Subretinal abscess due to nocardia in an immunosuppressed patient: a case report.

Systemic nocardiosis is a rarely occurring pathology, but its hematogenous spread across the eye is even less likely to occur, with only a few recorded cases. Therefore, it is not usually taken into account when a subretinal abscess is being considered for a diagnosis. However, when confronting a case with a history of immunosupression and pulmonary disease, the examination of the ocular fundus may be a very successful approach. With such aim we introduce the case of a 45-year-old immunosupressed male, without a history of pulmonary disease, whose subretinal mass evolution is accordant with an abscess. In the end, being etiologically diagnosed by means of a vitrectomy, it was concluded that the abscess was due to an infection of nocardia cyriacigeorgica, an emergent pathogen. Thus the aforementioned case is to be considered in the present study, along others, in order to shed more light on a disease which may not be readily diagnosed on account of its infrequency.

Passive Cycle Training Promotes Bone Recovery after Spinal Cord Injury without Altering Resting-State Bone Perfusion.

INTRODUCTION: Spinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g., bodyweight-supported treadmill training (BWSTT) and passive-isokinetic bicycle training) transiently promote lower-extremity blood flow (BF). However, it remains unknown whether ABPT alter resting-state bone BF or improve skeletal integrity after SCI. METHODS: Four-month-old male Sprague-Dawley rats received T 9 laminectomy alone (SHAM; n = 13) or T 9 laminectomy with severe contusion SCI ( n = 48). On postsurgery day 7, SCI rats were stratified to undergo 3 wk of no ABPT, quadrupedal (q)BWSTT, or passive-isokinetic hindlimb bicycle training. Both ABPT regimens involved two 20-min bouts per day, performed 5 d·wk -1 . We assessed locomotor recovery, bone turnover with serum assays and histomorphometry, distal femur bone microstructure using in vivo microcomputed tomography, and femur and tibia resting-state bone BF after in vivo microsphere infusion. RESULTS: All SCI animals displayed immediate hindlimb paralysis. SCI without ABPT exhibited uncoupled bone turnover and progressive cancellous and cortical bone loss. qBWSTT did not prevent these deficits. In comparison, hindlimb bicycle training suppressed surface-level bone resorption indices without suppressing bone formation indices and produced robust cancellous and cortical bone recovery at the distal femur. No bone BF deficits existed 4 wk after SCI, and neither qBWSTT nor bicycle altered resting-state bone perfusion or locomotor recovery. However, proximal tibia BF correlated with several histomorphometry-derived bone formation and resorption indices at this skeletal site across SCI groups. CONCLUSIONS: These data indicate that passive-isokinetic bicycle training reversed cancellous and cortical bone loss after severe SCI through antiresorptive and/or bone anabolic actions, independent of locomotor recovery or changes in resting-state bone perfusion.

Role of immune mediators in predicting hospitalization of SARS-CoV-2 positive patients.

BACKGROUND: Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity. AIM: To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility. METHODS: A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19. RESULTS: In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman's ρ = 0.48, P=<0.0001). CONCLUSIONS: IM profiles between non-hospitalized and hospitalized patients were distinct. IL-6 was the best predictor of COVID-19 severity among all the IMs tested.

Pectus excavatum em uma ninhada de Buldogue Francês: relato de caso / Pectus excavatum in a French Bulldog Litter: case report

RESUMO O pectus excavatum é considerado uma patologia da parede torácica, onde há convexidade no aspecto ventral do esterno, o que gera complicações secundárias, como alongamento ventrodorsal do tórax e aumento da pressão intratorácica, entre outras. No presente caso, o corpo de um cachorro Buldogue Francês nasceu com sinais prévios de decaimento e baixo consumo de leito materno, além de uma avaliação médica forense. De acordo com a avaliação patológica, foi encontrada uma fenda no peito esternal relacionada às esternas caudais próximas à cartilagem xifóide, conteúdo espumoso na cartilagem epiglótica da laringe e sinais graves de enfisema nos lobos caudal, craniano e médio pulmonar. Na avaliação cardiológica, foi observada assimetria morfológica invaginante no septo interventricular na mesma área em que a fenda esternal ocorre, por sua vez, na avaliação radiográfica, evidencia uma depressão dorsal do terço caudal do esterno com alterações consideráveis na silhueta cardíaca. Na Colômbia não há relatos de ninhadas completas que apresentem esta alteração, portanto, pretende-se que este seja o primeiro relatório anatomopatológico e de imagem que descreva a patologia em caninos.

