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Biomedical subjects

R E Ellis

Publications and source records attributed to R E Ellis.

At least 37 records · Page 2Linked to original sources
PubMed2000

Disruption of the CED-9.CED-4 complex by EGL-1 is a critical step for programmed cell death in Caenorhabditis elegans.

In the nematode Caenorhabditis elegans, the apoptotic machinery is composed of four basic elements: the caspase CED-3, the Apaf-1 homologue CED-4, and the Bcl-2 family members CED-9 and EGL-1. The ced-9(n1950) gain-of-function mutation prevents most, if not all, somatic cell deaths in C. elegans. It encodes a CED-9 protein with a glycine-to-glutamate substitution at position 169, which is located within the highly conserved Bcl-2 homology 1 domain. We performed biochemical analyses with the CED-9G169E protein to gain insight into the mechanism of programmed cell death. We find that CED-9G169E retains the ability to bind both EGL-1 and CED-4, although its affinity for EGL-1 is reduced. In contrast to the behavior of wild-type CED-9, the interaction between CED-9G169E and CED-4 is not disrupted by expression of EGL-1. Furthermore, CED-4 and CED-9G169E co-localizes with EGL-1 to the mitochondria in mammalian cells, and expression of EGL-1 does not induce translocation of CED-4 to the cytosol. Finally, the ability of EGL-1 to promote apoptosis is impaired by the replacement of wild-type CED-9 with CED-9G169E, and this effect is correlated with the inability of EGL-1 to induce the displacement of CED-4 from the CED-9.CED-4 complex. These studies suggest that the release of CED-4 from the CED-9.CED-4 complex is a necessary step for induction of programmed cell death in C. elegans.

Amino Acid Sequence↗
PubMed2000

A novel member of the tob family of proteins controls sexual fate in Caenorhabditis elegans germ cells.

Although many cell fates differ between males and females, probably the most ancient type of sexual dimorphism is the decision of germ cells to develop as sperm or as oocytes. Genetic analyses of Caenorhabditis elegans suggest that fog-3 might directly control this decision. We used transformation rescue to clone the fog-3 gene and show that it produces a single major transcript of approximately 1150 nucleotides. This transcript is predicted to encode a protein of 263 amino acids. One mutation causes a frame shift at the sixth codon and is thus likely to define the null phenotype of fog-3. Although the carboxyl-terminus of FOG-3 is novel, the amino-terminal domain is similar to that of the Tob, BTG1, and BTG2 proteins from vertebrates, which might suppress proliferation or promote differentiation. This domain is essential for FOG-3 activity, since six of eight missense mutations map to this region. Furthermore, this domain of BTG1 and BTG2 interacts with a transcriptional regulatory complex that has been conserved in all eukaryotes. Thus, one possibility is that FOG-3 controls transcription of genes required for germ cells to initiate spermatogenesis rather than oogenesis. This model implies that FOG-3 is required throughout an animal's life for germ cells to initiate spermatogenesis. We used RNA-mediated interference to demonstrate that fog-3 is indeed required continuously, which is consistent with this model.

Amino Acid Sequence↗
PubMed2000

Non-invasive assessment of swallowing and respiration in Parkinson's disease.

Oro-pharyngeal dysphagia is well recognised but often underestimated in people with Parkinson's disease. Asymptomatic patients may fail to receive timely advice or therapy, thus placing them at risk. The aim of this study was to determine whether subclinical abnormalities in swallowing and discrete changes in function such as those produced by prompting can be detected by non-invasive methods. We examined 12 people with idiopathic Parkinson's disease and 14 elderly comparison subjects. Five components of respiratory synchronisation and swallowing efficiency were monitored using the Exeter Dysphagia Assessment Technique. Ten feeding trials were administered under standard quiet conditions. The patients were then restudied using verbal prompts when the spoon was presented to the mouth. The duration of two oro-pharyngeal events and the frequency of respiratory variables were compared for unrelated and related samples. Results showed the oral and pharyngeal parts of the swallow to be significantly slower in those with Parkinson's disease. These patients required significantly more swallows to clear a 5-ml bolus, and fewer swallows were followed by expiration. When the patients were verbally prompted, there was a significant reduction in the duration of the oral part. This study demonstrates that non-invasive methods can be used to detect subclinical difficulties with swallowing amongst a group of asymptomatic patients with PD and that these methods are sensitive to small changes in function produced by a verbal cue.

