Experimental localization of metal-binding sites reveals the role of metal ions in type II DNA topoisomerases.

Metal ions have important roles in supporting the catalytic activity of DNA-regulating enzymes such as topoisomerases (topos). Bacterial type II topos, gyrases and topo IV, are primary drug targets for fluoroquinolones, a class of clinically relevant antibacterials requiring metal ions for efficient drug binding. While the presence of metal ions in topos has been elucidated in biochemical studies, accurate location and assignment of metal ions in structural studies have historically posed significant challenges.

Changes in soluble LDL receptor and lipoprotein fractions in response to diet in the DIETFITS weight loss study.

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology.

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound , which has potent activity against Gram-positive bacteria, a favorable safety profile, and excellent pharmacokinetic properties. Compound was found to be efficacious against fluoroquinolone-sensitive infection in a mouse thigh model at lower doses than moxifloxacin.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1)-ones, exemplified by , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens.

Prospective Evaluation of a Smartphone Otoscope for Home Tympanostomy Tube Surveillance: A Pilot Study.

Objectives: Recent technological advances have led to the capability of performing high resolution imaging of the tympanic membrane. Smartphone technologies and applications have provided the opportunity to capture digital images and easily share them. The smartphone otoscope device was developed as a simple system that can convert a smartphone into a digital otoscope.

Prevalence of Tinnitus and Associated Factors Among Asian Americans: Results From a National Sample.

Objectives: A previous study demonstrated low rates of high-frequency hearing loss and noise exposure among Asian Americans (AAs). This study examined the prevalence of tinnitus and associated factors among AAs using the first nationally representative sample of AAs.

Study Design: Cross-sectional analysis of a national health survey.

Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase.

Type II topoisomerases alter DNA topology to control DNA supercoiling and chromosome segregation and are targets of clinically important anti-infective and anticancer therapeutics. They act as ATP-operated clamps to trap a DNA helix and transport it through a transient break in a second DNA. Here, we present the first X-ray crystal structure solved at 2.

Speech and Communicative Participation in Patients With Facial Paralysis.

Importance: Problems with speech in patients with facial paralysis are frequently noted by both clinicians and the patients themselves, but limited research exists describing how facial paralysis affects verbal communication.

Objective: To assess the influence of facial paralysis on communicative participation.

Design, Setting, And Participants: A nationwide online survey of 160 adults with unilateral facial paralysis was conducted from March 1 to June 1, 2017.

Abnormal Cochleovestibular Anatomy and Hearing Outcomes: Pediatric Patients with a Questionable Cochleovestibular Nerve Status May Benefit from Cochlear Implantation and/or Hearing Aids.

Objective: Imaging characteristics and hearing outcomes in children with cochleovestibular or cochleovestibular nerve (CVN) abnormalities.

Study Design: Retrospective, critical review.

Setting: Tertiary referral academic center.

Early Communication Development of Children with Auditory Brainstem Implants.

The auditory brainstem implant (ABI) is an auditory sensory device that is surgically placed on the cochlear nucleus of the brainstem for individuals who are deaf but unable to benefit from a cochlear implant (CI) due to anatomical abnormalities of the cochlea and/or eighth nerve, specific disease processes, or temporal bone fractures. In the United States, the Food and Drug Administration has authorized a Phase I clinical trial to determine safety and feasibility of the ABI in up to 10 eligible young children who are deaf and either derived no benefit from the CI or were anatomically unable to receive a CI. In this paper, we describe the study protocol and the children who have enrolled in the study thus far.

Prevalence of Hearing Loss and Hearing Care Use Among Asian Americans: A Nationally Representative Sample.

Objective: To assess the prevalence of hearing loss and factors affecting hearing care use among Asian Americans, using the first nationally representative sample of Asian Americans.

Study Design: National cross-sectional survey.

Setting: Ambulatory examination centers.

Age-related histologic and biochemical changes in auricular and septal cartilage.

Objectives/hypothesis: To characterize the histologic and biochemical properties of auricular and septal cartilage and analyze age-related changes in middle-aged to older adults.

Study Design: Cross-sectional study of auricular and septal cartilage from 33 fresh cadavers.

Methods: Auricular and septal cartilage specimens were stained using Safranin O for glycosaminoglycans, Verhoeff's stain for elastin, and Masson's trichrome for collagen.

Initiation, dropout, and outcome from evidence-based psychotherapies in a VA PTSD outpatient clinic.

Trauma-focused, evidence-based psychotherapies (TF-EBPs) for posttraumatic stress disorder (PTSD) have been widely promoted in the Veterans Health Administration to provide access to state-of-the-art treatments, but dropout rates may affect the impact of TF-EBPs. The current study summarizes findings from a program evaluation of 67 veterans assigned to trauma-focused treatment in a Veterans Affairs outpatient PTSD clinic. Outcomes of interest include attendance rates, dropout rates and patterns, treatment paths, changes in self-reported symptoms, and clinician ratings.

Assessing the Benefit-Risk Profile for Pediatric Implantable Auditory Prostheses.

Background/aims: Children with congenital cochleovestibular abnormalities associated with profound hearing loss have few treatment options if cochlear implantation does not yield benefit. An alternative is the auditory brainstem implant (ABI). Regulatory authority device approvals currently include a structured benefit-risk assessment.

Initial Results of a Safety and Feasibility Study of Auditory Brainstem Implantation in Congenitally Deaf Children.

Objective: To determine the safety and feasibility of the auditory brainstem implant (ABI) in congenitally deaf children with cochlear aplasia and/or cochlear nerve deficiency.

Study Design: Phase I feasibility clinical trial of surgery in 10 children, ages 2 to 5 years, over a 3-year period.

Setting: Tertiary children's hospital and university-based pediatric speech/language/hearing center.

Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.

As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J.

Structure of a quinolone-stabilized cleavage complex of topoisomerase IV from Klebsiella pneumoniae and comparison with a related Streptococcus pneumoniae complex.

Klebsiella pneumoniae is a Gram-negative bacterium that is responsible for a range of common infections, including pulmonary pneumonia, bloodstream infections and meningitis. Certain strains of Klebsiella have become highly resistant to antibiotics. Despite the vast amount of research carried out on this class of bacteria, the molecular structure of its topoisomerase IV, a type II topoisomerase essential for catalysing chromosomal segregation, had remained unknown.

Sentence Recognition in Quiet and Noise by Pediatric Cochlear Implant Users: Relationships to Spoken Language.

Objective: We investigated associations between sentence recognition and spoken language for children with cochlear implants (CI) enrolled in the Childhood Development after Cochlear Implantation (CDaCI) study.

Study Design: In a prospective longitudinal study, sentence recognition percent-correct scores and language standard scores were correlated at 48-, 60-, and 72-months post-CI activation.

Setting: Six tertiary CI centers in the United States.

Device Life of Two Generations of Provox Voice Prostheses.

Background: Tracheoesophageal voice prostheses are invaluable for speech rehabilitation in patients who have received total laryngectomy, but device failure impedes communication and creates psychosocial and financial burdens. This study compares the Provox 2 and Provox Vega voice prostheses on the parameter of device life.

Methods: This was a retrospective observational study of 21 patients with 181 device replacements at an academic tertiary care medical center.

Prognostic implications of and audiometric evidence for hearing fluctuation in Meniere's disease.

Objectives/hypothesis: 1) To establish criteria for significant hearing fluctuation by assessing the range and occurrence of hearing fluctuations over the course of Meniere's disease; 2) to determine if audiometric evidence exists to support the notion that Meniere's disease is a pathophysiologic process involving the whole cochlea; and 3) to suggest prognostic implications for initial hearing fluctuation in patients with Meniere's disease.

Study Design: Retrospective case series review.

Methods: A total of 488 patients diagnosed by 1995 American Academy of Otolaryngology-Head and Neck Surgery Meniere's disease criteria for whom audiometric data were prospectively collected (2 cohorts: 341 and 146 patients initially seen between April 2002 to July 2003 and between January to December 2010, respectively).

A Prospective Longitudinal Study of U.S. Children Unable to Achieve Open-Set Speech Recognition 5 Years After Cochlear Implantation.

Objective: To identify characteristics associated with the inability to progress to open-set speech recognition in children 5 years after cochlear implantation.

Study Design: Prospective, longitudinal, and multidimensional assessment of auditory development for 5 years.

Setting: Six tertiary cochlear implant (CI) referral centers in the United States.

An open label study to evaluate the safety and efficacy of intratympanic golimumab therapy in patients with autoimmune inner ear disease.

Objective: To evaluate the safety and efficacy of intratympanically injected golimumab (GLM), a TNF-α inhibitor, as a steroid-sparing agent for patients with steroid-dependent autoimmune inner ear disease (AIED).

Study Design: Open label.

Setting: Tertiary referral center.

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach.