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1
Geoffrion, Roxana, Danny Lovatsis, Jens-Erik Walter, Queena Chou, William Easton, Annette Epp, Roxana Geoffrion, et al. "Traitements visant la vessie hyperactive : Accent sur la pharmacothérapie." Journal of Obstetrics and Gynaecology Canada 34, no. 11 (November 2012): 1102–4. http://dx.doi.org/10.1016/s1701-2163(16)35441-x.
2
Geoffrion, Roxana. "Traitements visant la vessie hyperactive : Accent sur la pharmacothérapie." Journal of Obstetrics and Gynaecology Canada 38, no. 12 (December 2016): S158—S170. http://dx.doi.org/10.1016/j.jogc.2016.09.027.
3
Geoffrion, Roxana. "N o 283-Traitements visant la vessie hyperactive : Accent sur la pharmacothérapie." Journal of Obstetrics and Gynaecology Canada 40, no. 1 (January 2018): e33-e44. http://dx.doi.org/10.1016/j.jogc.2017.11.006.
4
Bolduc, S., A. Fortin, V. Morin, and P. Gervais. "P-032 – Observance au traitement chez les enfants atteints de vessie hyperactive." Archives de Pédiatrie 22, no. 5 (May 2015): 241. http://dx.doi.org/10.1016/s0929-693x(15)30217-7.
5
Geoffrion, Roxana. "N o 353 – Traitements visant la vessie hyperactive : Accent sur la pharmacothérapie – Addenda." Journal of Obstetrics and Gynaecology Canada 39, no. 12 (December 2017): 1230–39. http://dx.doi.org/10.1016/j.jogc.2017.08.042.
6
Zenner-Weber, Marietta. "Les symptômes d’urgence mictionnelle en cas de vessie hyperactive ont un retentissement considérable sur la qualité de vie." Revue Médicale Suisse 5, no. 196 (2009): 687. http://dx.doi.org/10.53738/revmed.2009.5.196.0687.
7
Leon, P., A. Binet, C. Jolly, and M. L. Poli-Merol. "Usage de la toxine botulique dans les vessies hyperactives non neurologiques chez l’enfant." Progrès en Urologie 22, no. 13 (November 2012): 758. http://dx.doi.org/10.1016/j.purol.2012.08.041.
8
Denys, P., E. Chartier-Kastler, P. Azouvi, O. Remy-Neris, and B. Bussel. "Effet urodynamique de la neurostimulation S3 test sur les vessies hyperactives résistantes des blessés médullaires." Annales de Réadaptation et de Médecine Physique 41, no. 6 (January 1998): 348. http://dx.doi.org/10.1016/s0168-6054(98)80142-6.
9
Amarenco, G., A. Le Cocquen, D. Lagauche, M. Chevignard, and S. Bosc. "Étude cystomanométrique de 153 vessies neurologiques hyperactives avant et après test au bromure de prifinium." Annales de Réadaptation et de Médecine Physique 41, no. 7 (January 1998): 417–20. http://dx.doi.org/10.1016/s0168-6054(98)80263-8.
10
Lardon, Renaud, and Alain Ruffion. "Quelles peuvent être les futures applications de la toxine botulique en urologie en dehors des vessies hyperactives des patients neurologiques ?" Progrès en Urologie - FMC 19, no. 3 (September 2009): F91—F94. http://dx.doi.org/10.1016/j.fpurol.2009.02.003.
11
Park, Jae Sung, and Kwan Park. "Operative Findings of over 5000 Microvascular Decompression Surgeries for Hemifacial Spasm: Our Perspective and Current Updates." Life 13, no. 9 (September 13, 2023): 1904. http://dx.doi.org/10.3390/life13091904.
Анотація:
Hemifacial spasm (HFS) is a hyperactive cranial neuropathy, and it has been well established that the cause of primary HFS is compression on the root exit zone (REZ) of the facial–vestibulocochlear nerve complex (CN VII-VIII) by a vessel or vessels. MVD is the only curative treatment option for HFS with a high success rate and low incidence of recurrence and complications. We categorize six classical compressive patterns on the REZ as well as five challenging types. Knowledge of these patterns may help in achieving a better surgical outcome.
12
Barg, Alexej, Rainer Ossig, Tobias Goerge, Hermann Schillers, Hans Oberleithner, Stefan Schneider, and Matthias Schneider. "Soluble plasma-derived von Willebrand factor assembles to a haemostatically active filamentous network." Thrombosis and Haemostasis 97, no. 04 (2007): 514–26. http://dx.doi.org/10.1160/th06-05-0274.
Анотація:
SummaryThe large glycoprotein vonWillebrand factor (VWF) is involved in the initial haemostatic reaction mediating the interaction between platelets and the injured vessel wall. It has been demonstrated that unusually large VWF (ULVWF) multimers after being released from endothelium are capable of developing elongated membrane-anchored strings that are hyperactive to bind platelets. In the present study we investigated whether soluble plasma-derived VWF is competent to develop similar thrombotically active multimers. We demonstrated that soluble VWF multimers isolated from human plasma self-assemble to a network of fibers immobilized on a collagen matrix and are functionally active to bind platelets. Formation of these VWF fibers depends on shear flow, concentration of solubleVWF, and a suitable binding surface. Self-assembly of soluble VWF does not require the presence of cellular membrane ligands. The network of fibers is subjected to rapid degradation by proteolytic activity of plasma ADAMTS-13.Atomic force microscopy images elucidate the nanostructure of VWF fibers and illustrate self-association and -aggregation of several filamentous multimers. Together, these results suggest that circulatingVWF can contribute to a formation of hyperactive VWF fibers on exposed subendothelial collagen during vascular injury.
13
Zhou, Zhou, Molly Behymer, and Prasenjit Guchhait. "Role of Extracellular Hemoglobin in Thrombosis and Vascular Occlusion in Patients with Sickle Cell Anemia." Anemia 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/918916.
Анотація:
Sickle cell anemia (SCA) is a common hemolytic disorder caused by a gene mutation in theβ-globin subunit of hemoglobin (Hb) and affects millions of people. The intravascular hemolysis releases excessive amount of extracellular hemoglobin (ECHb) into plasma that causes many cellular dysfunctions in patients with SCA. ECHb scavenges NO which promotes crisis events such as vasoconstriction, thrombosis and hypercoagulation. ECHb and its degradation product, heme, are known to cause oxidative damage to the vessel wall and stimulate the expression of adhesive protein ligands on vascular endothelium. Our study shows that ECHb binds potently to VWF—largest multimeric glycoprotein in circulation—through the A2-domain, and significantly inhibits its cleavage by the metalloprotease ADAMTS13. Furthermore, a subpopulation of VWF multimers bound to ECHb exists in significant amount, accounting for about 14% of total plasma VWF, in SCD patients. The Hb-bound VWF multimers are resistant to ADAMTS13, and are hyperactive in aggregating platelets. Thus, the data suggest that Hb-bound VWF multimers are ultralarge and hyperactive because they are resistant to the protease. The Hb-bound VWF multimers are elevated parallely with the level of ECHb in patients' plasma, and is associated with the pathogenesis of thrombosis and vascular occlusion in SCA.
14
Fang, Yulin, Veeraraghavan Meyyur Aravamudan, Gurusaravanan Kutti Sridharan, Keyur Kamlesh Mehta, Ramkumar Sekhar, Nagendra Boopathy Senguttuvan, Indumathi Venkatachalam, and Muhammad Bilal Abid. "Kawasaki like illness due to COVID-19: a review of the literature." Journal of Infection in Developing Countries 15, no. 05 (May 31, 2021): 630–38. http://dx.doi.org/10.3855/jidc.14185.
Анотація:
Introduction: Viral infections have been described as triggers for Kawasaki Disease (KD), a medium vessel vasculitis that affects young children. Akin to the H1N1 pandemic in 2009, there is a similar rise in the incidence of KD in children affected with Coronavirus disease 2019 (COVID-19). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) has been reported to induce an exaggerated systemic inflammatory response resulting in multi-organ involvement, particularly initiated with pulmonary parenchymal damage. This review article will discuss KD-like manifestations in COVID-19 patients in the pediatric cohort.
Methodology: Search terms “Kawasaki” “COVID-19” “SARS-COV-2” “PIM-TS” and “MIS-C” were used to look for relevant articles in PubMed and Google Scholar published in the last 5 years.
Results: There is some evidence to suggest that SARS-CoV-2 stimulates dysfunctional and hyperactive immune reactions mimicking KD in young patients.
Conclusions: Therapeutic options, both investigational and repurposed, include intravenous immunoglobulins, steroids and anticoagulation. More studies are required to evaluate the effectiveness of these treatment options.
15
Johnson, Dennis L. "Intractable hiccups: treatment by microvascular decompression of the vagus nerve." Journal of Neurosurgery 78, no. 5 (May 1993): 813–16. http://dx.doi.org/10.3171/jns.1993.78.5.0813.
