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Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.

Purpose To determine the sensitivity of the 18F-radiolabelled dihydroethidine analogue ([18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures The sensitivity of [18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [18F]DHE (50–150 kBq.min−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results [18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion [18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.

Clinically available imaging tools for diagnosing infections rely on structural changes in the affected tissues. They therefore lack specificity and cannot differentiate between oncologic, inflammatory and infectious processes. We have developed 2-deoxy-2-[18F]fluoro-d-sorbitol (18F-FDS) as an imaging agent to visualize infections caused by Enterobacterales, which represent the largest group of bacterial pathogens in humans and are responsible for severe infections, often resulting in sepsis or death. A clinical study in 26 prospectively enrolled patients demonstrated that 18F-FDS positron emission tomography (PET) was safe, and could detect and localize infections due to drug-susceptible or multi-drug-resistant Enterobacterales strains as well as differentiate them from other pathologies (sterile inflammation or cancer). 18F-FDS is cleared almost exclusively through renal filtration and has also shown potential as a PET agent for functional renal imaging. Since most PET radionuclides have a short half-life, maximal clinical impact will require fast, on-demand synthesis with limited infrastructure and personnel. To meet this demand, we developed a kit-based solid phase method that uses commercially and widely available 2-deoxy-2-[18F]fluoro-d-glucose as the precursor and allows 18F-FDS to be produced and purified in one step at room temperature. The 18F-FDS kit consists of a solid-phase extraction cartridge packed with solid supported borohydride (MP-borohydride), which can be attached to a second cartridge to reduce pH. We evaluated the effects of different solid supported borohydride reagents, cartridge size, starting radioactivity, volumes and flow rates in the radiochemical yield and purity. The optimized protocol can be completed in 70% radiochemical yield and >90% radiochemical purity. Mota et al. describe a protocol for the rapid, room-temperature, kit-based synthesis of 18F-FDS for positron emission tomography imaging.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]3+ and [Re═O]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aβ1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.

Pretomanid is a nitroimidazole antimicrobial with potent activity against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) for the treatment of multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of pretomanid into privileged sites such as the brain, as well as the efficacy of the BPaL regimen for TB meningitis, remain unknown. Importantly, there are no well accepted treatments for TB meningitis due to MDR strains, resulting in high mortality. We developed a new synthetic route to obtain 18F-pretomanid (chemically identical to the parent antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure intralesional pretomanid concentration-time profiles in the central nervous system (CNS). Dynamic PET in mouse and rabbit models of TB meningitis demonstrated excellent CNS penetration of pretomanid. Antibiotic levels were spatially compartmentalized and cerebrospinal fluid (CSF) levels did not correlate with those in the brain parenchyma. Post-mortem autoradiography and mass spectrometry corroborated the imaging findings. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis was substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrated excellent penetration of pretomanid into the CNS, with significantly higher levels in the brain parenchyma versus CSF (P

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize

Introdução: O internamento do recém-nascido implica uma fonte contínua de stress para os pais. Ao adotar medidas de apoio individualizadas e em parceria com os pais, o enfermeiro potencia o desenvolvimento harmonioso e competente do recém-nascido, favorecendo o desenvolvimento das competências parentais. Materiais e métodos: Estudo quantitativo, tipo descritivo simples, com recurso à aplicação da Escala de Apoio dos Enfermeiros aos Pais, cuja validação de conteúdo para a população portuguesa, foi efetuada por Sandra Valadão em 2012. A amostra foi constituída por 100 pais de recém-nascidos internados numa Unidade de Cuidados Intensivos Neonatais de um Hospital do Norte de Portugal. Resultados: A avaliação média dos quatro domínios apresentou um resultado de 4,67. Dos quatro domínios que constituem a Escala, os pais demonstraram maior satisfação relativamente ao domínio instrumental com uma média de 4,75, seguido do domínio apreciativo com 4,73. Os domínios emocional e informativo, obtiveram resultados mais baixos, de 4,59e 4,58 respetivamente. Discussão: Os resultados obtidos vão de encontro aos resultados de Valadão de 2012, em que o domínio instrumental também foi o que obteve um maior resultado, seguido dos domínios cognitivo/apreciativo, emocional e informativo e também estão em concordância com o estudo de Tran et al. de 2009. No entanto, o domínio emocional foi o que obteve menor resultado, não indo ao encontro dos nossos resultados. Conclusão: A satisfação dos pais em relação aos cuidados de enfermagem prestados aos seus filhos é elevada, existindo áreas passíveis de melhoria de que são exemplo a comunicação estabelecida e a informação fornecida.

