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Biomedical subjects

J H Lawrence

Publications and source records attributed to J H Lawrence.

At least 37 records · Page 2Linked to original sources
PubMed1995

Prospects for genetic manipulation of cardiac excitability.

Despite impressive advances in the therapy of a number of types of heart disease in the last two decades, sudden cardiac death remains a public health problem of staggering dimensions. Current treatment options include antiarrhythmic drugs that have higher than desired failure rates and implantable defibrillators that incur significant costs to the patient and society. The development of therapies that better suppress the cardiac arrhythmias responsible for sudden cardiac death requires a broad and comprehensive understanding of the basic mechanisms underlying electrical instability in the heart. This study explores the scientific basis for a molecular genetic approach to modify cardiac excitability and thereby to create animal models of sudden cardiac death. The availability of such models will open up new avenues of research in arrhythmogenesis and facilitate the development of novel antiarrhythmic agents.

Animals↗
PubMed1995

Adenovirus-mediated expression of a voltage-gated potassium channel in vitro (rat cardiac myocytes) and in vivo (rat liver). A novel strategy for modifying excitability.

Excitability is governed primarily by the complement of ion channels in the cell membrane that shape the contour of the action potential. To modify excitability by gene transfer, we created a recombinant adenovirus designed to overexpress a Drosophila Shaker potassium channel (AdShK). In vitro, a variety of mammalian cell types infected with AdShK demonstrated robust expression of the exogenous channel. Spontaneous action potentials recorded from cardiac myocytes in primary culture were abbreviated compared with noninfected myocytes. Intravascular infusion of AdShK in neonatal rats induced Shaker potassium channel mRNA expression in the liver, and large potassium currents could be recorded from explanted hepatocytes. Thus, recombinant adenovirus technology has been used for in vitro and in vivo gene transfer of ion channel genes designed to modify cellular action potentials. With appropriate targeting, such a strategy may be useful in gene therapy of arrhythmias, seizure disorders, and myotonic muscle diseases.

3T3 Cells↗
PubMed1994

Sudden cardiac death in heart failure. The role of abnormal repolarization.

Congestive heart failure is a common, highly lethal cardiovascular disorder claiming over 200,000 lives a year in the United States alone. Some 50% of the deaths in heart failure patients are sudden, and most of these are probably the result of ventricular tachyarrhythmias. Methods designed to identify patients at risk have been remarkably unrewarding, as have attempts to intervene and prevent sudden death in these patients. The failure to impact favorably on the incidence of sudden death in heart failure patients stems largely from a lack of understanding of the underlying mechanisms of arrhythmogenesis. This article explores the role of abnormalities of ventricular repolarization in heart failure patients. We will examine evidence for the hypothesis that alteration of repolarizing K+ channel expression in failing myocardium predisposes to abnormalities in repolarization that are arrhythmogenic. The possible utility of novel electrophysiological and ECG measures of altered ventricular repolarization will be explored. Understanding the mechanism of sudden death in heart failure may lead to effective therapy and more accurate identification of patients at greatest risk.

Action Potentials↗
PubMed1993

Control of torque direction by spinal pathways at the cat ankle joint.

To study the biomechanics of the calcaneal tendon's complex insertion onto the calcaneus, we measured torque-time trajectories exerted by the triceps surae and tibialis anterior muscles in eight unanesthetized decerebrate cats using a multi-axis force-moment sensor placed at the ankle joint. The ankle was constrained to an angle of 110 degrees plantarflexion. Muscles were activated using crossed-extension (XER), flexion (FWR), and caudal cutaneous sural nerve (SNR) reflexes. Torque contributions of other muscles activated by these reflexes were eliminated by denervation or tenotomy. In two animals, miniature pressure transducers were implanted among tendon fibers from the lateral gastrocnemius (LG) muscle that insert straight into the calcaneus or among tendon fibers from the medial gastrocnemius (MG) that cross over and insert on the lateral aspect of calcaneus. Reflexively evoked torques had the following directions: FWR, dorsiflexion and adduction; SNR, plantarflexion and abduction; and XER, plantarflexion and modest abduction or adduction. The proportion of abduction torque to plantarflexion torque was always greater for SNR than XER; this difference was about 50% of the magnitude of abduction torque generated by tetanic stimulation of the peronei. During SNR, pressures were higher in regions of the calcaneal tendon originating from MG than regions originating from LG. Similarly, pressures within the MG portion of the calcaneal tendon were higher during SNR than during XER, although these two reflexes produced matched ankle plantarflexion forces. Selective tenotomies and electromyographic recordings further demonstrated that MG generated most of the torque in response to SNR, while soleus, LG, and MG all generated torques in response to XER.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Histologic determination of the ischemic threshold of muscle in the canine compartment syndrome model.

