Vascular Side Effects Research Articles

Assessment of Prescribing Pattern of Antihypertensive Medications in Elderly Hypertensive

Introduction : In elderly hypertensive patients, blood pressure is over 140/90mmHg. Diuretics, renin angiotensin aldosterone system inhibitors, beta blockers, calcium channel blockers, alpha blockers and direct vasodilators are commonly prescribed to treat geriatric hypertensive patients. The choice of drugs for a particular patient changes at short intervals because of factors like changes in vascular compliance, efficacy, side effects, cost and launch of new drugs in pharmaceutical market. These facts indicate the need for assessment of prescribing pattern of antihypertensives. Objective: The prescribing pattern of antihypertensive medications was assessed in elderly patients who were suffering from hypertension. Methodology: It was a prospective observational study for six months carried out on in-patients who were admitted to general medicine units. The study protocol was approved by the human ethical committee. The patients of either sex and aged above 60 years and satisfying the study criteria such as diagnosed newly as suffering from hypertension as per Joint National Committee (JNC-7) guidelines and prescribed with antihypertensive medications were enrolled. The clinical, social and medication data was collected from the case records into a specialised patient profile form to analyze prescribing pattern of medications. All the data was analyzed using descriptive statistics. Results and Discussion: Totally 93 prescriptions were collected from the study patients. The proportion of male to female patients was 53:46 and their mean age was 68.74 ± 8.6years. Of 93 prescriptions, 50 (53.76%) prescriptions were containing antihypertensive medications as monotherapy and 43 (46.23%) prescriptions were containing antihypertensive medications as combination drug therapy. Of 50 prescriptions that were containing single antihypertensive medications, amlodepine was frequently 26 (52%) found prescribed among others. The results obtained in our study were similar to the study results conducted by Mohammed A et al. Among 43 prescriptions that were containing combination of antihypertensive medications, telmisartan+ hydrochlorothiazide were the drug combinations that were frequently 22 (51.16%) found prescribed among others.The results obtained in our study were similar to the study results conducted by Arshad HM et al. This combination was reported as fixed dose combinations used in hospitals in for treating patients enrolled in other studies. Conclusion: The medications such as amlodipine and telmisartanand hydrochlorothiazide are frequently prescribed as monotherapy and combination therapy respectievely to treat elderly patients suffering from hypertension.

VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study.

VEGF-C156S, a lymphangiogenesis-specific form of vascular endothelial growth factor C (VEGF-C), has been considered as a promising candidate for the experimental pro-lymphangiogenic treatment, as it lacks potential angiogenic effects. As a precursor to future clinical trials, the therapeutic efficacy and blood vascular side effects of VEGF-C and VEGF-C156S were compared in a large animal model of secondary lymphedema. Combination of lymphatic growth factor treatment and autologous lymph node transfer was used to normalize the lymphatic anatomy after surgical excision of lymphatic tissue. Lymph vessels around the inguinal lymph node of female domestic pigs were destroyed in order to impair the normal lymphatic drainage from the hind limb. Local injections of adenoviruses (Ad) encoding VEGF-C or VEGF-C156S were used to enhance the regrowth of the lymphatic vasculature. AdLacZ (β-galactosidase) and saline injections served as controls. Both VEGF-C and VEGF-C156S induced growth of new lymphatic vessels in the area of excision, although lymphangiogenesis was notably stronger after VEGF-C treatment. Also the transferred lymph nodes were best-preserved in the VEGF-C-treated pigs. Despite the enlargement of blood vessels following the VEGF-C therapy, no signs of sprouting angiogenesis or increased blood vascular permeability in the form of increased wound exudate volumes were observed. Our results show that VEGF-C provides the preferred alternative for growth factor therapy of lymphedema when compared to VEGF-C156S, due to the superior lymphangiogenic response and minor blood vessel effects. Furthermore, these observations suggest that activation of both VEGFR-2 and VEGFR-3 might be needed for efficient lymphangiogenesis.

Reported sildenafil side effects in pediatric pulmonary hypertension patients.

Background: Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil’s side effects in this population.Methods: Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects.Results: Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic.Conclusion: Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy.

NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke.

Despite the effectiveness of recombinant tissue-type plasminogen activator (r-tPA) during the acute phase of ischemic stroke, the therapy remains limited by a narrow time window and the occurrence of occasional vascular side effects, particularly symptomatic hemorrhages. Our aim was to investigate the mechanisms underlying the endothelial damage resulting from r-tPA treatment in ischemic-like conditions. Microarray analyses were performed on cerebral endothelial cells submitted to r-tPA treatment during oxygen and glucose deprivation to identify novel biomarker candidates. Validation was then performed in vivo in a mouse model of thromboembolic stroke and culminated in an analysis in a clinical cohort of patients with ischemic stroke treated with thrombolysis. The transcription factor NURR1 (NR4A2) was identified as a downstream target induced by r-tPA during oxygen and glucose deprivation. Silencing NURR1 expression reversed the endothelial-toxicity induced by the combined stimuli, a protective effect attributable to reduced levels of proinflammatory mediators, such as nuclear factor-kappa-beta 2 (NF-κ-B2), interleukin 1 alpha (IL1α), intercellular adhesion molecule 1 (ICAM1), SMAD family member 3 (SMAD3), colony stimulating factor 2 (granulocyte-macrophage; CSF2). The detrimental effect of delayed thrombolysis, in conditions in which NURR1 gene expression was enhanced, was confirmed in the preclinical stroke model. Finally, we determined that patients with stroke who had a symptomatic hemorrhagic transformation after r-tPA treatment exhibited higher baseline serum NURR1 levels than did patients with an asymptomatic or absence of cerebral bleedings. Our results suggest that NURR1 upregulation by r-tPA during ischemic stroke is associated with endothelial dysfunction and inflammation and the enhancement of hemorrhagic complications associated to thrombolysis.

BGB324 Represents an Axl and BCR-ABL1 Inhibitor with Activity in the T315I Mutant

