ABSTRACT
OBJECTIVE: We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). METHOD: We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. RESULTS: Testing early vs delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks (wks) following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1-4 wks post-surgery or moderate, 4-8 wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. CONCLUSIONS: Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.
Subject(s)
Benzoxazines/pharmacology , Bone and Bones/drug effects , Cartilage, Articular/drug effects , Chondrocytes/drug effects , Menisci, Tibial/drug effects , Osteoarthritis/pathology , Receptors, CCR2/antagonists & inhibitors , Spiro Compounds/pharmacology , Animals , Bone and Bones/pathology , Disease Models, Animal , Disease Progression , Hypertrophy , Matrix Metalloproteinase 13/drug effects , Matrix Metalloproteinase 13/metabolism , Menisci, Tibial/surgery , Mice , Osteoarthritis/metabolism , Osteophyte , Receptors, CCR2/physiology , Sclerosis , Tibial Meniscus InjuriesABSTRACT
We report an unusual lethal complication of sickle cell anemia. The patient was admitted with a diagnosis of acute chest syndrome and died shortly after that of respiratory failure. Autopsy revealed numerous deposits of bone marrow hematopoietic tissue occluding the microvascular circulation of the lung. Many causes of acute chest syndrome in sickle cell anemia have been identified, including bone marrow infarction leading to embolism of bone marrow fat. However, the release of bone marrow hematopoietic tissue leading to pulmonary vascular occlusion is not generally recognized premortem by treating physicians.
Subject(s)
Bone Marrow/pathology , Embolism, Fat/pathology , Hemoglobin SC Disease/pathology , Pulmonary Embolism/pathology , Adult , Diagnosis, Differential , Fatal Outcome , Female , Hematopoietic Stem Cells/pathology , Humans , Pulmonary Artery/pathologyABSTRACT
Tendonitis is a common diagnosis in sports medicine. The traditional view of tendonitis is a tendon injury resulting from repetitive mechanical load with a subsequent inflammatory response. The English literature from 1966 to the present on the etiology, diagnosis, and treatment of tendonitis was evaluated. There is some scientific support in the literature for the diagnosis of tenosynovitis and tendinosis as a pathologic entity. Actual inflammation of tendon tissue consistent with tendonitis has not been seen clearly in patho-anatomic studies. Conclusive evidence confirming that repetitive mechanical load is a major etiologic factor could not be found. Similarly, strength deficits, inflexibility, and improper equipment have not been studied in a controlled prospective manner. Other factors such as age and tendon vascularity have been consistently correlated with these injuries although their overall importance remains difficult to assess. There are no controlled studies on treatment through physical therapy aimed at flexibility and/or strengthening. Treatment with anti-inflammatory drugs has been studied extensively. However, only nine of 32 studies are prospective and placebo controlled. Some pain relief was found in five of the nine controlled studies, but healing of the tendon problem was not studied in these short follow-up studies. Twenty-three studies on steroid injections were found. Eight were prospective and placebo controlled studies, with three showing beneficial effects of the injection at follow-up. It was concluded that much of the pathology and etiology of tendonitis remains unclear. The possibility must be considered that current treatment methods may not significantly affect the natural history.
Subject(s)
Tendinopathy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Chronic Disease , Exercise Therapy , Humans , Tendinopathy/diagnosis , Tendinopathy/etiology , Tendinopathy/therapy , Tenosynovitis/diagnosis , Tenosynovitis/etiology , Tenosynovitis/therapyABSTRACT
We report the successful and maintained response of lymphomatoid granulomatosis using a new approach to therapy, cyclosporin-A, after failure of aggressive multiagent chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Lung Diseases/therapy , Lymphomatoid Granulomatosis/therapy , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/pathology , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclosporine/pharmacology , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Humans , Immunosuppressive Agents/pharmacology , Lung Diseases/diagnosis , Lung Diseases/drug therapy , Lung Diseases/pathology , Lymphomatoid Granulomatosis/diagnosis , Lymphomatoid Granulomatosis/drug therapy , Lymphomatoid Granulomatosis/pathology , Male , Mechlorethamine/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Prednisone/administration & dosage , Procarbazine/administration & dosage , Recurrence , Remission Induction , Salvage Therapy , Vincristine/administration & dosageABSTRACT
We report a patient who at the time of kidney transplantation for polycystic kidney disease was found to have an enlarged inguinal lymph node which later demonstrated evidence of extra medullary granulopoiesis. During the first two weeks following kidney transplantation, a striking leukemoid pattern developed and 2 months after transplant the patient was diagnosed with acute myelogenous leukemia (AML). Retrospective analysis of peripheral blood cytokines over this time revealed elevated levels of GMCSF and gamma IFN at the time of peak peripheral blood WBC with subsequent peaks in IL-4, IL-6 and IL-2 as the peripheral blood WBC fell. A rise in levels of TNF alpha also preceded the peripheral blood WBC rise (although these concentrations were at or below those following uncomplicated kidney transplants). The clinical course of AML in this patient was marked by relentless relapse despite chemotherapy. The possibility of cytokine facilitated tumor growth is discussed.
Subject(s)
Cytokines/blood , Kidney Transplantation/immunology , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/immunology , Adult , Female , Follow-Up Studies , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Humans , Interferon-gamma/blood , Interleukin-2/blood , Interleukin-4/blood , Interleukin-6/blood , Kidney Failure, Chronic/surgery , Polycystic Kidney Diseases/complications , Polycystic Kidney Diseases/surgery , Retrospective Studies , Time Factors , Tumor Necrosis Factor-alpha/analysisABSTRACT
The high incidence of cancer in the rapidly expanding geriatric population presents a major challenge to the health care field. Since most cancers present and behave similarly in both older and younger persons, similar approaches to management must be considered in both. The elderly, however, are a heterogeneous group with individuals demonstrating varying degrees of comorbidity and physiologic change. Decisions, therefore, should be based on a sound knowledge of geriatric assessment and the factors important for "successful" aging rather than on chronological age alone.