Our objective was to define the critical tissue pressure at which irreversible muscle damage occurs and to compare our results to those thresholds advocated in the orthopaedic literature. A standard plasma infusion compartment syndrome model was created in a canine model. Four dogs were in each of four experimental groups with compartment pressure maintained as follows: (a) 30 mm Hg with support of diastolic blood pressure to a level > 50 mm Hg; (b) 20 mm Hg less than diastolic pressure; (c) 10 mm Hg less than diastolic blood pressure; (d) a level equal to the animal's diastolic blood pressure. All animals were sacrificed 14 days after the procedure. Histology revealed the following: (a) tissues pressurized to 30 mm Hg in a normotensive dog demonstrated no significant abnormalities; (b) tissues pressurized to 20 mm Hg less than diastolic revealed occasional cells undergoing regeneration but no evidence of infarction or fibrosis; (c) tissues pressurized to 10 mm Hg less than diastolic showed scattered small areas of infarction and fibrosis; and (d) tissues pressurized to diastolic blood pressure demonstrated more widespread infarction and scarring. The ischemic threshold of muscle, beyond which irreversible tissue damage occurs, is directly related to the difference in compartment and perfusion pressure. Our findings document this pressure to be 10 mm Hg less than diastolic blood pressure or within 30 mm Hg of mean arterial pressure. This data refutes the use of absolute tissue pressure values as a guide to the necessity of fasciotomy. To abort an impending compartment syndrome and avoid irreversible tissue injury and their sequelae, fasciotomy should be done if tissue pressure reaches within 10-20 mm Hg of diastolic pressure.

Animals↗
PubMed1993

Cat hindlimb muscles exert substantial torques outside the sagittal plane.

1. We studied the contributions of several hindlimb muscles to ankle torque in adult cats deeply anesthetized with pentobarbital sodium. Isometric torques were measured with a multiaxis, force-moment sensor connected to the plantar surface of the foot. 2. Individual muscle torques were provoked by using a combination of muscle nerve stimulation and selective denervations and tenotomies. Torques were represented by three orthogonal components; defined as dorsiflexion/plantarflexion, inversion/eversion (rotation about the long axis of the foot), and toe-in/toe-out (rotation about the axis of the tibia). 3. Most of the muscles tested exerted substantial torques about more than one of the orthogonal axes, each of which shared a common origin centered midway between the medial and lateral malleoli. The lateral and especially the medial head of the gastrocnemius muscle exhibited large toe-out torques and eversion torques as well as the classical plantarflexion components. 4. The torque exerted by tibialis anterior was seen to oppose that of both medial and lateral gastrocnemius in each of the three directions. The toe-in and inversion torques exerted by tibialis posterior was opposed in these directions by both peroneus brevis and peroneus longus. Flexor hallucis longus exerted approximately 10 times more plantarflexion torque than did flexor digitorum longus; therefore, these two muscles cannot be considered pure synergists. 5. The major plantarflexors and dorsiflexor of the cat ankle joint contribute substantial torques outside the sagittal plane. Their opposing torques lead to increased joint stiffness; the net effect of coactivation of these muscles causes ground reaction forces oriented so as to maintain stability during quadrupedal stance.

Animals↗
PubMed1992

Molecular localization of an ion-binding site within the pore of mammalian sodium channels.

Sodium channels are the major proteins that underlie excitability in nerve, heart, and skeletal muscle. Chemical reaction rate theory was used to analyze the blockage of single wild-type and mutant sodium channels by cadmium ions. The affinity of cadmium for the native tetrodotoxin (TTX)-resistant cardiac channel was much higher than its affinity for the TTX-sensitive skeletal muscle isoform of the channel (microliters). Mutation of Tyr401 to Cys, the corresponding residue in the cardiac sequence, rendered microliters highly susceptible to cadmium blockage but resistant to TTX. The binding site was localized approximately 20% of the distance down the electrical field, thus defining the position of a critical residue within the sodium channel pore.

