CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3.

PURPOSE: To define the clinical characteristics and determine the gene localization for a previously undescribed form of congenital fibrosis of the extraocular muscles (CFEOM), referred to as CFEOM type 3 (CFEOM3). METHODS: A large family with CFEOM was identified, and participating individuals underwent ophthalmologic examination and donated blood for genetic analysis. The family's disorder was tested for linkage to the known CFEOM loci, followed by a genome-wide search and linkage refinement using polymorphic DNA markers. RESULTS: Thirty-eight members of this Canadian family participated in the study. Affected individuals are born with a nonprogressive eye movement disorder characterized by variable expression of ptosis and restrictive external ophthalmoplegia. Severely affected individuals have ptosis, primary gaze fixed in a hypo- and exotropic position, and marked restriction of eye movement bilaterally. Mildly affected individuals have normally positioned globes with a limitation of vertical gaze. Moderately affected individuals have asymmetrical involvement with one eye severely and one eye mildly affected. The disorder is autosomal dominant with variable expression and probable incomplete penetrance. Genetic analysis reveals linkage to markers on 16q24.2q24.3. A maximum lod score of 5.8 occurs at markers D16S3063 and D16S689, and the CFEOM3 disease gene is located within a 5.6-cM region flanked by D16S486 and D16S671. CONCLUSIONS: These data establish that CFEOM3 is a phenotypically variant and genotypically distinct form of CFEOM with linkage to chromosome 16qter. The authors have previously demonstrated that CFEOM1 results from a developmental absence of the superior division of the oculomotor nerve. The authors hypothesize that CFEOM3 results from a defect analogous to, but distinct from CFEOM1.

Intraventricular encapsulated calf adrenal chromaffin cells: viable for at least 500 days in vivo without detectable adverse effects on behavioral/cognitive function or host immune sensitization in rats.

Numerous studies have reported that adrenal chromaffin cell transplants, including encapsulated xenogeneic adrenal chromaffin cells, have analgesic effects. However, in addition to efficacy, the clinical utility of encapsulated xenogeneic adrenal chromaffin cells for treatment of chronic pain is dependent on the duration of cell viability in vivo, and their relative safety. The objectives of the present study in rats were to: (1) examine encapsulated calf adrenal chromaffin (CAC) cells for evidence of viable cells and continued release of analgesic agents after an extended period in vivo; (2) determine if intraventricular encapsulated CAC cells produce detectable adverse effects on behavioral/cognitive function; and (3) test for evidence of host immune sensitization after an extended period of exposure to encapsulated xenogeneic adrenal chromaffin cells. Results of the present study suggest that some encapsulated CAC cells remain viable for nearly 1.5 years in vivo and continue to produce catecholamines and met-enkephalin. Post-explant device norepinephrine output was equivalent to amounts previously shown to produce analgesic effects with intrathecal implants. Encapsulated adrenal chromaffin cells also appeared relatively safe, even when implanted in the cerebral ventricals, with a lower side-effect profile than systemic morphine (4 mg/kg). There was no evidence that encapsulated CAC-cells implanted in the ventricles affected body weight, spontaneous activity levels, or performance in the delayed matching to position operant task which is sensitive to deficits in learning, memory, attention, motivation, and motor function. Finally, encapsulated CAC cells produced no detectable evidence of host immune sensitization after 16.7 months in vivo, although unencapsulated CAC cells produced a robust immune response even in aged rats. The results of the present study suggest that adrenal chromaffin cells remain viable in vivo for long periods of time, and that long-term exposure to encapsulated xenogeneic adrenal chromaffin cell implants appears relatively safe.

Transport characterization of membranes for immunoisolation.

This study relates to the diffusive transport characterization of hollow fibre membranes used in implantable bio-hybrid organs and other immunoisolatory devices. Techniques were developed to accurately determine the mass transfer coefficients for diffusing species in the 10(2)-10(5) MW range, validated and then used to study one membrane type known to effectively immunoisolate both allografts and xenografts in vivo. Low-molecular-weight diffusing markers included glucose, vitamin B12 and cytochrome C; higher-molecular-weight molecules were bovine serum albumin, immunoglobulin G, apoferritin and a range of fluorescein-tagged dextrans. Overall and fractional mass transfer coefficients through the hollow fibres were determined using a resistance-in-series model for transport. A flowing dialysis-type apparatus was used for the small-molecular-weight diffusants, whereas a static diffusion chamber was used for large-molecular-weight markers. For diffusion measurements of small-molecular-weight solutes, convective artefacts were minimized and the effect of boundary layers on both sides of the membrane were accounted for in the model. In measuring diffusion coefficients of large-molecular-weight species, boundary layer effects were shown to be negligible. Results showed that for small-molecular-weight species (< 13,000 MW) the diffusion coefficient in the membrane was reduced relative to diffusion in water by two to four times. The diffusion rate of large-molecular-weight species was hindered by several thousand-fold over their rate of diffusion in water.

Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects.

Human islets were macroencapsulated in permselective hollow fiber membrane devices and successfully allotransplanted subcutaneously with > 90% viability after 2 weeks in situ. Recipients were patients with type I or type II diabetes and normal control subjects; none was immunosuppressed. Between 150 and 200 islet equivalents were implanted in each of the nine patients. No adverse patient complications were observed. Biocompatibility of devices was excellent. Insulin-positive beta-cells were confirmed in encapsulated islets recovered from the implanted devices in all patient populations including the type I diabetic patients. Glucose-stimulated insulin release could be demonstrated in vitro from recovered islets. These data demonstrate that macroencapsulated human islets can survive at the subcutaneous site and that permselective membranes can be designed to protect against both allogeneic immune responses as well as the autoimmune component of type I diabetes.