Aged↗
PubMed2000

Air swallowing in Rett syndrome.

The possible causes of excessive swallowing of air leading to bloating, which is common in Rett syndrome (RS), were investigated during feeding and at rest. Seven individuals with RS aged between 4 and 33 years (three with air bloat) underwent feeding videoflouroscopy and concurrent respiration monitoring. The results were compared with a randomly selected group of 11 individuals, aged between 2 and 16 years, with quadriplegic cerebral palsy and feeding problems, some of whom had mild air bloat. All individuals from both groups had isolated pharyngeal swallows and several mouth breathed; this may account for some air swallowing but not the severe air bloat characteristic of RS. Thirty-three individuals with RS aged between 3 and 44 years were monitored for nasal respiration, chest movements, swallowing, and vocal cord position at rest (between feeding). Twenty had air bloat, 17 of whom swallowed air during breath-holding in the same way, and three gulped air during hyperventilation. Of the 13 without air bloat, eight did not have recurrent breath-holding and five did, but without concurrent air swallowing. Several methods for reducing air swallowing in apnoea were investigated. The most successful was a dummy with an air leak, but this was poorly tolerated and could only be used for short periods of time. Apnoeas and air bloat are often worse when individuals are distressed and may in some individuals be reduced by anxiolytic medications.

Adolescent↗
PubMed2000

Non-invasive technique for assessment and management planning of oral-pharyngeal dysphagia in children with cerebral palsy.

The non-invasive Exeter Dysphagia Assessment Technique (EDAT) was evaluated as a method of assessing the aetiology of dysphagia in children with cerebral palsy (CP). Data were collected from a group of 20 typically developing children (nine girls, 11 boys; age range 7 to 14 years) for comparison with 125 dysphagic children with CP (81 boys, 44 girls; age range 1 to 18 years). The swallowing mechanism has been separated into physiological phases: anticipatory, delivery, oral transit, and oral-pharyngeal. Normal or abnormal function in each phase was recorded and the common causes of any impaired phase were considered, starting with generalized possibilities before focusing on specific parts of swallowing physiology. Data from 125 dysphagic children with CP show marked differences from the data for the typically developing children. Interpreting individual results was valuable in assisting the assessment team to formulate management strategies; two examples are presented. The technique appears to provide a cost-effective, non-invasive, and valuable clinical tool.

Adolescent↗
PubMed2000

Feeding efficiency and respiratory integration in infants with acute viral bronchiolitis.

OBJECTIVE: To examine the effects of bronchiolitis on feeding efficiency and respiratory integration. STUDY DESIGN: We studied 21 infants with bronchiolitis and 21 bottle-fed healthy infants who formed a comparison group. Repeat evaluations of half the bronchiolitis group were performed during recovery. During each feeding study we measured the duration and frequency of sucking, the frequency of single and multiple swallows, the respiratory rate, the postswallow respiratory direction, and the suck and swallow volumes. RESULTS: The infants with bronchiolitis devoted significantly less time to sucking than their healthy peers (P <.05), and the mean suck volume was reduced. Although the frequency of swallowing was slightly higher, the volume of milk consumed per swallow was almost half the amount consumed by the comparison group (P <.01). Coordination of breathing with swallowing was also less effective (P <.01). CONCLUSION: Although most aspects of feeding are less efficient during periods of respiratory illness, others are preserved or recover rapidly. Coordination of breathing during feeding is also significantly impaired.

Acute Disease↗
PubMed2000

TRA-1A regulates transcription of fog-3, which controls germ cell fate in C. elegans.

In C. elegans, the zinc-finger protein TRA-1A is thought to be the final arbiter of somatic sexual identity. We show that fog-3, which is required for germ cells to become sperm rather than oocytes, is a target of TRA-1A. First, northern analyses and RT-PCR experiments indicate that expression of fog-3 is controlled by tra-1. Second, studies of double mutants show that this control could be direct. Third, the fog-3 promoter contains multiple sites that bind TRA-1A in gel shift assays, and mutations in these sites alter activity of fog-3 in vivo. These results establish fog-3 as one of the first known targets of transcriptional regulation by TRA-1A. Furthermore, they show that tra-1 controls a terminal regulator of sexual fate in germ cells, just as it is thought to do in the soma.

Animals↗
PubMed1999

A surgical planning and guidance system for high tibial osteotomy.