Анотація:
✓ Idiopathic hiccups are usually managed with pharyngeal stimulation or a plethora of pharmacological agents. Hiccups that persist and prove intractable to these medical measures are treated by crush or ablation of the phrenic nerve, which denervates the major respiratory muscle. This is the first reported case of nondestructive microvascular decompression of the vagus nerve for the treatment of intractable idiopathic hiccups. The success of microvascular decompression has been documented with other conditions, such as trigeminal neuralgia and hemifacial spasm, that are characterized by hyperactive dysfunctional neurovascular contact. The vagus nerve was separated from the posterior inferior cerebellar artery by inserting a Teflon pledget between the nerve and vessel which eliminated the neurovascular contact. One year after the initial surgery, the hiccups recurred. The Teflon pledget had fallen out of place and the nerve was once again in contact with the artery. Once the contact was eliminated by wrapping the artery with a tuft of Teflon, the hiccups stopped. The patient has remained free of hiccups for 3 years. It is concluded that patients with intractable idiopathic hiccups who fail medical therapy should be considered for microvascular decompression of the vagus nerve.
16
Perez-Roman, Roberto J., Stephanie H. Chen, Samir Sur, Roberto Leon-Correa, and Jacques J. Morcos. "A Unique Case of Microvascular Triple Decompression for Combined Simultaneous Trigeminal Neuralgia, Hemifacial Spasm, and Glossopharyngeal Neuralgia Because of the Dolichoectatic Vertebrobasilar System." Operative Neurosurgery 18, no. 6 (July 23, 2019): 692–97. http://dx.doi.org/10.1093/ons/opz205.
Анотація:
Abstract BACKGROUND Trigeminal neuralgia (TN), hemifacial spasm (HFS), and glossopharyngeal neuralgia (GPN) are hyperactive dysfunction syndromes (HDS) commonly caused by microvascular compression of their root entry zone. Cases of combined HDS involving 2 or more of these entities are extremely rare. Although microvascular decompression is the surgical treatment of choice, there are additional techniques that have been described as efficient methods to accomplish vessel transposition. OBJECTIVE To our knowledge, we present the first reported case of triple simultaneous HDS successfully treated using the clip-sling technique to achieve microvascular decompression. We discuss several technical pearls and pitfalls relevant to the use of the sling suspension technique. METHODS We report the rare case of a 66-yr-old male with combined simultaneous unilateral right-sided TN, HFS, and GPN because of a dolichoectatic vertebrobasilar system compressing the exit zones of the right trigeminal, facial, and glossopharyngeal nerves and present a literature review of combined HDS and their different surgical treatments. RESULTS Symptomatic TN, HFS, and GPN have been reported 8 times in the literature with our case being the ninth. A retrosigmoid craniotomy was performed for microvascular decompression of the brainstem with a clip-sling suspension technique augmented with Teflon felt pledgets. The patient had immediate complete relief from TN, HFS, and GPN postoperatively. CONCLUSION Microvascular decompression using the clip-sling technique via a retrosigmoid approach should be considered as a safe and effective option for transposition and suspension of the offending artery and decompression of the affected nerve roots in cases of combined HDS.
17
Zhang, Yuan, Yanfei Wang, Li Zhang, Luoxing Xia, Minhui Zheng, Zhi Zeng, Yingying Liu та ін. "Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis". Circulation Research 127, № 7 (11 вересня 2020): 855–73. http://dx.doi.org/10.1161/circresaha.120.316951.
Анотація:
Rationale: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. Objective: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. Methods and Results: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRβ (platelet-derived growth factor receptor β). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD ( Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRβ inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort. Conclusions: Platelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.
18
Naik, Meghna Ulhas, and Ulhas P. Naik. "Junctional Adhesion Molecule-A Is a Novel Csk-Binding Protein Which Recruits Csk to the Integrin aIIbb3 and Suppresses Outside-In Signaling In Platelets." Blood 116, no. 21 (November 19, 2010): 2120. http://dx.doi.org/10.1182/blood.v116.21.2120.2120.
