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Biomedical subjects

D Norris

Publications and source records attributed to D Norris.

At least 37 records · Page 2Linked to original sources
PubMed1998

The SFP1 gene product of Saccharomyces cerevisiae regulates G2/M transitions during the mitotic cell cycle and DNA-damage response.

In eukaryotic cells, checkpoint pathways arrest cell-cycle progression if a particular event has failed to complete appropriately or if an important intracellular structure is defective or damaged. Saccharomyces cerevisiae strains that lack the SFP1 gene fail to arrest at the G2 DNA-damage checkpoint in response to genomic injury, but maintain their ability to arrest at the replication and spindle-assembly checkpoints. sfp1Delta mutants are characterized by a premature entrance into mitosis during a normal (undamaged) cell cycle, while strains that overexpress Sfp1p exhibit delays in G2. Sfp1p therefore acts as a repressor of the G2/M transition, both in the normal cell cycle and in the G2 checkpoint pathway. Sfp1 is a nuclear protein with two Cys2His2 zinc-finger domains commonly found in transcription factors. We propose that Sfp1p regulates the expression of gene products involved in the G2/M transition during the mitotic cell cycle and the DNA-damage response. In support of this model, overexpression of Sfp1p induces the expression of the PDS1 gene, which is known to encode a protein that regulates the G2 checkpoint.

Amino Acid Sequence↗
PubMed1998

Human acquired naevi are clonal.

Naevi are nearly universal in humans, yet their cellular origin remains obscure. Understanding the cellular and molecular mechanisms involved in naevus development may be important in understanding the pathogenesis of malignant melanoma. This study aimed to discover whether human acquired naevi are premalignant by examining whether they are clonal. To determine clonality naevi were removed and separated into epithelial and naevus cell fractions and the DNA prepared and digested by a methylase-sensitive restriction enzyme. The highly polymorphic X-linked human androgen receptor (HUMARA) gene was then amplified by a polymerase chain reaction and examined by gel electrophoresis and autoradiography. In polyclonal cell populations both alleles are usually seen as two distinct bands, whilst clonal populations yield a single band. Using these techniques 35 junctional naevi, 11 compound naevi and one congenital naevus from 40 women were examined. Of these, 81% (37 out of 47) of the naevi were clonal, while all of the epithelial cell controls were polyclonal. These data are novel and have great importance for understanding the development of human acquired naevi and cutaneous malignant melanoma. Because monoclonality is a marker of neoplasia, or preneoplasia, our data support the hypothesis that common acquired naevi should be considered to be premalignant lesions, similar to colonic polyps. Such lesions may have undergone the first molecular step(s) in the development of cutaneous malignant melanoma. Understanding the events involved may lead to new methods of prevention and treatment.

Clone Cells↗
PubMed1997

Ho endonuclease cleaves MAT DNA in vitro by an inefficient stoichiometric reaction mechanism.

Mating type switching in Saccharomyces cerevisiae initiates when Ho endonuclease makes a double-stranded DNA break at the yeast MAT locus. In this report, we characterize the fundamental biochemical properties of Ho. Using an assay that monitors cleavage of a MAT plasmid, we define an optimal in vitro reaction, showing in particular that the enzyme has a stringent requirement for zinc ions. This suggests that zinc finger motifs present in Ho are important for cleavage. The most unexpected feature of Ho, however, is its extreme inefficiency. Maximal cleavage occurs when Ho is present at a concentration of 1 molecule/3 base pairs of substrate DNA. Even under these conditions, complete digestion requires >2 h. This inefficiency results from two characteristics of Ho. First, Ho recycles slowly from cleaved product to new substrate, in part because the enzyme has an affinity for one end of its double strand break product. Second, high levels of cleavage in the in vitro reaction correlate with the appearance of large protein-DNA aggregates. At optimal Ho concentrations, these latter aggregates, referred to as "florettes," have an ordered structure consisting of a densely staining central region and loops of radiating DNA. These unusual properties may indicate that Ho plays a role in other aspects of mating type switching subsequent to double strand break formation.

DNA, Fungal↗
PubMed1997

The possible-word constraint in the segmentation of continuous speech.

