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Biomedical subjects

C J Brown

Publications and source records attributed to C J Brown.

At least 37 records · Page 2Linked to original sources
PubMed2001

Skewed X inactivation and recurrent spontaneous abortion.

Recent studies show that women experiencing recurrent spontaneous abortion exhibit nonrandom X-chromosome inactivation (XCI) more often than in controls. This suggests that genetic factors may be important in explaining the losses in this subset of women. Nonetheless there are a number of possible explanations for this finding and the underlying causes may be heterogeneous. One hypothesis commonly cited is that a mutation on the X chromosome results in both preferential inactivation of the mutated X as well as lethality of male embryos inheriting this mutated X. However, this hypothesis does not explain the increase in chromosome abnormalities observed in the karyotyped losses from women with recurrent pregnancy loss and skewed XCI. This finding leads us to suggest that the mechanism involved may be associated with a reduction in number of ovarian follicles, either due to X mutations affecting oocyte atresia or a restriction in precursor pool size during development.

Abortion, Habitual↗
PubMed2001

A longitudinal study of electrode impedance, the electrically evoked compound action potential, and behavioral measures in nucleus 24 cochlear implant users.

OBJECTIVE: The primary goal of this study was to examine changes that may occur in electrode impedance, electrically evoked compound action potential (EAP) threshold and slope of the EAP growth function, and behavioral measures of threshold T-level) and maximum comfort (C-level) over time in both adult and child cochlear implant users. Secondary goals were to determine whether changes in these measures are consistent between children and adults, and to determine whether behavioral measures (MAP T- and C-levels) and electrophysiologic measures (EAP thresholds) exhibit the same trends over time. DESIGN: Thirty-five children and 33 adults implanted with the Nucleus CI24M between November 1996 and August 1999 participated in this study. Subjects were included in this study if 1) they had used their implant for at least 1 yr after device connection, and 2) they had participated in the necessary data collection at a minimum number of the time intervals assessed in this study. EAP threshold, slope of the EAP growth function, and common ground electrode impedance measures were collected intraoperatively, at initial stimulation, and at several subsequent visits up to 2 yr post initial stimulation. MAP T- an d C-levels weremeasured at initial stimulation and at the same time intervals as described above. RESULTS: Changes in electrode impedance, EAP thresholds, and slope of the EAP growth function from measures made intraoperatively, at initial stimulation, and at 1 to 2 mo post initial stimulation were similar in both children and adults. Beyond the 1- to 2-mo visit, children exhibited significant increases in electrode impedance, EAP thresholds, slope, and MAP T-levels, whereas these samemeasures in adults remained relatively stable. EAP thresholds in children stabilized by the 3- to 8-mo visit, and electrode impedance stabilized by the 6- to 8-mo visit, while slope of the EAP growth function, MAP T-levels,and MAP C-levels werestable by 1 yr post initial stimulation. C-levels in adults increased up to 1 yr post initial stimulation; however, the amount of increase was much smaller than that seen in children. In both children and adults, longitudinal trends in EAP thresholds mirrored T-level more closely than C-level. CONCLUSIONS: The results of this study suggest that peripheral changes occur in many children that do not generally occur in adults within the first year of cochlear implant use. One implication of these results is that if EAP thresholds are to be used to assist in programming the speech processor for children, it is best to make those measures at the same time interval as device programming rather than using measures made intraoperatively or at the initial programming session to set MAP levels at later visits.

Acoustic Impedance Tests↗
PubMed2001

Identification of intrinsic order and disorder in the DNA repair protein XPA.

