Pregnancy outcomes in the medical management of glaucoma: An international multicenter descriptive survey.

PURPOSE: To determine if glaucoma medications are associated with pregnancy and/or postnatal complications. METHODS: Multicenter descriptive survey. Subjects were female patients 18-45 years who were previously pregnant with a diagnosis of glaucoma or ocular hypertension prior to pregnancy. Chart review queried diagnosis, glaucoma severity, and race. Survey questions were asked for each pregnancy and queried pregnancy age, medications used, and pregnancy outcomes/complications. RESULTS: 114 pregnancies of 56 patients (mean 2.0 pregnancies per patient) were included. Three pregnancies with therapeutic abortion were excluded from further analysis. Mean age during pregnancy was 29.1 ± 5.7 years. Of the 111 pregnancies, 20 (18.0%) used no medications and 91 (82.0%) used at least one medication. Medications were topical carbonic anhydrase inhibitors (n = 45), beta-blockers (n = 55), alpha-agonists (n = 56), and prostaglandin analogues (n = 28). Outcomes were: preterm contractions/labour (6.3%), miscarriage (4.5%), stillbirth (4.5%), induction of labour (11.9%), emergency/unplanned caesarean delivery (13.9%), neonatal intensive care unit (NICU) stay (15.8%), congenital anomalies (8.1%), and low birth weight (10.9%). Fisher exact test assessed outcome associations with individual agents, use of any agent, and different number of agents. Alpha-agonist use was associated with NICU stay: 25.5% rate (p = 0.012) in alpha-agonist use. Most of the alpha-agonist use NICU stays occurred in pregnancies with third trimester use. All other associations were not statistically significant. CONCLUSIONS: The data from this survey suggest an overall favourable safety profile for topical glaucoma medications in pregnancy, but further investigation is needed. Caution should be employed regarding third trimester alpha-agonist use owing to association with NICU stay.

Validation of a Deep Learning Algorithm for Continuous, Real-Time Detection of Atrial Fibrillation Using a Wrist-Worn Device in an Ambulatory Environment.

BACKGROUND: Wearable devices may be useful for identification, quantification and characterization, and management of atrial fibrillation (AF). To date, consumer wrist-worn devices for AF detection using photoplethysmography-based algorithms perform only periodic checks when the user is stationary and are US Food and Drug Administration cleared for prediagnostic uses without intended use for clinical decision-making. There is an unmet need for medical-grade diagnostic wrist-worn devices that provide long-term, continuous AF monitoring. METHODS AND RESULTS: We evaluated the performance of a wrist-worn device with lead-I ECG and continuous photoplethysmography (Verily Study Watch) and photoplethysmography-based convolutional neural network for AF detection and burden estimation in a prospective multicenter study that enrolled 117 patients with paroxysmal AF. A 14-day continuous ECG monitor (Zio XT) served as the reference device to evaluate algorithm sensitivity and specificity for detection of AF in 15-minute intervals. A total of 91 857 intervals were contributed by 111 subjects with evaluable reference and test data (18.3 h/d median watch wear time). The watch was 96.1% sensitive (95% CI, 92.7%-98.0%) and 98.1% specific (95% CI, 97.2%-99.1%) for interval-level AF detection. Photoplethysmography-derived AF burden estimation was highly correlated with the reference device burden (R2=0.986) with a mean difference of 0.8% (95% limits of agreement, -6.6% to 8.2%). CONCLUSIONS: Continuous monitoring using a photoplethysmography-based convolutional neural network incorporated in a wrist-worn device has clinical-grade performance for AF detection and burden estimation. These findings suggest that monitoring can be performed with wrist-worn wearables for diagnosis and clinical management of AF. REGISTRATION INFORMATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04546763.

Mean rate of progression of visual fields in patients with primary open-angle glaucoma and ocular hypertension attending a tertiary care center in South India - A prospective cohort study using FORUM® Glaucoma Workplace software.

Purpose: To find out the mean rate of progression (MROP) of visual fields (VF) in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT) using FORUM® Glaucoma Workplace. Methods: Two hundred and one eyes of 105 patients were included in this prospective cohort study. Patients with POAG and OHT were recruited, and VF analysis with 24-2 and or 10-2 was done using SITA standard strategy in Zeiss Humphrey Visual Field Analyzer (HFA). All the previous VFs were identified from FORUM software, and the baseline indices were recorded from the first reliable VF analysis. The present VF analysis was compared to the previous one using FORUM software, and the rate of progression (ROP) in VF was obtained by Guided Progression Analysis. Results: MROP of VF in the POAG group was - 0.085 dB/year, ranging from -2.8 to 2.8 dB/year with a standard deviation (SD) of 0.69. In the OHT group, the MROP of VF was -0.003 dB/year, ranging from - 0.8 to 0.5 dB/year with an SD of 0.27. The MROP of VF in medically treated eyes with POAG was -0.14 dB/year with an SD of 0.61 and in surgically treated eyes was -0.02 dB/year with an SD of 0.78. The overall baseline mean VF index (VFI) was 83.19% and the final mean VFI was 79.80%. There was a statistically significant decrease in the mean VFI value from baseline to the final visit (P-value 0.0005). Conclusion: The mean ROP of VF in the POAG group was -0.085 dB/year and in the OHT group was - 0.003 dB/year.

Randomized prospective evaluation of same-day discharge after cryoballoon ablation of atrial fibrillation: results of the EASY PVI study.

BACKGROUND: With advancements in technology and ablation techniques, catheter ablation for the treatment of atrial fibrillation (AF) has become safer with time. In the past, standard-of-care recommended overnight stay for outpatient procedures. As safety has improved and procedure times have shortened, some centers have allowed for same-day discharge. We report the results of a multi-center, randomized clinical trial investigating the safety of same-day discharge post-cryoballoon ablation. METHODS: Patients with paroxysmal atrial fibrillation underwent pulmonary vein isolation (PVI) with the Medtronic Arctic Advance cryoballoon at 3 US centers. Six hours after the procedure, patients were randomized to either stay overnight or be discharged same day. RESULTS: A total of 49 patients were enrolled. Two patients were withdrawn prior to randomization. One patient chose to withdraw after randomization. Of the 22 patients randomized to same-day discharge and the 23 patients randomized the overnight stay, no significant adverse outcomes were reported in either group. Occurrence of adverse events did not differ significantly between the two groups. Procedure time and fluoroscopy time did not significantly differ between groups. CONCLUSIONS: This is the first randomized trial examining the safety of same-day discharge post-cryoballoon ablation. Based on our results, same-day discharge following cryoballoon ablation for paroxysmal AF is a safe option following uncomplicated ablation for PVI. Operators should use their discretion in selecting patients for same-day discharge.

Outcomes of bleb needling in primary glaucoma: A prospective interventional study in a South Indian population.

Purpose: This study was conducted to assess the outcomes of bleb needling for the treatment of failure of filtration surgeries in primary glaucoma with a follow-up of six months. Methods: This prospective interventional study included patients with primary glaucoma who underwent trabeculectomy or combined glaucoma and cataract surgery with failed or failing bleb after six weeks of surgery and less than two years. A comprehensive examination including best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurement, gonioscopy, slit-lamp examination, and bleb morphology grading was done. Selected patients underwent a subconjunctival bleb needling with mitomycin C (MMC) (dose 0.2 mg/ml). Postoperatively, patients were followed up on the first, third, and sixth months and were assessed with respect to IOP, need for antiglaucoma medication (AGM), and complications. Results: Sixty eyes of 59 patients were included. Preoperatively, 33.3% of patients were on one AGM, whereas postoperatively at the third month 51.7% and at the sixth month 50% of patients were on no AGM. There was a statistically significant decrease in IOP (P < 0.001) from preoperative (mean: 23.8 ± 7.86 mmHg) to postoperative first month (mean: 19.8 ± 9.08 mmHg), third month (mean: 17.4 ± 5.4 mmHg) and sixth month (mean 16.6 ± 4.39). According to the defined criteria in the current study, we achieved 22 (37.9%) successes, 31 qualified successes (53.4%), and 5 (8.6%) failures. Univariate regression analysis showed a higher failure rate among younger age groups. Gender, laterality, and intraoperative complications were not significant statistically. Conclusion: Bleb needling is a safe and effective procedure for the treatment of failed filtration surgeries.

Identification, characterization and evaluation of novel antifungal cyclic peptides from Neobacillus drentensis.

Marine microbes secrete exopolymeric substances (EPS), which surrounds the biofilm and inhibits the fungal growth. Elucidation of the structure and function of the extracellular exopolymeric substances is of vital relevance therapeutically. The active compound responsible for bioactivity was purified and characterized using TLC, LC/MS/MS, GC/MS and FT-IR. Bioactivity of the characterized cyclic peptides (CLPs) against azole resistant and susceptible Candida strains were examined for growth and biofilm formation using scanning electron microscopy, flow cytometry, confocal microscopy. In the present study we identified bioactive cyclic peptides from marine isolated Neobacillus drentensis that exhibited promising tensio-active properties and antifungal efficacy against azole resistant and susceptible Candida albicans. The cluster is composed of five CLP isoforms which were sequenced and identified as new peptides with compositional and structural variations in the amino acid sequence and fatty acid chain. In vitro cytotoxic activity of CLPs was tested in human fibroblast normal cells. We have observed that the CLPs repressed the Candida albicans growth and multiplication by inhibiting the biofilm formation and disruption of branching filamentous hyphae. CLPs have been found to arrest the C. albicans cell cycle by a block at G1-S transition followed by apoptotic cell death. The current studies suggest these natural marine derived CLPs function as potential anti-biofilm agents against azole C. albicans resistant strains.

Acute Safety and Efficacy of Fluoroless Cryoballoon Ablation for Atrial Fibrillation.

Pulmonary vein isolation (PVI) is widely used for the ablation of atrial fibrillation, with prior reports suggesting good efficacy. Due to the widespread use of three-dimensional electroanatomic mapping systems and advances in intracardiac echocardiography, fluoroless ablation has been made possible. Fluoroless ablation with a cryoballoon (CB), however, has not been widely performed because of the need to prove occlusion of the vein with contrast dye and fluoroscopy. The objective of this study is to show that CB ablation can be performed safely and effectively without fluoroscopy. A dual-center, case-control study was performed of patients undergoing CB PVI with a fluoroless approach and a control group with traditional fluoroscopic techniques. The absence of color-flow Doppler signals around the periphery of the CB on intracardiac echocardiography and an increase in mean pressure by 5 mmHg, loss of the A-wave, and an increase in the V-wave as measured with continuous-wave pressure monitoring were adopted as indicators of vein occlusion in the absence of fluoroscopy. Temperature at 30 seconds, minimum temperature, time to isolation, procedure length, and complications were evaluated. During the study period of November 15, 2018 to November 15, 2019, a total of 100 patients underwent CB PVI at the participating centers. A total of 50 patients were enrolled in the fluoroless arm [35 men (70%), mean age: 64.9 ± 12 years, mean left atrium size: 44.2 ± 16 mL/m2, left ventricular ejection fraction: 61% ± 5%], while 50 patients were enrolled in the control arm with similar characteristics. Four hundred forty-one 441 PVs were evaluated in the study cohort compared to 339 PVs in the control arm. When comparing fluoroless and traditional techniques, the mean temperature at 30 seconds was -31.7°C ± 6°C versus -32.8°C ± 5°C (p = 0.037), the minimum temperature was -47.4°C ± 6°C versus -47.7°C ± 9°C (p = 0.677), the time to isolation was 56.8 ± 28 seconds versus 74.8 ± 45 seconds (p = 0.212), and the procedure time was 102.2 ± 27.3 seconds versus 104.5 ± 16.9 seconds (p = 0.6436). Ultimately, this proof-of-concept study revealed that fluoroless ablation can be performed with success and efficiency outcomes similar to those of a traditional ablation approach. This suggests that the ablation of atrial fibrillation with CB can be performed safely and effectively without the use of fluoroscopy by experienced operators.

Detailed thrombogenicity phenotyping and 1 year outcomes in patients undergoing WATCHMAN implantation: (TARGET-WATCHMAN) a case-control study.

