Distribution of thrombi in acute lower extremity deep venous thrombosis: implications for sonography and CT and MR venography

OBJECTIVE: Our objective was to determine the typical distribution of thrombi in acute lower extremity deep venous thrombosis as a means of evaluating the validity of imaging techniques that only include the common femoral and popliteal veins, but not the superficial femoral vein. MATERIALS AND METHODS: The results of 2704 lower extremity venous sonograms, obtained in 2026 consecutive patients over a 4-year interval, were reviewed retrospectively. The distribution of acute deep venous thromboses across various lower extremity venous segments was analyzed for this population, which consisted of both symptomatic and asymptomatic patients. RESULTS: Of 2704 lower extremities studied with duplex sonography, acute deep venous thrombosis was identified in 269 (9.9%). Of these 269 cases, acute deep venous thrombosis was isolated to the superficial femoral vein in 60 (22.3%). The remaining 209 cases (77.7%) showed thrombus that extended into the common femoral or popliteal veins (or both). CONClUSION: An abbreviated imaging study that evaluates only the common femoral and popliteal veins would fail to identify more than 20% of lower extremity acute deep venous thromboses in a population like ours. Although evaluation of the superficial femoral vein requires additional time and resources, evaluation of this segment may prevent a substantial number of thrombi from being missed.     

Morphologic characteristics of varicose veins: possible role of metalloproteinases

BACKGROUND: Although varicose veins are a common cause of morbidity, etiologic factors predisposing to dilatation, elongation, and tortuosity of the saphenous vein and its tributaries are poorly understood. We compared histologic features of normal and varicose saphenous veins and investigated the role of enzyme or inhibitor imbalance in development of varicosities. METHODS: Eight normal and 10 varicose (C(2,3)E(P,S)A(S)P(R,O)) vein segments were used for this analysis. Matrix metalloproteinase (MMP) expression and activity were analyzed with Western blotting and zymography. Venous architecture and protein localization were determined with histology and immunohistochemistry. RESULTS: Western blot analysis demonstrated the presence of MMP- 1, MMP-2, MMP-9, and MMP-12, as well as small quantities of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 in protein isolates from normal and varicose veins. Both vein types demonstrated MMP-2, MMP-9, and MMP-12 activity by gelatin zymography, although varicose vein expressed less MMP-9 activity than normal vein did. Compared with normal veins, changes in varicose veins were not uniformly distributed along the circumference; areas of intimal thickening were often interspersed with focal areas of dilatation. Fragmentation of elastic lamellae and loss of circular and longitudinal muscle fibers were evident in the varicosities. Focal aggregates of macrophages were detected within the media and adventitia of both normal and varicose veins. MMP-1 and MMP-9 were expressed in both types of vein segments; however, their immunohistochemical localization was distinctly different. In normal vein, endothelial cells, occasional smooth muscle cells (SMC), and adventitial microvessels expressed MMP-1, whereas its expression was localized to fibroblasts, SMC, and endothelial cells throughout involved portions of varicose veins. MMP-9 was localized to endothelial cells, medial SMC, and adventitial microvessels in both normal and varicose veins, although varicose veins demonstrated increased medial smooth muscle cell staining. MMP-12 was found in SMC and fibroblasts in both normal and varicose veins. Neither TIMP-1 nor TIMP-2 were detected with immunohistochemistry in any specimens examined. CONCLUSIONS: There are distinct differences in the structural architecture and localization of MMP expression in normal and varicose veins. Although the changes observed are not sufficiently definitive to enable a causal relationship, they do suggest a possible mechanism for the alterations in matrix composition observed between normal and varicose veins.     

Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy

A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.     

