Biomedical subjects

M E Harrington

Publications and source records attributed to M E Harrington.

At least 19 recordsLinked to original sources

PubMed2003

Dynamic foot movement in children treated for congenital talipes equinovarus.

The aim of this study was to define objectively gait function in children with treated congenital talipes equinovarus (CTEV) and a good clinical result. The study also attempted an analysis of movement within the foot during gait. We compared 20 children with treated CTEV with 15 control subjects. Clinical assessment demonstrated good results from treatment. Three-dimensional gait analysis provided kinematic and kinetic data describing movement and moments at the joints of the lower limb during gait. A new method was used to study movement within the foot during gait. The data on gait showed significantly increased internal rotation of the foot during walking which was partially compensated for by external rotation at the hip. A mild foot drop and reduced plantar flexor power were also observed. Dorsiflexion at the midfoot was significantly increased, which probably compensated for reduced mobility at the hindfoot. Patients treated for CTEV with a good clinical result should be expected to have nearly normal gait and dynamic foot movement, but there may be residual intoeing, mild foot drop, loss of plantar flexor power with compensatory increased midfoot dorsiflexion and external hip rotation.

Adolescent↗

PubMed2002

Is novel wheel inhibition of per1 and per2 expression linked to phase shift occurrence?

We studied whether access to a novel running wheel in vivo could reset the suprachiasmatic nuclei (SCN) in vitro. Golden hamsters were transferred to dim red light at Zeitgeber time (ZT) 4, given their first exposure to a running wheel for 3 h, and killed at either ZT7 or ZT9. Using a brain slice preparation, the SCN firing rate rhythm in vitro was advanced relative to controls only in the slices prepared at ZT9 (phase shift: 2.36+/-0.06 h, n=4) but not ZT7 (-0.26+/-0.16 h, n=4). Transitions to dim red light or brain slice preparation at ZT7 or ZT9 alone do not shift the rhythm. Hamsters with wheels had significantly lower levels of SCN per1 mRNA compared with controls at ZT7, and lower per2 mRNA when examined at ZT9. We conclude that 3 h of novel wheel access appears to require some extended time in vivo in order for the SCN to be reset, even beyond the time when per1 mRNA levels have been altered.

Animals↗

PubMed2001

Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus.

The mammalian suprachiasmatic nucleus (SCN) contains the main circadian clock. Neuropeptide Y (NPY) that is released from the intergeniculate leaflet of the lateral geniculate body to the SCN, acts in the SCN to advance circadian phase in the subjective day via the NPY Y2 receptor. We used semi-quantitative in situ hybridization to determine the effect of NPY on circadian clock genes, Period 1 (Per1) and Period 2 (Per2), expression in SCN slices. Addition of NPY to the brain slices in the subjective day resulted in reduction of Per1 and Per2 mRNA levels 0.5 and 2 h after treatment. NPY Y1/Y5 and Y2 agonists decreased Per1 within 0.5 h. These results suggest that NPY may induce phase shifts by mechanisms involving or resulting in reduction of Per1 and Per2 mRNA levels.

Animals↗

PubMed2001

The neuropeptide Y Y5 receptor mediates the blockade of "photic-like" NMDA-induced phase shifts in the golden hamster.

Circadian or daily rhythms generated from the mammalian suprachiasmatic nuclei (SCN) of the hypothalamus can be synchronized by light and nonphotic stimuli. Whereas glutamate mediates photic information, nonphotic information can in some cases be mediated by neuropeptide Y (NPY) or serotonin. NPY or serotonin can reduce the phase-resetting effect of light or glutamate; however, the mechanisms and level of interaction of these two kinds of stimuli are unknown. Here we investigate the effect of NPY on the NMDA-induced phase shift of the hamster SCN circadian neural activity rhythm by means of single-unit recording techniques. NMDA (10-100 microm) applied in the early subjective night induced phase delays in the time of peak firing, whereas doses in the millimolar range disrupted firing patterns. The NMDA-induced phase delay was blocked by coapplication of NPY (0.02-200 microm). NPY Y1/Y5 and Y5 receptor agonists, but not the Y2 receptor agonist, blocked the NMDA-induced phase delay in a similar manner as NPY. The coapplication of a Y5 but not Y1 receptor antagonist eliminated NPY blockade of NMDA-induced phase delays, suggesting that the Y5 receptor is capable of mediating the inhibitory effect of NPY on photic responses. These results indicate that nonphotic and photic stimuli may interact at a level at or beyond NMDA receptor response and indicate that the Y5 receptor is involved in this interaction. Alteration of Y5 receptor function may therefore be expected to alter synchronization of circadian rhythms to light.

Animals↗

PubMed2001

Kinematic analysis of a multi-segment foot model for research and clinical applications: a repeatability analysis.

An unbiased understanding of foot kinematics has been difficult to achieve due to the complexity of foot structure and motion. We have developed a protocol for evaluation of foot kinematics during barefoot walking based on a multi-segment foot model. Stereophotogrammetry was used to measure retroreflective markers on three segments of the foot plus the tibia. Repeatability was evaluated between-trial, between-day and between-tester using two subjects and two testers. Subtle patterns and ranges of motion between segments of the foot were consistently detected. We found that repeatability between different days or different testers is primarily subject to variability of marker placement more than inter-tester variability or skin movement. Differences between inter-segment angle curves primarily represent a shift in the absolute value of joint angles from one set of trials to another. In the hallux, variability was greater than desired due to vibration of the marker array used. The method permits objective foot measurement in gait analysis using skin-mounted markers. Quantitative and objective characterisation of the kinematics of the foot during activity is an important area of clinical and research evaluation. With this work we hope to have provided a firm basis for a common protocol for in vivo foot study.

Biomechanical Phenomena↗

PubMed2001

Neuropeptide Y in the mammalian circadian system: effects on light-induced circadian responses.

The present review examine the role of neuropeptide (NPY) in the circadian system, focusing on the interactions between light and NPY, especially during the subjective night. NPY has two different effects on the circadian system of mammals. On one hand, NPY, similar to behavioral stimulation, can change the phase of the clock by itself during the subjective day. On the other hand, NPY, again similar to behavioral stimulation, can inhibit the phase-shifting effect of light during the night. These effects of NPY may occur through different receptor subtypes, the Y2 receptor mediating day-time effects and the Y5 receptor mediating night-time effects of NPY. Our results also indicate that there are differences between in vivo and in vitro studies: NPY inhibition of in vivo light-induced phase shifts was observed only late in the subjective night; however, NPY applied in vitro could block light-induced phase shifts early in the subjective night as well. Contrasting these in vivo and in vitro results led us to suggest that the time of day of maximal effect of NPY in the intact animal may be a time when exogenous administration of NPY has little effect, due to saturation of the system. This situation could be an example of how the measurable output of the clock can be affected by the behavioral state in a different way at different time points, depending not only on the clock itself but also on behavior. If verified in human beings, the ability of NPY to modulate the circadian-clock responses to light may be of clinical importance.

Animals↗

PubMed2000

Neuropeptide Y applied in vitro can block the phase shifts induced by light in vivo.

The mammalian suprachiasmatic nuclei (SCN) can be synchronized by light, with direct glutamatergic input from the retina. Input to the SCN from the intergeniculate leaflet contains neuropeptide Y (NPY) and can modulate photic responses. NPY can reduce the phase-resetting effect of light or glutamate. We investigated the effect of NPY applied in vitro on light-induced phase shifts of the SCN neural activity rhythm. Light pulses delivered in vivo induced phase shifts in brain slice preparations similar to those as measured by behavioral activity rhythms. NPY applied after the light pulse blocked the phase shifts during both the early and late subjective night. NPY applied 30 min after the light pulse could block the phase delay induced by light. Our results show that NPY can inhibit photic resetting of the clock during the subjective night. The time course of this inhibitory effect suggests a mechanism downstream of the glutamate receptor.

Animals↗

PubMed2000

Neuropeptide Y phase advances the in vitro hamster circadian clock during the subjective day with no effect on phase during the subjective night.

