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At least 1,711 records · Page 95Linked to original sources
PubMed2002

Early-stage idiopathic (primary) myelofibrosis--current issues of diagnostic features.

Idiopathic myelofibrosis (IMF) is generally characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and a leuko-erythroblastic blood picture. Although, histopathology is in keeping with the assumption of a stepwise evolution of the disease, little hematological data are available for patients with prefibrotic and early stages of disease. Therefore a clinicopathological study was performed that included firstly an exploratory sample of 68 patients with minor supportive therapy in whom BM biopsies during follow-up (41 +/- 32 months) revealed an evolution of a prefibrotic or very early fibrotic lesion into overt IMF. The validation sample consisted of 556 patients with pretreatment marrow specimens on admission. Diagnostic features and BM lesions were identical compared with the patients of the exploratory sample at their first examination. BM biopsies were processed by routine stainings including silver impregnation (reticulin fibers) and frequently also by immunohistochemistry to identify megakaryocytes and erythroid precursor cells more properly. Apart from minor hemorrhage and peripheral thrombosis patients with early stage IMF presented with non-specific symptoms including varying degrees of leukocytosis (51%), anemia (38%), a platelet count exceeding 600 x 10(9)/l (86%), splenomegaly (15%) and increase in leukocyte alkaline phosphatase (LAP) (24%) and serum lactate dehydrogenase (LDH) (20%). BM histology confirmed a moderate increase in hematopoiesis with a mixed granulocytic and megakaryocytic myeloproliferation, a reduction of erythroid precursors and significant megakaryocytic abnormalities. In keeping with the first BM examination of the exploratory sample no or only a borderline to slight increase in reticulin fibers was detectable, however, in 68 of 134 patients follow-up biopsies revealed a transition into overt IMF (intervals about three years). Median survival of this cohort with early-stage IMF was 129 months thus contrasting manifest IMF with an usually more unfavorable prognosis. Recognition of early stage IMF certainly alters the generally applied diagnostic criteria of this disorder. Regarding patients with associated thrombocytosis, differentiation from essential thrombocythemia is recommended. Moreover, characterization of early stage IMF probably exerts an impact on survival and may influence the decision to perform a BM transplantation.

Adult↗
PubMed2005

Importance of plasma matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinase (TIMP) in development of fibrosis in agnogenic myeloid metaplasia.

Tissue inhibitors of metalloproteinase (TIMP) and matrix metalloproteinases (MMP) are key elements in the formation, remodeling and degradation of matrix protein. Bone marrow fibrosis in AMM, with deposition, not only of interstitial and basement membrane collagen but also of fibronectin, vitronectin, laminin and proteoglycans, results from a disturbed balance between synthesis and proteolytic degradation of matrix protein. Although TIMP and MMP play important roles in the development of fibrosing diseases of skin, liver and lung, only a few studies of TIMP and MMP in the formation of bone marrow fibrosis in AMM have been published. The literature shows that TIMP-1 (both the total, complex and the free form) is significantly increased in AMM and other myeloproliferative syndromes (including polycythemia vera (PV) and essential thrombocytosis (ET)), while MMP-3 is significantly decreased, and levels of MMP-2 and MMP-9 are not different from control values. Variance from control values for both TIMP-1 and MMP-3 is more evident in AMM than in PV and ET, thus further suggesting bone marrow fibrosis in AMM results from enhanced TIMP and decreased MMP activities.

Cell Proliferation↗
PubMed2006

JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?

Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.

Animals↗
PubMed1992

Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus.

