The Physical Foundation of Vasoocclusion in Sickle Cell Disease

AbstractThe pathology of sickle cell disease arises from the occlusion of small blood vessels because of polymerization of the sickle hemoglobin within the red cells. We present measurements using a microfluidic method we have developed to determine the pressure required to eject individual red cells from a capillary-sized channel after the cell has sickled. We find that the maximum pressure is only ∼100 Pa, much smaller than typically found in the microcirculation. This explains why experiments using animal models have not observed occlusion beginning in capillaries. The magnitude of the pressure and its dependence on intracellular concentration are both well described as consequences of sickle hemoglobin polymerization acting as a Brownian ratchet. Given the recently determined stiffness of sickle hemoglobin gels, the observed obstruction seen in sickle cell disease as mediated by adherent cells can now be rationalized, and surprisingly suggests a window of maximum vulnerability during circulation of sickle cells

State of morbidity & mortality in Orenburg region due to cerebrovascular diseases (5 years study)

The article gives results of analysis of morbidity & mortality indicators in Orenburg region due to cerebrovascular diseases, which enter circulatory system diseases class, for the period 2009 - 2013 years. It was set, that cerebrovascular diseases have 25.1% in structure of primary morbidity & 20,9% in overall morbidity. Cerebral infarction leads among overall morbidity of cerebrovascular diseases, which reached 91,5% to 2013 years. A hospitalization for 5 years reached 8,6 for 1000 of Orenburg region population due to cerebrovascular diseases. We found out a high mortality due to that pathology, which has an average long-term rate -1 1 ,6 % ; where in a main cause of mortality is a cerebral infarction - 62,8% .В статье представлены результаты анализа показателей заболеваемости и смертности населения Оренбургской области по причине цереброваскулярных болезней, входящих в класс болезней системы кровообращения. Установлено, что в структуре первичной заболеваемости болезнями системы кровообращения цереброваскулярные болезни занимают 25.1% . а в структуре общей заболеваемости - 20,9% . Среди общей заболеваемости цереброваскулярными болезнями лидирует инфаркт мозга (ишемический инсульт), доля которого в 2013 году достигла 91,5% . Уровень госпитализации по причине цереброваскулярных болезней взрослого населения Оренбургской области в среднем за пять лет составил 8.6 на 1000 населения. В регионе отмечается высокая летальность по причине данной патологии, которая имеет среднемноголетний показатель -1 1 ,6 % . при этом ведущей причиной летальности является инфаркт мозга (62,8% )

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo

Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood- tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface- targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site- specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM- 1 (CD31) and ICAM- 1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post- injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding- detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one- to- one protein conjugates. Bivalent mAb- TM was superior to monovalent scFv- TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end- to- end anti- ICAM mAb- TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/3/fsb220760_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/2/fsb220760-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/1/fsb220760.pd

Monitoring of regional indicators of morbidity, mortality and lethality Orendurg region population as result of vascular diseases

The paper analyzes the morbidity, mortality in the adult population of the Orenburg region due to cardiovascular diseases. Noticed increase in overall incidence of diseases characterized by high blood pressure. Marked increase in overall incidence of diseases characterized by high blood pressure. In 2013, the proportion of cardiovascular disease accounted for 56.3% of all causes of mortality. In the structure of primary morbidity of diseases of the circulatory system the proportion of cerebrovascular diseases was 25.1%, and in the structure of overall morbidity - 20.9%. Among the cerebrovascular diseases cerebral infarction (ischemic stroke) - 91,5% - was leading. Average annual rate of hospitalization due to cerebrovascular diseases in the adult population of the Orenburg region was 8,6 per 1,000 population, rate of mortality - 11.6%, and the leading cause of mortality was cerebral infarction (62.8%)