Biomedical subjects

S A Wood

Publications and source records attributed to S A Wood.

At least 19 recordsLinked to original sources

PubMed2002

Hypothalamic-pituitary-adrenal function.

Basal hypothalamic-pituitary-adrenal (HPA) function is characterised by pulses of corticosterone secretion followed by a transient refractory period when the axis appears to be inhibited. In females pulses of corticosterone secretion occur approximately once per hour with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Pulsatility is altered by genetic programming, early life experiences and reproductive status. Activation of the HPA axis during adjuvant induced arthritis results in an increase in the pulse frequency. This is associated with a marked change in hypothalamic gene expression with a diminution of CRH mRNA and a marked increase of AVP mRNA which becomes the predominant HPA secretagogue.

Adrenal Glands↗

PubMed2001

Measurement of the high energy two-body deuteron photodisintegration differential cross section.

The first measurements of the d(gamma,p)n differential cross section at forward angles and photon energies above 4 GeV were performed at the Thomas Jefferson National Accelerator Facility (JLab). The results indicate evidence of an angular dependent scaling threshold. Results at straight theta(cm) = 37 degrees are consistent with the constituent counting rules for E(gamma) greater, similar 4 GeV, while those at 70 degrees are consistent with the constituent counting rules for E(gamma) greater, similar 1.5 GeV.

Journal Article↗

PubMed2001

An investigation into mechanisms of reflex reinforcement by the Jendrassik manoeuvre.

Tendon jerk and H-reflexes are both potentiated by the Jendrassik manoeuvre, but the mechanism of potentiation remains uncertain. We investigated several possibilities in human subjects. Evidence for fusimotor activation during the Jendrassik manoeuvre was sought by recording the tendon jerk reflex as surface EMG in triceps surae after the muscles had been conditioned to leave their spindles in a slack, insensitive state. Interposing a Jendrassik manoeuvre between conditioning and the test reflex should have increased reflex amplitude by restoring spindle sensitivity, but this was not the case. In humans, a close synergist of the triceps surae is the quadriceps. A possible presynaptic disinhibitory mechanism was investigated by testing the effect of a Jendrassik manoeuvre on facilitation of the soleus H-reflex produced by a quadriceps afferent volley. The Jendrassik manoeuvre failed to increase facilitation, contrary to what would be expected if it reduced the level of tonic presynaptic inhibition; the assumption being that the inhibition acts on both homonymous and synergist afferent terminals. The Jendrassik manoeuvre did not increase the level of ongoing EMG in the soleus during a weak voluntary contraction, indicating that it does not operate by direct facilitation of motoneurones. There was found to be less potentiation of soleus tendon jerk and H-reflexes by the Jendrassik manoeuvre under conditions when spindles in the soleus were likely to have a high resting discharge rate. A remaining possibility is discussed: that the Jendrassik manoeuvre operates by modulation of oligosynaptic pathways that may contribute to the largely monosynaptic reflex response. These experiments demonstrate, with new, more sensitive methods than previously used, that neither is the fusimotor system involved in reinforcement nor are direct excitatory or presynaptic disinhibitory effects on motoneurones. While this confirms the previously prevailing view, none of the lingering uncertainties associated with the methods used now remains.

Adult↗

PubMed2001

Peripartum plasticity within the hypothalamo-pituitary-adrenal axis.

The hypothalamo-pituitary-adrenal (HPA) axis plays important roles in the adaptive changes in physiology that occur during pregnancy and lactation. Although the axis still exhibits a pulsatile pattern of secretion, the normal diurnal rhythm of pulse amplitude is lost during lactation, such that mean basal levels remain constant throughout the day. In addition, the peripartum period is associated with a remarkable plasticity in stress-induced HPA activity, in that the increase of HPA activity normally seen in response to either physical or psychological stresses in the non-reproductive state become severely attenuated or absent in the lactating animal. This stabilization of both basal and stress-induced HPA activity may be important for maintaining a constant endocrine environment, thereby preventing any programming effects on the developing offspring. Attenuation of the stress response is initiated in late pregnancy and is temporally associated with luteolysis, indicating possible steroid hormone involvement. Indeed, mimicking the luteolytic changes in oestrogen and progesterone levels in non-pregnant animals induces a similar attenuation of the stress response. Furthermore down-regulation of the stress response is, at least in part, centrally mediated since in the period following luteolysis rats will show a decreased level of stress-induced neuronal activation of the PVN, as measured by the expression of either c-fos or CRH mRNAs. Persistence of this adapted state is dependent upon the continued suckling stimulus, as removal of the offspring litter rapidly leads to resumption of HPA responses to and the appearance of an exaggerated diurnal rhythm. The underlying mechanisms responsible for this stress hyporesponsiveness may include plasticity of noradrenergic and oxytocin pathways. In view of its role in other reproductive behaviors, a stress-inhibiting effect of oxytocin may reflect a more widespread co-ordinating role in the peripartum animal.

Animals↗

PubMed2001

FAM deubiquitylating enzyme is essential for preimplantation mouse embryo development.

FAM is a developmentally regulated substrate-specific deubiquitylating enzyme. It binds the cell adhesion and signalling molecules beta-catenin and AF-6 in vitro, and stabilises both in mammalian cell culture. To determine if FAM is required at the earliest stages of mouse development we examined its expression and function in preimplantation mouse embryos. FAM is expressed at all stages of preimplantation development from ovulation to implantation. Exposure of two-cell embryos to FAM-specific antisense, but not sense, oligodeoxynucleotides resulted in depletion of the FAM protein and failure of the embryos to develop to blastocysts. Loss of FAM had two physiological effects, namely, a decrease in cleavage rate and an inhibition of cell adhesive events. Depletion of FAM protein was mirrored by a loss of beta-catenin such that very little of either protein remained following 72h culture. The residual beta-catenin was localised to sites of cell-cell contact suggesting that the cytoplasmic pool of beta-catenin is stabilised by FAM. Although AF-6 levels initially decreased they returned to normal. However, the nascent protein was mislocalised at the apical surface of blastomeres. Therefore FAM is required for preimplantation mouse embryo development and regulates beta-catenin and AF-6 in vivo.

Animals↗

PubMed2001

Increased corticosterone pulse frequency during adjuvant-induced arthritis and its relationship to alterations in stress responsiveness.

Frequent blood sampling from males rats was used to study hypothalamic-pituitary-adrenal (HPA) axis activation during arthritis and its association with diminished responses to acute psychological stress. In control rats, corticosterone release occurred in a series of 13 +/- 1 pulses per 24 h. Induction of arthritis by Mycobacterium-adjuvant injection initially increased the rate of hormone release within each pulse and, by day 14 postinjection, when hind-paw inflammation was established, caused a marked increase in pulse frequency to 22 +/- 1 per 24 h leading directly to elevated circulating corticosterone levels. In both control and adjuvant-treated rats, there was a marked response to a 10-min noise stress when the stimulus coincided with a rising or interpulse phase of the endogenous corticosterone rhythm. However, when the noise stress coincided with a falling phase of this rhythm, the response was greatly diminished. Since corticosterone pulse frequency was markedly increased and hence interpulse interval decreased by day 14, there was an increased probability of the noise stress occurring during the nonstress responsive falling phase of the corticosterone secretory cycle. As a result, the group mean response to noise stress was significantly smaller in the arthritic than the controls (70.2 +/- 9.2 versus 107.8 +/- 13.0 ng/ml, respectively). In contrast to the differential response to noise stress, all rats showed similar responses to the acute immunological challenge with i.v. lipopolysaccharide. Thus, altered basal pulse frequency is a major factor influencing HPA activation during acute psychological stress.

Animals↗

PubMed2001

Lack of effect of protein deprivation-induced intrauterine growth retardation on behavior and corticosterone and growth hormone secretion in adult male rats: a long-term follow-up study.

To further define the neuroendocrine consequences of intrauterine growth retardation (IUGR), we have used a rat model of maternal protein restriction throughout pregnancy to examine the pattern of corticosterone and GH secretion under basal conditions and in response to psychological stress in male offspring at 4, 9, and 18 months of age. The findings were correlated with studies of behavioral activity. Despite a consistent reduction in birth weight and failure of catch-up growth, there were no significant differences in GH secretory profiles between IUGR and control rats at any age. We were unable to demonstrate a difference in the number, amplitude, length, or area of corticosterone secretory pulses between control and IUGR animals; although again, there was a significant decrease with age. The mean peak plasma concentration of corticosterone in response to a noise stress also declined with age but was unaffected by IUGR. There were no consistent, statistically significant differences in behavioral responses between normal control and IUGR animals or between groups of animals at different ages. These results do not, therefore, support the presence of major functional abnormalities in either GH or corticosterone secretory responses in adult male rats subjected to IUGR.

Aging↗

PubMed2001

An investigation of the Jendrassik manoeuvre.

Several mechanisms were investigated by which the Jendrassik manoeuvre might potentiate tendon jerk and H-reflexes, recorded here as surface EMG from the triceps surae muscle group. If fusimotor activation is involved, then, after muscle conditioning designed to leave spindles in a slack state, interposing a Jendrassik manoeuvre before reflex testing should have increased reflex amplitude by restoring spindle sensitivity; but this was not the case. The Jendrassik manoeuvre failed to increase facilitation of the soleus H-reflex by a quadriceps volley, contrary to expectations if it operates by presynaptic disinhibition. There was no increase in the level of ongoing EMG during a Jendrassik manoeuvre, indicating that it does not operate by direct facilitation of motoneurones. The Jendrassik manoeuvre produced less reflex potentiation when spindles had a high rate of resting discharge. A remaining, untested mechanism is the modulation of oligosynaptic pathways that may contribute to the largely monosynaptic reflex response.

Electromyography↗

PubMed2000

Co-localization of FAM and AF-6, the mammalian homologues of Drosophila faf and canoe, in mouse eye development.

The Drosophila fat facets and canoe genes regulate non-neural cell fate decisions during ommatidium formation. We have shown previously that the FAM (fat facets in mouse) de-ubiquitinating enzyme regulates the function of AF-6, (mammalian canoe homologue), in the MDCK epithelial cell line (Taya et al., 1998. The Ras target AF-6 is a substrate of the fam de-ubiquitinating enzyme. J. Cell Biol. 142, 1053-1062). We report here that the expression of the FAM and AF-6 proteins overlaps extensively in the mouse eye from embryogenesis to maturity, especially in the non-neural epithelia including the retinal pigment epithelium, subcapsular epithelium of the lens and corneal epithelium. Expression is not limited to the epithelia however, as FAM and AF-6 also co-localize during lens fibre development as well as in sub-populations of the neural retina.

Amino Acid Sequence↗

PubMed2000

Significance of pulsatility in the HPA axis.

A stress-free automated blood sampling system has been employed to demonstrate pulsatile hypothalamo-pituitary-adrenal (HPA) activity in the rat. In females, pulses of corticosterone secretion occur approximately once/hour throughout the 24 h cycle, with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Ageing does not affect the occurrence of pulses but the diurnal variation is lost. Analysis of the relationship between the HPA response to an acute noise stress and its coincidence with the various phases of the pulse, suggests that pulsatile activity arises from alternating periods of activation and suppression. Responses to i.v. corticotropin-releasing factor are not affected by pulse phase, indicating that this relationship is not generated at the pituitary-adrenal level. This phase relationship holds for all strains of rat except the hyperresponsive Fischer-344 in which an exaggerated stress response arises from a lack of phase-dependent suppression. Patterns of pulsatile activity are also modulated by neonatal programming or chronic HPA activation arising from adjuvant-induced arthritis, with consequent impact upon the response to acute stimuli. Thus, variations in the patterns of pulsatile activity are important determinants of both basal secretion and acute responses of the HPA axis.

Animals↗

PubMed2000

On the conservation of function of the Drosophila fat facets deubiquitinating enzyme and Fam, its mouse homolog.

Fat facets is a Drosophila deubiquitinating enzyme required for eye development and early embryogenesis. Genetic evidence suggests that Fat facets deubiquitinates and thereby prevents the proteasomal degradation of specific substrates. The Drosophila Liquid facets protein is implicated as the critical substrate of Fat facets in the eye. A mouse homolog of Fat facets, called Fam, has been identified. The results of biochemical experiments implicate two different proteins, Af-6 and beta-catenin, as substrates for Fam. Here, the functional relationship between Fat facets and Fam is explored. We show that Fam can substitute for Fat facets in all of its essential functions in Drosophila. In addition, we tested the hypothesis that Canoe and Armadillo, the Drosophila homologs of Af-6 and beta-catenin, respectively, are important substrates for Fat facets in the Drosophila eye. We found no genetic evidence to support a role for either Canoe or Armadillo in the essential Fat facets pathways in Drosophila eye development. The significance of these results is discussed in light of the biochemical experiments that suggest that Af-6 and beta-catenin are substrates of Fam.

Animals↗

PubMed2000

Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats.

Many millions of people throughout the world are at risk of developing iodine deficiency-associated disorders. The underlying effects of iodine deficiency on neuroendocrine function are poorly defined. We have studied stress-induced and diurnal variation in corticosterone secretion in female rats rendered chronically hypothyroid by feeding them an iodine-free diet for 6 months. Corticosterone secretory responses in iodine deficient animals were compared to those seen in animals rendered hypothyroid with propylthiouracil and untreated controls. By using a well-validated, automated blood sampling system to collect small samples of blood over the complete daily cycle in unrestrained animals, we have demonstrated for the first time that the normal diurnal rhythm of corticosterone secretion is lost in chronic iodine deficiency and that the corticosterone secretory response to the psychological stress of 10 min exposure to white noise is attenuated. Despite restoration of circulating triiodothyronine and thyrotropin releasing hormone- and thyroid stimulating hormone beta-transcript prevalence in the hypothalamus and pituitary, respectively, 1 month after restoration of normal iodine-containing diet both the diurnal variation in corticosterone levels and the corticosterone secretory response to the noise stress remained reduced in amplitude compared to control animals. Thus, chronic hypothyroidism induced by iodine deficiency significantly attenuates hypothalamo-pituitary-adrenal axis activity, an effect that persists after functional recovery of the thyroid axis.

Acoustic Stimulation↗

PubMed2000

Potential contribution of computer-aided detection to the sensitivity of screening mammography.

PURPOSE: To determine the false-negative rate in screening mammography, the capability of computer-aided detection (CAD) to identify these missed lesions, and whether or not CAD increases the radiologists' recall rate. MATERIALS AND METHODS: All available screening mammograms that led to the detection of biopsy-proved cancer (n = 1,083) and the most recent corresponding prior mammograms (n = 427) were collected from 13 facilities. Panels of radiologists evaluated the retrospectively visible prior mammograms by means of blinded review. All mammograms were analyzed by a CAD system that marks features associated with cancer. The recall rates of 14 radiologists were prospectively measured before and after installation of the CAD system. RESULTS: At retrospective review, 67% (286 of 427) of screening mammography-detected breast cancers were visible on the prior mammograms. At independent, blinded review by panels of radiologists, 27% (115 of 427) were interpreted as warranting recall on the basis of a statistical evaluation index; and the CAD system correctly marked 77% (89 of 115) of these cases. The original attending radiologists' sensitivity was 79% (427 of [427 + 115]). There was no statistically significant increase in the radiologists' recall rate when comparing the values before (8.3%) with those after (7.6%) installation of the CAD system. CONCLUSION: The original attending radiologists had a false-negative rate of 21% (115 of [427 + 115]). CAD prompting could have potentially helped reduce this false-negative rate by 77% (89 of 115) without an increase in the recall rate.

Adult↗

PubMed1999

Retinoic acid-dependent upregulation of mouse folate receptor-alpha expression in embryonic stem cells, and conservation of alternative splicing patterns.

The action of retinoic acid (RA) in normal development and differentiation is mediated by changes in the expression of RA-responsive target genes. We used differential display reverse transcriptase polymerase chain reaction (RT-PCR) to identify RA-responsive genes expressed in embryonic stem (ES) cells and found that murine folate receptor-alpha (FR-alpha) expression is rapidly induced by RA treatment. The observed increase in FR-alpha expression occurs within 3h, is independent of protein synthesis and does not occur when ES cells are differentiated by removal of leukaemia inhibitory factor (LIF), evidence that the response to RA is both direct and specific. Two messenger RNA (mRNA) isoforms of FR-alpha featuring novel sequence in the 5' untranslated region (UTR) were cloned, and both were found to be upregulated by RA. Other splice variants in both the 5' UTR and 3' UTR of FR-alpha mRNA were also identified. There is a striking similarity between these splicing patterns and those reported for human FR-alpha, which also generates multiple isoforms by alternative splicing in the 5' and 3' UTR. The conservation of these splicing patterns in the non-coding regions of the FR-alpha gene between mouse and human suggests that these regions, and in particular the 5' UTR, play an important role in regulating expression of this gene.

3' Untranslated Regions↗

PubMed1999

The deubiquitinating enzyme Fam interacts with and stabilizes beta-catenin.

BACKGROUND: In the ubiquitin-proteasome pathway, the ubiquitinated substrates either undergo degradation by the proteasome or stabilization through the action of the deubiquitinating enzyme. We have previously found that the deubiquitinating enzyme Fam is colocalized with AF-6, one of the effectors of the Ras small GTPase, at cell-cell contact sites in epithelial cells and interacts with AF-6 in vivo and in vitro. Fam has deubiquitinating activity in vitro and prevents the ubiquitination of AF-6 in intact cells. The degradation of beta-catenin, which accumulates at the cell-cell contact sites as a cadherin/catenin complex, is thought to be regulated by the ubiquitin-proteasome pathway. These observations prompted us to examine the possible Fam regulation of the stabilization of beta-catenin. RESULTS: We found that Fam interacted with beta-catenin both in vivo and in vitro. The Fam-binding site of beta-catenin mapped to the region close to the APC or Axin-binding site of beta-catenin. Over-expression of Fam in mouse L cells resulted in an elevation of beta-catenin levels and in an elongation of the half-life of beta-catenin. In these L cells, Fam was colocalized with beta-catenin at the dot-like structures in the cytoplasm. CONCLUSION: These results indicate that Fam interacts with and stabilizes beta-catenin in vivo, presumably through the deubiquitination of beta-catenin.

Animals↗

PubMed1998

Muscle history, fusimotor activity and the human stretch reflex.

1. The previous history of contraction and length changes of a muscle influences the size of the stretch reflex and H reflex. Here we ask, is this dependence due to changes in mechanical properties of extrafusal fibres, intrafusal fibres of spindles, or both? 2. The soleus muscle of human subjects was conditioned using either a voluntary contraction or a contraction evoked by low-strength electrical stimulation, in the range 0-25 % of maximum. Following conditioning, reflexes were increased by more than twofold above the no-contraction value by a voluntary contraction of 5 % of maximum, or more, but not by electrical stimulation which presumably did not contract the intrafusal fibres of spindles. 3. When the muscle was conditioned with a contraction at a length shorter than the test length, rather than at the test length, a depressing effect on reflexes was attributed to both the burst of impulses generated in spindles when the muscle was stretched back to the test length and to a reduced stretch sensitivity of muscle spindles. 4. The experiments demonstrate the importance of keeping the muscle and its spindles in a defined mechanical state when measuring reflexes. They also point to the powerful facilitating influences of conditioning muscle contractions provided they recruit the intrafusal fibres of spindles.

Adult↗

PubMed1998

Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity.

FKBP ligand homodimers can be used to activate signaling events inside cells and animals that have been engineered to express fusions between appropriate signaling domains and FKBP. However, use of these dimerizers in vivo is potentially limited by ligand binding to endogenous FKBP. We have designed ligands that bind specifically to a mutated FKBP over the wild-type protein by remodeling an FKBP-ligand interface to introduce a specificity binding pocket. A compound bearing an ethyl substituent in place of a carbonyl group exhibited sub-nanomolar affinity and 1,000-fold selectivity for a mutant FKBP with a compensating truncation of a phenylalanine residue. Structural and functional analysis of the new pocket showed that recognition is surprisingly relaxed, with the modified ligand only partially filling the engineered cavity. We incorporated the specificity pocket into a fusion protein containing FKBP and the intracellular domain of the Fas receptor. Cells expressing this modified chimeric protein potently underwent apoptosis in response to AP1903, a homodimer of the modified ligand, both in culture and when implanted into mice. Remodeled dimerizers such as AP1903 are ideal reagents for controlling the activities of cells that have been modified by gene therapy procedures, without interference from endogenous FKBP.

Amino Acid Sequence↗

PubMed1998

The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme.

The Ras target AF-6 has been shown to serve as one of the peripheral components of cell-cell adhesions, and is thought to participate in cell-cell adhesion regulation downstream of Ras. We here purified an AF-6-interacting protein with a molecular mass of approximately 220 kD (p220) to investigate the function of AF-6 at cell-cell adhesions. The peptide sequences of p220 were identical to the amino acid sequences of mouse Fam. Fam is homologous to a deubiquitinating enzyme in Drosophila, the product of the fat facets gene. Recent genetic analyses indicate that the deubiquitinating activity of the fat facets product plays a critical role in controlling the cell fate. We found that Fam accumulated at the cell-cell contact sites of MDCKII cells, but not at free ends of plasma membranes. Fam was partially colocalized with AF-6 and interacted with AF-6 in vivo and in vitro. We also showed that AF-6 was ubiquitinated in intact cells, and that Fam prevented the ubiquitination of AF-6.

Animals↗