(1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure The work was partially supported by the European Union’s Horizon 2020 research and innovation programme under the Marie-Skłodowska-Curie Actions grant agreement N◦ 813440 (ORBITAL-Ocular Research by Integrated Training and Learning) SI

Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their ex...

There is still a paucity of information on how in vitro release profiles from drug-loaded contact lenses (CLs) recorded in 3D printed eye models correlate with in vivo profiles. This work aims to evaluate the release profiles of two drug-loaded CLs in a 3D in vitro eye blink model and compare the obtained results with the release in a vial and the drug levels in tear fluid previously obtained from an animal in vivo study. In vitro release in the eye model was tested at two different flow rates (5 and 10 µL/min) and a blink speed of 1 blink/10 s. Model CLs were loaded with two different drugs, hydrophilic pravastatin and hydrophobic resveratrol. The release of both drugs was more sustained and lower in the 3D eye model compared to the in vitro release in vials. Interestingly, both drugs presented similar release patterns in the eye model and in vivo, although the total amount of drugs released in the eye model was significantly lower, especially for resveratrol. Strong correlations between percentages of pravastatin released in the eye model and in vivo were found. These findings suggest that the current 3D printed eye blink model could be a useful tool to measure the release of ophthalmic drugs from medicated CLs. Nevertheless, physiological parameters such as the composition of the tear fluid and eyeball surface, tear flow rates, and temperature should be optimized in further studies Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This project was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions grant agreement N° 813440 (ORBITAL–Ocular Research by Integrated Training And Learning). The work was also partially supported by MCIN [PID 2020-113881RB-I00/AEI/10.13039/501100011033], Spain, Xunta de Galicia [ED431C 2020/17], FEDER, and the Hong Kong Special Administrative Region Government and InnoHK. M. Vivero-Lopez acknowledges Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria) for a predoctoral research fellowship [ED481A-2019/120]. P. Garg acknowledges the support of the Collaborative Research and Training Experience (CREATE) Program awarded by the Natural Sciences and Engineering Research Council of Canada (NSERC) SI

Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.

Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF‐B growth factor is involved in cell survival, anti‐apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin‐1 (NRP1). We employed surface plasmon resonance technology and X‐ray crystallography to analyse the molecular basis of the interaction between VEGF‐B and the b1 domain of NRP1, and developed VEGF‐B C‐terminus derived peptides to be used as chemical tools for studying VEGF‐B ‐ NRP1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF‐B‐derived peptides containing a C‐terminal arginine show potent binding to NRP1‐b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP1 demonstrated that VEGF‐B peptides bind at the canonical C‐terminal arginine binding site. VEGF‐B C‐terminus imparts higher affinity for NRP1 than the corresponding VEGF‐A165 region. This tight binding may impact on the activity and selectivity of the full‐length protein. The VEGF‐B167 derived peptides were more effective than VEGF‐A165 peptides in blocking functional phosphorylation events. Blockers of VEGF‐B function have potential applications in diabetes and non‐alcoholic fatty liver disease., VEGF‐B binds to the b1 domain of neuropilin‐1. VEGF‐B‐derived peptides show potent binding to neuropilin‐1 (KD=0.13 to 9.55 μM) and inhibit binding of VEGF‐A in a cell‐based assay (IC50=0.3 to 2.0 μM). Peptide lipidation increased binding and plasma half‐lives.

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

In the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males compared with females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8-10 weeks of age) were inoculated intranasally with 105TCID50of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developing more extensive pneumonia as noted on chest computed tomography, and recovering more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including IFNβ and TNFα, were comparable between the sexes. However, during the recovery phase of infection, females mounted two-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole inactivated SARS-CoV-2 and mutant S-RBDs, as well as virus neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population.ImportanceMen experience more severe outcomes from COVID-19 than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human clinical isolate of SARS-CoV-2. After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in females than male hamsters. Greater lung pathology during the acute phase combined with reduced antiviral antibody responses during the recovery phase of infection in males than females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.One Sentence SummaryFollowing SARS-CoV-2 infection, male hamsters experience worse clinical disease and have lower antiviral antibody responses than females.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]

Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for (76)Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 hours. After the intravenous injection, (76)Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography and same section hematoxylin / eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multi-compartment and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.

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To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.

