Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Infection ; 47(5): 817-825, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31093923

RESUMO

PURPOSE: NTM are ubiquitous bacteria that can cause colonisation and infection in immunocompetent and compromised hosts. The aim of this study was to elucidate the epidemiology of infection or colonisation with NTM for the metropolitan region of Frankfurt, Germany. METHODS: All patients from whom NTM were isolated within the period from 2006 to 2016 were included in this retrospective analysis. Patient data were retrieved using the local patient data management system. Different groups were formed according to clinical manifestations, underlying diseases and mycobacterial species. They were compared in regard to mortality, duration of infection/colonisation and their geographical origins. RESULTS: A total of 297 patients with a median of 28 new patients each year were included. Most patients suffered from lung infection or colonisation (72.7%, n = 216), followed by disseminated mycobacteriosis (12.5%, n = 37). The majority were HIV-positive, suffering from malignoma or cystic fibrosis (29.3%, n = 87, 16.2%, n = 48, and 13.8%, n = 41, respectively). 17.2% of patients showed no predisposing condition (n = 51). Mycobacterium avium complex (MAC) species were most frequently isolated (40.7%, n = 121). Infection/colonisation was longest in CF patients (median of 1094 days). The mortality was highest in malignoma patients (52.4%), while CF patients had the lowest overall mortality rate (5.3%). But mortality analysis showed non-significant results within different mycobacterial species and clinical manifestations. CONCLUSION: NTM remain rare but underestimated pathogens in lung and disseminated disease. MAC were the species most frequently isolated. Depending on species and underlying predispositions, the duration of infection/colonisation can be unexpectedly long.

2.
J Acquir Immune Defic Syndr ; 80(3): 292-300, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531492

RESUMO

BACKGROUND: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. METHODS: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. RESULTS: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm. DISCUSSION: Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Relação CD4-CD8 , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Contagem de Linfócitos , Adolescente , Adulto , Estudos Transversais , Feminino , HIV-1 , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Carga Viral/efeitos dos fármacos , Adulto Jovem
3.
Zentralbl Chir ; 2018 Nov 23.
Artigo em Alemão | MEDLINE | ID: mdl-30469159

RESUMO

Prolonged air leak is one of the most common postoperative complications in thoracic surgery. For elective partial lung resections, postoperative air leak lasting longer than 5 - 7 days is arbitrarily defined as prolonged. There are several predictive factors for the development of prolonged air leak that can be subdivided as either preoperative, such as obstructive pulmonary disease, or intraoperative risk factors, such as pleural adhesions or fused fissures. The treatment of postoperative prolonged air leak is performed on an individual basis for each patient and may vary considerably. Four major treatment options can be varied in sequence and use: intensified conservative therapy, installation of sclerosing agents or autologous blood, endoscopic procedures and surgical revision. Prevention, detection and treatment of postoperative prolonged air leak are common aspects of thoracic surgery with high clinical relevance. In contrast to standardised procedures in risk identification and diagnostic work-up, the treatment of prolonged air leak is performed on an individual basis and requires a great deal of surgical expertise. For effective targeted therapy, it seems advisable to agree on a specific standardised therapy sequence within a clinic.

4.
Hepatology ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30298608

RESUMO

BACKGROUND: The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with HIV is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment trial (START) for liver fibrosis using the AST to platelet ratio index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed antiretroviral therapy (ART) on liver fibrosis progression. DESIGN AND INTERVENTION: ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrolment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI>0.5 or FIB-4>1.45), significant fibrosis (APRI>1.5 or FIB-4>3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. RESULTS: Of the 4684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4580 participants (2273 immediate treatment; 2307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651 and 5.3% had HIV RNA≤200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR]=0.66; 95% confidence interval [CI]=0.57-0.78; p<0.001), and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; p<0.001). CONCLUSIONS: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis. This article is protected by copyright. All rights reserved.