The mammalian daily (circadian) clock is located in the suprachiasmatic nuclei of the hypothalamus. Clock function can be detected by the measurement of the circadian change in spontaneous firing rate of suprachiasmatic nuclei cells in a brain slice preparation in vitro. We investigated the effects of neuropeptide Y on this rhythm of firing rate in hamster suprachiasmatic nuclei neurons. Slices were prepared using standard techniques. On the 1st day in vitro, neuropeptide Y (200 ng/200 nL; 47 pmol) was applied as a microdrop to the suprachiasmatic nuclei region at various times. Spontaneous single-unit firing was measured for 6-12 h on the 2nd day in vitro. Peak firing rate in treated slices was compared with that of untreated control slices to measure phase shifts induced by the peptide. Neuropeptide Y induced phase advances of circa-3h when applied during the subjective day (ZT 2-10) but did not significantly alter phase when applied during the subjective night. The phase shifts to neuropeptide Y in the hamster tissue in vitro are similar in phase dependency and magnitude to shifts measured in vivo.

Animals↗

PubMed1999

Protein kinase C inhibition and activation phase advances the hamster circadian clock.

The mammalian circadian clock is located in the suprachiasmatic nuclei (SCN). Clock function can be detected by the measurement of the circadian change in cellular firing rate of SCN cells in vitro. We investigated the effects of protein kinase C (PKC) inhibition and activation on this rhythm of firing rate in hamster SCN neurons. PKC inhibition by chelerythrine chloride application phase advances the in vitro circadian rhythm during the late subjective night and early subjective morning, Zeitgeber time (ZT) 20-24 and ZT 0-4. No effect of PKC inhibition on clock phase was seen during ZT 6-18. Activation of PKC via phorbol 12-myristate 13-acetate (PMA) phase advanced the clock at all phases tested. Thus, at some circadian phases both inhibition and activation of PKC can advance circadian rhythms.

Alkaloids↗

PubMed1999

Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light.

The endogenous circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase, thereby entraining the internal rhythm to the environmental cycle, and these effects can be investigated using an in vitro method to measure phase shifts of the SCN. Although pituitary adenylate cyclase activating peptide (PACAP) is localized in retinal inputs to the SCN, it has been reported to alter clock phase only during the subjective day (Hannibal et al., 1997), whereas light alters phase only in the subjective night. In this study we show that PACAP can reset the clock in the photic pattern during the subjective night when applied in 10 pM to 1 nM doses. This appears to be mediated via a glutamatergic mechanism, possibly by potentiation of NMDA currents as is seen at 10-100 pM. Given at higher doses (>10 nM), PACAP shifts in the subjective day, apparently via activation of adenylate cyclase and increased intracellular cAMP. These results indicate dose and phase specificity of the effects of PACAP, and a new role as a transmitter in the retinohypothalamic tract.

Animals↗

PubMed1999

Inhibition of protein kinase A phase delays the mammalian circadian clock.

The suprachiasmatic nuclei (SCN) contain the mammalian circadian clock whose rhythm of firing rate can be recorded in vitro for several days. Application of a protein kinase A (PKA) inhibitor onto the SCN at Zeitgeber time (ZT) 10 on the first day in vitro phase delayed the rhythm of firing rate expressed by SCN neurons on the subsequent day in vitro. Application of the inhibitor (Rp-cAMPS) at other circadian phases did not phase shift the rhythm. These results suggest that during approximately 1 h in the late subjective day the presence and activity of PKA plays a role in setting the phase of the mammalian circadian clock.

Animals↗

PubMed1999

Circadian modulation of the ryanodine receptor type 2 in the SCN of rodents.

We examined the temporal modulation of intracellular calcium release channels in the suprachiasmatic nucleus (SCN). We found a circadian rhythm in [3H]ryanodine binding that was specific to the SCN. The peak in the rhythm occurred at CT 7 and was due to an increase in Bmax, which correlated well with immunoblots showing an increase in RyR-2 expression in the SCN. Double immunohistochemical studies showed that RyR-2 was expressed exclusively in neurons. Ryanodine and caffeine applied around CT 7-9 advanced the clock phase in a hamster brain slice preparation. No rhythm of IP3R was seen in any of the brain areas studied. Our results indicate that RyR-2 exhibits an endogenous rhythm, which influences the intracellular calcium dynamics and thus modulates SCN activity.

Animals↗

PubMed1999

Role of membrane conductances and protein synthesis in subjective day phase advances of the hamster circadian clock by neuropeptide Y.

