Gravedad de COVID-19 atribuible a obesidad según IMC y CUN-BAE / Severity of COVID-19 attributable to obesity according to BMI and CUN-BAE

Introducción La obesidad es considerada un factor de riesgo en casos graves de la COVID-19, habiendo sido analizada mediante el índice de masa corporal (IMC), estimador que no correlaciona adecuadamente con el porcentaje de grasa corporal (GC). El objetivo de este estudio ha sido analizar la fracción atribuible poblacional a la GC en formas graves de COVID-19 atendiendo al IMC y al CUN-BAE. Material y métodos Estudio multicéntrico observacional de prevalencia. Se recogió información sociodemográfica, antecedentes personales, IMC y CUN-BAE, de casos positivos SARS-CoV-2, de las provincias de León y La Rioja. Mediante modelos de regresión logística se calcularon odds ratio con sus respectivos intervalos de confianza del 95% ajustando por edad y antecedentes personales, así como la fracción atribuible poblacional a la GC. Resultados Participaron 785 pacientes, 123 (15,7%) fueron graves. Se detectaron como factores de riesgo la edad, la obesidad (tanto por IMC como por CUN-BAE) y los antecedentes personales. Un 51,6% de casos graves podrían ser atribuidos a un exceso de IMC y un 61,4% a exceso de GC estimada según CUN-BAE, observándose una mayor infraestimación del riesgo en mujeres. Conclusiones El exceso de GC es un factor de riesgo para formas graves de la COVID-19 junto con la edad avanzada y la presencia de enfermedades cardiovasculares, respiratorias crónicas u oncohematológicas. El IMC infraestima el riesgo, especialmente en mujeres, siendo el CUN-BAE el predictor seleccionado por su mejor estimación del porcentaje de GC (AU)

Introduction Obesity is considered a risk factor in severe cases of COVID-19, which has been analysed using body mass index (BMI), an estimator that does not correlate adequately with body fat (BF) percentage. The aim of this study was to analyse the population attributable fraction to BF in severe forms of COVID-19 based on BMI and CUN-BAE. Material and methods Multicentre observational prevalence study. Sociodemographic information, personal history, BMI and CUN-BAE were collected in SARS-CoV-2 positive cases from the provinces of León and La Rioja. Logistic regression models were used to calculate odds ratios with their respective 95% confidence intervals adjusting for age and personal history, as well as the population attributable fraction to BF. Results Seven hundred eighty-five patients participated, 123 (15.7%) were severe. Age, obesity (both by BMI and CUN-BAE) and personal history were detected as risk factors. 51.6% of severe cases could be attributed to excess BMI and 61.4% to excess BF estimated according to CUN-BAE, with a higher underestimation of risk in women. Conclusions Excess BF is a risk factor for severe forms of COVID-19 together with advanced age and the presence of cardiovascular, chronic respiratory or oncohematological diseases. BMI underestimates the risk especially in women, being CUN-BAE the predictor selected for its better estimation of the percentage of BF (AU)

[Severity of COVID-19 attributable to obesity according to BMI and CUN-BAE]. / Gravedad de COVID-19 atribuible a obesidad según IMC y CUN-BAE.

INTRODUCTION: Obesity is considered a risk factor in severe cases of COVID-19, which has been analysed using body mass index (BMI), an estimator that does not correlate adequately with body fat (BF) percentage. The aim of this study was to analyse the population attributable fraction to BF in severe forms of COVID-19 based on BMI and CUN-BAE. MATERIAL AND METHODS: Multicentre observational prevalence study. Sociodemographic information, personal history, BMI and CUN-BAE were collected in SARS-CoV-2 positive cases from the provinces of León and La Rioja. Logistic regression models were used to calculate odds ratios with their respective 95% confidence intervals adjusting for age and personal history, as well as the population attributable fraction to BF. RESULTS: Seven hundred eighty-five patients participated, 123 (15.7%) were severe. Age, obesity (both by BMI and CUN-BAE) and personal history were detected as risk factors. 51.6% of severe cases could be attributed to excess BMI and 61.4% to excess BF estimated according to CUN-BAE, with a higher underestimation of risk in women. CONCLUSIONS: Excess BF is a risk factor for severe forms of COVID-19 together with advanced age and the presence of cardiovascular, chronic respiratory or oncohematological diseases. BMI underestimates the risk especially in women, being CUN-BAE the predictor selected for its better estimation of the percentage of BF.

