Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

Thermally induced shrinkage of joint capsule.

Thermal shrinkage of collagen currently is being used in orthopaedic surgery to treat ligamentous laxity. Understanding the kinetics of collagen shrinkage is key to revealing the events that take place during application of thermal energy. To elucidate the thermokinetic properties of collagen, punch biopsies of bovine joint capsule were immersed in a heated saline bath at temperatures between 20 degrees and 90 degrees C for periods up to 60 minutes. The resulting tissue thermal shrinkage was measured by the change in the cross-sectional area of the specimens. Only a small amount of shrinkage occurred at temperatures below 63 degrees C, and increasing amounts and rates of shrinkage were seen at temperatures between 63 degrees and 72 degrees C. The denaturation kinetics of bovine knee collagen, which could be described by a first order reaction rate, had an activation energy of 2.3 x 10(5) kJ/mol.

Limiting spectral resolution in speech for listeners with sensorineural hearing loss.

Consonant recognition was measured as a function of the degree of spectral resolution of the speech stimulus in normally hearing listeners and listeners with moderate sensorineural hearing loss. Previous work (Turner, Souza, and Forget, 1995) has shown that listeners with sensorineural hearing loss could recognize consonants as well as listeners with normal hearing when speech was processed to have only one channel of spectral resolution. The hypothesis tested in the present experiment was that when speech was limited to a small number of spectral channels, both normally hearing and hearing-impaired listeners would continue to perform similarly. As the stimuli were presented with finer degrees of spectral resolution, and the poorer-than-normal spectral resolving abilities of the hearing-impaired listeners became a limiting factor, one would predict that the performance of the hearing-impaired listeners would then become poorer than the normally hearing listeners. Previous research on the frequency-resolution abilities of listeners with mild-to-moderate hearing loss suggests that these listeners have critical bandwidths three to four times larger than do listeners with normal hearing. In the present experiment, speech stimuli were processed to have 1, 2, 4, or 8 channels of spectral information. Results for the 1-channel speech condition were consistent with the previous study in that both groups of listeners performed similarly. However, the hearing-impaired listeners performed more poorly than the normally hearing listeners for all other conditions, including the 2-channel speech condition. These results would appear to contradict the original hypothesis, in that listeners with moderate sensorineural hearing loss would be expected to have at least 2 channels of frequency resolution. One possibility is that the frequency resolution of hearing-impaired listeners may be much poorer than previously estimated; however, a subsequent filtered speech experiment did not support this explanation. The present results do indicate that although listeners with hearing loss are able to use the temporal-envelope information of a single channel in a normal fashion, when given the opportunity to combine information across more than one channel, they show deficient performance.

Syntheses of some polyunsaturated sulfur- and oxygen-containing fatty acids related to eicosapentaenoic and docosahexaenoic acids.

With the aim of enhancing selectively the beneficial biological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) a number of polyunsaturated fatty acids containing sulfur or oxygen atoms in the chain has been synthesized starting from EPA and DHA, respectively. Oxidative degradation of these acids led to the corresponding aldehydes all-(Z)-3,6,9,12-pentadecatetraenal and all-(Z)-3,6,9,12,15-octadecapentaenal. Reactions with DBU converted these aldehydes quantitatively into the conjugated isomers (2E,6Z,9Z,12Z)-pentadecatetraenal and (2E,6Z,9Z,12Z,15Z)-octadecapentaenal, respectively. The four aldehydes were transformed by a sequence of reactions comprising reduction to the alcohols, halogenation and substitution with mercapto esters into the corresponding sulfur containing polyunsaturated fatty acid esters. The oxygen containing esters were prepared from the respective alcohol by boron trifluoride catalysed reaction with ethyl diazoacetate.

A comparison of language achievement in children with cochlear implants and children using hearing aids.

English language achievement of 29 prelingually deaf children with 3 or more years of cochlear implant (CI) experience was compared to the achievement levels of prelingually deaf children who did not have such CI experience. Language achievement was measured by the Rhode Island Test of Language Structure (RITLS), a measure of signed and spoken sentence comprehension, and the Index of Productive Syntax (IPSyn), a measure of expressive (signed and spoken) English grammar. When the CI users were compared with their deaf age mates who contributed to the norms of the RITLS, it was found that CI users achieved significantly better scores. Likewise, we found that CI users performed better than 29 deaf children who used hearing aids (HAs) with respect to English grammar achievement as indexed by the IPSyn. Additionally, we found that chronological age highly correlated with IPSyn levels only among the non-CI users, whereas length of CI experience was significantly correlated with IPSyn scores for CI users. Finally, clear differences between those with and without CI experience were found by 2 years of post-implant experience. These data provide evidence that children who receive CIs benefit in the form of improved English language comprehension and production.

Q-switched neodymium:yttrium-aluminum-garnet laser treatment of lentigo maligna.

Lentigo maligna is a premalignant lesion of atypical melanocytes that typically arises on the head and neck of elderly patients. It is considered a melanoma in situ with a significant risk for transformation to invasive lentigo maligna melanoma. Surgery is the preferred method of treatment; however, because of the advanced age of the typical patient with lentigo maligna, the frequency of complicating medical problems, and the cosmetic or functional aspects of treatment, surgical excision is not always feasible. The purpose of this pilot study was to evaluate the efficacy and safety of Q-switched neodymium:yttrium-aluminum-garnet laser treatment of lentigo maligna. Eight patients were treated with 532 and/or 1064 nm wavelengths from the laser. All patients showed a response to laser therapy, and 2 patients treated with 1 treatment from each wavelength had complete eradication of the LM, with no evidence of recurrence in 42 months. Further study is warranted, but Q-switched neodymium:yttrium-aluminum-garnet laser is a promising alternative treatment for lentigo maligna.

Flash pump dye laser treatment of laryngeal papillomas.

To evaluate the feasibility and safety of the flash pump dye (FPD) laser for the treatment of laryngeal papillomas, we performed a prospective nonrandomized trial comparing FPD and carbon dioxide (CO2) laser treatment of laryngeal papillomas in a tertiary care children's hospital. Nine patients from 2 to 20 years of age with severe recurrent laryngeal papillomas were enrolled in the study. All patients underwent CO2 laser debulking of papillomas on the left hemilarynx, with 8 W continuous or pulsed energy. The right hemilarynx was treated with the FPD laser with 12 to 77 pulses at 8 to 12 J, through a custom-designed 90 degrees firing fiber. An end point of blanching and purpura of the papillomas was used. The main outcome measures were the safety and ease of operation with the FPD laser, and decreased papilloma size based on visual inspection at 2 weeks postoperative and at the next laser procedure. Seven patients were irradiated I time with an FPD laser, and 2 patients 2 times. No intraoperative complications were noted. One patient developed early postoperative stridor. No patients described more discomfort, and 5 patients described their voice as being the same as or better than it was after prior CO2 laser procedures. Five patients had a 90% or more decrease in size of papillomas on the FPD-irradiated side 2 weeks postoperatively. Three patients had approximately a 50% reduction. A treatment effect was noted in all patients, and was similar to the results noted on the CO2 laser-treated side. Early results with FPD laser treatment of laryngeal papillomas suggest the protocol is relatively safe and feasible. Long-term results are pending. Because the FPD laser coagulates rather than vaporizing tissue, potential advantages may include decreased scarring relative to CO2 laser treatment, and improved patient and operator safety.

Alpha- and beta- alkyl-substituted eicosapentaenoic acids: incorporation into phospholipids and effects on prostaglandin H synthase and 5-lipoxygenase.

