Barry R. Dworkin

Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms

Non‐technical summary  Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete ‘mechanical silencing’ of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time‐resolved analyses. It is suggested the ‘mechanical silencing’ of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.

Pain perception decrement produced through repeated stimulation

&NA; Pain responses (pain detection and pain discomfort) to electrical dental stimulation were studied in 16 normal subjects. The repetition of the dental stimuli induced a significant and long‐lasting (60 min) decrease in pain sensitivity at both sensory levels (after 60 min of repetitive stimulation, 79% increase in pain detection, P < 0.0001, 45% increase in pain discomfort, P < 0.0004). The sensory response decrement through repeated elicitation was not influenced by naloxone administration (1.2 mg i.m.). This study clearly demonstrates the induction of pain sensory decrease through repetitive stimulation which differs from peripheral sensory receptor adaptation, from the inhibitory gating mechanism or from diffuse inhibitory controls activation; its unresponsiveness to naloxone suggests that this phenomenon is not opioid‐dependent. A technique has been standardized which will enable the systematic study of pain decrease under sustained nociceptive stimulation in chronic pain patients.

Failure to replicate visceral learning in the acute curarized rat preparation.

An attempt was made to replicate a series of experiments reported to demonstrate robust visceral learning (autonomic instrumental learning) in rats during acute (2-4 hr) pharmacological paralysis. The results of exploratory procedures involving more than 2,000 animals are described, and six complete experiments, representing systematic observations on an additional 500 animals, are presented. In the first three experiments, which closely followed the original procedures, the characteristics of the preparation were reproduced with the exception of initial heart rhythm and visceral learning. In the second three, the respiration procedure was modified to satisfactorily reproduce the heart rhythm, and the PaO2, PaCO2, and pH were verified to be within the range of freely moving, normally behaving animals; nevertheless, visceral learning was not observed in these experiments either. After more than 2,500 rats were studied, it is concluded that the original visceral learning experiments are not replicable and that the existence of visceral learning remains unproven; however, neither the original experiments nor the replication attempt included the necessary controls to support a general negative conclusion about visceral learning. Because continuing and extensive citation of the original experiments indicates their widely perceived significance, specific requirements for critically testing the visceral learning hypothesis are given, and the limited theoretical implications and practical value of neuromuscular blockade are discussed.

Learning of physiological responses: I. Habituation, sensitization, and classical conditioning.

Rats with chronic neuromuscular block (NMB) maintained by continuous infusion of alpha-bungarotoxin were classically conditioned. All rats showed reliable discriminative-conditioned tibial nerve firing, hind limb vasoconstriction, hypertension, bradycardia, and electroencephalographic (EEG) desynchronization. A regression analysis indicated that the conditioned vasoconstriction was neither centrally mediated by, nor inextricably linked to, skeletal (tibial) nerve firing. Throughout the experiment there were normal blood gases, pH, Na, serum protein, hematocrit, blood pressure, heart rate, vasomotor tone, and tibial nerve activity. The vital signs, EEG spectra, and cortical evoked potentials reflected regular sleep-wakefulness cycles and responsiveness to mild stimuli. The NMB rat preparation with its stable physiological state and fully intact central nervous system may be a useful model for a variety of physiological, medical, and neurobehavioral studies.

Effects of Learning on Visceral Functions — Biofeedback

The brain has a major role in regulation of respiration, heart rate, blood pressure and release of hormones such as ACTH, and in the complex control of temperature and electrolyte balance. The lowe...

Behavioral treatment of scoliosis and kyphosis

A behavioral treatment of scoliosis and kyphosis was tested with 27 adolescent patients (19 scoliosis, eight kyphosis patients) to determine in which cases the conspicuous and restraining brace treatment could be replaced. In 22 compliant patients, posture biofeedback (PB) was highly effective compared to five non-compliant patients. Biologically more mature scoliosis patients (menarche at the beginning of treatment) seemed to profit more from PB. With kyphosis patients the PB treatment resulted in rapid straightening of the spine and removal of structural deformities of Scheuermanns disease. PB may serve as an unobtrusive yet effective treatment alternative for both juvenile scoliosis and kyphosis.

Learning of physiological responses. II: Classical conditioning of the Baroreflex

The baroreflex can be classically conditioned. In neuromuscular blocked (NMB) rats, electrical stimulation of the aortic depressor nerve (ADN) and dopamine-produced blood pressure rise were effective unconditioned stimuli (UCS) for auditory discriminative classical conditioning. The conditioned response (CR) pattern (bradycardia, vasodilatation, and hypotension > 10 torr) closely resembled that of the unconditioned baroreflex. Conditioned stimulus (CS) specificity was demonstrated by discrimination of baroreflex-associated and nonassociated auditory stimuli, and also by elaborating depressor and pressor CRs to auditory CSs, which respectively had been associated with either baro-afferent (depressor) or tail-shock (pressor) UCSs. The conditioned-baroreflex-magnitude increased with trials. These findings support quantitative models in which CRs interact with and calibrate the gain and dynamic properties of natural reflexes.

Time course analysis of mechanical ventilation‐induced diaphragm contractile muscle dysfunction in the rat

Weaning from mechanical ventilation (MV) of long‐term intensive care unit (ICU) patients is delayed by impaired respiratory muscle function; however, the mechanisms that cause the impairment are not fully understood. A novel experimental rat ICU model was used for time‐resolved analyses (6 h to 2 weeks) of the effects of MV on diaphragm muscle fibre structure and function, and on gene and protein expression. A prompt and progressive decline of diaphragm muscle fibre function, preceding atrophy, occurred with MV, and at the end of 2 weeks residual diaphragm muscle fibre function was <15% of control levels. Cellular and subcellular analyses indicated that oxidative stress‐triggered protein modifications had significantly diminished diaphragm muscle fibre function. The novel finding that activation of proteolytic pathways and regulation of contractile protein synthesis were different in diaphragm and limb muscles has direct implications for the design of muscle‐specific intervention strategies.

Cigarette smoking, blood lipids, and baroreceptor-modulated nociception

Activation of arterial blood pressure has been shown to influence higher central nervous activity. In animals, induction of sleep-like states and increases of seizure and pain thresholds in response to baroreceptor stimulation have been reported. In certain human groups, mechanical stimulation of the carotid baroreceptors also increases pain thresholds. The present paper examines the hypothesis that smokers show baroreceptor dependent antinociception as compared to non-smokers. It is speculated that one effect which rewards smoking is the nicotine induced phasic blood pressure increase which leads to baroreceptor stimulation and dampens pain perception. One hundred and twenty subjects were investigated using a recently developed mechanical baroreceptor stimulation technique and an electrical pain stimulus. The group of heavy smokers showed the predicted effect: their pain thresholds were enhanced during conditions of increased baroreceptor activity as compared to the control condition. The group of medium, light and non-smokers, however, did not show this effect. Neither blood lipid levels nor diastolic or systolic blood pressure paralleled the group differences on baroreceptor dependent antinociception. In heavy smokers, the nicotine induced phasic blood pressure increase might have baroreceptor dependent pain dampening effects, which might be among the reinforcing qualities of smoking.

The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction.

BGP-15 reduces ventilation-induced diaphragm dysfunction by improving diaphragm fiber and myosin function and enhancing mitochondrial activity. A little help for the diaphragm Ventilation-induced diaphragm dysfunction is a common complication of intensive care, where mechanically ventilated patients have to be gradually weaned off ventilator support over an extended period of time until they are finally strong enough to breathe on their own. Salah et al. used a rat model to study the detailed effects of prolonged mechanical ventilation on diaphragm muscles and demonstrate the beneficial effects of a pharmacological intervention with a heat shock protein co-inducer. Through a combination of effects on lipid rafts, mitochondrial efficiency, and other cellular functions, this treatment improved diaphragm muscle force-generating capacity even after multiple days of mechanical ventilation. Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients’ quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by posttranslational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.