The influence of interferon ß-1b on gut microbiota composition in patients with multiple sclerosis.

INTRODUCTION: The association between gut microbiota and animal models of multiple sclerosis has been well established; however, studies in humans are scarce. METHODS: We performed a descriptive, cross-sectional study comparing the relative composition of gut microbiota in 30 patients with multiple sclerosis (15 treated with interferon ß-1b, 15 not receiving this treatment) and 14 healthy controls using next generation sequencing. RESULTS: Patients with multiple sclerosis and controls showed differences in the proportion of Euryarchaeota, Firmicutes, Proteobacteria, Actinobacteria, and Lentisphaerae phyla and in 17 bacterial species. More specifically, we found significant differences in the proportion of Firmicutes, Actinobacteria, and Lentisphaerae and 6 bacteria species between controls and untreated patients; however, these differences disappeared when compared with treated patients. Untreated patients showed a significant reduction in the proportion of Prevotella copri compared to controls, while the bacteria was significantly more abundant in patients treated with interferon ß-1b than in untreated patients, with levels resembling those observed in the healthy control group. CONCLUSION: We observed differences in gut microbiota composition between patients with multiple sclerosis and controls, and between patients treated and not treated with interferon ß-1b. In most cases, no differences were observed between treated patients and healthy controls, particularly for P. copri levels. This suggests that the clinical improvements observed in patients with multiple sclerosis receiving interferon ß-1b may result from the effect of the drug on gut microbiota. Longitudinal and functional studies are necessary to establish a causal relationship.

Composición de la microbiota intestinal en pacientes con esclerosis múltiple. Influencia del tratamiento con interferón B-1b / The influence of interferon B–1b on gut microbiota composition in patients with multiple sclerosis

Introducción. El papel de la microbiota en los modelos animales de esclerosis múltiple está bien establecido; por el contrario, los estudios en humanos son escasos.MétodosEstudio transversal descriptivo que compara la composición relativa de la microbiota intestinal en 30 pacientes con esclerosis múltiple (15 tratados con interferón β-1b, 15 sin tratamiento) y 14 controles sanos utilizando la secuenciación de última generación.ResultadosLos sujetos control y los pacientes con esclerosis múltiple presentaron diferente abundancia de los filos Euryarchaeota, Firmicutes, Proteobacteria, Actinobacteria, y Lentisphaerae y 17 especies bacterianas. Concretamente, la abundancia en Firmicutes, Actinobacteria y Lentisphaerae y 6 especies mostró diferencias al comparar los grupos control y sin tratamiento, desapareciendo esta diferencia cuando se compararon con los pacientes tratados. Se observó reducción estadísticamente significativa en la abundancia de Prevotella copri en pacientes sin tratamiento en comparación con controles, mientras que los tratados con interferón β-1b presentaron un aumento significativo frente a pacientes sin tratamiento, asemejándose al grupo de pacientes sanos control.ConclusiónLa composición de la microbiota intestinal fue diferente entre los pacientes con esclerosis múltiple y los controles, y entre los pacientes sin tratamiento y los tratados con interferón β-1b. En la mayoría de los casos, no se encontraron diferencias entre los pacientes tratados y los controles sanos, siendo especialmente evidente con P. copri. Esto podría indicar que la influencia del interferón β-1b sobre la microbiota intestinal podría subyacer en los beneficios clínicos observados en pacientes con esclerosis múltiple que siguen este tratamiento. Serán necesarios estudios longitudinales y funcionales para poder mostrar causalidad. (AU)

Introduction: The association between gut microbiota and animal models of multiple sclerosis has been well established; however, studies in humans are scarce.MethodsWe performed a descriptive, cross-sectional study comparing the relative composition of gut microbiota in 30 patients with multiple sclerosis (15 treated with interferon β–1b, 15 not receiving this treatment) and 14 healthy controls using next generation sequencing.ResultsPatients with multiple sclerosis and controls showed differences in the proportion of Euryarchaeota, Firmicutes, Proteobacteria, Actinobacteria, and Lentisphaerae phyla and in 17 bacterial species. More specifically, we found significant differences in the proportion of Firmicutes, Actinobacteria, and Lentisphaerae and 6 bacteria species between controls and untreated patients; however, these differences disappeared when compared with treated patients. Untreated patients showed a significant reduction in the proportion of Prevotella copri compared to controls, while the bacteria was significantly more abundant in patients treated with interferon β–1b than in untreated patients, with levels resembling those observed in the healthy control group.ConclusionWe observed differences in gut microbiota composition between patients with multiple sclerosis and controls, and between patients treated and not treated with interferon β–1b. In most cases, no differences were observed between treated patients and healthy controls, particularly for P. copri levels. This suggests that the clinical improvements observed in patients with multiple sclerosis receiving interferon β–1b may result from the effect of the drug on gut microbiota. Longitudinal and functional studies are necessary to establish a causal relationship. (AU)

Determinants of the current and future distribution of the West Nile virus mosquito vector Culex pipiens in Spain.

Changes in environmental conditions, whether related or not to human activities, are continuously modifying the geographic distribution of vectors, which in turn affects the dynamics and distribution of vector-borne infectious diseases. Determining the main ecological drivers of vector distribution and how predicted changes in these drivers may alter their future distributions is therefore of major importance. However, the drivers of vector populations are largely specific to each vector species and region. Here, we identify the most important human-activity-related and bioclimatic predictors affecting the current distribution and habitat suitability of the mosquito Culex pipiens and potential future changes in its distribution in Spain. We determined the niche of occurrence (NOO) of the species, which considers only those areas lying within the range of suitable environmental conditions using presence data. Although almost ubiquitous, the distribution of Cx. pipiens is mostly explained by elevation and the degree of urbanization but also, to a lesser extent, by mean temperatures during the wettest season and temperature seasonality. The combination of these predictors highlights the existence of a heterogeneous pattern of habitat suitability, with most suitable areas located in the southern and northeastern coastal areas of Spain, and unsuitable areas located at higher altitude and in colder regions. Future climatic predictions indicate a net decrease in distribution of up to 29.55%, probably due to warming and greater temperature oscillations. Despite these predicted changes in vector distribution, their effects on the incidence of infectious diseases are, however, difficult to forecast since different processes such as local adaptation to temperature, vector-pathogen interactions, and human-derived changes in landscape may play important roles in shaping the future dynamics of pathogen transmission.

Healthcare-associated pneumonia: a prospective study in Spain.

OBJECTIVE: The aim of the study was to describe the epidemiological characteristics and factors related to outcome in Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) healthcare-associated pneumonia (HCAP). METHODS: A 3-year prospective observational epidemiological case study of HCAP was conducted in seven Spanish hospitals. Microbiological and patient characteristics and outcomes were collected and classified by causative pathogen into 4 categories: "S. pneumoniae", "MRSA", "Others" and "Unknown". Patients were followed up 30 days after discharge. RESULTS: A total of 258 (84.6%) patients were enrolled (170 were men [65.9%]). Mean age was 72.4 years ± 15 years (95% CI [70.54-74.25]). The etiology of pneumonia was identified in 73 cases (28.3%): S. pneumoniae in 35 patients (13.6%), MRSA in 8 (3.1%), and other microorganisms in 30 patients (11.6%). Significant differences in rates of chronic obstructive pulmonary disease (p < 0.05), previous antibiotic treatment (p<0.05), other chronic respiratory diseases, inhaled corticosteroids (p <0.01), and lymphoma (p < 0.05) were observed among the four groups. Patients with MRSA pneumonia had received more previous antibiotic treatment (87.5%). Thirty-three (12.8%) patients died during hospitalisation; death in 27 (81.2%) was related to pneumonia. CONCLUSIONS: The etiology of HCAP was identified in only one quarter of patients, with S. pneumoniae being the most prevalent microorganism. Patients with chronic respiratory diseases more frequently presented HCAP due to MRSA than to S. pneumoniae. Death at hospital discharge was related in most cases to pneumonia.

Retinol-binding protein 4 (RBP4), a potential biomarker of frailty in HIV-infected people on stable antiretroviral therapy.