Background Pretomanid is used in combination with bedaquiline and linezolid (BPaL regimen) in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, the penetration of pretomanid in privileged sites remain unknown. Antimicrobial pharmacokinetic (PK) parameters are traditionally derived from clinical samples (blood and cerebrospinal fluid), which may not accurately represent the intralesional tissue PK, affected by drug properties, vascular supply, barrier permeability, and the microenvironment. Methods We developed 18F-pretomanid (chemically identical to pretomanid) for in vivo multi-compartment PK by positron emission tomography (PET). Dynamic 18F-pretomanid PET was used to obtain cross species pretomanid concentration-time profiles in animal models of TB (mice and rabbits) to quantify penetration into pulmonary and brain lesions. A subset of animals underwent PET/CT imaging with 18F-py-albumin and 18F-FDG to assess vascular supply and inflammation. Postmortem 18F-pretomanid autoradiography (high-resolution) and mass spectrometry were performed in infected tissues. A mouse model of TB meningitis was used to evaluate the bactericidal activity of the BPaL regimen (Figure 1). Figure 1. Experimental schematics. (A) A new synthetic approach was developed to obtain radiofluorinated pretomanid (18F-pretomanid), which is chemically identical to pretomanid and therefore undergoes identical PK and metabolism in vivo. Dynamic 18F-pretomanid PET/CT imaging was performed in validated preclinical models of tuberculosis following intravenous administration of 18F-pretomanid. (B) PET signal was quantified in multiple compartments to generate time activity curves (TACs) used to calculate area under the curve (AUC) over 0-60 minutes. A subset of animals also underwent PET/CT imaging of 18F-py-albumin to assess vascular supply to lung and brain lesions, and with 18F-FDG to confirm the presence of neuroinflammation in the mouse and rabbit models of TB meningitis. Tissue resection post-mortem was used to visualize the intralesional retention of 18F-pretomanid using high-resolution (10 µm) autoradiography. The efficacy of the BPaL regimen in TB meningitis was compared to that of standard treatment with rifampin, isoniazid, and pyrazinamide in the mouse model. Mass spectrometry was performed following oral administration of BPaL to determine brain drug levels. (C) These data provide multicompartment PK analysis, intralesional levels of pretomanid, and insights into the mechanism that govern pretomanid tissue distribution. Results 18F-Pretomanid PET provided detailed concentration-time profiles in infected tissues demonstrating excellent lung and brain tissue penetration (AUC ratio to plasma > 1) in both animal species, which was spatially compartmentalized, likely due to differential vascular supply (18F-py-albumin PET) (Figure 2). Brain lesions (identified by 18F-FDG PET) demonstrated localized leakiness on 18F-py-albumin PET. Autoradiography and mass spectrometry corroborated the imaging findings. The efficacy of the BPaL regimen in TB meningitis was substantially lower than standard TB treatment (Figure 3), likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Figure 2. Spatial heterogeneity of 18F-Pretomanid penetration and vascular supply to pulmonary TB lesions. (A) A novel synthetic was devised to obtain 18F-pretomanid, which is chemically identical to pretomanid. (B) Maximum intensity projection (MIP) of 18F-Pretomanid PET/CT in M.tb.-infected mice over 3 hrs shows hepatobiliary and renal excretion, high uptake into brown fat, brain, and lungs. (C) Resection of infected lungs 30 minutes post intravenous administration of 18F-pretomanid shows heterogenous distribution of 18F-pretomanid into the lungs visible by high resolution autoradiography. Areas of pneumonia are identifiable by hematoxylin and eosin (H&E) staining of the same tissue section used for autoradiography. (D) Time-activity curves of 18F-Pretomanid in infected mouse lung (0-3 hours) and derived area under the curve (AUC) ratios to plasma (E) in infected mouse lung. Representative MIP of 18F-pretomanid (F) and 18F-py-albumin (H) PET/CT in a rabbit with cavitary TB and quantification of the AUC ratios to plasma show reduced penetration into lung lesions and cavitary wall compared to areas of unaffected lung (G and I). Data are represented as median ± interquartile range, n=3-4 group. Figure 3. Exposure levels of 18/19F-pretomanid in models of TB meningitis. (A) Experimental timeline used to assess the penetration of pretomanid into infected mouse brain before and during treatment with antimicrobials bedaquiline (B), pretomanid (Pa), and linezolid (L), and corticosteroid dexamethasone (D). (B) Representative three-dimensional MIP of 18F-pretomanid PET/CT in the CNS-TB model, 10 min post-injection, and transverse section showing high and heterogeneous brain uptake. (C) High-resolution autoradiography was performed to confirm heterogeneous penetration of 18F-pretomanid into infected brain lesions in the mouse. (D). 8F-pretomanid AUC ratios of tissue to plasma in mouse brain before (day 0) and two weeks into treatment show a reduction in penetration at week 2. (E). Pretomanid concentrations (µg/mL) in mouse plasma and brain, at day 0 and two weeks into treatment, measured by mass spectrometry and derived concentration ratios of brain to plasma (F) suggest drug accumulation due to the long half-life. (G) While 18F-py-albumin and 18F-FDG PET/CT show vascular leakage and neuroinflammation in the rabbit model of TB meningitis, the penetration of 18F-pretomanid is heterogeneous and reduced at the lesion site (indicated by white arrow). (H) Quantification of the PET signal shows variability within the same animal. Data are represented as median ± interquartile range, n=3-5 group. Figure 4. Evaluation of a pretomanid-containing regimen in TB meningitis. (A) Mice with experimentally induced TB meningitis were treated with Bedaquiline (25 mg/day), Pretomanid (100 mg/day), Linezolid (100 mg/day), and Dexamethasone (2 mg/day) or Rifampin (10 mg/day), Isoniazid (10 mg/day), Pyrazinamide (150 mg/day) and Dexamethasone (2mg/day) for 8 weeks. Treatment efficacy was determined based on the brain bacterial burden after 2, 4, 6, and 8 weeks of treatment. (B) The penetration of 76Br-bedaquiline, 18F-linezolid, and 18F-pretomanid into the brain parenchyma was measured non-invasively by PET and revealed low penetration of 76Br-bedaquiline (AUC radio to plasma 0.15) and 18F-linezolid (AUC radio to plasma 0.3). (C) Mass spectrometry analysis was performed to confirm the brain penetration of bedaquiline, linezolid, and pretomanid following oral administration. Conclusion Dynamic 18F-pretomanid PET provided holistic data on pretomanid exposures showing excellent penetration into infected lung and brain tissues. The BPaL regimen was inferior to standard TB treatment for TB meningitis. Thus, new pretomanid-containing regimens need to be developed for the treatment of MDR-TB meningitis. Disclosures Charles A. Peloquin, Pharm.D., Nothing to disclose Alvaro A. Ordonez, MD, Cubresa (Consultant)Fujirebio Diagnostics (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Research Grant or Support)Novobiotic LLC, USA (Research Grant or Support)T3 Pharma, Switzerland (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Individual(s) Involved: Self): Research Grant or Support; Novobiotic LLC, USA (Individual(s) Involved: Self): Research Grant or Support; T3 Pharma, Switzerland (Individual(s) Involved: Self): Research Grant or Support