Анотація:
Abstract Abstract 2120 Platelet activation is regulated by both positive and negative regulators present within the platelets so that unwanted activation is suppressed, but, when needed, occurs rapidly. A significant amount of effort has been devoted towards understanding the positive regulators of platelet function. However, very little is known about the negative regulators. Dysregulation of the endogenous negative regulators may aid the thrombotic complications seen in various diseases. Upon ligand binding to integrin aIIbb3, a cascade of signaling known as outside-in signaling is induced through the integrin that regulates platelet aggregation and clot retraction. How endogenous negative regulators suppress these events is not well understood. We have previously identified junctional adhesion molecule A (JAM-A), on the platelet surface. We found that Jam-a knockout mice show a prothrombotic phenotype as assessed by significantly (P<0.00001) shortened tail bleeding time, decreased carotid vessel occlusion time and increased pulmonary thromboembolism. Platelet functional studies revealed that Jam-a null platelets were hyperactive to physiological agonists. Surprisingly, inside-out signaling events were not affected in Jam-a null platelets. It is therefore possible that observed hyper-reactivity of Jam-a null platelets could be due to enhanced outside-in signaling. To test this, we performed a clot retraction assay. The clot retraction in wild type (Wt) occurred normally, which began after 1 h and about 50% was completed by 2 h. On the contrary, in Jam-a null platelets, the process of clot retraction was significantly enhanced (P<0.0001). It was initiated before 1h and was completed within 2 h. When analyzed for outside-in signaling events such as b3 tyrosine phosphorylation and c-Src phosphorylation, we found both significantly enhanced in Jam-a null platelets. To assess the mechanism by which JAM-A suppresses outside-in signaling, we analyzed the phosphorylation status of JAM-A. Interestingly, JAM-A was found to be phosphorylated on Y280 in unactivated platelets and rapidly dephosphorylated upon initiation of outside-in signaling. On the other hand, in resting platelets, a minimally phosphorylated S284 residue of JAM-A is rapidly phosphorylated, suggesting that there is a dephosphorylation/phosphorylation switch that may be involved in regulating outside-in signaling. Furthermore, we found that JAM-A associates with integrin aIIbb3 in unactivated human platelets, but this association was disrupted during outside-in signaling as determined by co-immunoprecipitation. We also found Csk, a C-terminal Src kinase, coimmunoprecipitating (IP) with JAM-A from resting, but not activated, platelet lysates, suggesting that JAM-A may be recruiting Csk to unactivated integrins and thus suppressing signaling. To test this, we analyzed association of Csk with integrin in Jam-a null platelets and found that in Wt platelets Csk was abundantly present in the integrin IP, but was completely absent in the integrin IP of the Jam-a null platelet lysates. These results clearly suggest that JAM-A recruits Csk to the integrin and thus suppresses outside-in signaling. Disclosures: No relevant conflicts of interest to declare.
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Sangkatumvong, Suvimol, Rachna Khanna, Michael Khoo, and Thomas D. Coates. "Sickle Cell Patients Have Exagerated Autonomic Response to Transient Hypoxia." Blood 112, no. 11 (November 16, 2008): 124. http://dx.doi.org/10.1182/blood.v112.11.124.124.
Анотація:
Abstract Sickle cell anemia (SCA) is a devastating disorder that results from a single amino acid substitution in the beta chain of hemoglobin causing polymerization of hemoglobin S when oxygen is removed. This causes normally flexible sickle red cells (SRBC) to become rigid, obstruct vasculature resulting in ischemic organ damage and decreased longevity. Anything which decreases microvasculature flow will promote the sickling process. Inflammation and adhesion of cellular elements to the vessel wall are known to increase the probability of vasoocclusive crisis (VOC). However, the precise event that triggers the cascade called “crisis” is not known. Microvascular flow changes rapidly in response to autonomic signals which can be assessed by measurement of heart rate variability (HRV). These autonomic signals may be the trigger that causes regional decrease in flow and initiates the events resulting in crisis. We have established a model of induced hypoxia in human subjects that was designed to mimic the transient hypoxia occuring naturally during sleep. Calibrated tidal volume, O2 saturation, and electrocardiogram, were recorded up to 200 times per second using a LifeShirt physiological monitoring garment and tissue oxygenation and microvascular blood flow was assessed by laser Doppler flowmetry or magnetic resonance imaging. The report focuses on safety and on HRV results. Subjects breathed 5 breaths of 100% N2 twice separated by a 5 to 10 minte recovery period on up to 4 separate days per subject. 