OBJECTIVES: A quantitative biomarker for identification of pre-frail and frail persons is still lacking. This study aimed to identify biomarker predictors of frailty in HIV-infected patients. METHODS: A cross-sectional study of HIV-infected patients who had been on antiretroviral therapy (ART) for at least 1 year and who presented an undetectable viral load (< 50 HIV-1 RNA copies/mL) at baseline was carried out. For each frail patient, up to four pre-frail and robust patients were randomly selected. The frailty status assessment was based on the five-item criteria described by Fried et al. Sociodemographic, anthropometric, biochemical and HIV-related characteristics were evaluated. Multiple potential biomarkers of frailty and a biological age biomarker were analysed. RESULTS: A total of 73 HIV-infected patients on ART for at least 1 year were evaluated. The patients were categorized as robust (n = 33), pre-frail (n = 32) and frail (n = 8) using the Fried criteria. All patients were on ART, with 100% undetectable viral load (< 50 copies/mL) at baseline. No significant differences in demographic, clinical or analytical characteristics were observed among patients in the different categories based on Fried criteria, with the exception of the veterans aging cohort study index (VACS). Similarly, no differences were observed in HIV-related characteristics, although nucleoside reverse transcriptase inhibitor (NRTI) use was less common in frail persons. The distribution of biomarker values varied according to frailty status, with frail persons having higher levels of interleukin (IL)-8, IL-18, CXC chemokine ligand 10 (CXCL10) and retinol-binding protein 4 (RBP4). In multivariable analysis, the assocation of frailty with RBP4 showed a tendency to statistical significance (odds ratio 1.0; 95% confidence interval 0.99-1.00; P < 0.05). CONCLUSIONS: Differential biomarker expression was present according to Fried status. Longitudinal studies will clarify the utility of these biomarkers as targets for diagnostic or therapeutic intervention.

'Candidatus Neoehrlichia mikurensis' in Europe.

'Candidatus Neoehrlichia mikurensis' is an uncultured emerging bacterium that is provisionally included in the family Anaplasmataceae. In Europe, it is transmitted by Ixodes ricinus ticks. Rodents are the reservoirs. It is widely distributed in mammals (both wild and domestic) and birds. It causes an inflammatory disease in humans with underlying diseases, but the microorganism also affects immunocompetent individuals in which asymptomatic infection has been recognized. A high degree of suspicion and the use of molecular tools are needed for the correct diagnosis. Efforts to cultivate it and to investigate its pathogenesis should be a priority.

Isolation of Rickettsia amblyommatis in HUVEC line.

Rickettsia amblyommatis, formerly named Rickettsia amblyommii and 'Candidatus Rickettsia amblyommii' is an intracellular bacterium belonging to the spotted fever group Rickettsia. It is highly prevalent in Amblyomma americanum and in other Amblyomma spp. throughout the Western Hemisphere. R. amblyommatis has been cultivated in chicken fibroblast, primary embryonated chicken eggs, Vero cells and arthropod-derived cells. Because of the affinity of rickettsiae to invade vascular endothelial cells, we tried to isolate R. amblyommatis from a nymph of Amblyomma cajennense s.l. collected in Saltillo (Coahulia, Mexico) using human umbilical vein endothelial cells (HUVEC). One tick half was analysed by ompA PCR and was found to be positive for R. amblyommatis. The other half was selected for in vitro culture of Rickettsia spp. It was triturated in 1 mL of endothelial cell growth medium with 1% antibiotic-antimycotic solution, and the homogenate was inoculated into a HUVEC line. Culture was maintained at 33°C in endothelial cell growth medium plus 2 mM l-glutamine and 2% fetal calf serum, with 5% CO2. The medium was changed weekly. Culture was checked by Gimenez stain for Rickettsia-like intracellular organisms. After 48 days of incubation, Rickettsia-like organisms were observed in HUVEC. PCR assays and sequencing of ompA gene in the culture suspension showed 100% identity with R. amblyommatis. This isolate was successfully established in HUVEC, and it has been deposited in the collection of the Center of Rickettsioses and Arthropod-Borne Diseases, Infectious Diseases Department, Hospital San Pedro-Center of Biomedical Research from La Rioja, Logroño, Spain. The HUVEC line is a useful tool for the isolation of R. amblyommatis.

IgE to α-Gal in Foresters and Forest Workers From La Rioja, North of Spain.

OBJECTIVE: To investigate the prevalence of and factors associated with the presence of α-gal-specific IgE in a risk group of foresters and forest workers from La Rioja, Spain and in a control group. METHODS: The study population comprised 169 workers and 100 individuals who did not recall having had tick bites. A questionnaire including demographic data and number of tick bites per year was completed by a physician. α-Gal sIgE was assessed using ImmunoCAP with serum samples that had been taken in 2010. In 2015, second serum specimens were taken from all but 1 of the workers, who had positive specific IgE to α-gal in 2010. These new samples were tested for IgE to the α-gal epitope and to mammalian meat. RESULTS: The prevalence of positive sIgE to α-gal was 15% in the risk population and 4% in the control population. α-Gal sIgE positivity was associated with the number of tick bites per year and with seniority. Thirteen out of 21 patients sensitized to α-gal in 2010 showed positive specific IgE to α-gal in serum samples from 2015. Eleven had specific IgE to mammalian meat, but none reported symptoms of meat allergy. CONCLUSIONS: The prevalence of α-gal sIgE antibodies in this risk population was higher than in the control group and was associated with the number of tick bites per year and with seniority. None of the workers sensitized to mammalian meat developed meat allergy, possibly owing to the low levels of sIgE to α-gal.

