Crosslinking of fibrinogen and fibronectin by free radicals: a possible initial step in adhesion formation in osteoarthritis of the temporomandibular joint.

PURPOSE: Adhesion formation in osteoarthritis (OA) of the temporomandibular joint (TMJ) typically results in a sustained limitation of joint movement. We propose the hypothesis that free-radical-mediated crosslinking of proteins underlies this adhesion formation in affected joints. Free radicals may cause oxidative modification of proteins, creating an opportunity for the formation of intramolecular and intermolecular crosslinks via covalent bonds. This may stabilize protein aggregates, rendering them more resistant to degradation. In this study, the free-radical-mediated crosslinking of model proteins (fibrinogen and fibronectin) was investigated to test our hypothesis that free radicals contribute to adhesion formation via this mechanism in OA of the TMJ. MATERIALS AND METHODS: Physiological clot formation of fibrinogen by thrombin and free-radical-induced crosslinking of fibrinogen and of fibronectin were analyzed using spectrophotometric turbidity measurements, light-scattering techniques, polyacrylamide gel electrophoresis (PAGE), and rotary shadowing. RESULTS: Fibrinogen was shown to aggregate after free radical treatment, as detected using turbidity measurements and light-scattering techniques. Using PAGE, fibrinogen as well as fibronectin was shown to degrade under low oxidative stress. Under high oxidative stress, however, fragments from both proteins were found to be covalently crosslinked, resulting in high-molecular-weight protein aggregates. The aggregation was shown to be at random with rotary shadowing. CONCLUSION: The study shows that high oxidative stress contributes to the formation of crosslinked proteins that may serve as an initial scaffolding for the development of adhesions frequently seen in OA of the TMJ.     

Molecular Pharmacology of Topiramate: Managing Seizures and Preventing Migraine

Topiramate is a neuromodulatory compound with stabilizing properties that was initially introduced for the management of partial seizures. Topiramate has been demonstrated to modify several receptor-gated and voltage-sensitive ion channels, including voltage-activated Na⁺ and Ca²⁺ channels and non-NMDA receptors. These receptors have been implicated in the pathophysiology of both epilepsy and migraine. The pharmacological mechanisms of action for topiramate that may explain its antiepileptic and migraine preventive activities will be discussed in this review. In addition, the potential relationship between the molecular activities of topiramate and its efficacy in epilepsy and migraine prevention will be emphasized.     

Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus.

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.     

Preliminary assessment of the Dex Frame for assisting children with specific learning difficulties

A device called the Dex Frame has recently been marketed as an aid for children with specific learning difficulties. Using a test of reading speed and a test of reading accuracy we have attempted to evaluate the device. Two groups of children with learning difficulties were used, one having sole use of the device and being allowed to carry it with them and a second group who only used the device when attending for remedial tuition and assessment. The results show that no significant improvement occurred in reading performance of the groups with learning difficulties using the Dex Frame as compared with a control group. The teachers of the groups did, however, feel that on an individual basis some children (< 10%) expressed that they felt more comfortable using the device.     

Prospective assessment of biofeedback for the treatment of paradoxical puborectalis contraction

Eighteen patients with chronic constipation were diagnosed as having paradoxical puborectalis contraction (PPC) as the cause for their constipation. The diagnosis of PPC was made after office evaluation, colonic transit study, manometry, cinedefecography, and electromyography (EMG). These 18 patients had a mean duration of symptoms of 26.9 years; none of these patients had unassisted bowel movements. Fourteen patients had a mean of 4.6 laxative-induced bowel evacuations per week, and 11 patients had a mean of 4.4 enema-induced bowel evacuations per week. Patients underwent a mean of 8.9 one-hour EMG-based biofeedback sessions. At a mean follow-up of 9.1 (range, 0.5–12) months, these 18 patients had a mean of 7.3 unassisted bowel actions per week ( P <0.0001). In addition, persistent laxative use was reported by only two patients, and, in both cases, this was once a week or less ( P <0.001). Similarly, enema use was reported by only three patients, one once weekly and the other two thrice weekly ( P <0.002). No biofeedback-related complications were identified. EMG-based biofeedback is a valuable technique associated with an 89 percent success rate in the treatment of PPC.Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991.     

Changes in the human vocal tract due to aging and the acoustic correlates of speech production: a pilot study.

This investigation used a derivation of acoustic reflection (AR) technology to make cross-sectional measurements of changes due to aging in the oral and pharyngeal lumina of male and female speakers. The purpose of the study was to establish preliminary normative data for such changes and to obtain acoustic measurements of changes due to aging in the formant frequencies of selected spoken vowels and their long-term average spectra (LTAS) analysis. Thirty-eight young men and women and 38 elderly men and women were involved in the study. The oral and pharyngeal lumina of the participants were measured with AR technology, and their formant frequencies were analyzed using the Kay Elemetrics Computerized Speech Lab. The findings have delineated specific and similar patterns of aging changes in human vocal tract configurations in speakers of both genders. Namely, the oral cavity length and volume of elderly speakers increased significantly compared to their young cohorts. The total vocal tract volume of elderly speakers also showed a significant increment, whereas the total vocal tract length of elderly speakers did not differ significantly from their young cohorts. Elderly speakers of both genders also showed similar patterns of acoustic changes of speech production, that is, consistent lowering of formant frequencies (especially F1) across selected vowel productions. Although new research models are still needed to succinctly account for the speech acoustic changes of the elderly, especially for their specific patterns of human vocal tract dimensional changes, this study has innovatively applied the noninvasive and cost-effective AR technology to monitor age-related human oral and pharyngeal lumina changes that have direct consequences for speech production.     

Single dose ciprofloxacin for the eradication of pharyngeal carriage of Neisseria meningitidis

Single dose oral ciprofloxacin was given to all personnel in a naval training establishment as part of the management of an outbreak of meningococcal meningitis. Two thousand one hundred personnel received the drug and Neisseria meningitidis was eradicated from the pharynx of 97% of 570 who were swabbed two to four days later. In a cohort of 277 personnel who were followed for up to nine weeks, pharyngeal carriage was eliminated from 93% of 104 carriers. The overall prevalence of carriage fell from 19% to less than 1.5% as a result of the use of ciprofloxacin. Few side effects were encountered, compliance was good and meningococci resistant to the antibiotic were not found after therapy. A single oral dose of ciprofloxacin 500 mg eliminates pharyngeal carriage of N. meningitidis effectively and has few adverse reactions.