We propose that word recognition in continuous speech is subject to constraints on what may constitute a viable word of the language. This Possible-Word Constraint (PWC) reduces activation of candidate words if their recognition would imply word status for adjacent input which could not be a word--for instance, a single consonant. In two word-spotting experiments, listeners found it much harder to detect apple, for example, in fapple (where [f] alone would be an impossible word), than in vuffapple (where vuff could be a word of English). We demonstrate that the PWC can readily be implemented in a competition-based model of continuous speech recognition, as a constraint on the process of competition between candidate words; where a stretch of speech between a candidate word and a (known or likely) word boundary is not a possible word, activation of the candidate word is reduced. This implementation accurately simulates both the present results and data from a range of earlier studies of speech segmentation.

Analysis of Variance↗
PubMed1997

Progression into the first meiotic division is sensitive to histone H2A-H2B dimer concentration in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae contains two genes for histone H2A and two for histone H2B located in two divergently transcribed gene pairs: HTA1-HTB1 and HTA2-HTB2. Diploid strains lacking HTA1-HTB1 (hta1-htb1 delta/hta1-htb1 delta, HTA2-HTB2/HTA2-HTB2) grow vegetatively, but will not sporulate. This sporulation phenotype results from a partial depletion of H2A-H2B dimers. Since the expression patterns of HTA1-HTB1 and HTA2-HTB2 are similar in mitosis and meiosis, the sporulation pathway is therefore more sensitive than the mitotic cycle to depletion of H2A-H2B dimers. After completing premeiotic DNA replication, commitment to meiotic recombination, and chiasma resolution, the hta1-htb1 delta/hta1-htb1 delta, HTA2-HTB2/HTA2-HTB2 mutant arrests before the first meiotic division. The arrest is not due to any obvious disruptions in spindle pole bodies or microtubules. The meiotic block is not bypassed in backgrounds homozygous for spo13, rad50 delta, or rad9 delta mutations, but is bypassed in the presence of hydroxyurea, a drug known to inhibit DNA chain elongation. We hypothesize that the deposition of H2A-H2B dimers in the mutant is unable to keep pace with the replication fork, thereby leading to a disruption in chromosome structure that interferes with the meiotic divisions.

Histones↗
PubMed1997

Identification of a protein that binds to the Ho endonuclease recognition sequence at the yeast mating type locus.

Mating type switching in Saccharomyces cerevisiae initiates when Ho endonuclease makes a site-specific double-stranded break at MAT, the yeast mating type locus. To identify other proteins involved in this process, we examined whether extracts prepared from ho- mutants contain additional factors that bind near the recognition sequence for Ho. Using an electrophoretic mobility shift assay, we isolated a chromatographic fraction that contains an activity, named YZbp, which binds to two sequences flanking the recognition sequence at MATalpha and to one sequence overlapping it at MATa. MAT plasmids carrying mutations in the YZbp recognition sequence are cleaved by purified Ho at wild-type efficiencies in an in vitro assay. These same plasmids, however, are not cleaved by Ho inside cells, demonstrating that YZbp acts as a positive activator of in vivo cleavage. YZbp is present in all cell types, even those not undergoing mating type switching, suggesting that it has additional cellular functions.

Binding Sites↗
PubMed1996

Delayed bilateral spinal anaesthesia following interscalene brachial plexus block.

PURPOSE: To present a case of delayed neuraxial blockade after interscalene brachial plexus block. CLINICAL FEATURES: A 65-yr-old lady presenting for radial head excision underwent a right interscalene block using bupivacaine and lidocaine. She experienced excellent anaesthesia and had stable vital signs for the duration of surgery. However, after 65 min, she developed signs of bilateral neuraxial block, progressing over the following hour to involve the cervical to lumbar dermatomes, with sparing of the phrenic nerves. The patient remained alert and communicative throughout with haemodynamic stability. Two days following the block, the patient experienced severe frontal and occipital pain, typical of a post dural puncture headache, which responded to fluids and recumbency. CONCLUSION: This example of delayed central neural blockade complicating interscalene block is presented in contrast to other reports, which have usually occurred promptly after injection, accompanied by complete sensory and motor block requiring cardio-respiratory support. The presumed mechanism of the delayed onset of bilateral neuraxial spread was a dural cuff puncture with slow CSF spread from a plexus sheath "depot" of local anaesthetic.

Aged↗
PubMed1996

The mouse Smcx gene exhibits developmental and tissue specific variation in degree of escape from X inactivation.

The Smcx gene is the first known example of a non-pseudoautosomal X-linked gene in mouse that normally escapes X chromosome inactivation. We have analysed the kinetics of escape at different stages of development, and in adult tissues. Our results demonstrate that Smcx exhibits partial escape from X inactivation in embryos, in extraembryonic lineages where paternally imprinted X inactivation occurs and also in adult tissues. The degree of escape in different tissues is highly variable, the level of transcript from the inactive X allele representing between 20% and 70% of the active X allele. Partial escape is also seen in clones derived from haematopoietic stem cells, suggesting that partial repression of the inactive X allele is at the level of individual cells. This contrasts with classical position effect variegation (PEV), where a given gene is either active or silent in a given cell and its clonal derivatives. We discuss the implications of these results with respect to mechanisms of X inactivation and escape.

Alleles↗
PubMed1996

A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2.

The Sox gene family consists of a large number of embryonically expressed genes related via the possession of a 79-amino-acid DNA-binding domain known as the HMG box. Partial clones for the first three Sox genes (al-a3) were isolated by homology to the HMG box of the testis-determining gene Sry and are now termed Sox-1, Sox-2 and Sox-3, Sox-3 is highly conserved amongst mammalian species and is located on the X chromosome. This has led to the proposal that Sry evolved from Sox-3. We present the cloning and sequencing of Sox-1, Sox-2 and Sox-3 from the mouse and show that Sox-3 is most closely relate to Sry. We also confirm that mouse Sox-3 is located on the X chromosome between Hprt and Dmd. Analysis of the distribution of Sox-3 RNA shows that its main site of expression is in the developing central nervous system, suggesting a role for Sox-3 in neural development. Moreover, we demonstrate that Sox-3, as well as Sox-1 and Sox-2, are expressed in the urogenital ridge and that their protein products are able to bind the same DNA sequence motif as Sry in vitro, but with different affinities. These observations prompt discussion of an evolutionary link between the genes and support the model that Sry has evolved from Sox-3. However our findings imply that if this is true, then Sry has undergone concomitant changes resulting in loss of CNS expression and altered DNA-binding properties.

Amino Acid Sequence↗
PubMed1996

Speeded detection of vowels: a cross-linguistic study.

In four experiments, listeners' response times to detect vowel targets in spoken input were measured. The first three experiments were conducted in English. In two, one using real words and the other, nonwords, detection accuracy was low, targets in initial syllables were detected more slowly than targets in final syllables, and both response time and missed-response rate were inversely correlated with vowel duration. In a third experiment, the speech context for some subjects included all English vowels, while for others, only five relatively distinct vowels occurred. This manipulation had essentially no effect, and the same response pattern was again observed. A fourth experiment, conducted in Spanish, replicated the results in the first three experiments, except that miss rate was here unrelated to vowel duration. We propose that listeners' responses to vowel targets in naturally spoken input are effectively cautious, reflecting realistic appreciation of vowel variability in natural context.

Adult↗
PubMed1995

Competition and segmentation in spoken-word recognition.

Spoken utterances contain few reliable cues to word boundaries, but listeners nonetheless experience little difficulty identifying words in continuous speech. The authors present data and simulations that suggest that this ability is best accounted for by a model of spoken-word recognition combining competition between alternative lexical candidates, and sensitivity to prosodic structure. In a word-spotting experiment, stress pattern effects emerged most clearly when there were many competing lexical candidates for part of the input. Thus, competition between simultaneously active word candidates can modulate the size of prosodic effects, which suggests that spoken-word recognition must be sensitive both to prosodic structure and to the effects of competition. A version of the Shortlist model (D. G. Norris, 1994b) incorporating the Metrical Segmentation Strategy (A. Cutler & D. Norris, 1988) accurately simulates the results using a lexicon of more than 25,000 words.

Adolescent↗
PubMed1994

Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome).

OBJECTIVE: To review recent studies of systemic therapy for mycosis fungoides and the Sézary syndrome (cutaneous T-cell lymphomas). DATA SOURCES: English-language articles indexed in MEDLINE from 1988 through 1994. STUDY SELECTION: All therapeutic studies were selected. DATA EXTRACTION: The data were abstracted without judgments on response criteria or patient numbers. Data quality and validity were assessed by independent author reviews. DATA SYNTHESIS: No systemic therapy cures patients with cutaneous T-cell lymphomas. Single and combined chemotherapeutic agents produce high response rates. Whether any of these is preferred is not established. A randomized trial comparing combination chemotherapy plus radiation therapy with topical therapy showed no survival benefit for the combination. Several adenosine analogs and retinoids were active, but their optimal use is uncertain. Interferons are as active as chemotherapeutic agents and may be less toxic. Interferon combined with psoralen plus ultraviolet A light therapy produces high complete response rates and long-lasting remissions. Combinations with other systemic therapies do not increase response rates. Photopheresis therapy should be regarded as experimental. Promising preliminary results were seen with interleukin-2 fusion toxins and several antibody conjugates. CONCLUSIONS: Systemic therapy should be considered effective and palliative. The principles of treating all low-grade lymphomas can be applied. Randomized trials are needed to evaluate new agents (such as a comparison of psoralen plus ultraviolet light with or without interferon), and large phase II trials are needed for new agents such as photopheresis, interleukin-2 fusion toxin, temozolomide, and others.