The relation of device related thrombosis (DRT) and major bleeding after left atrial appendage closure (LAAC) to laboratory thrombosis and hemostasis markers has not been studied. We performed a prospective case control study to identify clinical characteristics and laboratory markers in patients who developed DRT and major bleeding following WATCHMAN LAAC. Thromboelastography, platelet aggregation (PA), urinary 11-dehydrothromboxane B2 (UTX), fibrinogen, D-dimer, thrombin time and von Willebrand factor activity were determined at baseline, immediately following, and at 45 and 180 days post-LAAC (n = 32) and outcomes were followed for 1 year. Baseline characteristics and thrombogenic profiles of patients with and without DRT and/or BARC bleeding were compared. Mean age was 76 ± 8 years and CHADS2 VASc score was 4.4 ± 1.4. There were 3 DRTs (2 within 6 months, and 1 at 12 months), 4 Type 3A BARC bleeds, and 2 non-cardiac deaths. Patients with DRT had higher baseline thrombin-induced platelet-fibrin clot strength (68.0 ± 1.8 vs. 62.7 ± 4.7 mm, p = 0.06); FCS (35.6 ± 6.0 vs. 24.4 ± 6.6 mm, p = 0.009); and D-dimer (1712 ± 2330 vs. 283 ± 213 ng/mL, p = 0.001). At baseline, 5 patients had all 3 factors associated with high thrombotic risk and 2 experienced a DRT within 6 months. Patients with Type 3A BARC bleeding had lower baseline collagen-induced and 45-day ADP-induced PA (p < 0.01 for both). DRT following LAAC was associated with a baseline prothrombogenic profile whereas bleeding was associated with low platelet reactivity. These preliminary findings warrant further validation and have future implications on patient selection and adjunctive antithrombotic therapy following LAAC.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622 .

A randomized comparison of manual pressure versus figure-of-eight suture for hemostasis after cryoballoon ablation for atrial fibrillation.

INTRODUCTION: Cryoballoon ablation is commonly used to treat atrial fibrillation (AF). Femoral vein hemostasis after cryoballoon ablation for AF is routinely achieved with manual pressure (MP) after reversal of heparin and reassessment of the activated clotting time, or with a figure-of-eight suture (F8). The purpose of this randomized trial was to compare these two techniques for femoral vein hemostasis after cryoballoon ablation for AF in a patient population predominantly on novel anticoagulants (NOAC). METHODS AND RESULTS: Seventy consecutive patients who underwent cryoballoon ablation were randomized to either the MP or F8 for femoral vein hemostasis. Clinical and procedural characteristics were similar between the groups with the majority of patients treated with a NOAC. The total time in the electrophysiology laboratory for the MP group and the F8 group (197 ± 37 minutes vs 167 ± 36 minutes, respectively; P = .02), and the time from sheath removal until the patient left the laboratory (28 ± 9 minutes vs 20 ± 5 minutes, respectively; P < .0001) were significantly less in the F8 group. Additional pressure for hemostasis in the recovery suite was required more often in the MP Group, as opposed to the F8 group (29% vs 3%; P = .003). No major bleeding occurred and the rate of minor hematomas was statistically similar. CONCLUSIONS: Hemostasis obtained with a F8 suture after cryoballoon ablation for AF is associated with significantly less patient time in the electrophysiology laboratory, and an improved safety profile, compared with manual hemostasis, even amongst patients treated with a NOAC.

Short-term safety and efficacy of left atrial appendage closure with the WATCHMAN device in patients with small left atrial appendage ostia.

INTRODUCTION: Left atrial appendage (LAA) closure with the WATCHMAN device, according to FDA labelling, is recommended in patients with a maximal LAA ostial width between 17 and 31 mm. The safety and efficacy of LAA closure in patients with a maximal LAA ostial width < 17 mm has not been evaluated. The goal of this study was to determine the acute and short-term safety and efficacy of LAA closure with the WATCHMAN device in patients with a maximal LAA ostial width < 17 mm. METHODS AND RESULTS: Thirty-two consecutive patients with a maximal LAA ostial width < 17 mm as determined by a screening transesophageal echocardiogram (TEE) underwent LAA closure with the WATCHMAN device between March 2015 and November 2016 at five medical centers, and were included in this study. Mean age, body mass index (BMI), and CHA2 DS2 -VASC score were 70.8 ± 8.6 years, 29.3 ± 6.5 kg/m2 , and 3.9 ±1.2, respectively. At the screening TEE, mean maximal LAA ostial width and depth were 15.6 ± 0.6 mm (range 14-16) and 23.2 ± 4.5 mm (range 13-31), respectively. Successful LAA closure with the WATCHMAN device was achieved in 31 of 32 patients (97%), with no major complications. TEE performed 45 days after LAA closure demonstrated no peridevice leak > 5 mm and no device related thrombi. Warfarin was discontinued in all 31 patients 45 days after LAA closure. CONCLUSIONS: LAA closure with the WATCHMAN device can be successfully and safely achieved in patients with a maximal LAA ostial width < 17 mm.

