The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin

The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.     

小儿淋巴管瘤的MRI诊断

目的分析小儿淋巴管瘤的磁共振表现及其病理基础。方法对６例经手术病理证实的、年龄７天至７岁的小儿淋巴管瘤患者的磁共振表现进行回顾性分析。结果淋巴管瘤磁共振表现为Ｔ１ＷＩ上呈与肌肉相似或稍高的信号，Ｔ２ＷＩ上高于脂肪信号。５例瘤内可见低信号分隔，１例瘤内见血管流空影，３例见明显包膜，３例边界不清。２例病理诊断为海绵状淋巴管瘤，４例诊断为囊状淋巴管瘤。结论磁共振成像可较好地显示肿瘤的大小、形态及范围，从而指导手术治疗。     

Antihypertensive drugs, dietary salt, and renal protection: how low should you go and with which therapy?

Although it is clear that hypertension accelerates the rate of progression of most forms of chronic renal disease, many unanswered questions remain concerning how to optimally preserve kidney function in patients with hypertension and renal insufficiency. The mechanisms by which hypertension accelerates progression of renal disease have been extensively studied in experimental models. Glomerular capillary hypertension, consequent to an increase in systemic blood pressure combined with a reduction in preglomerular resistance and/or an increase in postglomerular resistance, results in increased hydraulic stress to the glomerular capillary wall. This and other mechanisms result in the release of growth-promoting cytokines and soluble mediators of fibrosis that stimulate cellular proliferation and matrix accumulation, ultimately leading to glomerular sclerosis and interstitial fibrosis. Almost without exception, studies in animals demonstrate that blood pressure reduction reduces the rate of progression of experimental renal disease. Angiotensin-converting enzyme inhibitors and, possibly, calcium antagonists may have a therapeutic advantage compared with other antihypertensive drugs in preventing kidney damage. This has been linked to both blood pressure-dependent and -independent actions. However, most experimental studies have failed to reduce blood pressure to a level sufficient to establish the clinical relevance of potential blood pressure-independent effects. Experimental studies comparing various types of antihypertensive drugs in which a mean arterial pressure (MAP) of approximately 92 mm Hg is achieved are necessary to determine whether clinically important differences in the effects of these drugs on the rate of progression of renal disease exist. Clinical experience with high blood pressure and kidney disease in humans suggests that the risk of developing hypertension-associated renal disease is a continuous variable across the entire range of systolic and diastolic blood pressures. Logically, optimal protection of kidney function may therefore be a continuous function of declining systemic blood pressure. Consistent with this view, recent clinical trials suggest that reducing MAP to 92 mm Hg, corresponding to a blood pressure reading of 125/75 mm Hg, provides more optimal stabilization of renal function in patients with nondiabetic proteinuric kidney disease (>1 g/d) compared with more conventional therapy with a blood pressure goal of 140/90 mm Hg (MAP 107 mm Hg). Clinical trials in patients with diabetes mellitus and renal insufficiency also demonstrate the benefits of reducing blood pressure to approximately 95 mm Hg MAP. Dietary salt consumption may be another important variable affecting the rate of progression of renal disease due to both direct, salt-dependent effects on renal growth and the action of decreased salt intake to augment the antihypertensive and antiproteinuric properties of many drugs. The precise role of alterations in dietary salt consumption on progression of renal disease directly as well as on the effectiveness of various antihypertensive drugs has yet to be examined in clinical trials.     

FDG-PET/CT-guided intensity modulated head and neck radiotherapy: a pilot investigation

BACKGROUND: 2-deoxy-2[(18)F]fluoro-D-glucose-positron emission tomography (FDG-PET) imaging can be registered with CT images and can potentially improve neck staging sensitivity and specificity in patients with head and neck squamous cell cancer. The intent of this study was to examine the use of registered FDG-PET/CT imaging to guide head and neck intensity modulated radiotherapy (IMRT) planning. METHODS: Twenty patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx underwent FDG-PET and contrast-enhanced CT imaging of the head and neck before neck dissection surgery. Combined FDG-PET/CT images were created by use of a nonrigid image registration algorithm. All IMRT plans were theoretical and were not used for treatment. We prescribed 66 Gy in 30 fractions to FDG-avid CT abnormalities and nodal zones directly involved with disease, without prophylactic coverage of uninvolved neck levels. Matched CT-guided IMRT plans designed according to the specifications of Radiation Therapy Oncology Group (RTOG) H-0022 were available for comparison. We investigated the feasibility of FDG-PET/CT-directed IMRT dose escalation in five patients with FDG-avid disease located away from critical normal structures. After 66 Gy, FDG-avid disease with 0.5-cm margins was boosted in 220 cGy increments until dose-limiting criteria were reached. RESULTS: Elimination of prophylactic coverage to FDG-PET/CT-negative neck levels markedly reduced mean dose (Dmean) to the contralateral parotid gland (p < .001) and Dmean to the laryngeal cartilage (p = .001). No FDG-PET/CT-directed plan missed pathologically verified nodal disease. During the dose escalation exercise, we successfully increased the dose to 95% of the planning target volume (PTV95%) to a mean of 7490 cGy (range, 7153-8098 cGy). CONCLUSIONS: We demonstrate early proof of the principle that FDG-PET/CT-guided IMRT planning can selectively target and intensify treatment of head and neck disease while reducing critical normal tissue doses. Routine clinical use of such planning should not be engaged until the accuracy of FDG-PET/CT is fully validated. Future directions, including refinement of treatment to gross disease and radiologically uninvolved neck nodal levels, are discussed.     

Red cell membrane stiffness in iron deficiency

The purpose of this study was to characterize red blood cell (RBC) deformability by iron deficiency. We measured RBC deformability to ektacytometry, a laser diffraction method for determining the elongation of suspended red cells subjected to shear stress. Isotonic deformability of RBC from iron-deficient human subjects was consistently and significantly lower than that of normal controls. In groups of rats with severe and moderate dietary iron deficiency, RBC deformability was also reduced in proportion to the severity of iron deficiency. At any given shear stress value, deformability of resealed RBC ghosts from both iron-deficient humans and rats was lower than that of control ghosts. However, increase of applied shear stress resulted in progressive increase in ghost deformation, indicating that ghost deformability was primarily limited by membrane stiffness rather than by reduced surface area-to-volume ratio. This was consistent with the finding that iron-deficient cells had a normal membrane surface area. In addition, the reduced mean corpuscular hemoglobin concentration (MCHC) and buoyant density of the iron-deficient rat cells indicated that a high hemoglobin concentration was not responsible for impaired whole cell deformability. Biochemical studies of rat RBC showed increased membrane lipid and protein crosslinking and reduced intracellular cation content, findings that are consistent with in vivo peroxidative damage. RBC from iron-deficient rats incubated in vitro with hydrogen peroxide showed increased generation of malonyldialdehyde, an end-product of lipid peroxidation, compared to control RBC. Taken together, these findings suggest that peroxidation could contribute in part to increased membrane stiffness in iron- deficient RBC. This reduced membrane deformability may in turn contribute to impaired red cell survival in iron deficiency.