BCR-ABL1 inhibitors have revolutionized the treatment of CML patients. However several drawbacks remain, including clinical resistance of T315I-mutated CML. Further, the clinical success of ponatinib, a selective inhibitor of T315I-mutated BCR-ABL1 is hampered by vascular side effects. Therefore, novel treatment strategies are warranted especially in T315I-mutated CML.We investigated the relevance of the Gas6-Axl axis in CML patients and the therapeutic potential of the clinically applicable small molecule Axl inhibitor BGB324 in primary CML (stem cell) samples, cell lines and preclinical models. We previously found that Gas6 and Axl represent potential novel targets in this disease and that BGB324 inhibits CML growth in vitro and in vivo (Erdmann et al., ASH meeting 2013, New Orleans, #1469).We next wished to confirm Axl as specific therapeutic target and therefore down regulated its expression in KCL-22 and K562 cells by means of shRNA. In these experiments blockade of Axl inhibited CML cell proliferation in comparison to control-transduced cells, thereby confirming that Axl promotes CML growth. Subsequently, we added BGB324 to shAxl- and shcontrol-transduced cells. Surprisingly BGB324 inhibited cell growth significantly more in shAxl-transduced cells in comparison to control-treated shAxl-transduced cells (p<0.05). These experiments indicated that BGB324 was inhibiting an additional target which supported CML cell proliferation, besides Axl. In order to identify this target we carried out a Kinome Scan revealing that BGB324 binds to native and mutated ABL1. Interestingly, the affinity of BGB324 for ABL1 carrying different mutations including T315I was 5 to 50 fold higher compared to unmutated ABL1 (Table 1).Next, we incubated BaF3 cells stably transfected with BCR-ABL1p210, BCR-ABL1T315I, BCR-ABL1M351T and BCR-ABL1E255K with various concentrations of BGB324 in order to determine its IC50 in the different cell lines. These experiments showed in concordance with the Kinome Scan that BGB324 was more potently inhibiting growth of mutated BCR-ABL1 compared to BCR-ABL1p210 (IC50 BCR-ABL1p210 1266 ± 126 nM; BCR-ABL1T315I 726 ± 194 nM; BCR-ABL1M351T 847 ± 10 nM and BCR-ABL1E255K 794 ± 39 nM; n=2-3; p<0.05 compared to BCR-ABL1p210).Notably, further experiments revealed that BGB324 inhibited KCL-22 cells and K526 cells to a similar extent compared to the combination of imatinib (IM) and shAxl. Thus, BGB324 is a dual inhibitor of BCR-ABL1 and Axl.As the inhibition of BCR-ABL1T315I is of special clinical interest we wished to confirm this finding further in vivo. Therefore we inoculated BCR-ABL1p210 and BCR-ABL1T315I cells subcutaneously into NSG mice. After the tumors reached a size of 80-100 mm3 mice were randomized to receive either placebo control or 50 mg/kg BGB324 delivered twice daily by oral gavage. This experiment showed potent inhibition of tumor growth after 12 days with higher activity of BGB324 in mice bearing BCR-ABL1T315I tumors (placebo: 1751 ± 606 mm3, BGB324: 614 ± 224 mm3; p=0.001) compared to mice bearing BCR-ABL1p210 tumors (placebo: 1432 ± 403 mm3; BGB324: 632 ± 229 mm3; p=0.05) (Figure 1).Subsequently, tissue harvested at end-stage was subjected to immunohistochemical staining for the proliferation marker phospho-histone H3 and Western Blot analyses of cleaved caspase 3 in order to determine whether reduced proliferation and/or increased apoptosis was responsible for reduced growth of BCR-ABL1T315I tumors upon treatment with BGB324. These analyses revealed that proliferation as determined by histomorphometric analysis of phosho-histone H3 was reduced while cleaved caspase 3 levels were unchanged. These data were further corroborated by the finding that treatment with BGB324 reduced the level of phosphorylated MapK as determined by immunoblotting and densitometry. Thus, BGB324 inhibits proliferation of BCR-ABL1T315I cells in vivo.Altogether, our findings show that BGB324 represents a dual inhibitor of Axl and ABL kinase with therapeutic potential in CML, in particular in BCR-ABL1T315I disease. As BGB324 was shown to be well tolerated in healthy volunteers (Wnuk-Lipinska et al., AACR meeting 2013 San Diego #1747), our findings pave the way for clinical investigation of BGB324 in (T315I-mutated) CML.Table 1GeneKinomeScan Kd (nM)KinaseProfiler IC50 (nM)Axl0.43ABL151.8851ABL1(E255K)1.15n/aABL1(T315I)10.134ABL1(Y253F)18.1926 [Display omitted] [Display omitted] DisclosuresLoges:BerGenBio: Research Funding, travel support, advisory boards Other.

Glucocorticoids exert direct toxicity on microvasculature: analysis of cell death mechanisms.

Glucocorticoids (GCs) are routinely administered systemically or injected into the eye when treating numerous ocular diseases; however, their toxicity on the retinal microvasculature has not been previously investigated. In this article, the effects of hydrocortisone (Hydro), dexamethasone, dexamethasone-phosphate and triamcinolone acetonide (TA) were evaluated in vitro on human skin microcirculation cells and, bovine endothelial retinal cells, ex-vivo, on flat mounted rat retinas. The degree of GCs induced endothelial cell death varied according to the endothelial cell type and GCs chemical properties. GCs toxicity was higher in skin microvascular endothelial cells and for hydrophobic GC formulations. The mechanism of cell death differed between GCs, Hydro and TA activated the leukocyte elastase inhibitor/L-DNase II pathways but did not activate caspases. The mechanisms of cell death observed in cell cultures were similar to those observed in rat retinal explants. Taken together these results indicate that particular attention should be paid to the potential vascular side effects when administrating GCs clinically and in particular when developing sustained-release intraocular devices.

New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease.

There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (FcγR) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking FcγR by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that FcγR expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of FcγR in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of FcγR in the healthy and diseased brain. Here we review the literature on FcγR expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy.

Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, and 40 weeks after irradiation. Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.