Thromboembolism after WATCHMANTM in a clopidogrel non-responder: A case for concern?

Atrial fibrillation (AF) is associated with an increased risk of stroke and thromboembolism (TE). The WATCHMANTM left atrial appendage (LAA) closure device is indicated to reduce the risk of TE from the LAA in patients with non-valvular AF. Here, we present a case of a patient with device-related thrombus who suffered a TE event two months after WATCHMANTM LAA closure and two weeks after switching from aspirin plus warfarin to aspirin plus clopidogrel therapy. Laboratory investigation identified the patient to be hypercoagulable and to be a non-responder to clopidogrel therapy. We discuss the potential role of platelet function testing to prevent device-related thrombi.

Right Ventricular Pacing for Assessment of Cavo-Tricuspid Isthmus Block.

Background: Cavo-tricuspid isthmus (CTI) dependent atrial flutter is typically treated with cardiac ablation. Standard techniques to assess CTI block after ablation can be technically challenging. Right ventricular (RV) pacing may allow for another technique to assess CTI block after ablation. Objective: The purpose of this study was to evaluate RV pacing as a method to assess CTI block after ablation of CTI dependent atrial flutter, and define endpoints of ablation using this technique. Methods: 28 patients undergoing ablation of CTI dependent atrial flutter with intact ventriculoatrial (VA) conduction were prospectively enrolled in this study and underwent the RV pacing protocol, as well as standard coronary sinus (CS) pacing techniques to assess CTI block. Results: The mean trans-isthmus conduction interval during CS pacing (TICICS) at 600 and 400ms after CTI ablation was 168 +/- 9ms and 175 +/- 18ms, respectively. The mean trans-isthmus conduction interval during RV pacing (TICIRV) at 600ms and 400ms after CTI ablation was 109 +/- 5ms and 111 +/- 5ms, respectively. A TICIRV >100ms was associated with a successful outcome after CTI ablation. Conclusions: RV pacing may add incremental value in the assessment of CTI block in patients undergoing ablation of CTI dependent atrial flutter.

Comparison of eri and tasar silk fibroin scaffolds for biomedical applications.

The cultivated silk, mulberry, is being used as biomaterial in different forms. Eri, tasar and muga are some of the known wild silk varieties. The studies on biomedical applications of electrospun mats produced from these wild silks are limited though few studies on eri silk are available. In this work, comparison was made between eri and tasar silk fibroin scaffolds for biomedical application. The scaffolds were produced from eri silk fibroin (ESF) and tasar silk fibroin (TSF) by electrospinning method and they were treated with ethanol to improve dimensional stability. Ethanol treatment increased the crystallinity% of both ESF and TSF scaffolds. The crystallinity percentage of the ESF and TSF scaffolds was found to be 46.7 and 42.8 % respectively. Thermal stability was higher for ESF than that of TSF scaffold. The hemolytic % of ESF and TSF scaffolds was found to be 1.3 and 7.7 % respectively. The platelet adhesion on the surface of ESF scaffold was lower than that found on TSF scaffold. Better fibroblast cell attachment, binding and spreading was found on the ESF scaffold. The cell viability on ESF scaffold was 83.78 % and in TSF was 78.01 % for 48 h. The results showed that ESF electrospun scaffold can be considered as a better biomaterial for biomedical applications compared to that of TSF scaffold.

Comparison of ICD implantation in obese and nonobese patients.

