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Biomedical subjects

R Wheeler

Publications and source records attributed to R Wheeler.

At least 19 recordsLinked to original sources
PubMed2001

Evidence that an imprinted gene on the X chromosome increases ovulation rate in sheep.

Ovulation rate records from 1311 female progeny of 50 Coopworth rams were used to study the inheritance of ovulation rate in a screened high prolificacy sheep flock. Breeding values (BV) for ovulation rate for 33 sires used within the screened flock and ovulation rate deviations for a further 17 sires progeny tested in commercial flocks suggest that a major gene (WOODLANDS: gene) for ovulation rate with a non-Mendelian inheritance pattern is segregating in a family line. Rams assigned as carriers of the putative gene did not produce carrier sons (zero of three), and this coupled with the observation that daughters of carrier rams had ovulation rates of 0. 39 (standard error of difference [SED] = 0.06) higher than contemporaries without a significant increase in the variance of log ovulation rate strongly suggests that the gene is on the X chromosome. The evidence suggests that the gene is also maternally imprinted because ovulation rate data indicate that it is expressed where females inherit a paternal allele but is silenced when inherited on a maternal allele. Maternal granddaughters of carrier rams had mean ovulation rates that were only 0.02 (SED = 0.06) higher than noncarrier ewes from the same flock. Furthermore, carrier dams expressing the gene (paternal allele) had 24 sons, none of which had female offspring that expressed the gene, whereas carrier dams not expressing the gene (maternal allele) had 7 out of 17 sons that had female progeny expressing the gene. There is no evidence of the infertility that occurs in homozygous ewes carrying the X-linked Inverdale gene. Collectively, these results suggest the existence of a novel gene for prolificacy located on the X chromosome that is maternally imprinted. The WOODLANDS: gene was only expressed upon paternal inheritance from carrier males that were the progeny of nonexpressing carrier dams. The gene was not expressed in ewes that received it from either carrier dams (expressing or nonexpressing) or from carrier males that were the progeny of expressing carrier dams.

Animals↗
PubMed2000

Optimizing reduced-space sequence analysis.

MOTIVATION: Dynamic programming is the core algorithm of sequence comparison, alignment and linear hidden Markov model (HMM) training. For a pair of sequence lengths m and n, the problem can be solved readily in O(mn)time and O(mn)space. The checkpoint algorithm introduced by Grice et al. (CABIOS, 13, 45--53, 1997) runs in O(Lmn)time and O(Lm(L) square root of n)space, where L is a positive integer determined by m, n, and the amount of available workspace. The algorithm is appropriate for many string comparison problems, including all-paths and single-best-path hidden Markov model training, and is readily parallelizable. The checkpoint algorithm has a diagonal version that can solve the single-best-path alignment problem in O(mn)time and O(m + n)space. RESULTS: In this work, we improve performance by analyzing optimal checkpoint placement. The improved row checkpoint algorithm performs up to one half the computation of the original algorithm. The improved diagonal checkpoint algorithm performs up to 35% fewer computational steps than the original. We modified the SAM hidden Markov modeling package to use the improved row checkpoint algorithm. For a fixed sequence length, the new version is up to 33% faster for all-paths and 56% faster for single-best-path HMM training, depending on sequence length and allocated memory. Over a typical set of protein sequence lengths, the improvement is approximately 10%.

Algorithms↗
PubMed2000

Use of membrane vesicles to investigate drug interactions with transporter proteins, P-glycoprotein and multidrug resistance-associated protein.