Enterobacterales represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-sorbitol (18F-FDS) can selectively detect Enterobacterales infections in murine models. Here, we demonstrate that uptake of 18F-FDS by bacteria occurs via a metabolically conserved sorbitol-specific pathway with rapid in vitro 18F-FDS uptake noted in clinical strains, including MDR isolates. Whole-body 18F-FDS PET/computerized tomography (CT) in 26 prospectively enrolled patients with either microbiologically confirmed Enterobacterales infection or other pathologies demonstrated that 18F-FDS PET/CT was safe, could rapidly detect and localize Enterobacterales infections due to drug-susceptible or MDR strains, and differentiated them from sterile inflammation or cancerous lesions. Repeat imaging in the same patients monitored antibiotic efficacy with decreases in PET signal correlating with clinical improvement. To facilitate the use of 18F-FDS, we developed a self-contained, solid-phase cartridge to rapidly (

Enterobacterales represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-sorbitol ((18)F-FDS) can selectively detect Enterobacterales infections in murine models. Here, we demonstrate that uptake of (18)F-FDS by bacteria occurs via a metabolically conserved sorbitol-specific pathway with rapid in vitro (18)F-FDS uptake noted in clinical strains, including MDR isolates. Whole-body (18)F-FDS PET/computerized tomography (CT) in 26 prospectively enrolled patients with either microbiologically confirmed Enterobacterales infection or other pathologies demonstrated that (18)F-FDS PET/CT was safe, could rapidly detect and localize Enterobacterales infections due to drug-susceptible or MDR strains, and differentiated them from sterile inflammation or cancerous lesions. Repeat imaging in the same patients monitored antibiotic efficacy with decreases in PET signal correlating with clinical improvement. To facilitate the use of (18)F-FDS, we developed a self-contained, solid-phase cartridge to rapidly (

