The Role of High Molecular Weight Kininogen (Fitzgerald Factor) in the Activation of Various Plasma Proteolytic Enzyme Systems

Bovine high molecular weight kininogen (bHMWK) partially corrects the aPTT of Fitzgerald-trait plasma, which is congenitally deficient in HMWK. The relationship between the structure and activity of HMWK was clarified by studying the effects of different fragments of bHMWK on the aPTT of Fitzgerald-trait plasma. The peptides studied, all in equimolar concentrations, were lys-bradykinin-free HMWK, bradyk In In-fragment 1-2-tree HMWK, heavy chain, fragment 1 -2-Hght chain, and light chain. Bradykinin- fragment 1-2-free HMWK, heavy chain, and light chain have little or no correcting activity upon Eitzgeraldtrait plasma aPTT. Fragment 1-2 light chain has the same correcting activity as intact bHMWK, while that of lysbradykinin-free HMWK appears to be higher. Both fragment 1-2 and fragment 2 inhibit the clotting time of normal human plasma. On a molar basis, fragment 2 is a more active inhibitor than fragment 1-2. Bovine plasma kallikrein released kinins from both bHMWK and hHMWK; however, while the correcting activity of bHMWK was completely destroyed after sixty minutes of incubation, that of hHMWK was fully retained. These data suggest that: (1) the active part of bHMWK is comprised of the fragment 1-2 light chain portion; (2) fragment 1-2 or fragment 2 is the binding site to negatively charged surfaces, while the light chain interacts with other components of the surface-mediated reactions; and (3) bovine plasma kallikrein releases kinins but probably does not cause the release of fragment 1-2 from hHMWK

ROCK CLIMBING HELMET IMPACT PERFORMANCE VARIES BY HELMET MODEL TYPE

The purpose of this study was to compare the impact performance of a sample of rock climbing helmets. Each helmet was impacted at three locations (front, side, and back) and three impact speeds (2 m/s, 3.85 m/s, and 5 m/s) using a custom pendulum impactor. Peak resultant linear and rotational accelerations were compared by impact speed. The results of this study show that acceleration varies by helmet model and impact location. Differences in acceleration by helmet model support the need for relative performance ratings of rock climbing helmets. These tests can be used as the basis of methods to compare relative helmet performance. Relative performance evaluation would inform consumers of the safety of different helmet types, and would also inform manufacturers where improvements in helmet designs should be made

Human Cord Blood-Derived AC133+ Progenitor Cells Preserve Endothelial Progenitor Characteristics after Long Term In Vitro Expansion

Stem cells/progenitors are central to the development of cell therapy approaches for vascular ischemic diseases. The crucial step in rescuing tissues from ischemia is improvement of vascularization that can be achieved by promoting neovascularization. Endothelial progenitor cells (EPCs) are the best candidates for developing such an approach due to their ability to self-renew, circulate and differentiate into mature endothelial cells (ECs). Studies showed that intravenously administered progenitors isolated from bone marrow, peripheral or cord blood home to ischemic sites. However, the successful clinical application of such transplantation therapy is limited by low quantities of EPCs that can be generated from patients. Hence, the ability to amplify the numbers of autologous EPCs by long term in vitro expansion while preserving their angiogenic potential is critically important for developing EPC based therapies. Therefore, the objective of this study was to evaluate the capacity of cord blood (CB)-derived AC133+ cells to differentiate, in vitro, towards functional, mature endothelial cells (ECs) after long term in vitro expansion.We systematically characterized the properties of CB AC133+ cells over the 30 days of in vitro expansion. During 30 days of culturing, CB AC133+ cells exhibited significant growth potential that was manifested as 148-fold increase in cell numbers. Flow cytometry and immunocytochemistry demonstrated that CB AC133+ cells' expression of endothelial progenitor markers was not affected by long term in vitro culturing. After culturing under EC differentiation conditions, cells exhibited high expression of mature ECs markers, such as CD31, VEGFR-2 and von Willebrand factor, as well as the morphological changes indicative of differentiation towards mature ECs. In addition, throughout the 30 day culture cells preserved their functional capacity that was demonstrated by high uptake of DiI fluorescently conjugated-acetylated-low density lipoprotein (DiI-Ac-LDL), in vitro and in vivo migration towards chemotactic stimuli and in vitro tube formation.These studies demonstrate that primary CB AC133+ culture contained mainly EPCs and that long term in vitro conditions facilitated the maintenance of these cells in the state of commitment towards endothelial lineage

Real-world experience with ultrasound renal denervation utilizing home blood pressure monitoring:the Global Paradise System registry study design

Background: Hypertension is a major public health issue due to its association with cardiovascular disease risk. Despite the availability of effective antihypertensive drugs, rates of blood pressure (BP) control remain suboptimal. Renal denervation (RDN) has emerged as an effective non-pharmacological, device-based treatment option for patients with hypertension. The multicenter, single-arm, observational Global Paradise™ System (GPS) registry has been designed to examine the long-term safety and effectiveness of ultrasound RDN (uRDN) with the Paradise System in a large population of patients with hypertension. Methods: The study aims to enroll up to 3000 patients undergoing uRDN in routine clinical practice. Patients will be recruited over a 4-year period and followed for 5 years (at 3, 6, and 12 months after the uRDN procedure and annually thereafter). Standardized home BP measurements will be taken every 3 months with automatic upload to the cloud. Office and ambulatory BP and adverse events will be collected as per routine clinical practice. Quality-of-Life questionnaires will be used to capture patient-reported outcomes. Conclusions: This observational registry will provide real-world information on the safety and effectiveness of uRDN in a large population of patients treated during routine clinical practice, and also allow for a better understanding of responses in prespecified subgroups. The focus on home BP in this registry is expected to improve completeness of long-term follow-up and provide unique insights into BP over time. Graphical abstract: Global Paradise System registry study design. ABP, ambulatory blood pressure; BP, blood pressure; FU, follow-up; M, month; OBP, office blood pressure. [Figure not available: see fulltext.].</p

Lithium treatment reduces the renal kallikrein excretion rate

Lithium treatment reduces the renal kallikrein excretion rate. Lithium salts are widely used agents for the prophylactic treatment of affective disorders. Lithium salts may be associated with distal nephron dysfunction. Kallikrein is a protease which is generated by the distal nephron. We used an amidolytic assay of chromatographically purified enzyme to determine the urinary excretion rate of active kallikrein in relation to lithium treatment. All plasma lithium concentrations were within the therapeutic range (0.4 to 0.9 mmol/liter). In 15 patients the urinary excretion rate of active kallikrein was 267.4 65.6 mU/24 hrs before lithium treatment, and fell to 117.8 39.6 mU/24 hrs (P < 0.05) on day 14 of lithium treatment. This reduction was associated with a decrease of immunoreactive kallikrein in the same urines by 66%. In another 15 patients who had undergone lithium therapy for an average period of 5.6 years, the urinary excretion rate of active kallikrein was 86.1 14.5 mU/24 hrs, while 21 age-matched healthy controls had an excretion rate of 364.1 58.4 mU/24 hrs (P < 0.05). Measurements of immunoreactive kallikrein in the same urine samples demonstrated a reduction of kallikrein after long-term lithium treatment by 78%. These observations could not be attributed to changes in creatinine clearance, renal sodium or potassium excretion rates or plasma concentrations of aldosterone and vasopressin. Addition of lithium to the urine in vitro had no demonstrable effect on kallikrein measurement by amidolytic assay. We conclude that lithium in therapeutic plasma concentrations may directly suppress the secretion of kallikrein by renal connecting tubule cells

A Study into the Standard Safety Accreditations for Rock Climbing Helmets and the Concussion Risk Asscociated with Different Helmets

In collaboration with the Helmet Testing Lab at Virginia Tech we have looked into the current safety regulations for rock climbing helmets provided by accrediting bodies to see how well these accreditations translate into consumer safety and concussion risk. We have also been able to independently look at how each helmet model tested is affected by high and low velocity impacts. As well, we have looked into how repeated hits on these helmets in specific locations affect their structural integrity