Preferential liver gene expression with polypropylenimine dendrimers.

Previously, the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (<1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations. In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration.     

Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration.

Due to limited aqueous solubility of dorzolamide at physiologic pH, the pH of Trusopt eye drops (cont. 2% dorzolamide) has to be kept at about 5.65, and to increase the topical bioavailability of the drug from Trusopt the contact time of the drug with the eye surface is increased by increasing the viscosity of the eye drops to 100 cps. This low pH and high viscosity can lead to local irritation. In this study, dorzolamide hydrochloride was formulated as 2% and 4% low viscosity solutions (viscosity 3 to 5 cps) containing randomly methylated beta-cyclodextrin at pH 7.45. These formulations were evaluated in rabbits. The animals were sacrificed at various time points after topical administration of the drug and the dorzolamide concentration determined in the different parts of the eye. Trusopt was used as a reference standard. The topical availability of dorzolamide from the cyclodextrin-containing eye drops appeared to be comparable to that from Trusopt and the drug reached retina and optic nerve to give measurable concentrations for at least 8 h after administration of the eye drops.     

Electron beam therapy for eyelid carcinomas

Forty-six (85%) basal cell and eight (15%) squamous cell carcinomas of the eyelids were treated with electron beams between 1963 and 1983. Lesion sizes ranged from microscopic to 4 cm, with 28 lesions larger than 1 cm. Thirty-eight lesions were treated with radiotherapy after incisional biopsy, and 16 were treated after excisional biopsy (specimens showed positive margins). Doses varied from 45 to 72 Gy, with daily fractions ranging from 2.12 to 4.0 Gy. There were six disease recurrences (10.9%): three in the treatment field and three at the treatment margin. Four of six recurrences were subsequently controlled by limited surgical excision and repair with preservation of the eye, whereas the other two required enucleation. Treatment sequelae such as skin atrophy, telangiectasis, and cosmetic results were evaluated in terms of radiotherapy parameters, pretreatment surgery, and size of the lesion. In 44 patients, the overall cosmetic result was judged as good to excellent, five patients had a mild to modest degree of deformity, and five had significant deformity. Such deformity was usually associated with tumor destruction or previous surgery. No major complications were noted.     

Serum protein electrophoresis patterns in chronic lymphocytic leukemia. Clinical and epidemiologic correlations

Serum protein electrophoresis (SPEP) data obtained at diagnosis were available for 98 of 342 patients with chronic lymphocytic leukemia (CLL) identified in a population-based case-control epidemiologic study. Patients tested with SPEP at diagnosis were significantly younger, more likely to have lymphadenopathy, and more likely to have had their conditions diagnosed at a university hospital than those not tested. Four categories of electrophoretic patterns were identified: normal (N = 56), hypogammaglobulinemia (N = 28), hypergammaglobulinemia (N = 11), and monoclonal gammopathy (N = 3). A higher proportion of those with hypergammaglobulinemia were black, and patients with hypergammaglobulinemia and monoclonal gammopathy were more likely to die within the first year following diagnosis than patients in the other SPEP groups. No association was found, however, between SPEP pattern and a clinical staging classification for CLL. These findings suggest that SPEP may be a useful adjunct in categorizing possible subtypes of CLL and developing future clinical staging classifications.     

Differences between mentally retarded and nonretarded persons' efficiency of auditory sentence processing

Mentally retarded adolescents and MA-matched nonretarded children participated in three experiments designed to examine differences in language-processing efficiency. A compressed speech technique was used in Experiments 1 and 2. Experiment 3 relied on a sentence-picture verification procedure. Our results suggest that retarded and nonretarded individuals differ in the speed with which they are able to execute the semantic-analytic processes but not necessarily the phonological encoding processes that are involved in auditory language comprehension. In addition, the data suggest a possible group difference in the quality of the semantic representation encoded during sentence processing.     

Characteristics and motives of women choosing elective induction of labour

Personal characteristics of healthy term pregnant women who chose elective induction or spontaneous onset of labour and the motives for their choice were assessed. Almost 50% of 237 women with uncomplicated pregnancies opted for elective induction when offered the opportunity. These women appeared to have had more complaints during their pregnancy and menstrual periods, more complications in their obstetrical history and to be more anxious about their labour than women who chose a spontaneous onset of labour. Predominant motives were a feeling of safety and the desire to shorten the duration of pregnancy. These characteristics and motives seem to reflect a lack of trust in physical reproductive functions. It is concluded that in evaluating effects of elective induction of labour, pre-existing differences between women who choose elective induction and women who opt for a spontaneous onset must be taken into account.