Dissemination and clinical implications of multidrug-resistant Klebsiella pneumoniae isolates producing OXA-48 in a Spanish hospital.

BACKGROUND: Healthcare-associated infections caused by Klebsiella pneumoniae isolates are increasing and few effective antibiotics are currently available to treat patients. AIM: To assess the epidemiology, molecular basis, clinical features, and outcomes in the acquisition and dissemination of OXA-48-producing K. pneumoniae (OXA48KP) in a tertiary Spanish hospital between October 2013 and December 2015. METHODS: Clinical, demographic, and microbiological data of patients with OXA48KP in clinical samples were collected from medical records. Carbapenemase genes were detected by polymerase chain reaction. Genetic relationships were determined by pulsed-field gel electrophoresis and multi-locus sequence typing. FINDINGS: In all, 116 episodes of OXA48KP in clinical samples were identified. The most frequent types of infection were urinary tract (N = 43, 42%), secondary bloodstream (N = 18, 17%), and surgical site infection (N = 17, 17%). More than one-quarter (28%) of infected patients died in hospital. Among infected patients (N = 90, 78%), infections were mainly classified as hospital-acquired (N = 70, 88%). A high number of OXA48KP isolates showed multidrug resistance, with highest susceptibility to colistin (86%), gentamicin (69%) and amikacin (59%). Most (87%) isolates were included in a main cluster. Seven (N = 8, 88%) isolates showed an identical allelic profile, associated with ST15. Only the isolate from cluster P8 was associated with ST29. The results confirm high dissemination of OXA48KP in our hospital due to the main clone ST15. OXA48KP infection was associated with a high mortality and was mainly hospital-acquired. CONCLUSION: This study highlights the importance of active surveillance programmes, especially those focusing on hospital readmissions in order to control the spread of carbapenemase-producing Enterobacteriaceae.

Rickettsia conorii is a potent complement activator in vivo and combined inhibition of complement and CD14 is required for attenuation of the cytokine response ex vivo.

Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii-infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co-receptor CD14 (sCD14) in plasma from R. conorii-infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii. Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood.

Detection of tick-borne Anaplasma bovis, Anaplasma phagocytophilum and Anaplasma centrale in Spain.

The genus Anaplasma (Rickettsiales: Anaplasmataceae) includes species of medical and veterinary importance. The presence of Anaplasma spp. in ticks from birds, as well as in Haemaphysalis punctata (Ixodida: Ixodidae) specimens collected from cattle and vegetation in northern Spain was investigated. A total of 336 ticks from birds [174 Ixodes frontalis (Ixodida: Ixodidae), 108 H. punctata, 34 Hyalomma marginatum (Ixodida: Ixodidae), 17 Ixodes ricinus (Ixodida: Ixodidae) and three Ixodes spp.], and 181 H. punctata specimens collected from cattle (n = 71) and vegetation (n = 110) were analysed. Anaplasma bovis was detected in five H. punctata, including two from birds (1.9%) and three from vegetation (2.7%). Four I. frontalis (2.3%) (one co-infected with 'Candidatus Midichloria mitochondrii') and one I. ricinus (5.9%) removed from birds, as well as four H. punctata (5.6%) collected from cattle showed Anaplasma phagocytophilum infection. In addition, Anaplasma centrale was found in two H. punctata, one from a cow (1.4%) and the other from vegetation (0.9%). This study represents the first evidence of the presence of A. bovis in European ticks, and reports the first detection of A. bovis and A. centrale in H. punctata, and the first finding of A. phagocytophilum and 'Ca. Midichloria mitochondrii' in I. frontalis.

Gut microbiota: a key player in health and disease. A review focused on obesity.