Feasibility of Intensive Multimodal Therapy in Infants Affected by Rhabdoid Tumors – Experience of the EU-RHAB registry

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

Inflammatory vocal fold lesions associated with angiogenesis inhibition

Background The vascular side effects of angiogenesis inhibitors are well known, but laryngeal effects are not widely reported. We report the first 5 cases, to our knowledge, of objective vocal fold lesions attributable to these therapies. Methods Four patients treated with bevacizumab-paclitaxel or bevacizumab for metastatic breast or lung cancer and 1 patient treated with a pan-fibroblast growth factor receptor (FGFR) inhibitor presented with spontaneous dysphonia without other etiologic factors. Results In all cases, we observed a well-limited mucosal lesion on the superior surface of the anterior portion both vocal folds, symmetrical, sparing the anterior commissure and the vocal process. Histopathology showed necrosis and inflammation. After discontinuation of treatment in 3 patients, their voices improved, but with persistent inflammation in 2 patients and vocal fold scarring in 1 patient. Conclusion Clinicians should systematically perform laryngoscopy in case of dysphonia in patients treated with angiogenesis inhibitors in order to diagnose laryngeal lesions and rule out differential diagnoses. © 2014 Wiley Periodicals, Inc. Head Neck 36: E81–E85, 2014

Association between rigors and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose interleukin-2 (HD IL-2).

487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. Patients belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. The mean total dose received was 1097 MIU (range: 160 – 3048 MIU). The prevalence of grade 3 AEs is presented in the table. Median survival of patients with ≥grade 3 rigors after HD IL-2 administration was 1501 days vs 533 days for those without (p = 0.0005, HR 2.54). Presence of rigors was also associated with a significant improvement in progression free survival, time to next treatment and response rates. No other AEs predicted response to HD IL-2. Conclusions: Presence of grade 3 rigors predicts improved survival during HD IL-2 therapy. Notably, grade 3 fever was rarely observed because of our institutional protocol of routinely using scheduled antipyretics to diminish fevers. [Table: see text]

Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis.

The main purpose of anticoagulants is to diminish fibrin formation, thereby decreasing the risk of venous or arterial thrombosis. Vitamin K antagonist have been used for many decades in order to achieve reduced thrombotic risk, despite major drawbacks of this class of drugs such as cumbersome dossing and monitoring of anticoagulant status. To overcome these drawbacks of VKA, new classes of anticoagulants have been developed including oral anticoagulants for direct inhibition of either thrombin or factor Xa, which can be administrated in a fixed dose without monitoring. Coagulation factors can activate cellular protease-activated receptors, thereby inducing cellular processes as inflammation, apoptosis, migration, and fibrosis. Therefore, inhibition of coagulation proteases not only attenuates fibrin formation, but may also influence pathophysiological processes like vascular calcification and atherosclerosis. Animal models revealed that VKA therapy induced both intima and media calcification and accelerated plaque vulnerability, whereas specific and direct inhibition of thrombin or factor Xa attenuated atherosclerosis. In this review we provide an overview of old and new oral anticoagulants, as well discuss potential pleiotropic effects with regard to calcification and atherosclerosis. Although translation from animal model to clinical patients seems difficult at first sight, effort should be made to fully understand the clinical implications of long-term oral anticoagulant therapy on vascular side effects.

Thrombin generation and atherosclerosis

Atherosclerosis is a major cause of mortality worldwide. The important role inflammation plays in atherosclerosis is evident through the participation of inflammatory cells in the development and progression of the disease. Thrombin is the central protease of the coagulation cascade, involved in the formation of a hemostatic plug to avoid severe bleeding. In addition, thrombin is a key factor in regulating inflammatory processes, signaling through protease activated receptors. We propose that thrombin may be a relevant factor in the atherosclerosis coagulation-inflammation axis. Human histological data show abundant coagulation activity within atherosclerotic lesions with thrombin activity being related to atherosclerotic plaque development and (in)stability. Animal studies establish that the generated thrombin level relates to progression of atherosclerosis, with hypercoagulability producing advanced atherosclerosis in mice with an Apolipoprotein E-deficient (ApoE(-/-)) background. Several studies show that administration of direct oral anticoagulants, like dabigatran and rivaroxaban, attenuate atherosclerosis development in ApoE(-/-) mice. In this review we explore several mechanisms by which thrombin may operate in modifying the chronic process of atherosclerosis. One of the key elements may be the conversion of thrombin, from a physiological regulator of hemostasis towards an inflammation-mediator under pathophysiological conditions, contributing to a switch in the thrombin-activated protein C (APC) regulation. The ongoing inflammatory activity, indicated by the activation of pro-inflammatory cytokines, neutrophils and neutrophil extracellular traps, drive thrombin generation, while diminishing APC formation. The net result is accelerated pro-inflammatory and pro-thrombotic changes in blood and in the vessel wall. We conclude that these atherogenic influences of thrombin may be clinically relevant in the long-term. Further the treatment with long-term anticoagulant therapy deserves further attention as to its potential, vascular side effects.