BACKGROUND: The ATP-dependent drug transporter proteins, P-glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP) are known to be involved in drug efflux that reduces drug accumulation and so renders tumor cells resistant to the cytotoxic effects of a number of anticancer agents. The ways in which these transporters bring about drug expulsion are not fully explained and may involve intracellular factors as well. Thus detailed evidence may be difficult to obtain from studies on intact cells. MATERIAL AND METHODS: Inside-out plasma membrane vesicles prepared from multidrug-resistant cells expressing high amounts of Pgp or of MRP provide a simpler system for investigating the interactions of putative substrates and resistance modifiers with the transport process. We consider here some aspects of the accumulation of radiolabelled vincristine and of dinitrophenol glutathione conjugate by these vesicles and demonstrate the usefulness of this approach for determining whether potential inhibitors have their effects on transport at the cell membrane or by more indirect means. CONCLUSIONS: We show that information gained from analysis of the ATP-dependence, time course and osmotic sensitivity of accumulation is helpful in distinguishing between transport and changes in binding. We have also used the technique to demonstrate the effects of the resistance modifier, XR-9051 on Pgp-mediated transport and to explore interactions of MK571, indomethacin and ethacrynic acid with MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Basic electrocardiogram interpretation for the OR nurse.

A basic understanding of electrocardiogram (EKG) interpretation is necessary for all perioperative nurses. This includes knowledge of the conduction system of the heart and skill at identification of normal and abnormal EKG rhythms. This article discusses basic EKG interpretation for OR nurses.

Arrhythmias, Cardiac↗
PubMed1999

The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8.

The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation. Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C-->G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.

Amino Acid Sequence↗
PubMed1999

Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: preliminary results of two pilot trials using paclitaxel and cisplatin.

Chemotherapy has been integrated into the initial treatment of patients with locally advanced squamous cell cancer of the head and neck to improve locoregional control and survival. Two strategies for improving these outcomes are the use of new, potentially more effective drugs either with concurrent radiotherapy or as induction regimens. Because of its inherent activity against squamous cell cancer of the head and neck and its radiation-sensitizing properties, paclitaxel may be a valuable agent in the treatment of this patient population. We describe the preliminary results of two trials that evaluated the combination of paclitaxel and cisplatin in patients with locally advanced disease: a phase I trial of weekly paclitaxel and cisplatin with concurrent postoperative radiation therapy in patients with high-risk disease and a phase I/II trial of paclitaxel as a 96-hour infusion in combination with cisplatin as induction therapy. These studies identified tolerable doses of paclitaxel and cisplatin administered in these settings, with apparent clinical activity. These trials formed the basis for subsequent evaluation of induction paclitaxel and cisplatin followed by definitive radiotherapy and concurrent weekly paclitaxel and cisplatin plus radiotherapy.

Adult↗
PubMed1998

Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells.

T helper cell type 1 (Th1) and 2 (Th2) are central to immune regulation. However, no stable cell surface marker capable of distinguishing and separating these two subsets of CD4(+) cells has yet been found. Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli. Antibody against a peptide derived from ST2L strongly and stably labeled the surface of cloned Th2s but not Th1s, and Th2s but not Th1s derived from naive T cells of ovalbumin T cell receptor-alpha/beta transgenic mice. Three-color single cell flow cytometric analysis shows that cell surface ST2L coexpressed with intracellular interleukin (IL)-4, but not with interferon (IFN)-gamma. The antibody selectively lysed Th2s in vitro in a complement-dependent manner. In vivo, it enhanced Th1 responses by increasing IFN-gamma production and decreasing IL-4 and IL-5 synthesis. It induced resistance to Leishmania major infection in BALB/c mice and exacerbated collagen-induced arthritis in DBA/1 mice. Thus, ST2L is a stable marker distinguishing Th2s from Th1s and is also associated with Th2 functions. Hence, it may be a target for therapeutic intervention.

Animals↗
PubMed1997

Transcriptional analysis of the Caulobacter 4.5 S RNA ffs gene and the physiological basis of an ffs mutant with a Ts phenotype.