5.
AIDS ; 32(16): 2405-2416, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30134296

RESUMO

OBJECTIVES: To describe changes in the prevalence of comorbidities and risk factors among HIV-positive individuals in the EuroSIDA study. DESIGN: Comparison of two cross-sectional cohorts of HIV-positive adults under active follow-up in 2006 and 2014. METHODS: Baseline demographics and prevalence of comorbidities were described. Factors associated with the prevalence of chronic kidney disease (CKD) and cardiovascular disease (CVD) were assessed by logistic regression modelling using generalized estimating equations. RESULTS: Nine thousand, seven hundred and ninety-eight individuals were under active follow-up in EuroSIDA during 2006 and 12 882 during 2014. Compared with study participants in 2006, those in 2014 were older [median age 48.6 years (IQR 40.3-55.1) vs. 43.1 years (37.2-50.0) in 2006] and had higher prevalence of hypertension (59.6 vs. 47% in 2006), diabetes (6.3 vs. 5.4%), CKD (6.9 vs. 4.1%) and CVD (5.0 vs. 3.7%). Individuals in the 2014 cohort had higher odds for CKD (unadjusted OR 2.62, 95% CI 2.30-2.99, P < 0.0001) and CVD (OR 1.88, CI 1.68-2.10, P < 0.0001), but after multivariable adjustment for age group, comorbidities and other factors, year of cohort was no longer significantly associated with the odds of CKD [adjusted OR (aOR) 0.97, CI 0.52-1.82, P = 0.92) or of CVD (aOR 0.94, CI 0.54-1.63, P = 0.82). CONCLUSION: Between 2006 and 2014, the population aged and experienced an overall higher prevalence of non-AIDS comorbidities, including CKD and CVD. The increase in CVD could be explained by the aging population, and the increase in CKD by aging and changes in other factors. Treatment strategies balancing HIV outcomes with long-term management of comorbidities remain a priority.

6.
Clin Infect Dis ; 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29912307

RESUMO

Background: Both immediate or deferred switching from a PI/r to DTG may improve lipid profile. Methods: NEAT022 is a European, open label, randomized, trial. HIV-infected adults ≥ 50 years or with a Framingham score ≥10% were eligible if HIV RNA < 50 copies/mL. Patients were randomized to switch the PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D) . Week 96 end-points were: proportion of patients with HIV RNA < 50 copies/ml, percentage change of lipid fractions and adverse events. Results: 415 patients were randomized: 205 to DTG-I and 210 to continue PI/r plus a deferred switch (DTG-D) at week 48 . The primary objective of non-inferiority at week 48 was met. At week 96, treatment success rate was 92.2 % in DTG-I arm and 87% in DTG-D arm (difference 5.2%, 95% CI -0.6 to 11). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AE´s or treatment modifying AE´s. Total cholesterol and other lipid fractions (except HDL) significantly (p<0.001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV patients ≥ 50 years old or with a Framingham score ≥10% was highly efficacious, well tolerated and improved lipid profile.

7.
J Periodontol ; 89(8): 966-972, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29742276

RESUMO

BACKGROUND: To assess the association between HLA-B57.01 (Human leukocyte antigen) and clinical parameters of chronic periodontitis in people living with HIV (PLWHIV). METHODS: All patients were recruited from the HIVCENTER at the University Hospital Frankfurt during April 2014 and July 2015. Periodontal examination included Periodontal Screening Index (PSI), Gingivalindex (GI), Bleeding on Probing Index (BOP), Periodontal Probing Depth (PD), Clinical Attachment Level (CAL) and DMF-T Score (decayed, missing, filled teeth). Associations among periodontitis, HLA-system and additional risk factors in PLWHIV were evaluated in multivariate analyses. RESULTS: One hundred PLWHIV were enrolled. Forty-five patients were naive, meaning that these patients never took antiretroviral (ARV) drugs before, 55 patients treated with combined antiretroviral therapy (cART). Nineteen patients presented a positive HLA-B 57.01 status. PLWHIV who were carriers of HLA-B 57.01 had significantly lower PSI-scores (Grade 3 or higher; 0/19 [0%] versus 16/41 [39%] versus 17/40 [42%]; p = < 0.001), GI-scores (Grade 2 or higher; 0/19 [0%] versus 19/41 [46%] versus 28/40 [70%]; p = < 0.001) and BOP-Scores (2/19 [1%] versus 38/41 [92%] versus 40/40 [100%]; p = < 0.001) in comparison to naive PLWHIV and PLWHIV receiving cART, who were both not carriers of HLA-B 57.01. A lower value of PSI-, GI- and BOP-Score is associated with improved periodontal health. The adjusted odds ratio (OR) of periodontitis was decreased in patients who were carriers of HLA-B 57.01 by measurement of PSI-Score (OR = 0.006, 95% confidence interval (CI) = 0.001 to 0.026), GI-Score (OR = 0.018, 95% confidence interval (CI) = 0.003 to 0.104) and BOP-Score (OR = 0.003, 95% confidence interval (CI) = < 0.001 to 0.011). CONCLUSIONS: HLA-B 57.01 is an independent resistance indicator for generalized periodontitis in PLWHIV with respect to established cofactors.