ABSTRACT Pectus excavatum is considered a pathology of the chest wall where there is convexity in the ventral aspect of the sternum, which generates secondary complications, such as ventrodorsal stretching of the chest and increased intrathoracic pressure, among others. In the present case, the body of a French bulldog dog was born with previous signs of decay and low consumption of maternal waste, in addition to a forensic medical evaluation. According to the pathological evaluation, a crack was found in the sternal chest related to the caudal sternum close to the xiphoid cartilage, frothy content in the laryngeal epiglottis cartilage and severe signs of emphysema in the caudal, cranial and middle lung lobes. In the cardiological evaluation, an invaginating morphological asymmetry was observed in the interventricular septum in the same area in which the sternal cleft occurs, in turn, in the radiographic evaluation, it shows a dorsal depression of the caudal third of the sternum with considerable changes in the cardiac silhouette. In Colombia there are no reports of complete litters that present this alteration, so it is intended that this is the first anatomopathological and imaging report that describes the pathology in canines.

[Optoacoustic imaging-Applications and advancements of innovative imaging techniques]. / Optoakustische Bildgebung ­ innovative Bildgebungsverfahren auf dem Vormarsch.

Optoacoustic imaging (OAB) has developed steadily in recent years. By means of partly pulsed light, in a wide variety of wavelengths, different colour carriers (chromophores) are excited to form sound waves. These in turn are detected by the newly developed systems and converted into three-dimensional images by means of various algorithms. The technique is characterised by a good ratio between contrast and penetration depth and can create macro-, meso- and microscopic images due to its scalability. Optoacoustic macroscopy broadly irradiates the area to be examined with laser light. This can produce images with a high penetration depth, but only with a moderate resolution. Clinically interesting fields of application are for example the results of sentinel lymph nodes (SLNs) examined ex vivo using macroscopic optoacoustics. Due to the ability of OAB to visualise melanin, the detection rate of metastases was superior to previous methods, but not to histology. The ability to visualise dermal and epidermal structures, especially vessels, with good resolution makes optoacoustic mesoscopy useful in the examination of inflammatory skin diseases and could contribute to the verification of the success of therapy, e.g., with biologics for psoriasis vulgaris or atopic eczema (AE), in the future. Optoacoustic microscopy, which has so far been limited mainly to preclinical in vivo research, could be used in the future to detect even finer vascular structures and their changes. The clinical possibilities of OAB seem to be of great benefit and continue to be the subject of intensive research.

Biologic and pathologic aspects of osteocytes in the setting of medication-related osteonecrosis of the jaw (MRONJ).

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe, debilitating condition affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). Oral risk factors associated with the development of MRONJ include tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection). In bone tissues, osteocytes play a bidirectional role in which they not only act as the "receiver" of systemic signals from blood vessels, such as hormones and drugs, or local signals from the mineralized matrix as it is deformed, but they also play a critical role as "transmitter" of signals to the cells that execute bone modeling and remodeling (osteoclasts, osteoblasts and lining cells). When the survival capacity of osteocytes is overwhelmed, they can die. Osteocyte death has been associated with several pathological conditions. Whereas the causes and mechanisms of osteocyte death have been studied in conditions like osteonecrosis of the femoral head (ONFH), few studies of the causes and mechanisms of osteocyte death have been done in MRONJ. The three forms of cell death that affect most of the different cells in the body (apoptosis, autophagy, and necrosis) have been recognized in osteocytes. Notably, necroptosis, a form of regulated cell death with "a necrotic cell death phenotype," has also been identified as a form of cell death in osteocytes under certain pathologic conditions. Improving the understanding of osteocyte death in MRONJ may be critical for preventing disease and developing treatment approaches. In this review, we intend to provide insight into the biology of osteocytes, cell death, in general, and osteocyte death, in particular, and discuss hypothetical mechanisms involved in osteocyte death associated with MRONJ.

Bone loss after severe spinal cord injury coincides with reduced bone formation and precedes bone blood flow deficits.