15 SCA had two hypoxic exposures on 38 days. Subjects were contacted 1, 12, and 24 hrs and 7 to 14 days later and symptom questionnaires completed. On only 4 occasions, subjects reported mild transient sicklelike pain that required no or non-narcotic treatment within 24 hours of hypoxia and was deemed possibly related to the hypoxic exposure. About sixty percent of the exposures were associated with lightheadedness lasting 10 to 15 seconds at the nadir of the SpO2. The drop in SpO2 was greater in the SCA patients (p<.05) and lasted 15 to 20 seconds. However, when we used the subjects’ individually measured oxyhemoglobin saturation curve to calculate change in pO2, there was no difference between SCA and normals. Using a novel algorithm we developed which allows second to second comparison of autonomic nervous system (ANS) balance to change in SaO2, we found that the high frequency component of HRV representing parasympathetic (HFP) and low frequency component representing mixed sympathetic activity (LFP) were significantly different between SCA and control (p<.001). SCA patients have a dramatic loss of parasympathetic signal in response to transient hypoxia resulting in significant loss of heart rate variability. These data suggest than SCA patients have a greatly amplified autonomic nervous system response, at least to hypoxia. Since these same ANS signals are also responsible for control of regional microvascular blood flow, it is reasonable to speculate that this hyperactive ANS response leads to regional drop in perfusion which, on a background of hyper-adhesiveness, nitric oxide depletion, inflammation, and dehydration, triggers the sickling cascade. It is important to note that loss of HRV is a powerful predicator of sudden death in several other settings of vascular disease and that 15 to 20% of SCA deaths are otherwise unexplained sudden deaths. These data demonstrate that transient hypoxia can be safely induced in SCA subjects and used to study the relation between hypoxia and physiological responses and SCA patients have a marked abnormality in autonomic nervous system regulation in response to transient hypoxia that likely plays a role in the pathophysiology of this disorder.
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Stoller, Michelle L., Indranil Basak, James Alsobrooks, Paul F. Bray, and Robert A. Campbell. "Cathepsin G Cleavage of PAR4 Generates a Novel Tethered Ligand That Induces Platelet Activation." Blood 136, Supplement 1 (November 5, 2020): 2. http://dx.doi.org/10.1182/blood-2020-134931.
Анотація:
Atherosclerotic vessel injury induces recruitment of both platelets and neutrophils where multiple proteases induce platelet activation and aggregation. Platelets contain two protease activated receptors, PAR1 and PAR4, the cleavage of which results in exposure of a new amino terminus to serve as a tethered ligand. Released neutrophil cathepsin G (CatG) has been shown to be a physiologic modulator of platelet thrombus formation in mice. CatG activates PAR4 and not PAR1, presumably because CatG cleaves PAR1 by removing its tethered ligand. However, neither the CatG biochemical cleavage of PAR4 nor the resulting tethered ligands have been reported. The goals of the current study are to (1) identify the CatG-PAR4 cleavage sites and resulting tethered ligands and (2) determine how CatG-stimulated PAR4 signaling is altered by the PAR4 Ala120Thr variant. We synthesized two portions of the PAR4 extracellular N-terminus: amino acids Asp38-Ser58 (PAR4-B) and Asp57-Arg78 (PAR4-C) and exposed each peptide to purified CatG. Mass spectrometry identified two major cleavage sites for PAR4-B: the previously documented CatG and thrombin site Arg47-Gly48 and a novel Cys54-Ala55. Analysis of PAR4-C digestion yielded an additional three novel CatG cleavage sites, two major: Arg68-Ala69 and Leu71-Leu72, and one minor: Leu70-Leu71. Neither concentration or time of exposure appeared to alter the CatG cleavage sites. To assess functionality, we generated peptides based on the novel cleavage sites produced by CatG cleavage. Human washed platelets were treated with each peptide, and platelet activation was assessed by PAC-1 binding. As expected, the known tethered ligand sequence GYPGQV showed a statistically significant increase in PAC-1 binding (p=.02) compared to resting platelets. Three of the remaining four novel peptides generated no significant change in PAC-1 binding compared to baseline. However, peptide 3, representing novel tethered ligand ALLLGW, induced a substantial increase (462%) in PAC-1 binding compared to resting platelets. To assess the effect of the PAR4Ala120Thr variant on CatG-stimulated platelet reactivity, human washed platelets were collected from donors homozygous for Ala120 or Thr120 and stimulated with CatG. Platelets expressing the Thr120 variant displayed a significant increase in PAC-1 compared to Ala120 platelets (54%; p=.004). Addition of a CatG inhibitor caused a significant decrease in platelet activation triggered by CatG for both groups (Thr: -81%, p=.000001; Ala: -78%, p=.00017), and abrogated the significant increase in platelet activation displayed by Thr120 platelets (p=.99). To further examine the relationship between the PAR4 Ala120Thr variant and CatG, platelets from each variant were subjected to increasing amounts of CatG. Platelet activation was measured by PAC-1 binding and P-selectin expression. Both PAC-1 binding and P-selectin expression were significantly increased in platelets from Thr120 donors compared to Ala120 platelets (PAC-1, p=.026; P-selectin, p=.025). Overall, our study identified a previously unidentified CatG cleavage site in PAR4, which produced a novel tethered ligand capable of activating platelets. Because cleavage resulting in the ALLLGW ligand is downstream of the thrombin cleavage site, CatG may modulate in vivo thrombin-induced signaling in platelets or other cell types. Our findings also indicate the hyperactive response of 120Thr platelets is not dependent on a specific PAR4 protease. These new insights into PAR4 biology may provide targets for future antithrombotic therapies. Disclosures No relevant conflicts of interest to declare.