Optical coherence tomography to reveal vascular lesions after catheter-based renal nerve ablation with a novel multi-electrode EnligHTNTM system

A 72-year-old female with a history of sleep apnoea syndrome was referred to the Andreas Gruentzig Catheterisation Laboratories for catheter-based renal nerve ablation (RNA) due to drug-resistant, uncontrolled hypertension. After intravenously loading with aspirin, the RNA was obtained using the first generation multi-electrode EnligHTNTM system (St. Jude Medical, Westford, MA, USA) delivering 8 ablation runs on both the left and the right renal artery. Before and after the RNA procedure, optical coherence tomography (OCT) was performed using the C7-XR imaging system (LightLab Imaging, Inc., Westford, MA, USA) with a non-occlusive technique and a single-mode optical fibre catheter (frequency domain-OCT-catheter, DragonFlyTM, St. Jude Medical, Westford, MA, USA). The OCT catheter was advanced over a standard 0.014’’ angioplasty guidewire using a monorail lumen at the tip. To optimise pullback recordings, renal arteries were flashed of blood with Ultravist 300 (Bayer House, Berkshire, United Kingdom) at a flow rate of 8.0 mL/s and the application of an automated pullback speed of 20 mm/s. The post-procedural pullback visualised local oedemas (Fig. 1A, B) concomitant with significant thrombi formations (Fig. 1A, C) and small disruptions (Fig. 1D, arrow). The clinical course was uneventful and the patient was discharged home on the second day of hospitalisation. Catheter-based RNA has been recently approved for the treatment of resistant hypertension. During the RNA procedure, transmural lesions are delivered along the walls of the renal arteries to disrupt the sympathetic nerve network located within the arterial adventitia. Here, we report a case in which OCT was performed to reveal potential periprocedural vascular side effects. The RNA was obtained using a novel EnligHTNTM catheter delivering a basket with 4 radiopaque electrodes (Fig. 1E, inset). The design of the EnligHTNTM system enabled simultaneous ablation runs, minimising catheter manipulation (Fig. 1E, arrows). However, the performance of OCT revealed several local lesions including post-ablation oedemas, thrombi formations and tissue disruptions. OCT provides novel insights on vascular effects of RNA, suggesting the potential need for double antiplatelet therapy before the procedure. However, the safety and efficacy of the new catheter-based RNA devices require soon to be evaluated in greater detail.

Small arteries of gestational rats are less sensitive to relaxation induced by inhibition of rho A‐associated kinase (ROK).

Inhibition of ROK has been proposed as a method to arrest uterine contractions during preterm labor. Because of concern about vascular side effects, we studied the effects of the ROK inhibitor g‐H1152 (g‐H) on relaxation of mesenteric and uterine arteries.Arteries from non‐pregnant (n=5) and pregnant (gestation day17–21; n=6) rats were studied using wire myography. Concentration response curves (CRC) to calculate IC50 for g‐H were obtained following phenylephrine (PE) or endothelin‐1 (ET‐1) induced constriction. Using vessels from pregnant rats, CRC for PE were performed before and after a 20‐min incubation with g‐H at 300 nM, 1 and 3 μM.Mesenteric arteries were more sensitive than uterine arteries to g‐H‐induced relaxation in both non‐pregnant and pregnant rats. Both arteries were significantly less sensitive to g‐H‐induced relaxation during pregnancy. Sensitivity to PE was not changed with any dose of g‐H. However, using 2‐factor ANOVA, the maximal PE‐induced tension was significantly reduced by the two highest concentrations of g‐H in both vessels from pregnant rats but to a greater extent in mesenteric vessels (34±5.6%, 18±4.1%) compared to uterine (14±4%, 7±2.7%).The ROK pathway plays a significant role in agonist‐induced constriction of mesenteric and uterine vessels, though less so during gestation. If ROK inhibitors are used during pregnancy in vivo, maternal blood pressure and uterine blood flow will be assessed.

