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BACKGROUND: C. auris has become a growing concern worldwide due to increases in incidence of colonization and reports of invasive infections. There are limited data on clinical factors associated with poor outcomes in patients with C. auris bloodstream infection (BSI). METHODS: We assembled a multicenter retrospective cohort of patients with C. auris BSI from two geographics areas in US healthcare settings. We collected data on demographic, clinical, and microbiologic characteristics to describe the cohort and constructed multivariate logistic regression models to understand risk factors for two clinical outcomes, all-cause mortality during facility admission, and blood culture clearance. RESULTS: Our cohort consisted of 187 patients with C. auris BSI (56.1% male, 55.6% age >65 years); 54.6% died by facility discharge and 66.9% (of 142 with available data) experienced blood culture clearance. Pitt bacteremia score at infection onset was associated with mortality (odds-ratio [95% confidence interval]: 1.19 [1.01,1.40] per 1-point increase). Hemodialysis was associated with a reduced odds of microbiologic clearance (0.15 [0.05,0.43]) and with mortality (3.08 [1.27,7.50]). CONCLUSIONS: The Pitt bacteremia score at the onset of C. auris BSI may be a useful tool in identifying patients at risk for mortality. Targeted infection prevention practices in patients receiving hemodialysis may be useful to limit poor outcomes.
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Pseudomonas aeruginosa harboring Verona Integron-encoded metallo-ß-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant P. aeruginosa. Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated (n = 15/21; 71.4%); 47.6% (n = 10/21) received renal replacement therapy at the time of index culture. Respiratory (n = 20/39; 51.3%) or bloodstream (n = 13/39; 33.3%) were the most common sources. Most infections (n = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried blaVIM-2 chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated.
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Antibacterianos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , beta-Lactamases , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Gestão de Antimicrobianos , Compostos Azabicíclicos/uso terapêutico , Aztreonam/uso terapêutico , Aztreonam/farmacologia , beta-Lactamases/genética , Carbapenêmicos/uso terapêutico , Carbapenêmicos/farmacologia , Ceftazidima/uso terapêutico , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Integrons/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Estudos RetrospectivosRESUMO
OBJECTIVES: Despite the clinical use of dignity therapy (DT) to enhance end-of-life experiences and promote an increased sense of meaning and purpose, little is known about the cost in practice settings. The aim is to examine the costs of implementing DT, including transcriptions, editing of legacy document, and dignity-therapists' time for interviews/patient's validation. METHODS: Analysis of a prior six-site, randomized controlled trial with a stepped-wedge design and chaplains or nurses delivering the DT. RESULTS: The mean cost per transcript was $84.30 (SD = 24.0), and the mean time required for transcription was 52.3 minutes (SD = 14.7). Chaplain interviews were more expensive and longer than nurse interviews. The mean cost and time required for transcription varied across the study sites. The typical total cost for each DT protocol was $331-$356. SIGNIFICANCE OF RESULTS: DT implementation costs varied by provider type and study site. The study's findings will be useful for translating DT in clinical practice and future research.
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The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.
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Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiologia , Humanos , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , ObesidadeRESUMO
BACKGROUND: Candida auris is an emerging nosocomial pathogen worldwide. However, there has been little published on the management of C. auris in solid organ transplant recipients. METHODS: A single-center, retrospective cohort study was conducted to evaluate C. auris bloodstream infections in solid organ transplant recipients between January 2020 and December 2021. Patient-related and outcomes data were extracted from electronic medical records. RESULTS: Of the 42 patients identified with C. auris bloodstream infections, five were in solid organ transplant recipients (1 heart, 3 liver, and 1 combined liver-kidney). The median time to fungemia from hospital admission was 43 days, and the median time to fungemia from transplant was 18 days. All patients received micafungin as initial treatment, at a median of 6 hours from pathogen detection. Four patients achieved blood clearance, two patients had persistent fungemia, and two patients developed secondary complications from hematogenous spread. One patient died, resulting in a mortality rate of 20%. CONCLUSIONS: Solid organ transplant recipients are at high risk for developing C. auris bloodstream infections. In order to prevent graft loss and mortality, best practices for the management of C.auris should include rapid screening, diagnosis, and treatment. While echinocandins are considered first-line, antifungal selection should be based on susceptibilities and site of infection. Data to support routine use of combination therapy are lacking, however there may be a role for refractory cases. Prevention efforts against C. auris infection are especially important given the lack of effective decolonization strategies. For transplant recipients, hospitals should seek opportunities to restore patients' gut microbiome by curtailing unnecessary hospital procedures and inappropriate antimicrobial use. Further research and national guidelines are needed to better direct stewardship in this field.
