Antineoplastic busulfan encapsulated in a metal organic framework nanocarrier: first in vivo results.

Nanoparticles of a mesoporous iron(iii) trimesate MIL-100 nanocarrier encapsulating high amounts of the challenging antineoplastic busulfan were administered to rats and compared with the commercial Busilvex®. Large differences in serum concentration of both busulfan and trimesate revealed the great impact of drug encapsulation both on the drug and on nanoparticle pharmacokinetics during the first 24 h of administration.

Roles of extracellular and cytoplasmic domains of the prolactin receptor in signal transduction to milk protein genes.

We have previously shown that the long form of the PRL receptor is able to activate milk protein gene transcription. In the present study, we have determined the respective contribution of the extracellular and the intracellular domains of this receptor to transcriptional activation of a milk protein gene by PRL. The membrane-anchored intracellular domain (pTMI) expressed alone was devoid of PRL binding activity, as expected, and did not constitutively stimulate expression of the target gene. The extracellular domain (pE), expressed alone as a soluble receptor form, binds PRL with 10-fold higher affinity than the full-length membrane receptor. This form was also unable to stimulate the expression of the reporter gene. However, expression of both mutants (pE + pTMI) in the same cell partially restored the ability of PRL to activate the beta-lactoglobulin promoter. Replacement of cysteine 184 by a serine in the extracellular domain of the receptor impairs this restoration of the biological response. However, introduction of the same mutation in the full-length receptor did not affect its functional activity. These results indicate that the membrane-anchored cytoplasmic domain of the PRL receptor has no constitutive activity, and that coexpression of individual extracellular and intracellular domains leads to restoration of receptor function. We propose that restoration may be the result of reconstitution of the holoreceptor through disulfide bonding, or it may be the result of interaction of the extracellular region with an external transducing molecule.

The Nb2 form of prolactin receptor is able to activate a milk protein gene promoter.

We have recently cloned a cDNA encoding a mutant form of PRL receptor (PRL-R) from Nb2 cells, a PRL-dependent T lymphocyte-derived cell line. This cDNA is identical to the long form of the rat PRL-R, except for a deletion of 594 base pairs in the cytoplasmic domain, resulting in a mature receptor protein of 393 amino acids. Although a segment containing three cytoplasmic regions of moderate to high amino acid sequence identity with members of the PRL/GH receptor family is missing in this receptor form, the region of highest (70%) identity is retained. In the following studies, a homologous functional assay was developed to test the activity of three forms of receptor with respect to their ability to transmit a lactogenic signal. In this system, CHO cells were transiently transfected with a construct containing 2300 base pairs of the 5'-flanking sequence of the rat beta-casein gene fused to the chloramphenicol acetyltransferase (CAT) gene and an expression vector containing the various forms of rat PRL-R cDNA. The transfected cells were grown in serum-free medium in the absence or presence of PRL. In cells transfected with the long form of the PRL-R and beta-casein/CAT construct, a 7.2- +/- 0.9-fold induction (n = 3) of CAT activity was seen when cells were cultured in the presence of 400 ng/ml PRL and 1 micrograms/ml hydrocortisone. This level of stimulation was similar to that observed for the ovine beta-lactoglobulin/CAT construct in which a 5.7- +/- 1.2-fold (n = 3) effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells.

Human PRL receptor cDNA clones from hepatoma (Hep G2) and breast cancer (T-47D) libraries were isolated by using a rat PRL receptor cDNA probe. The nucleotide sequence predicts a mature protein of 598 amino acids with a much longer cytoplasmic domain than the rat liver PRL receptor. Although this extended region has additional segments of localized sequence identity with the human GH receptor, there is no identity with any consensus sequences known to be involved in hormonal signal transduction. This cDNA will be a valuable tool to better understand the role of PRL in the development and growth of human breast cancer.

Language dominance determined by whole brain functional MRI in patients with brain lesions.

BACKGROUND: Functional MRI (fMRI) is of potential value in determining hemisphere dominance for language in epileptic patients. OBJECTIVE: To develop and validate an fMRI-based method of determining language dominance for patients with a wide range of potentially operable brain lesions in addition to epilepsy. METHODS: Initially, a within-subjects design was used with 19 healthy volunteers (11 strongly right-handed, 8 left-handed) to determine the relative lateralizing usefulness of three different language tasks in fMRI. An automated, hemispheric analysis of laterality was used to analyze whole brain fMRI data sets. To evaluate the clinical usefulness of this method, we compared fMRI-determined laterality with laterality determined by Wada testing or electrocortical stimulation mapping, or both, in 23 consecutive patients undergoing presurgical evaluation of language dominance. RESULTS: Only the verb generation task was reliably lateralizing. fMRI, using the verb generation task and an automated hemispheric analysis method, was concordant with invasive measures in 22 of 23 patients (12 Wada, 11 cortical stimulation). For the single patient who was discordant, in whom a tumor involved one-third of the left hemisphere, fMRI became concordant when the tumor and its reflection in the right hemisphere were excluded from laterality analysis. No significant negative correlation was obtained between lesion size and strength of laterality for the patients with lesions involving the dominant hemisphere. CONCLUSION: This fMRI method shows potential for evaluating language dominance in patients with a variety of brain lesions.

The role of the corpus callosum in the representation of lateral orientation.

How do people recognize objects when they face in a novel lateral (left/right) orientation? The results of three experiments with a split-brain patient, who has a totally nonfunctional corpus callosum, demonstrate that the corpus callosum cannot play a critical role in allowing one to recognize mirror-reversed objects. First, both cerebral hemispheres could recognize mirror-reversed versions of pictures as accurately as the original renditions in an incidental memory task. Second, when asked to decide whether pictures faced the same way that they had originally, neither hemisphere performed better than chance in an incidental memory task--suggesting that the shape representations in the hemispheres do not specify lateral orientation. Third, neither hemisphere exhibited "priming" for lateral orientation, as assessed in an "object decision task", and only the left hemisphere exhibited priming for encoding the shape (independent of its lateral orientation).

Prolactin stimulates milk protein promoter in CHO cells cotransfected with prolactin receptor cDNA.

A functional biological system was developed by cotransfecting mammalian cell lines with the cDNA of the prolactin receptor (PRL-R) and a fusion gene containing the promoter of the milk protein, ovine beta-lactoglobulin linked to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. Surprisingly, this system is effective even if a non-mammary cell line is used, since Chinese hamster ovary (CHO) cells transfected both transiently and stably with PRL-R cDNA respond to PRL, as observed by stimulation of the reporter gene. This newly developed system should help precisely define the functional domains of both the PRL-R molecule and of the regulatory elements of a PRL target gene.

Visual outcome after paediatric cataract surgery: is age a major factor?

AIMS: To determine functional results after unilateral and bilateral cataract surgery in children with different aphakic optical correction. METHODS: In this retrospective study, we evaluated visual acuity and binocular vision in 107 children who underwent cataract surgery during the 10 year period from 1985 to 1995. Aphakia was corrected by an intracapsular intraocular lens (IOL), spectacles or contact lenses. RESULTS: Mean visual acuity was > 20/40 (< 0.3 log MAR) with normal binocular vision in 58 children over 7 months of age operated on for bilateral cataracts. Pseudophakic eyes regained visual acuity > 20/63 (< 0.5 log MAR) more often (90%) than aphakic eyes (46%) (p < 0.001). Binocular vision was also achieved more often after IOL implantation (p < 0.001). Visual outcome of early bilateral cataracts was less satisfactory in children with abnormal foveolar function. For 49 children who had surgery for unilateral cataracts, prognosis was poor when surgery was performed before the age of 7 months. For cataract surgery in older children (> or = 7 months) mean visual acuities were better with IOL implantation (p < 0.05). CONCLUSION: Cataract surgery with unilateral and bilateral IOL implantation can provide a beneficial effect on final visual outcome in children who are operated on before abnormal foveolar function develops.

Phakic posterior chamber lens implantation in children with high myopia.

PURPOSE: To evaluate the anatomical and functional results after implantation of a phakic posterior chamber lens (implantable contact lens [ICL]) to correct high myopia with amblyopia in pediatric patients in whom conventional treatments had failed. SETTING: Department of Ophthalmology, Purpan Hospital, University of Toulouse, France. METHODS: An ICL was implanted in 5 eyes with amblyopic high myopia in 4 children aged 3 to 16 years. Mean preoperative spherical equivalent refraction was -12.8 diopters (D) (range -8.0 to -18.0 D) and best spectacle-corrected visual acuity (BSCVA) was counting fingers to 20/200. Mean follow-up was 11.8 months (range 4 to 21 months). RESULTS: Postoperatively, the ICLs appeared to be well tolerated, with no inflammatory reactions, stable intraocular pressure, and good positioning in all eyes. Predictability was +0.5 D (range -0.5 to +2.0 D) and BSCVA improved, with a gain of 3 or more Snellen lines with recovery of binocular vision in 2 cases and orthotropia in 3 patients. All parents reported an improvement in their children's quality of life. CONCLUSION: This preliminary study indicates that ICL implantation is a safe surgical procedure to correct amblyopia resulting from high myopia in children when conventional amblyopia treatments have failed. Longer follow-up of more patients is needed.

Phakic posterior chamber lenses for high myopia: functional and anatomical outcomes.

PURPOSE: To evaluate the functional and the anatomical outcomes after implantation of phakic posterior chamber intraocular lenses (IOLs) in highly myopic eyes. SETTING: Service d'Ophtalmologie, Hôpital Purpan, Toulouse, France. METHODS: Fifty-eight eyes of 46 patients that had implantation of phakic posterior chamber lenses for high myopia were evaluated. Predictability, efficiency, safety, and subjective and objective quality of vision were evaluated preoperatively and at least 6 months postoperatively. The effect of the procedure on the cornea, aqueous humor, pupil, anterior chamber angle, crystalline lens, and retina were studied. RESULTS: Mean preoperative myopia was -13.85 diopters (D) +/- 3.1 (SD) (range -8.00 to -19.25 D). Mean postoperative spherical equivalent was -1.22 +/- 0.83 D (range +0.75 to -3.50 D); 56.9% of eyes were within +/-1.00 D of the predicted result, and 77.6% gained 1 or more lines of best corrected visual acuity. All contact-lens-intolerant patients had improved quality of vision for day and night driving, distance vision, and vision under dim illumination. The mean postoperative level of contrast sensitivity without correction was higher than the mean preoperative level with correction. Adverse events were 2 cases of crystalline lens opacification 16 and 18 months after surgery and 2 cases of pigment deposits in the angle with increased intraocular pressure, which was controlled by beta-blockers. CONCLUSION: Implantation of posterior chamber phakic IOLs is effective and predictable; however, long-term follow-up is needed.