Search PubMed⌕ Search

Biomedical subjects

M J Kelly

Publications and source records attributed to M J Kelly.

At least 37 records · Page 2Linked to original sources
PubMed2001

Influence of metacarpophalangeal joint position on basal joint-loading in the thumb.

BACKGROUND: Conventional wisdom holds that hyperextension of the metacarpophalangeal joint of the thumb is secondary to degenerative subluxation of the trapeziometacarpal joint as occurs in osteoarthritis. We propose that a hypermobile metacarpophalangeal joint may have a causative role in the development of primary osteoarthritis at the base of the thumb by concentrating forces on the palmar aspect of the trapeziometacarpal joint. METHODS: Twenty fresh-frozen cadaveric forearm specimens were obtained post mortem from donors with no history of connective-tissue disease. Each specimen was categorized by its passive range of metacarpophalangeal joint motion. Testing was conducted with Fuji ultra-low-pressure-sensitive film while the hand was in the lateral-pinch mode with the metacarpophalangeal joint in each of the following positions: unrestrained, pinned in neutral, pinned in 30 degrees of flexion, and pinned in maximal hyperextension. Quantitative analysis of the trapezial contact surface at each of the metacarpophalangeal joint positions was performed, and the center of pressure was determined. Each specimen was then classified according to the extent of arthritic disease (nonarthritic, moderately arthritic, or affected by end-stage arthritis). RESULTS: In specimens affected by end-stage osteoarthritis, the center of pressure on the trapeziometacarpal joint moved dorsally by 56.8% of the length of the trapezial surface with metacarpophalangeal joint flexions of 30 degrees (p < 0.01), whereas the corresponding values were 28.2% and 40.9% in the hyperextended and neutral metacarpophalangeal joint positions, respectively. In specimens with moderate osteoarthritis, 30 degrees of metacarpophalangeal joint flexion also produced the most dorsal trapeziometacarpal center of pressure (44.8%); however, this center of pressure was not significantly different from the centers of pressure at the other metacarpophalangeal joint positions. In nonarthritic specimens, the center of pressure was again significantly more dorsal with metacarpophalangeal joint flexion of 30 degrees than it was at the other positions (p < 0.01). CONCLUSION: Metacarpophalangeal joint flexion effectively unloaded the most palmar surfaces of the trapeziometacarpal joint regardless of the presence or severity of arthritic disease in this joint.

Aged↗
PubMed2001

The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis.

The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the preoptic area (POA), a brain region important in controlling reproduction. We used an ovariectomized, female guinea pig model to test two hypotheses: 1) the current associated with the AHP (I(AHP)) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including gamma-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding I(AHP) was sensitive to antagonism by CdCl2 (200 microM), apamin (0.3-1 microM), and dequalinium (3 microM). The beta-adrenergic receptor agonist isoproterenol inhibited the I(AHP) in a dose-dependent, timolol-sensitive fashion. In addition, the alpha1-adrenergic receptor agonist methoxamine dose dependently inhibited the I(AHP) in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 microg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the I(AHP), whereas that for isoproterenol was unaffected. Similarly, bath application of 17beta-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the I(AHP). Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the I(AHP), and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the alpha1-adrenergic receptor-mediated inhibition of this current.

Animals↗
PubMed2000

The role of intrinsic and agonist-activated conductances in determining the firing patterns of preoptic area neurons in the guinea pig.

Whole-cell and intracellular recordings were made in coronal hypothalamic slices prepared from ovariectomized female guinea pigs. 62% of preoptic area (POA) neurons fired action potentials in a bursting manner, and exhibited a significantly greater afterhyperpolarization (AHP) than did non-bursting POA neurons. The majority (70%) of POA neurons (n=76) displayed a time-dependent inward rectification (I(h)) that was blocked by CsCl (3 mM) or by ZD 7288 (30 microM). In addition, 51% of the cells expressed a low-threshold spike (LTS) associated with a transient inward current (I(T)) that was blocked by NiCl(2) (200 microM). A smaller percentage of POA neurons (29%) expressed a transient outward, A-type K(+) current that was antagonized by a high concentration of 4-aminopyridine (3 mM). Moreover, POA neurons responded to bath application of the mu-opioid receptor agonist DAMGO (93%) or the GABA(B) receptor agonist baclofen (83%) with a membrane hyperpolarization or an outward current. These responses were accompanied by a decrease in input resistance or an increase in conductance, respectively, and were attenuated by BaCl(2) (100 microM). In addition, the reversal potential for these responses closely approximated the Nernst equilibrium potential for K(+). These results suggest that POA neurons endogenously express to varying degrees an AHP, an I(h), an I(T) and an A-type K(+) current. The vast majority of these neurons also are inhibited upon mu-opioid or GABA(B) receptor stimulation via the activation of an inwardly-rectifying K(+) conductance. Such intrinsic and transmitter-activated conductances likely serve as important determinants of the firing patterns of POA neurons.