Lethally irradiated mice transplanted with bone marrow cells infected with a novel recombinant retrovirus (murine stem cell virus-interleukin 6 [MSCV-IL-6]) bearing a mouse IL-6 gene developed a fatal myeloproliferative disease within 4 wk of engraftment. The hematologic manifestations of the syndrome included elevated peripheral leukocyte counts (up to 430 x 10(3) cells/mm3) with a predominance of neutrophilic granulocytes, microcytic anemia, and thrombocytosis or thrombocytopenia. The mice showed extensive neutrophil infiltration of the lungs, liver, and occasionally lymph nodes, plus splenomegaly resulting from enhanced splenic myelopoiesis (30-60-fold increase in progenitor numbers). Despite the chronic stimulation of neutrophil excess by IL-6, bone marrow from affected mice was capable of repopulating the hematopoietic tissues (bone marrow and spleen) of lethally irradiated hosts during repeated serial transplantation. In the longest documented case, the progeny of a single MSCV-IL-6-marked cell transferred the myeloproliferative disease to two secondary, four tertiary, and two quaternary recipients (the clone endured for a total of 72 wk). These results, demonstrating considerable proliferative longevity of the IL-6-producing cells, support an in vivo role of IL-6 in the maintenance of hematopoietic precursors. Dysregulated IL-6 production also had significant systemic effects. The mice displayed increased mesangial cell proliferation in the kidney, frequent liver abnormalities, and marked alterations in plasma protein levels. Unlike previous studies where constitutive expression of exogenous IL-6 genes resulted in lymphoproliferative disorders characterized by massive plasmacytosis, minimal plasma cell expansion occurred in the MSCV-IL-6 mice during the observation period. Potential explanations for the differences in disease phenotypes observed in the present and previous studies are different cell types expressing the exogenous IL-6 genes, higher sustained circulating levels of IL-6 achieved using the MSCV-IL-6 retroviral delivery system, and/or the premature death (3-15 wk after transplantation) of the MSCV-IL-6 mice before the onset of plasmacytosis. This animal model should prove useful for further investigation of the function of IL-6 in normal and abnormal hematopoiesis and in inflammatory responses.

Animals↗
PubMed2003

Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema.

Taiwan experienced several epidemics of enterovirus 71 (EV71) infections, which were associated with brainstem encephalitis (BE) and pulmonary edema (PE). To elucidate the role of immune mechanisms in the pathogenesis of BE caused by EV71 and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of 73 EV71-infected patients with BE. Patients were stratified by disease: PE (n=14), autonomic nervous system (ANS) dysregulation (n=25), and isolated BE (n=34). The mortality rate for PE was 64.3%. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma interleukin (IL)-10, IL-13, and interferon (IFN)-gamma levels observed in patients with PE. Patients with PE also had lower circulating CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.

Brain Stem↗
PubMed1984

An analysis of the platelet and polyploid megakaryocyte response to acute thrombocytopenia and its biological implications.

Thrombocytopenia was induced in rabbit by a single injection of anti-platelet serum. The circulating platelet number and concomitant mean platelet volume were measured 6 h after the injection and daily thereafter. The megakaryocyte nuclear DNA content was measured in control rabbits and after 2 h and 24 h of thrombocytopenia respectively. The observed recovery of circulating platelet number is used to construct the variation of platelet destruction rate and platelet production rate with time during thrombocytopenia. The observed rebound thrombocytosis is explained by using a balance equation of these two rates. Platelet production is linked to the megakaryocyte by physical fragmentation theory and an explanation of the observed variation of mean platelet volume is used to obtain an estimated bleeding time and circulating platelet biomass during recovery from thrombocytopenia. An interpretation is given of the homeostatic control of megakaryocytopoiesis and thrombopoiesis.

Acute Disease↗
PubMed1979

Hemostatic abnormalities in malignancy, a prospective study of one hundred eight patients. Part I. Coagulation studies.

A prospective study of hemostatic abnormalities in 108 cancer patients was undertken at an oncology clinic in a university teaching hospital. Tests included Quick prothrombin time, activated partial thromboplastin time, thrombin time, platelet count, modified Ivy bleeding time, fibrinogen, fibrin degradation products (FDP), euglobulin lysis time, protamine sulfate test, and factor V, VII, VIII and X assays. Ninety-eight per cent of the patients had one or more abnormal coagulation tests. The commonest abnormalities were elevated fibrin degradation products and prolonged thrombin time. Thrombocytosis occurred in 57% of patients, hyperfibrinogenemia in 46%, thrombocytopenia in 11%, and non had hypofibrinogenmia. It is suggested that platelet count, fibrinogen concentration, and serum FDP assay are the most useful tests in assessing the hemostatic abnormalities in cancer patients, although thrombin time, factor V assay, and bleeding time may also be helpful. The peripheral blood smears of 53 patients were reviewed, and only one showed microangiopathic hemolytic anemia. The data illustrate that subclinical coagulopathy is relatively frequent in patients with malignancy.