Alpha-ethyl-, alpha-methyl- and beta-methyl eicosapentaenoic acid (EPA) were prepared and their incorporation into cell lipids and effects on eicosanoid synthesis compared with EPA and docosahexaenoic acid (DHA). alpha- and beta-methyl EPA were incorporated into hepatocyte triacylglycerols as efficiently as EPA, whereas lesser amounts were found in phospholipids. alpha-ethyl EPA was not incorporated into phospholipids but small amounts were detected in triacylglycerol. All derivatives inhibited the synthesis of arachidonic acid, although less efficiently than EPA and DHA. The derivatives were poor substrates of prostaglandin H (PGH) synthase and 5-lipoxygenase, and they all inactivated PGH synthase. In isolated platelets, alpha-methyl EPA was a stronger inhibitor of TxB2 production than EPA, alpha-ethyl- and beta-methyl EPA. All derivatives were stronger inducers of peroxisomal beta-oxidation than EPA and DHA. This increased induction probably is a consequence of the blocked mitochondrial beta-oxidation of the derivatives.

Effect of glycine on DNA structural transitions induced by multivalent cationic compounds.

We have investigated the effect of glycine (an organic osmolyte) on several DNA transitions induced by Tb3+, spermidine3+ and spermine4+ addition, using light scattering, circular dichroism, UV spectroscopy and electric linear dichroism techniques. DNA condensation and B-Z transition by the three compounds is perturbed by glycine: more Tb3+, spermidine3+ and spermine4+ must be added to obtain the same extent of condensation or Z-form as compared to the behaviour in the absence of this organic osmolyte. However, according to the light scattering experiments, glycine has also a structural effect on the DNA condensation that could be explained by an influence of the medium dielectric constant on the morphology of particles formed or on the rate of the condensation process. Contrary to these transitions, the particular B-B'-psi transition resulting from the addition of Tb3+ to a DNA solution is not observed in the presence of glycine. Since the chelation of Tb3+ by the phosphate group and the N-7 of guanine is presumably responsible for this transition, the glycine effect could probably be explained by a perturbation of this chelation by the change in solvent polarity and the chelating ability of the organic osmolyte.

An erbium:YAG laser to obtain capillary blood samples without a needle for point-of-care laboratory testing.

BACKGROUND: Needlestick injury poses an occupational hazard to health care workers that will increase with the increasing availability of point-of-care testing using capillary blood obtained with a lancet. OBJECTIVES: To demonstrate the safety and efficacy of a portable pulsed erbium:yttrium-aluminum-garnet (Er:YAG) laser in obtaining a blood sample from patients in a clinical setting and to determine whether the laser radiant energy alters the level of various components of blood, resulting in misleading laboratory results. DESIGN: Comparison of laboratory values of blood samples obtained with the laser and conventional lancet and comparison of patient and user preferences by questionnaire. PATIENTS AND METHODS: One hundred patients with diabetes mellitus attending a diabetes clinic were randomized to have capillary blood sampling from the fingertip performed either by the laser or a conventional lancet first, then with the other device. MAIN OUTCOME MEASURES: A comparison of pain, healing, hematocrit, and glycosylated hemoglobin (HbAlc), blood urea nitrogen, sodium, potassium, bicarbonate, and glucose levels. RESULTS: Adequate blood was obtained with both devices 97% of the time. Blood flow was greater with the laser perforation, resulting in higher operator preference. Although patients felt greater pain and experienced slower healing with the laser, these were not serious problems. Modification of the laser energy output led to a reduction in pain. Possibly owing to hemolysis, the potassium level in the blood obtained with the laser was significantly elevated and unsuitable for clinical decision making in many cases. None of the other measurements were similarly affected. CONCLUSIONS: We conclude that the laser device has the potential to obtain a blood sample for routine tests without a needle. This needle-free method will decrease the risk of bloodborne infections caused by needlestick injuries and thus lead to considerable cost savings and public health advantages. Further work is needed to alter the laser energy so that hemolysis can be decreased, thus enabling a more reliable potassium estimation.

Effects of compensatory solutes on DNA and chromatin structural organization in solution.