The DNA-repair protein XPA is required to recognize a wide variety of bulky lesions during nucleotide excision repair. Independent NMR solution structures of a human XPA fragment comprising approximately 40% of the full-length protein, the minimal DNA-binding domain, revealed that one-third of this molecule was disordered. To better characterize structural features of full-length XPA, we performed time-resolved trypsin proteolysis on active recombinant Xenopus XPA (xXPA). The resulting proteolytic fragments were analyzed by electrospray ionization interface coupled to a Fourier transform ion cyclotron resonance mass spectrometry and SDS-PAGE. The molecular weight of the full-length xXPA determined by mass spectrometry (30922.02 daltons) was consistent with that calculated from the sequence (30922.45 daltons). Moreover, the mass spectrometric data allowed the assignment of multiple xXPA fragments not resolvable by SDS-PAGE. The neural network program Predictor of Natural Disordered Regions (PONDR) applied to xXPA predicted extended disordered N- and C-terminal regions with an ordered internal core. This prediction agreed with our partial proteolysis results, thereby indicating that disorder in XPA shares sequence features with other well-characterized intrinsically unstructured proteins. Trypsin cleavages at 30 of the possible 48 sites were detected and no cleavage was observed in an internal region (Q85-I179) despite 14 possible cut sites. For the full-length xXPA, there was strong agreement among PONDR, partial proteolysis data, and the NMR structure for the corresponding XPA fragment.

Amino Acid Motifs↗
PubMed2001

The protein non-folding problem: amino acid determinants of intrinsic order and disorder.

To investigate the determinants of protein order and disorder, three primary and one derivative database of intrinsically disordered proteins were compiled. The segments in each primary database were characterized by one of the following: X-ray crystallography, nuclear magnetic resonance (NMR), or circular dichroism (CD). The derivative database was based on homology. The three primary disordered databases have a combined total of 157 proteins or segments of length.30 with 18,010 residues, while the derivative database contains 572 proteins from 32 families with 52,688 putatively disordered residues. For the four disordered databases, the amino acid compositions were compared with those from a database of ordered structure. Relative to the ordered protein, the intrinsically disordered segments in all four databases were significantly depleted in W, C, F, I, Y, V, L and N, significantly enriched in A, R, G, Q, S, P, E and K, and inconsistently different in H, M, T, and D, suggesting that the first set be called order-promoting and the second set disorder-promoting. Also, 265 amino acid properties were ranked by their ability to discriminate order and disorder and then pruned to remove the most highly correlated pairs. The 10 highest-ranking properties after pruning consisted of 2 residue contact scales, 4 hydrophobicity scales, 3 scales associated with.-sheets and one polarity scale. Using these 10 properties for comparisons of the 3 primary databases suggests that disorder in all 3 databases is very similar, but with those characterized by NMR and CD being the most similar, those by CD and X-ray being next, and those by NMR and X-ray being the least similar.

Amino Acids↗
PubMed2000

Determination of X-chromosome inactivation status using X-linked expressed polymorphisms identified by database searching.

The large number of redundant sequences available in nucleotide databases provides a resource for the identification of polymorphisms. Expressed polymorphisms in X-linked genes can be used to determine the inactivation status of the genes, and polymorphisms in genes that are subject to inactivation can then be used as tools to examine X-chromosome inactivation status in heterozygous females. In this study, we have identified six new X-linked single-nucleotide polymorphisms and determined the inactivation status of these genes by examination of expression patterns in female cells previously demonstrated to have skewed inactivation, as well as by analysis of somatic cell hybrids retaining the inactive human X chromosome. Expression was seen from both alleles in females heterozygous for the RPS4X gene, confirming the previously reported expression from the inactive X chromosome. Expression of only a single allele was seen in females heterozygous for polymorphisms in the BGN, TM4SF2, ATP6S1, VBP1, and PDHA1 genes, suggesting that these genes are subject to X-chromosome inactivation.

Algorithms↗
PubMed2000

Mechanisms underlying the formation and enlargement of noncommunicating syringomyelia: experimental studies.

