Genicular Nerve Radiofrequency Ablation for Painful Knee Arthritis: The Why and the How.

BackgroundGenicular nerve radiofrequency ablation (GNRFA), including conventional, cooled, and pulsed techniques, has been used in the management of symptomatic knee osteoarthritis (OA). This new and innovative treatment option has the capacity to decrease pain and improve function and quality of life in certain patients. GNRFA is reserved for patients with symptomatic knee OA who have had failure of conservative treatment and have had failure of or are poor candidates for surgery. GNRFA has been shown to consistently provide short-term (3 to 6-month), and sometimes longer, pain relief in patients. GNRFA has been demonstrated to be safe to administer repeatedly in patients who respond well to this minimally invasive procedure.DescriptionGNRFA is a 2-step procedure. First, patients are given a diagnostic block under fluoroscopy or ultrasound guidance. Specifically, 1 mL of lidocaine is injected using a 20-gauge, 3.5-in (8.9-cm) spinal needle around the superior lateral, superior medial, and inferior medial genicular nerve branches. The diagnostic block is extra-articular. If the patient reports a ≥50% reduction in baseline pain for a minimum of 24 hours following the injection, then the patient is a candidate for genicular ablation. The osseous landmarks for the diagnostic block are exactly the same as for the ablation procedure. Both procedures are well tolerated in the office setting under local skin anesthesia or can be done in the operating room under conscious sedation using a low-dose sedative such as midazolam for anxious patients. General anesthesia is not required for GNRFA. This procedure is most commonly performed by interventional pain specialists but may also be performed by any physician with appropriate training. In some jurisdictions, physician assistants and nurse practitioners may perform this procedure subject to their supervision requirements.AlternativesConservative treatment for symptomatic knee OA includes weight loss management, physical and aquatic therapy, bracing, lateral wedge insoles, transcutaneous nerve stimulation, nonsteroidal anti-inflammatory drugs in combination with a proton pump inhibitor, autologous blood-based therapies, and cortisone and hyaluronic acid injections1,2. Surgical treatment for symptomatic knee OA includes knee arthroscopy, high tibial osteotomy, total knee replacement, and unicompartmental knee replacement in patients without lateral compartment disease2. It should be noted that there is some evidence suggesting that steroid injection, viscosupplements, and arthroscopy are not effective for the management of knee OA.RationaleThermal GNRFA differs from all other treatment alternatives because this procedure causes denaturing of the 3 sensory nerves primarily responsible for transmitting knee pain from an arthritic joint to the central nervous system. In this procedure, heating occurs from an intense alternating electrical field at the tip of the cannula, which produces sufficient heat to denature the proteins in the target tissue. The accepted heating parameters for this procedure are 70° to 80°C for 60 or 90 seconds. A commonly raised question is whether this procedure precipitates a Charcot-type joint. The Charcot joint involves much more than reduced innervation; it occurs in the context of chronically compromised vascularity and altered soft-tissue characteristics as well as peripheral neuropathy. Moreover, a Charcot-type joint does not develop because the deafferentation of the weight-bearing joint is partial3. To our knowledge, no Charcot-type joints have been reported after this procedure. Conversely, data from an animal study have shown that selective joint denervation may lead to the progression of knee OA4. The ablation procedure is done outside the knee joint, unlike alternatives such as intra-articular therapies and surgery. The effectiveness of nonsurgical knee OA interventions in alleviating pain and improving joint function is generally inadequate1. However, GNRFA appears to be an emerging alternative for patients who have had failure of conservative and surgical treatments. It is not uncommon in our clinical practice for patients to achieve adequate pain control following ablation for up to 1 year. GNRFA provides temporary relief from symptomatic knee OA because it does not eliminate the potential for peripheral nerve regrowth and regeneration, and thus pain, to return

Automated Assignments of N- and O‑Site Specific Glycosylation with Extensive Glycan Heterogeneity of Glycoprotein Mixtures

Site-specific glycosylation (SSG) of glycoproteins remains a considerable challenge and limits further progress in the areas of proteomics and glycomics. Effective methods require new approaches in sample preparation, detection, and data analysis. While the field has advanced in sample preparation and detection, automated data analysis remains an important goal. A new bioinformatics approach implemented in software called GP Finder automatically distinguishes correct assignments from random matches and complements experimental techniques that are optimal for glycopeptides, including nonspecific proteolysis and high mass resolution liquid chromatography/tandem mass spectrometry (LC/MS/MS). SSG for multiple N- and O-glycosylation sites, including extensive glycan heterogeneity, was annotated for single proteins and protein mixtures with a 5% false-discovery rate, generating hundreds of nonrandom glycopeptide matches and demonstrating the proof-of-concept for a self-consistency scoring algorithm shown to be compliant with the target-decoy approach (TDA). The approach was further applied to a mixture of N-glycoproteins from unprocessed human milk and O-glycoproteins from very-low-density-lipoprotein (vLDL) particles

Discovery of Selective Small Molecule Type III Phosphatidylinositol 4‑Kinase Alpha (PI4KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents

Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIIIα is an essential component of these replication organelles. RNA interference of PI4KIIIα results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIIIα is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients. We investigated if small molecule inhibitors of PI4KIIIα could inhibit HCV replication in vitro. The synthesis and structure–activity relationships associated with the biological inhibition of PI4KIIIα and HCV replication are described. These efforts led directly to identification of quinazolinone <b>28</b> that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro