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Biomedical subjects

R J Miller

Publications and source records attributed to R J Miller.

At least 145 records · Page 8Linked to original sources
PubMed1994

Scapholunate advanced collapse wrist: proximal row carpectomy or limited wrist arthrodesis with scaphoid excision?

Proximal row carpectomy (PRC) and limited intercarpal arthrodesis with scaphoid excision (LWF) are useful alternatives to wrist arthrodesis for treatment of degenerative wrist disorders secondary to scapholunate advanced collapse. Because consensus regarding the ideal motion-preserving option is lacking, we sought to better define the indications for and relative merits of PRC versus LWF. Twenty-four wrists treated for symptomatic scapholunate advanced collapse arthritis between 1980 and 1990 with either PRC or LWF were retrospectively reviewed at an average of 5.5 years postoperatively. At follow-up evaluation, satisfactory pain relief, grip strength, and functional performance were observed except in three patients with PRC, one of whom had developed symptomatic radiocarpal arthritis requiring conversion to arthrodesis. Differences in subjective and objective results between the two treatment groups were not statistically significant except for residual range of motion. Incomplete correction of lunate extension when LWF was performed resulted in diminished wrist extension, compared to PRC. Improvements in grip strength and range of motion were noted for at least 1 year after both procedures, and neither declined with time. A stage-dependent surgical approach to the symptomatic scapholunate advanced collapse wrist is advocated in light of comparable outcomes following both PRC and LWF. For wrists without capitolunate arthritis, PRC avoids the technical demands, lengthy postoperative immobilization, and risk of nonunion associated with LWF, but for stage III disease (capitolunate arthritis) pain relief may be unsatisfactory, and LWF is recommended.

Adult↗
PubMed1994

Percutaneous transperineal cryosurgical ablation of the prostate for the primary treatment of clinical stage C adenocarcinoma of the prostate.

OBJECTIVES: To assess short-term response rate and local tissue destructive capabilities of cryosurgical ablation of the prostate (CSAP) in patients with clinical Stage C adenocarcinoma of the prostate. METHODS: A retrospective chart review of 62 patients (mean age, 66 years; range, 49 to 79 years) treated on an institutional review board approved protocol at Allegheny General Hospital between June 1990 and December 1993 was performed. Standard follow-up examination included serial prostate-specific antigens (PSAs), digital rectal examination, and extensive biopsies at 3 months after CSAP. RESULTS: Average hospital stay was 2 days and morbidity was minimal. Biopsy findings showed no residual detectable prostatic tumor in 79% of patients 3 months after 1 CSAP treatment and in 94.8% 3 months after 1 or 2 treatments. Mean/median 3-month postoperative PSAs for patients with negative biopsy findings were 0.59 +/- 1.66 and 0.10 ng/mL, respectively, compared with 14.0 +/- 12.1 and 8.90 ng/mL preoperatively. CONCLUSIONS: CSAP appears to produce controllable, reproducible local tissue destructive effects. Long-term (more than 5 years) crude and disease-free survival rates are not known for CSAP.

Adenocarcinoma↗
PubMed1994

Outcome assessment following limited wrist fusion: objective wrist scoring versus patient satisfaction.

Eighteen nonrheumatoid patients were reviewed an average of 4.4 years following limited wrist fusion to evaluate whether patient satisfaction or objective wrist scoring more closely correlated with functional outcome. Range of motion, grip strength, pain relief, radiographs, and patient satisfaction were assessed by examination and interview, and each wrist was scored based on a clinical scoring system described by Cooney. Twelve patients (67%) were very satisfied with their results, and six (33%) were dissatisfied. Thirteen (72%) experienced good pain relief, 12 of whom denied functional restrictions. Six patients (33%) reported suboptimal wrist function, and four indicated they had inadequate pain relief. Despite high levels of satisfaction in 12 patients, the objective wrist scores were only fair and poor. These low wrist scores unreliably reflected functional outcome. Patient self-assessment of wrist performance, however, was uniformly predictive. Pain relief was more critical to patient satisfaction than residual range of motion. Therefore, compared to objective wrist scoring, consideration of patient satisfaction may allow more accurate prediction and assessment of functional outcome following limited wrist fusion. Satisfactory postoperative function appears to be more dependent on pain relief than residual motion.

