Strategies to improve electrode positioning and safety in cochlear implants

An injection-molded internal supporting rib has been produced to control the flexibility of silicone rubber encapsulated electrodes designed to electrically stimulate the auditory nerve in human subjects with severe to profound hearing loss. The rib molding dies, and molds for silicone rubber encapsulation of the electrode, were designed and machined using AutoCad and MasterCam software packages in a PC environment. After molding, the prototype plastic ribs were iteratively modified based on observations of the performance of the rib/silicone composite insert in a clear plastic model of the human scala tympani cavity. The rib-based electrodes were reliably inserted farther into these models, required less insertion force and were positioned closer to the target auditory neural elements than currently available cochlear implant electrodes. With further design improvements the injection-molded rib may also function to accurately support metal stimulating contacts and wire leads during assembly to significantly increase the manufacturing efficiency of these devices. This method to reliably control the mechanical properties of miniature implantable devices with multiple electrical leads may be valuable in other areas of biomedical device design.     

Factors associated with implementation of preventive care measures in patients with diabetes mellitus

BACKGROUND: There is only limited information on the extent to which physicians' characteristics affect the level of care and implementation of guidelines in patients with diabetes mellitus. OBJECTIVE: To identify physician characteristics associated with implementation of measures for preventive care in patients with diabetes mellitus and the distribution of implementation of these measures among them. PATIENTS AND METHODS: A retrospective chart audit of 519 patients eligible for health maintenance organization insurance on December 31, 1994, representing patients with diabetes receiving care from 22 primary care physician-providers of a managed care medical group in suburban North Los Angeles, Calif, and seen by physicians between January 1993 and December 1994. A short retroactive questionnaire for participating physicians was also used. The outcome measures were (1) measurement of serum high-density lipoprotein cholesterol; (2) urinalysis for the detection of proteinuria; and (3) ophthalmology referral for dilated fundus examination. RESULTS: Over a period of 2 years 78% of the patients had a high-density lipoprotein cholesterol determination, 80% had a test for proteinuria, and 62% were referred to an ophthalmologist. After adjustment for patient pool differences, physicians who were perceived by the administration of the medical group as "fast," based on a blinded evaluation of their number of patient encounters per unit time, had an odds ratio of 0.60 (95% confidence interval [CI], 0.37-0.95; P=.03) to obtain a high-density lipoprotein cholesterol determination in their patients and an odds ratio of 0.53 (95% CI, 0.32-0.87; P=.01) to test their patients for proteinuria. In patients requiring insulin, of fast physicians, the odds ratio for a referral for ophthalmology screening was 0.25 (95% CI, 0.07-0.85; P= .03). Duration of time in practice of over 15 years and disagreement with practice guidelines were associated with better outcomes. There was no association between physician sex, internal medicine training, or number of patients with diabetes in the practice and the implementation of outcomes. There was a highly significant association between the implementation of an outcome and the implementation of the other 2, resulting in a nonhomogeneous distribution of health care delivery. Physicians' estimate of their rate of implementation of outcomes, as assessed by the questionnaires, overestimated their actual performance while being in proportion with the documented rates. Most physicians took responsibility for the nonimplementation, accepting that it was an oversight on their part as opposed to an encounter with patient resistance. CONCLUSIONS: Most physicians believe that the lack of implementation of the measures for preventive care in patients with diabetes mellitus is an oversight. The oversight is more prevalent in the practices of busy physicians. The result is a nonhomogeneous distribution of health care. Computer reminders might be the solution.     

The expectation-maximization algorithm for symbol unsynchronizedsequence detection

The expectation-maximization (EM) algorithm for maximizing likelihood functions, combined with the Viterbi algorithm, is applied to the problem of sequence detection when symbol timing information is not present. Although the EM algorithm is noncausal, results obtained using the algorithm on the problem of nonsynchronized sequence detection indicate that it converges most of the time in three iterations, making it both of theoretical and of practical interest. A practical algorithm based on the EM algorithm is introduced. It reduces the computational burden and improves performance by making use of timing estimates in previous observation windows     

The guideline interchange format: a model for representing guidelines

Carboxylate and sulfate groups were introduced at the surface of poly(ethylene) (PE) samples. This was accomplished by coating and immobilizing sodium 10-undecenoate (C11(:)) and 10-undecene sulfate (S11(:)) on the polymer by means of an argon plasma treatment. The composition of the coated surfactant layer was proportional to the composition of the coating solution. The thickness of the surfactant layer on the surface of PE samples, which were precoated from an aqueous solution with a total surfactant concentration of 0.30 M, was about 55 A. The presence of carboxylate and sulfate groups after plasma treatment of the precoated surfaces was confirmed by X-ray photoelectron spectroscopy (XPS). About 20% of the initial amount of functional groups of the coated surfactants was retained at the PE surface. The ratio of carboxylate/sulfate groups at the plasma treated surfaces was dependent on the composition of the precoated surfaces. The minimum surface density of these groups on the resulting samples was about one group per 40 A2.     

Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists

A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.     

Identification and purification of diphosphoinositol pentakisphosphate kinase, which synthesizes the inositol pyrophosphate bis(diphospho)inositol tetrakisphosphate

Diphosphoinositol pentakisphosphate (PP-IP5) and bis(diphospho)inositol tetrakisphosphate (bis-PP-IP4) were recently identified as inositol phosphates which possess pyrophosphate bonds. The molecular mechanisms that regulate the cellular levels of these compounds are not yet characterized. To pursue this question, we have previously purified an inositol hexakisphosphate (IP6) kinase from rat brain supernatants [Voglmaier, S. M., et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 4305-4310]. We now report the identification and purification of another novel kinase, diphosphoinositol pentakisphosphate (PP-IP5) kinase, which uses PP-IP5 as a substrate to form bis(diphospho)inositol tetrakisphosphate (bis-PP-IP4) in soluble fractions of rat forebrain. The purified protein, a monomer of 56 kDa, displays high affinity (Km = 0.7 microM) and selectivity for PP-IP5 as a substrate. The purified enzyme also can transfer a phosphate from bis-PP-IP4 to ADP to form ATP. This ATP synthase activity is an indication of the high phosphoryl group transfer potential of bis-PP-IP4 and may represent a physiological role for PP-IP5 and bis-PP-IP4.