Adolescent↗
PubMed1987

Evaluation of BCDE, a microcomputer program to analyze automated blood counts and differentials.

A microcomputer program (BCDE) has been developed to analyze automated blood cell counts and differentials' similarity to normal values or to 36 disease categories. In 50 normal subjects, the analytic program listed the correct diagnosis as the first diagnosis in 49 cases (the only diagnosis in 44) and second of two diagnoses in one case. In 182 subjects with known hematologic disorders, the correct diagnosis was listed first in 134 and second or third in an additional 40. Subjects with iron deficiency, heterozygous thalassemia, immune thrombocytopenia, anemia of chronic disease, reactive thrombocytosis, acute infection, and chronic leukemia had the disorder identified as the most likely one by the analytic program with both sensitivity greater than 80% and specificity greater than 98%. Subjects with acute leukemia, folate deficiency, sickle cell anemia, cytotoxic chemotherapy, and chronic liver disease had the disorder identified as most likely by the program with a sensitivity less than 80%. In a different 11 cases with known hematologic status, a panel of 37 physicians identified the disorder(s) or normality only 72% of the time, whereas the analytic program listed the correct diagnosis first in 10 of 11 (91%). The analytic program appears useful for both triage of normal from abnormal data and for the initial differential analysis of abnormal data.

Blood Cell Count↗
PubMed1989

Platelet vacuoles in acute megakaryoblastic leukemia.

The case of a 53-year-old man with acute megakaryoblastic leukemia (M7) was studied. At time of diagnosis, the platelet count was 980 X 10(9)/L and abnormal platelet vacuoles were present. The vacuoles were periodic acid-Schiff (PAS) positive. Electron microscopic examination showed large aggregates of glycogen. Findings of qualitative platelet function studies were abnormal. The authors' study and review of the literature indicates that thrombocytosis with large platelet vacuoles accompanying a blast cell population suggests a diagnosis of M7 and indicates the need for appropriate confirmatory studies.

Blood Platelets↗
PubMedDate not supplied

Imipenem/cilastatin therapy for serious bacterial infections.

Imipenem was administered intravenously with cilastatin to patients with suspected or documented significant infections. The mean peak serum level of imipenem 30 min after infusion of a 500 mg dose was 18.4 micrograms/ml, and the mean trough level (30 min before infusion) was 2.4 micrograms/ml. The organisms isolated before therapy included Enterobacteriaceae, Staphylococcus aureus, streptococci, Pseudomonas aeruginosa, and anaerobes. The response rate in 25 assessable patients was 96%, with 40% experiencing a complete cure and 56% improvement. Therapy failed in only one instance because an isolate of P. aeruginosa was mistakenly reported to be susceptible on disk testing. Toxicity in the 33 patients treated was generally minimal and included phlebitis, mild liver function abnormalities, eosinophilia, and thrombocytosis. The emergence of resistant organisms during therapy was very uncommon. Imipenem/cilastatin is a promising agent for the treatment of complicated infections.

Aged↗
PubMed1981

Kawasaki syndrome: a new infectious disease?

Kawasaki syndrome is a newly described, acute symptom complex of children that has a predictable clinical course. The acute febrile phase of the syndrome is characterized by multisystem acute inflammatory changes. The subacute phase follows with the rheumatic manifestations of arthritis, myocarditis, and thrombocytosis. The syndrome is self-limited in most children but is associated with coronary artery aneurysms in 15%--20% and sudden death due to coronary thrombosis in 2%. Vasculitis of coronary and other medium-sized muscular arteries characterizes fatal cases. The peak age affected is 12 months (range, six weeks to eight years). Japanese children are overrepresented among cases, whereas Caucasian children are underrepresented. Cases have been reported worldwide with the highest prevalence in Japan and among Japanese in Hawaii. Epidemic outbreaks have occurred in scattered areas of the United States and Japan. The etiology is unknown, although clinical, epidemiologic, and immunologic features suggest an acute infectious trigger to an immunologically mediated, generalized vasculitis.

