Use of Intravascular Ultrasound and Coronary Angiography to Measure the Prevalence of Myocardial Bridge in Heart Transplant Patients.

Myocardial bridge (MB) detection rates vary across methods and most studies that have assessed MB include symptomatic patients. Intravascular ultrasound (IVUS) is a sensitive tool for MB detection and donor hearts may serve as a surrogate measure of asymptomatic patients. We used IVUS and coronary angiography to measure MB prevalence in heart transplant patients during routine follow-up invasive coronary assessments. This was a retrospective, single-center study of heart transplant patients who received follow-up coronary assessments at the University of Chicago Heart and Vascular Center between December 2014 and December 2021. A single experienced interventional cardiologist assessed incidental findings of MB in IVUS and coronary angiography. Detection rates were compared with meta-analysis-reported prevalence. Of 129 patients, IVUS-detected MB in 87 patients (67.4%), whereas coronary angiography detected 41 (31.8%). All MB found by coronary angiography were detected by IVUS. Some level of cardiac allograft vasculopathy was found in 92 patients (71.3%). Our IVUS-detected MB prevalence was greater than meta-analysis-reported pooled prevalence across all methods: autopsy, computed tomography angiography, and coronary angiography (67.4% [95% confidence interval [CI] 59.4 to 75.5] vs 42% [95% CI 30 to 55]; 22% [95% CI 18 to 25]; 6% [95% CI 5 to 8], p ≤0.005). The difference between our observed IVUS-detected MB prevalence and meta-analysis autopsy reported MB prevalence was 1.25 (95% CI 1.11 to 1.40). In conclusion, the high prevalence of MB recorded in donor hearts emphasizes the need to further investigate the causes of chest pain in patients who are found to have MB.

The Transulnar Approach to Coronary Angiography and Intervention: Assessing the Anatomy of the Ulnar Artery Using Angiography.

BACKGROUND: The transulnar approach (TUA) has been proposed as a safe alternative to the more established transradial approach (TRA) for cardiac catheterization. However, no study has assessed the anatomy and variability of the ulnar artery using angiography. METHODS: A retrospective analysis of patients who underwent transradial cardiac catheterization during routine clinical care was conducted. Both quantitative and qualitative measurements of artery diameter were collected. RESULTS: Among 700 consecutive patients, mean distal ulnar artery diameter (UAD) was larger in men (3.2 ± 0.9 mm) compared with women (2.7 ± 0.7 mm; P<.001). UAD was larger than radial artery diameter (RAD) at all measured sites (distal ulnar, 3.0 ± 0.8 mm; distal radial, 2.9 ± 0.7 mm; P=.046). Compared with the radial artery, the ulnar artery had more atresia (4.3% ulnar vs 0% radial; P<.001), fewer loops (0.6% ulnar vs 2.4% radial; P<.01), and less spasm (2.7% ulnar vs 23.4% radial; P<.001). UAD had more variability (distal variance, 0.68) as compared with the RAD (distal variance, 0.53; P<.001). CONCLUSION: We found that the ulnar artery has a larger diameter, fewer loops, and less spasm, but more variance than the radial artery. Additionally, males have larger ulnar arteries than women. These findings have implications on the application of TUA either as an alternative to TRA or as the primary point of access.

Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions.

The histone demethylase KDM5A erases histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDRs). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites. We have identified a noncanonical poly(ADP-ribose) (PAR)-binding region unique to KDM5A. Loss of the PAR-binding region or treatment with PAR polymerase (PARP) inhibitors (PARPi's) blocks KDM5A-PAR interactions and DNA repair functions of KDM5A. The histone variant macroH2A1.2 is also specifically required for KDM5A recruitment and function at DNA damage sites, including homology-directed repair of DNA double-strand breaks and repression of transcription at DNA breaks. Overall, this work reveals the importance of PAR binding and macroH2A1.2 in KDM5A recognition of DNA lesion sites that drive transcriptional and repair activities at DNA breaks within chromatin that are essential for maintaining genome integrity.

Use of Prospective Radiobrachial Angiography in Transradial Cardiac Catheterization and Intervention.

OBJECTIVES: This study examined the utility of prospective radiobrachial angiography (pRBA) in transradial coronary angiography and intervention as a method for reducing procedural complications. BACKGROUND: A growing body of evidence has supported the transradial approach (TRA) as superior to the transfemoral approach (TFA) due to advantages such as reduced bleeding and improved outcomes in high-risk patients. However, TRA has a higher failure rate than TFA, and has seen slow rates of adoption among United States operators. METHODS: This was a retrospective, single center, case-control analysis of coronary angiography procedures, performed by two experienced operators at the University of Chicago Medical Center between October 28, 2015 and July 21, 2017. Operator 1 began using pRBA during the study, whereas Operator 2 used pRBA in all TRA procedures. There were 567 patients stratified into three groups based on operator and pRBA use. Comparisons of procedural outcomes for Operator 1 before and after adoption of pRBA, and of outcomes between Operator 1 and Operator 2 were made. RESULTS: Use of pRBA was associated with reduced overall procedural complication rates (2.5% versus 10.4%, p = 0.004), driven primarily by reflexive radiobrachial angiography (rRBA) after resistance or pain was encountered (8.6% versus 0.0%, p = 0.0001) for Operator 1. A slight reduction in contrast associated with pRBA for Operator 1 was noted, but no difference in procedural time, radiation dose, or additional equipment used across groups was found. No significant difference in adverse procedural outcomes between the pRBA groups of Operator 1 and Operator 2 were observed. In patients with radiobrachial variants in anatomy, use of pRBA was associated with shorter times to cross anatomic lesions, shorter procedure times, reduced use of extra catheters, and less perforations and crossovers compared to patients requiring rRBA. Lack of pRBA was associated with higher procedural complications (hazard ratio 1.08, 95% CI, 1.03-1.13, p = 0.004). CONCLUSION: pRBA may be a useful tool for mitigating procedural complications, reducing time needed to cross difficult radiobrachial anatomy, and reducing the need to utilize additional equipment in TRA. pRBA may offer operators a tool to improve outcomes and increase adoption of this approach.

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus.

Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

CE: Managing Movement Disorders: A Clinical Review.

: Neuromuscular disorders are complex, difficult both to differentiate and to manage. Yet nurses, who encounter a symptomatically diverse neuromuscular patient population in various practice settings, are expected to be well versed in managing the variable associated symptoms of these disorders. Here the authors discuss how to assess such neuromuscular conditions as muscle tightness, spasticity, and clonus; the pathophysiology underlying each; and the available recommended treatments, an understanding of which is necessary for successful symptom management and clear provider-patient communication.

Activated RhoA is a positive feedback regulator of the Lbc family of Rho guanine nucleotide exchange factor proteins.

The monomeric Rho GTPases are essential for cellular regulation including cell architecture and movement. A direct mechanism for hormonal regulation of the RhoA-type GTPases is their modulation by the G12 and G13 proteins via RH (RGS homology) containing RhoGEFs. In addition to the interaction of the G protein α subunits with the RH domain, activated RhoA also binds to the pleckstrin homology (PH) domain of PDZRhoGEF. The latter interaction is now extended to all seven members of the homologous Lbc family of RhoGEFs which includes the RH-RhoGEFs. This is evinced by direct measurements of binding or through effects on selected signaling pathways in cells. Overexpression of these PH domains alone can block RhoA-dependent signaling in cells to various extents. Whereas activated RhoA does not modulate the intrinsic activity of the RhoGEFs, activated RhoA associated with phospholipid vesicles can facilitate increased activity of soluble RhoGEFs on vesicle-delimited substrate (RhoA-GDP). This demonstrates feasibility of the hypothesis that binding of activated RhoA to the PH domains acts as a positive feedback mechanism. This is supported by cellular studies in which mutation of this binding site on PH strongly attenuates the stimulation of RhoA observed by overexpression of five of the RhoGEF DH-PH domains. This mutation is even more dramatic in the context of full-length p115RhoGEF. The utilization of this mechanism by multiple RhoGEFs suggests that this regulatory paradigm may be a common feature in the broader family of RhoGEFs.

Next generation orthopaedic implants by additive manufacturing using electron beam melting.

This paper presents some examples of knee and hip implant components containing porous structures and fabricated in monolithic forms utilizing electron beam melting (EBM). In addition, utilizing stiffness or relative stiffness versus relative density design plots for open-cellular structures (mesh and foam components) of Ti-6Al-4V and Co-29Cr-6Mo alloy fabricated by EBM, it is demonstrated that stiffness-compatible implants can be fabricated for optimal stress shielding for bone regimes as well as bone cell ingrowth. Implications for the fabrication of patient-specific, monolithic, multifunctional orthopaedic implants using EBM are described along with microstructures and mechanical properties characteristic of both Ti-6Al-4V and Co-29Cr-6Mo alloy prototypes, including both solid and open-cellular prototypes manufactured by additive manufacturing (AM) using EBM.

Open-Cellular Co-Base and Ni-Base Superalloys Fabricated by Electron Beam Melting.

Reticulated mesh samples of Co-29Cr-6Mo alloy and Ni-21Cr-9Mo-4Nb alloy (625) and stochastic foam samples of Co-29Cr-6Mo alloy fabricated by electron beam melting were characterized by optical metallography, and the dynamic stiffness (Young's modulus) was measured by resonant frequency analysis. The relative stiffness (E/Es) versus relative density (ρ/ρs) plotted on a log-log basis resulted in a fitted straight line with a slope n ≅ 2, consistent with that for ideal open cellular materials.

Activated RhoA binds to the pleckstrin homology (PH) domain of PDZ-RhoGEF, a potential site for autoregulation.

Guanine nucleotide exchange factors (GEFs) catalyze exchange of GDP for GTP by stabilizing the nucleotide-free state of the small GTPases through their Dbl homology/pleckstrin homology (DH.PH) domains. Unconventionally, PDZ-RhoGEF (PRG), a member of the RGS-RhoGEFs, binds tightly to both nucleotide-free and activated RhoA (RhoA.GTP). We have characterized the interaction between PRG and activated RhoA and determined the structure of the PRG-DH.PH-RhoA.GTPgammaS (guanosine 5'-O-[gamma-thio]triphosphate) complex. The interface bears striking similarity to a GTPase-effector interface and involves the switch regions in RhoA and a hydrophobic patch in PRG-PH that is conserved among all Lbc RhoGEFs. The two surfaces that bind activated and nucleotide-free RhoA on PRG-DH.PH do not overlap, and a ternary complex of PRG-DH.PH bound to both forms of RhoA can be isolated by size-exclusion chromatography. This novel interaction between activated RhoA and PH could play a key role in regulation of RhoGEF activity in vivo.