Aeromonas sobria Induced Sepsis Complicated with Necrotizing Fasciitis in a Child with Acute Lymphoblastic Leukemia

Aeromonas species are gram negative and able to induce systemic diseases (i.e., gastrointestinal, respiratory, and cardiovascular, diseases, in addition to infection of brain and soft tissues). In this study, we describe the development of necrotizing fasciitis in a young immunocompromised girl, with a low response to drug treatment and who died after some months

Reduced platelet glycoprotein Ibα shedding accelerates thrombopoiesis and COX-1 recovery: implications for aspirin dosing regimen

Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity during the 24-hour dosing interval. We previously showed that incomplete suppression of TXA2 over 24 hours can be rescued by a twice daily aspirin regimen. Here we show that reduced PLT glycoprotein (GP)Ibα shedding characterizes patients with accelerated COX-1 recovery and may contribute to higher thrombopoietin (TPO) production and higher rates of newly formed PLT, escaping aspirin inhibition over 24 hours. Two hundred aspirin-treated patients with high CV risk (100 with type 2 diabetes mellitus) were stratified according to the kinetics of PLT COX-1 activity recovery during the 10- to 24-hour dosing interval. Whole proteome analysis showed that PLT from patients with accelerated COX-1 recovery were enriched in proteins involved in cell survival, inhibition of apoptosis and cellular protrusion formation. In agreement, we documented increased plasma TPO, megakaryocyte maturation and proplatelet formation, and conversely increased PLT galactose and reduced caspase 3, phosphatidylserine exposure and ADAM17 activation, translating into diminished GPIbα cleavage and glycocalicin (GC) release. Treatment of HepG2 cells with recombinant GC led to a dose-dependent reduction of TPO mRNA in the liver, suggesting that reduced GPIbα ectodomain shedding may unleash thrombopoiesis. A cluster of clinical markers, including younger age, non-alcoholic fatty liver disease, visceral obesity and higher TPO/GC ratio, predicted with significant accuracy the likelihood of faster COX-1 recovery and suboptimal aspirin response. Circulating TPO/GC ratio, reflecting a dysregulation of PLT lifespan and production, may provide a simple tool to identify patients amenable to more frequent aspirin daily dosing

Destructive, multifocal squamous-cell carcinoma nodules on the cheecks and neck of an elderly woman with a dementia syndrome

Introduction: Squamous-cell carcinoma is the second most common form of skin cancer. It can develop on normal skin, actinic keratoses, leukoplakia, and burn scars. The tumor is characterized by remarkable variability at the macroscopic and histopathologic levels. Case report: A 93-year-old woman was admitted to nursing home with a diagnosis of dementia syndrome and squamous cell nodular carcinoma on cheeks and neck region. The physical examination revealed firm, black excrescences with irregular surfaces over both cheekbones, which were roughly the size of hazelnuts. Similar nodules were present with ulcers on other areas of the face. The patient was admitted to the day hospital twice for wide excision of the tumors in the zygomatic region. Later, the neck tumors were removed, and the wound was repaired with a rotation flap after careful control of bleeding. For the latter surgery, the patient was hospitalized for a few days in a geriatric ward to ensure optimal medical care and psychological support. The histological examination revealed ulcerated, well-differentiated squamous-cell carcinoma that extended down to the subcutaneous layer. Shortly after surgery, she returned to the nursing home to resume rehabilitation and group therapy

Destructive, multifocal squamous-cell carcinoma nodules on the cheecks and neck of an elderly woman with a dementia syndrome

Introduction: Squamous-cell carcinoma is the second most common form of skin cancer. It can develop on normal skin, actinic keratoses, leukoplakia, and burn scars. The tumor is characterized by remarkable variability at the macroscopic and histopathologic levels. Case report: A 93-year-old woman was admitted to nursing home with a diagnosis of dementia syndrome and squamous cell nodular carcinoma on cheeks and neck region. The physical examination revealed firm, black excrescences with irregular surfaces over both cheekbones, which were roughly the size of hazelnuts. Similar nodules were present with ulcers on other areas of the face. The patient was admitted to the day hospital twice for wide excision of the tumors in the zygomatic region. Later, the neck tumors were removed, and the wound was repaired with a rotation flap after careful control of bleeding. For the latter surgery, the patient was hospitalized for a few days in a geriatric ward to ensure optimal medical care and psychological support. The histological examination revealed ulcerated, well-differentiated squamous-cell carcinoma that extended down to the subcutaneous layer. Shortly after surgery, she returned to the nursing home to resume rehabilitation and group therapy