Cessation of Neoangiogenesis in Alzheimer's Disease Follows Amyloid-beta Immunization

Pathogenic neoangiogenesis in Alzheimer's disease (AD) is due to amyloid-beta (Aβ) and results in blood-brain barrier (BBB) leakiness in AD. It likely occurs as a compensatory response to impaired cerebral blood flow and provides a strong link between brain vascularity and AD. Aβ immunotherapy is an experimental treatment for AD; however, unexpected negative vascular side effects seen in early human clinical trials demonstrate that our knowledge of Aβ and AD pathogenesis is incomplete. We demonstrate that immunization with Aβ peptides neutralizes the amyloid trigger leading to neoangiogenesis and reverses hypervascularity in Tg2576 AD mice. This process resolves plaque burden suggesting that neoangiogenesis is a key mechanism underlying plaque formation. A meta-analysis demonstrated that hypervascular reversion in vaccinated Alzheimer's patients. This appears to be the first example of vascular reversion following any therapeutic intervention and supports the conclusion that modulation of neoangiogenesis may repair damage in the AD brain.

Complications of endovascular treatment of cerebral aneurysms

The number of neuroendovascular treatments of both ruptured and unruptured aneurysms has increased substantially in the last two decades. Complications of endovascular treatments of cerebral aneurysms are rare but can potentially lead to acute worsening of the neurological status, to new neurological deficits or death. Some of the possible complications, such as vascular access site complications or systemic side effects associated with contrast medium (e.g. contrast medium allergy, contrast induced nephropathy) can also be encountered in diagnostic angiography. The most common complications of endovascular treatment of cerebral aneurysms are related to acute thromboembolic events and perforation of the aneurysm. Overall, the reported rate of thromboembolic complications ranges between 4.7% and 12.5% while the rate of intraprocedural rupture of cerebral aneurysms is about 0.7% in patients with unruptured aneurysms and about 4.1% in patients with previously ruptured aneurysms.Thromboembolic and hemorrhagic complications may occur during different phases of endovascular procedures and are related to different technical, clinical and anatomic reasons. A thorough knowledge of the different aspects of these complications can reduce the risk of their occurrence and minimize their clinical sequelae. A deep understanding of complications and of their management is thus part of the best standard of care.

Menopause, cessation of menses, vs. “menopause”, a primary brain disorder?

The “menopause” (not menopause, the cessation of menses) mechanism responsible for its symptom complex (Menopausal Symptom Complex) (or, Climacteric Syndrome) including chronic fatigue, fibromyalgia, depression, tension headache, cervical vertigo, sleep disturbances, irritability, anxiety/panic attacks, cognitive changes (decreased concentration to obsessional/delusional thought), decreased libido, and vasomotor dysfunction remains elusive. And MSC, other than vasomotor dysfunction, is not significantly altered by treatment with sex hormones (estrogen/progesterone), which have major neoplastic and vascular side effects. Thus at present, there are minimal indications for treatment with these compounds. Confusion between menopause and “menopause” (MSC) as well as research money made available by pharma advocating ERT/HRT (estrogen replacement therapy/hormone replacement therapy) has produced both therapeutic and research inertia. Presently, there would appear to be mismanagement of a symptom complex which infers primary brainlimbic system dysfunction and for which there is no correlation with falling sex hormone levels. Pharmacological modification of the proposed aberrant limbic circuitry responsible for the MSC has been successfully accomplished using specific NT/MMs (neurotransmission/modulation modifiers) i.e. a combination of alpha-1 and norepinephrine reuptake blockers, and thus providing initial elucidation of this particular brain pathophysiology as well as an efficient treatment of a problem affecting up to 60% of women ages 35 to 55. Specific NT/MMs capable of affecting a number of neurotransmitter/receptor types within limbic circuitry appear to reverse the MSC which includes chronic fatigue and fibromyalgia, pointing to aberrant limbic circuitry as their etiology as well.

