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Biomedical subjects

H A Martin

Publications and source records attributed to H A Martin.

14 recordsLinked to original sources
PubMed2000

Effect of muscle pain and intrathecal AP-5 on electromyographic patterns during treadmill walking in the rat.

1. A physio-neuropharmacological model to assess in the rat the contribution of muscular nociceptive input to motor dysfunction and pharmacological aspects of spinal sensorimotor interaction, during treadmill walking, is presented. 2. Rats were trained to walk on a treadmill prior to chronic electromyographic electrode implantation and intrathecal catheterization. 3. Changes in electromyographic activities were recorded from the median gastrocnemius and tibialis anterior muscles of the right hindlimb, during rhythmic locomotor movements. 4. Intramuscular hypertonic saline 6% was injected into the right triceps surae muscles to produce an experimental muscle pain during treadmill walking. 5. Pain produced a decrease in both median gastrocnemius and tibialis anterior electromyographic activities during rhythmic locomotion. Mean gastrocnemius burst duration decreased while tibialis anterior burst duration increased. 6. AP-5, an NMDA receptor antagonist known to block the synaptic excitatory drive to central pattern generators, was injected intrathecally at the level of the lumbar spinal cord to validate this neuropharmacological model. 7. Intrathecal AP-5 induced a decrease of both median gastrocnemius and tibialis anterior muscle activities during treadmill walking. This pharmacological intervention aggravated behavioural and motor effects of muscle pain.

2-Amino-5-phosphonovalerate↗
PubMed1996

Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells.

Prior studies demonstrated that ceramide promotes apoptotic cell death in the human myeloid leukemia cell lines HL-60 and U937 (Jarvis, W. D., Kolesnick, R. N., Fornari, F. A., Jr., Traylor, R. S., Gewirtz, D. A., and Grant, S. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 73-77), and that this lethal process is potently suppressed by diglyceride (Jarvis, W. D., Fornari, F. A., Jr., Browning, J. L., Gewirtz, D. A., Kolesnick, R. N., and Grant, S. (1994) J. Biol. Chem. 269, 31685-31692). The present findings document the intrinsic ability of sphingoid bases to induce apoptosis in HL-60 and U937 cells. Exposure to either sphingosine or sphinganine (0. 001 10 microM) for 6 h promoted apoptotic degradation of genomic DNA as indicated by (a) electrophoretic resolution of 50-kilobase pair DNA loop fragments and 0.2-1.2-kilobase pair DNA fragment ladders on agarose gels, and (b) spectrofluorophotometric determination of the formation and release of double-stranded fragments and corresponding loss of integrity of bulk DNA. DNA damage correlated directly with reduced cloning efficiency and was associated with the appearance of apoptotic cytoarchitectural traits. At sublethal concentrations (</=750 nM), however, sphingoid bases synergistically augmented the apoptotic capacity of ceramide (10 microM), producing both a leftward shift in the ceramide concentration-response profile and a pronounced increase in the response to maximally effective levels of ceramide. Thus, sphingosine and sphinganine increased both the potency and efficacy of ceramide. The apoptotic capacity of bacterial sphingomyelinase (50 milliunits/ml) was similarly enhanced by either (a) acute co-exposure to highly selective pharmacological inhibitors of protein kinase C such as calphostin C and chelerythrine or (b) chronic pre-exposure to the non-tumor-promoting protein kinase C activator bryostatin 1, which completely down-modulated total assayable protein kinase C activity. These findings demonstrate that inhibition of protein kinase C by physiological or pharmacological agents potentiates the lethal actions of ceramide in human leukemia cells, providing further support for the emerging concept of a cytoprotective function of the protein kinase C isoenzyme family in the regulation of leukemic cell survival.

Apoptosis↗
PubMed1996

Bradykinin potentiates the chemoresponsiveness of rat cutaneous C-fibre polymodal nociceptors to interleukin-2.

We have recently reported that IL-2 activates a third of cutaneous C-fibre polymodal nociceptors. Responses were dose-dependent and concentration threshold was below 1.2 U/3 microliters. Potent tachyphylaxis characterized the response to subsequent injections of the same dose. These nociceptors were also activated by histamine and bradykinin. However, the cross-reactivity between inflammatory mediators was not assessed due to experimental limitations. Nevertheless, we found in preliminary studies that BK enhanced the responsiveness of polymodal nociceptors to IL-2 by reversing IL-2-induced tachyphylaxis and increasing response magnitude. The fact that BK potentiated the responsiveness of nociceptors to a chemical stimulus was unexpected and needed further investigation. In the present study, 40 cutaneous C-fibre polymodal nociceptors were isolated in 26 rat saphenous nerve preparations. Nociceptors were identified by their conduction velocity and response thresholds to electrical, mechanical and thermal stimuli. Two series of experiments were conducted: in the first series of experiments, IL-2 (1.2 U/3 microliters) was injected twice prior to BK (150 ng/3 microliters) and injected again twice after BK. In the second series of experiments, BK preceded the two injections of IL-2. In the first series of experiments, responses to IL-2 were increased by 55% after BK and this difference was statistically significant in a paired-sample t-test (P < 0.02). In the second series of experiments, units responded to IL-2 with a vigorous and irregular (bursting) sustained discharge (255 +/- 35 action potentials/300 s) and no tachyphylaxis appeared to the second IL-2 injection. In addition, potent thermal sensitization occurred after BK. Possible cellular and sub-cellular mechanisms of BK-induced potentiation to IL-2 are discussed. We conclude that BK enhances the responsiveness of cutaneous C-fibre polymodal nociceptors to IL-2, which may explain the occurrence of pruritus in the healing process of inflamed skin.

Animals↗
PubMed1996

Effect of 1-beta-D-arabinofuranosylcytosine on apoptosis and differentiation in human monocytic leukemia cells (U937) expressing a c-Jun dominant-negative mutant protein (TAM67).

The proto-oncogene c-jun encodes a component of the AP-1 transcription-activating complex and has been implicated in the regulation of diverse cellular processes, including cell proliferation, differentiation, transformation, and most recently, apoptosis. We have used a U937 monocytic leukemia cell line stably expressing a c-jun dominant-negative, transactivation-domain deletion mutant (TAM67) to assess the role of c-jun in apoptotic events induced by exposure to the antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C). Mutant cells produce a truncated M(r) 29,000 protein that interferes with the function of normal c-Jun (and c-Fos) proteins through a quenching mechanism. Parental U937, cells expressing TAM67, and cells carrying only the empty vector (pMM) were exposed to ara-C for 6 h, and apoptosis was monitored by cell morphology as well as qualitative and quantitative assays of DNA damage. No differences in apoptosis could be detected between the three cell lines at any of the ara-C concentrations evaluated. In addition, ara-C concentrations > or = 1.0 x 10(-6) M were equally inhibitory to the clonogenic growth of U937 and TAM67-expressing cells. In contrast, lower concentrations of ara-C (i.e., < 5.0 x 10(-7) M) were significantly less inhibitory to mutant U937 cell colony formation than to their parental counterparts. The reduced sensitivity of TAM67-expressing cells to low concentrations of ara-C could not be attributed to biochemical or cytokinetic factors, since the two cell lines were indistinguishable with respect to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) formation, ara-CTP:dCTP ratios, and S-phase fraction. However, a significantly lower percentage of TAM67-expressing cells exposed to submicromolar concentrations of ara-C exhibited features associated with a differentiated monocytoid phenotype (i.e., increased plastic adherence and CD11b expression) compared to their parental counterparts. Lower concentrations of ara-C were also significantly less effective in decreasing the percentage of S-phase cells and in down-regulating c-myc mRNA levels in the mutant line, events associated with induction of leukemic cell differentiation. Finally, ara-C-induced up-regulation of c-jun message and protein was markedly attenuated in TAM67-expressing cells, findings consistent with a c-jun dominant-negative model. Collectively, these findings suggest that dysregulation of c-jun in U937 cells antagonizes low-dose ara-C-mediated cellular maturation but does not prevent higher concentration of this agent from triggering apoptosis. They also raise the possibility that separate aspects of the antiproliferative actions of ara-C may be differentially regulated by c-jun.

Antimetabolites, Antineoplastic↗
PubMed1995

Fusimotor neurone responses to medial plantar nerve stimulation in the decerebrate cat.

1. The effect of single shock electrical stimulation, up to 20 x threshold (T), of the medial plantar nerve on the discharges of single medial gastrocnemius static and dynamic gamma-efferents has been investigated in the decerebrate cat. 2. The neurones were classified as static (15) or dynamic (8) indirectly on the basis of their locomotor and/or resting discharge characteristics. 3. All gamma-efferents were affected by stimulation of the medial plantar nerve. Dynamic units showed net inhibition while facilitation dominated the responses of static neurones. 4. The responses of dynamic units consisted of powerful short latency (15 +/- 1.2 ms, mean +/- S.D.) spinal inhibition followed by weaker facilitation that was difficult to characterize due to concomitant rephasing of neuronal discharge. 5. Static neurones showed two patterns of response. Some units (7 of 15) were facilitated at medium latency (39.9 +/- 12.2 ms) while the remainder showed mixed effects in which short latency (18 +/- 3.6 ms) spinal inhibition was followed by stronger facilitation (latency, 38.1 +/- 5.3 ms). 6. Fusimotor facilitation and inhibition were generally present at 2T. The inhibition of dynamic and static gamma-efferents, and the facilitation of the latter type, increased with stimulus intensity. Thus low and high threshold afferents contributed to the effects without changing their qualitative nature. 7. We conclude that low threshold cutaneous mechanoreceptors in the plantar surface of the foot are capable of influencing the discharges of medial gastrocnemius static and dynamic gamma-efferents. Further, the cutaneous responses of fusimotor neurones appear to vary according to both the source of the afferent input and the type of unit involved. 8. The results are discussed in relation to the control and function of fusimotor neurones and the possible existence of subdivisions within the static system.

Animals↗
PubMed1995

Interleukin-2 activates a sub-population of cutaneous C-fibre polymodal nociceptors in the rat hairy skin.

We have investigated the effects of interleukin-2 on identified cutaneous C- and A delta- fibre nociceptors in an in vivo rat saphenous nerve preparation. A fraction of C-polymodal (33%), A delta- (22%) and C- (7.5%) mechanical nociceptors were activated by intradermal injection of interleukin-2. For C-fibre polymodal nociceptors, concentration thresholds were < or = 0.12 unit/3 microliters and the percentage of interleukin-2-activated nociceptors did not increase with concentrations above 0.06 unit/3 microliters. Responses were dose-dependent and characterized by potent tachyphylaxis for subsequent injections of the same dose. C-fibre polymodal nociceptors activated by interleukin-2 were also activated by subsequent chemical stimuli as follows: 81% were activated by histamine (300 ng/3 microliters), 87% by bradykinin (75 ng/3 microliters), 100% by topical acetic acid and 87% by capsaicin (3 micrograms/3 microliters). In contrast, C-fibre polymodal nociceptors that could not be activated by interleukin-2 responded less frequently to histamine (17%) and bradykinin (24%) but were generally activated by noxious chemicals, including acetic acid (82%) and capsaicin (70%). In conclusion, this study demonstrates that interleukin-2 is a potent activator of a discrete population of cutaneous C-polymodal nociceptors, which are chemosensitive to endogenous inflammatory mediators. The fact that these nociceptors respond to a variety of endogenous mediators is consistent with the concept of multiple humoral mechanisms of itch and, consequently, the difficulties in reducing itch associated with inflammation.

Animals↗
PubMed1995

Induction of apoptotic DNA fragmentation and c-jun downregulation in human myeloid leukemia cells by the permeant Ca2+ chelator BAPTA/AM.

The permeant Ca2+ chelator acetoxymethyl-1,2-bis(2-aminopheoxy)ethane- N,N,N',N'-tetraacetic acid (BAPTA/AM), an agent previously used to characterize drug-induced apoptosis in neoplastic cells, has been examined with respect to induction of DNA fragmentation and cytotoxicity in the human leukemia cell lines HL-60 and U937. Exposure of cells to various concentrations of BAPTA/AM for 6 h resulted in a biphasic induction of internucleosomal DNA cleavage, with maximal damage occurring at 10-microM concentrations. Higher BAPTA/AM concentrations were associated with the loss of internucleosomal cleavage products, but with the appearance of larger (i.e., 50-kilobase) fragments on pulsed-field gel electrophoresis. Cells exposed to 10 microM BAPTA/AM exhibited classic apoptotic morphology, whereas cells exposed to 50-microM concentrations displayed atypical features (e.g., cell swelling, chromatin clumping); in each case, substantial cytotoxicity was noted. The actions of BAPTA/AM did not depend upon the presence of extracellular Ca2+, nor were they affected by impermeant Ca2+ chelators. Measurement of cytosolic Ca2+ by Fura-2/AM or Indo-1 revealed late but not early increases in intracellular Ca2+ in BAPTA/AM-treated cells. Finally, BAPTA/AM-induced apoptosis was accompanied by the concentration-dependent downregulation of the immediate early response gene c-jun. These findings suggest a complex role for Ca2+ chelators such as BAPTA/AM in the regulation of human myeloid leukemic cell apoptosis, and indicate that this agent may selectively antagonize internucleosomal DNA fragmentation without interfering with other aspects of the apoptotic response and/or cell lethality.

Apoptosis↗
PubMed1993

Fusimotor discharge patterns during rhythmic movements.

Sensory information from muscle is a major factor in the control of posture and movement. The central nervous system can greatly vary this proprioceptive feedback via the fusimotor (gamma) system that innervates the muscle spindle, a length receptor. Despite 50 years of intensive research, the role of the fusimotor system still remains controversial. One of the major reasons for this state of affairs is, because of technical difficulties, the complete lack of direct recordings from classified gamma-motoneurones (that is, static or dynamic) in intact animals. However, such recordings have been achieved in reduced feline preparations during three types of rhythmic movement: respiration, jaw movements and locomotion. The recordings indicate that the patterns of discharge of static and dynamic fusimotor neurones can vary in different types of movement, or in different muscles during the same behaviour. Notwithstanding such variation, a generalization has emerged in which it is proposed that, for rhythmic movements, extrafusal muscle contraction is accompanied by coactivity in static and dynamic gamma-efferents. Such coactivity serves to optimize spindle afferent feedback for reflex contributions to muscle contraction.

Animals↗
PubMed1990

Leukotriene B4 induced decrease in mechanical and thermal thresholds of C-fiber mechanonociceptors in rat hairy skin.

We have recently shown that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, sensitizes nociceptors to mechanical stimuli. The present study examined whether LTB4 also induces a thermal sensitization of cutaneous C-fiber high-threshold mechanonociceptors (C-HTMs). C-HTMs were characterized according to their responsiveness to noxious mechanical, thermal and chemical stimuli, including glacial acetic acid, bradykinin and capsaicin. C-HTMs were found to be either heat responsive (heat C-HTMs) or heat and chemically responsive (polymodal C-HTMs). Ninety-four percent of polymodal C-HTMs and 60% of C-HTMs were sensitized to thermal and mechanical stimuli by LTB4 (75 ng). All sensitized C-HTMs showed decreases in both thermal and mechanical thresholds. LTB4 lowered in both subclasses of C-HTMs average thermal threshold from 45 to 35 degrees C and produced an average decrease in the mechanical threshold of approximately 82-86%. For both heat and polymodal C-HTMs, the magnitude of LTB4-evoked decreases in thermal and mechanical thresholds was similar to that produced by 75 ng of PGE2. The possibility was discussed that LTB4 may contribute to the component of hyperalgesia that is resistant to non-steroidal anti-inflammatory agents.

Action Potentials↗
PubMed1988

Leukotriene B4 decreases the mechanical and thermal thresholds of C-fiber nociceptors in the hairy skin of the rat.

1. We have recently shown that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, sensitizes nociceptors to mechanical stimuli. The present study examined whether LTB4 also induces a heat sensitization of cutaneous C-fiber nociceptors. The C-fiber nociceptors studied had von Frey hair thresholds greater than 5 g and were characterized according to their responses to noxious heat and chemical stimuli, including glacial acetic acid, bradykinin, and capsaicin. Thirty-four of the C-fibers that were activated by intense thermal stimulation were also activated by topical application of glacial acetic acid. They were classified as C-polymodal nociceptors (2, 28). Those that were activated by intense mechanical and thermal stimulation, but were unresponsive to acid, were classified as C-mechanoheat nociceptors (27). 2. Ninety-four percent of C-polymodal nociceptors and 60% of C-mechanoheat nociceptors were sensitized by LTB4. All C-fiber nociceptors that showed a decrease of their heat threshold also had a decrease of their mechanical threshold. LTB4 (75 ng) lowered the average heat threshold from 45 degrees C to 35 degrees C and produced an average decrease in the mechanical threshold of 86%. 3. The magnitude of the LTB4-evoked decrease in thermal threshold was similar to that produced by 75 ng of prostaglandin E2 (PGE2). These data demonstrate that LTB4 sensitizes C-mechanoheat nociceptors to both mechanical and thermal stimuli. 4. We conclude that LTB4 may contribute to the component of hyperalgesia that is resistant to nonsteroidal anti-inflammatory agents.

Action Potentials↗
PubMed1987

Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs.

Single C- and A-delta fibers were isolated from dissected filaments of the saphenous nerve in pentobarbital anesthetized rats and the corresponding cutaneous receptive fields mapped with calibrated von Frey hairs. Nociceptors were characterized by their responses to noxious mechanical, thermal and chemical stimuli, including intradermal injections of leukotriene B4, prostaglandin E2, bradykinin and capsaicin. Leukotriene B4 decreased the mean mechanical threshold by a maximum of 80% within 10 min and for more than 3 h after intradermal injection of 75 ng of leukotriene B4. The degrees of sensitization of a fiber by leukotriene B4 and prostaglandin E2 were highly correlated. A potentiation effect also was observed, in that injection of prostaglandin E2 or leukotriene B4 1 h after the other eicosanoid further lowered the mechanical threshold of a sensitized fiber, whereas fibers that were not sensitized by leukotriene B4 were unaffected by prostaglandin E2. The sensitizing action of leukotriene B4 and prostaglandin E2 was directed to multiple classes of cutaneous nociceptors including 73% of C-polymodal, 60% of C-mechano-heat, 42% of C-mechano-cold nociceptors and 70% of A-delta high-threshold mechanonociceptors. The pain-evoking substances bradykinin and capsaicin activated 81% and 88%, respectively, of the sensitized C-polymodal nociceptors, 17% and 84% of the sensitized-C-mechano-heat nociceptors, 12% and 37% of the sensitized C-mechano-cold nociceptors, and 17% and none of the sensitized A-delta high-threshold mechanociceptors. The responses of C-fibers to bradykinin and capsaicin were highly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1977

Traumatic right coronary artery-right ventricular fistula with retained intramyocardial bullet.

A case of traumatic right coronary artery-right ventricular fistula secondary to a gunshot wound is presented. In addition, the bullet was retained within the interventricular septum. The diagnostic approach, surgical findings and operative procedure of this and other reported cases are discussed. Several key points are emphasized. First, extended follow-up is necessary after trauma to the heart since fistulas may develop years after the initial injury. Second, surgery is generally indicated for fistulas although some data are presented suggesting that small to moderate fistulas may be treated medically. Third, if surgery is undertaken, very careful operative technique must be utilized to locate and close the fistula. Surgical treatment of choice may be coronary arterial ligation with a distal bypass graft if necessary. Postoperative evaluation is mandatory because fistulas may recur. Indications for removal of a foreign body within the myocardium are also discussed.

Adult↗