Doxorubicin delivery into tumor cells with ultrasound and microbubbles.

Doxorubicin is a potent chemotherapeutic whose severe side effects limit its application. Drug-targeted delivery with noninvasive techniques is required to increase the drug concentration locally and to reduce systemic side effects. Microbubble-assisted ultrasound has become a promising strategy for noninvasive local drug delivery. The aim of this study is to evaluate the applicability and the effectiveness of administration of doxorubicin combined with microbubble-assisted ultrasound in human U-87MG glioblastoma and MDA-MB-231 breast cancer cells. In the present study, the doxorubicin delivery aided by microbubble-assisted ultrasound enhanced the death of breast cancer and glioblastoma cells, including the induction of apoptosis. Various microbubbles were evaluated including Vevo Micromarker, BR14, SonoVue and experimental polymer shelled microbubbles. The results showed that Vevo Micromarker microbubble-assisted ultrasound could induce an enhancement of doxorubicin in glioblastoma and breast cancer cell death. Polylactide-Shelled PEG and Vevo Micromarker microbubbles were the best microbubbles for efficient doxorubicin delivery in the U-87 MG and MDA-MB-231 cells, respectively. Moreover, the induction of apoptosis by doxorubicin and Vevo Micromarker microbubble-assisted ultrasound was examined and results showed a positive increment for acoustic pressures above 600 kPa. The conclusions drawn from in vitro study show the potential of this strategy for an in vivo application.

Tertatolol in hypertension. Long-term therapy in 2,338 patients.

Tertatolol has been studied in 2,338 patients with mild to moderate hypertension over a one year period. Tertatolol (T) was initiated alone (5 mg once daily) and if satisfactory control of blood pressure (BP) (diastolic BP less than 95 mm Hg) was not achieved, treatment was adapted at the third or sixth month either by increasing the dosage (heart rate greater than 70 beats/min), or by adding a potassium-sparing diuretic (heart rate less than or equal to 70 beats/min). Blood pressure normalization was achieved in 88.8% of the study population: 66.1% on single and 22.7% on dual therapy. The decrease of diastolic BP was 18.4 mm Hg (from 102.8 +/- 0.2 to 84.4 +/- 0.2 mm Hg, P less than .001). Tertatolol alone or associated with diuretic (T + D) induced a significant and continuous decrease in supine systolic and diastolic BP. Overall side effects were rare, leading in only 6.5% of the cases to the discontinuation of the drug. Plasma creatinine significantly decreased in the single therapy group only (from 92.2 +/- 0.5 to 90.1 +/- 0.5 mumol/L, P less than .01). In patients with initial plasma creatinine greater than or equal to 100 mumol/L (n = 661), plasma creatinine markedly decreased (-10%, from 114.6 +/- 0.7 to 103.4 +/- 0.8 mumol/L, P less than .01), and to the same extent with T or T + D. Thus, this large-scale study confirms that tertatolol is an efficient and well-tolerated antihypertensive drug, which improves renal function, especially when initially reduced.

Monoclonal antibodies against progesterone: effect of steroid-carrier coupling position on antibody specificity.

Monoclonal anti-progesterone antibodies were raised by immunizing mice with progesterone coupled through either the C3, C6 or C11 positions to protein carrier (bovine serum albumin, BSA). The specificity of four antibodies for a range of steroids related to progesterone, some carrying substitutions at various ring positions, was studied by competitive inhibition in an ELISA system. The results demonstrated that the ring coupling position has a determining effect on the cross-reactivity of the antibodies obtained. The patterns of cross-reaction were interpreted in the light of the structure of the combining site of an anti-progesterone antibody (DB3) recently determined by X-ray crystallography, and inferences drawn about the orientation of steroid in the combining sites of the antibodies studied. Specifically, in two antibodies raised against progesterone-11-BSA, the orientation of steroid resembled that of the progesterone-DB3 complex, with positions C11 and C3 exposed and C6 and C20 buried; an antibody raised against progesterone-6-BSA bound steroid in an apparently similar disposition, except that C6 was exposed and C11 buried; finally, in an antibody raised against progesterone-3-BSA, all steroid positions other than C3 were apparently buried in the steroid-antibody complex.

Influence of communication mode on speech intelligibility and syntactic structure of sentences in profoundly hearing impaired French children implanted between 5 and 9 years of age.

OBJECTIVE: The purpose of this study was to examine the speech production in French profoundly hearing impaired children, focusing on word intelligibility, sentences syntax, and sentence pattern stages, by incorporating direct comparisons between speech production skills and communication modes in the same children. DESIGN: The design of the study incorporated a within-subject, repeated measures design for assessing speech production intelligibility and syntax. SETTING: Montpellier Pediatric Cochlear Implant Center. SUBJECTS: Twelve prelingually deafened French children who received a Nucleus multichannel cochlear implant (mean age at the time of implantation was 7 years 2 months) served as subjects for the speech production assessment. MAIN OUTCOME MEASURES: Speech production intelligibility, syntax, and sentence pattern stages were assessed at 1, 2 and 3 years postimplant. Speech production skills were related to the communication mode of the children (auditory-oral, four children; cued-speech, four children; sign-language, four children). RESULTS: Scores on word intelligibility steadily improved with increased experience with the implant, ranging from 18% before implantation to 54.5% at 36 months postimplantation in the overall population. The highest scores were found in the cued-speech group with an averaged score of 66.8% at 36 months postimplant. The number of syntactic elements increased over time with implant experience. Children receiving cued-speech education had higher scores by 3 years postimplantation than children receiving either auditory-oral or sign-language modes of communication. Language level (sentence pattern stages) also improved with increased experience with the device. By 3 years postimplantation, children receiving auditory-oral or cued-speech instruction were able to produce sentences; however, the sign-language children failed to do so at a rate comparable to the other children. Language level was significantly higher in the oralist or cued-speech educated children than in the sign-language group. CONCLUSIONS: Speech production skills improved with increased experience using a cochlear implant. Word intelligibility, syntactic structure of sentences, sentence pattern stages improved gradually over time. Production skills were greater in the cued-speech educated children group than in the auditory oral or sign-language groups. Statistically better sentence pattern stages were found in the auditory oral and sign-language groups.

Functional maturation of the medial efferent olivocochlear system in human neonates.

The effect of contralateral acoustic stimulation on transient evoked otoacoustic emissions (TEOAE) was used to investigate the functional maturity of the medial efferent olivocochlear system in full term neonates and a 6-week-old baby. The technique used was to record the TEOAE alternately with and without contralateral noise. The result was a reduction in TEOAE amplitude and latency. This was best illustrated with a difference waveform obtained from the subtraction of the TEOAE waveform recorded with contralateral noise, from the waveform recorded without contralateral noise. All the full term neonates and also the 6-week-old baby showed significant effects indicating functional maturity of the medial olivocochlear system.

High-frequency vestibulo-ocular reflex activation through forced head rotation in man.

The dynamic characteristics of the human vestibulo-ocular system were studied in the 0.5-30 Hz frequency range by rotating the head around a vertical axis. The rotation produced by a powerful servo-controlled vibrator was transmitted to the head by a hard-cushioned helmet and a rigid bite bar. The vestibulo-ocular reflex (VOR) gain and phase were measured during fixation of a mobile or stationary visual target and in total darkness. In a second set of experiments, the subjects evaluated the amplitude of the perceived visual instability of the target in the two fixation conditions. The results confirm earlier observations describing the VOR gain and phase in the 0.5-8 Hz range: the gain starts to decrease beyond 2 Hz and the phase rises towards 90 degrees. Beyond 8 Hz, the gain curve reverses direction and increases continuously toward 3-4 at 25-30 Hz in the three tested situations. Meanwhile, the phase curves do not vary much. In the same frequency range, the perceived visual instability is significantly altered. Therefore, the gain variation at high frequency may, in part, explain the perceived visual target instability and may be suspected of altering visually controlled tracking executed in vibrating environments.

Kinetics of metapramine and its demethylated metabolites after single and chronic oral administration in man.

The kinetics of metapramine and two of its demethylated metabolites were determined in six normal subjects after oral administration of a single 150 mg dose on day 1 and 3 X 50 mg dose on day 2-6. This study has shown that three demethylated metabolites are found in plasma beside metapramine. The monodemethylated metabolite I appeared to be the predominant one and the mean area under the plasma concentration curve (AUCo24) was 49% of the metapramine value. Its half-life was shorter (5.92 h) than that of metapramine (8.29 h). The kinetic profiles of metapramine and its major metabolites I and II were similar and data over 24 h could be fitted by a tri-exponential equation even though entero-hepatic cycles were observed. A high interindividual variability of data was found for both metapramine and its metabolites. There were no significant differences between men and women. The minimal plasma level (Cmin) seemed in agreement with the half-life of the drug.

Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man.

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found. First, the extent of bioavailability was identical for the two formulations but the rate of bioavailability seemed to be different, with the p.o. solution, being more rapidly absorbed (tmax = 1.50 h). The effect of administration time was more obvious for the solution as shown by a lower quantitative absorption as well as a delay in time to reach the maximal concentration. Regardless of formulation and administration time, the t1/2 beta was about 10 hours and the mean MRT value was 11 hours.

[Development and training of monocular motor control]. / Développement et apprentissage du contrôle moteur monoculaire.

Misalignment of the visual axes of the eyes observed in strabismus may result from sensory, motor, and/or central nervous system disorders. The functional properties of a technique designed to increase, through training, the monocular motor control of normal human subjects was evaluated, the ultimate goal being obviously to apply the technique to cases of minor strabismus. The subject is seated in front of a television screen. A diaphragm extending from the subject's head to the screen divides the picture into two visually separated half fields. A micro-computer was programmed to project two patterns on the screen, made up of vertical green and grey bars (spatial frequency, 3 deg.). Displacement of the two visually superposable half fields could be independently achieved. The subject's task was to fixate, with one eye, the corresponding half field maintained stationary and track, with the other eye, the motion of the second half field. Perfect fusion of the two half fields has to be preserved during movements of the mobile half field over 2 to 6 degrees at a frequency of 0.4 Hz. The results show that after a few training sessions, subjects developed a high gain monocular motor control. This observation suggests that the method may be used as therapy to correct minor strabismus with or without anomalous retinal correspondence, and offers the possibility to study static and dynamic characteristics of Panum's areas and particularly their modifications as a function of training of monocular motor control.

[Pediatric cochlear implants]. / Les implants cochléaires pédiatriques.

Indications for cochlear implants have been widened since 1995. Most implant candidates are children with severe congenital deafness. The cochlear implant must be inserted as early as possible for these children in order to optimize development of perception and language. A cochlear implant can also be discussed in certain particular cases for children with associated diseases, malformation of the inner ear, or severe deafness. The educational project must be realistic and take into account the future difficulties as well as an established set of criteria for successful language acquisition.

[The test for the evaluation speech perception and production]. / Test d'évaluation des perceptions et productions de la parole.

The aim of this paper is to present a Test to evaluate the speech perception and production in french profoundly hearing impaired children fitted with cochlear implant or traditional hearing aids. This test materials have been developed for children from 2 to 10 years old. This test fall into two basic categories known as speech perception and speech production. The assessment of the perceptual abilities through the use of the TEPPP is achieved across the hierarchy of perception which spans: detection, discrimination, identification, comprehension. The assessment of the speech production makes it possible to observe the speech production changes across three levels: phonetical, linguistical, intelligibility. The TEPPP, Test of Speech Perception and Production evaluation, enable us to observe if children, who receive a cochlear implant or a conventional hearing aids, obtain some degree of benefit in both speech perception and speech production.

Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-D-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold.

The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

Normative findings of electrically evoked compound action potential measurements using the neural response telemetry of the Nucleus CI24M cochlear implant system.

One hundred and forty-seven adult recipients of the Nucleus 24 cochlear implant system, from 13 different European countries, were tested using neural response telemetry to measure the electrically evoked compound action potential (ECAP), according to a standardised postoperative measurement procedure. Recordings were obtained in 96% of these subjects with this standardised procedure. The group results are presented in terms of peak amplitude and latency, slope of the amplitude growth function and ECAP threshold. The effects of aetiological factors and the duration of deafness on the ECAP were also studied. While large intersubject variability and intrasubject variability (across electrodes) were found, results fell within a consistent pattern and a normative range of peak amplitudes and latencies was established. The aetiological factors had little effect on the ECAP characteristics. However, age affected ECAP amplitude and slope of the amplitude growth function significantly; i.e., the amplitude is higher in the lowest age category (15-30 years). Principal component analysis of the ECAP thresholds shows that the thresholds across 5 electrodes can be described by two factors accounting for 92% of the total variance. The two factors represent the overall level of the threshold profiles ('shift') and their slopes across the electrode array ('tilt'). Correlation between these two factors and the same factors describing the T- and C-levels appeared to be moderate, in the range of 0.5-0.6.

Evoked otoacoustic emissions from normal newborns and babies admitted to an intensive care baby unit.

Click-evoked otoacoustic emissions (OAEs) were recorded from both ears in two groups of neonates ranging in age from a few days to two months after birth. The first group consisted of 55 full-term neonates with normal developmental history and health status, including absence of middle ear disease and familial history of hearing loss. The second group consisted of 40 infants admitted to an intensive care baby unit for various pathological conditions (anoxia, prematurity, hyperbilirubinemia, meningitis). The method achieved 97% success in assessing cochlear function in the normal group; it was possible to identify a clear and reproducible response in all ears, except 3, at 70 dB SPL (i.e. approximately 30 dB nHL). The detection-threshold of OAEs was comparable to that measured in adult ears. Several babies from the second group produced no OAEs and were also tested by auditory brainstem responses (ABR): these infants demonstrated ABR thresholds higher than 30 dB nHL. OAEs provide an objective tool for a rapid and effective screening test for cochlear impairment in neonates.

A correlative study of evoked otoacoustic emission properties and audiometric thresholds.

Correlations were made between the detection thresholds of evoked otoacoustic emissions (EOAEs), subjective click thresholds, and mean audiometric thresholds in 240 normal and hearing-impaired ears. EOAEs have never been observed when subjective click thresholds or mean audiometric thresholds were equal to or greater than 35 dB HL. EOAEs were always found when click thresholds were equal to or lower than 15 dB HL and when mean audiometric thresholds were equal to or lower than 22 dB HL. The incidence of EOAEs decreased and EOAE thresholds increased with increasing click or mean audiometric thresholds.

Speech-perception performance in prelingually deafened French children using the nucleus multichannel cochlear implant.

PURPOSE: The speech-perception abilities of 36 French children, whose onset of deafness occurred before 2 years of age, was longitudinally examined after they received a Nucleus multichannel cochlear implant. METHODS: Speech perception was assessed in four areas: phoneme detection, closed-set word and sentence recognition; and modified open-set recognition. RESULTS: All children achieved phoneme detection by 3 months after implantation. Closed-set word and sentence recognition appeared initially less accurate in children with congenital deafness than in the prelingually deafened children; however, these differences disappeared by 18 months after implantation. Some modified open-set recognition was evident by 12 months after implantation and continued to improve 3 years after implantation. CONCLUSIONS: Data demonstrate significant improvements in speech perception with implant experience: 15 (60%) of 25 of the children identified sentences in closed sets, 22 (88%) of 25 identified words in closed sets after 12 months' experience, and 13 (81%) of 16 demonstrated open-set recognition after 24 months of implant use.