Nos últimos anos, nosso grupo de pesquisa vem descrevendo vários efeitos da SAA em células do sistema imune no que diz respeito à expressão e liberação de citocinas pró-inflamatórias. Neste estudo centramos nossa atenção na verificação dos efeitos da SAA sobre células mononucleares. Para isto, usamos três modelos experimentais. Em murinos, descrevemos a habilidade da SAA induzir a produção de NO por macrófagos peritoneais e, com uso de animais knockout para TLR4, sugerimos que SAA seja um ligante endógeno do TLR4. Em células mononucleares de sangue periférico humano, a SAA induz a expressão e liberação de CCL20, uma quimiocina importante na transição da resposta imune inata para adaptativa, bem como a expressão dos fatores M-CSF e VEGF. Em células THP-1, mostramos a cinética de fosforilação de proteínas tirosina quinases promovida pela SAA e comparamos com LPS, um estímulo pró-inflamatório clássico. Ainda em células THP-1 mostramos que a SAA induz a fosforilação de duas proteínas importantes no processo inflamatório por induzirem a ativação de NFκB; a p38 e a ERK1/2. Com este estudo contribuímos com o conhecimento a respeito do papel regulatório da SAA em células mononucleares. A ação da SAA sobre estas células torna-se importante, pois estas são cruciais na resposta imune inata e também atuam como células acessórias na resposta imune adaptativa. Desta forma, evidencia-se que, no processo de fase aguda, a expressão e a síntese de SAA resultam na modulação de etapas que controlam este processo e sua progressão. / In the past few years, our research group has described various effects of serum amyloid A (SAA) on cells of the immune system regarding the expression and release of pro-inflammatory cytokines. In this study we have focused on the effects of SAA on mononuclear cells. In order to do this, we have used three experimental models. In the murine experimental model, we described SAA\'s ability to induce the production of NO through peritoneal macrophages and, by using knockout animals for TLR4, we suggested that SAA is an endogenous agonist of TLR4. In mononuclear cells of peripheral human blood, SAA induced the expression and release of CCL20, an important chemokine in the transition from the innate to the adaptive immune response, as well as the expression of M-CSF and VEGF-factors. In THP-1 cells, we showed the phosporylation kinetics of tyrosine protein kinases induced by SAA, and we compared it to LPS, a classic pro-inflammatory stimulus. We also demonstrated, in THP-1 cells, that SAA induced the phosphorylation of two proteins, namely p38 and ERK1/2, that are crucial in the inflammatory process because they induce the activation of transcription factors. With this study, we contributed to the knowledge of the regulatory role of SAA in mononuclear cells. Activity of SAA on these cells is highly important, for they are crucial in the innate immune response and act as accessory cells in the adaptive immune response. Hence it is evident that, in the acute phase process, the expression and synthesis of SAA result in the modulation of the phases that control this process and its progression.

Amyloidoses comprise a group of gain-of-toxic function protein misfolding diseases, in which normally soluble proteins in their functional state undergo conformational changes into highly organized and generally intractable thread-like aggregates, termed amyloid fibrils. These structures accumulate predominantly in the extracellular space but growing evidence suggests that amyloids may start to form intracellularly. At least 26 different human proteins, intact or in fragmented form, are known to form amyloid, which is linked with many debilitating neurodegenerative diseases such as Alzheimer’s disease (AD), Creutzfeldt-Jakob disease, and transthyretin (TTR)-related amyloidosis (ATTR). In this work, we focus on ATTR, which is one of the most frequent systemic amyloid diseases. A functional link was established between hereditary ATTR, a severe and fatal disorder and the enhanced propensity of the human plasma protein transthyretin (TTR) to form aggregates, caused by single point mutations in the TTR gene. The disease is heterogeneous and clinical symptoms vary from cardiomyopathy to progressing sensorimotor polyneuropathy depending on TTR variant involved and the amyloid deposition site. Despite the fact that TTR-derived amyloid accumulates in different organs such as heart, kidney, eyes, and predominantly in the peripheral nerves of ATTR patients, the exact mechanism of the disease development is not understood. In contrast to the case of AD, it has been difficult to generate an animal model for ATTR in transgenic mice that would be useful in understanding TTR aggregation processes and the mechanisms of the associated toxicity as these mice did not develop any neuropathic phenotype besides amyloid deposits. Therefore, we created a disease-model in Drosophila due to its huge repertoire of genetic techniques and easy genotype – phenotype translation, as well as its success in modeling human neurodegeneration. We have generated transgenic flies that over-express the clinical amyloidogenic variant TTRL55P, the engineered variant TTR-A (TTRV14N ⁄ V16E), and the wild-type protein. All TTR variants were found in the secreted form in the hemolymph where misfolding occurred and depending on the pool of toxic species, the fate of the fly was decided. Within a few weeks, both mutants (but not the wild-type TTR) demonstrated a time-dependent aggregation of misfolded molecules in vivo. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability, and shortened life span. In contrast, expression of the wild-type TTR had no discernible effect on either longevity or fly behavior. In this work, we also addressed the correlation between TTR transgene dosage and thus, protein levels, with the severity of the phenotypes observed in TTR-A flies which developed a “dragged wing” phenotype. Remarkably, we established that degenerative changes such as damage to the retina strictly correlated with increased levels of mutated TTR but inversely with behavioral alterations and the dragged wing phenotype. We characterized formation of aggregates in the form of 20 nm spherules and amyloid filaments intracellularly in the thoracic adipose tissue and brain glia (both tissues that do not express the transgene). Moreover, we detected a fraction of neurotoxic TTR-A in the hemolymph of young but not old flies. We proposed that these animals counteract formation and persistence of toxic TTR-A species by removal from the circulation into intracellular compartments of glial and fat body cells and this is part of a mechanism that neutralizes the toxic effects of TTR. We validated the fly model for ATTR by applying a genetic screen during study of modifier genes. We found Serum amyloid P component (a product of the APCS gene) as a potent modifier of TTR amyloid-induced toxicity that was effective in preventing the apoptotic response in cell culture assay and capable of reducing the dragged wings when co-expressed in TTR-A flies. Finally, we optimized this fly model in order to screen for therapeutic compounds effective against ATTR. Feeding assays showed the effectiveness of several compounds among known native-state kinetic stabilizers of TTR against its aggregation. We described several early endpoints in this model, which can be used as a rapid and cost-effective method for optimizing concentrations and pre-screening of drug candidates. As the proof of principle, by feeding flies with increasing doses of diflunisal analogue (an FDA-approved Non-Steroidal Anti-Inflammatory Drug) a dose-dependent reduction of the dragged wings was observed.

INTRODUÇÃO: Sepse e choque séptico são doenças comuns em pacientes gravemente enfermos, evoluindo muitas vezes com síndrome de disfunção de múltiplos órgãos (SDMO) e morte. Este trabalho investiga a eficácia da administração precoce de dexametasona em evitar a progressão do choque séptico para SDMO e morte e o comportamento da proteína amilóide A sérica (SAA) e da proteína C-reativa (PCR) como marcadores da evolução e gravidade dos pacientes em choque séptico no período pós-operatório. MÉTODOS: Estudo prospectivo, aleatório, duplamente encoberto, realizado na Unidade de Terapia Intensiva pós-operatória do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, com 29 pacientes que no período pós-operatório evoluíram com choque séptico. Os participantes foram divididos de forma aleatória em dois grupos, de acordo com a solução administrada: dexametasona 0,2 mg/kg (grupo D) ou placebo (grupo P), repetidas a cada 36 horas. Os pacientes foram acompanhados durante sete dias de internação na UTI através do escore SOFA (Sequential Organ Failure Assessment) e dosagens séricas diárias de PCR, SAA e lactato. RESULTADOS: Os pacientes do grupo D, quando comparados aos pacientes do grupo P, permaneceram mais dias sem necessidade do uso do vasopressor (respectivamente 2,9±2,7 e 0,7±0,6, p=0,01) e mais tempo livre de ventilação mecânica (respectivamente 2,6±2,5 e 0,6±0,5, p=0,03). A mortalidade no grupo P foi de 67% (10 em 15) e no grupo D foi de 21% (3 em 14) (Risco Relativo=0,31, IC95% 0,11-0,88). Os valores de PCR e SAA apresentaram forte correlação durante o período de observação (R=0,91/p=0,002). PCR e SAA não tiveram correlação com o escore SOFA (respectivamente R=0,71/p=0,05 e R=0,52/p=0,18), nem com o lactato (p=0,88 e p=0,67). CONCLUSÕES: O tratamento precoce com dexametasona nos pacientes com choque séptico reduziu a mortalidade em 7 dias de acompanhamento. Os níveis séricos de PCR e SAA apresentaram-se elevados nos pacientes em choque séptico e tiveram forte correlação, porém não foram preditores de disfunção orgânica nem de mortalidade. / INTRODUCTION: Sepsis and septic shock are a very common condition in critically ill patients, leading to multiple organ dysfunction syndrome (MODS) and death. This study aimed at investigating the efficacy of early administration of dexamethasone in patients with septic shock in order to block the evolution to MODS and death. It also evaluated serum amyloid A protein (SAA) and C-reactive protein (CRP) as evolution and organ dysfunction markers in postoperative septic shock patients. METHODS: Prospective, randomized, double-blind study, developed in a surgical intensive care unit of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo that involved 29 patients with septic shock. All eligible patients were prospectively randomized to receive either a dose of 0.2 mg/kg of dexamethasone (group D) or placebo (group P), repeated every 36 hours intervals. Patients were monitored over a 7- day period by Sequential Organ Failure Assessment score (SOFA) and daily measurements of CRP, SAA and lactate. RESULTS: Patients treated with dexamethasone had more vasopressor therapy-free days (2.9±2.7 versus 0.7±0.6, p=0.01) and more mechanical ventilation-free days (2.6±2.5 e 0.6±0.5, p=0.03). Mortality in group P was 67% (10 in 15) and in group D was 21% (3 in 14) (Relative Risk=0.31, 95%CI 0.11 to 0.88). CRP and SAA were strongly correlated during the 7 day period of observation (R=0.91/p=0.002). CRP and SAA did not correlate with SOFA (respectively R=0.71/p=0.05 and R=0.52/p=0.18) and lactate (p=0.88 and p=0.67). CONCLUSIONS: Early treatment with dexamethasone reduced 7-day mortality in septic shock patients. CRP and SAA levels were significantly elevated in septic shock and were strongly correlated to each other, but did neither correlate with organ dysfunction nor predict mortality.

Nos últimos anos, nosso grupo de pesquisa vem descrevendo vários efeitos da SAA em células do sistema imune no que diz respeito à expressão e liberação de citocinas pró-inflamatórias. Neste estudo centramos nossa atenção na verificação dos efeitos da SAA sobre células mononucleares. Para isto, usamos três modelos experimentais. Em murinos, descrevemos a habilidade da SAA induzir a produção de NO por macrófagos peritoneais e, com uso de animais knockout para TLR4, sugerimos que SAA seja um ligante endógeno do TLR4. Em células mononucleares de sangue periférico humano, a SAA induz a expressão e liberação de CCL20, uma quimiocina importante na transição da resposta imune inata para adaptativa, bem como a expressão dos fatores M-CSF e VEGF. Em células THP-1, mostramos a cinética de fosforilação de proteínas tirosina quinases promovida pela SAA e comparamos com LPS, um estímulo pró-inflamatório clássico. Ainda em células THP-1 mostramos que a SAA induz a fosforilação de duas proteínas importantes no processo inflamatório por induzirem a ativação de NFκB; a p38 e a ERK1/2. Com este estudo contribuímos com o conhecimento a respeito do papel regulatório da SAA em células mononucleares. A ação da SAA sobre estas células torna-se importante, pois estas são cruciais na resposta imune inata e também atuam como células acessórias na resposta imune adaptativa. Desta forma, evidencia-se que, no processo de fase aguda, a expressão e a síntese de SAA resultam na modulação de etapas que controlam este processo e sua progressão. / In the past few years, our research group has described various effects of serum amyloid A (SAA) on cells of the immune system regarding the expression and release of pro-inflammatory cytokines. In this study we have focused on the effects of SAA on mononuclear cells. In order to do this, we have used three experimental models. In the murine experimental model, we described SAA\'s ability to induce the production of NO through peritoneal macrophages and, by using knockout animals for TLR4, we suggested that SAA is an endogenous agonist of TLR4. In mononuclear cells of peripheral human blood, SAA induced the expression and release of CCL20, an important chemokine in the transition from the innate to the adaptive immune response, as well as the expression of M-CSF and VEGF-factors. In THP-1 cells, we showed the phosporylation kinetics of tyrosine protein kinases induced by SAA, and we compared it to LPS, a classic pro-inflammatory stimulus. We also demonstrated, in THP-1 cells, that SAA induced the phosphorylation of two proteins, namely p38 and ERK1/2, that are crucial in the inflammatory process because they induce the activation of transcription factors. With this study, we contributed to the knowledge of the regulatory role of SAA in mononuclear cells. Activity of SAA on these cells is highly important, for they are crucial in the innate immune response and act as accessory cells in the adaptive immune response. Hence it is evident that, in the acute phase process, the expression and synthesis of SAA result in the modulation of the phases that control this process and its progression.

Linfomas pertencem a um grupo de neoplasias que têm em comum a origem em células linforreticulares, manifestando-se geralmente em tecidos linfóides. Em sua evolução, há uma reação generalizada do organismo de forma não específica contra as alterações sistêmicas que comprometem a homeostase, conhecida como resposta de fase aguda, a qual leva a uma importante alteração na síntese de proteínas pelo fígado, resultando no aumento de algumas proteínas conhecidas como proteínas de fase aguda, sendo as de maior relevância a amiloide sérica A, &alpha;-1 glicoproteína ácida e proteína C reativa. Foram objetivos deste estudo, definir o perfil eletroforético do felino com linfoma e avaliar as concentrações séricas de amilóide sérica A (ASA), &alpha;-1 glicoproteína ácida (GPA) e proteína C reativa (PCR) destes animais durante a quimioterapia, avaliando-se como possíveis indicadores de remissão de doença. Os grupos de estudo foram constituídos por 20 felinos clinicamente normais (controle) e 16 felinos com linfoma (experimental). Foram excluídos pacientes que apresentavam tratamentos prévios e/ou doenças concomitantes. A eletroforese das proteínas séricas foi realizada em tiras de acetato de celulose. Para as mensurações de ASA, GPA e PCR utilizaram-se kits comerciais, sendo as mesmas determinadas no grupo controle, uma única vez e, no grupo experimental, quando do diagnóstico e a cada 2 semanas durante 3 meses de tratamento. A análise estatística foi realizada com testes paramétricos, sendo o teste t não pareado utilizado para comparações entre os grupos controle e experimental no momento do diagnóstico e análise de variância simples (ANOVA), seguida do teste de comparações múltiplas de Tukey, para comparar o grupo experimental no diagnóstico e semanas de tratamento. Foram observadas diferenças significantes entre os grupos controle e experimental no momento do diagnóstico, com relação à GPA (p<0,0001), ASA (p=0,0028), PCR (p=0,0003), globulina (p=0,0087), relação albumina: globulinas (p<0,0001) e &alpha;-2 globulinas (p=0,0082). Quando se compararam os achados do grupo experimental no diagnóstico e nas semanas de tratamento houve diferença nos resultados referente à GPA (p=0,0021) e ASA (p=0,0053), enquanto os níveis de PCR não se alteraram significativamente (p=0,4510). Concluiu-se que os felinos com linfoma apresentaram uma expressiva resposta de fase aguda, caracterizada por aumento das concentrações séricas de &alpha;-1 glicoproteína ácida, amiloide sérica A e proteína C reativa, sendo a amilóide sérica A e &alpha;-1 glicoproteína ácida potenciais indicadores de remissão de doença naqueles pacientes que estavam com suas concentrações elevadas quando do diagnóstico. / Lymphoma belongs to a group of malignancies that have in common their origin in lymphoreticular cells, and is generally manifested in lymphoid tissues. In its evolution, there is a generalized reaction of the organism against a non-specific systemic conditions that compromises the homeostasis, known as acute phase response, which leads to a significant change in protein synthesis by the liver, resulting in an increase of some proteins known as acute phase proteins, and the most relevant are serum amyloid A, &alpha;-1 acid glycoprotein and C-reactive protein. This study was designed to define the electrophoretic profile of feline lymphoma and to evaluate serum concentrations of serum amyloid A (ASA), &alpha;-1 acid glycoprotein (GPA) and C-reactive protein (PCR) of these animals during chemotherapy, evaluated as possible indicators of disease remission. The study groups consisted of 20 clinically normal cats (control) and 16 cats with lymphoma (experimental). We excluded patients who had previous treatments and/or concomitant diseases. Electrophoresis of serum proteins was conducted on strips of cellulose acetate. For measurements of ASA, GPA and PCR we used commercial kits, which are then determined, in the control group, only once and, in the experimental group, at diagnosis and every 2 weeks during 3 months of treatment. Statistical analysis was performed with parametric tests, where unparied t test was used for comparisons between control and experimental groups at diagnosis and simple analysis of variance (ANOVA) test followed by Tukey\'s multiple comparisons to compare the experimental group in the diagnosis and weeks of treatment. There were significant differences between control and experimental groups at diagnosis of &alpha;-1 acid glycoprotein (p<0,0001), serum amyloid A (p=0,0028), C-reactive protein (p=0,0003), total globulin (p=0,0087), albumin: globulin (p<0,0001) and &alpha;-2 globulins (p=0,0082). When comparing the experimental group in the diagnosis and weeks of treatment was significant in the results of &alpha;-1 acid glycoprotein (p=0,0021) and serum amyloid A (p=0,0053), whereas C-reactive protein did not change significantly (p=0,4510). It is concluded that cats with lymphoma have an expressive acute phase response, characterized by increased in serum concentrations of serum amyloid A, &alpha;-1 acid glycoprotein and C-reactive protein, and the serum amyloid A and alpha-1 acid glycoprotein reference potential indicators of remission in those patients who were with their high concentrations at diagnosis.

This work documents the first case of idiopathic AA amyloidosis in humans caused by mutation in the promoter region of SAA1 gene. Knowledge of the mechanism of the disease may be an indication for targeted treatment in the future. Mutations in the SAA1 promoter should be considered in all cases of idiopathic forms of AA amyloidosis in which neither the immune nor the inflammatory component of the disease are clearly present.

<p>Inflammation and oxidative stress may be involved in atherogenesis. This thesis describes clinical studies of prostaglandin F_2α (PGF_2α), an inflammatory mediator, and the isoprostane 8-iso-PGF_2α, a reliable indicator of oxidative stress, and cytokine-related inflammatory mediators and indicators in healthy subjects and in a population-based cohort of Swedish men. </p><p>PGF_2α and 8-iso-PGF_2α formation in healthy subjects varied considerably between days with a mean intra-individual coefficient of variation of 41 % and 42 %, respectively. A morning urine sample reflected the basal level of 8-iso-PGF_2α formation as accurately as a 24-hour urine collection, and represents a more practical alternative to the 24-hour urine collection in clinical studies. PGF_2α formation (as measured by urinary 15-keto-dihydro-PGF_2α) was increased in patients with type 2 diabetes and in smokers independent of other cardiovascular risk factors. These results indicated an on-going cyclooxygenase (COX)-mediated inflammatory reaction related to these conditions. Further, an increased formation of isoprostanes (as measured by urinary 8-iso-PGF_2α) was found in patients with type 2 diabetes and in smokers, indicating a high level of oxidative stress in these men. The smokers had also increased levels of the cytokine interleukin-6, indicating an on-going cytokine-related inflammatory reaction. The inflammatory indicators C-reactive protein and serum amyloid A were related to overweight but not independently associated to type 2 diabetes. High levels of serum selenium in middle-aged men predicted reduced formation of PGF_2α and 8-iso-PGF_2α 27 years later.</p><p>In summary, low-grade, chronic COX-mediated and possibly cytokine-related inflammation, and oxidative stress, seem to be joint features of type 2 diabetes and smoking, two major risk factors of atherosclerosis, in elderly men. Inflammation and oxidative stress may represent a possible common pathogenetic link between established risk factors for atherosclerosis and atherogenesis.</p>

<p>Serum amyloid A protein (SAA) is an acute phase protein that has recently gained increasing interest as a potential marker for disease and treatment monitoring. We investigated SAA and CRP levels in (a) patients with various common infectious diseases (n=98), (b) patients with pyelonephritis (n=37) versus patients with cystitis (n=32), (c) healthy individuals of varying ages (n=231), (d) very immature newborn infants with or without nosocomial infections (NIs) (n=72) and (e) patients with bacterial infections treated with cefuroxime (n=81). </p><p>SAA significantly correlated with CRP in viral as well as in bacterial infections (for the total group: r²=0.757, p<0.0001) and showed a systemic inflammatory response in 90% of the patients with cystitis as compared with 23% for CRP. Equally high efficiencies (0.96 and 0.94 for SAA and CRP, respectively) were observed in discriminating between pyelonephritis and cystitis. SAA and high sensitive (hs) CRP were lower in umbilical cords (p<0.0001) and higher in elderly adults (p<0.0001-0.03) than in the other age groups; higher in immature newborn infants than in term infants; and higher in the NI group than in the non-NI group. Interindividual variabilities of the time course of the biomarkers SAA and CRP were considerable. Because of the smoothed distribution of SAA and CRP (i.e. elevations were both essentially unchanged during the first 3 days of cefuroxime treatment), these markers were not useful when deciding parenteral-oral switch of therapy, which occurred within this time period in most cases.</p><p>SAA is a sensitive systemic marker in cystitis. SAA and hsCRP in umbilical cord blood are close to the detection limit and increase with age. They increase in relation to NI in very immature newborn infants and might therefore be used in diagnosis and monitoring. Finally, SAA and CRP in adults with bacterial infections could not predict an early parenteral-oral switch of antimicrobial therapy.</p>

Inflammation and oxidative stress may be involved in atherogenesis. This thesis describes clinical studies of prostaglandin F2α (PGF2α), an inflammatory mediator, and the isoprostane 8-iso-PGF2α, a reliable indicator of oxidative stress, and cytokine-related inflammatory mediators and indicators in healthy subjects and in a population-based cohort of Swedish men. PGF2α and 8-iso-PGF2α formation in healthy subjects varied considerably between days with a mean intra-individual coefficient of variation of 41 % and 42 %, respectively. A morning urine sample reflected the basal level of 8-iso-PGF2α formation as accurately as a 24-hour urine collection, and represents a more practical alternative to the 24-hour urine collection in clinical studies. PGF2α formation (as measured by urinary 15-keto-dihydro-PGF2α) was increased in patients with type 2 diabetes and in smokers independent of other cardiovascular risk factors. These results indicated an on-going cyclooxygenase (COX)-mediated inflammatory reaction related to these conditions. Further, an increased formation of isoprostanes (as measured by urinary 8-iso-PGF2α) was found in patients with type 2 diabetes and in smokers, indicating a high level of oxidative stress in these men. The smokers had also increased levels of the cytokine interleukin-6, indicating an on-going cytokine-related inflammatory reaction. The inflammatory indicators C-reactive protein and serum amyloid A were related to overweight but not independently associated to type 2 diabetes. High levels of serum selenium in middle-aged men predicted reduced formation of PGF2α and 8-iso-PGF2α 27 years later. In summary, low-grade, chronic COX-mediated and possibly cytokine-related inflammation, and oxidative stress, seem to be joint features of type 2 diabetes and smoking, two major risk factors of atherosclerosis, in elderly men. Inflammation and oxidative stress may represent a possible common pathogenetic link between established risk factors for atherosclerosis and atherogenesis.

Serum amyloid A protein (SAA) is an acute phase protein that has recently gained increasing interest as a potential marker for disease and treatment monitoring. We investigated SAA and CRP levels in (a) patients with various common infectious diseases (n=98), (b) patients with pyelonephritis (n=37) versus patients with cystitis (n=32), (c) healthy individuals of varying ages (n=231), (d) very immature newborn infants with or without nosocomial infections (NIs) (n=72) and (e) patients with bacterial infections treated with cefuroxime (n=81). SAA significantly correlated with CRP in viral as well as in bacterial infections (for the total group: r2=0.757, p&lt;0.0001) and showed a systemic inflammatory response in 90% of the patients with cystitis as compared with 23% for CRP. Equally high efficiencies (0.96 and 0.94 for SAA and CRP, respectively) were observed in discriminating between pyelonephritis and cystitis. SAA and high sensitive (hs) CRP were lower in umbilical cords (p&lt;0.0001) and higher in elderly adults (p&lt;0.0001-0.03) than in the other age groups; higher in immature newborn infants than in term infants; and higher in the NI group than in the non-NI group. Interindividual variabilities of the time course of the biomarkers SAA and CRP were considerable. Because of the smoothed distribution of SAA and CRP (i.e. elevations were both essentially unchanged during the first 3 days of cefuroxime treatment), these markers were not useful when deciding parenteral-oral switch of therapy, which occurred within this time period in most cases. SAA is a sensitive systemic marker in cystitis. SAA and hsCRP in umbilical cord blood are close to the detection limit and increase with age. They increase in relation to NI in very immature newborn infants and might therefore be used in diagnosis and monitoring. Finally, SAA and CRP in adults with bacterial infections could not predict an early parenteral-oral switch of antimicrobial therapy.