OBJECTIVE: To develop a three-dimensional pre-surgical planner and an intraoperative guidance system for high tibial osteotomy. The parameters that describe the placement and orientation of the osteotomy resection planes were to be transmitted to an accompanying guidance system that allowed the surgeon to reproducibly perform the planned procedure. MATERIALS AND METHODS: The planning system and guidance system were coded using OpenGL on UNIX workstations. In vitro tests were performed to compare the reproducibility of the computer-enhanced technique to that of the traditional technique, and an in vivo pilot study was initiated. RESULTS: In vitro, the computer-enhanced technique produced a significant reduction, by one half, in both the maximum error of correction and the standard deviation of the correction error. Preliminary in vivo results on six patients suggest that similar error diminution will occur during regular clinical application of the technique. CONCLUSIONS: Both studies showed that the computer system is simple to use. The work suggests that three-dimensional planning and performance of high tibial osteotomy is essential for accurate correction of the alignment of the lower limb.

Computer Simulation↗
PubMed1999

Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.

Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that show superiority of any particular dose are lacking. We compared metabolic ratios from six different dextromethorphan phenotyping doses to ascertain whether linearity existed over a dosage range. Forty subjects were enrolled in the study. Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and 1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6 activity. Single blood samples were obtained for CYP2D6 genotyping, which revealed one poor metabolizer and 39 extensive metabolizers. A statistical difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg dose compared with the other four doses. None of the 39 genotypic extensive metabolizers were incorrectly phenotyped with any of these doses. These data support the use of moderate doses of dextromethorphan for phenotyping to avoid dose dependency.

Adult↗
PubMed1999

C. elegans MAC-1, an essential member of the AAA family of ATPases, can bind CED-4 and prevent cell death.

In the nematode Caenorhabditis elegans, CED-4 plays a central role in the regulation of programmed cell death. To identify proteins with essential or pleiotropic activities that might also regulate cell death, we used the yeast two-hybrid system to screen for CED-4-binding proteins. We identified MAC-1, a member of the AAA family of ATPases that is similar to Smallminded of Drosophila. Immunoprecipitation studies confirm that MAC-1 interacts with CED-4, and also with Apaf-1, the mammalian homologue of CED-4. Furthermore, MAC-1 can form a multi-protein complex that also includes CED-3 or CED-9. A MAC-1 transgene under the control of a heat shock promoter prevents some natural cell deaths in C. elegans, and this protection is enhanced in a ced-9(n1950sd)/+ genetic background. We observe a similar effect in mammalian cells, where expression of MAC-1 can prevent CED-4 and CED-3 from inducing apoptosis. Finally, mac-1 is an essential gene, since inactivation by RNA-mediated interference causes worms to arrest early in larval development. This arrest is similar to that observed in Smallminded mutants, but is not related to the ability of MAC-1 to bind CED-4, since it still occurs in ced-3 or ced-4 null mutants. These results suggest that MAC-1 identifies a new class of proteins that are essential for development, and which might regulate cell death in specific circumstances.

Adenosine Triphosphatases↗
PubMed1998

Total knee arthroplasty kinematics. Computer simulation and intraoperative evaluation.

The goal of this work was to develop computer simulations for intraoperative testing of the passive kinematics of knee prostheses. These are based on an anatomic model of the reconstructed joint, represented in the sagittal plane. A femoral component and a tibial component are linked by 3 springs that model the relevant ligaments, with the posterior cruciate providing the primary constraint. The components' behavior at each flexion angle is obtained by minimizing the total strain energy stored in the ligaments. Simulations were performed in vivo on 10 Interax implants (Howmedica International, Stain, UK) and showed good agreement with intraoperative observations, allowing monitoring of new parameters such as contact point motion, ligament strains, and the energetic state of the knee. This work contributes to the comprehension of individual knee kinematics after total knee arthroplasty, to improve long-term results and standardize the evaluation of the results of joint restoration.

Arthroplasty, Replacement, Knee↗
PubMed1997

Comparative review of techniques for recording respiratory events at rest and during deglutition.

The coordination between swallowing and respiration is essential for safe feeding, and noninvasive feeding-respiratory instrumentation has been used in feeding and dysphagia assessment. Sometimes there are differences of interpretation of the data produced by the various respiratory monitoring techniques, some of which may be inappropriate for observing the rapid respiratory events associated with deglutition. Following a review of each of the main techniques employed for recording resting, pre-feeding, feeding, and post-feeding respiration on different subject groups (infants, children, and adults), a critical comparison of the methods is illustrated by simultaneous recordings from various respiratory transducers. As a result, a minimal combination of instruments is recommended which can provide the necessary respiratory information for routine feeding assessments in a clinical environment.