We investigated the effect of glycine and other osmotic effectors on DNA and chromatin precipitation by mono-, di- and multivalent cations and histone H1. The addition of these compounds drastically reduces the precipitation effects with an efficiency in the order taurine > glycine > proline and sorbitol > inositol > betaine. Aminocarboxylic acids with increasing distance between the charged C- and N-terminal groups displayed enhanced efficiency in the protection effect against DNA precipitation. We interpreted these observations on the basis of Manning's counterion condensation theory, taking into account the increase in dielectric constant upon osmotic effector addition. 23Na-NMR was used to evidence sodium counterions release as a result of this increase in dielectric constant.

Port-wine stains. An assessment of 5 years of treatment.

OBJECTIVE: To assess objectively the results of flashlamp-pumped dye laser treatment of port-wine stains (PWS). DESIGN: Pretreatment and posttreatment photographs were compared with the appearance of the lesion at follow-up examination. Clinical response was determined by assigning a percentage of lesional lightening score by 2 physicians and the patient, and by reflectance spectrophotometric measurements. SETTING: University and university-affiliated health center. PATIENTS: One hundred two patients (118 PWS) aged 1 month to 66 years (mean, 20 years; median, 16 years) treated from July 1, 1989, to June 30, 1994. RESULTS: Eighteen (15.3%) of the 118 PWS had more than 90% lesional lightening (complete or almost complete response), 77 (65.3%) had lightening from 50% to 90% (good response), 21 (17.8%) had lightening from 11% to 49% (poor response), and 2 (1.7%) had lightening less than 10% (no response). Clinical response did not vary among age groups, but showed statistically significant differences between anatomical locations. A return of PWS after initial response was observed in patients who were seen more than 1 year following completion of treatment. CONCLUSIONS: Treatment of PWS by flashlamp-pumped dye laser results in a good to complete response in most patients. Anatomical location of the lesion is a valuable prognostic indicator of response to treatment. The initially impressive results of flashlamp-pumped dye laser treatment of PWS may be tempered by the gradual return of the vascular lesion as time elapses after completion of therapy. Our experience indicates that PWS show a tendency to recur at a rate approaching 50% between 3 and 4 years after completion of treatment.

23Na NMR study of the effect of organic osmolytes on DNA counterion atmosphere.

The effect of different organic osmolytes on the DNA counterion condensation layer has been investigated by 23Na NMR relaxation measurements. The zwitterionic compounds glycine, beta-alanine, 4-aminobutyric acid, and 6-aminocaproic acid have shown an increasing capacity to decrease the amount of sodium ions in the vicinity of the macromolecule. The experimental data have been correlated with the dielectric constant increase in their corresponding solutions and have been compared with the prediction of counterion condensation theory. Polyols (sorbitol and mannitol) did not display the same effect. These compounds largely increase the relaxation rate of sodium ions in the proximity of DNA, unlike the zwitterionic compounds. This probably results from a perturbation of the water dynamic around the macromolecule, of the primary or secondary hydration shell of the sodium nuclei involved, or both.

Efficacy of corneal eye shields in protecting patients' eyes from laser irradiation.

BACKGROUND: The continuing development of new types and applications of lasers has appeared to surpass the development of specific eye protection for these lasers. There are a variety of eye shields on the market, but few are specifically designed for laser protection. OBJECTIVE: Our purpose was to test a variety of eye shields by two parameters, light transmission and temperature rise, and to determine from these measurements the most protective shield for patients. METHODS: We tested four plastic shields, one metal shield, and two sets of tanning goggles for temperature rise and light transmission when irradiated with a beam from a flashlamp-pumped, pulsed-dye laser. RESULTS: The temperature rise at the surface of the shield opposite the laser impacts was no more than 0.2 degree C in any case. White light was transmitted at significant levels through several of the shields, but yellow light transmittance was noted only through the green eye shield. CONCLUSION: Our measurements indicate that all except the green shield appeared safe from transmission of the 585-nm radiant energy. However, the optimal laser eye shield, in our opinion, would be a composite of several different shields' characteristics.

Dielectric constant and ionic strength effects on DNA precipitation.