Adolescent↗
PubMed1994

Inhibition of phosphoprotein phosphatases blocks metabotropic glutamate receptor effects in the rat nucleus tractus solitarii.

Whole-cell recordings were made from dorsomedial nucleus tractus solitarii neurons in thin coronal medullary slices of the rat, at the level of the area postrema. Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked in the tractus solitarius by electrical stimulation in the presence of D-2-amino-5-phosphonopentanoic acid (AP5) and bicuculline. Currents were also evoked by pressure ejection of (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) in the presence of AP5, bicuculline, and tetrodotoxin or muscimol in the presence of 6,7-dinitroquinoxaline-2,3-dione and AP5. The metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] reversibly depressed the EPSC and muscimol currents and reversibly potentiated AMPA currents. The effects of (1S,3R)-ACPD were blocked in the presence of a low concentration of the phosphoprotein phosphatase (PP)1 and PP2A inhibitor okadaic acid (OA) but not by a low concentration of the PP inhibitor calyculin A. The immunosuppressant agent FK506 failed to block (1S,3R)-ACPD effects on AMPA currents. However, (1S,3R)-ACPD applied in the presence of FK506 produced a reversible potentiation of muscimol currents. We previously demonstrated that the cell-permeant cGMP analog 8-Br-cGMP can mimic many of the effects of (1S,3R)-ACPD. OA antagonized the effects of 8-Br-cGMP in the present investigation. Finally, we previously demonstrated that brief tetanic stimulation results in the activation of a presynaptic mGluR autoreceptor and depression of subsequently evoked EPSCs. OA similarly blocked tetanus-induced depression of EPSCs. These findings suggest that mGluRs on tractus solitarius afferents and first-order nucleus tractus solitarii neurons may modulate glutamate release and AMPA and gamma-aminobutyric acid type A receptor activity via activation of one or more PPs, such as PP2A and/or calcineurin.

Animals↗
PubMed1994

Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells.

Initial studies of glutamate receptors activated by kainate (KA) found them to be Ca2+ impermeable. Activation of these receptors was thought to produce Ca2+ influx into neurons only indirectly by Na(+)-dependent depolarization. However, Ca2+ entry via AMPA/KA receptors has now been demonstrated in several neuronal types, including cerebellar Purkinje cells. We have investigated whether such Ca2+ influx is sufficient to induce excitotoxicity in cultures of cerebellar neurons enriched for Purkinje cells. Agonists at non-NMDA receptors induced Ca2+ influx in the majority of these cells, as measured by whole-cell voltage clamp and by fura-2 [Ca2+]i microfluorimetry. To assess excitotoxicity, neurons were exposed to agonists for 20 min and cell survival was evaluated by a fluorescence assay 24 hr later. KA (100 microM) reduced neuronal survival relative to controls to 43 +/- 3% when applied in Na(+)-containing solution and to 45 +/- 3% in Na(+)-free solution. This toxicity was blocked completely by CNQX but only slightly by 100 microM Cd2+ and 50 microM D-(-)-2-amino-5-phosphonovaleric acid. Both Purkinje neurons and non-Purkinje cell types present in the cultures were similarly vulnerable to toxic KA exposure, but the population marked by KA-induced Co2+ uptake was selectively diminished by the excitotoxicity. Na(+)-independent excitotoxicity could also be induced by domoate, AMPA, or glutamate. Compared to KA, NMDA was relatively ineffective in inducing cell death. Most of the KA-induced excitotoxicity could be blocked by removal of extracellular Ca2+ during the KA exposure and for a 5 min period thereafter. Furthermore, antagonists of the Ca(2+)-activated enzymes nitric oxide synthase and calpain significantly reduced the KA-induced cell death. These results show that non-NMDA receptor activation can cause excitotoxicity in cerebellar Purkinje neurons by mechanisms not involving Na+ influx, but rather depending on direct Ca2+ permeation and activation of Ca(2+)-dependent enzymatic processes.

Animals↗
PubMed1994

Opioid receptors modulate diverse types of calcium channels in the nucleus tractus solitarius of the rat.

We have investigated the coupling between opioid receptors and different types of Ca2+ channels in neurons acutely isolated from the nucleus tractus solitarius (NTS) of the rat. Using fura-2-based imaging we found that Ca2+ transients evoked by depolarization with 50 mM KCl were suppressed by the mu-opioid receptor agonist D-Ala2,N-MePhe4,Gly5-ol-enkephalin (DAMGO) and less effectively by the kappa-receptor agonist U-69,593. The delta-receptor agonist D-Pen2,D-Pen5-enkephalin (DPDPE) was ineffective. In whole-cell voltage-clamp recordings from these neurons, depolarizing voltage steps elicited high-threshold Ca2+ currents that could be distinguished pharmacologically into different components. Part of the current could be blocked by dihydropyridines, part by omega-conotoxin-GVIA and part by omega-agatoxin-IVA. This suggests that the neurons contained L-, N-, and P/Q-type Ca2+ channels. DAMGO and U-69,593 both blocked part of the Ca2+ current but DPDPE was ineffective. Perfusion of GTP-gamma-S into the cells produced a rapid rundown of the Ca2+ current and occluded further effects of the opioid agonists, suggesting the involvement of a G-protein in the coupling mechanism. Inhibition of L-channels did not alter the effect of DAMGO. On the other hand inhibition of N-channels occluded about 80% of the effect of DAMGO. Inhibition of the P/Q-current occluded the remainder of the DAMGO effect. Thus, it appears that activation of opioid receptors can inhibit N- and P/Q-type Ca2+ channels but not L-channels in these cells. It is likely that such effects are important in opioid-mediated inhibition of transmitter release in the brain.

Animals↗
PubMed1994

Inhibitory actions of delta 1-, delta 2-, and mu-opioid receptor agonists on excitatory transmission in lamina II neurons of adult rat spinal cord.

This study examined the electrophysiological consequences of selective activation of delta 1-, delta 2-, or mu-opioid receptors using whole-cell recordings made from visually identified lamina II neurons in thin transverse slices of young adult rat lumbar spinal cord. Excitatory postsynaptic currents (EPSCs) or potentials (EPSPs) were evoked electrically at the ipsilateral dorsal root entry zone after blocking inhibitory inputs with bicuculline and strychnine, and NMDA receptors with D-2-amino-5-phosphonopentanoic acid. Bath application of the mu receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO) or the delta 1 receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) produced a long-linear, concentration-dependent reduction in the amplitude of the evoked EPSP/EPSC. By comparison, the delta 2 receptor agonist [D-Ala2,Glu4]deltorphin (DELT) was unable to reduce the evoked EPSP/EPSC by more than 50% at 100 microM, the highest concentration tested. At concentrations that reduced evoked EPSP/EPSCs by 40-60%, neither DAMGO, DPDPE, nor DELT decreased the amplitude of the postsynaptic current produced by brief pressure ejection of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, suggesting a presynaptic site of action of these opioid receptor agonists. Bath application of 200 nM naltriben (NTB), a delta 2 receptor antagonist, competitively increased the EC75 of DELT by 15.3-fold, but did not antagonize either DPDPE or DAMGO. The EC75 of DELT was further increased by 169.7-fold in the presence of 1 microM NTB. However, this high concentration of NTB also increased the EC50 of DPDPE by about threefold in a noncompetitive manner and antagonized DAMGO in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Glutamate receptor agonists stimulate diverse calcium responses in different types of cultured rat cortical glial cells.

