Biomedical subjects
Publications and source records attributed to Owen P Smith.
We report a case of successful allogeneic hematopoietic stem cell transplantation (HSCT) with full myeloablative conditioning in a patient with pre-existing invasive mucormycosis. The mucormycosis involved the maxilla, the nasal septum, and the hard palate. Sustained antifungal therapy and aggressive surgery both before and after HSCT were required.
Microparticles (MP) derived from vascular endothelium or circulating blood cells circulate in the peripheral blood. They originate from blebbing and shedding from cell membrane surfaces in physiological and pathological conditions and are present in low concentrations in normal plasma. Increased levels are generated by a number of mechanisms including platelet activation, direct vascular endothelial damage, thrombin activity on the cell surface, C5b-9 activation, and PF4-heparin-antibody interaction. Several techniques are currently used to study the generation and nature of circulating microparticles. In particular, the genesis and role of microparticles, derived from platelets, endothelial cells and monocytes, in sepsis (especially meningococcal-induced), heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD) have been well studied, and provide important insights into the underlying diseases. A defect in the ability to form microparticles leads to the severe bleeding disorder of Scott syndrome, which in turn provides a revealing insight into the physiology of coagulation. In addition the complex role of microparticles in vascular and cardiovascular diseases is an area of immense interest, that promises to yield important advances into diagnosis and therapy.
Unfractionated heparin (UFH) and low-molecular weight heparin (LMWH) are well defined anticoagulant agents. Recent data suggest that both LMWH and UFH may also have potent anti-inflammatory properties; however, their mechanism of action responsible for the anti-inflammatory effect is not yet fully elucidated. This study was designed to assess the effect of LMWH and UFH on human monocytes production of inflammatory markers and nuclear translocation of nuclear factor (NF)-kappaB. Cultured monocytes were pretreated for 15 min with LMWH or UFH (10 microg and 1 microg/million cells) before stimulation with lipopolysaccharide (LPS) at a dose of 1 ng/million cells. Proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-8, IL-6 and IL-1beta release were subsequently measured by enzyme-linked immunosorbent assay at 6 h, and nuclear translocation of the proinflammatory NF-kappaB was assessed at 2 h. Treatment with pharmacological doses of LMWH and UFH significantly attenuated LPS-induced production of TNF-alpha, IL-8, IL-6 and IL-1beta as well as NF-kappaB translocation. These results indicate equivalent and significant heparin anti-inflammatory properties at low doses on monocyte-mediated immune response. The inhibition of NF-kappaB activation certainly represents one of the mechanisms by which heparin exerts its anti-inflammatory effect. LMWH and UFH therefore appear as potential therapeutic inhibitors of inflammation.
The authors present a case of osteopetrosis due to carbonic anhydrase II deficiency. Clinical, laboratory and radiologic findings are reported. The genetics of osteopetrosis are reviewed.
The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.
Severe chronic neutropenia (SCN) is a heterogeneous group of conditions characterized by chronically low neutrophil counts and recurrent infections. Granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, and evidence exists that G-CSF may promote angiogenesis. To evaluate the effects of G-CSF on angiogenesis in children with SCN, the authors assessed microvessel density in bone marrow biopsies from nine children with SCN before starting G-CSF treatment and while receiving G-CSF. In all patients, microvessel density was greater in the on-treatment biopsy. Increased angiogenesis may result from a direct effect of G-CSF on endothelial cells or may be an indirect effect from increased neutrophils.
BACKGROUND: Recombinant FVIIa (rFVIIa/NovoSeven) is a novel hemostatic agent originally developed to treat patients with hemophilia who had developed inhibitors. Several case reports have suggested that rFVIIa may be effective in treating patients without a pre-existing bleeding disorder who have uncontrolled bleeding. STUDY DESIGN AND METHODS: Data on the efficacy and safety of rFVIIa in the treatment of massive hemorrhage were obtained retrospectively from the NovoSeven extended-use data collection system. RESULTS: A total of 40 patients received rFVIIa for uncontrolled bleeding, and in these patients, bleeding stopped or decreased in 32 (80%). Blood product usage was significantly decreased after rFVIIa administration. Thromboembolic events occurred in three patients with additional risk factors for thrombosis. Of 40 patients, 23 (57.5%) died. Bleeding was the direct cause of death in seven cases (all within 24 hr of administration of rFVIIa). The remaining 16 deaths were the result of sepsis, multi-organ failure, or the underlying disease. CONCLUSIONS: In this retrospective study of data voluntarily submitted to a web-based drug surveillance program, we present preliminary results on the use of rFVIIa in nonhemophilia patients with bleeding. Although some efficacy is suggested, there was a high mortality rate from nonhemorrhagic causes. Randomized controlled trials are needed to properly assess the role of rFVIIa in the management of hemorrhage.
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This paper describes the analysis of recombinant factor VIIa (rFVIIa; NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) use in 40 patients with intractable bleeding in the UK. All cases were reported on the 'rFVIIa extended use database' (Traumanet) between its launch in February 1999 and 12 March 2002. Twenty-one other cases reporting rFVIIa use in different circumstances were excluded from the analysis. Recombinant FVIIa was effective in stopping or markedly reducing blood loss in 80% of patients; 20% of patients did not respond to treatment. Non-responders tended to have more deranged coagulation and lower platelet counts compared with responders. Despite a wide range of underlying illnesses, including malignancy and sepsis, few patients suffered adverse events. Thrombotic events occurred in three of 40 (7.5%) patients and these patients were considered as already at risk of thrombosis from other causes. The data suggest that rFVIIa is safe and effective therapy in patients with uncontrollable haemorrhage.