Serum Alkaline Phosphatase in Cryptogenic Stroke Cases with Active Cancer

Objective We assessed the relationship between the levels of serum alkaline phosphatase, which is often increased with biliary obstruction and bone metastasis, and active cancer in patients with cryptogenic stroke. Methods Serum alkaline phosphatase levels in patients with cryptogenic stroke sampled upon admission were measured using the Japan Society of Clinical Chemistry method used in Japan. Active cancer was defined as a new diagnosis, treatment, progression, or recurrence within six months before admission or metastatic cancer. Multivariate logistic regression analyses were performed to explore the relationship between serum alkaline phosphatase and active cancer in these patients. Results Among the 249 patients classified as having cryptogenic stroke, 64 had active cancer. Patients with cryptogenic stroke with active cancer had significantly higher serum alkaline phosphatase levels (486±497 vs. 259±88.2 U/L; p<0.001) than those without cancer. Multivariate logistic analysis revealed that serum alkaline phosphatase levels ≥286 U/L were associated with cryptogenic stroke with active cancer [odds ratio (OR), 2.669, 95% confidence interval (CI), 1.291-5.517; p=0.008] independent of age ≤70 years old (OR, 3.303, 95% CI, 1.569-6.994; p=0.002), male sex (OR, 0.806, 95% CI, 0.380-1.710; p=0.573), and serum D-dimer levels ≥2.6 μg/mL (OR, 18.78, 95% CI, 8.130-43.40; p<0.001). Conclusion In patients with cryptogenic stroke, high serum alkaline phosphatase levels may be related to active cancer.     

Enzymatic kinetics regarding reversible metabolism of CS-0777, a sphingosine 1-phosphate receptor modulator,via phosphorylation and dephosphorylation in humans

1.?CS-0777, a candidate compound for autoimmune diseases, becomes phosphorylated active metabolite, M1, by fructosamine 3-kinase (FN3K), FN3K-related protein (FN3K-RP); and M1 is reverted back to CS-0777 by alkaline phosphatase (ALP) in the body. We performed enzyme kinetic analysis of phosphorylation of CS-0777 by FN3K, FN3K-RP, human erythrocytes and human platelets; and dephosphorylation of M1 by various ALP isozymes and human liver, kidney, lung and small intestine microsomes.

2.?The Michaelis constants of human FN3K, FN3K-RP and erythrocytes for CS-0777 phosphorylation were in the range from 498?μM to 1060?μM. FN3K inhibitor, 1-deoxy-1-morpholinofructose, suppressed only about 20% of CS-0777 phosphorylation activity in human erythrocyte lysate. Immunodepletion of FN3K and FN3K-RP decreased M1 formation activity by about 25% and 50%, respectively, in human erythrocyte lysate.

3.?The Michaelis constants of four human ALPs and microsomes were in the range from 10.9?μM to 32.1?μM. The ALP inhibitor, levamisole, suppressed over 50% of M1 dephosphorylation activity in liver, kidney and lung microsomes.

4.?FN3K-RP is expected to take a prominent role in the phosphorylation of CS-0777 in human erythrocytes; dephosphorylation of M1 was observed in all ALPs and human tissue microsomes examined, with a similar affinity towards M1 among them.     

Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model

OBJECTIVE: To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood-brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10-12 months of age. METHODS: We assessed BBB integrity using well-established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate. RESULTS: BBB permeability is increased in the cerebral cortex of 10-month-old Tg2576 mice preceding Alzheimer disease pathology presentation. Furthermore, when compared with their nontransgenic littermates, 4-month-old Tg2576 mice exhibit compromised BBB integrity in some areas of the cerebral cortex. An age-related increase in albumin uptake by the brains of Tg2576 mice, compared with nontransgenic mice, was also observed. These findings were supported by quantitative Evans blue analysis (p = 0.07, two-way analysis of variance). CONCLUSION: A breakdown of BBB was evident in young 4- to 10-month-old Tg2576 mice. Compromised barrier function could explain the mechanisms of Abeta entry into the brain observed in experimental Alzheimer disease vaccination models. Such structural changes to the BBB caused by elevated Abeta could play a central role in Alzheimer disease development and might define an early point of intervention for designing effective therapy against the disease.