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiological consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T9 laminectomy (SHAM) or laminectomy with severe contusion SCI (n = 20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wk postsurgery via microcomputed tomography (microCT) and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial postsurgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1 wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30%-40% lower in SCI versus SHAM at 2 wk, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating that bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.NEW & NOTEWORTHY We provide the first direct evidence indicating femur and tibia blood flow (BF) deficits exist in conscious (awake) rats after severe contusion spinal cord injury (SCI), with the distal femur displaying the largest BF deficits. Reduced bone perfusion temporally coincided with unopposed bone resorption, as indicated by ongoing osteoclast-mediated bone resorption and a near absence of surface-level bone formation indices, which resulted in severe cancellous and cortical microstructural deterioration after SCI.

Preclinical models of medication-related osteonecrosis of the jaw (MRONJ).

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.

Neuroinflammation is able to downregulate cytochrome P450 epoxygenases 2J3 and 2C11 in the rat brain.

Cytochrome P450 (CYP) epoxygenases have been considered the main producers of epoxyeicosatrienoic acids (EETs) through the oxidation of arachidonic acid (AA). EETs display various biological properties, notably their powerful anti-inflammatory activities. In the brain, EETs have proven to be neuroprotective and to improve neuroinflammation. However, it is known that inflammation could modify CYP expression. We have previously reported that an inflammatory process in astrocytes is able to down-regulate CYP2J3 and CYP2C11 mRNA, protein levels, and activity (Navarro-Mabarak et al., 2019). In this work, we evaluated the effect of neuroinflammation in protein expression of CYP epoxygenases in the brain. Neuroinflammation was induced by the intraperitoneal administration of LPS (1 mg/kg) to male Wistar rats and was corroborated by IL-6, GFAP, and Iba-1 protein levels in the cortex over time. CYP2J3 and CYP2C11 protein levels were also evaluated in the cortex after 6, 12, 24, 48, and 72 h of LPS treatment. Our results show for the first time that neuroinflammation is able to downregulate CYP2J3 and CYP2C11 protein expression in the brain cortex.

Reduction in CYP1A1 and 2B2 activity at low oxygen tension.

The Cytochrome P450 (CYP) enzyme family comprises a wide array of monooxygenases involved in the oxidation of endobiotic and xenobiotic molecules. The active site of a CYP enzyme contains an iron protoporphyrin center coordinated to a cysteine thiolate, and then, molecular oxygen is associated with the iron to be converted into dioxygen complex plus substrate. Reduction by CYP reductase expedites hydroxylation of the compound. In this oxidation reaction, insufficient oxygen molecules would affect enzyme catalysis. Nevertheless, biochemical data about CYP kinetics at low oxygen concentrations are not available. In this work, we present the results on the variation in rat liver microsomal CYP Vmax app and Km app under normal and hypoxic conditions. Using alkoxyresorufin molecules as substrates, the Vmax/Km ratios for resorufin production decreased from 426 to 393 for CYP1A1 and from 343 to 202 for CYP2B1 at a low oxygen concentration (4.1 ppm) compared to the ratios observed at a normal oxygen concentration (6.5 ppm). Additionally, the bacterial mutagenicity of 2-aminoanthracene and cyclophosphamide, decreased by 32% and 42%, respectively, at low oxygen concentrations. These results support the hypothesis that low oxygen availability is implicated in the low efficiency of substrate oxidation by CYP.

Role of epoxyeicosatrienoic acids in the lung.

Epoxyeicosatrienoic acids (EETs) are synthetized from arachidonic acid by the action of members of the CYP2C and CYP2J subfamilies of cytochrome P450 (CYPs). The effects of EETs on cardiovascular function, the nervous system, the kidney and metabolic disease have been reviewed. In the lungs, the presence of these CYPs and EETs has been documented. In general, EETs play a beneficial role in this essential tissue. Among the most important effects of EETs in the lungs are the induction of vasorelaxation in the bronchi, the stimulation of Ca2+-activated K+ channels, the induction of vasoconstriction of pulmonary arteries, anti-inflammatory effects induced by asthma, and protection against infection or exposure to chemical substances such as cigarette smoke. EETs also participate in tissue regeneration, but on the downside, they are possibly involved in the progression of lung cancer. More research is necessary to design therapies with EETs for the treatment of lung disease.

Human CYP1A1 inhibition by flavonoids.