We examined the effects of different types of glutamate receptor agonists on the intracellular calcium concentration, ([Ca2+]i), in cultured rat cortical glial cells. The cells in these cultures were characterized immunocytochemically using antibodies against glial fibrillary acidic protein, A2B5, and OX-42. The metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3- dicarboxylic acid produced Ca2+ mobilization from intracellular stores in all classes of cells. Agonists at non-NMDA glutamate receptors also produced large increases in [Ca2+]i, primarily in cells of the O-2A lineage. Disruption of intracellular Ca2+ stores with thapsigargin showed that increases in [Ca2+]i produced by activating AMPA/kainate receptors were primarily due to Ca2+ influx rather than Ca(2+)-induced Ca2+ release. Agonists at NMDA receptors were ineffective. Electrophysiological studies revealed that cells of the O-2A lineage exhibited moderate inward currents in response to kainate in Na(+)-containing solutions, but only small inward currents and outward rectification in Na(+)-free solutions. However, in the presence of cyclothiazide, the kainate-induced currents were increased in size and a rightward shift of the reversal potential with increased [Ca2+]o could be demonstrated. Activation of cells by kainate, but not by depolarizing stimuli, stimulated the uptake of Co2+. Polymerase chain reaction studies showed that the glutamate receptor subunits GluR1-4 and GluR6 were all expressed in these cultures, but GluR5 was absent. The nature of the Ca2+ uptake pathway activated by non-NMDA receptor agonists in the O-2A lineage population is discussed. It is considered most likely that the O-2A lineage cells express both non-NMDA receptors that are relatively impermeable to divalent cations, as well as a smaller population that are Ca2+ permeable.

Animals↗
PubMed1994

Basic anatomy of the shoulder by magnetic resonance imaging.

An understanding of the normal magnetic resonance (MR) infrastructural details of musculotendinous elements of the rotator cuff forms the basis for analysis of its pathology. The muscular bellies of the teres minor, infraspinatus, supraspinatus, and subscapularis are easily identified in MR images. In their lateral course both the supraspinatus and infraspinatus muscles transition to tendons gradually. Their lateral tendinous portions partially overlap and form a layered appearance on MR images. The subscapularis, with its fan-like tendinous insertional slips at the lesser tuberosity, can be identified easily in all imaging planes. The ligamentous structures of the shoulder, including the coracoacromial and coracohumeral ligaments, are visualized as low signal bands in all imaging planes. The capsuloligamentous structures including the superior, middle, and inferior glenohumeral ligament and glenoid labrum present considerable anatomic variations. This is especially true with respect to the anterior labrum, which varies from absent to a well-formed triangular appearance. Understanding the basic MRI anatomy of all soft tissue structures of the shoulder is essential for appropriate interpretation of lesions related to the shoulder.

Humans↗
PubMed1993

Mechanism of presynaptic inhibition by neuropeptide Y at sympathetic nerve terminals.

Calcium influx through voltage-sensitive Ca2+ channels is the normal physiological stimulus for the activity-dependent release of neurotransmitters at synaptic contacts. It has been postulated that presynaptic inhibition of transmitter release is due to a reduction in Ca2+ influx at the nerve terminal, which could result from the direct inhibition of Ca2+ channels. Neuropeptide Y and noradrenaline act as cotransmitters at many sympathetic synapses. Both of these substances produce presynaptic inhibition and can inhibit Ca2+ currents in the soma of sympathetic neurons. Here we provide direct evidence that presynaptic inhibition produced by neuropeptide Y at sympathetic nerve terminals is associated with a reduction in Ca2+ influx and that this is due to the selective inhibition of neuronal N-type Ca2+ channels.

Action Potentials↗
PubMed1993

Calmodulin binding to and cAMP-dependent phosphorylation of kinesin light chains modulate kinesin ATPase activity.

