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BACKGROUND: A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis. METHODS: Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes. RESULTS: The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1% (51 deaths) in the placebo arm and 18.5% (56 deaths) in the clarithromycin arm (P = 0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1%) compared with 15 out of 28 clarithromycin-treated patients (53.6%, P = 0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P = 0.037). The cost of hospitalization was lower after treatment with clarithromycin (P = 0.044). Serious adverse events were observed in 1.3% and 0.7% of placebo- and clarithromycin-treated patients, respectively (P = 0.502). CONCLUSIONS: Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.
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Antibacterianos/administração & dosagem , Claritromicina/administração & dosagem , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Sepse/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/economia , Claritromicina/economia , Método Duplo-Cego , Feminino , Infecções por Bactérias Gram-Negativas/mortalidade , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Estudos Prospectivos , Sepse/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
One prospective, open-label, non-randomized study was conducted in 100 patients to define the antipyretic and analgesic effect of a new intravenous formulation of 1 g of paracetamol; 71 received paracetamol for the management of fever and 29 received paracetamol for pain relief after abdominal surgery or for neoplastic pain. Serial follow-up measurements of core temperature and of pain intensity were done for 6 h. Additional rescue medications were recorded for 5 days. Blood was sampled for the measurement of free paracetamol (APAP) and of glucuronide-APAP and N-sulfate-APAP by an HPLC assay. Defervescence, defined as core temperature below or equal to 37.1°C, was achieved in 52 patients (73.2%) within a median time of 3 h. Patients failing to become afebrile with the first dose of paracetamol became afebrile when administered other agents as rescue medications. Analgesia was achieved in 25 patients (86.4%) within a median time of 2 h. Serum levels of glucuronide-APAP were greater among non-responders to paracetamol. The presented results suggest that the intravenous formulation of paracetamol is clinically effective depending on drug metabolism.
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Dor Abdominal/tratamento farmacológico , Acetaminofen/administração & dosagem , Acetaminofen/metabolismo , Febre/tratamento farmacológico , Dor Intratável/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Acetaminofen/sangue , Acetaminofen/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Febre/etiologia , Humanos , Infecções/complicações , Infusões Intravenosas , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
This study investigates the forecasting of cardiovascular mortality trends in Greece's elderly population. Utilizing mortality data from 2001 to 2020, we employ two forecasting models: the Autoregressive Integrated Moving Average (ARIMA) and Facebook's Prophet model. Our study evaluates the efficacy of these models in predicting cardiovascular mortality trends over 2020-2030. The ARIMA model showcased predictive accuracy for the general and male population within the 65-79 age group, whereas the Prophet model provided better forecasts for females in the same age bracket. Our findings emphasize the need for adaptive forecasting tools that accommodate demographic-specific characteristics and highlight the role of advanced statistical methods in health policy planning.
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Doenças Cardiovasculares , Previsões , Política de Saúde , Aprendizado de Máquina , Humanos , Grécia/epidemiologia , Idoso , Doenças Cardiovasculares/mortalidade , Masculino , Feminino , Modelos EstatísticosRESUMO
Enteroviruses and rhinoviruses (EV-RV) are small RNA viruses that usually cause the common cold and asthma exacerbations. Although EV-RV-induced acute respiratory distress syndrome (ARDS) is common in children, only scattered reports of ARDS in adults have been published. The diagnosis has been greatly facilitated by the advent of molecular techniques, namely, real-time polymerase chain reaction (RT-PCR). EV-RV can cause ARDS by stimulating a cytokine cascade. No antiviral therapy has yet been approved, and treatment is entirely supportive. Herein, we report a rare case of EV-RV infection in an afebrile adult with dyspnea that rapidly progressed to acute lung injury and ARDS. EV-RV was isolated with multiple real-time PCR in nasopharyngeal and bronchial specimens, while no other pathogen was detected. We also present an up-to-date review of relevant literature, in an attempt to stress the importance of the early identification of viral culprits, which can minimize the use of invasive diagnostic procedures and antibiotic agents.
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One recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-α) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-α, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.
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Claritromicina/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Pneumonia Associada à Ventilação Mecânica/sangue , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Sepse/sangue , Sepse/tratamento farmacológico , Apoptose/efeitos dos fármacos , Antígeno B7-2/sangue , Ligante de CD40/sangue , Método Duplo-Cego , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Current knowledge on the exact ligand causing expression of TREM-1 on neutrophils and monocytes is limited. The present study aimed at the role of underlying infection and of the causative pathogen in the expression of TREM-1 in sepsis. METHODS: Peripheral venous blood was sampled from 125 patients with sepsis and 88 with severe sepsis/septic shock. The causative pathogen was isolated in 91 patients. Patients were suffering from acute pyelonephritis, community-acquired pneumonia (CAP), intra-abdominal infections (IAIs), primary bacteremia and ventilator-associated pneumonia or hospital-acquired pneumonia (VAP/HAP). Blood monocytes and neutrophils were isolated. Flow cytometry was used to estimate the TREM-1 expression from septic patients. RESULTS: Within patients bearing intrabdominal infections, expression of TREM-1 was significantly lower on neutrophils and on monocytes at severe sepsis/shock than at sepsis. That was also the case for severe sepsis/shock developed in the field of VAP/HAP. Among patients who suffered infections by Gram-negative community-acquired pathogens or among patients who suffered polymicrobial infections, expression of TREM-1 on monocytes was significantly lower at the stage of severe sepsis/shock than at the stage of sepsis. CONCLUSIONS: Decrease of the expression of TREM-1 on the membrane of monocytes and neutrophils upon transition from sepsis to severe sepsis/septic shock depends on the underlying type of infection and the causative pathogen.
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Glicoproteínas de Membrana/análise , Monócitos/química , Monócitos/imunologia , Neutrófilos/química , Neutrófilos/imunologia , Receptores Imunológicos/análise , Sepse/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/etiologia , Índice de Gravidade de Doença , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND: Pseudomonas aeruginosa is a cause of infections of the lower respiratory tract among patients with chronic lung disorders. It is questionable whether virulence of this species may be influenced by multidrug resistance (MDR). OBJECTIVES: To define the impact of MDR in experimental lung infection. METHODS: Experimental empyema was induced in rabbits by MDR (group A, n = 16) and by susceptible isolates (group B, n = 10). Pleural fluid was sampled for quantitative culture and estimation of cell apoptosis and of tumor necrosis factor-alpha (TNFα) and malondialdehyde (MDA). Survival was recorded. Cytokine production was stimulated in U937 monocytes by samples of pleural fluid. Whole blood of rabbits was incubated with the isolates; induction of apoptosis was assessed. RESULTS: Survival of group A was prolonged compared to group B. This was accompanied by lower bacterial counts of the inoculated pathogens in pleural fluid and in the lungs of group A compared with group B. Early apoptosis of neutrophils of pleural fluid of group A was lower compared with group B. Pleural fluid concentrations of TNFα and MDA did not differ between the groups. Cytokine production by U937 monocytes after stimulation with pleural fluid was greater in group B than in group A. The susceptible isolate induced apoptosis of neutrophils in vitro at a greater rate than the MDR isolate. CONCLUSIONS: Experimental empyema by susceptible P. aeruginosa is accompanied by greater mortality compared with MDR P. aeruginosa. This phenomenon may be attributed to the different growth pattern of the pathogens or to their interaction with the innate immune system.
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Farmacorresistência Bacteriana Múltipla , Empiema/microbiologia , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Animais , Carga Bacteriana , Citocinas/biossíntese , Suscetibilidade a Doenças , Farmacorresistência Bacteriana Múltipla/fisiologia , Empiema/mortalidade , Humanos , Imunidade Inata/fisiologia , Pulmão/microbiologia , Masculino , Malondialdeído/metabolismo , Monócitos/metabolismo , Neutrófilos , Derrame Pleural/patologia , Derrame Pleural/fisiopatologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/patogenicidade , Coelhos , Especificidade da Espécie , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/metabolismo , Células U937/metabolismo , Virulência/fisiologiaRESUMO
Human coronavirus 229E (HCoV-229E) is one of the first coronavirus strains being described. It is linked to common cold symptoms in healthy adults. Younger children and the elderly are considered vulnerable to developing lower respiratory tract infections (LRTIs). In particular, immunocompromised patients have been reported with severe and life-threatening LRTIs attributed to HCoV-229E. We report for the first time a case of LRTI and acute respiratory distress syndrome developed in a healthy adult with no comorbidities and HCoV-229E strain identified as the only causative agent. A 45-year-old female with a clear medical history presented with fever, cough, and headache. Respiratory tract infection was diagnosed, and empirical antibiotics were started. Within two days, she developed bilateral pleural effusions, diffuse consolidations, and ground glass opacities involving all lung fields. She needed immediate oxygen supply, while ABGs deteriorated and chest imaging and PaO2/FiO2 indicated ARDS. Early administration of systemic corticosteroids led to gradual clinical improvement. Multiplex PCR from nasal secretions was positive only for HCoV-229E and negative for multiple other pathogens. It remains to be elucidated how an immunocompetent adult developed a life-threatening LRTI caused by a "benign considered" coronavirus strain, the HCoV-229E.
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Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFα). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the ß-lactam.
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Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Empiema Pleural/tratamento farmacológico , Empiema Pleural/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Animais , Antibacterianos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Claritromicina/administração & dosagem , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Empiema Pleural/imunologia , Humanos , Interleucina-6/biossíntese , Masculino , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/análogos & derivados , Piperacilina/administração & dosagem , Combinação Piperacilina e Tazobactam , Derrame Pleural/imunologia , Derrame Pleural/microbiologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/efeitos dos fármacos , Coelhos , Fator de Necrose Tumoral alfa/biossíntese , Células U937RESUMO
OBJECTIVES: To investigate the effect of dexamethasone on triggering receptor expressed on myeloid cells-1 (TREM-1). METHODS: Wild-type and tumor necrosis factor (TNF (-/-)) mice were pre-treated with saline, dexamethasone, or hydrocortisone and exposed to a lethal infection of Pseudomonas aeruginosa. Mortality and TREM-1 on neutrophil membranes was measured after sacrifice. U937 human monocytic cells were stimulated with lipopolysaccharide (LPS) or heat-killed P. aeruginosa without or with dexamethasone or hydrocortisone, and cell-surface TREM-1 and soluble TREM-1 (sTREM-1) were quantified. Expression of TREM-1 and sTREM-1 was also studied in LPS-stimulated U937 cells incubated in the absence or presence of TNFα or anti-TNFα antibody. RESULTS: Pre-treatment with dexamethasone, but not hydrocortisone, prolonged animal survival. Mice pre-treated with dexamethasone showed decreased expression of TREM-1 on neutrophils. In U937 cells, LPS or heat-killed P. aeruginosa induced the expression of TREM-1 and the release of sTREM-1. U937 TREM-1 and sTREM-1 were decreased upon addition of dexamethasone but not hydrocortisone. The suppressive effect of dexamethasone was enhanced in the presence of exogenous TNFα and lost in the presence of anti-TNFα antibody. In TNF (-/-) mice, dexamethasone suppression of mortality and TREM-1 neutrophil expression was lost. Gene expression of TREM-1 in U937 monocytes was decreased after treatment with dexamethasone. CONCLUSION: TREM-1/sTREM-1 is a novel site of action of dexamethasone. This action is associated with down-regulation of gene expression and is mediated by TNFα.
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OBJECTIVES: To identify the role of single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) gene in the natural course of 2009 influenza A H1N1 virus infection. METHODS: Genomic DNA was isolated from 109 patients with an H1N1 infection and from 108 healthy volunteers. SNPs of the TNF gene were assessed after electrophoresis of the digested PCR products by restriction enzymes. RESULTS: The frequency of the -238 A allele was significantly greater among patients than among controls. Viral pneumonia developed in 20 of 96 non-carriers of at least one -238 A allele (20.8%) and in seven of 13 carriers of at least one -238 A allele (53.8%, p=0.016). Logistic regression analysis showed that the most important factors associated with the development of pneumonia were the presence of an underlying disease (p=0.021, odds ratio (OR) 3.08) and the carriage of at least one -238 A allele (p=0.041, OR 3.74). Gene transcripts of the TNF gene were greater among non-carriers of the -238 A allele than among carriers of the -238 A allele. CONCLUSIONS: The -238 A SNP allele of the TNF gene imposes on the course of 2009 H1N1 virus infection and is an independent risk factor for pneumonia.
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Influenza Humana/epidemiologia , Influenza Humana/genética , Leucócitos Mononucleares/virologia , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/virologia , Leucócitos Mononucleares/metabolismo , Modelos Logísticos , Masculino , Fatores de RiscoRESUMO
We hypothesized that a factor may circulate in serum early during sepsis, modulating apoptosis of monocytes and lymphocytes. Serum was collected from 20 healthy volunteers and from 48 patients with severe sepsis/shock within 12 h from signs of the first failing organ. PBMCs were isolated from 20 healthy volunteers and incubated with collected sera. Apoptosis and expression of CD95 were determined by flow cytometry; experiments were run in the presence of caspase-8 and caspase-9 inhibitors and of CaCl(2). Activity of caspase-3 was determined in cell lysates by a chromogenic kinetic assay. Incubation with serum of patients induced apoptosis of CD4 lymphocytes and inhibited apoptosis of CD14 monocytes. This was attenuated after diluting serum or mixing with healthy serum. Activity of caspase-3 was consistent with these findings. Induced apoptosis of CD4 lymphocytes was greater among nonsurvivors, and it was inhibited in the presence of caspase inhibitors. Inhibitors did not modify the effect of patients' serum on apoptosis of CD14 monocytes. CaCl(2) reversed the inhibitory effect on apoptosis of CD14 moncytes. The above findings support the hypothesis for the existence of an early circulating factor in severe sepsis/shock, modulating apoptosis of CD4 lymphocytes and of CD14 monocytes by interaction with the two apoptotic pathways.