Amino Acid Sequence↗
PubMed1991

Sodium channel inactivation from resting states in guinea-pig ventricular myocytes.

1. Unitary Na+ channel currents were recorded from isolated guinea-pig ventricular myocytes using the cell-attached patch-clamp technique with high [Na+] in the pipette to enhance the signal-to-noise ratio. 2. The probability that the channel enters the inactivated state (I) directly from resting states (C) was investigated over a wide range of membrane potentials. 3. At membrane potentials of -60 mV or more positive, Markov chain theory was used to estimate the probability of C----I from histograms of the number of channel openings per depolarizing period. Holding potentials at least as negative as -136 were required to ensure that all channels resided in C prior to depolarization. 4. At membrane potentials negative to -60 mV, a two-pulse protocol was employed to determine the probability of C----I from the fraction of blank sweeps during the pre-pulse with correction for missed events. 5. The probability of C----I was found to be steeply voltage dependent at negative potentials, falling from 0.87 +/- 0.03 (mean +/- S.D.) at -91 mV to 0.42 +/- 0.01 at -76 mV. At potentials positive to -60 mV, this probability was less steeply voltage dependent and decayed to near zero at 0 mV. 6. Under physiological conditions, C----I transitions may produce appreciable Na+ channel inactivation at diastolic potentials. At potentials above the action potential threshold, inactivation is much more likely to occur from the open state.

Action Potentials↗
PubMed1991

Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients.

Since 1954, 840 patients have been treated at Lawrence Berkeley Laboratory with stereotactic charged-particle radiosurgery of the pituitary gland. The initial 30 patients were treated with proton beams; the subsequent 810 patients were treated with helium ion beams. In the great majority of the 475 patients treated for pituitary tumors, marked and sustained biochemical and clinical improvement was observed. Variable degrees of hypopituitarism developed in about one-third of patients treated solely with radiosurgery. In the earlier years of the program, 365 patients underwent radiosurgery to treat selected systemic diseases by inducing hypopituitarism. Focal temporal lobe necrosis and cranial nerve injury occurred in about 1% of patients who were treated with doses less than 230 Gy.

Acromegaly↗
PubMed1990

Effects of haemorrhage induced hypotension on coronary blood flow in an anaesthetised two vessel canine coronary stenosis-occlusion model.

STUDY OBJECTIVE: Previous experiments from our group have shown that left anterior descending coronary occlusion in the presence of hypotension caused by intravenous glyceryl trinitrate in an open chest canine model caused endocardial flow to fall in myocardium supplied by a stenosed circumflex coronary artery. The aim of the present study was to assess the effects of hypotension in a similar open chest model but without the vasodilating effect of glyceryl trinitrate on coronary vessels. DESIGN: Blood flow to and function of remote myocardium supplied by a stenosed circumflex coronary artery [gradient 27(SEM 3) mm Hg] was determined in anaesthetised dogs after haemorrhage induced hypotension [mean aortic pressure 70(3) mm Hg] and after left anterior descending coronary occlusion. Transmural blood flow was measured using microspheres and myocardial wall thickness with sonomicrometer crystals. SUBJECTS: 11 healthy mongrel dogs were used, weight 25 kg (range 19-33). MEASUREMENTS AND MAIN RESULTS: Haemorrhage induced hypotension in the setting of a circumflex stenosis reduced endocardial blood flow to the posterior myocardial bed from 0.84 (0.14) to 0.57(0.07) ml.min-1.g-1 but did not alter percent myocardial thickening. When the left anterior descending coronary artery was occluded in the presence of the circumflex stenosis and haemorrhage induced hypotension, there was no further decrease in endocardial blood flow to or thickening of the posterior myocardial bed, despite a reduction in mean coronary artery pressure from 54(3) to 43(3) mm Hg. CONCLUSIONS: These findings are in contrast to our previous findings where hypotension was induced by glyceryl trinitrate. Remote myocardial ischaemia appears to be attenuated in this two vessel stenosis-occlusion model in which hypotension is produced by haemorrhage.

Animals↗
PubMed1989

Two molecular transitions influence cardiac sodium channel gating.