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Fungemia , Transplante de Órgãos , Antifúngicos/uso terapêutico , Candida , Candida auris , Candidíase Invasiva , Equinocandinas/uso terapêutico , Fungemia/tratamento farmacológico , Humanos , Micafungina , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos , TransplantadosRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing. Nowadays, very few drugs effectively reduce AD symptoms and thus, a better understanding of its pathophysiology is vital to design new effective schemes. Presymptomatic neuronal damage caused by the accumulation of Amyloid ß peptide and Tau protein abnormalities remains a challenge, despite recent efforts in drug development. Importantly, therapeutic targets, biomarkers, and diagnostic techniques have emerged to detect and treat AD. Of note, the compromised blood-brain barrier (BBB) and peripheral inflammation in AD are becoming more evident, being harmful factors that contribute to the development of the disease. Perspectives from different pre-clinical and clinical studies link peripheral inflammation with the onset and progression of AD. This review aims to analyze the main factors and the contribution of impaired BBB in AD development. Additionally, we describe the potential therapeutic strategies using stem cells for AD treatment.
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Doença de Alzheimer , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Humanos , Inflamação/metabolismo , Células-Tronco/metabolismoRESUMO
Sucrose consumption impairs behavioral and cognitive functions that correlate with decreased neurogenesis in animal models. When consumed during early adolescence, this disaccharide promotes anxious and depressive behaviors, along with a reduction in the generation of new neurons in the dentate gyrus of the hippocampus. Data concerning sucrose consumption during late adolescence are lacking, and the effect of sucrose intake on the ventral dentate gyrus of the hippocampus (which modulates anxiety and depression) remains elusive. Here, we tested whether sucrose intake during late adolescence causes anxiety or impaired neurogenesis in the ventral dentate gyrus. Rats did not display anxiety-like behaviors neither at the light−dark box test nor at the open field exploration. However, there was a significant increase in proliferative cells in the subgranular zone of the ventral dentate gyrus in rats exposed to sucrose (p < 0.05). This increased proliferation corresponded to neural stem cells (Radial Type 1 cells) in the group exposed to sucrose until adulthood but was not present in rats exposed to sucrose only during late adolescence. Remarkably, the phosphorylation of ERK1/2 kinases was increased in the hippocampi of rats exposed to sucrose only during late adolescence, suggesting that the increased proliferation in this group could be mediated by the MAPK pathway. On the other hand, although no differences were found in the number of immature granular neurons, we observed more immature granular neurons with impaired dendritic orientation in both groups exposed to sucrose. Finally, GAD65/67 and BCL2 levels did not change between groups, suggesting an unaltered hippocampal GABAergic system and similar apoptosis, respectively. This information provides the first piece of evidence of how sucrose intake, starting in late adolescence, impacts ventral dentate gyrus neurogenesis and contributes to a better understanding of the effects of this carbohydrate on the brain at postnatal stages.
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Giro Denteado , Células-Tronco Neurais , Ratos , Animais , Giro Denteado/metabolismo , Sacarose/metabolismo , Neurogênese/fisiologia , Células-Tronco Neurais/metabolismo , AnsiedadeRESUMO
427 women were included in this observational cohort study to determine the rate of exclusive (EB), mixed (MB) and artificial breastfeeding (AB) and the personal reasons and social factors influencing this decision. An initial survey was conducted within the first 36 h postpartum and a second wave was carried out 3 months after delivery. 55.74% (238) of the patients intended to EB, 32.55% (139) AB and 11.71% (50) MB. After 3 months, a high percentage in group EB (75.23%) maintained EB. The main reason for switching to AB was the absence of milk or weight loss of the newborn. In conclusion, EB is the preferred form for feeding newborns. When these women returned to their workplace, most of them wanted to continue with EB. Women with higher academic degrees chose more often EB.IMPACT STATEMENTWhat is already known on this subject? The benefits of exclusive breastfeeding are well known. However, in modern western societies, it is not easy to combine breastfeeding with day-to-day activity. Work activity, age or previous parity are some of the factors that may influence the election of the type of lactation.What do the results of this study add? Exclusive breastfeeding is the preferred method for feeding newborns immediately postpartum and 3 months later. Work activity does not seem to influence or to switch the choice. However, the level of education could be a determinant of adherence to exclusive breastfeeding.What are the implications of these findings for clinical practice and/or further research? Assessing the factors that favour adherence to exclusive breastfeeding might be a useful tool to its promotion. This study warrants further multivariate analyses on the same topic and additional studies in other social contexts.
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Aleitamento Materno , Lactação , Feminino , Humanos , Lactente , Recém-Nascido , Estilo de Vida , Mães , Período Pós-Parto , Gravidez , Local de TrabalhoRESUMO
BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aß) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aß neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aß rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1-42 (Aß1-42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aß rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot. RESULTS: We observed that the i.c.v injection of Aß decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aß-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aß rats, which was prevented by the APN treatment. CONCLUSION: The present study describes the olfactory impairment of Aß treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aß1-42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.
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Adiponectina/farmacologia , Doença de Alzheimer , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos do Olfato , Peptídeos beta-Amiloides/toxicidade , Animais , Modelos Animais de Doenças , Injeções Intraventriculares , Masculino , Transtornos do Olfato/etiologia , Ratos , Ratos WistarRESUMO
The process of freezing cells or tissues and depositing them in liquid nitrogen at -196 °C is called cryopreservation. Sub-zero temperature is not a physiological condition for cells and water ice crystals represent the main problem since they induce cell death, principally in large cells like oocytes, which have a meiotic spindle that degenerates during this process. Significantly, cryopreservation represents an option for fertility preservation in patients who develop gonadal failure for any condition and those who want to freeze their germ cells for later use. The possibility of freezing sperm, oocytes, and embryos has been available for a long time, and in 1983 the first birth with thawed oocytes was achieved. From the mid-2000s forward, the use of egg vitrification through intracytoplasmic sperm injection has improved pregnancy rates. Births using assisted reproductive technologies (ART) have some adverse conditions and events. These risks could be associated with ART procedures or related to infertility. Cryopreservation generates changes in the epigenome of gametes and embryos, given that ART occurs when the epigenome is most vulnerable. Furthermore, cryoprotective agents induce alterations in the integrity of germ cells and embryos. Notably, cryopreservation extensively affects cell viability, generates proteomic profile changes, compromises crucial cellular functions, and alters sperm motility. This technique has been widely employed since the 1980s and there is a lack of knowledge about molecular changes. The emerging view is that molecular changes are associated with cryopreservation, affecting metabolism, cytoarchitecture, calcium homeostasis, epigenetic state, and cell survival, which compromise the fertilization in ART.
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Cálcio/metabolismo , Criopreservação/normas , Embrião de Mamíferos/citologia , Epigênese Genética , Células Germinativas/citologia , Infertilidade/terapia , Proteoma/metabolismo , Sobrevivência Celular , Crioprotetores/química , Feminino , Preservação da Fertilidade/normas , Fertilização in vitro , Células Germinativas/metabolismo , Humanos , Infertilidade/metabolismo , Infertilidade/patologia , Masculino , Oócitos/citologia , Oócitos/metabolismo , Gravidez , Espermatozoides/citologia , Espermatozoides/metabolismoRESUMO
We describe an outbreak caused by Serratia marcescens carrying blaKPC-3 that was sourced to a long-term care facility in Florida, USA. Whole-genome sequencing and plasmid profiling showed involvement of 3 clonal lineages of S. marcescens and 2 blaKPC-3-carrying plasmids. Determining the resistance mechanism is critical for timely implementation of infection control measures.