BACKGROUND: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of lactic acidosis after cardiac surgery.
The management of acute and surgical bleeding episodes in children with severe factor VIII or IX deficiency who develop high responding inhibitors presents a major therapeutic challenge to clinicians. Recombinant factor VIIa (rVIIa) is an effective, reliable and safe treatment that can be used to treat acute bleeding episodes prior to commencing an immune tolerance programme and to cover surgical procedures until the immune tolerance programme is successful. In a significant minority of patients, immune tolerance therapy is ineffective and an alternative haemostatic agent such as rVIIa is required for life-long treatment. The present study evaluated the use of rVIIa in a paediatric setting. Twelve children, aged 1-16 years, were treated successfully with rVIIa to prevent surgical bleeding in 20 surgical procedures (19 central venous access device insertion or removal, 1 dental extraction). Minor postoperative haematomata developed in 2 out of 20 cases after regular rVIIa therapy had been discontinued and resolved with a short course of rVIIa in both cases. Three children had six life- or limb-threatening bleeding episodes. All bleeding episodes resolved with regular rVIIa treatment although topical fibrin glue was needed in one child with a frenulum tear. One patient required two red cell transfusions for symptomatic anaemia resulting from two separate bleeding episodes. The rVIIa therapy was well tolerated and there was no evidence of treatment-related complications. We conclude that rVIIa is the treatment of choice for the management of surgery and acute life- or limb-threatening bleeding in children with haemophilia and high responding inhibitors.
Severe bacterial sepsis, particularly secondary to meningococcaemia, is a well-recognized cause of purpura fulminans resulting from severe acquired protein C (PC) deficiency. Recently, PC and activated protein C (APC) concentrate replacement therapy has been shown to improve outcome in patients with meningococcaemia- associated purpura fulminans and severe sepsis respectively. Despite these impressive findings, PC and APC concentrates are not currently widely available. We describe a 31-year-old patient with pneumococcal septic shock, purpura fulminans (PF) and severe acquired PC deficiency, whom we successfully treated with conventional therapy and high-volume plasma exchange as a source of PC.
The importance of angiogenesis for the growth and viability of solid tumours has been established. Similarly, prognostic information may be gained from the extent of angiogenesis in these tumours. Haematopoietic malignancies should have equal requirements for angiogenesis and important prognostic information may be derived from quantification of bone marrow angiogenic activity. We retrospectively investigated 82 bone marrow trephine biopsies from 41 children with acute lymphoblastic leukaemia (ALL) at diagnosis and following treatment. Nine normal bone marrow trephines from age-matched children were also analysed as controls. The microvessels were stained immunohistochemically with anti-Factor VIII-related antigen (antivWF) and antithrombomodulin (anti-THR). Angiogenesis was quantified manually by two independent observers and was highly reproducible (Pearson's r = 0.91). Staining with anti-vWF and anti-THR was highly specific for microvessels and thetwo stains closely correlated (r = 0.68). Microvessel densities (MVD) at presentation were significantly increased in the majority of patients in comparison with controls (P < 0.0001) and MVD dropped towards normal in remission (P < 0.0001). Of interest, the difference in total vessel counts between leukaemic and normal/remission marrows was contributed solely by small microvessels. There was no significant difference in MVD at presentation or remission from children in poor prognostic groups or those who subsequently relapsed. Similarly, we could not find an association with age, sex, cytogenetic abnormality or disease phenotype.
Severe factor X (FX) deficiency is one of the severest inherited coagulation disorders. Clinical manifestations include umbilical cord, mucosal, joint and central nervous system bleeding. Four Irish children with severe FX deficiency presented with umbilical cord bleeding. One developed an intraperitoneal haemorrhage and another an intracranial bleed. Prophylaxis, using intermediate purity Factor IX concentrate, was commenced within the first month of life, necessitating the insertion of central venous access devices in two of the children. All children have normal joint function, suggesting that prophylaxis commenced early in life reduces the incidence of arthropathy and improves quality of life.
The development of inhibitors to therapeutic factor concentrates in children with haemophilia A or B is a troublesome complication of factor replacement therapy. Immune tolerance protocols have been developed to eliminate the inhibitors, and these are successful in approximately 80% of children. However, acute bleeding episodes require treatment with a factor (F)VIII or FIX bypassing agent to prevent an anamnestic rise in the inhibitor level before starting immune tolerance. In addition, central venous access is necessary to help parents administer frequent, high dose factor concentrate. In view of the benefits of rFVIIa seen in adults, a study has been carried out on the use of this agent as haemostatic cover in children with severe FVIII or FIX deficiency with high responding inhibitors. Information was obtained retrospectively from the National Children's Hospital, Dublin and Great Ormond Street Hospital, London. Twelve children aged 1-16 years were treated successfully with rFVIIa to prevent surgical bleeding in 20 surgical procedures. Minor post-operative haematomata developed in 2 of 20 cases after regular rFVIIa therapy had been discontinued. In both cases, resolution of bleeding occurred after a short course of rFVIIa. Three children experienced a total of six life- or limb-threatening bleeds. All bleeding episodes resolved with regular rFVIIa treatment, although topical fibrin glue was needed in one child with a frenulum tear. The rFVIIa therapy was well tolerated and there was no evidence of any treatment-related complications. In conclusion, rFVIIa is the treatment of choice for the management of surgery and acute life- or limb-threatening bleeding in children with haemophilia and high responding inhibitors.
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Explore the source record for details and available documents.