Pulmonary hypertension is a highly morbid disease with no cure. Available treatments are limited by systemic adverse effects due to non‐specific biodistribution. Self‐assembled peptide amphiphile ...(PA) nanofibers are biocompatible nanomaterials that can be modified to recognize specific biological markers to provide targeted drug delivery and reduce off‐target toxicity. Here, PA nanofibers that target the angiotensin I‐converting enzyme and the receptor for advanced glycation end‐products (RAGE) are developed, as both proteins are overexpressed in the lung with pulmonary hypertension. It is demonstrated that intravenous delivery of RAGE‐targeted nanofibers containing the targeting epitope LVFFAED (LVFF) significantly accumulated within the lung in a chronic hypoxia‐induced pulmonary hypertension mouse model. Using 3D light sheet fluorescence microscopy, it is shown that LVFF nanofiber localization is specific to the diseased pulmonary tissue with immunofluorescence analysis demonstrating colocalization of the targeted nanofiber to RAGE in the hypoxic lung. Furthermore, biodistribution studies show that significantly more LVFF nanofibers localized to the lung compared to major off‐target organs. Targeted nanofibers are retained within the pulmonary tissue for 24 h after injection. Collectively, these data demonstrate the potential of a RAGE‐targeted nanomaterial as a drug delivery platform to treat pulmonary hypertension.
Peptide amphiphile nanofibers targeted to the receptor for advanced glycation end‐products (RAGE) significantly accumulate within diseased lungs of mice with hypoxia‐induced pulmonary hypertension following intravascular delivery. The targeted nanofibers remain localized to the pulmonary tissue for up to 24 h after injection. PA nanofibers may be effective delivery vehicles to provide targeted therapies for pulmonary hypertension.
We previously showed that HIV infection leads to expansion of a rapidly proliferating pool (s1) of CD4 and CD8 T lymphocytes. In the current study, we used in vivo labeling with bromodeoxyuridine to ...characterize the kinetics of naive, memory, and activated (HLA-DR+/CD38+) subpopulations of CD4 and CD8 T lymphocytes, and to examine the relationship between kinetic parameters and baseline CD4 counts, HIV viral load, potential markers of microbial translocation, and cytokine levels. Activated cells showed the highest proliferation rates, followed by effector and central memory cells, with naive cells showing the lowest rates, for both CD4 and CD8 T cells. HIV viral load correlated with s1 of CD4 and CD8 effector memory cells, as well as CD8 naive cells, whereas CD4 cell counts correlated inversely with naive CD4 s1. Endotoxin levels showed a weak negative association with CD4 but not CD8 s1. INF-γ and TNF-α were associated with s1 for CD4 and CD8 cells, respectively. Thus, HIV is the primary driving force behind the activation and proliferation of most subsets of both CD4 and CD8 T lymphocytes, whereas naive CD4 cell proliferation likely represents a homeostatic response. Microbial translocation does not appear to play an important role in this proliferation.
Acute appendicitis, while common in younger patients, is an unusual cause for hospitalization among older adults. We report a case series of 3 individuals who had been previously implanted with a ...continuous-flow left ventricular assist device (CF-LVAD) for end-stage heart failure, and who subsequently developed acute appendicitis. Both axial-flow technology and nonpulsatile systemic blood flow have been implicated as potential causes for bleeding and thrombosis in contemporary LVAD populations(1-3). This case series represents the first report of acute appendicitis as an adverse event following LVAD implantation and represents a patient demographic that would historically be at very low-risk for this illness. Our patients, their presentation, and the associated pathologic findings raise the possibility of a unique link between appendiceal inflammation and CF-LVAD support that warrants attention.
Many pollutants cause endocrine disruption in aquatic organisms. While studies of the direct effects of toxicants on exposed organisms are commonplace, little is known about the potential for ...toxicant exposures in a parental (F0) generation to affect unexposed F1 or F2 generations (multigenerational and transgenerational effects, respectively), particularly in estuarine fishes. To investigate this possibility, we exposed inland silversides (Menidia beryllina) to environmentally relevant (low ng/L) concentrations of ethinylestradiol, bifenthrin, trenbolone, and levonorgestrel from 8 hpf to 21 dph. We then measured development, immune response, reproduction, gene expression, and DNA methylation for two subsequent generations following the exposure. Larval exposure (F0) to each compound resulted in negative effects in the F0 and F1 generations, and for ethinylestradiol and levonorgestrel, the F2 also. The specific endpoints that were responsive to exposure in each generation varied, but included increased incidence of larval deformities, reduced larval growth and survival, impaired immune function, skewed sex ratios, ovarian atresia, reduced egg production, and altered gene expression. Additionally, exposed fish exhibited differences in DNA methylation in selected genes, across all three generations, indicating epigenetic transfer of effects. These findings suggest that assessments across multiple generations are key to determining the full magnitude of adverse effects from contaminant exposure in early life.
Abstract
Neuroangiography (NA) is a minimally invasive procedure used to diagnose patients with neurovascular diseases. Noninvasive imaging has improved dramatically in recent years and is utilized ...more frequently; however, further evaluation with NA is still required in certain cases. NA indications include intracranial (cerebral aneurysms, arteriovenous malformations, dural arteriovenous fistula, cerebral vasculitis, cerebral vasospasm, ischemic stroke, nontraumatic subarachnoid hemorrhage, intracerebral hemorrhage, Moyamoya, vein of Galen malformation, intracranial tumors, and pseudotumor cerebri) and extracranial (internal and common carotid artery stenosis, vertebral artery stenosis, carotid artery blowout, vertebral artery blowout, epistaxis, oropharyngeal bleeding, and carotid body tumor) pathologies which can help with diagnosis and potential subsequent endovascular treatment. A thorough understanding of normal and variant cervical/cranial vascular anatomy is required. In addition, periprocedural management, catheter technique, equipment needed, and underlying disease pathology are paramount to successful and safe outcomes. This article will review basic neurovascular anatomy, periprocedural management, NA technique, and tips for safe and successful outcomes.
Wide-necked intracranial aneurysms present unique treatment challenges in the setting of subarachnoid hemorrhage. New generations of endoluminal devices (stents) have expanded our ability to treat ...complex aneurysms. The PulseRider Aneurysm Neck Reconstruction Device (PulseRider Cerenovus, Irvine, California, USA) is new to the U.S. market after receiving Food and Drug Administration approval in June 2017. Official recommendation for use of the PulseRider is with dual antiplatelet therapy (DAPT). Its design has been hypothesized to carry a lower risk of thromboembolic complications in the circumstance that DAPT needs to be discontinued.
Between March and June 2018, we treated 4 cases of ruptured wide-necked basilar tip aneurysms at the University of Colorado Hospital, Aurora, Colorado, with PulseRider-assisted coil embolization. Imaging and chart reviews were performed retrospectively on each of these patients.
All 4 aneurysms were successfully treated with PulseRider-assisted coil embolization. There were no periprocedural hemorrhages and no postprocedural reruptures. Two patients developed nonocclusive thrombi in the posterior cerebral arteries at the time of coiling, which was resolved with intra-arterial glycoprotein IIb/IIIa receptor antagonists. Two patients developed external ventricular drain–associated hemorrhages, only one of which developed after the administration of DAPT. All patients were eventually discharged to home.
The PulseRider device represents a novel design for stent-assisted coil embolization. We report a small but promising series of its successful use in the acute treatment of wide-necked, ruptured basilar artery aneurysms. Additional experience is needed to determine if this device has a place in our armamentarium for treatment of ruptured aneurysms.
The repair of unruptured intracranial aneurysms has increased since 2000. In this study, we analyzed the Nationwide Readmission Database (NRD) to determine the rate of 90-day readmission. Our ...objective is to examine readmission trends after unruptured aneurysm repair.
This study used the 2013 and 2014 NRD. Patient data included standard demographic, comorbidity, and payer information. We selected patients who had undergone microsurgical or endovascular repair for a nonruptured aneurysm. We excluded patients who were under 18 years of age, had a subarachnoid hemorrhage, or were discharged to home the same day. Readmission was calculated by counting the number of days between the end of the index visit and earliest readmission date.
A total of 2180 of 29,694 patients (7.34%) were readmitted within 90 days of their initial hospitalization. They were younger (mean, 52.6 years; 95% confidence interval CI, 51.4–53.8) than patients not readmitted (mean, 57.4 years; 95% CI, 57.1–57.8; P < 0.0001). In total, endovascular repair was more frequent than microsurgery (79.8% vs. 20.2%, respectively). Mean days to readmission was 41.8 (95% CI, 39.7–43.9) and was higher for women (P < 0.0001). The odds ratio for readmission after an endovascular repair was 1.54 (95% CI, 1.27–1.86).
In this study of over 28,000 patients treated for an unruptured aneurysm, the 90-day readmission rate was 7.34%. Endovascular patients had higher odds of readmission than microsurgical patients. Patients with common medical comorbidities (hypertension, obesity, renal failure, and diabetes) were less likely to be readmitted than patients without those conditions.
Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We ...aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel.
Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant.
580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group 2.8%, 8.5% patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group 0.6%, 3.8% ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients 1.5%, 8.2% and 3.5% 1.8%, 6.3% of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9).
Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.
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