Pathological angiogenesis contributes to morbidity in a number of diseases including cancer, diabetic retinopathy and the neovascular form of age-related macular degeneration, leading to significant efforts to develop effective anti-angiogenic therapeutics for these conditions. The field is dominated by inhibitors of vascular endothelial growth factor (VEGF), yet angiogenesis can also be driven and modified by other factors. We have previously demonstrated that leucine-rich alpha-2-glycoprotein 1 (LRG1) contributes to abnormal vessel growth by activating a TGFß switch. Here we report the development and characterisation of a function-blocking fully humanised IgG4 and its Fab fragment, that bind to LRG1 with high affinity and specificity and inhibit vascular leakage in the mouse model of laser-induced choroidal neovascularisation. In summary, we have developed a therapeutic antibody that targets a VEGF-independent signalling axis, which may be effective in a number of conditions either as monotherapy or in combination with other vascular targeted therapies.

Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their excellent efficacy, optimal dosing strategies to limit their toxicities are still under development. Here, we developed a novel synthetic strategy for fluorine-18-radiolabeled oxazolidinones. As proof-of-concept, we performed whole-body 18F-linezolid positron emission tomography (PET) in a mouse model of pulmonary TB for noninvasive in situ measurements of time–activity curves in multiple compartments with subsequent confirmation by ex vivo tissue gamma counting. After intravenous injection, (18)F-linezolid rapidly distributed to all organs with excellent penetration into Mycobacterium tuberculosis-infected lungs. Drug biodistribution studies with PET can provide unbiased, in situ drug measurements, which could boost efforts to optimize antibiotic dosing strategies.

Bacterial infections remain a major threat to humanity and are a leading cause of death and disability. Antimicrobial resistance has been declared as one of the top ten threats to human health by the World Health Organization, and new technologies are urgently needed for the early diagnosis and monitoring of deep-seated and complicated infections in hospitalized patients. This review summarizes the radiotracers as applied to imaging of bacterial infections. We summarize the recent progress in the development of pathogen-specific imaging and the application of radiotracers in understanding drug pharmacokinetics as well as the local biology at the infection sites. We also highlight the opportunities for medicinal chemists in radiotracer development for bacterial infections, with an emphasis on target selection and radiosynthetic approaches. Imaging of infections is an emerging field. Beyond clinical applications, these technologies could provide unique insights into disease pathogenesis and expedite bench-to-bedside translation of new therapeutics.

Submitted by Ana Costa (apcosta@porto.ucp.pt) on 2021-05-24T10:06:45Z No. of bitstreams: 1 00104_01_filipa-mota-345017073-dissertacao-integral.pdf: 487804 bytes, checksum: 66daa8b4801dfaf9d16fe60f817527cc (MD5) Approved for entry into archive by Maria Helena Ribeiro (helena.ribeiro@lisboa.ucp.pt) on 2021-06-17T11:16:15Z (GMT) No. of bitstreams: 1 00104_01_filipa-mota-345017073-dissertacao-integral.pdf: 487804 bytes, checksum: 66daa8b4801dfaf9d16fe60f817527cc (MD5) Made available in DSpace on 2021-06-17T11:16:15Z (GMT). No. of bitstreams: 1 00104_01_filipa-mota-345017073-dissertacao-integral.pdf: 487804 bytes, checksum: 66daa8b4801dfaf9d16fe60f817527cc (MD5) Previous issue date: 2021-02-05

This paper analyzes the coordinated effects of corporate social responsibility (CSR) in a setting where firms take into account in their objective function the consumer’s welfare in addition to their profits, produce differentiated products, and compete in quantities. We consider a symmetric case, where firms have the same level of CSR and an asymmetric case, where firms have different levels of CSR. Our results confirm that assigning a positive weight to consumer surplus makes collusion harder to sustain, as shown in the literature. However, for a sufficiently high level of CSR, collusion sustainability is actually increasing in the degree of product substitutability when firms are CSR-symmetric. When firms are CSR-asymmetric, collusion sustainability is increasing in the degree of product differentiation if products are complements. Furthermore, we show that collusion may be welfare-improving when firms adopt a socially responsible behavior, which provides an interesting background to competition authorities when analysing cartel cases.