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Fernandes, Lorenzo M., Jeffrey Tresemer, Jing Zhang, Jonathan J. Rios, Joshua P. Scallan, and Michael T. Dellinger. "Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function." Frontiers in Cell and Developmental Biology 11 (September 25, 2023). http://dx.doi.org/10.3389/fcell.2023.1276333.
Анотація:
Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.
22
Marianayagam, Neelan J., Hanya M. Qureshi, Sagar Vasandani, Shaurey Vetsa, Muhammad Jalal, Kun Wu, and Jennifer Moliterno. "Simultaneous microvascular decompression for trigeminal neuralgia and hemifacial spasm involving a dolichoectatic vertebral artery in an elderly patient: illustrative case." Journal of Neurosurgery: Case Lessons 4, no. 3 (July 18, 2022). http://dx.doi.org/10.3171/case22176.
Анотація:
BACKGROUND Hyperactive cranial neuropathies refractory to medical management can often be debilitating to patients. While microvascular decompression (MVD) surgery can provide relief to such patients when an aberrant vessel is compressing the root entry zone (REZ) of the nerve, the arteries of elderly patients over 65 years of age can be less amenable to manipulation because of calcifications and other morphological changes. A dolichoectatic vertebral artery (DVA), in fact, can lead to multiple cranial neuropathies; therefore, a strategy for MVDs in elderly patients is useful. OBSERVATIONS A 76-year-old man presented with medically refractory trigeminal neuralgia (TN) and hemifacial spasm (HFS). A DVA was the conflicting vessel at the left REZs of the trigeminal and facial nerves. The authors performed a retrosigmoid craniotomy for MVD of the DVA with Teflon padding at both REZs in approximately 1 hour of operative time. The patient was free of facial pain and spasm immediately after surgery and at follow-up. LESSONS The authors described the case of an elderly patient with both TN and HFS caused by compression of a DVA. Simultaneous MVD with Teflon padding at both REZs provided symptomatic relief with limited surgical time. This can be a particularly useful and straightforward surgical strategy in the elderly population.
23
Morse, Paul T., Junmei Wan, Jamie Bell, Icksoo Lee, Dennis J. Goebel, Moh H. Malek, Thomas H. Sanderson, and Maik Hüttemann. "Sometimes less is more: inhibitory infrared light during early reperfusion calms hyperactive mitochondria and suppresses reperfusion injury." Biochemical Society Transactions, September 6, 2022. http://dx.doi.org/10.1042/bst20220446.
Анотація:
Ischemic stroke affects over 77 million people annually around the globe. Due to the blockage of a blood vessel caused by a stroke, brain tissue becomes ischemic. While prompt restoration of blood flow is necessary to save brain tissue, it also causes reperfusion injury. Mitochondria play a crucial role in early ischemia-reperfusion injury due to the generation of reactive oxygen species (ROS). During ischemia, mitochondria sense energy depletion and futilely attempt to up-regulate energy production. When reperfusion occurs, mitochondria become hyperactive and produce large amounts of ROS which damages neuronal tissue. This ROS burst damages mitochondria and the cell, which results in an eventual decrease in mitochondrial activity and pushes the fate of the cell toward death. This review covers the relationship between the mitochondrial membrane potential (ΔΨm) and ROS production. We also discuss physiological mechanisms that couple mitochondrial energy production to cellular energy demand, focusing on serine 47 dephosphorylation of cytochrome c (Cytc) in the brain during ischemia, which contributes to ischemia-reperfusion injury. Finally, we discuss the use of near infrared light (IRL) to treat stroke. IRL can both stimulate or inhibit mitochondrial activity depending on the wavelength. We emphasize that the use of the correct wavelength is crucial for outcome: inhibitory IRL, applied early during reperfusion, can prevent the ROS burst from occurring, thus preserving neurological tissue.