Adrenal Cortex Hormones↗
PubMed1994

Clinical safety, tolerability, and pharmacokinetics of murine monoclonal antibody to human tumor necrosis factor-alpha.

The safety, tolerability, and pharmacokinetic profile of murine monoclonal antibody to human tumor necrosis factor-alpha (TNF alpha MAb) were evaluated in 20 uninfected patients at risk of sepsis and 16 septic patients. TNF alpha MAb was well tolerated in all patients, with no immediate or delayed signs of allergic reaction. During the 28-day evaluation, side effects included thrombocytosis (11), hepatic enzyme elevations (8), cardiac arrhythmias (3), and deaths (5). Each was attributed to the patient's severe underlying disease and not to TNF alpha MAb; however, a relationship between TNF alpha MAb and these events cannot be ruled out. The half-life was 52 h for a single infusion of TNF alpha MAb. Human antibody against TNF alpha MAb was observed in 13 (76.5%) of 17 phase IA patients and 10 of 10 phase IB patients and anti-idiotype antibodies in 11 (91.7%) of 12 phase IA patients and 2 (33.3%) of 6 phase IB patients. TNF alpha MAb should be evaluated as adjunctive therapy for patients with sepsis.

Adult↗
PubMed1984

Twice daily ceftriaxone therapy for serious bacterial infections in children.

The clinical efficacy and safety of ceftriaxone, a long half-life cephalosporin were evaluated in 48 children with a variety of serious bacterial infections. Clinical cure was achieved in 92% (44 of 48) of patients. Peak serum bactericidal titres for Haemophilus influenzae type b, Streptococcus pneumoniae, Str. pyogenes and Escherichia coli were greater than or equal to 1:1024. Mean peak and trough ceftriaxone levels were 173 and 42 mg/l, respectively. Mild and transient diarrhoea was observed in 10% of patients. Laboratory side effects encountered were eosinophilia, thrombocytosis and neutropenia in another 8%. Ceftriaxone is a useful antibiotic for common childhood infections. Its prolonged half-life allows twice daily administration which reduces problems related to intravenous therapy as well as the cost and personnel time.

Adolescent↗
PubMed1988

Treatment of bacterial meningitis with once daily ceftriaxone therapy.

Ceftriaxone, a cephalosporin with an extended half-life and excellent antibacterial activity was used to treat bacterial meningitis, given as a single daily intravenous dose of 100 mg/kg on day one, followed by 80 mg/kg daily. A total of 22 patients were treated, of whom 14 had Haemophilus influenzae type b, five had Streptococcus pneumoniae and three Neisseria meningitidis isolated from their CSF. The CSF of all patients became sterile within 24-48 h. The CSF ceftriaxone concentrations 24 h after dosing were 10 to 100-fold higher than the MIC of the pathogenic bacteria early in therapy, and five to 50-fold higher at the end of therapy. Side effects encountered included mild diarrhoea (32%), thrombocytosis (77%) and neutropenia (9%), but none caused therapy to be stopped. Ceftriaxone is a safe and effective antibiotic for the treatment of bacterial meningitis when administered once daily.

Adolescent↗
PubMed1995

Safety profile of meropenem: international clinical experience based on the first 3125 patients treated with meropenem.