The pathogenesis of noncommunicating syringomyelia is unknown, and none of the existing theories adequately explains the production of cysts that occur in association with conditions other than Chiari malformation. The authors' hypothesis is that an arterial pulsation-driven perivascular flow of cerebrospinal fluid (CSF) is responsible for syrinx formation and enlargement. They investigated normal CSF flow patterns in 20 rats and five sheep by using the tracer horseradish peroxidase; the effect of reducing arterial pulse pressure was examined in four sheep by partially ligating the brachiocephalic trunk; CSF flow was examined in 78 rats with the intraparenchymal kaolin model of noncommunicating syringomyelia; and extracanalicular cysts were examined using the excitotoxic model in 38 rats. In the normal animals there was a rapid flow of CSF from the spinal subarachnoid space into the spinal cord perivascular spaces and then into the central canal. This flow ceased when arterial pulsations were diminished. In animals with noncommunicating syringomyelia, there was rapid CSF flow into isolated and enlarged segments of central canal, even when these cysts were causing pressure damage to the surrounding spinal cord. Exitotoxic injury of the spinal cord caused the formation of extracanalicular cysts, and larger cysts were produced when this injury was combined with arachnoiditis, which impaired subarachnoid CSF flow. The results of these experiments support the hypothesis that arterial pulsation-driven perivascular fluid flow is responsible for syrinx formation and enlargement.

Animals↗
PubMed2000

Intramedullary femoral nails: one or two lag screws? A preliminary study.

Failures of proximal femoral nails that treat unstable femoral fractures have been reported. In this communication, a finite element model to include a proximal femoral nail within a fractured femur was used to carry out preliminary investigations into configurations of single or double lag screws. The effects of the different types of fracture were investigated. The results show that in order to share the load evenly between two lag screws, a good configuration seems to be to have a slightly larger screw above the lower screw. This also ameliorates stresses in the nail at the lag screw insertion holes. However, using two screws in this way can lead to large stresses in the cancellous bone in the femoral head, and these stresses may be significant in the initiation of cut-out.

Bone Screws↗
PubMed2000

The causes and consequences of random and non-random X chromosome inactivation in humans.

X chromosome (X) inactivation is a remarkable biological process including the choice and cis-limited inactivation of one X, as well as the stable maintenance of this silencing by epigenetic chromatin alterations. The process results in females generally being mosaic for two populations of cells--one with each parental X active. In this review, we discuss recent advances in our understanding of how inactivation works, as well as the causes and clinical implications of deviations from random inactivation.

Chromatin↗
PubMed2000

An association between skewed X-chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta.

Skewed X-chromosome inactivation (XCI) is frequently found in the diploid fetal tissues of individuals with mosaic trisomy that originated from a 'trisomic zygote rescue' event. This may result from a high number of trisomic cells in the embryonic cell pool at the time of XCI, which are subsequently eliminated by selection. We hypothesize that extremely skewed XCI in these mosaic cases will be associated with a poor fetal outcome due to failure to completely eliminate the trisomy from all fetal tissues. To test this hypothesis, XCI status was evaluated in 17 cases of prenatally detected trisomy 16 mosaicism. Ten of the 15 informative cases showed extreme XCI skewing ( > or = 90% inactivation of one allele) in blood or other diploid fetal tissues compared to six of the 111 controls (p < 0.001). Among these 10 'skewed' cases, 6 showed an abnormal outcome, defined as developmental abnormalities and/or intrauterine or neonatal death. In contrast, of the 5 cases without extreme skewing, none showed abnormal outcome, although outcome information was incomplete in 1 case. An additional 6 cases analyzed, involving trisomy mosaicism for other chromosomes, showed similar results. Further studies are warranted to determine if XCI status adds useful information to the prediction of pregnancy outcome in prenatally detected mosaic trisomy.

Adolescent↗
PubMed2000

HLA-A, -B and -DR antigen frequencies of the London Cord Blood Bank units differ from those found in established bone marrow donor registries.

Patients requiring allogeneic stem cell transplantation who do not have an HLA-matched related donor can sometimes obtain an unrelated donor by searching volunteer registries. The majority of donors in the registries are Caucasoid, which results in a lower probability of a non-Caucasoid patient finding a suitable donor. Cord blood is increasingly used as a source of haematopoietic stem cells for allogeneic bone marrow reconstitution and so far the London Cord Blood Bank has banked almost 3000 cord blood units. An analysis of the first 1500 units banked showed that more than 30% of the London Cord Blood Bank units are derived from UK ethnic minorities compared with only 2% of individuals recruited locally for the British Bone Marrow Registry (BBMR). The HLA types found in these cord blood units reflect their ethnic diversity and include: HLA-A34, A36, A80, B75, B61, B53, B78, B81 and B82. The units stored by the London Cord Blood Bank show an HLA profile which differs considerably from that of locally typed adult volunteers for the BBMR panel and this should help to increase the chances of obtaining acceptably HLA-matched donors for patients from ethnic minorities. Bone Marrow Transplantation (2000) 25, 475-481.

Adult↗
PubMed2000

Dyskeratosis congenita: report of a case.

Dyskeratosis congenita is a rare multisystem condition involving mainly the ectoderm. It is characterized by a triad of reticular skin pigmentation, nail dystrophy and leukoplakia of mucous membranes. Oral and dental abnormalities may also be present. Complications are a predisposition to malignancy and bone marrow involvement with pancytopenia. The case of a 14-year-old girl is described who presented with several of the characteristic systemic features of this condition, together with the following oral features: hypodontia, diminutive maxillary lateral incisors, delayed dental eruption, crowding in the maxillary premolar region, short roots, poor oral hygiene, gingival inflammation and bleeding, alveolar bone loss, caries and a smooth atrophic tongue with leukoplakia. Although this condition is rare, dental surgeons should be aware of the dental abnormalities that exist and the risk of malignant transformation within the areas of leukoplakia.

Adolescent↗
PubMed2000

The relationship between EAP and EABR thresholds and levels used to program the nucleus 24 speech processor: data from adults.

OBJECTIVE: The objective of this study was to determine the relationship between electrically evoked whole nerve action potential (EAP) and electrical auditory brain stem response (EABR) thresholds and MAP threshold (T-level) and maximum comfort level (C-level) for subjects who use the Nucleus 24 cochlear implant system. DESIGN: Forty-four adult Nucleus 24 cochlear implant users participated in this study. EAP thresholds were recorded using the Neural Response Telemetry System developed by Cochlear Corporation. EABR thresholds were measured for a subset of 14 subjects using standard evoked potential techniques. These physiologic thresholds were collected on a set of five electrodes spaced across the cochlea, and were then compared with behavioral measures of T-level and C-level used to program the speech processor. RESULTS: EAP thresholds were correlated with MAP T- and C-levels; however, the correlation was not strong. A technique for improving the correlation by combining measures of T- and C-levels made on one electrode with the EAP thresholds was presented. Correlations between predicted and measured T- and C-levels using this technique were 0.83 and 0.77, respectively. Similar results were obtained using the EABR thresholds for a smaller set of subjects. In general, EABR thresholds were recorded at levels that were approximately 4.7 programming units lower than EAP thresholds. CONCLUSIONS: Either EAP or EABR thresholds can be used in combination with a limited amount of behavioral information to predict MAP T- and C-levels with reasonable accuracy.

Acoustic Stimulation↗
PubMed2000

Comparison of EAP thresholds with MAP levels in the nucleus 24 cochlear implant: data from children.

OBJECTIVE: The purpose of this study is to examine the relationship between the electrically evoked compound action potential (EAP) thresholds and the MAP thresholds (T-levels) and maximum comfort levels (C-levels) in children implanted with the Nucleus 24 device. DESIGN: EAP thresholds were measured using the Neural Response Telemetry system of the Nucleus 24 device. Twenty children implanted with the Nucleus 24 cochlear implant participated in this study. EAP thresholds were compared with the behavioral measures of T- and C-level used to construct the MAP these children used on a daily basis. For these subjects, both EAP and MAP T- and C-levels were obtained the same visit, which occurred at 3 to 5 mo postconnection. RESULTS: EAP thresholds were shown to fall between MAP T- and C-level for 18 of 20 subjects tested; however, considerable variability across subjects was noted. On average, EAP thresholds fell at 53% of the MAP dynamic range. Correlations between EAP threshold and MAP T- and C-level improved substantially when combined with behavioral measures obtained from one electrode in the array. CONCLUSIONS: Moderate correlations were found between EAP thresholds and MAP T- and C-levels for the children participating in this study. However, a technique is described for improving the accuracy of predictions of MAP T- and C-levels based on EAP data combined with a small amount of behavioral information.

Acoustic Stimulation↗
PubMed2000

An improved method of reducing stimulus artifact in the electrically evoked whole-nerve potential.

OBJECTIVE: Recording a compound action potential in response to electrical stimulation requires attention to minimize contamination due to electrical stimulus artifact. In patients implanted with the Nucleus 24 device, the electrically evoked whole-nerve potential (EAP) is recorded using a neural response telemetry (NRT) system. This system employs a forward-masking technique that greatly reduces stimulus artifact. However, theoretical considerations and experimental animal data suggest that the technique may distort the acquired EAP waveform under some situations. We proposed and evaluated a modification to the forward-masking technique that addresses this concern, particularly during collection of refractory recovery data. DESIGN: We first examined neural responses of the electrically stimulated auditory nerve using cat preparations. Through single-fiber recordings from cats, we demonstrated underlying physiological limitations likely encountered with the "standard" forward masking technique. We then recorded feline EAP waveforms using both the standard technique and our proposed, modified, technique. Finally, we collected EAP data from human cochlear implant patients using both artifact reduction methods. These comparisons allowed us to evaluate the effectiveness of our modification. RESULTS: The cat EAP data demonstrated that the standard forward-masking technique currently in use in the Nucleus NRT system can distort the EAP waveform when the nerve is partially refractory. In the cat, this distortion resulted in forward-masking recovery curves with artifactually prolonged recovery times and inaccurate latency trends. Similar effects were observed in the comparison of human recovery curves obtained using both the standard and modified techniques. In some cases, the modified technique produced EAP waveforms with more clearly defined peaks than were obtainable with the standard method. CONCLUSIONS: Consideration should be given to implementing our modified forward-masking artifact reduction scheme, because it introduces less distortion of the EAP waveform and accordingly provides for more accurate assessment of the refractory properties of the electrically stimulated nerve.

Action Potentials↗
PubMed2000

NMR structure of a concatemer of the first and second ligand-binding modules of the human low-density lipoprotein receptor.

The ligand-binding domain of the human low-density lipoprotein receptor consists of seven modules, each of 40-45 residues. In the presence of calcium, these modules adopt a common polypeptide fold with three conserved disulfide bonds. A concatemer of the first and second modules (LB(1-2)) folds efficiently in the presence of calcium ions, forming the same disulfide connectivities as in the isolated modules. The three-dimensional structure of LB(1-2) has now been solved using two-dimensional 1H NMR spectroscopy and restrained molecular dynamics calculations. No intermodule nuclear Overhauser effects were observed, indicating the absence of persistent interaction between them. The near random-coil NH and H alpha chemical shifts and the low phi and psi angle order parameters of the four-residue linker suggest that it has considerable flexibility. The family of LB(1-2) structures superimposed well over LB1 or LB2, but not over both modules simultaneously. LB1 and LB2 have a similar pattern of calcium ligands, but the orientations of the indole rings of the tryptophan residues W23 and W66 differ, with the latter limiting solvent access to the calcium ion. From these studies, it appears that although most of the modules in the ligand-binding region of the receptor are joined by short segments, these linkers may impart considerable flexibility on this region.

Amino Acid Sequence↗
PubMed2000

Electrically evoked compound action potentials recorded from subjects who use the nucleus CI24M device.

The ability to directly measure the response to a pulse with the NRT opens the possibility of using this system to characterize the responses to more complex stimuli. An example is the responses to constant-amplitude pulse trains. With further changes in the software that controls the implant, it may be possible to characterize the responses to modulated pulse trains or other stimuli that better approximate the type of stimuli that are normally used with a cochlear implant speech processor.

Action Potentials↗