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Surtos de Doenças , Infecções por Serratia/epidemiologia , Serratia marcescens , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Feminino , Florida/epidemiologia , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Casas de Saúde , Plasmídeos/genética , Serratia marcescens/genética , Adulto Jovem , beta-Lactamases/genéticaRESUMO
Type 2 diabetes (T2D) is associated with cognitive decline and dementia. Both neurodegenerative conditions are characterized by olfactory dysfunction (OD) which is also observed in diabetic patients. Diabetes and neurodegeneration display altered miRNAs expression; therefore, the study of miRNAs in the diabetic olfactory system is important in order to know the mechanisms involved in neurodegeneration induced by T2D. In this work we evaluated the expression of miRs206, 451, 146a and 34a in the olfactory bulb (OB) of T2D rats and its association with OD. T2D induction was performed by administering streptozotocin to neonatal rats. The olfactory function was evaluated after reaching the adulthood by employing the buried pellet and social recognition tests. After 18 weeks, animals were sacrificed to determinate miRNAs and protein expression in the OB. T2D animals showed a significant increase in the latency to find the odor stimulus in the buried pellet test and a significant reduction in the interest to investigate the novel juvenile subjects in the social recognition test, indicating OD. In miRNAs analysis we observed a significant increase of miR-146a expression in the OB of T2D rats when compared to controls. This increase in miR-146a correlated with the overexpression of IL-1ß in the OB of T2D rats. The present results showed that OD in T2D rats is associated with IL-1ß mediated-inflammation and miR-146a overexpression, suggesting that high levels of IL-1ß could trigger miR-146a upregulation as a negative feedback of the inflammatory response in the OB of T2D rats.
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Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Inflamação/fisiopatologia , MicroRNAs/metabolismo , Transtornos do Olfato/fisiopatologia , Bulbo Olfatório/metabolismo , Animais , Inflamação/epidemiologia , Interleucina-1beta/metabolismo , Masculino , Transtornos do Olfato/epidemiologia , Ratos WistarRESUMO
BACKGROUND: Vancomycin-resistant enterococci are an important cause of healthcare-associated infections and are inherently resistant to many commonly used antibiotics. Linezolid is the only drug currently approved by the US Food and Drug Administration to treat vancomycin-resistant enterococci; however, resistance to this antibiotic appears to be increasing. Although outbreaks of linezolid- and vancomycin-resistant Enterococcus faecium (LR-VRE) in solid organ transplant recipients remain uncommon, they represent a major challenge for infection control and hospital epidemiology. METHODS: We describe a cluster of 4 LR-VRE infections among a group of liver and multivisceral transplant recipients in a single intensive care unit. Failure of treatment with linezolid in 2 cases led to a review of standard clinical laboratory methods for susceptibility determination. Testing by alternative methods including whole genome sequencing (WGS) and a comprehensive outbreak investigation including sampling of staff members and surfaces was performed. RESULTS: Review of laboratory testing methods revealed a limitation in the VITEK 2 system with regard to reporting resistance to linezolid. Linezolid resistance in all cases was confirmed by E-test method. The use of WGS identified a resistant subpopulation with the G2376C mutation in the 23S ribosomal RNA. Sampling of staff members' dominant hands as well as sampling of surfaces in the unit identified no contaminated sources for transmission. CONCLUSIONS: This cluster of LR-VRE in transplant recipients highlights the possible shortcomings of standard microbiology laboratory methods and underscores the importance of WGS to identify resistance mechanisms that can inform patient care, as well as infection control and antibiotic stewardship measures.