A new path to platelet production through matrix sensing Title: A new path to platelet production through matrix sensing

Haematologica 2017 [Epub ahead of print] Citation: Abbonante V, Di Buduo CA, Gruppi C, De Maria C, Spedden E, De Acutis A, Staii C, Raspanti M, Vozzi G, Kaplan D, Moccia F, Ravid K, and Balduini A. A new path to platelet production through matrix sensing. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2016

Expression and functional characterization of the large-conductance calcium and voltage-activated potassium channel Kca 1.1 in megakaryocytes and platelets

BACKGROUND: Ion channels are transmembrane proteins that play important roles in cell function regulation modulating ionic cell permeability. In megakaryocytes and platelets, regulated ion flows have been demonstrated to modulate platelet production and function. However, a relatively limited characterization of ion channel expression and function is available in the human megakaryocyte-platelet lineage.OBJECTIVE: We analyzed the expression and function of the large-conductance calcium and voltage-activated potassium channel Kca 1.1 (also known as Maxi-K, BK, slo1) in human megakaryocytes and platelets.METHODS: To investigate the functionality of Kca 1.1, we exploited different agonists (BMS-191011, NS1619, NS11021, epoxyeicosatrienoic acid isoforms) and inhibitors (iberiotoxin, penitrem A) of the channel.RESULTS: In megakaryocytes, Kca 1.1 agonists determined a decreased proplatelet formation and altered interaction with the extracellular matrix. Analysis of the actin cytoskeleton demonstrated a significant decrease in megakaryocyte spreading and adhesion to collagen. In platelets, the opening of the channel Kca 1.1 led to a reduced sensitivity to agonists with blunted aggregation in response to ADP, with an inhibitory capacity additive to that of aspirin. The Kca 1.1 agonists, but not the inhibitors, determined a reduction of platelet adhesion and aggregation onto immobilized collagen underflow to an extent similar to that of aspirin and ticagrelor. The opening of the Kca 1.1 resulted in cell hyperpolarization impairing free intracellular calcium in ADP-stimulated platelets and megakaryocytes.CONCLUSIONS: The present study reveals new mechanisms in platelet formation and activation, suggesting that targeting Kca 1.1 channels might be of potential pharmacological interest in hemostasis and thrombosis

A new path to platelet production through matrix sensing

Megakaryocytes (MK) in the bone marrow (BM) are immersed in a network of extracellular matrix components that regulates platelet release into the circulation. Combining biological and bioengineering approaches, we found that the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4), a mechano-sensitive ion channel, is induced upon MK adhesion on softer matrices. This response promoted platelet production by triggering a cascade of events that lead to calcium influx, \uce\ub21 integrin activation and internalization, and Akt phosphorylation, responses not found on stiffer matrices. Lysyl oxidase (LOX) is a physiological modulator of BM matrix stiffness via collagen crosslinking. In vivo inhibition of LOX and consequent matrix softening lead to TRPV4 activation cascade and increased platelet levels. At the same time, in vitro proplatelet formation was reduced on a recombinant enzyme-mediated stiffer collagen. These results suggest a novel mechanism by which MKs, through TRPV4, sense extracellular matrix environmental rigidity and release platelets accordingly

Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients withmyeloproliferative neoplasms

About one fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of CALR, the gene encoding for calreticulin. A 52-bp deletion (Type I mutation) and a 5-bp insertion (Type II mutation) are the most frequent genetic lesions. The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and Store Operated Calcium (Ca2+) Entry (SOCE) machinery in megakaryocytes from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms. In megakaryocytes from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of STAT5, AKT and ERK1/2, determining inositol triphosphate (IP3)-dependent Ca2+ release from the endoplasmic reticulum. This resulted in the dissociation of the ERp57-mediated complex between calreticulin and STIM1, a protein of the SOCE machinery that leads to Ca2+ mobilization. In megakaryocytes from patients with CALR-mutated myeloproliferative neoplasms, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal megakaryocyte proliferation that was reverted employing a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca2+ flows in megakaryocytes contributes to the pathophysiology of CALR-mutated myeloproliferative neoplasms. In perspective, SOCE may represent a new therapeutic target to counteract megakaryocyte proliferation and its clinical consequences in myeloproliferative neoplasms