Kinesin is an ubiquitous heterotetrameric microtubule-based motor which translocates membrane-bound organelles. Since organelle motility and motor protein function can be regulated by components of signaling pathways, the ability of purified bovine brain kinesin (kinesin) to be phosphorylated and to recognize calmodulin (CaM) was tested. Extensively purified "kinesin" was found to consist of several forms of both heavy (KHC) and light (KLC) chains. Phosphorylation of kinesin by a variety of protein kinases was examined; cAMP-dependent protein kinase (cAMP-PK) was the most active enzyme leading to the incorporation of up to 8 mol P/mol kinesin. Phosphorylation occurred predominantly on the KLCs and led to substantial acidic pI shifts. Peptide maps indicated that multiple phosphorylation sites exist on each KLC. Incubation of kinesin in vitro with protein kinase C (PKC) led to the phosphorylation of both KHCs and KLCs. In vivo phosphorylation of KHC and KLCs was demonstrated by immunoprecipitation of [32P]-labeled kinesin from cultured rat hippocampal pyramidal neurons; kinesin phosphorylation was stimulated by 8-chlorophenyl-thio-cAMP or 12-O-tetradecanoylphorbol-13-acetate. Native bovine brain kinesin was shown to bind 125I-CaM by nucleotide-dependent pelleting with stable microtubules. Specific calcium-dependent binding of 125I-CaM to KLCs but not KHC was found using a ligand blotting assay. cAMP-PK phosphorylated kinesin bound 125I-CaM less well than untreated protein in both ligand blotting and microtubule-pelleting paradigms. Calcium-dependent binding of CaM to kinesin inhibited the ATPase activity of native kinesin but not of cAMP-PK phosphorylated kinesin. These results suggest that the KLCs have a regulatory function and integrate information coming from diverse signaling pathways to modulate the activity and function of kinesin.

Adenosine Triphosphatases↗
PubMed1993

Calcium homeostasis in rat septal neurons in tissue culture.

Septal neurons from embryonic rats were grown in tissue culture. Microfluorimetric and electrophysiological techniques were used to study Ca2+ homeostasis in these neurons. The estimated basal intracellular free ionized calcium concentration ([Ca2+]i) in the neurons was low (50-100 nM). Depolarization of the neurons with 50 mM K+ resulted in rapid elevation of [Ca2+]i to 500-1,000 nM showing recovery to baseline [Ca2+]i over several minutes. The increases in [Ca2+]i caused by K+ depolarization were completely abolished by the removal of extracellular Ca2+, and were reduced by approximately 80% by the 'L-type' Ca2+ channel blocker, nimodipine (1 microM). [Ca2+]i was also increased by the excitatory amino acid L-glutamate, quisqualate, AMPA and kainate. Responses to AMPA and kainate were blocked by CNQX and DNQX. In the absence of extracellular Mg2+, large fluctuations in [Ca2+]i were observed that were blocked by removal of extracellular Ca2+, by tetrodotoxin (TTX), or by antagonists of N-methyl D-aspartate (NMDA) such as 2-amino 5-phosphonovalerate (APV). In zero Mg2+ and TTX, NMDA caused dose-dependent increases in [Ca2+]i that were blocked by APV. Caffeine (10 mM) caused transient increases in [Ca2+]i in the absence of extracellular Ca2+, which were prevented by thapsigargin, suggesting the existence of caffeine-sensitive ATP-dependent intracellular Ca2+ stores. Thapsigargin (2 microM) had little effect on [Ca2+]i, or on the recovery from K+ depolarization. Removal of extracellular Na+ had little effect on basal [Ca2+]i or on responses to high K+, suggesting that Na+/Ca2+ exchange mechanisms do not play a significant role in the short-term control of [Ca2+]i in septal neurons. The mitochondrial uncoupler, CCCP, caused a slowly developing increase in basal [Ca2+]i; however, [Ca2+]i recovered as normal from high K+ stimulation in the presence of CCCP, which suggests that the mitochondria are not involved in the rapid buffering of moderate increases in [Ca2+]i. In simultaneous electrophysiological and microfluorimetric recordings, the increase in [Ca2+]i associated with action potential activity was measured. The amplitude of the [Ca2+]i increase induced by a train of action potentials increased with the duration of the train, and with the frequency of firing, over a range of frequencies between 5 and 200 Hz. Recovery of [Ca2+]i from the modest Ca2+ loads imposed on the neuron by action potential trains follows a simple exponential decay (tau = 3-5 s).

Amino Acids↗
PubMed1993

Characteristics of voltage sensitive calcium channels in dendrites of cultured rat cerebellar neurons.

We examined the effects of various pharmacological agents on the Ca2+ channels existing in the dendrites of cultured rat cerebellar neurons. The cultures consisted of Purkinje cells and non-Purkinje cells (deep cerebellar nuclear neurons and other non-granule neurons). Changes in intracellular free calcium concentration, [Ca2+]i, were monitored by digital imaging microfluorimetry using fura-2 as the indicator dye. In the Purkinje cell population increases in dendritic [Ca2+]i evoked by brief pulses of high K+ were very effectively blocked by (> 80%) by omega-Aga-IVA at low concentrations. Nimodipine and omega-conotoxins GVIA and MVIIC only blocked small components of the [Ca2+]i rise. In the non-Purkinje cells, omega-Aga-IVA was much less effective. omega-Conotoxin-GVIA blocked somewhat more and nimodipine blocked a similar percentage of the [Ca2+]i rise. omega-Conotoxin-MVIIC was quite ineffective in these cells. The results are discussed in terms of the types of voltage sensitive Ca2+ channels existing in the dendrites of these cells.

Animals↗
PubMed1993

The actions of phenylglycine derived metabotropic glutamate receptor antagonists on multiple (1S,3R)-ACPD responses in the rat nucleus of the tractus solitarius.

The effects of the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] and a series of phenylglycine-derived putative mGluR antagonists were examined on electrophysiological responses mediated by glutamate and GABA receptors in the nucleus of the tractus solitarius (NTS) in transverse brainstem slices of the rat. Monosynaptic excitatory currents (EPSC's) evoked by electrical stimulation in the region of the tractus solitarius (TS) were reduced in the presence of (1S,3R)-ACPD in > 90% of neurons recorded in the dorsomedial subdivision of the NTS adjacent to the area postrema (AP). Monosynaptic evoked inhibitory currents (IPSC's) were similarly inhibited by (1S,3R)-ACPD. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the gamma-amino-butyric acid-A (GABA-A) receptor agonist muscimol (IMUSC) was inhibited. (1S,3R)-APCD also produced a postsynaptic inward current (IK(ACPD)) associated with a decrease in membrane conductance in approximately 50% of cells. The novel mGluR antagonists (S)-4-carboxy-3-hydroxy-phenylglycine (4C3H-PG), (R,S)-4-carboxy-phenylglycine (4C-PG) and (R,S)-alpha-methyl-4-carboxy-phenylglycine (alpha M4C-PG) reversibly antagonized the effects of (1S,3R)-ACPD on EPSC's IPSC's, IAMPA and IMUSC. The first two compounds also displayed weak agonist activity. However, none of the antagonists significantly inhibited IK(ACPD) at concentrations which blocked (1S,3R)-ACPD effects on synaptic transmission. These results suggest that pharmacologically distinct mGluR's may be present in the NTS.

Animals↗
PubMed1993

Tachykinins potentiate N-methyl-D-aspartate responses in acutely isolated neurons from the dorsal horn.

Substance P and neurokinin A both potentiated N-methyl-D-aspartate (NMDA)-induced currents recorded in acutely isolated neurons from the dorsal horn of the rat. To elucidate the mechanism underlying this phenomenon, we measured the effects of tachykinins and glutamate receptor agonists on [Ca2+]i in these cells. Substance P, but not neurokinin A, increased [Ca2+]i in a subpopulation of neurons. The increase in [Ca2+]i was found to be due to Ca2+ influx through voltage-sensitive Ca2+ channels. Substance P and neurokinin A also potentiated the increase in [Ca2+]i produced by NMDA, but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, or 50 mM K+. Phorbol esters enhanced the effects of NMDA and staurosporine inhibited the potentiation of NMDA effects by tachykinins. It is concluded that activation of protein kinase C may mediate the enhancement of NMDA effects by tachykinins in these cells. However, the effects of tachykinins on [Ca2+]i can be dissociated from their effects on NMDA receptors.

Animals↗