A temperature-sensitive (ts) mutation in the ffs gene, encoding 4.5 S RNA, gives rise to cell division and DNA replication defects in Caulobacter crescentus. The ffs gene is transcribed throughout the cell-cycle and is transcribed at similar rates in mutant (ffs36) and wild-type strains, but in the mutant the 4.5 S RNA is unstable leading to lower 4.5 S RNA levels. The ffs36 phenotype results from a single base change in one of the non-conserved stems of the mature RNA, and is completely rescued by a compensating mutation in the opposite strand, providing confirmation of the predicted secondary structure of the 4.5 S RNA. The Caulobacter ffs gene was shown to be functionally comparable to the Escherichia coli ffs gene by complementation. Comparison of the ffs36 strain to a ts secA strain of Caulobacter, also having cell-cycle and DNA replication phenotypes, showed that both exhibit a permanent induction of a heat shock response at the restrictive temperature. To explain the phenotype of both the secA and ffs36 strains, we propose that a cell-cycle checkpoint prevents further progression through the cell-cycle in response to increased intracellular levels of heat shock and misfolded proteins.

Amino Acid Sequence↗
PubMed1997

Genetic linkage analysis of a variant of juvenile onset neuronal ceroid lipofuscinosis with granular osmiophilic deposits.

A number of variant forms of the neuronal ceroid lipofuscinoses (NCL) have been described and remain unmapped. The genes for infantile (CLN1), juvenile (CLN3) and Finnish-variant late-infantile (CLN5) have previously been mapped to chromosome regions 1p32, 16p12 and 13q21.1-32 respectively. The locus for a variant form of juvenile onset NCL characterised by cytosomal granular osmiophilic deposits (GROD) has been excluded from the CLN3 region of chromosome 16. This study describes the outcome of genetic linkage analysis in four families with this variant at the loci for the CLN1 and CLN5 genes. Using highly informative microsatellite markers tightly linked to the CLN5 locus we have excluded the JNCL variant with GROD from this region. Marker typing across the CLN1 region suggests that JNCL with GROD may be an allelic variant of infantile NCL.

Adolescent↗
PubMed1997

Neonatal encephalopathy with a pungent body odour.

A neonate had transient unexplained bleeding into the gut, severe encephalopathy, and an abnormal pungent body odour. An inherited metabolic defect was excluded. The malodour was due to methanethiol and hydrogen sulphide, identified in urine. These sulphur compounds may have contributed to encephalopathy. Colonic bacteria were the probable source.

Brain Diseases↗
PubMed1996

Resection and primary anastomosis in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the most common surgical emergency in the newborn. Up to half of babies with NEC develop advanced disease requiring surgical intervention. Options include peritoneal drainage under local anaesthetic, enterostomy only, resection and enterostomies, and resection with primary anastomosis. Resection with enterostomies is favoured by many paediatric surgeons but management of neonatal enterostomies can be difficult. The outcome of 26 infants undergoing surgery for advanced NEC over a 2-year period is reviewed. Resection and primary anastomosis was possible in 18 infants of whom two (11%) died. Recurrent NEC developed in four (22%) and strictures in three (17%) of these infants. An initial enterostomy was fashioned in eight infants, three following resection of necrotic intestine and five as a proximal diverting stoma in infants with pan-intestinal involvement. Five of these eight infants died (63%), giving an overall mortality of 27%. Primary anastomosis is an effective procedure following resection of grossly involved intestine in infants with NEC. The mortality and morbidity in this series compared well with those reported for staged procedures.

Anastomosis, Surgical↗
PubMed1996

Gastrostomy and growth in dystrophic epidermolysis bullosa.

Chronic malnutrition and growth failure are features of severe dystrophic epidermolysis bullosa (DEB). Conventional dietetic intervention is of limited benefit. Oesophageal dilatation or reconstruction to alleviate stricture is associated with substantial risks. Surgical placement of a feeding gastrostomy is a comparatively straightforward procedure, provided that specialized anaesthetic and surgical techniques are employed. Gastrostomy insertion was undertaken in 18 children with severe DEB and the effects of this intervention were retrospectively evaluated. The majority received button devices (inserted primarily) and gastrostomy feeding supplemented oral intake. One year postoperatively, the average increase in weight standard deviation scores (SDS) of 13 patients was 0.9 SDS (95% confidence interval 0.44, 1.35) and in height 0.42 SDS (95% confidence interval 0.05, 0.79). One patient developed an incisional hernia and four patients experienced minor leakage around the gastrostomy entry site. Two patients never accepted their gastrostomies, which were therefore removed. Two further patients died for reasons unrelated to the procedure. Our observations suggest that gastrostomy feeding can play a valuable role in severe DEB and is associated with minimal morbidity. Such intervention is best undertaken before growth failure is established, and prior to puberty.

