO
Bacterial programmed cell death and quorum sensing are direct examples of prokaryote group behaviors, wherein cells coordinate their actions to function cooperatively like one organism for the benefit of the whole culture. We demonstrate here that 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO), a Pseudomonas aeruginosa quorum-sensing-regulated low-molecular-weight excreted molecule, triggers autolysis by self-perturbing the electron transfer reactions of the cytochrome bc1 complex. HQNO induces specific self-poisoning by disrupting the flow of electrons through the respiratory chain at the cytochrome bc1 complex, causing a leak of reducing equivalents to O2 whereby electrons that would normally be passed to cytochrome c are donated directly to O2. The subsequent mass production of reactive oxygen species (ROS) reduces membrane potential and disrupts membrane integrity, causing bacterial cell autolysis and DNA release. DNA subsequently promotes biofilm formation and increases antibiotic tolerance to beta-lactams, suggesting that HQNO-dependent cell autolysis is advantageous to the bacterial populations. These data identify both a new programmed cell death system and a novel role for HQNO as a critical inducer of biofilm formation and antibiotic tolerance. This newly identified pathway suggests intriguing mechanistic similarities with the initial mitochondrial-mediated steps of eukaryotic apoptosis.