Sodium channels from diverse excitable membranes are very similar in their structure, yet surprisingly heterogeneous in their behavior. The processes that govern the opening and closing of sodium channels have appeared difficult to describe in terms of a single, unifying molecular scheme. Now cardiac sodium channels have been analyzed by high-resolution single-channel recordings over a broad range of potentials. Channels exhibited both complex and simple gating patterns at different voltages. Such behavioral diversity can be explained by the balance between two molecular transitions whereby channels can exit the open state.

Electric Conductivity↗
PubMed1986

The characterization of human transmyocardial impedance during implantation of the automatic internal cardioverter defibrillator.

We set out to determine in a prospective fashion the characteristics of energy delivery related to defibrillation in a population of patients receiving the AICD. Specifically, we examined the characteristics of the delivered current, transmyocardial voltage, and transmyocardial impedance. Secondly, we determined the relationship between the energy delivered, the impedance encountered and the defibrillation threshold. Since the AICD will deliver a succession of shocks if the initial shock does not cardiovert, the effects of consecutive shocks at different energy levels on the transmyocardial impedance were also assessed.

Cardiac Surgical Procedures↗
PubMed1984

Delayed sequelae of pituitary irradiation.

Since 1958, 781 patients at Lawrence Berkeley Laboratory have received helium-particle stereotactic radiosurgery to the adenohypophysis. Autopsy findings in 15 of these patients are reported. Ten patients received pituitary radiation (average dose, 116 Gy in six fractions) for progressive neovascularization retinopathy due to diabetes mellitus. Evidence of a time-dependent course of progressive fibrosis in their pituitary glands was found. Five patients were treated for eosinophilic adenomas. Although they had lower average doses of radiation (56 Gy in six fractions), their pituitary glands showed cystic cavitation of the adenomas. The adenomas thus appeared more radiosensitive than the normal pars anterior, which, in turn, was more radiosensitive than the adjacent neurohypophysis. No significant radiation changes were found in the surrounding brain or cranial nerves. The endocrine organs under pituitary control showed varying degrees of atrophy, and clinical tests revealed progressive hypofunction. It was concluded that charged-particle therapy produced a sharply delineated focal radiation lesion confined to the pituitary gland but did not cause injury to the critical structures of the surrounding central nervous system.

Acromegaly↗
PubMed1983

Myoelectric signal versus force relationship in different human muscles.

An analytic study was initiated to investigate whether the normalized surface myoelectric signal vs. normalized force relationship varies in different human muscles and whether it is dependent on training level and rate of force production. The data were obtained from experiments that involved the biceps, deltoid, and first dorsal interosseous of three pianists, four long-distance swimmers, three power lifters, and six normal subjects. The elite performers (among the world's best) were chosen because they exhibited varying degrees of fine motor control, endurance training, and power training in different muscles. Approximately 200 isometric linearly force-varying contractions peaking at 80% of the maximal voluntary contraction level were processed. The results indicated that the myoelectric signal-force relationship was primarily determined by the muscle under investigation and was generally independent of the subject group and the force rate. Whereas this relationship was quasilinear for the first dorsal interosseous, it was nonlinear for the biceps and deltoid. Several possible physiological causes of the observed behavior of the myoelectric signal-force relationship are discussed.

Adolescent↗
PubMed1980

Treatment of acromegaly, Cushing disease and Nelson syndrome.

Since 1957 we have treated more than 429 patients who had pituitary neoplasms, most of which were hormone-secreting tumors. Long-term follow-up in the large group of patients treated for acromegaly shows a median survival of better than 16 years, with improvement over time. The short-term follow-up results in patients with Cushing* disease, Nelson syndrome and chromophobe adenoma are very encouraging. To compare these excellent results with those following surgical procedures, a large study of patients followed for a long period after the operations is needed.

Acromegaly↗
PubMed1979

Prolonged survival in chronic lymphocytic leukemia: a case report.

A patient with long-standing chronic lymphocytic leukemia with both humoral and cellular immunodeficiency had lymph node receptor evidence of a B lymphocyte disorder. He was also found to secrete the Epstein--Barr virus and, late in his illness, developed a markedly positive antinuclear antibody. Interrelationship of these findings may be important in the ultimate determination of the etiology and functional mechanisms in lymphocyte malignancies.

Adult↗