9.
Dtsch Med Wochenschr ; 143(8): e59-e67, 2018 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-29237206

RESUMO

BACKGROUND: Drug supply bottleneck is a worldwide challenge, e. g. the antibiotics Piperacillin/Tazobactam shortage in 2016/2017. The efficacy of an appropriate replacement management was evaluated at the University Hospital Frankfurt (UHF). METHODS: The Antibiotic-Stewardship (ABS)-Team at UHF decreed a restriction of PIP/TAZ and provided alternative antibiotic therapy recommendations during the shortage period. Consequences of this intervention on antibiotic consumption and overall costs were investigated. RESULTS: Over 12-weeks, PIP/TAZ-mean application rate was reduced by 71 % and was predominantly used to treat hospital acquired pneumonia (62 %), febrile neutropenian children (12 %), followed by other indications (< 10 %, each). Alternative substances' use increased (Ceftazidim + 229 %, Imipenem/Cilastatin + 18 %, Meropenem + 27 %, Ceftriaxon + 26 %, Levofloxacin + 11 %, Ciprofloxacin + 14 %, Ampicillin/Sulbactam + 83 %), however the overall antibiotic consumption declined by -5.8 % (cost savings: 13 %). Simultaneously, additional personnel costs have been noted (+ 4300 €). The evidence rate of bloodstream infections with resistant bacteria and detection of Clostridium-difficile-toxin were both not significantly elevated, compared to windows just ahead, after and one year before intervention period. CONCLUSION: Drug shortages challenge hospital antibiotic-stewardship programs by enforced use of broad spectrum-antibiotics, endanger patient safety and require rational replacement strategies, following infectious diseases- and microbiological outlines. Whilst personnel expenditures are higher, antimicrobial-stewardship interventions may successfully contribute to prevent additional medication costs.


Assuntos
Antibacterianos/provisão & distribução , Gestão de Antimicrobianos , Ácido Penicilânico/análogos & derivados , Antibacterianos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Hospitais , Humanos , Ácido Penicilânico/provisão & distribução , Ácido Penicilânico/uso terapêutico , Piperacilina/provisão & distribução , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Pneumonia Bacteriana/tratamento farmacológico , Guias de Prática Clínica como Assunto
10.
AIDS Res Hum Retroviruses ; 34(4): 365-374, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29262692

RESUMO

The analysis of patient derived HIV neutralizing antibodies (nAbs) and their target epitopes in the viral envelope (Env) protein provides important basic information for vaccine design. In this study we optimized an epitope, EC26-2A4, that is targeted by neutralizing antibodies from an elite controller (EC26) and localizes in the membrane-proximal external region from the gp41 transmembrane protein. Due to its overlap with the epitope of the first generation broadly neutralizing monoclonal Ab (mAb) 2F5 associated with autoreactivity, we first defined the minimal core epitope reacting with antibodies from EC26 plasma, but not with mAb 2F5. The optimized minimal epitope, EC26-2A4ΔM, was able to induce neutralizing antibodies in vaccinated mice. We further analyzed the frequency of antibodies against the EC26-2A4ΔM peptide in HIV-positive patient sera from a treated cohort and an untreated long-term nonprogressor (LTNP) cohort. Interestingly, 27% of the LTNP sera reacted with the peptide, whereas only 9% showed reactivity in the treated cohort. Although there was no association between the presence of antibodies against the EC26-2A4ΔM epitope and viral load or CD4 count in these patients, the CD4 nadir in the treated cohort was higher in patients positive for EC26-2A4ΔM antibodies, in particular in patients having such antibodies at an early and a late timepoint after infection.

