Subacute Neurotoxicity as an Adverse Reaction to Ceftazidime: A Case Report.

Neurotoxicity associated with cephalosporins is an increasingly recognized complication, although among cephalosporins, ceftazidime is rarely reported for such an adverse reaction. Moreover, subacute, rather than acute, presentation of neurotoxicity associated with cephalosporins is rare. A 77-year-old female patient with stage 4 chronic renal disease was admitted due to cellulitis in her right lower limb, multiorgan dysfunction complicated by oliguric acute kidney injury, and a need for hemodialysis via a central venous catheter. On the 13th day after admission, she became febrile, and bacteremia associated with a central venous catheter was identified, which prompted the initiation of empirical antibiotic therapy with vancomycin and ceftazidime. After 13 days of antibiotic therapy with vancomycin and ceftazidime, the patient became confused, with temporal-spatial disorientation and myoclonus, especially in the upper limbs, with worsening renal function. Ceftazidime was discontinued, and the patient's condition improved with complete remission of symptoms on the 8th day after symptom onset. Neurotoxicity associated with ceftazidime is a rare but probably underdiagnosed adverse reaction. It is more frequent in elderly patients with previous neurological dysfunction and end-stage kidney disease and/or acute kidney injury, and it usually manifests soon after starting treatment. Early identification and monitoring of risk factors and symptoms should lead the physician to a rapid withdrawal of the offending drug.

Nanoparticle-encapsulated retinoic acid for the modulation of bone marrow hematopoietic stem cell niche.

More effective approaches are needed in the treatment of blood cancers, in particular acute myeloid leukemia (AML), that are able to eliminate resistant leukemia stem cells (LSCs) at the bone marrow (BM), after a chemotherapy session, and then enhance hematopoietic stem cell (HSC) engraftment for the re-establishment of the HSC compartment. Here, we investigate whether light-activatable nanoparticles (NPs) encapsulating all-trans-retinoic acid (RA+NPs) could solve both problems. Our in vitro results show that mouse AML cells transfected with RA+NPs differentiate towards antitumoral M1 macrophages through RIG.1 and OASL gene expression. Our in vivo results further show that mouse AML cells transfected with RA+NPs home at the BM after transplantation in an AML mouse model. The photo-disassembly of the NPs within the grafted cells by a blue laser enables their differentiation towards a macrophage lineage. This macrophage activation seems to have systemic anti-leukemic effect within the BM, with a significant reduction of leukemic cells in all BM compartments, of animals treated with RA+NPs, when compared with animals treated with empty NPs. In a separate group of experiments, we show for the first time that normal HSCs transfected with RA+NPs show superior engraftment at the BM niche than cells without treatment or treated with empty NPs. This is the first time that the activity of RA is tested in terms of long-term hematopoietic reconstitution after transplant using an in situ activation approach without any exogenous priming or genetic conditioning of the transplanted cells. Overall, the approach documented here has the potential to improve consolidation therapy in AML since it allows a dual intervention in the BM niche: to tackle resistant leukemia and improve HSC engraftment at the same time.

Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice.

Iron overload (IOL) is hypothesized to contribute to dysplastic erythropoiesis. Several conditions, including myelodysplastic syndrome, thalassemia and sickle cell anemia, are characterized by ineffective erythropoiesis and IOL. Iron is pro-oxidant and may participate in the pathophysiology of these conditions by increasing genomic instability and altering the microenvironment. There is, however, lack of in vivo evidence demonstrating a role of IOL and oxidative damage in dysplastic erythropoiesis. NRF2 transcription factor is the master regulator of antioxidant defenses, playing a crucial role in the cellular response to IOL in the liver. Here, we crossed Nrf2-/- with hemochromatosis (Hfe-/-) or hepcidin-null (Hamp1-/-) mice. Double-knockout mice developed features of ineffective erythropoiesis and myelodysplasia including macrocytic anemia, splenomegaly, and accumulation of immature dysplastic bone marrow (BM) cells. BM cells from Nrf2/Hamp1-/- mice showed increased in vitro clonogenic potential and, upon serial transplantation, recipients disclosed cytopenias, despite normal engraftment, suggesting defective differentiation. Unstimulated karyotype analysis showed increased chromosome instability and aneuploidy in Nrf2/Hamp1-/- BM cells. In HFE-related hemochromatosis patients, NRF2 promoter SNP rs35652124 genotype TT (predicted to decrease NRF2 expression) associated with increased MCV, consistent with erythroid dysplasia. Our results suggest that IOL induces ineffective erythropoiesis and dysplastic hematologic features through oxidative damage in Nrf2-deficient cells.

When a Hypersomnolent Hemodialyzed Patient Actually Has a Rare Stroke: A Case of Artery of Percheron Infarction With Paradoxical Embolism.

INTRODUCTION: Artery of Percheron (AOP) is an uncommon anatomic variant of the arterial supply of the medial thalami. Owing to variable clinical presentation, challenging imaging diagnosis, and its rarity, it is difficult to diagnose AOP infarctions. We present a clinical case of a unique presentation of AOP infarction associated with paradoxical embolism and highlight the atypical clinical manifestations and challenging diagnosis of this stroke syndrome. CASE REPORT: A 58-year-old White female with chronic renal insufficiency on hemodialysis was admitted to our center with a 10-hour course of hypersomnolence and right-sided ataxia. She had normal body temperature, blood pressure, peripheral oxygen saturation, and heart rate and scored 11 points in the Glasgow Coma Scale and 12 points in National Institutes of Health Stroke Scale. Initial brain computerized tomography scan, electrocardiogram, and thoracic radiography were normal; transcranial Doppler ultrasound showed >50% stenosis at the P2 segment of the right posterior cerebral artery, and transthoracic echocardiogram, a patent foramen ovale and thrombus adherent to the hemodialysis catheter. On day 3, she underwent brain magnetic resonance that showed acute ischemic lesions at the paramedian thalami and the superior cerebral peduncles. AOP infarction due to a paradoxical embolism from a patent foramen ovale with a right atrial thrombus was the final diagnosis. CONCLUSIONS: AOP infarctions are a rare type of stroke with elusive clinical presentations and frequently, initial imaging assessment is normal. Early recognition is crucial, and a high index of suspicion is needed to suspect this diagnosis.

Flow Cytometry Analysis of Murine Bone Marrow Hematopoietic Stem and Progenitor Cells and Stromal Niche Cells.

The bone marrow (BM) is the soft tissue found within bones where hematopoiesis, the process by which new blood cells are generated, primarily occurs. As such, it contains hematopoietic stem and progenitor cells (HSPCs), as well as supporting stromal cells that contribute to the maintenance and regulation of HSPCs. Hematological and other BM disorders disrupt hematopoiesis by affecting hematopoietic cells directly and/or through the alteration of the BM niche. Here, we describe a method to study hematopoiesis in health and malignancy through the phenotypic analysis of murine BM HSPCs and stromal niche populations by flow cytometry. Our method details the required steps to enrich BM cells in endosteal and central BM fractions, as well as the appropriate gating strategies to identify the two key niche cell types involved in HSPC regulation, endothelial cells and mesenchymal stem cells. The phenotypic analysis proposed here may be combined with mouse mutants, disease models, and functional assays to characterize the HSPC compartment and its niche.

Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.

Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness; therefore, we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation and lower AML infiltration, proliferation, and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

Acute organ failure and risk of admission to intensive medical care in cancer patients: a single center prospective cohort study. / Falência aguda de órgão e risco de admissão em unidade de terapia intensiva nos pacientes oncológicos: estudo de coorte prospectivo unicêntrico.

OBJECTIVE: To ascertain the cumulative incidence of acute organ failure and intensive care unit admission in cancer patients. METHODS: This was a single-center prospective cohort study of adult cancer patients admitted for unscheduled inpatient care while on systemic cancer treatment. RESULTS: Between August 2018 and February 2019, 10,392 patients were on systemic treatment, 358 had unscheduled inpatient care and were eligible for inclusion, and 285 were included. The mean age was 60.9 years, 50.9% were male, and 17.9% of patients had hematologic cancers. The cumulative risk of acute organ failure was 39.6% (95%CI: 35 - 44), and that of intensive care unit admission among patients with acute organ failure was 15.0% (95%CI: 12 - 18). On admission, 62.1% of patients were considered not eligible for artificial organ replacement therapy. The median follow-up time was 9.5 months. Inpatient mortality was 17.5%, with an intensive care unit mortality rate of 58.8% and a median cohort survival of 134 days (95%CI: 106 - 162). In multivariate analysis, acute organ failure was associated with 6-month postdischarge mortality (HR 1.6; 95%CI: 1.2 - 2.2). CONCLUSION: The risk of acute organ failure in cancer patients admitted for unscheduled inpatient care while on systemic treatment was 39.6%, and the risk of intensive care unit admission was 15.0%. Acute organ failure in cancer patients was an independent poor prognostic factor for inpatient hospital mortality and 6-month survival.

OBJETIVO: Determinar a incidência cumulativa de falência aguda de órgão e internamento em unidade de terapia intensiva em pacientes oncológicos. MÉTODOS: Estudo de coorte prospectivo de pacientes oncológicos adultos em tratamento sistêmico antineoplásico, internados de forma não programada. RESULTADOS: Entre agosto de 2018 e fevereiro de 2019, 10.392 pacientes foram submetidos a tratamento sistêmico antineoplásico, sendo que 358 necessitaram de internamento hospitalar não programado e foram elegíveis para inclusão; por fim, 258 desses pacientes foram incluídos. A média de idade foi de 60,9 anos, e 50,9% eram do sexo masculino; 17,9% dos pacientes tinham câncer hematológico. O risco acumulado de falência de órgãos foi de 39,6% (IC95% 35 - 44) e o risco de internamento na unidade de terapia intensiva em pacientes com falência aguda de órgão foi de 15,0% (IC95% 12 - 18). À admissão em internamento, 62,1% dos pacientes foram considerados não elegíveis para terapia de substituição artificial de órgãos. O tempo mediano de seguimento foi de 9,5 meses. A mortalidade hospitalar foi de 17,5%, na unidade de terapia intensiva de 58,8%. A mediana de sobrevivência da coorte foi de 134 dias (IC95% 106 - 162). Na análise multivariada, a falência aguda de órgão se associou com a mortalidade aos 6 meses após a alta (hazard ratio: 1,6; IC95% 1,2 - 2,2). CONCLUSÃO: O risco de falência aguda de órgão em pacientes oncológicos admitidos para tratamento hospitalar não programado durante o tratamento sistémico foi de 39,6% e o risco de internamento em unidade de terapia intensiva foi de 15,0%. A falência aguda de órgão em pacientes oncológicos foi um fator de prognóstico independente para maior mortalidade intra-hospitalar e menor sobrevivência aos 6 meses após a alta.

Falência aguda de órgão e risco de admissão em unidade de terapia intensiva nos pacientes oncológicos: estudo de coorte prospectivo unicêntrico / Acute organ failure and risk of admission to intensive medical care in cancer patients: a single center prospective cohort study

RESUMO Objetivo: Determinar a incidência cumulativa de falência aguda de órgão e internamento em unidade de terapia intensiva em pacientes oncológicos. Métodos: Estudo de coorte prospectivo de pacientes oncológicos adultos em tratamento sistêmico antineoplásico, internados de forma não programada. Resultados: Entre agosto de 2018 e fevereiro de 2019, 10.392 pacientes foram submetidos a tratamento sistêmico antineoplásico, sendo que 358 necessitaram de internamento hospitalar não programado e foram elegíveis para inclusão; por fim, 258 desses pacientes foram incluídos. A média de idade foi de 60,9 anos, e 50,9% eram do sexo masculino; 17,9% dos pacientes tinham câncer hematológico. O risco acumulado de falência de órgãos foi de 39,6% (IC95% 35 - 44) e o risco de internamento na unidade de terapia intensiva em pacientes com falência aguda de órgão foi de 15,0% (IC95% 12 - 18). À admissão em internamento, 62,1% dos pacientes foram considerados não elegíveis para terapia de substituição artificial de órgãos. O tempo mediano de seguimento foi de 9,5 meses. A mortalidade hospitalar foi de 17,5%, na unidade de terapia intensiva de 58,8%. A mediana de sobrevivência da coorte foi de 134 dias (IC95% 106 - 162). Na análise multivariada, a falência aguda de órgão se associou com a mortalidade aos 6 meses após a alta (hazard ratio: 1,6; IC95% 1,2 - 2,2). Conclusão: O risco de falência aguda de órgão em pacientes oncológicos admitidos para tratamento hospitalar não programado durante o tratamento sistémico foi de 39,6% e o risco de internamento em unidade de terapia intensiva foi de 15,0%. A falência aguda de órgão em pacientes oncológicos foi um fator de prognóstico independente para maior mortalidade intra-hospitalar e menor sobrevivência aos 6 meses após a alta.

ABSTRACT Objective: To ascertain the cumulative incidence of acute organ failure and intensive care unit admission in cancer patients. Methods: This was a single-center prospective cohort study of adult cancer patients admitted for unscheduled inpatient care while on systemic cancer treatment. Results: Between August 2018 and February 2019, 10,392 patients were on systemic treatment, 358 had unscheduled inpatient care and were eligible for inclusion, and 285 were included. The mean age was 60.9 years, 50.9% were male, and 17.9% of patients had hematologic cancers. The cumulative risk of acute organ failure was 39.6% (95%CI: 35 - 44), and that of intensive care unit admission among patients with acute organ failure was 15.0% (95%CI: 12 - 18). On admission, 62.1% of patients were considered not eligible for artificial organ replacement therapy. The median follow-up time was 9.5 months. Inpatient mortality was 17.5%, with an intensive care unit mortality rate of 58.8% and a median cohort survival of 134 days (95%CI: 106 - 162). In multivariate analysis, acute organ failure was associated with 6-month postdischarge mortality (HR 1.6; 95%CI: 1.2 - 2.2). Conclusion: The risk of acute organ failure in cancer patients admitted for unscheduled inpatient care while on systemic treatment was 39.6%, and the risk of intensive care unit admission was 15.0%. Acute organ failure in cancer patients was an independent poor prognostic factor for inpatient hospital mortality and 6-month survival.

Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications.

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer, but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in patients with AML at diagnosis and explored the mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile, not associated with inflammation or transfusion, characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.

Type I tympanoplasty in pediatric age - The results of a tertiary hospital.

INTRODUCTION: The performance of pediatric tympanoplasty is a matter of controversy in the literature, varying from 35 to 94%. Several authors argue that the performance of tympanoplasty should be delayed until 6-8 years old or even after 10 years old. OBJECTIVES: To analyze the results of type I tympanoplasty in pediatric age and to identify possible prognostic factors. MATERIAL AND METHODS: Retrospective study of children undergoing type I tympanoplasty (Portmann's classification) between January 2012 and December 2018 in our hospital. The following variables were analyzed: age, gender, etiology, size and location of the perforation, operated ear, season of the surgery, experience of the surgeon, condition of the contralateral ear, previous otologic surgery, previous adenoidectomy, presence of tympanosclerosis, surgical approach, type of graft, tympanoplasty technique, pre and postoperative audiometric results and follow-up time. The integrity of tympanic membrane (TM) was defined as anatomical success at 6 months postoperatively and as functional success we defined a pure tone average < 20 dB (mean of 0.5-4 KHz) in postoperative tonal audiometry, performed between 3 and 6 months after surgery. RESULTS: A total of 48 ears operated on 38 patients, aged between 8 and 17 years. Anatomical and functional success rates of 81.3% and 87.5%, respectively, were obtained. The only statistically significant poor prognostic factor was the presence of tympanosclerosis plaques in the middle ear, negatively affecting anatomical success (p = 0.007) and functional success (p = 0.008). There was an anatomical failure rate of 25% in the anterior and lower TM perforations, 14.3% in central and 7.7% in posterior perforations (p = 0.603). Perforations >50% of the TM surface showed a functional failure rate of 25% vs. 10% in perforations <50% of the TM (p = 0.242) and anatomical failure rates of 12.5% vs. 20%, respectively (p = 0.620). Regarding age, the group <12 years had an anatomical success rate of 85.7%, while the group ≥12 years had a rate of 79.4% (p = 0.611). As for the functional success rates, this was 92.9% and 85.3%, respectively (p = 0.471). Apart from the presence of tympanosclerosis, no other variable was statistically significantly associated with surgical success. CONCLUSIONS: Our study shows that type I tympanoplasty in pediatric age is a procedure with a high rate of anatomical and functional success. The presence of tympanosclerosis plaques in the middle ear was the only factor associated with poor anatomical and functional prognosis. Contrary to what has been described in some articles in the literature, in this study, the functional and anatomical success rates did not vary according to the age group.