Subject(s)
Aging , Neoplasms , Age Factors , Aged , Aged, 80 and over , Female , Humans , Male , Neoplasms/pathology , Neoplasms/prevention & control , Neoplasms/therapyABSTRACT
The optimum therapy for hairy cell leukemia (HCL) is controversial. Dramatic responses to interferon-alpha and 2'-deoxycoformycin overshadow the established role of splenectomy in HCL, and patients currently can avoid surgery altogether. A case is presented of clinical remission lasting 32 years after splenectomy--a prolonged normal life, without medication or medical intervention. When relapse occurred, the patient's response to interferon-alpha was prompt and predictable. Prognostic variables are an important consideration at the time of diagnosis in predicting the response to splenectomy.
Subject(s)
Leukemia, Hairy Cell/therapy , Aged , Humans , Interferon Type I/therapeutic use , Male , Recurrence , Remission Induction , Splenectomy , Time FactorsABSTRACT
The phagocytic activity of peripheral blood monocytes from sickle cell disease patients and normal controls was studied using a monocyte monolayer assay. Phagocytosis of antibody-coated red cells by monocytes from patients in stable condition and in normal controls did not differ significantly (7.1 +/- 1.5 vs. 5.3 +/- 0.9%). However, monocytes from sickle cell disease patients during vasoocclusive crises demonstrated increased phagocytic activity compared to the normal controls (11.0 +/- 2.7 vs. 5.3 +/- 0.9%, p less than 0.025). Numerous defects in immune response have been described in association with sickle cell disease. However, monocyte phagocytic activity is not deficient and is not a factor in the predisposition to infections.
Subject(s)
Anemia, Sickle Cell/blood , Monocytes/physiology , Phagocytosis , Adult , Anemia, Sickle Cell/complications , Humans , Vascular Diseases/blood , Vascular Diseases/etiologyABSTRACT
Infection by parvovirus B19 is common and may become chronic if the patient is immunocompromised, leading to persistent erythroid hypoplasia. Parvovirus should be added to the list of pathogens that can complicate the course of HIV infection and should be considered in the evaluation of severe anemia or red cell aplasia in any immunocompromised patient.
Subject(s)
Acquired Immunodeficiency Syndrome/complications , Parvoviridae Infections/complications , Parvoviridae/classification , Red-Cell Aplasia, Pure/etiology , Adult , DNA, Viral/analysis , Humans , Male , Parvoviridae/geneticsSubject(s)
Colony-Stimulating Factors/therapeutic use , Erythropoietin/therapeutic use , Hematologic Diseases/drug therapy , Acquired Immunodeficiency Syndrome/complications , Anemia, Aplastic/drug therapy , Hematologic Diseases/etiology , Hematopoiesis/drug effects , Humans , Myelodysplastic Syndromes/drug therapy , Recombinant Proteins/therapeutic useABSTRACT
A 28-year-old woman in the third trimester of her pregnancy was found to have acute myelocytic leukemia. The baby was delivered by Cesarean section and her leukemia underwent spontaneous remission. However, 3 months later, she presented with massive painful leukemic infiltration of the breasts as initial manifestation of relapse, followed by systemic symptoms of leukemia. In vitro culture of the leukemic cells demonstrated characteristics of macrophage cell line. This case illustrates a unique sequence of events: spontaneous remission after the termination of pregnancy, which has profound hormonal alterations, and relapse in a very hormone-sensitive organ, the breast, a few months later when the hormonal milieu was resumed. This suggests hormonal dependence of her leukemic cells and potential for hormonal manipulation in a certain subset of human leukemia.
Subject(s)
Leukemia, Myeloid, Acute/physiopathology , Pregnancy Complications, Neoplastic/physiopathology , Adult , Female , Humans , Pregnancy , Recurrence , Remission, SpontaneousABSTRACT
Danazol, an attenuated androgen, is useful in endometriosis, idiopathic thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AIHA). However, its mechanism of action is unknown. We investigated the possibility that danazol affects cell membranes directly. Red cell osmotic fragility was studied in patients receiving danazol. A significant decrease in osmotic fragility was observed. Accompanying the change, peripheral blood smears showed many target cells and electron microscopy revealed extra folds in erythrocyte membranes. Twenty-two patients were studied prospectively before and after danazol. Osmotic fragility decreased significantly (P less than 0.001) in 1 month of therapy and progressed with further treatment. A rebound increase (P less than 0.01) was observed in 1 month after discontinuation of danazol among 16 patients. Incubation experiments showed that danazol-induced changes are not reversed with normal sera. Patient sera did not induce the changes in normal red cells. Danazol in vitro protected red cells from osmotic lysis at low concentrations but enhanced lysis at high concentrations. We suggest that danazol alters red cell membranes directly to increase their surface area, inducing target cell formation and increasing their resistance to osmotic lysis.
Subject(s)
Danazol/pharmacology , Erythrocyte Membrane/drug effects , Osmotic Fragility/drug effects , Pregnadienes/pharmacology , Humans , In Vitro Techniques , Prospective StudiesABSTRACT
Corrosion of compressed air breathing tanks may result in dangerous oxygen depletion. In every SCUBA mishap the residual air should have, as one of the tests, a measurement of oxygen content. The tank should also have a visual inspection. All compressed air breathing tanks should have a routine visual inspection on a regular basis, even if the tank is made or lined with corrosion resistant material.