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Camillo, Chiara, Nicola Facchinello, Giulia Villari, Giulia Mana, Noemi Gioelli, Chiara Sandri, Matteo Astone, et al. "LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion." Journal of Cell Biology 220, no. 11 (September 28, 2021). http://dx.doi.org/10.1083/jcb.202006033.
Анотація:
Dynamic modulation of endothelial cell-to-cell and cell–to–extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein–coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in an LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable, and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.
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Shields, Lisa B. E., Vasudeva G. Iyer, Yi Ping Zhang, and Christopher B. Shields. "Etiology of spastic foot drop among 16 patients undergoing electrodiagnostic studies: patient series." Journal of Neurosurgery: Case Lessons 5, no. 21 (May 22, 2023). http://dx.doi.org/10.3171/case23154.
Анотація:
BACKGROUND Differentiating foot drop due to upper motor neuron (UMN) lesions from that due to lower motor neuron lesions is crucial to avoid unnecessary surgery or surgery at the wrong location. Electrodiagnostic (EDX) studies are useful in evaluating patients with spastic foot drop (SFD). OBSERVATIONS Among 16 patients with SFD, the cause was cervical myelopathy in 5 patients (31%), cerebrovascular accident in 3 (18%), hereditary spastic paraplegia in 2 (12%), multiple sclerosis in 2 (12%), chronic cerebral small vessel disease in 2 (12%), intracranial meningioma in 1 (6%), and diffuse brain injury in 1 (6%). Twelve patients (75%) had weakness of a single leg, whereas 2 others (12%) had bilateral weakness. Eleven patients (69%) had difficulty walking. The deep tendon reflexes of the legs were hyperactive in 15 patients (94%), with an extensor plantar response in 9 patients (56%). Twelve patients (75%) had normal motor and sensory conduction, 11 of whom had no denervation changes of the legs. LESSONS This study is intended to raise awareness among surgeons about the clinical features of SFD. EDX studies are valuable in ruling out peripheral causes of foot drop, which encourages diagnostic investigation into a UMN source for the foot drop.
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Olney, Kimberly C., Camila de Ávila, Kennedi T. Todd, Lauren E. Tallant, J. Hudson Barnett, Katelin A. Gibson, Piyush Hota, et al. "Commonly disrupted pathways in brain and kidney in a pig model of systemic endotoxemia." Journal of Neuroinflammation 21, no. 1 (January 4, 2024). http://dx.doi.org/10.1186/s12974-023-03002-6.
Анотація:
AbstractSepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation.
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Cui, Jieqiong, Huayan Li, Zongning Chen, Ting Dong, Xiying He, Yuanyuan Wei, Zhengkun Li, et al. "Thrombo-Inflammation and Immunological Response in Ischemic Stroke: Focusing on Platelet-Tregs Interaction." Frontiers in Cellular Neuroscience 16 (June 29, 2022). http://dx.doi.org/10.3389/fncel.2022.955385.
Анотація:
Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.
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Dominguez-Bali, A., C. Rey, C. Dominguez-Bali, R. Sharma, and A. Baqer. "(448) Sexual Emergencies." Journal of Sexual Medicine 20, Supplement_1 (May 2023). http://dx.doi.org/10.1093/jsxmed/qdad060.421.