4-Aminopyridine↗
PubMed2000

Similarities between the spectrin SH3 domain denatured state and its folding transition state.

We have expanded our description of the energy landscape for folding of the SH3 domain of chicken alpha-spectrin by a detailed structural characterization of its denatured state ensemble (DSE). This DSE is significantly populated under mildly acidic conditions in equilibrium with the folded state. Evidence from heteronuclear nuclear magnetic resonance (NMR) experiments on (2)H, (15)N-labeled protein suggests the presence of conformers whose residual structure bears some resemblence to the structure of the folding transition state of this protein. NMR analysis in a mutant with an engineered, non-native alpha-helical tendency shows a significant amount of local non-native structure in the mutant, while the overall characteristics of the DSE are unchanged. Comparison with recent theoretical predictions of SH3 domain folding reactions reveals an interesting correlation with the predicted early events. Based on these results and recent data from other systems, we propose that the DSE of a protein will resemble the intermediate or transition state of its nearest rate-limiting step, as a consequence of simple energetic and kinetic principles.

Acids↗
PubMed2000

Using genetics to control cattle parasites-the Rockhampton experience.

Ever since their accidental introduction, cattle ticks, gastrointestinal nematodes and buffalo flies have been major parasites of cattle in northern Australia. Enormous effort and resources have been directed at chemical control of these parasites but the problem persists in undiminished form. The principal control measure remains the use of breeds that have some degree of parasite resistance. No breed is completely resistant and all are at times adversely affected by parasites. Complete resistance is the ultimate solution but has been generally ignored as a commercial reality. Studies at Rockhampton have demonstrated that completely resistant lines can be developed by genetic means within a commercially acceptable timeframe from even the most parasite-susceptible breeds. Genetic changes in tick and worm resistance over 15 years in response to selection for increased tick resistance in the Belmont Adaptaur (Bos taurus) line are reported. Costs and benefits of achieving increased tick resistance are examined and the applicability of the results to other breeds is discussed. Breed differences in resistance to buffalo flies and their effects on live weight are also reported and the possibility of selecting for increased buffalo fly resistance is explored.

Animals↗
PubMed2000

Preservation of alpha-tocopherol in sunflower oil by herbs and spices.

The ability of some commercially available herb and spice extracts to preserve alpha-tocopherol in sunflower oil during heating at 85-105 degrees C was assessed using sunflower oil as a model system. The Rancimat was evaluated for the heating stage and was used throughout as it was shown to be viable: alpha-tocopherol did not evaporate under the test conditions. The delay in the onset of rancidity was found to be directly related to the initial alpha-tocopherol concentration (P < 0.01). Rosemary, thyme, turmeric, sage, oregano and cumin extracts (2000 mg.kg-1) delayed rancidity (P < 0.01) and preserved alpha-tocopherol (P < 0.01). Some preservation was observed with clove extract but coriander and cardamom extracts were pro-oxidants. With thyme extract, the log of the induction time (as an indicator of the delay in rancidity) was directly proportional to the temperature (85-100 degrees C). The ethyl acetate, hexane and methanol extracts of fresh sage were effective for preserving alpha-tocopherol (P < 0.01). With thyme, rosemary and sage extracts, the increase in the preservation of alpha-tocopherol was directly related to the concentration of the herb extract (P < 0.01) and was quite effective even at 100 mg.kg-1. The increased delay in the onset of rancidity was due directly to the improved preservation of alpha-tocopherol (P < 0.01). In further experiments, the preservative effect of turmeric was shown not to be due to its reported major antioxidant, curcumin, even though it delayed rancidity. When herb/spice extracts were examined mixed with thyme, bay and turmeric showed synergism (P < 0.01) whereas bay alone was slightly inhibitory. The mode of action appeared to be due to free radical activity rather than through singlet oxygen generation.

Drug Synergism↗
PubMed2000

Effect of the mu-opioid agonist DAMGO on medial basal hypothalamic neurons in beta-endorphin knockout mice.

The endogenous opioid neurotransmitter beta-endorphin (beta-END), a product of the proopiomelanocortin (POMC) gene, is strongly implicated in the control of the female reproductive cycle, stress responses, and antinociception. Using selective gene targeting, we have generated a strain of mice that do not express any beta-END. These mice exhibit both normal reproduction and normal basal and stress-induced hypothalamic-pituitary-axis activity, but exhibit a significantly attenuated opioid-mediated stress-induced analgesia. To further understand the cellular bases of these responses, we have studied mediobasal hypothalamic (MBH) neurons, including POMC neurons, using whole-cell patch recording in an in vitro slice preparation. Twenty-seven MBH cells were recorded in wild-type and 25 MBH cells were recorded in beta-END knockout mice. Neurons from both genotypes showed a significant positive correlation between DAMGO concentration (from 30 nM to 10 microM) and the induced outward K(+) current. The genotypes did not differ, however, in either the DAMGO-induced maximum outward current response or EC(50), or for the maximal response to the GABA(B) agonist baclofen. Furthermore, quantitative receptor autoradiography utilizing (3)H-DAMGO did not reveal any differences in total mu-opioid receptor binding between genotypes. Therefore, we conclude that the complete absence of beta-END throughout development did not alter either the expression of mu-opioid receptors or their coupling to K(+) channels in MBH neurons.