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Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Enterococcus faecium/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Linezolida/farmacologia , Transplantados , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Idoso , Gestão de Antimicrobianos , Gerenciamento Clínico , Surtos de Doenças , Enterococcus faecium/genética , Enterococcus faecium/isolamento & purificação , Infecções por Bactérias Gram-Positivas/epidemiologia , Humanos , Controle de Infecções/métodos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Mutação Puntual , RNA Ribossômico 23S/genética , Análise de Sequência de DNA , Enterococos Resistentes à Vancomicina/genética , Enterococos Resistentes à Vancomicina/isolamento & purificação , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Neurosyphilis is an infection of the central nervous system, caused by Treponema pallidum, a spirochete capable of infecting almost any organ or tissue in the body causing neurological complications due to the infection. This disease is a tertiary manifestation of syphilis. The first-line treatment for neurosyphilis is aqueous crystalline penicillin. However, in cases such as penicillin allergy, other regimes of antibiotic therapy can be used. OBJECTIVES: To assess the clinical effectiveness and safety of antibiotic therapy for adults with neurosyphilis. SEARCH METHODS: We searched the Cochrane Library, CENTRAL, MEDLINE, Embase, LILACS, World Health Organization International Clinical Trials Registry Platform and Opengrey up to April 2019. We also searched proceedings of eight congresses to a maximum of 10 years, and we contacted trial authors for additional information. SELECTION CRITERIA: We included randomised clinical trials that included men and women, regardless of age, with definitive diagnoses of neurosyphilis, including HIV-seropositive patients. We compared any antibiotic regime (concentration, dose, frequency, duration), compared to any other antibiotic regime for the treatment for neurosyphilis in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, extracted data, and evaluated risk of bias. We resolved disagreements by involving a third review author. For dichotomous data (serological cure, clinical cure, adverse events), we presented results as summary risk ratios (RR) with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We identified one trial, with 36 participantsâ diagnosed âwith syphilis and HIV. The participants were mainly men, with a median age of 34 years. This trial, âfunded by a pharmaceutical company, compared ceftriaxone in 18 participants (2 g daily for 10 days), with penicillin G, also in 18 participants (4 million/Units (MU)/intravenous (IV) every 4 hours for 10 days). The trial reported incomplete and inconclusive results. Three of 18 (16%) participants receiving ceftriaxone versus 2 of 18 (11%) receiving penicillin G achieved serological cure (RR 1.50; 95% CI: 0.28 to 7.93; 1 trial, 36 participants very low-quality evidence); and 8 of 18 (44%) participants receiving ceftriaxone versus 2 of 18 (18%) participants receiving penicillin G achieved clinical cure (RR 4.00; 95% CI: 0.98 to 16.30; 1 trial, 36 participants very low-quality evidence). Although more participants who received ceftriaxone achieved serological and clinical cure compared to those who received penicillin G, the evidence from this trial was insufficient to determine whether there was a difference between treatment with ceftriaxone or penicillin G.In this trial, the authors reported what would usually be adverse events as symptoms and signs in the follow-up of participants. Furthermore, this trial did not evaluate recurrence of neurosyphilis, time to recovery nor quality of life. We judged risk of bias in this clinical trial to be unclear for random sequence generation, allocation, âand blinding of participants, and high for incomplete outcome data, potential conflicts of interest (funding bias), and other bias, due to the lack of a sample size calculation. We rated the quality of evidence as very low. AUTHORS' CONCLUSIONS: Due to low quality and insufficient evidence, it was not possible to determine whether there was a difference between treatment with ceftriaxone or Penicillin G. Also, the benefits to people without HIV and neurosyphilis are unknown, as is the ceftriaxone safety profile.Therefore, these results should be interpreted with caution. This conclusion does not mean that antibiotics should not be used for treating this clinical entity. This Cochrane Review has identified the need of adequately powered trials, which should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations, conducted and reported as recommended by the CONSORT statement. Furthermore, the outcomes should be based on patients' perspectives taking into account Patient-Centered Outcomes Research Institute (PCORI) recommendations.
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Antibacterianos/uso terapêutico , Neurossífilis/tratamento farmacológico , Adulto , Ceftriaxona/uso terapêutico , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
GAS1 is a pleiotropic protein that has been investigated because of its ability to induce cell proliferation, cell arrest, and apoptosis, depending on the cellular or the physiological context in which it is expressed. At this point, we have information about the molecular mechanisms by which GAS1 induces proliferation and apoptosis; but very few studies have been focused on elucidating the mechanisms by which GAS1 induces cell arrest. With the aim of expanding our knowledge on this subject, we first focused our research on finding proteins that were preferentially expressed in cells arrested by serum deprivation. By using a proteomics approach and mass spectrometry analysis, we identified 17 proteins in the 2-DE protein profile of serum deprived NIH3T3 cells. Among them, Annexin A1 (Anxa1), Annexin A2 (Anxa2), dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B), and Eukaryotic translation initiation factor 3, F (eIf3f) were upregulated at transcriptional the level in proliferative NIH3T3 cells. Moreover, we demonstrated that Anxa1, Anxa2, and Dyrk1b are upregulated at both the transcriptional and translational levels by the overexpression of GAS1. Thus, our results suggest that the upregulation of Anxa1, Anxa2, and Dyrk1b could be related to the ability of GAS1 to induce cell arrest and maintain cell viability. Finally, we provided further evidence showing that GAS1 through Dyrk 1B leads not only to the arrest of NIH3T3 cells but also maintains cell viability.