Анотація:
Abstract Introduction Urologist, gynecologist, surgeons, sexologists, and ER physicians are familiarized with some of the sexual emergencies that called the attention of everybody. However, the broad spectrum of those disorders is not well-known. Objective 1. Show the magnitude of sexual emergencies in an important hospital of South Florida. 2. Show the magnitude of sexual emergencies nationally and internationally. 3. Describe how they can vary according with the place, culture, and societies. 4. To learn the methods of diagnosis and treatment of these ample variety of conditions. Methods Based on the multiple cases seen in our ER in Hialeah Hospital in Miami, Florida, extensive review of the literature was done, and the cases are presented to show the magnitude, variety, and diversity of cases in the different areas of the medical field. Results The review includes: I. The common coital emergencies in neurology (benign coital headache, subarachnoid hemorrhage, intracerebral bleeding, subdural hemorrhage, cerebral vascular accidents), urology (penile fracture, priapism, preputial tears, penile vessel rupture, penile strangulation, penile necrosis, ureterovesical foreign bodies, epididymitis., obstructive uropathies), cardiology (sudden cardiac death, myocardial infarction), gynecology (vaginal laceration and/or evisceration with/without previous gynecological surgeries), obstetrical (postpartum dyspareunia secondary or not to episiotomy or vaginal lacerations; postcoital preterm labor), immunological (local or systemic, anaphylactic allergic reactions). II. Common autoerotic emergencies in gastroenterology (foreign objects in rectum, vagina, oropharyngeal/mandibular lesions), as well as “body packers” cases (swallowed latex balloons for smuggling in the GI tract, rectum, or vagina). III. Sexual assault IV. Sexual dysfunction: Hyperactive arousal disorders (compulsive hunt for orgasms with/without attempt or real suicide, hypersexuality related to SSRI use). V. Sociosexual issues: Killings for jealousy during sex, infidelity, castration like Lorena Bobbitt case. gynecologicalgynecological Conclusions The epidemiology of these pathologies varies from country to country and includes subjects of any age, sex, race, religion, and culture. Finally, a review of these diagnostic methods and treatment are presented. Disclosure No
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Chauhan, Anil K., Chintan Gandhi, and Steven R. Lentz. "Abstract 43: The Metalloprotease ADAMTS13 Reduces VWF-Mediated Vascular Inflammation and Early Development of Atherosclerosis in Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 32, suppl_1 (May 2012). http://dx.doi.org/10.1161/atvb.32.suppl_1.a43.
Анотація:
Background and objective: ADAMTS13 prevents spontaneous thrombosis in the microvasculature by cleaving hyperactive ultra large von Willebrand factor (ULVWF) multimers into smaller and less active forms. Reduced ADAMTS13 activity and increased VWF levels have been described in many diseases associated with systemic inflammation. We hypothesized that, by cleaving ULVWF multimers and/or VWF multimers, ADAMTS13 reduces vascular inflammation and the development of early atherosclerotic plaques. Model and methods: ApoE -/-, Adamts13-/-/ApoE-/-, Adamts13 -/-/ Vwf -/-/ ApoE -/- and Vwf -/-/ApoE -/- mice were fed a high-fat Western diet (20% fat, 0.2% cholesterol) beginning at 6 weeks of age until they were sacrificed at 4 months. Intravital fluorescence microscopy was used to visualize leukocyte adhesion and plaque formation at the carotid sinus. We compared the extent of atherosclerosis in whole aortae, stained with Oil Red O and en face lesion area measured by morphometry, and in the cross section area of the aortic sinus using the VerHoeffs/Van Gieson stain. Inflammatory cells in the aortic lesions were quantitated by immunohistochemistry. Results: Using intravital microscopy, we observed a 4-fold increase ( P <0.001) in leukocyte adhesion and at the carotid sinus of Adamts13-/-/ApoE -/- mice compared with ApoE -/- mice. Interestingly, 100% of the Adamts13-/-/ApoE -/- mice had larger plaque (occluded vessel by ∼70-80 %) at the carotid sinus whereas only 20% of the ApoE- /- mice had plaques that were smaller in size ( P <0.0001). Next, we found that the atherosclerotic lesions in the aorta and aortic sinus of the Adamts13-/-/ApoE-/- mice were not only larger (2-fold, P <0.001) but also more inflammatory (increased neutrophil and macrophage infiltration) with decreased interstitial collagen compared with ApoE -/- mice, suggesting that ADAMTS13 reduces vascular inflammation and subsequent atherosclerotic plaque formation. Adamts13-/-/ApoE -/- mice fed a normal chow diet also demonstrated significantly accelerated atherosclerotic plaque formation compared with ApoE -/- mice. Total cholesterol and triglyceride levels were similar among groups fed high-fat Western or normal chow diets. Finally, atherosclerotic lesions in Adamts13-/-/Vwf-/-/ApoE -/- mice were similar to Vwf-/-/ApoE -/- mice, demonstrating that the accelerated atherosclerosis observed in ADAMTS13-deficient mice is VWF-dependent. Conclusion: These findings reveal a new role for the antithrombotic enzyme ADAMTS13 in reducing VWF-mediated plaque formation during early atherosclerosis.
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Fulvio, Giovanni, Chiara Baldini, Marta Mosca, Antonello di Paolo, Guido Bocci, Giuseppe Alberto Palumbo, Emma Cacciola, Paola Migliorini, Rossella Cacciola, and Sara Galimberti. "Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?" Frontiers in Medicine 10 (October 17, 2023). http://dx.doi.org/10.3389/fmed.2023.1254868.
Анотація:
In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7–2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a “disease-modifying therapy” that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.