Animals↗
PubMed2000

Porphyromonas gingivalis induces ultrastructural and cytoskeletal changes in adherent human polymorphonuclear leucocytes.

The response of polymorphonuclear leucocytes (PMN) from healthy humans to culture supernatant from the periodontopathogen, Porphyromonas gingivalis, was examined using light, fluorescence and electron microscopy. Exposure of adherent cells to bacterial culture supernatant resulted in a 4-fold increase in the proportion of spread, flattened PMN. Scanning and transmission electron microscopy demonstrated that these cells had long dendritic cytoplasmic projections closely adherent to the substratum, in contrast with the more rounded, less adherent, control PMN. These shape changes were accompanied by a mean reduction in granule density to 57% compared with control cells (p<0.05) and a reduction in F-actin levels to 62% of controls (p<0.001), but no loss of viability and suggest a bacterially-induced mechanism of suppression of PMN motility which is likely to contribute to the pathogenic potential of P. gingivalis.

Adult↗
PubMed1999

A powerful GABA(B) receptor-mediated inhibition of GABAergic neurons in arcuate nucleus.

We combined histofluorescence with in situ hybridization to identify GABAergic neurons in the arcuate nucleus (ARC) following electrophysiological recording, using GAD65 as a marker. Intracellular recordings 91 were made in hypothalamic slices prepared from ovariectomized guinea pigs. Over 90% of ARC neurons tested with the GABA(B) receptor agonist baclofen responded with a membrane hyperpolarization or an outward current. The hyperpolarization was dose dependent, and the GABA(B) receptor antagonist CGP 35,348 produced a rightward shift in the agonist dose-response curve. Agonist potency was lower, and the efficacy greater, in GAD-positive neurons. The use of this novel technique for identifying GABAergic neurons thus reveals differences in the pharmacodynamics of GABA(B) receptor activation between GABAergic and non-GABAergic ARC neurons.

Animals↗
PubMed1999

Application of amino acid type-specific 1H- and 14N-labeling in a 2H-, 15N-labeled background to a 47 kDa homodimer: potential for NMR structure determination of large proteins.

NMR investigations of larger macromolecules (> 20 kDa) are severely hindered by rapid 1H and 13C transverse relaxation. Replacement of non-exchangeable protons with deuterium removes many efficient 1H-1H and 1H-13C relaxation pathways. The main disadvantage of deuteration is that many of the protons which would normally be the source of NOE-based distance restraints are removed. We report the development of a novel labeling strategy which is based on specific protonation and 14N-labeling of the residues phenylalanine, tyrosine, threonine, isoleucine and valine in a fully deuterated, 15N-labeled background. This allows the application of heteronuclear half-filters, 15N-editing and 1H-TOCSY experiments to select for particular magnetization transfer pathways. Results from investigations of a 47 kDa dimeric protein labeled in this way demonstrated that the method provides useful information for the structure determination of large proteins.

Amino Acid Sequence↗
PubMed1999

Production and evaluation of guidelines for the management of inflammatory bowel disease: the Leicester experience.

Consensus guidelines for the management of patients with inflammatory bowel disease were produced by gastroenterologists, gastrointestinal surgeons and a cross-section of general practitioners (GPs) from Leicestershire in order to develop a seamless pattern of care with a common approach to diagnosis and treatment. It was hoped that the guidelines would encourage a movement towards care in the community for many patients with stable disease and so speed up new consultation rates. The study then assessed the impact of these guidelines on the referral letters of GPs to hospital consultants, the prediction of disease and adherence to them on re-referring patients after discharge. The guidelines were distributed to all 487 GPs in the Leicester Health Authority area and the gastroenterology teams within the hospitals. The value of the guidelines was assessed by an audit of referral letters, the length of time from referral letter to out-patient appointment, both before and after the launch of the guidelines, adherence to the guidelines on re-referral, and monitoring the outcome of the discharged patients. Whilst the guidelines may have helped GPs to manage stable patients in the community, the content of referral letters and the diagnostic abilities of GPs were not seen to improve since the launch of the guidelines. However, only 5% of stable patients who were discharged from one clinic were re-referred for inflammatory bowel disease.

Attitude↗