BACKGROUND: Implantable defibrillator (ICD) therapy improves mortality in patients at risk for sudden cardiac death. Obese patients pose challenges during ICD implantation and may have an increased risk of procedure-related complications. The comparison of acute procedural success and safety of ICD implantation in obese and nonobese patients has not been previously reported. METHODS: A total of 181 patients underwent ICD implantation at a single institution. Obesity was defined as a body mass index (BMI) greater than or equal to 30 kg/m(2) . Acute safety and efficacy data were collected and analyzed from a prospectively maintained database, with retrospective chart review, as required. RESULTS: Among the 181 patients, 58 (32.0%) were obese. Mean BMI was 36.7 ± 6.3 kg/m(2) among obese patients and was 24.6 ± 3.1 kg/m(2) among nonobese patients (P < 0.001). Successful ICD implantation occurred in 58 of 58 (100%) obese patients and 122 of 123 (99.2%) nonobese patients (P = 1.0). A complication was observed in three of 58 (5.2%) obese patients and in seven of 123 (5.7%) nonobese patients (P = 1.0). Similarly, there was no difference in acute procedural success and safety in patients receiving a cardiac resynchronization therapy (CRT)-ICD. CONCLUSIONS: Acute success and safety of ICD implantation is similar in both obese and nonobese patients. This finding extended to patients treated with a CRT-ICD and among patients with extreme obesity. Obesity should probably not be a factor in determining whether a patient is a candidate for ICD implantation.

Electrospun eri silk fibroin scaffold coated with hydroxyapatite for bone tissue engineering applications.

Natural biomaterials such as collagen, silk fibroin, and chitosan, and synthetic biopolymers such as polylactic acid, polycaprolactone, polyglycolic acid, and their copolymers are being used as scaffold for tissue engineering applications. In the present work, a fibrous mat was electrospun from eri silk fibroin (ESF). A composite of hydroxyapatite (Hap) and the ESF scaffold was prepared by soaking the ESF scaffold in a solution of calcium chloride and then in sodium diammonium phosphate. The average tensile stress of the pure ESF and hydroxyapatite-coated ESF scaffold (ESF-Hap) was found to be 1.84 and 0.378 MPa, respectively. Pure ESF and ESF-Hap scaffolds were evaluated for their characteristics by a themogravimetric analyzer and Fourier transform infrared spectroscope. The crystallinity and thermal stability of the ESF-Hap scaffold were found to be more than that of uncoated eri silk nanofiber scaffold. The water uptake of the pure ESF and ESF-Hap scaffolds was found to be 69% and 340%, respectively, in distilled water as well as phosphate buffer saline. The hemolysis percentage of both scaffolds was less than 5%, which indicate their good blood compatibility. The cytocompatibility studied by 3-(4,5-dimethyl) thiazol-2-yl-2,5-dimethyl tetrazolium bromide assay showed that the scaffold is biocompatible. To assess cell attachment and growth on the scaffold, human mesenchymal stem cells were cultured on the scaffolds. The results from scanning electron microscopy and fluorescent microscopy showed a notable cellular growth and favorable morphological features. Hence, the ESF-Hap scaffold is better suited for cell growth than the pure ESF scaffold.

Heparin and heparan sulfate: analyzing structure and microheterogeneity.

The structural microheterogeneity of heparin and heparan sulfate is one of the major reasons for the multifunctionality exhibited by this class of molecules. In a physiological context, these molecules primarily exert their effects extracellularly by mediating key processes of cellular cross-talk and signaling leading to the modulation of a number of different biological activities including development, cell proliferation, and inflammation. This structural diversity is biosynthetically imprinted in a nontemplate-driven manner and may also be dynamically remodeled as cellular function changes. Understanding the structural information encoded in these molecules forms the basis for attempting to understand the complex biology they mediate. This chapter provides an overview of the origin of the structural microheterogeneity observed in heparin and heparan sulfate, and the orthogonal analytical methodologies that are required to help decipher this information.

M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

Bioactivity screening of partially desulfated low-molecular-weight heparins: a structure/activity relationship study.

A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates.

The role of ventricular tachycardia ablation in the reduction of implantable defibrillator shocks.

Frequent shocks from an implantable defibrillator (ICD) can have adverse cardiac affects and lead to increased pain, anxiety, and a decreased quality of life. Pharmacologic attempts and ICD reprogramming strategies aimed at reducing ICD shocks have modest results, with frequent discontinuation of medicines because of side effects. Ventricular tachycardia (VT) ablation is recommended in the treatment of patients with frequent ICD shocks caused by VT. VT ablation may also be considered in patients with an initial ICD shock and as prophylactic treatment in patients with a history of sustained VT who are undergoing ICD implant.