Behavioral control of abnormal breathing in sleep

Behavioral control of abnormal breathing in sleep was studied to determine if an intervention procedure could reduce apnea duration and also SaO ₂ (blood oxygen) desaturation levels. Sleep apnea patients (n=11) were instructed while awake that tones would be presented in sleep whenever an apnea event occurred. They were told to breathe deeply to the tones and were given practice in doing so. Intervention and nonintervention hours alternated across 2 nights following 2 baseline nights. As expected, during the intervention hours, the duration but not the frequency of apneic events was reduced. The procedure also resulted in higher SaO ₂ levels during the intervention hours. Daytime sleepiness was not greater following intervention but sleep staging effects were observed. The results are sufficiently promising to warrant additional research.This research was supported by NIH Grants 2 HL 27149-84 and HL 34125 entitled Behavioral Control of Respiration in Sleep.     

Functional polymers and sequential copolymers by phase transfer catalysis, 27. Synthesis of aromatic-aliphatic polyformals by polyetherification of 1,4-bis(chloromethoxy)butane with 4,4′-isopropylidenediphenol

The first examples of aromatic-aliphatic polyformals were synthesized from 4,4′-isopropylidenediphenol ( 2 ) and 1,4-bis(chloromethoxy)butane ( 1 ) by a two-phase (aqueous NaOH/toluene), phase transfer catalyzed (PTC) polyetherification. The influence of the reaction conditions upon the polymerization was studied by varying the phase transfer catalyst concentration, NaOH concentration and nucleophile to electrophile ratio. Changes in these parameters and their effects upon the microstructure of these polymers were also examined by ¹H NMR (200 MHz) spectroscopy. The reactivity of 1 has permitted, according to our knowledge, the first examples of interfacial polyetherification. Further, this reactivity has also permitted the homopolymerization of 1 through its hydrolysis byproducts under PTC conditions.     

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

Human mini-chromosomes in mouse embryonal stem cells

We have introduced human mini-chromosomes of 4 Mb and approximately 15 Mb in size into mouse embryonal stem cells. Although these human mini- chromosomes are stable in hamster and chicken cells, they re-arrange or segregate aberrantly in the embryonal stem cells and are rapidly lost in the absence of selection. However, one of the mini-chromosomes re- arranged, acquired mouse centromeric sequences and was then stably maintained for at least 60 population doublings in culture. This mini- chromosome, which is 4 Mb in size, is a candidate for a mouse germ line chromosome vector.      

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

Background  

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.     

Cost effectiveness of individual vs. group cognitive behavior therapy for problems of depression and anxiety in an HMO population

Randomly assigned 44 outpatient Ss, enrollees of the George Washington University Health Plan, a Health Maintenance Organization (HMO), to one of three treatment modalities: (1) a cognitive behavior therapy group; (2) a traditional process-oriented interpersonal group; and (3) cognitive behavior therapy in an individual format. All Ss were referred by their physicians to the HMO Mental Health Practice for treatment for anxiety and/or depression. Beck's Depression Inventory, Speilberger's State-Trait Anxiety Inventory and Gay and Galassi's Adult Self-Expression Scale (an assertion measure) were administered pre- and post-treatment to all Ss. A subsample of these Ss also were rated pre- and post-treatment on the Hamilton Rating Scale for Depression by experienced clinicians blind to the treatment groups. All three experimental groups significantly improved on all dependent measures from pre- to post-treatment, and no differential treatment effects were found.     

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.      

Functional polymers and sequential copolymers by phase transfer catalysis, 21. Thermotropic aromatic poly(ether sulfone)s: A new class of thermotropic aromatic main-chain liquid crystalline polymers

Thermotropic aromatic poly(ether sulfone)s ( 3a — e ) were prepared by phase transfer catalyzed (PTC) polyetherification of bis(4-chloro-3-nitrophenyl) sulfone ( 1 ) with mesogenic aromatic diols. The synthesized polymers were characterized by differential scanning calorimetry and optical polarization microscopy to determine their phase behavior. All polymers appear to be amorphous. Only the polyethers based on 2,6-dihydroxyanthraquinone ( 2a ) and 1 exhibit enantiotropic liquid crystalline behavior. This demonstrates that fully aromatic polyethers can be prepared as thermotropic liquid crystalline polymers.     

Further characterization of 19 cases of rea(21q21q) and delineation as isochromosomes or robertsonian translocations in down syndrome

We have used 9 conventional RFLPs and 6 dinucleotide repeat polymorphisms on chromosome 21q to demonstrate that 17 of 19 cases of rea(21q21q) were consistent with isochromosomes i(21q) with the remaining 2 being true Robertsonian translocations. Eight of the 17 isochromosomes were of maternal origin and 9 cases were paternally derived. The 2 Robertsonian translocations were both maternally derived. Of the 17 isochromosomes, 7 were dicentric Wc(21q)I and 10 were monocentric M21q)l. Both rob(21q21q) were monocentric. Our findings agree with those made in 17 previously published cases of rea(21q21q). The parental origins of the i(21q) were equally divided between maternal (n = 17) and paternal (n = 15) origins. All 4 true rob(21q21q) reported to date are of maternal origin. Collectively, it appears that most homologous rearrangements of chromosome 21 are isochromosomes and only a small proportion are consistent with true Robertsonian translocations. © 1993 Wiley-Liss, Inc.