We have investigated the effect of different zwitterionic compounds on DNA precipitation induced by spermine4+. Glycine, beta-alanine, 4-aminobutyric acid, and 6-aminocaproic acid have shown an increasing capacity to attenuate DNA precipitation. This protection effect has been correlated with the dielectric constant increase of their corresponding solutions. Calculations based on these experimental data and counter-ion condensation theory have confirmed the importance of this parameter for DNA-ion interactions and precipitation mechanisms. We have also observed a resolubilization of DNA in the presence of 6-aminocaproic acid at high spermine4+ concentration and in the presence of glycine at high spermidine3+ concentration. This could be explained by an increase of screening effect with polyamine concentration.

Polyelectrolyte counterion condensation theory explains differential scanning calorimetry studies of salt-induced condensation of chicken erythrocyte chromatin.

The salt-induced chromatin condensation in chicken erythrocyte nuclei is studied by differential scanning calorimetry (DSC). The degree of chromatin condensation is measured for condensation induced by monovalent, divalent, trivalent, or tetravalent cations and by a mixture of sodium and magnesium. These last two cations show an evident competition effect. Salt-induced chromatin condensation is shown to be an entropy-driven process. A simple model of chromatin based on the polyelectrolyte counterion condensation theory is used in order to compute the charge neutralized by the cations in each chromatin domain. The degree of chromatin condensation is shown to be related to the weighed sum of the square of the phosphate charge of each domain. The model predicts the salt and the chromatin concentration dependence of the condensation and the effect of H1 removal.

Construction of a vein-pouch aneurysm at a surgically created carotid bifurcation in the rat.

Currently available animal models for the study of treatment of aneurysms are either expensive or yield unreliable results. An animal series was devised to address both of these problems by creating a new animal model. Twelve Sprague-Dawley rats were used to demonstrate that a vein-pouch aneurysm could be constructed at a surgically created carotid bifurcation. Patency rates, growth dynamics, and histologic morphology were studied at three time intervals. A 100% patency rate at the aneurysm orifice was achieved with one-third of the aneurysms showing varying degrees of partial apical thrombosis. A growth pattern was established over the study period. Magnetic resonance angiography and digital subtraction angiography were successfully employed to study a small number of additional aneurysms. Our conclusion is that a bifurcation aneurysm can be constructed in the rat with high patency rates and predictable saccular morphology which resembles most human intracranial aneurysms. This inexpensive animal model can be used to study novel modalities for the treatment of aneurysms.

Diffusion-enhanced resonance energy transfer shows that linker-DNA accessibility decreases during salt-induced chromatin condensation.

Accessibility of linker-DNA chromatin during salt-induced condensation of chicken erythrocytes chromatin was studied by diffusion-enhanced resonance energy transfer. A terbium complex was covalently bound to linker-DNA and fluorescein molecules bound to latex particles with diameters ranging from 14 to 2470 nm were used as acceptor. The accessibility of linker-DNA to molecules with a diameter superior to 14 nm diminished during condensation, but for an acceptor diameter of 14 nm or less, no accessibility variation was observed. It can be concluded that (1) linker-DNA is located inside the fiber when chromatin is in the condensed state, (2) chromatin condensation can prevent the approach to DNA due to steric hindrance, (3) salt-induced chromatin condensation is a gradual process, and (4) condensed chromatin models containing a central cavity are more likely.

Osmotic effectors and DNA structure: effect of glycine on precipitation of DNA by multivalent cations.

We have investigated the effect of glycine (an organic osmolyte) on DNA precipitation induced by spermine4+, spermidine3+ and Tb3+ addition, using circular dichroism (CD), UV spectroscopy (UV), and electric linear dichroism (ELD) techniques. DNA precipitation by the three compounds is perturbed by glycine: more spermine4+, spermidine3+ and Tb3+ must be added to obtain the same extent of precipitation as compared to the behaviour in absence of this organic osmolyte. It seems that glycine has a general effect on the DNA environment. Calculations based on experimental results and Manning's counterion condensation theory show that glycine could modify the electrostatic environment of DNA as a consequence of a change in dielectric constant.