13.
BMC Infect Dis ; 17(1): 450, 2017 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-28651522

RESUMO

BACKGROUND: Pyogenic liver abscesses (PLA) remain a significant clinical problem. Unfortunately, little is known about current bacterial susceptibility profiles and the incidence of multidrug resistant organisms (MDROs) causing PLA in Western countries. Yet, this crucial information is pivotal to guide empirical antibiotic therapy. Aim of this study was to provide detailed characteristics of PLA with a special focus on underlying bacterial pathogens and their susceptibility to antibiotics. METHODS: A retrospective study of patients diagnosed with PLA from 2009 to 2015 in a large tertiary reference center in Germany was performed in order to characterize PLA and antimicrobial susceptibility profiles of causative bacterial species. RESULTS: Overall, 86 patients were included. The most common causes of PLA were bile duct stenosis/obstruction (31.4%) and leakage of biliary anastomosis (15.1%). Frequent predisposing diseases were malignancies (34.9%), diabetes (24.4%) and the presence of liver cirrhosis (16.3%). Of note, Enterococcus spp. were the most frequently cultured bacterial isolates (28.9%), and in 1/3 of cases vancomycin resistance was observed. In addition, a relevant frequency of gram-negative MDROs was identified. In particular, an alarming 10% and 20% of gram-negative bacteria were resistant to carbapenems and tigecycline, respectively. Of note, MDRO status did not predict ICU stay or survival in multivariate regression analysis. The mortality rate in our series was 16.3%. CONCLUSION: Our study demonstrates an as yet underreported role of Enterococcus spp., often associated with vancomycin resistance, as well as of gram-negative MDROs causing PLA.


Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Abscesso Hepático Piogênico/microbiologia , Idoso , Carbapenêmicos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/fisiologia , Enterococcus/isolamento & purificação , Feminino , Alemanha , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Abscesso Hepático Piogênico/etiologia , Abscesso Hepático Piogênico/terapia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Minociclina/análogos & derivados , Minociclina/farmacologia , Estudos Retrospectivos , Tigeciclina , Resultado do Tratamento , Resistência a Vancomicina/efeitos dos fármacos
14.
BMC Infect Dis ; 17(1): 206, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28288577

RESUMO

BACKGROUND: Routes of transmission of multidrug-resistant gram-negative organisms (MDRGN) are not completely understood. Since sexual transmission of MDRGN might represent a potential mode that has not been noticed so far, this study evaluated transmission of MDRGN in HIV positive men. METHODS: Between November 2014 and March 2016, we retrospectively investigated the MDRGN prevalence in rectal swabs of n = 109 males tested positive for HIV (HP). These findings were compared to the MDRGN prevalence in n = 109 rectal swabs in age-matched males tested negative for HIV (HN) within the same period. According to the infection control protocol of University Hospital Frankfurt, Germany (UHF), patients admitted to intensive/intermediate care units have to be screened for MDRGN on day of admittance. Patients without HIV testing or MDRGN screening were excluded. RESULTS: MDRGN prevalence in rectal swabs was significantly higher (p = 0.002) in male HP (23.9%; 95% confidence interval 16.2-32.9%) than in age-matched male HN (8.3%; 3.8-15.1%). In total, 35 MDRGN species were detected. The most frequent MDRGN species was Escherichia coli with resistance due to ESBL expression and additional resistance to fluoroquinolones with n = 25/35 (71.4%; 53.7-85.4%). Thereof, n = 19/26 (73.1%; 52.2-88.4%) were detected in HP and n = 6/9 (66.7%; 29.9-92.5%) in HN, respectively. CONCLUSIONS: Prevalence of MDRGN is significantly higher in male HIV positive than in male HIV negative individuals. This might indicate sexual transmission of MDRGN within the male HIV positive population. As treatment options in case of MRGN infections are limited, prevention of MDRGN transmission is strongly emphasized.


Assuntos
Farmacorresistência Bacteriana Múltipla , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por HIV/epidemiologia , Infecções por HIV/microbiologia , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Alemanha/epidemiologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Humanos , Controle de Infecções , Masculino , Pessoa de Meia-Idade , Prevalência , Reto/microbiologia , Estudos Retrospectivos
15.
BMC Infect Dis ; 16(1): 654, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27825316

RESUMO

BACKGROUND: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children. METHODS: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen. RESULTS: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1-10.1), CD4 cell count 297 cells/mm3 (98-639), and HIV-RNA 5.2 log10copies/mL (4.7-5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5-10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4-23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2-54.8) versus 19.4 % (15.9-23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82-0.95; P < 0.001). CONCLUSIONS: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral/efeitos dos fármacos
16.
Open Biol ; 6(11)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27881736

RESUMO

The host immune system offers a hostile environment with antimicrobials and reactive oxygen species (ROS) that are detrimental to bacterial pathogens, forcing them to adapt and evolve for survival. However, the contribution of oxidative stress to pathogen evolution remains elusive. Using an experimental evolution strategy, we show that exposure of the opportunistic pathogen Pseudomonas aeruginosa to sub-lethal hydrogen peroxide (H2O2) levels over 120 generations led to the emergence of pro-biofilm rough small colony variants (RSCVs), which could be abrogated by l-glutathione antioxidants. Comparative genomic analysis of the RSCVs revealed that mutations in the wspF gene, which encodes for a repressor of WspR diguanylate cyclase (DGC), were responsible for increased intracellular cyclic-di-GMP content and production of Psl exopolysaccharide. Psl provides the first line of defence against ROS and macrophages, ensuring the survival fitness of RSCVs over wild-type P. aeruginosa Our study demonstrated that ROS is an essential driving force for the selection of pro-biofilm forming pathogenic variants. Understanding the fundamental mechanism of these genotypic and phenotypic adaptations will improve treatment strategies for combating chronic infections.


Assuntos
GMP Cíclico/análogos & derivados , Peróxido de Hidrogênio/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Evolução Biológica , GMP Cíclico/metabolismo , Regulação Bacteriana da Expressão Gênica , Glutationa/farmacologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo
17.
Med Microbiol Immunol ; 205(6): 575-583, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27469377

RESUMO

There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV-1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over time impaired HIV-1 suppression in CSF.


Assuntos
Viroses do Sistema Nervoso Central/tratamento farmacológico , Viroses do Sistema Nervoso Central/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/fisiologia , Replicação Viral , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto Jovem
19.
Clin Infect Dis ; 62(12): 1571-1577, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27025828

RESUMO

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.


Assuntos
Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Adolescente , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
AIDS Res Hum Retroviruses ; 32(6): 579-87, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26751176

RESUMO

HIV long-term nonprogressors (LTNPs) maintaining high CD4(+) T-cell counts without antiretroviral therapy (ART) are divided into elite controllers (ECs) with undetectable and viremic controllers (VCs) with low viral loads. Little is known about the long-term changes of T-cell subsets and inflammation patterns in ECs versus VCs. The aim of the study was to explore the long-term evolution of CD4(+) T-cell levels in LTNPs and to analyze cytokine profiles in ECs versus VCs. Nineteen ECs and 15 VCs were enrolled from the natural virus controller cohort (NaViC). T-cell counts were monitored over years, the mean annual change was calculated, and plasma concentrations of 25 cytokines were evaluated using a multiplex bead array. While absolute numbers of T cells did not differ between ECs and VCs over time, we observed a significant decrease of CD4(+) T-cell percentages in VCs, but not in ECs (median [interquartile range]: ECs: 37% [28-41] vs. VCs: 29% [25-34]; p = .02). ECs had lower levels of macrophage inflammatory protein-1ß (MIP-1ß, p = .003), interferon γ-induced protein-10 (IP-10, p = .03), and monokine induced by interferon-γ (MIG, p = .02). CD4(+) T-cell percentages inversely correlated with MIP 1-ß (r = -0.42, p = .017) and IP-10 (r = -0.77, p < .0001). A subtle decline of CD4(+) T-cell percentages could be observed in VCs, but not in ECs, which was associated with higher plasma levels of proinflammatory cytokines. Hence, even low levels of HIV replication might go along with a progressive decline in CD4(+) T-cell counts in LTNPs.


Assuntos
Citocinas/sangue , Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA