Validation of a quality-of-life instrument for laryngopharyngeal reflux

OBJECTIVES: To establish the reliability, validity, and responsiveness of a new, disease-specific assessment tool, the LPR-HRQL, which assesses patient-reported outcomes (PRO) with regard to health-related quality of life (HRQL) of patients with laryngopharyngeal reflux (LPR). DESIGN: A prospective, open-label, repeated-measures study. SETTING: Six centers in 4 states in the eastern United States. PATIENTS: Patients with LPR. INTERVENTIONS: Open-label treatment with 20 mg of omeprazole twice daily. Clinical and PRO HRQL data were collected. Several PRO instruments were administered to patients at each of several time points; these instruments included the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36), a general HRQL tool; the Voice Handicap Index (VHI), a symptom-specific tool for assessing voice problems; and the QOLRAD instrument (Quality of Life in Reflux and Dyspepsia), used to assess the impact of gastroesophageal reflux disease. RESULTS: Factor analyses of the LPR-HRQL scales confirmed single dimensions for each. All LPR-HRQL items contributed to internal consistency of scales and had substantial variability permitting useful information. Substantial evidence of convergent and divergent validity with SF-36, VHI, and QOLRAD items was observed. Test-retest validity was adequate for the time interval tested. Changes in domain scores of the LPR-HRQL at 4 and 6 months documented its responsiveness. CONCLUSIONS: The LPR-HRQL displays reliability, validity, and responsiveness, has face validity, and is simple and not burdensome to administer, score, and analyze. Accordingly, it may be used to assist physicians and patients in understanding the HRQL burden of LPR and the impact of therapy.     

Cephalometric comparison of adult anterior open bite treatment using clear aligners and fixed appliances

Objectives:To compare fixed appliances and clear aligner therapy in correcting anterior open bite and in controlling the vertical dimension in adult patients with hyperdivergent skeletal patterns.Materials and Methods:In this retrospective study, two treatment groups of adult (≥18 years old) hyperdivergent patients (mandibular plane angles of ≥38°) with anterior open bites were included: 17 fixed appliance patients and 36 clear aligner patients. Thirteen cephalometric measurements representing the vertical dimension were reported for each group. A two-sample t-test was used to assess differences in changes in mandibular plane angle and overbite between the two treatment groups.Results:There were no statistical differences found in the magnitude of overbite correction and the changes in any of the cephalometric measurements for vertical control. The clear aligner group showed a slightly greater amount of lower incisor extrusion (P = .009). The main mechanism of open bite correction was similar between the two treatment groups and was accomplished through retroclination of the upper and lower incisors while maintaining the vertical position of the upper and lower molars.Conclusions:Cephalometric comparison of anterior open bite correction and changes in the mandibular plane angle associated with use of clear aligners and fixed appliances did not demonstrate statistically significant differences in adult hyperdivergent patients.     

Synthesis and biological evaluation of pyrazolone analogues as potential anti-inflammatory agents targeting cyclooxygenases and 5-lipoxygenase

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) and their selectivity indices were calculated. The results showed that compounds 3f , 3h , 3l , and 3p have an excellent COX-2 selectivity index. Moreover, they showed potent 5-LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti-inflammatory activity using the carrageenan-induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX-2 and 5-LOX active sites was performed to rationalize their anti-inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual-acting COX-2/5-LOX inhibitors to be used as potent and safe anti-inflammatory agents.     

Design,synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC₅₀ values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC₅₀ value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC₅₀ values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC₅₀ values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC₅₀ values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC₅₀ = 0.8 µM). These promising derivatives, 3f , 3h , and 3j , were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.     

Microalbuminuria in hepatitis C-genotype 4:Effect of pegylated interferon and ribavirin

AIM:To study the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria and renal impairment in relation to hepatic histology, and viremia in the absence of cryoglobulinemia, and to examine the effect of treatment on microalbuminuria.METHODS: Three hundred subjects, including 233 HCV genotype-4 infected patients, were tested for cryoglobulinemia, microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine, and estimated glomerular filtration rate (eGFR). The parameters were measured...     

The AAA+ ClpX machine unfolds a keystone subunit to remodel the Mu transpososome

A hyperstable complex of the tetrameric MuA transposase with recombined DNA must be remodeled to allow subsequent DNA replication. ClpX, a AAA+ enzyme, fulfills this function by unfolding one transpososome subunit. Which MuA subunit is extracted, and how complex destabilization relates to establishment of the correct directionality (left to right) of Mu replication, is not known. Here, using altered-specificity MuA proteins/DNA sites, we demonstrate that transpososome destabilization requires preferential ClpX unfolding of either the catalytic-left or catalytic-right subunits, which make extensive intersubunit contacts in the tetramer. In contrast, ClpX recognizes the other two subunits in the tetramer much less efficiently, and their extraction does not substantially destabilize the complex. Thus, ClpX targets the most stable structural components of the complex. Left-end biased Mu replication is not, however, determined by ClpX’s intrinsic subunit preference. The specific targeting of a stabilizing “keystone subunit” within a complex for unfolding is an attractive general mechanism for remodeling by AAA+ enzymes.     

The impact of laryngopharyngeal reflux on patient-reported quality of life

OBJECTIVES/HYPOTHESIS: The objectives were to assess patient-reported outcomes, specifically, the health-related quality of life of patients with laryngopharyngeal reflux, and to compare those reported levels with the health-related quality of life of patients with gastroesophageal reflux disease and a general population. STUDY DESIGN: Prospective study. METHODS: As part of a prospective study to validate a health-related quality of life instrument for laryngopharyngeal reflux, patient-reported data were collected before the initiation of therapy. Use of the Short Form-36 (SF-36), a generic instrument, allowed the health-related quality of life of the patients with laryngopharyngeal reflux to be compared with benchmarks existing for patients with gastroesophageal reflux disease and a general U.S. population. RESULTS: The 117 patients with laryngopharyngeal reflux often reported multiple symptoms, most frequently, chronic throat-clearing (85.5%), globus (82.1%), and hoarseness (80.3%). Their mean health-related quality of life was statistically significantly worse than that of a general U.S. population in seven of the eight SF-36 domains. The most dramatic differences between patients with laryngopharyngeal reflux and the general population were in social functioning and bodily pain (P <.001). Mean scores for patients with laryngopharyngeal reflux were significantly lower than those for patients with gastroesophageal reflux disease in social functioning (P <.001) and vitality (P =.0017). In five of the six remaining domains, patients with laryngopharyngeal reflux reported lower mean scores than did patients with gastroesophageal reflux disease, but those differences were not statistically significant. CONCLUSION: The study's assessment of health-related quality of life suggests that laryngopharyngeal reflux has a significant negative impact on the lives of patients. Although its impact is similar in some respects to that of gastroesophageal reflux disease, laryngopharyngeal reflux has a more significant impact on patients' social functioning and vitality.