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Biomedical subjects

C Fromm

Publications and source records attributed to C Fromm.

At least 19 recordsLinked to original sources
PubMed1995

Antibodies cross-reactive with E- and P-selectin block both E- and P-selectin functions.

E- and P-selectin are inflammation-induced cell adhesion molecules that mediate leukocyte-endothelial cell and leukocyte-platelet interactions. Monoclonal antibodies (MoAbs) specific for either E-selectin or P-selectin are protective in several animal models of inflammatory disease. To generate an MoAb with broader therapeutic potential, MoAbs that bind to both E- and P-selectin were generated by immunization of mice with mouse pre-B cell lines transfected with human E- and P-selectin. Interestingly, although the only selection criterion was the ability to bind both E- and P-selectin, all three antibodies obtained efficiently block both E- and P-selectin-mediated functions. The inhibited functions include neutrophil or HL-60 cell binding to tumor necrosis factor-alpha-activated human umbilical vein endothelial cells, E- or P-selectin transfectant cell lines, and platelet-HL-60 rosetting. These antibodies, EP-5C7, EP-2C9, and EP-1D8, recognize the same or overlapping epitope within the lectin domains of E- and P-selectin. The data suggest that functionally important epitopes of homologous proteins can be targeted by selecting for antibodies with reactivity toward both proteins. Furthermore, a potent blocking antibody specific for both E- and P-selectin may provide a more effective and broadly useful reagent for treating acute and potentially certain chronic inflammatory conditions.

Animals↗
PubMed1993

Spinal dynorphin immunoreactivity increases bilaterally in a neuropathic pain model.

Increased spinal levels of dynorphin, an endogenous opioid kappa agonist, are seen in models of both chronic and acute hyperalgesia. This study determined the extent and localization of spinal immunoreactive dynorphin following sciatic cryoneurolysis (SCN), a neuropathic pain model produced by a peripheral nerve freeze lesion. SCN results in behaviors associated with neuropathic pain such as autotomy (the gnawing and scratching of the affected limb), touch-evoked and mechanical allodynia, and spontaneous nociceptive behavior. Following SCN, 4 rats that displayed autotomy and 3 rats that did not were randomly chosen for immunohistochemical staining of dynorphin-like immunoreactivity (DLIR). The area of DLIR above a standardized threshold level was quantified in both dorsal horns of each spinal cord section using a computer-assisted image analyzer to express DLIR in pixels. DLIR was observed both ipsilateral and contralateral to the injured peripheral nerve. In addition, the area of DLIR was significantly greater (P = 0.05) in rats that showed autotomy behavior (mean = 52.6 x 10(3) +/- 25.6) compared to rats with no autotomy (mean = 13.8 x 10(3) +/- 4.78). In sharp contrast to the ipsilateral dynorphin increases observed in other neuropathic pain models, we observe a bilateral increase at 21 days following SCN.

Animals↗
PubMed1993

Intrathecal catheterization alone reduces autotomy after sciatic cryoneurolysis in the rat.

There is substantial evidence that sciatic cryoneurolysis (SCN, freeze lesion of the sciatic nerve) is a neuropathic pain model in the rat. During characterization of this model, SCN was performed 4 days after either a sham operation or the insertion of an indwelling intrathecal catheter preparatory to selective spinal drug administration. Body weight and autotomy scores were recorded for the next 22 days until sacrifice. The catheter group experienced significant weight loss (7.5%) by 4 days but rapidly regained to parity with the sham group. Autotomy scores and the frequency of severe autotomy (score > 3) were less at day 22 in the catheter group as compared with the sham-control group (p < 0.005, p < 0.03, respectively). Intrathecal catheterization itself effects the degree of behavioral response to neurogenic pain and thus, should be controlled for in studies using nociceptive animal models.

Animals↗
PubMed1993

The ganglioside GM1 decreases autotomy but not substance P depletion in a peripheral mononeuropathy rat model.

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

Animals↗
PubMed1993

Benzodiazepine receptor ligands are elevated in an animal model of hepatic encephalopathy: relationship between brain concentration and severity of encephalopathy.

Elevated levels of benzodiazepine receptor agonists are found in both animal models of hepatic encephalopathy and in humans with this syndrome. The present study investigated the relationship between agonist levels and the severity of the encephalopathy, as well as the potential reversibility of the syndrome by benzodiazepine receptor antagonists. The concentrations of benzodiazepine receptor ligands in rat brains were measured at several intervals during the induction of liver failure with thioacetamide. Six hours after the first dose of thioacetamide, brain concentrations of benzodiazepine receptor ligands were increased and open field activity decreased compared to control rats. However, the brain concentrations of benzodiazepine receptor ligands correlated better with the stage of hepatic encephalopathy than time after initiation of thioacetamide treatment. The benzodiazepine receptor ligands Ro 15-3505, Ro 15-4513 and CGS-8216 ameliorated motor abnormalities in rats with stage 3 hepatic encephalopathy. Only Ro 15-3505 improved motor activity in rats in stage 2 encephalopathy to levels observed in rats with stage 1 encephalopathy. Furthermore, although Ro 15-4513 and CGS 8216 significantly increased motor activity in stage 4 hepatic encephalopathy, this may reflect their partial inverse agonist properties. These findings support the hypothesis that increased brain levels of benzodiazepine receptor agonists contribute to the severity of hepatic encephalopathy and suggest that high-affinity benzodiazepine receptor antagonists are efficacious in reversing this syndrome.

Animals↗
PubMed1991

Static firing rates of premotor and primary motor cortical neurons associated with torque and joint position.

Single cell activity was studied in the postarcuate premotor area (PMA) and primary motor cortex (MI) of two monkeys performing a load-bearing task with the contralateral hand. Steady-state discharge rates were examined in relation to positional maintenance of the wrist which was held in one of three given positions against graded torques directed towards flexion or extension. Significant and monotonic relationships between tonic firing rate and static torque were found in 41% of 477 MI cells and in only 26% of 470 units studied in PMA. However, for specific cell groups in the PMA the proportion of load-related neurons reached that of the MI samples; this was true for pyramidal tract neurons (PTNs) and for 'non-PTNs' if recorded in their vicinity. The most interesting difference pertains to the range of load over which cells in both areas modulated activity. MI neurons showed steepest change of firing rates over a limited range of small torques around zero external load; the population average displayed a sigmoidal relationship. Proportionally more PMA neurons increased their activity over the entire range of torques examined or showed the highest increase with stronger torques; the population average best fitted a quadratic function. The mean firing rate-torque slope of the PMA population was significantly smaller than that of MI. Many cells in either area were related to both torque and joint position and displayed correlates of length-tension properties of muscle. Change of position sensitivity with torque was found to parallel the rate-torque characteristics in individual neurons. Mean position sensitivity of PMA neurons increased with increasing torques in the 'preferred' direction. In contrast, greatest position sensitivity of the MI population occurred over the range of low torques, which means a clear quantitative dissociation from the muscular activities. The results suggest differential roles of MI and PMA in the control of 'fine' versus 'gross' muscular forces. Undoubtedly, some PMA cell elements (possibly certain output neurons) are involved in aspects of postural control of EMG adjustment to load and joint position.

Animals↗
PubMed1991

Phasic and tonic responses of premotor and primary motor cortex neurons to torque changes.

Responses to torque step perturbation of the wrist were compared in premotor area (PMA) and motor cortex (MI) neurons of the monkey. A substantial portion (39%) of cells recorded from the PMA had phasic responses with onset latencies as short as those found in MI (mostly between 15 and 50 ms). Responsiveness to small perturbations, directional specificity and linear correlation of phasic responses with the velocity of displacement are properties that were essentially present in the PMA. A role of somatosensory feedback to the PMA in accurate and fast up-dating of movement is suggested. Tonically sustained responses to torque change (mean latency around 60 ms) were encountered in both areas and preferentially in neurons that had a monotonic load-relationship under steady-state condition. Such cortical responses did not exhibit reflex-like features, i.e. no correlation with amplitude of torque step and resulting displacement. Instead, the new load condition seemed to be represented by the tonic response of any particular neuron in accordance with its individual firing rate-load characteristics. These tonic cortical responses may be involved in the swift and effective adaptation to the actual load.

Animals↗
PubMed1989

Corticostriatal cells in comparison with pyramidal tract neurons: contrasting properties in the behaving monkey.

Antidromically identified neurons projecting to the putamen (CPNs) and pyramidal tract neurons (PTNs) were recorded from motor and premotor cortex of a monkey which performed a load-bearing task with the wrist. CPNs appeared as a uniform population with very slowly conducting axons and low spontaneous activity. In contrast to PTNs, they exhibited weak, mostly insignificant correlation with graded steady-state forces, responded to torque perturbations with remarkably long latency, and seemed to discharge much later with active movement. Collateral branching of PTNs to the putamen was found to be infrequent (1%). We suggest that the putamen receives a cortical message that is strikingly different from that sent down the pyramidal tract.

Animals↗
PubMed1984

Sensory response properties of pyramidal tract neurons in the precentral motor cortex and postcentral gyrus of the rhesus monkey.

Pyramidal tract neurons (PTNs) were identified in precentral motor cortex (MI) and in postcentral cortex (PoC) of a monkey trained to pronate and supinate its forearm. PTN responses to passive, ramp-form displacements of the forearm were examined in relation to the size of the neuron (as reflected by its antidromic latency). Larger PTNs tended to exhibit transient responses to passive limb displacement, whereas smaller PTNs more frequently showed sustained responses. These findings suggest that smaller PTNs, that make up the majority of the total PTN population, receive continuous feedback during posture as well as during the dynamic phase of movement.

Afferent Pathways↗
PubMed1983

Changes of steady state activity in motor cortex consistent with the length-tension relation of muscle.

Steady state activity of motor cortex (MI) neurons and muscles was examined in relation to joint position. Two monkeys performed either isometric or load-bearing isotonic contractions, at different joint positions and during variation of steady torque. In either condition, MI steady state firing rate were found to be related to the amount of muscular excitation necessary to adjust muscle tension to length at any given position and load. The results obtained from 526 neurons (including pyramidal tract neurons) demonstrate for 206 neurons a correlate of the length-tension relation of muscle in the motor cortex.

Animals↗
PubMed1983

Somatosensory cortex activity related to position and force.

1. The relation of somatosensory cortex (SI) neuronal activity to actively maintained limb posture was examined by recording from single neurons in the SI of monkeys trained to hold the forearm at different pronation-supination postures and to exert different directions and magnitudes of steady torque. 2. Neurons related to limb position were, in most cases (89%), also related to torque exerted by the limb. Very few neurons related to only position or only torque were found. 3. Two categories of position- and torque-related neurons were found, type 1 and type 2. Type 1 eurneuronal activity resembled the pattern of activity seen in the pronator and supinator muscles; neurons more active with supinating torque also became more active with supinated position, while neurons related to pronating torque were also related to pronated position. Type 2 neurons had a noncongruent relation to position and torque; neurons more active with supinating torque became more active with pronated position, while neurons related to pronating torque were related to supinated position. 4. Position- and torque-related neurons were characterized by having predominantly noncutaneous peripheral inputs and were concentrated in two SI regions identified as area 3a and area 2. 5. It is hypothesized that during actively held limb postures, the activity of the type 1 and type 2 neuronal populations in SI is sufficient to signal uniquely the steady-state position of the limb and the force exerted by the limb.

Animals↗
PubMed1982

Pyramidal tract neurons in somatosensory cortex: central and peripheral inputs during voluntary movement.

Recordings with pyramidal tract neurons (PTNs) in the primary somatosensory cortex of the monkey show that these neurons have 3 properties in common with PTNs of primary motor cortex: (1) they exhibit discharge prior to the onset of voluntary movement, (2) their discharge frequency varies as a function of strength of muscular contraction, and (3) they show reflex responses to afferent stimuli that occur during movement. These findings support the view that in addition to its widely recognized role in somesthetic perception, somatosensory cortex has a direct role in the control of movement.

Afferent Pathways↗
PubMed1981

Transcortical reflexes and servo control of movement.

Sherrington proposed that the major role of proprioceptors is in processing afferent inputs generated by the active movements of the animal itself, and noted that the reflex effects of proprioceptive inputs are "mild." Current experimental results are consistent with the view that the major role of both segmental and transcortical proprioceptive reflexes is in small active movements and active postural stability, with muscle afferent inputs reducing "...errors of muscle length produced by fluctuating levels of motor discharge..." as stated by Goodwin and coworkers in 1978. Exteroceptive reflexes generate intense muscular responses and are of critical importance in prompt reprogramming essential for effective responses to environmental stimuli. Within the motor cortex (MI) there is a caudal region (MI/c) which receives exteroceptive cutaneous inputs and a rostral region (MI/r) which receives proprioceptive inputs. Transcortical reflexes mediated via pyramidal tract neurons (PTNs) of MI/r have properties which are analogous to segmental proprioceptive reflexes: changes of muscle length elicit PTN discharges which oppose the length change and so act to maintain stability. Furthermore, MI/r PTNs which are recruited earliest for small active movements are most sensitive to proprioceptive inputs. Data are not yet available concerning transcortical reflexes via MI/c during voluntary movement, but it is speculated that the cutaneous reflexes via MI/c might be functionally analogous to segmental cutaneous reflexes. Short-latency reflex responses also occur in postcentral (PoC) PTNs, and in this report we present results concerning the properties of PoC PTNs during active and passive movement. Caudal (area 2-5) PoC PTNs were similar to MI PTNs in that they often discharged prior to electromyogram (EMG) activity with active movement, and had different discharge frequencies with different steady state loads, but were unlike most MI PTNs in having the same changes of discharge with active and passive movement. Our finding of PoC discharge prior to movement onset, confirming that of Soso and Fetz in 1980, is discussed in connection with the concept of corollary discharge.

Afferent Pathways↗
PubMed1981

Relation of size and activity of motor cortex pyramidal tract neurons during skilled movements in the monkey.

Activity of motor cortex pyramidal tract neurons (PTNs) was recorded in monkeys making large (20 degrees), high velocity and small (1 to 2 degrees), low velocity pronation-supination arm movements in a visual pursuit-tracking paradigm. Antidromic response latencies (ADLs) or PTNs were examined in relation to PTN modulation with the large and small movements to test the hypothesis that PTNs would exhibit a "size principle" analogous to that of spinal cord motoneurons. It was found that smaller PTNs (i.e., those having longer ADLs) discharged just as strongly with small, slow movements as with large, fast movements, while about one-third of the larger PTNs (even those selected for a significant relation to small movement) discharged more intensely with the large movement. Another analysis dealing with PTNs in a selected set of penetrations in an area focal for pronation-supination showed that PTNs with longer ADLs (greater than 1 msec) were more likely to reach maximum frequency with small, slow movement. There was, however, much overlap in the behavior of small and large PTNs, and while there was a statistically significant relation between size and movement-related activity of PTNs, there did not seem to be a "size principle" in the strict sense that this term has been used with reference to spinal cord motoneurons.

Animals↗
PubMed1977

Depression of the recurrent inhibition of extensor motoneurons by the action of group II afferents.

The influence of varying the muscular afferent fiber input on both the normal firing rate (Fn) and the amount of recurrent inhibition (Fn-Fi) induced by a constant ventral root stimulation was investigated on tonic extensor motoneurons recorded from ventral root filaments in decerebrate cats. The afferent input was varied by graded electrical stimulation of the gastrocnemius nerves and by vibrating the triceps surae muscle (100 mum amplitude). When the input consisted solely of impulses in Ia afferents, as was the case during vibration, the mean recurrent inhibition Fn-Fi was 2.3 times greater than during nerve tetanization at 1.8 times threshold of group I (TI). This strength generally excited all group I and some low-threshold group II afferents. Between 1.8 TI and 8 TI, Fn-Fi decreased by some 50%. The average Fn increased slightly and motoneurons with a phasic discharge pattern were recruited when the stimulus strength was raised so as to excite group II afferents; these cells were never recruited during vibration and nerve tetanization at 1.8 TI. The results indicate the possibility of a disinhibitory action of secondary muscle spindle afferents on extensor motoneurons by reducing the recurrent inhibition.

Action Potentials↗