Aspirin Resistance in Chinese Stroke Patients Increased the Rate of Recurrent Stroke and other Vascular Events

To investigate the prevalent of aspirin resistance (AR) in Chinese stroke patients and its association with recurrent stroke and other vascular events, including cardiovascular disease and death. We prospectively enrolled 634 Chinese stroke patients. Aspirin was administrated to every patient from the first day of admission. Whole blood samples were collected for platelet aggregation testing after aspirin was administered for 7-10 days. A follow-up period of 12-24 months was performed to record vascular events and hemorrhagic side effects. Aspirin resistance (AR) was detected in 129 patients (20·4%), aspirin semi-resistance (ASR) in 28 patients (4·4%) and aspirin sensitivity (AS) in 477 patients (75·2%). Logistic regression analysis found that diabetes and high levels of low density lipoprotein cholesterol (LDL) were independent risk factors for ASR and AR. During a median follow-up period of 19·4 months, the prevalence of recurrent stroke, death from all causes, myocardial infarction and vascular events overall were higher in patients with AR + ASR than in patients with AS. Cox regression analysis found that diabetes and AR were independent risk factors for vascular events. Aspirin resistance is common in Chinese patient taking antiplatelet medications. Diabetes and high LDL may induce platelet activation and thrombosis and increase the occurrence of aspirin resistance. Patients who are detected to be aspirin resistant are at a greater risk of clinically important vascular events.

What is the best immunocytochemical marker for endogenous stem cells?

Endogenous populations of stem cells are proving to be highly relevant to the treatment of degenerative disease and to the initiation of cancer. It is crucial, therefore, to know how many of these cells exist in tissues and how their numbers are manipulated by disease and treatments. Markers for stem cells are constantly being discovered, and many are proving of great use. However, different markers do not always recognize the exact same populations of cells. Therefore, the confusion of the incidence of endogenous stem cells persists. The discrepancy between the recognition potential of different markers can be allocated, in part, to the bias in the experimental strategy to discover them. For example, the assumption that endogenous stem cells are dividing will lead to the discovery of markers of division, and may be adequate for the identification of stem cells in an actively proliferating state, and therefore in certain conditions (e.g. injury) or in certain locations (e.g. subventricular zone in the case of the adult brain). In contrast, the study of specific survival pathways operating in stem cells may lead to the discovery of markers that recognize both the proliferating and the quiescent stem cell sub-populations. I will discuss the advantages and disadvantages of these different strategies as well as the potential to use them in tandem to extract information from the tissue. I will also expand upon one strategy that was based on elucidating distinct signaling pathways in stem cells and subsequent establishment of a novel marker of neural stem cells: We have elucidated a novel signal transduction pathway that regulates stem cell numbers in vitro and in vivo. At the heart of this pathway lies a specific phosphorylation on the serine residue of STAT3. This modification is downstream of several cell surface receptors including Notch (through a non-canonical branch), Tie2, insulin, and FGF. Downstream of STAT3-serine phosphorylation is the transcription factor Hes3 and sonic hedgehog. Of particular value to in vivo interventions is that, unlike neural stem cells, many cell types do not rely on STAT3-serine phosporylation. This pathway, therefore, is of particular importance to immature cells, providing specificity when performing manipulations in vivo. Using Hes3 immuno-reactivity as a novel marker of neural stem cells, we have shown that the adult central nervous system contains a widespread multipotent precursor, suggesting relevance of this approach to diseases that affect many and multiple areas in the brain and spinal cord. Pharmacological activation induces many fold increases in the numbers of Hes3+ cells as well as rescue of neurons and motor skill recovery in models of neurodegenerative disease. The combined use of pro- and anti-angiogenic factors that have the same activating effect on neural stem cells allows for maximal stem cell stimulation with minimal vascular side-effects.