Ebselen was originally developed as a glutathione peroxidase mimic in the treatment of stroke (Parnham & Sies, 2013), and recently explored as a safer alternative to lithium in the treatment of bipolar disorder (Singh et al., 2013). Coincidentally, using magnetic resonance spectroscopy (MRS) we discovered that ebselen reduces glutamate and Glx (glutamate+glutamine) in the anterior cingulate cortex of healthy volunteers (Masaki et al., 2016), consistent with it being an inhibitor of glutaminase enzyme (Thomas et al., 2013).

Diabetic foot infections (DFIs) are a common, complex, and costly medical problem with increasing prevalence. Diagnosing DFIs is a clinical challenge due to the poor specificity of the available methods to accurately determine the presence of infection in these patients. However, failure to perform an opportune diagnosis and provide optimal antibiotic therapy can lead to higher morbidity for the patient, unnecessary amputations, and increased healthcare costs. Novel developments in bacteria-specific molecular imaging can provide a non-invasive assessment of the infection site to support diagnosis, determine the extension and location of the infection, guide the selection of antibiotics, and monitor the response to treatment. This is a review of recent research in molecular imaging of infections in the context of DFI. We summarize different clinical and preclinical methods and the translational implications aimed to improve the care of patients with DFI.

Neuropilin‐1 (NRP1) is emerging as an important molecule in immune signaling where it has been shown to modulate the actions of TGF‐β1 in macrophages and regulatory T cells. The development of cost‐effective and reliable assays for NRP1 binding is therefore important. We synthesized three new NRP1 small molecule fluorophores and examined their performance as fluorescent polarization probes. One molecule DS108 exhibited favorable binding and fluorescent characteristics and allowed us to establish a simple assay suitable for medium to high throughput screening of small molecules.

Submitted by azevedo@ufp.pt (azevedo@ufp.pt) on 2020-02-14T10:15:43Z No. of bitstreams: 1 PPG_28378.pdf: 407291 bytes, checksum: e3026fb78924a45d649eaf644b30af35 (MD5) Approved for entry into archive by halves@ufp.pt (halves@ufp.pt) on 2020-02-14T10:27:42Z (GMT) No. of bitstreams: 1 PPG_28378.pdf: 407291 bytes, checksum: e3026fb78924a45d649eaf644b30af35 (MD5) Made available in DSpace on 2020-02-14T10:27:42Z (GMT). No. of bitstreams: 1 PPG_28378.pdf: 407291 bytes, checksum: e3026fb78924a45d649eaf644b30af35 (MD5) Previous issue date: 2019-07-26

Submitted by Orísia Pereira (orisia@esenf.pt) on 2019-12-23T14:50:59Z No. of bitstreams: 1 Relatorio Filipa Ramos.pdf: 1324287 bytes, checksum: 8252e3cfa94784eb28372aacb33e748f (MD5) Made available in DSpace on 2019-12-23T14:50:59Z (GMT). No. of bitstreams: 1 Relatorio Filipa Ramos.pdf: 1324287 bytes, checksum: 8252e3cfa94784eb28372aacb33e748f (MD5) Previous issue date: 2019

Submitted by Ana Rebelo (amsr@isep.ipp.pt) on 2020-01-23T11:24:35Z No. of bitstreams: 1 DM_AnaMachado_2019_MEI.pdf: 7730020 bytes, checksum: 7258f76cbb68d0882c907a38147ccf81 (MD5) Approved for entry into archive by Ana Rebelo (amsr@isep.ipp.pt) on 2020-01-23T11:25:01Z (GMT) No. of bitstreams: 1 DM_AnaMachado_2019_MEI.pdf: 7730020 bytes, checksum: 7258f76cbb68d0882c907a38147ccf81 (MD5) Made available in DSpace on 2020-01-23T11:25:01Z (GMT). No. of bitstreams: 1 DM_AnaMachado_2019_MEI.pdf: 7730020 bytes, checksum: 7258f76cbb68d0882c907a38147ccf81 (MD5) Previous issue date: 2019