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Anexina A1/genética , Anexina A2/genética , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Fator de Iniciação 3 em Eucariotos/genética , Proteínas Ligadas por GPI/genética , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Células NIH 3T3 , Ativação Transcricional , Quinases DyrkRESUMO
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) may be associated with accelerated aging. Telomere shortening is a biomarker of aging. Cross-sectional studies describe shorter telomeres in COPD compared with matched controls. No studies have described telomere length trajectory and its relationship with COPD progression. We investigated telomere shortening over time and its relationship to clinical and lung function parameters in a COPD cohort and smoker controls without COPD. METHODS: At baseline leukocyte telomere length was measured by qPCR in 121 smokers with COPD and 121 without COPD matched by age (T/S0). The measurements were repeated in 70 of those patients with COPD and 73 non-COPD smokers after 3 years of follow up (T/S3). RESULTS: At initial measurement, telomeres were shorter in COPD patients when compared to smoker controls (T/S = 0.68 ± 0.25 vs. 0.88 ± 0.52, p = 0.003) independent from age and sex. During the follow-up period, we observed an accelerated telomere shortening in individuals with COPD in contrast to smoker controls (T/S0 = 0.66 ± 0.21 vs. T/S3 = 0.46 ± 0.16, p < 0.001, for the patients with COPD and T/S0 = 0.83 ± 0.56 vs. T/S3 = 0.74 ± 0.52, p = 0.023 for controls; GLIM, p = 0.001). This shortening was inversely related to the baseline telomere length (r = -0.49, p < 0.001). No significant relationship was found between the rate of change in telomere length and change in lung function in the patients with COPD (p > 0.05). CONCLUSIONS: Compared with smokers, patients with COPD have accelerated telomere shortening and this rate of attrition depends on baseline telomere length. Furthermore, the telomere length and its rate of shortening did not relate to clinical and lung function parameters changes over 3 years of follow-up.
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Senilidade Prematura/genética , Envelhecimento/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória/estatística & dados numéricos , Fumar/genética , Encurtamento do Telômero/genética , Telômero/genética , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Índice de Gravidade de Doença , Espanha/epidemiologiaRESUMO
Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation.
Assuntos
Produtos Biológicos/farmacologia , Metilação de DNA/efeitos dos fármacos , Genes Supressores de Tumor , Neoplasias/genética , Proteínas Supressoras de Tumor/genética , Animais , Citidina/farmacologia , Citidina/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polifenóis/farmacologia , Vitaminas/farmacologiaRESUMO
BACKGROUND: Dual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway. Downregulation of the dual specificity phosphatase 2 (DUSP2) has been reported in cancer. Epigenetic silencing of tumor suppressor genes by abnormal promoter methylation is a frequent mechanism in oncogenesis. It has been shown that the epigenetic factor CTCF is involved in the regulation of tumor suppressor genes. METHODS: We analyzed the promoter hypermethylation of DUSP2 in human cancer, including primary Merkel cell carcinoma by bisulfite restriction analysis and pyrosequencing. Moreover we analyzed the impact of a DNA methyltransferase inhibitor (5-Aza-dC) and CTCF on the epigenetic regulation of DUSP2 by qRT-PCR, promoter assay, chromatin immuno-precipitation and methylation analysis. RESULTS: Here we report a significant tumor-specific hypermethylation of DUSP2 in primary Merkel cell carcinoma (p = 0.05). An increase in methylation of DUSP2 was also found in 17 out of 24 (71%) cancer cell lines, including skin and lung cancer. Treatment of cancer cells with 5-Aza-dC induced DUSP2 expression by its promoter demethylation, Additionally we observed that CTCF induces DUSP2 expression in cell lines that exhibit silencing of DUSP2. This reactivation was accompanied by increased CTCF binding and demethylation of the DUSP2 promoter. CONCLUSIONS: Our data show that aberrant epigenetic inactivation of DUSP2 occurs in carcinogenesis and that CTCF is involved in the epigenetic regulation of DUSP2 expression.