Adolescent↗
PubMed1995

Seasonal respiratory viral infections. Impact on infants with chronic lung disease following discharge from the neonatal intensive care unit.

OBJECTIVE: To determine the frequency and severity of acute respiratory infections in infants with bronchopulmonary dysplasia following discharge from the neonatal intensive care unit. DESIGN: A prospective cohort study of 30 oxygen-dependent children who were younger than 2 years (mean age, 9.8 months; range, 3 to 24 months) were studied from September 1990 through April 1991. MEASUREMENTS/RESULTS: During the study, 101 (90.2%) of 112 visits for illness were prompted by new or worsening respiratory symptoms. Diagnoses included upper respiratory tract infection (30.4%), otitis media (26.0%), pneumonia (11.1%), acute exacerbation of bronchopulmonary dysplasia (10.4%), reactive airway disease (9.6%), and bronchiolitis (5.9%). Among these children, an increase in the fraction of inspired oxygen was necessary during 43% of visits. Ten children were hospitalized on 25 occasions for a mean of 37.6 hospital days per child (range, 1 to 107 days), and mean length of stay for each hospitalization was 15 days (median, 6 days). Five children were admitted to the pediatric intensive care unit. Respiratory viruses isolated included respiratory syncytial virus (n = 7), parainfluenza 3 virus (n = 3), and adenovirus (n = 2). No isolates of influenza A or B were detected. Anthropometrics at study entry and study end were converted to z scores as descriptors of weight for age, height for age, and weight for height. Growth improved during the 8 months of the study; however, overall, the children were leaner at study end than at study entry. CONCLUSIONS: In children with bronchopulmonary dysplasia, respiratory viral infections led to significant morbidity, which included long and frequent hospitalizations during the peak of the respiratory viral season. Although weight and linear growth increased throughout the study, patients were leaner at study conclusion than at study entry.

Bronchopulmonary Dysplasia↗
PubMed1995

Antegrade continence enemas in the management of intractable faecal incontinence.

The introduction of the Malone procedure has improved the outlook for children with severe faecal incontinence. Phosphate and saline enemas are administered through the exteriorized appendix in antegrade fashion to achieve evacuation and ensure cleanliness. The appendix functions as a non-refluxing catheterizable channel: If it is not available for use, a tubularized caecal flap is a safe alternative. We have constructed Malone stomas using the appendix in 20 patients and another seven patients have undergone the caecal flap modification. The mean age was 8.6 years. Eleven of the patients were boys and 16 (59%) were girls. Six children required dilatation or revision of their stomas for stenosis. One developed small bowel obstruction and another has stopped using the stoma. The results of the continence enemas were considered to be very good by the vast majority of patients and their carers. Our recent experience suggests that bisacodyl may be a valuable adjunct to the antegrade enemas of phosphate and saline. We believe that this procedure may be extended with benefit to adults with serious faecal incontinence in whom standard measures have failed.

Anastomosis, Surgical↗
PubMed1994

Object-oriented model-driven control.

A monitoring and control subsystem architecture has been developed that capitalizes on the use of model-driven monitoring and predictive control, knowledge-based data representation, and artificial reasoning in an operator support mode. We have developed an object-oriented model of a Controlled Ecological Life Support System (CELSS). The model, based on the NASA Kennedy Space Center CELSS breadboard data, tracks carbon, hydrogen, and oxygen, carbon dioxide, and water. It estimates and tracks resource-related parameters such as mass, energy, and manpower measurements such as growing area required for balance. We are developing an interface with the breadboard systems that is compatible with artificial reasoning. Initial work is being done on use of expert systems and user interface development. This paper presents our approach to defining universally applicable CELSS monitor and control issues, and implementing appropriate monitor and control capability for a particular instance: the KSC CELSS Breadboard Facility.

Animals↗