O atual relatório pretende demonstar o processo de aquisição de competências específicas no decorrer do estágio de natureza profissional, nas áreas de gravidez com complicações, trabalho de parto, parto e pós-parto, tendo subjacente ao seu desenvolvimento o Regulamento de Competências de Cuidados Especializados definidas pela Ordem dos Enfermeiros, bem como o regulamento do 2º Ciclo dos Cursos de Mestrado em Enfermagem de Saúde Materna e Obstétrica, da Escola Superior de Enfermagem do Porto. É descrito o processo de formulação do juízo diagnóstico, com os quais foram articuladas intervenções de enfermagem especializada, a reflexão sobre as mesmas, assim como o planeamento com a incorporação de padrões de investigação. Um método de resolução de problemas no âmbito da decisão clínica, que incorpora a pesquisa da melhor e mais recente evidência, experiência e avaliação clínica, bem como as preferências da mulher e casal no contexto do cuidar. Este permite a apropriação na prática da excelência de cuidados, traduzindo-se em ganhos em saúde e, consequentemente, no desenvolvimento da profissão. A OMS pugna por alterações urgentes na conduta da prática na assistência do parto e nascimento, alertando para a importância do resgate do parto enquanto evento natural. Ancorada a um perfil biomédico vigente emergiu, assim, a necessidade em realizar uma pesquisa sobre uma problemática de interesse inerente ao desenvolvimento de competências e relevante para problematizar as práticas, cuja finalidade foi reunir e sintetizar os resultados da pesquisa, de forma a munirmo-nos de conhecimento científico e, de modo a desenvolvermos cuidados seguros e de qualidade centrados na mulher, casal, família e Recém-nascido. Neste contexto, é realizada uma revisão integrativa da literatura com o objetivo de conhecer a eficácia e a segurança da estimulação mamária, enquanto método de indução do trabalho de parto normal, em grávidas de termo. O recurso a métodos não farmacológicos para a indução não é uma prática desconhecida. Pois, muitos métodos têm sido utilizados desde há muitos anos e em diferentes culturas. Deste modo, a estimulação mamária enquanto meio indutor, natural, não farmacológico, de amadurecimento do colo uterino e estimulador de contrações uterinas está associado a excelentes níveis de satisfação por parte da mulher e, ainda, à redução dos riscos de hemorragia pós-parto. Relativamente à segurança, foi demonstrado que este método é seguro, mas pela falta de estudos noutra população é indicado apenas para mulheres com gravidez de baixo risco.

Biomedical optics express 10(9), 4353 (2019). doi:10.1364/BOE.10.004353 special issue: "Recent Progress in Optical Probing and Manipulation of Tissue", Published by OSA, Washington, DC

Este trabalho aborda a intervenção com menores delinquentes, bem como o papel da educação no seu processo de reintegração social. Visa, considerando os dados da reincidência social, ler o quotidiano de um Centro Educativo localizado no Norte de Portugal à luz da literatura sobre a intervenção e reinserção de menores delinquentes. Através de uma análise qualitativa, analisam-se os fatores de risco associados à reincidência e a forma como são trabalhados ao longo da intervenção. Ao mesmo tempo, analisa-se e aprofunda-se a questão dos fatores de proteção e a forma como estes são trabalhados e potenciados para inverter a trajetória do jovem, bem como o papel ocupado pela educação na possível inversão do comportamento delinquente. Outro foco de investigação foi o trabalho desenvolvido pelos Centros Educativos e pela Direção Geral de Reinserção e Serviços Prisionais após a saída do jovem do Centro. Constatou-se que a falta de estruturas de continuidade influencia a reintegração social do jovem. Para além da falta de estruturas de continuidade, influenciam ainda o sucesso da reintegração social do jovem a falta de apoio familiar, a ausência de um projeto de vida, o regresso ao seu antigo grupo de pares e, talvez o mais importante de todos os fatores, a falta de oportunidades. Para além disto, verifica-se que a educação se apresenta, por um lado, como um fator de risco devido aos altos valores de absentismo, por outro, no momento da saída, e tendo em conta a idade dos jovens, apresenta-se como um fator de proteção. Contudo, apesar da escola assumir um importante papel, constata-se a existência de um amplo espaço para melhorias na relação entre a escola e os jovens.

Endothelium‐derived C‐type natriuretic peptide possesses cytoprotective and anti‐atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C‐type natriuretic peptide are somewhat mediated by the natriuretic peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic peptide receptors. Assay conditions are investigated to explore the feasibility and dynamic range of each method, and peptide‐based agonists and antagonists are used as controls to validate these conditions. Once established, each technique was compared and contrasted with respect to their drug discovery utility. We foresee that such techniques will facilitate the discovery and development of potential therapeutic agents for NPR‐C and other large extracellular domain membrane receptors., C‐type natriuretic peptide and its cognate receptor, natriuretic peptide receptor C, represent a novel therapeutic target for the treatment of cardiovascular diseases. To facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic peptide receptors.

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.

