Transient hypercapnia reveals an underlying cerebrovascular pathology in a murine model for HIV-1 associated neuroinflammation: role of NO-cGMP signaling and normalization by inhibition of cyclic nucleotide phosphodiesterase-5.

BACKGROUND: Cerebral blood flow (CBF) is known to be dysregulated in persons with human immunodeficiency virus 1 (HIV-1), for uncertain reasons. This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment. METHODS: To test whether dysregulation of CBF might be due to virally-induced neuroinflammation, we used a well-defined animal model (GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic (Tat-tg) mice). We then exposed the mice to a brief hypercapnic stimulus, and assessed cerebrovascular reactivity by measuring 1) changes in cerebral blood flow, using laser Doppler flowmetry and 2) changes in vascular dilation, using in vivo two-photon imaging. RESULTS: Exposure to brief hypercapnia revealed an underlying cerebrovascular pathology in Tat-tg mice. In control animals, brief hypercapnia induced a brisk increase in cortical flow (20.8% above baseline) and vascular dilation, as measured by laser Doppler flowmetry and in vivo two-photon microscopy. These responses were significantly attenuated in Tat-tg mice (11.6% above baseline), but cortical microvascular morphology and capillary density were unaltered, suggesting that the functional pathology was not secondary to vascular remodeling. To examine the mechanistic basis for the diminished cerebrovascular response to brief hypercapnia, Tat-tg mice were treated with 1) gisadenafil, a phosphodiesterase 5 (PDE5) inhibitor and 2) tetrahydrobiopterin (BH4). Gisadenafil largely restored the normal increase in cortical flow following hypercapnia in Tat-tg mice (17.5% above baseline), whereas BH4 had little effect. Gisadenafil also restored the dilation of small (<25 µm) arterioles following hypercapnia (19.1% versus 20.6% diameter increase in control and Tat-tg plus gisadenafil, respectively), although it failed to restore full dilation of larger (>25 µm) vessels. CONCLUSIONS: Taken together, these data show that HIV-associated neuroinflammation can cause cerebrovascular pathology through effects on cyclic guanosine monophosphate (cGMP) metabolism and possibly on PDE5 metabolism.

Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents.

The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for acute treatment of the disease. We investigate whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can decrease SARS-CoV-2 replication without impacting ACE2's natural enzymatic function. Initial screening of a diversity library resulted in hit compounds active in an ACE2-binding assay, which showed little inhibition of ACE2 enzymatic activity (116 actives, success rate ∼4%), suggesting they were allosteric binders. Subsequent application of in silico techniques boosted success rates to ∼14% and resulted in 73 novel confirmed ACE2 binders with K d values as low as 6 nM. A subsequent SARS-CoV-2 assay revealed that five of these compounds inhibit the viral life cycle in human cells. Further effort is required to completely elucidate the antiviral mechanism of these ACE2-binders, but they present a valuable starting point for both the development of acute treatments for COVID-19 and research into the host-directed therapy.

Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents.

The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection.

Outcomes of the TrapEase inferior vena cava filter over 10 years at a single health care system.

PURPOSE: To retrospectively investigate the safety, efficacy, and complications associated with TrapEase inferior vena cava filters. METHODS: All patients who received a TrapEase filter at a single institution between April 2003 and January 2013 were identified, and outcomes were reviewed and analyzed. RESULTS: During the study period, 594 patients (278 women; mean age, 68.9 ± 13.6 years; range, 19.2-96.3 years) received a TrapEase filter. The duration of this study was 88 months, with a median clinical follow-up of 3.6 months (range, 0-148.3 months). During follow-up, 489 of 594 patients (82.3%) died and 105 remained alive with filters in situ. Nine cases of breakthrough pulmonary embolism occurred among the 582 patients with clinical follow-up (1.5%). Among 128 patients with imaging that contained the filter, there were 17 cases of filter fracture (13.3%). Of the 39 patients with available computed tomography scans, eight had filling defects within the filter suggestive of thrombus or embolus (20.5%), including two patients with complete caval occlusion. Recurrent deep vein thrombosis occurred in 109 out of 582 patients (18.7%) with clinical follow-up. CONCLUSIONS: Most patients who received TrapEase filters died during follow-up, possibly because operators chose to implant a permanent filter in patients with known terminal illnesses. The filter fracture rate seemed to be high, but there were no instances of free fracture fragment or distant migration. Although the filter may theoretically be effective in preventing thrombus migration owing to the double basket design, pulmonary embolism breakthrough rates were comparable with rates seen with other filters.