Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury

Exposure to a moderate or high total-body dose of radiation induces not only acute bone marrow suppression but also residual (or long-term) bone marrow injury. The induction of residual bone marrow injury is primarily attributed to the induction of hematopoietic cell senescence by ionizing radiation. However, the mechanisms underlying radiation-induced hematopoietic cell senescence are not known and thus were investigated in the present study. Using a well-established long-term bone marrow cell culture system, we found that radiation induced hematopoietic cell senescence at least in part via activation of p38 mitogen-activated protein kinase (p38). This suggestion is supported by the finding that exposure to radiation selectively activated p38 in bone marrow hematopoietic cells. The activation was associated with a significant reduction in hematopoietic cell clonogenic function, an increased expression of p16(INK4a) (p16), and an elevated senescence-associated β-galactosidase (SA-β-gal) activity. All these changes were attenuated by p38 inhibition with a specific p38 inhibitor, SB203580 (SB). Selective activation of p38 was also observed in bone marrow hematopoietic stem cells (HSCs) after mice were exposed to a sublethal total-body dose (6.5 Gy) of radiation. Treatment of the irradiated mice with SB after total-body irradiation (TBI) increased the frequencies of HSCs and hematopoietic progenitor cells (HPCs) in their bone marrow and the clonogenic functions of the irradiated HSCs and HPCs. These findings suggest that activation of p38 plays a role in mediating radiation-induced hematopoietic cell senescence and residual bone marrow suppression.     

Chronic renal failure in Nottingham and requirements for dialysis and transplantfacilities.

A retrospective study of uraemic patients covering 12 months of 1970 and a prospective survey covering six months in 1973-4 is reported for a population of almost 3/4million. The number of patients requiring regular dialysis treatment or transplantation or both is considered to be 45 per million of population under 65, 39 per million under 60, and 29 per million under 50 years of age.     

Chronic myelomonocytic leukemia: light and electron microscopy of the bone marrow.

Clinical data and light and electron microscopic findings are presented in a patient with chromic myelomonocytic leukemia of about 5 years' duration and no need for specific therapy. Cytogenetic studies failed to demonstrate a Philadelphia-chromosome. The leading clinical symptoms were anemia, moderate hepatomegaly, and leukocytosis with monocytes in the peripheral blood count. Light microscopy of bone marrow cores showed hypercellularity of neutrophil granulocytic and monocytic cell lines including some precursor forms. Electron microscopy confirmed the existence of a biphasic myelomonocytic cell proliferation with predominance of mature forms in both lineages; there were no gross cellular abnormalities and no "hiatus leukaemicus". Consupicuous were cells of an undeterminated origin apparently neither belonging to the neutrophil granulocytic nor monocytic series and large histiocytic cells, possibly corresponding to the so-called sea-blue histiocytes of light microscopy. The high degree of maturation of both cell lines in the bone marrow is in accordance with the relatively benign and prolongated course of this rare type of leukemia.     

Chronic renal failure and anterior hypophysial hormones

Kidneys are not only organs with an excretory function but they produce their own endocrine factors which are involved in supporting homeostasis in the organism. The kidneys are the organs in which metabolism and biodegradation of many hormones take place. Together with the liver, the kidneys actively take part in the catabolism of hormones.     

骨髓基质细胞与神经损伤和神经退行性疾病

骨髓基质细胞(bone marrow stromal cells,BMSCs)又名成纤维细胞样克隆形成单位(fibroblast colonyforming units,CFU-F)、间质干细胞(mesenchymal stem cells,MSCs)、间质祖细胞(mesenchymal progenitor cells．MPCs)。本文统一用BMSCs这一概念,对其生物学特性及其神经损伤修复作用进行综述。     

Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure

Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired β-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.     

Role of apoptosis in congenital hematologic disorders and bone marrow failure

Apoptosis, the cell's intrinsic death program, plays a critical role in the regulation of tissue homeostasis, especially in cell systems with a high turnover rate such as hematopoiesis. Imbalances between survival, proliferation and death of precursor cells or mature cells may result in accelerated loss or impaired output or uncontrolled polyclonal or monoclonal expansion and may pave the way to the development of leukemia. Congenital hematologic disorders are characterized by disturbed growth control of hematopoietic cells. In the previous years, it has become clear that deregulated apoptosis contributes or is even a key determinator of the pathophysiology of diseases such as lymphoproliferation, aplastic anemia or chronic neutropenia. Hematopoietic growth factors have been shown not only to stimulate proliferation of hematopoietic stem cells and committed precursor cells, but also to act as survival factors protecting developing precursor cells from apoptotic signals. The molecular delineation of pathways of apoptosis signaling or survival in hematopoietic cells is expected to provide tools for molecular understanding of the pathophysiology of congenital and acquired hematopoietic disorders and to identify targets for therapeutic intervention strategies.