Purpose of Review In this review, we outline the potential for hypoxia imaging as a diagnostic and prognostic tool in cardiology. We describe the lead hypoxia PET radiotracers currently in development and propose a rationale for how they should most appropriately be screened and validated. Recent Findings While the majority of hypoxia imaging agents has been developed for oncology, the requirements for hypoxia imaging in cardiology are different. Recent work suggests that the bis(thiosemicarbazone) family of compounds may be capable of detecting the subtle degrees of hypoxia associated with cardiovascular syndromes, and that they have the potential to be “tuned” to provide different tracers for different applications. Summary New tracers currently in development show significant promise for imaging evolving cardiovascular disease. Fundamental to their exploitation is their careful, considered validation and characterization so that the information they provide delivers the greatest prognostic insight achievable.

Neuropilin‐1 (NRP1) is a transmembrane co‐receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP1 has been considered a therapeutic target and is the focus of multiple drug discovery initiatives. Vascular endothelial growth factor (VEGF) binds to the b1 domain of NRP1 through interactions between the C‐terminal arginine of VEGF and residues in the NRP1‐binding site including Tyr297, Tyr353, Asp320, Ser346 and Thr349. We obtained several complexes of the synthetic ligands and the NRP1‐b1 domain and used X‐ray crystallography and computational methods to analyse atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the six new high‐resolution crystal structures of arginine analogues bound to NRP1. In addition, we identified conserved water molecules in binding site regions which can be targeted for drug design. The computational prediction of the VEGF ligand‐binding site hydration map of NRP1 was in agreement with the experimentally derived, conserved hydration structure. Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein–ligand bridges. Our report provides a comprehensive description of the binding site for the peptidic ligands’ C‐terminal arginines in the b1 domain of NRP1, highlights the importance of conserved structural waters in drug design and validates the utility of the computational hydration map prediction method in the context of neuropilin. Database The structures were deposited to the PDB with accession numbers PDB ID: 5IJR, 5IYY, 5JHK, 5J1X, 5JGQ, 5JGI.

Introducao: As criancas que abandonam a Unidade de Urgencia Pediatrica antes do seu processo de atendimento estar terminado podem apresentar um agravamento clinico posterior, relacionado com a falta de avaliacao medica atempada. Objectivos: Este estudo teve como objectivo avaliar os casos de abandono na nossa Unidade de Urgencia Pediatrica, caracterizar este grupo de criancas e a sua evolucao clinica. Material e Metodos: Analise retrospectiva e descritiva dos processos de urgencia das criancas que abandonaram a Unidade de Urgencia Pediatrica do Hospital de Sao Bernardo antes de terminar o processo de atendimento, entre 1 de Janeiro e 31 de Dezembro de 2012. Resultados: Um total de 538 criancas abandonou a Unidade de Urgencia Pediatrica (1,35% de todas as admissoes). A maioria (89,5%) nao apresentava criterio de observacao urgente e abandonou antes da observacao medica inicial (82,7%). A percentagem de abandonos foi maior nos meses de Dezembro, Janeiro e Fevereiro (64%), a terca-feira (19,3%) e durante o turno da tarde (60,8%). Estes periodos coincidiram com os picos de maior afluencia a Unidade de Urgencia Pediatrica. O tempo de espera para observacao medica foi na maioria (94,4%) adequado a gravidade clinica. Seis doentes regressaram nas 72 horas seguintes, dos quais dois necessitaram de internamento. Discussao: Verificou-se uma percentagem de abandonos dentro do expectavel. A menor gravidade aferida na triagem e os tempos de espera prolongados foram factores predisponentes ao abandono. Conclusao: A sobrelotacao das Urgencias Pediatricas com doentes sem criterios de urgencia, que aumentam os tempos de espera, pode conduzir ao abandono com posterior readmissao em situacao clinica de agravamento, o que na nossa serie aconteceu em apenas dois casos. Palavras-chave: Crianca; Desistencia; Servico de Urgencia Hospitalar; Tempos de Espera; Portugal.

O eritema multiforme é uma alteração cutânea de etiologia e fisiopatologia mal conhecidas, mas tem sido descrito em associação a múltiplas patologias infecciosas e inflamatórias. A Ricketsia conori é um agente bem conhecido e descrito na literatura, podendo apresentar um leque variado de manifestações clínicas. A associação entre este agente infeccioso e o eritema multiforme, apesar de referida em algumas revisões na literatura, é extremamente rara e mal conhecida. Neste artigo, descrevemos um caso clínico de infecção a Ricketsia Conori, com confirmação laboratorial numa criança de 9 anos que se apresentou com síndrome febril e eritema multiforme.