Cytochrome P4501A1 (CYP1A1) is involved in the metabolism of several genotoxic/carcinogenic environmental xenobiotics including polycyclic aromatic hydrocarbons (PAHs) like benzo[a]pyrene. Several authors had proposed CYP1A inhibition as a plausible strategy for cancer chemoprevention. Using ethoxyresorufin O-deethylase activity (EROD), we tested the inhibitory properties of nine flavonoids: quercetin, miricetin, luteolin, fisetin, morin, kaempferol, 5-hydroxyflavone (5-HF), 3-hydroxyflavone (3-HF), and flavone (F) against human recombinant CYP1A1. The last three compounds exerted the highest inhibitory effect with IC50 values of 0.07, 0.10 and 0.08 µM respectively; the more hydroxyl-groups were present, the lower the potency of inhibition was. Biochemical characterization leads to the conclusion that flavone and its hydroxy derivatives are mixed-type inhibitors. In silico studies have shown that, Phe224 and other aromatic residues in the human CYP1A1 active site play an important role in flavonoid-CYP interaction, through a π/π stacking between the aminoacid and the flavonoid C-ring. Outside the active site, the three flavonoids bind preferentially between A and K helices of the enzyme. Results from the Ames test using human S9 fraction revealed that none of the three compounds was mutagenic. We can consider 5-HF, 3-HF, and F as potential chemopreventive agents against genotoxic damage caused by metabolites resulting from CYP1A1 activity.

Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris).

OBJECTIVE: Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. METHODS: At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 µg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. RESULTS: 40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. CONCLUSIONS: Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.

Sacral neuromodulation for fecal incontinence in Latin America: initial results of a multicenter study.

BACKGROUND: Sacral neuromodulation (SNM) is a widely used therapeutic option for fecal incontinence (FI). Larger series are mainly from Western countries, while few reports address the results of SNM in less developed or less wealthy countries. The aim of the present study was to evaluate the efficacy of SNM in patients with FI in Latin America. METHODS: A retrospective study was conducted on patients with FI who had SNM between 2009 and 2016 at 15 specialized colorectal surgery centers in Latin America. Main outcomes measures were functional outcomes, postoperative complications, requirement of revisional surgery, and requirement of device removal. All patients had failed conservative management and had clinical assessment including recording of the validated Cleveland Clinic Florida Fecal Incontinence Score (CCF-FIS) and, when available, anal manometry and endoanal ultrasound. Patients were followed up for a median of 36.7 (1-84) months. RESULTS: One hundred and thirty-one patients [119 females, median age of 62.2 (range 19-87) years] were included. The most common etiology of FI was obstetric injury (n = 60; 45.8%). After successful test lead implantation, the stimulator was permanently placed in 129 patients (98.5%). One patient failed to respond in the test phase and one patient did not proceed to permanent implantation for insurance reasons. Nineteen patients (14.7%) had 19 complications including infection (n = 5, 3.8%), persistent implant site pain (n = 5, 3.8%), generator/lead dislodgment (n = 5, 3.8%), malfunctioning device (n = 3, 2.3%), and hematoma (n = 1, 0.7%). Reimplantation after the first and second stages was necessary in 2 (1.5%) and 3 patients (2.3%), respectively. The device removal rate was 2.2%. At a median follow-up of 36.7 (range 1-84) months, the CCF-FIS significantly improved from a preoperative baseline of 15.9 ± 2.98 to 5.2 ± 3.92 (95%CI: 15.46 vs 4.43; p < 0.0001). Overall, 90% of patients rated their improvement as "significant". CONCLUSIONS: Sacral nerve stimulation for FI is safe and efficient, even in less wealthy or less developed countries.

Zoledronate treatment duration is linked to bisphosphonate-related osteonecrosis of the jaw prevalence in rice rats with generalized periodontitis.

OBJECTIVES: To determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue-level features of BRONJ-like lesions in this model, and examine the specific anti-resorptive role of ZOL in BRONJ. MATERIALS AND METHODS: Rice rats (n = 228) consumed high sucrose-casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9-16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ-like lesion prevalence and tissue-level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling. RESULTS: Prevalence of BRONJ-like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose-related plateau in the systemic anti-resorptive effect of ZOL. ZOL and BRONJ-like lesions also altered the structural and tissue-level features of the jaw. CONCLUSION: The relationship between BRONJ-like lesion prevalence and ZOL dose and duration varies depending on the co- or pre-existing oral risk factor. At clinically relevant doses of ZOL, BRONJ-like lesions are associated with anti-resorptive activity.