Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.

/pdf/macrophage-phagocytosis-of-aging-neutrophils-in-inflammation-44m282ek1c.pdf

Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.

The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system. These defects result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defects of cell-mediated immunity. These two broad categories of illness correspond roughly to defects in the two principal types of immunocompetent cells, B lymphocytes and T lymphocytes. Defective development of B cells results in abnormalities in humoral immunity, whereas defects in the development of T cells cause problems with cellular immunity. When pathogens are taken up by macrophages or dendritic cells, . . .

The Primary Immunodeficiencies

Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin and pentostatin. Cardiotoxicity is rare with some agents, but may occur in >20% of patients treated with doxorubicin, daunorubicin or fluorouracil. Cardiac events may include mild blood pressure changes, thrombosis, electrocardiographic changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure) and congestive heart failure. These may occur during or shortly after treatment, within days or weeks after treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy. A number of risk factors may predispose a patient to cardiotoxicity. These are: cumulative dose (anthracyclines, mitomycin); total dose administered during a day or a course (cyclophosphamide, ifosfamide, carmustine, fluorouracil, cytarabine); rate of administration (anthracyclines, fluorouracil); schedule of administration (anthracyclines); mediastinal radiation; age; female gender; concurrent administration of cardiotoxic agents; prior anthracycline chemotherapy; history of or pre-existing cardiovascular disorders; and electrolyte imbalances such as hypokalaemia and hypomagnesaemia. The potential for cardiotoxicity should be recognised before therapy is initiated. Patients should be screened for risk factors, and an attempt to modify them should be made. Monitoring for cardiac events and their treatment will usually depend on the signs and symptoms anticipated and exhibited. Patients may be asymptomatic, with the only manifestation being electrocardiographic changes. Continuous cardiac monitoring, baseline and regular electrocardiographic and echocardiographic studies, radionuclide angiography and measurement of serum electrolytes and cardiac enzymes may be considered in patients with risk factors or those with a history of cardiotoxicity. Treatment of most cardiac events induced by chemotherapy is symptomatic. Agents that can be used prophylactically are few, although dexrazoxane, a cardioprotective agent specific for anthracycline chemotherapy, has been approved by the US Food and Drug Administration. Cardiotoxicity can be prevented by screening and modifying risk factors, aggressively monitoring for signs and symptoms as chemotherapy is administered, and continuing follow-up after completion of a course or the entire treatment. Prompt measures such as discontinuation or modification of chemotherapy or use of appropriate drug therapy should be initiated on the basis of changes in monitoring parameters before the patient exhibits signs and symptoms of cardiotoxicity.

Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention.

Familial hemophagocytic lymphohistiocytosis (FHL) is probably a genetically transmitted disease affecting infants and very young children. Cardinal symptoms are fever, hepatosplenomegaly, and pancytopenia. Frequently meningeal involvement is seen, manifested by neurologic symptoms and a lymphohistocytic pleocytosis with increased protein levels in the cerebrospinal fluid. Characteristic laboratory findings in FHL are hypertriglyceridemia and hypofibrinogenemia, which are reversible with treatment. The disease has been rapidly fatal in most patients, but recently longterm remissions have been achieved with cytotoxic agents.

https://www.hemonc.theclinics.com/article/S0889-8588(05)70520-7/pdf

Familial hemophagocytic lymphohistiocytosis

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

Fatal epstein-barr virus-associated hemophagocytic syndrome

Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection

Four patients with non-Hodgkin lymphoma and two with acute lymphocytic leukemia (ages 4 and 4 months to 16 years 6 months) exhibited a unique reaction to intravenously administered cytosine arabinoside (Ara-C) given alone as a part of the previously reported LSA2-L2 treatment protocol. The syndrome was characterized by fever, myalgia, bone pain, and occasionally by chest pain, maculopapular rash, and conjunctivitis. Each of the eleven episodes of this syndrome occurred within 6-12 hours of drug infusion and always abated after cessation of Ara-C. Prior to the reaction, patients had been on therapy for an average of 13.5 months during which they were exposed to 2298-5387 mg/m2 (mean of 3200 mg/m2) of Ara-C. The high incidence of this syndrome (50% of our patients on the LSA2-L2 regimen and 33% of those receiving Ara-C) has not been previously reported. Considering the prolonged exposure to Ara-C and our inability to document infections in the patients or pyrogens contaminating the drug lots, the most likely explanation for this syndrome is a hypersensitivity reaction to Ara-C. Prevention of these symptoms with corticosteroids supports this contention and provides a reasonable alternative to discontinuing Ara-C.

The cytosine arabinoside (Ara-C) syndrome.

Congenital dysgranulopoietic neutropenia: clinical, serologic, ultrastructural, and in vitro proliferative characteristics.

Previous ultrastructural investigation have not identified abnormal lysosomes in platelets obtained from humans or animals with the Chediak-Higashi Syndrome. We report here a patient whose megakaryocytes and platelets were found to contain giant granules when viewed by light and electron microscopy. The granules measured up to 1.5 micrometer in diameter, contained either homogeneous or heterogeneous material, were acid phosphatase positive, and were present in approximately 30% of bone marrow megakaryocytes and 5% of circulating platelets. A decrease was observed in serotonin containing dense granules, serotonin uptake and serotonin release as reported previously. Microtubules in platelets and megakaryocytes were intact and no other morphologic abnormalities were identified. No clinical evidence of bleeding was observed in this patient and platelet counts have been normal. The lack of giant platelet lysosomes in other reported cases of Chediak-Higashi Syndrome attests to significant heterogeneity in this disease with a spectrum of clinical and laboratory findings.

Ahmad Malluh

Papers

Fatal epstein-barr virus-associated hemophagocytic syndrome

Wiskott-Aldrich syndrome: cellular impairments and their implication for carrier detection

The cytosine arabinoside (Ara-C) syndrome.

Congenital dysgranulopoietic neutropenia: clinical, serologic, ultrastructural, and in vitro proliferative characteristics.

Giant platelet granules in a child with the Chediak-Higashi syndrome.