Combined Modality Therapy↗
PubMed1994

Melanoma: 2. Diagnosis and treatment.

The tumors can progress rapidly from superficial lesions of the epidermis, which are nearly all curable by excision, to invasive cancers unresponsive to current therapy. New strategies for regional and systemic spread include multiagent chemotherapy combined with biologic response modifiers, such as alpha-interferon or interleukin-2. On the early evidence, some of these approaches are promising.

Adult↗
PubMed1994

Melanoma: 1. Clinical characteristics.

The disease is perhaps the clearest instance of a cancer for which early treatment is crucial. Increasing knowledge of risk factors (including brief, intense sun exposure and sunburn damage early in life) aids the identification of persons at highest risk--one reason for physicians not to be pessimistic about the value of urging patients to limit their sun exposure.

Humans↗
PubMed1994

Use of 'split' plateletpheresis products for alloimmunized patients.

Single donor platelets obtained using the COBE Spectra were split into two halves and administered to alloimmunized patients with leukemia at two different points in time. The mean platelet yield was 6.83 x 10(11) (n = 63) with 56% of collections having yields of > 6.0 x 10(11) (i.e. twice the current AABB recommendation for an apheresis platelet transfusion). In 58 instances, the two halves were administered to the same patient 24-96 h apart. The differences in the correct increments of the split transfusions administered 24-48 h apart were not statistically significant, although there were decreased increments after 72 and 96 h of storage. In 5 instances when the CCI for first transfusion was unacceptably low, the second half was successfully transfused to another patient. This study proves it is feasible to split apheresis platelets into two transfusions, and discusses approaches to optimally use this strategy for the transfusion support of alloimmunized patients.

Blood Platelets↗
PubMed1994

Quality improvement through use of medication incident reports.

This paper describes the background to the development of a Medication Incident Report pro forma, for use throughout the Liverpool Health Service. This pro forma is used by Medical, Pharmacy and Nursing staff to report prescription, dispensing and administration of medication errors.

Humans↗
PubMed1993

Correlation of function and energy metabolism in rat ischemic skeletal muscle by 31P-NMR spectroscopy: effects of torbafylline.

The aim of this study was to correlate function of rat ischemic skeletal muscle directly with energy metabolism, to investigate the effects of torbafylline, a novel xanthine derivative potentially useful for the treatment of peripheral vascular occlusive disease and other ailments of skeletal muscle, and to get insight into its mechanism of action. Phosphocreatine (PCr), inorganic phosphate (Pi) and pH were estimated at rest, during induced contractions and during the recovery phase after cessation of electrical stimulation in rat hind limb muscles with two weeks unilateral chronic ligation of the femoral artery. Concomitantly, contraction force was measured in terms of tension developed during the stimulation interval. The effects of torbafylline [7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)3-methylxanthine] on the above parameters were studied after chronic oral gavage (25 mg/kg body weight per day); treatment started the day after surgery and the last drug application was performed the day of the final experiments. Control animals received physiological saline under the same conditions. During rest no major differences could be detected either in PCr and Pi levels or in pH between the different muscles, ischemic or not and treated or not. During compelled contractions, PCr and pH decreased and Pi increased in all muscles. Differences between muscles and treatments emerged as the PCr drop was more pronounced in ischemic saline treated muscles and the Pi increase in drug treated muscles (normal and ischemic) were clearly less marked than in saline treated ones. Contraction force decreased rapidly during the 12 min electrical direct stimulation and fatigability increased from 67% in normal muscle to 88% in ischemic muscle. Drug treatment induced strikingly less fatigability as it was 44.5% in normal and only 62% in ischemic muscle. However, most marked differences in metabolite levels and pH were measured during the recovery period. As an indication of disturbed energy balance, the recovery of PCr, Pi and pH was seriously hampered in ischemic saline treated muscles; especially pH being still significantly decreased during the entire chosen recovery period of 15 min. Torbafylline not only restored function, but also helped the muscle recover faster and better from exhaustion, as all the parameters returned gradually to normal levels.

Animals↗