Gut microbiota, its evolutive dynamics and influence on host through its protective, trophic and metabolic actions, has a key role in health and opens unique opportunities for the identification of new markers of the physiopathological state of each individual. Alterations in gut microbiota composition have been associated with plenty disorders. Of interest, the vast number of studies demonstrates the role of microbiota in obesity, a serious public health problem that has reached epidemic proportions in many developed and middle-income countries. The economic and health costs of this condition and its comorbidities such as fatty liver, insulin resistance/diabetes, or cardiovascular events are considerable. Therefore, every strategy designed to reduce obesity would imply important savings. Targeting microbiota, in order to restore/modulate the microbiota composition with antibiotics, probiotics, prebiotics, or even fecal transplants, is considered as a promising strategy for the development of new solutions for the treatment of obesity. However, there is still lot to do in this field in order to identify the exact composition of microbiota in "health" and the specific mechanisms that regulate the host-microbiotal crosstalk. In addition, it is important to note that changes not only in the gut microbiota profile (abundance) but also in its metabolism and functions need to be taken into account in the context of contribution in the physiopathology of obesity and related disorders.

Concurrent interspecies and clonal dissemination of OXA-48 carbapenemase.

Several isolates of four different carbapenemase-producing Enterobacteriaceae species were recovered from a patient hospitalized for 4 months in a teaching hospital in Madrid. These species comprised seven Klebsiella pneumoniae belonging to ST15, four Escherichia coli belonging to ST2531, two Serratia marcescens and one Citrobacter freundii. This patient was the index case of a small outbreak of four patients infected and/or colonized by carbapenemase-producing K. pneumoniae. Molecular results identified the bla(OXA-48) gene in all Enterobacteriaceae isolates from the index case and in all isolates from the other three patients, suggesting intra- and interpatient dissemination. Our results highlight the great ability of OXA-48 carbapenemase to spread among different enterobacterial species by both clonal and nonclonal dissemination.

Design of clone-specific probes from genome sequences for rapid PCR-typing of outbreak pathogens.

The genome sequence of one OXA-48-producing Klebsiella pneumoniae belonging to sequence type (ST) 405, and three belonging to ST11, were used to design and test ST-specific PCR assays for typing OXA-48-producing K. pneumoniae. The approach proved to be useful for in-house development of rapid PCR typing assays for local outbreak surveillance.

Role of mitochondria in HIV infection and associated metabolic disorders: focus on nonalcoholic fatty liver disease and lipodystrophy syndrome.

Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the "Pol- γ hypothesis." HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.

Novel mechanisms of resistance to ß-lactam antibiotics in Haemophilus parainfluenzae: ß-lactamase-negative ampicillin resistance and inhibitor-resistant TEM ß-lactamases.

OBJECTIVES: To determine the mechanisms of resistance to ß-lactam antibiotics in clinical isolates of Haemophilus parainfluenzae. METHODS: Twenty clinical isolates of H. parainfluenzae with decreased susceptibility to aminopenicillins were examined and compared with a control group of 20 fully susceptible isolates. In this collection, the presence of amino acid substitutions in the transpeptidase domain of penicillin-binding protein 3 (PBP3), ß-lactamase production and the surrounding genetic regions of blaTEM genes in selected isolates were analysed. RESULTS: Of the 20 non-susceptible isolates, 8 produced TEM ß-lactamase (gBLPAR), 7 had mutations in the transpeptidase domain of the ftsI gene related to decreased susceptibility to ß-lactams (gBLNAR) and 5 had both resistance mechanisms (gBLPACR). No resistance mechanisms were identified in the susceptible control group (gBLNAS). gBLNAR isolates had MIC90 values 4- to 16-fold higher than gBLNAS isolates for ampicillin, amoxicillin/clavulanic acid, cefuroxime, cefotaxime and cefixime, and the most common PBP3 mutation was Asn526Ser. The additional Ser385Thr substitution (III-like group) may confer decreased susceptibility to cefotaxime, cefixime and aztreonam, as in Haemophilus influenzae. In two ß-lactamase-positive isolates without PBP3 mutations, the inhibitor-resistant TEM (IRT) ß-lactamases TEM-34 and the novel TEM-182 were detected and carried by a TnA transposon of the Tn2 type; both isolates had an amoxicillin/clavulanic acid MIC of ≥8 mg/L. The TnA transposons of two ß-lactamase-positive isolates (TEM-1 and TEM-182) were inserted between the tfc20 and tfc21 genes, typically associated with integrative and conjugative elements in Haemophilus spp.; the TEM-34 IRT ß-lactamase was harboured in a ∼5.5 kb plasmid. CONCLUSIONS: Clinical isolates of H. parainfluenzae express a variety of aminopenicillin resistance mechanisms, either alone or in combination, including PBP3 modifications, blaTEM-1 and IRT ß-lactamase production.