Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives

Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3–73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.     

The prevalence of thrombophilia in patients with chronic venous leg ulceration

BACKGROUND: Thrombophilia is increasingly recognized as a risk factor for deep venous thrombosis (DVT), which in turn is a major risk factor for chronic venous ulceration (CVU). However, the relationship between thrombophilia and CVU remains unknown. The aim of this study was to define the prevalence of thrombophilia in patients with CVU and to determine whether this is associated with a history or duplex scan evidence of DVT. METHODS: Eighty-eight patients with CVU were prospectively studied. The patients underwent clinical assessment and duplex ultrasound scanning. Blood was drawn for antithrombin, proteins C and S, activated protein C resistance, factor V Leiden, prothrombin 20210A, lupus anticoagulant, and anticardiolipin antibodies. RESULTS: The study included 35 men with a median age of 61 years (interquartile range, 45 to 72 years) and 53 women with a median age of 76 years (interquartile range, 69 to 82 years). Thirty-six percent of the patients had either a history or duplex scan evidence suggestive of previous DVT. The following abnormalities were detected: four, five, and six cases of antithrombin, protein C, and protein S deficiencies, respectively; 14 cases of activated protein C resistance; 11 cases of factor V Leiden mutation; three cases of prothrombin 20210A mutation; eight cases of lupus anticoagulant; and 12 cases of anticardiolipin antibodies. Thrombophilia was not significantly related to previous DVT, deep reflux, or disease severity. CONCLUSION: Patients with CVU have a 41% prevalence rate of thrombophilia. This rate is two to 30 times higher than the rate of the general population but is similar to that reported for patients with previous DVT. However, in patients with CVU, thrombophilia does not appear to be related to a history of DVT, a pattern of reflux, or severity of disease. Many patients with CVU may have unsuspected postthrombotic disease.     

Preserved endothelial vasomotion and fibrinolytic function in patients with acute stent thrombosis or in-stent restenosis

Introduction: Acute stent thrombosis and in-stent restenosis are serious complications of percutaneous coronary intervention (PCI) and may be associated with vascular or platelet abnormalities. We aimed to assess endothelium-dependent vasomotion, endogenous fibrinolysis and platelet function in patients with acute stent thrombosis or in-stent restenosis. Materials and methods: Thirty-six subjects were enrolled into four groups: acute stent thrombosis, in-stent restenosis, uncomplicated PCI with stent implantation and healthy matched controls. Forearm blood flow was measured using bilateral venous occlusion plethysmography during intra-brachial acetylcholine, substance P and sodium nitroprusside infusion. Venous blood samples were withdrawn for estimation of plasma fibrinolytic variables and platelet aggregometry. Results: Acetylcholine, substance P and sodium nitroprusside caused dose-dependent increases in blood flow (P<0.001) and substance P caused a dose-dependent increase in tissue-type plasminogen activator (t-PA) release (P<0.001) in all groups. Thrombin, collagen, adenosine diphosphate (ADP) and the thromboxane A2 analogue, U46619, caused dose-dependent platelet aggregation (P<0.001) in all groups. There were no significant between group differences in these responses except that, in keeping with aspirin therapy, collagen-induced platelet aggregation was impaired in patient groups compared with healthy controls (P<0.01). Post-hoc analysis demonstrated a significant impairment of acute t-PA release in current smokers compared to non-smokers (P<0.05). Conclusions: Despite previous reports suggesting impaired vascular function, endothelium-dependent vasomotion, endogenous fibrinolysis and platelet aggregation do not appear to play a major role in the pathogenesis of acute stent thrombosis or in-stent restenosis.     

The incidence of lymphoma in the UK haemophilia population between 1978 and 1999

OBJECTIVE: To determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999. DESIGN AND METHODS: An analysis of patient data included on the UK Haemophilia Centre Doctors' Organisation lymphoma register. The number of cases of NHL and HD occurring in HIV-positive and negative patients in each 3-year period were compared with the expected incidence in the general male population. RESULTS: Eighty-nine cases of lymphoma were identified. Seventy-two cases (81%) occurred in HIV-positive patients (67 NHL, five HD), and 17 cases (19%) in HIV-negative patients (nine NHL, eight HD). The incidence of NHL in the HIV-positive cohort was significantly increased, with a ratio of observed to expected cases of 83.92 (P < 0.001) in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). There was a significant excess of HD in HIV-positive patients, with an observed to expected ratio of 10.50 between 1985 and 1999 (based on five cases, P < 0.001). During the whole observation period, there was a significant excess of HD in HIV-negative patients, with an observed to expected ratio of 2.66 (based on eight cases, P < 0.05). CONCLUSION: The incidence of lymphoma is significantly higher in HIV-positive UK haemophilia patients compared with HIV-negative individuals. Since the introduction of HAART, the incidence of lymphoma has tended to fall in the HIV-positive group.     

Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease. Role of interleukin-6

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.     

下肢骨肉瘤的MRI与X线对照研究

目的 对比分析下肢骨肉瘤的X线与MRI表现，探讨MRI对骨肉瘤的诊断价值。方法 收集经手术或病理穿刺活检证实的下肢骨肉瘤15例，男11例，女4例，均行MRI平扫及增强扫描（4例行CT扫描），并摄有X线平片，对其MRI征象与X线征象作逐一对比。结果 MRI及X线平片对下肢骨肉瘤的诊断准确率均为100％，MRI在显示病变范围、放射状骨针、Codman三角两层结构以及跳跃病灶等方面明显优于X线平片检查。结论 X线平片是诊断骨肉瘤最简便而实用的方法，但MRI可以更好的显示病变的范围，发现早期病变。     

头皮原发性皮肤神经节细胞瘤

神经节细胞瘤是一种神经内分泌肿瘤，其发生与自主神经系统的交感或副交感神经节有关。罕见发生于膀胱、前列腺和子宫。本文作者报道1例发生于儿童头皮的原发性皮肤神经节细胞瘤。对此肿瘤进行了组织学、免疫组化和超微结构研究。该病例可能代表神经嵴细胞向鳃弓发育过程中的一种异常迁移。此外，研究结果还强调在胚胎发育过程中神经嵴和鳃弓／裂之间有复杂的相互作用。     

Individualized heparin and protamine management in infants and children undergoing cardiac operations

BACKGROUND: Measurements of activated coagulation time do not correlate with plasma concentration of heparin. This study investigated the effects of a patient-specific method to manage anticoagulation and its reversal in pediatric patients undergoing cardiopulmonary bypass. METHODS: Infants and children were randomly assigned to receive either a standard dose of heparin (300 IU/kg; group C, n = 13) or an individualized dose, calculated by an in vitro heparin dose-response test (group HC, n = 13). Protamine dose was based on a 1 mg/l mg ratio of total administered heparin for patients in group C and of the residual heparin concentration in group HC. RESULTS: Administered heparin was significantly higher and total protamine dose was significantly reduced in the HC group (both p < or = 0.001). There was less thrombin generation (p = 0.02) and fibrinolysis (p = 0.05) in group HC. Blood loss and requirement for transfusion of blood and fresh frozen plasma were also lower in group HC (all p < or =0.05). CONCLUSIONS: An individualized management of anticoagulation and its reversal results in less activation of the coagulation cascade, less fibrinolysis, and reduced blood loss and need for transfusions. Further studies are warranted to better define the clinical impact of these findings.