Adult↗
PubMed1997

Feeding ability in Rett syndrome.

Feeding abilities in 20 individuals with Rett syndrome aged 1 1/2 to 33 years were investigated by history and clinical assessment during a meal, followed by videofluoroscopy of feeding. All were shown to have reduced movements of the mid and posterior tongue, with premature spillover of food and liquid from the mouth into the pharynx. They also showed delayed pharyngeal swallow, but otherwise pharyngeal problems were minimal. These findings were noted to be similar to those in Parkinson's disease. Those individuals with the most general neurological impairment tended to have the worst feeding problems and were smaller and malnourished.

Activities of Daily Living↗
PubMed1997

Deglutition apnoea as indicator of maturation of suckle feeding in bottle-fed preterm infants.

The maturation of deglutition apnoea time was investigated in 42 bottle-fed preterm infants, 28 to 37 weeks gestation, and in 29 normal term infants as a comparison group. Deglutition apnoea times reduced as infants matured, as did the number and length of episodes of multiple-swallow deglutition apnoea. The maturation appears related to developmental age (gestation) rather than feeding experience (postnatal age). Prolonged (> 4 seconds) episodes of deglutition apnoea remained significantly more frequent in preterm infants reaching term postconceptual age compared to term infants. However, multiple-swallow deglutition apnoeas also occurred in the term comparison group, showing that maturation of this aspect is not complete at term gestation. The establishment of normal data for maturation should be valuable in assessing infants with feeding difficulties as well as for evaluation of neurological maturity and functioning of ventilatory control during feeding.

Apnea↗
PubMed1997

Respiration patterns during feeding in Rett syndrome.

Feeding problems are common in Rett syndrome in which there are characteristic oropharyngeal abnormalities. This study investigated the ways in which individuals regulated their respiration accordingly, and how this affected their overall feeding ability. Respiration during feeding was studied in 28 individuals, recording nasal airflow, chest and abdominal movements, and swallow sounds. Time to first swallow was defined as that between introduction of liquid/solid on a spoon and the first swallow. Six individuals also had videofluoroscopy with simultaneous respiration monitoring. Results indicated different respiratory patterns according to the time to first swallow and neurological status; the amount of time spent in apnoea was particularly important. Videofluoroscopy showed that apnoeas occurred most often when liquid was delayed in the pharynx, but this could be overcome in subjects with a lower level of disability. The carer's estimate of the time for feeding was significantly related to the time spent in apnoea with liquids.

Adolescent↗
PubMed1996

Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2.

The ces (for cell-death specification) genes of the nematode Caenorhabditis elegans control the cell-death fate of individual cell types and are candidates for being the regulators of an evolutionarily conserved general pathway of programmed cell death. Here we present what we believe is the first molecular characterization of a ces gene. We cloned the gene ces-2, which is required to activate programmed cell death in the sister cells of the serotoninergic neurosecretory motor (NSM) neurons, and found that ces-2 encodes a basic region leucine-zipper (bZIP) transcription factor. The CES-2 protein is most similar to members of the PAR (proline- and acid-rich) subfamily of bZIP proteins and has DNA-binding specificity like that of PAR-family proteins. An oncogenic form of the mammalian PAR-family protein, hepatic leukaemia factor (HLF), is reported to effect programmed cell death in mammalian cells. On the basis of these observations, we suggest that some CES-2/PAR family transcription factors are evolutionary conserved regulators of programmed cell death.

Amino Acid Sequence↗
PubMed1996

Effortful touch with minimum movement: revisited.

The ecological static moment-torque model proposed by C. Carello, P. Fitzpatrick, I. Domaniewicz, T.C. Chan, and M.T. Turvey (1992) does not uniquely explain the perception of rod length by static holding. Guided by a mechanical analysis of the gravitational forces and torques produced in the hand as it statically holds rods of different lengths and materials at different orientations, we offer 2 additional theoretical explanations, the force-torque and weight-percept models. Experiment 1 demonstrates that all 3 models predict perceived rod length with considerable success. Experiment 2 provides clear experimental support for the force-torque and weight-percept models over the static moment-torque model. Experiment 3 pits the former 2 models against each other. Current results favor the weight-percept model. Implications for theories of haptic weight perception and design of a new tactile sensor are also considered.

Adolescent↗