Disseminated Saprochaete capitata fungal infection in a patient with acute myeloid leukemia.

The case highlights the importance of actively obtaining informative samples at an early stage and of prompt initiation of combination therapy with antifungal drugs.

Foreign Body in the Eustachian Tube: A Challenging Diagnosis and Management.

Foreign bodies in the external ear are very common. The same cannot be said about foreign bodies in the Eustachian tube (ET). We report the case of a 63-year-old woman with a history of painless left side otorrhea and hearing loss. She reported a left ear surgery when she was 30-year-old but she did not know the diagnosis that was made at that time neither the kind of surgery performed. Otoscopic examination revealed an inferior perforation of the eardrum. Audiologic evaluation demonstrated a unilateral, moderate-severe mixed hearing loss. Computed tomography scan showed, in left ear, a soft tissue density filling the middle ear cavity and a foreign body in ET. The patient underwent middle ear exploration which required endoscopic assistance to visualize and remove the foreign body. It appeared to be a stapes prothesis of Robinson type. The displacement of a stapes prosthesis to the ET has not been reported in the literature. Surgeries in this region are challenging. This case highlights the importance of the integration of endoscopy into otologic surgery.

The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy.

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in "inflamm-aging" and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

Otolaryngologist's role in the diagnosis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive and late-onset fatal neurodegenerative disease characterised by selective death of motor neurons. The aetiology of ALS is still unknown and it is extremely heterogeneous in genetics and clinical presentation, being the respiratory failure the usual cause of death. We describe a case of a 61-year-old male patient referred to the otolaryngology consultation for a 6-month history of progressive solid dysphagia and dysphonia. The patient presented several voice alterations such as a dysarthric speech with hypernasal voice which evoked the hypothesis of a neuromuscular disease. That patient was observed by a neurologist and was submitted to an electromyography that confirmed the ALS diagnosis. This case highlights the key role of otolaryngologists in the diagnosis of ALS, in a way that many patients with a bulbar ALS form are initially studied by an otolaryngologist.

Generation of neighbor-labeling cells to study intercellular interactions in vivo.

Understanding cell-cell interactions is critical in most, if not all, research fields in biology. Nevertheless, studying intercellular crosstalk in vivo remains a relevant challenge, due mainly to the difficulty in spatially locating the surroundings of particular cells in the tissue. Cherry-niche is a powerful new method that enables cells expressing a fluorescent protein to label their surrounding cells, facilitating their specific isolation from the whole tissue as live cells. We previously applied Cherry-niche in cancer research to study the tumor microenvironment (TME) in metastasis. Here we describe how to generate cancer cells with the ability to label their neighboring cells (within the tumor niche) by transferring a liposoluble fluorescent protein. Live niche cells can be isolated and compared with cells distant from the tumor bulk, using a variety of ex vivo approaches. As previously shown, this system has the potential to identify novel components in the TME and improve our understanding of their local interactions. Importantly, Cherry-niche can also be applied to study potential cell-cell interactions due to in vivo proximity in research fields beyond cancer. This protocol takes 2-3 weeks to generate the labeling cells and 1-2 weeks to test their labeling ability.