Neurons of the mammalian circadian pacemaker in the hypothalamic suprachiasmatic nuclei exhibit a rhythm in firing rate that can be reset by neuropeptide Y. We recorded the effects of neuropeptide Y on Na+ and K+ conductances of hamster suprachiasmatic nuclei neurons using whole-cell, perforated-patch and cell-attached patch-clamp recordings, both in dissociated and brain slice preparations. While neuropeptide Y had no effect on voltage-gated Na+ currents, neuropeptide Y activated a leak K+ current. Neuropeptide Y phase advances in the suprachiasmatic nuclei brain slice preparation were blocked by a number of K+ channel blockers (tetraethylammonium chloride, dendrotoxin-I, glybenclamide). However, a K+ ionophore, valinomycin, did not shift the rhythm. The inhibition by tetraethylammonium chloride did not persist in the presence of glutamatergic receptor blockers. We have previously shown that glutamate can oppose neuropeptide Y phase-shifting actions, suggesting that K+ channel inhibition acts by inducing glutamate release. Protein synthesis inhibitors had no effect on clock phase when applied during the subjective day, and had no influence on neuropeptide Y-induced phase shifts. On the other hand, glutamate's ability to inhibit neuropeptide Y shifts was abolished by protein synthesis inhibition. Thus, while neuropeptide Y phase shifts do not require protein synthesis, glutamate blocks neuropeptide Y shifts via increased gene expression during the subjective day, at a time when it does not reset the clock. These results indicate that neuropeptide Y phase shifts via a mechanism that does not involve changes in membrane conductance or protein synthesis.

2-Amino-5-phosphonovalerate↗

PubMed1998

Histamine phase shifts the hamster circadian pacemaker via an NMDA dependent mechanism.

The SCN acts as the central pacemaker for circadian rhythms in mammals. Histamine has been shown to affect circadian rhythms both in vivo and in vitro. We investigated the mechanism by which histamine phase shifts circadian rhythms in vitro. Hypothalamic slices containing the SCN were prepared from golden hamsters, and spontaneous firing rates of individual cells were recorded on the second day in vitro. Application of histamine (1 microM-10 mM) at the extrapolated time of 2 h after lights off (ZT 14) on day 1 in vitro delayed the time of peak firing in a dose-dependent manner. Pre-exposure to the N-methyl-D-aspartate (NMDA) receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (AP-5; 100 microM-1 mM) 5 min before histamine (1 microM) was applied to the slice blocked the phase-delaying effects of histamine. Application of the H1 blocker mepryamine (100 nM) or the H2 blocker cimetidine (10 microM) followed by histamine had no effect on the phase delay induced by histamine. In whole cell recordings from acutely dissociated neurons of hamster SCN, histamine (50 microM) was shown to potentiate NMDA-evoked currents by 52 +/- 12%. These experiments demonstrate that histamine phase shifts of the circadian clock are dependent on NMDA receptor activation and that histamine can directly potentiate NMDA currents in SCN neurons. Histamine may alter circadian clock function by acting directly on NMDA receptors, possibly via binding to the polyamine site.

Animals↗

PubMed1997

Circadian phase shifts to neuropeptide Y In vitro: cellular communication and signal transduction.

Mammalian circadian rhythms originate in the hypothalamic suprachiasmatic nuclei (SCN), from which rhythmic neural activity can be recorded in vitro. Application of neurochemicals can reset this rhythm. Here we determine cellular correlates of the phase-shifting properties of neuropeptide Y (NPY) on the hamster circadian clock in vitro. Drug or control treatments were applied to hypothalamic slices containing the SCN on the first day in vitro. The firing rates of individual cells were sampled on the second day in vitro. Control slices exhibited a peak in firing rate in the middle of the day. Microdrop application of NPY to the SCN phase advanced the time of peak firing rate. This phase-shifting effect of NPY was not altered by block of sodium channels with tetrodotoxin or block of calcium channels with cadmium and nickel, consistent with a direct postsynaptic site of action. Pretreatment with the glutamate receptor antagonists (DL-2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione disodium) also did not alter phase shifts to NPY. Blocking GABAA receptors with bicuculline (Bic) had effects only at very high (millimolar) doses of Bic, whereas blocking GABAB receptors did not alter effects of NPY. Phase shifts to NPY were blocked by pretreatment with inhibitors of protein kinase C (PKC), suggesting that PKC activation may be necessary for these effects. Bathing the slice in low Ca2+/high Mg2+ can block phase shifts to NPY, possibly via a depolarizing action. A depolarizing high K+ bath can also block NPY phase shifts. The results are consistent with direct action of NPY on pacemaker neurons, mediated through a signal transduction pathway that depends on activation of PKC.