Data from 3125 patients (3220 patient exposures) treated with meropenem were compared with those from 2886 patients (2960 patient exposures) treated with a variety of comparator agents including cephalosporins (alone or in combination with aminoglycosides or an anti-anaerobe agent) and imipenem/cilastatin. Patients treated included those with bacterial infections of the lower respiratory tract, urinary tract and skin and soft tissues, abdominal, obstetric and gynaecological infections, meningitis, febrile episodes in neutropenic patients and paediatric patients with infections. In three studies, meropenem was administered intramuscularly; in the remainder, meropenem was given by 15-30 min iv infusion or by bolus injection over approximately 5 min. The usual dosages were 500 mg or 1 g 8 hourly in adults and 10 or 20 mg/kg 8 hourly in children. In bacterial meningitis, the meropenem dosage in adults was 2 g 8 hourly and 40 mg/kg 8 hourly in children. The overall pattern and frequency of adverse events with meropenem were similar to those of the other beta-lactam antibiotics with which it was compared. The most frequently reported adverse events were diarrhoea, rash, nausea and vomiting, thrombocytosis, eosinophilia and changes in hepatic biochemistry. Abnormal laboratory tests occurred with similar frequencies between meropenem and the comparator agents. The safety profile of meropenem was similar in adults and children, and the presence of renal impairment did not alter the safety profile of meropenem. Experience in clinical studies in 3220 patient exposures has revealed no unusual or unexpected toxicity. The possibility of administration by either iv infusion or bolus injection with a low incidence of nausea and vomiting also provides flexibility in the clinical management of patients. Moreover, the low incidence of reported seizures and good tolerability at high doses, make meropenem particularly useful for the treatment of meningitis and other indications which carry a risk of seizures, or in the treatment of serious infections where high doses of antibiotics are frequently indicated.

Bacterial Infections↗
PubMed1980

Hematological changes due to vitamin C deficiency in Channa punctatus Bloch.

Hematological changes in Channa punctatus based on examination of blood at regular monthly intervals in fishes fed a vitamin C-deficient diet for 210 days followed by 30 days' recovery treatment have been reported. Normochromic normocytic type of anemia was observed after 120 days of vitamin C deficiency which developed into a normochromic macrocytic type eventually becoming hypochromic macrocytic during the last 30 days of deficiency. Correlated erythropoietic studies revealed a decrease in small lymphoid hemoblast with simultaneous increase in the later stages of red blood cell development. Deficiency also resulted in leukocytosis, basically due to thrombocytosis. Differential leukocyte counts revealed relative decrease in all other cell types particularly neutrophils and lymphocytes. Recovery treatment was found effective in arresting and in most cases reversing the pathological trends set in by the deficiency.

Animals↗
PubMed2006

The uORF-containing thrombopoietin mRNA escapes nonsense-mediated decay (NMD).

Platelet production is induced by the cytokine thrombopoietin (TPO). It is physiologically critical that TPO expression is tightly regulated, because lack of TPO causes life-threatening thrombocytopenia while an excess of TPO results in thrombocytosis. The plasma concentration of TPO is controlled by a negative feedback loop involving receptor-mediated uptake of TPO by platelets. Furthermore, TPO biosynthesis is limited by upstream open reading frames (uORFs) that curtail the translation of the TPO mRNA. uORFs are suggested to activate RNA degradation by nonsense-mediated decay (NMD) in a number of physiological transcripts. Here, we determine whether NMD affects TPO expression. We show that reporter mRNAs bearing the seventh TPO uORF escape NMD. Importantly, endogenously expressed TPO mRNA from HuH7 cells is unaffected by abrogation of NMD by RNAi. Thus, regulation of TPO expression is independent of NMD, implying that mRNAs bearing uORFs cannot generally be considered to represent NMD targets.

Cell Line, Tumor↗
PubMed1999

Familial Mediterranean fever--renal involvement by diseases other than amyloid.

BACKGROUND: In patients with familial Mediterranean fever (FMF) renal involvement is usually in the form of AA amyloidosis. There is increasing evidence that renal involvement may be due to diseases other than amyloid as well. METHODS: Amongst 302 children with FMF we observed and followed 28 with typical clinical and laboratory features of vasculitis. The diagnosis of FMF was established according to the Tel Hashomer criteria. RESULTS: Polyarteritis nodosa, protracted febrile attacks and Henoch-Schönlein purpura were diagnosed in 4, 13, and 11 patients, respectively. The presentation was often difficult to distinguish from FMF attacks, but protracted febrile attacks lasting several weeks, hypertension, thrombocytosis, and dramatic responses to corticosteroid therapy that were observed in many cases were different from what is observed in classical FMF. CONCLUSIONS: We suggest that FMF, perhaps as a consequence of impaired control of inflammatory responses, predisposes to vasculitis with renal involvement.

Child↗