2-Amino-5-phosphonovalerate↗

PubMed1997

NPY opposes PACAP phase shifts via receptors different from those involved in NPY phase shifts.

The suprachiasmatic nuclei (SCN) of the hamster can be maintained for several days in vitro, allowing electrophysiological investigation of the mammalian circadian clock. Application of pituitary adenylate cyclase activating peptide (PACAP) at Zeitgeber time (ZT) 6 on the first day in vitro can phase shift the rhythm of firing rate expressed by SCN neurons on a subsequent day in vitro. Here we report that co-application of neuropeptide Y (NPY) will block the phase-shifting action of PACAP. This blocking action is mimicked by [Leu31,Pro34]NPY and [D-Trp32]NPY but not by NPY(22-36) or avian pancreatic polypeptide. The results indicate that NPY has actions in the SCN via receptors distinct from the Y2 receptor, which mediates the phase-shifting action of NPY.

Animals↗

PubMed1997

A classification system to evaluate weight maintainers, gainers, and losers.

OBJECTIVES: To study natural weight changes and to develop a weight classification system that can identify weight maintainers, gainers, and losers. DESIGN/OUTCOME: A prospective, observational study in which weight changes over five annual measurements were evaluated. In the weight classification system used, changes greater than 5 lb defined weight maintenance, gain, or loss. SUBJECTS/SETTINGS: Subjects were healthy, normal-weight and over weight, men and women (mean age = 44.1 +/- 14.1 years) in the Relationships of Energy, Nutrition, and Obesity to Cardiovascular Disease Risk Study. Prospective data for 385 of the original 508 subjects for whom actual weights were available for each of the 5 years (1985 to 1990) were used to classify and characterize subjects by weight-change categories. STATISTICAL ANALYSES: Cross-tabulations (with chi 2 tests) and hterarchical log-linear analyses (with partial chi 2 tests) to examine the relationships of categorical variables; analyses of variance (with F tests) for continuous measures. RESULTS: Over the 4-year interval, 46% of subjects were classified as maintainers, 34% as gainers, and 20% as losers. Over shorter 1-year epochs, more subjects were maintainers (62%) and fewer subjects were gainers (22%) or losers (16%). Maintainers had fewer and smaller magnitudes of weight fluctuations and showed fewer deleterious changes in health risk factors than gainers. APPLICATIONS: Weight changes of greater than +/-5 lb can classify a person as a weight maintainer, or loser. Although annual weight changes were used in this study, a weight change of more than 5 lb between any two points in time may suggest nonmaintenance of weight or weight instability that needs further evaluation.

Adult↗

PubMed1997

The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems.

The ventral lateral geniculate nucleus (vLGN) and the intergeniculate leaflet (IGL) are retinorecipient subcortical nuclei. This paper attempts a comprehensive summary of research on these thalamic areas, drawing on anatomical, electrophysiological, and behavioral studies. From the current perspective, the vLGN and IGL appear closely linked, in that they share many neurochemicals, projections, and physiological properties. Neurochemicals commonly reported in the vLGN and IGL are neuropeptide Y, GABA, enkephalin, and nitric oxide synthase (localized in cells) and serotonin, acetylcholine, histamine, dopamine and noradrenalin (localized in fibers). Afferent and efferent connections are also similar, with both areas commonly receiving input from the retina, locus coreuleus, and raphe, having reciprocal connections with superior colliculus, pretectum and hypothalamus, and also showing connections to zona incerta, accessory optic system, pons, the contralateral vLGN/IGL, and other thalamic nuclei. Physiological studies indicate species differences, with spectral-sensitive responses common in some species, and varying populations of motion-sensitive units or units linked to optokinetic stimulation. A high percentage of IGL neurons show light intensity-coding responses. Behavioral studies suggest that the vLGN and IGL play a major role in mediating non-photic phase shifts of circadian rhythms, largely via neuropeptide Y, but may also play a role in photic phase shifts and in photoperiodic responses. The vLGN and IGL may participate in two major functional systems, those controlling visuomotor responses and those controlling circadian rhythms. Future research should be directed toward further integration of these diverse findings.

Animals↗