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Biomedical subjects

B F Hoffman

Publications and source records attributed to B F Hoffman.

At least 19 recordsLinked to original sources
PubMed1992

Immunological rejection of heart transplant: how lytic granules from cytotoxic T lymphocytes damage guinea pig ventricular myocytes.

We investigated the mechanism by which lytic granules extracted from cytotoxic T lymphocytes (CTL) damage guinea pig ventricular myocytes in order to determine whether their actions can be related to the overall immunological rejection of the transplanted heart. Granule-induced myocyte morphological changes and final destruction were preceded by shortening of action potential duration (APD) and reductions of the resting potential and the action potential amplitude. APD shortening was probably caused by a granule-induced increase in outward current (most likely non-specific). Ryanodine, which blocks Ca2+ release from the sarcoplasmic reticulum, did not interfere with the morphological and electrophysiological effects of lytic granules. Fura-2 imaging indicated that [Ca2+]i initially increased about 2-fold from 90.0 +/- 11.5 nM, while cell length decreased less than 5% from a mean value of 99.0 +/- 9.0 microns. A further increase in [Ca2+]i (greater than 10 fold) was associated with progressive contracture and destruction, suggesting that the structural damage inflicted by lytic granules is caused by [Ca2+]i overload. The results indicate that the cytocidal action of CTL-derived lytic granules may be involved in immunologically induced damage, even to the extent of rejection of the transplanted heart.

Action Potentials↗
PubMed1992

A study of competence to consent to treatment in a psychiatric hospital.

Sixty patients admitted to an acute treatment ward in a provincial psychiatric hospital were assessed for their competence to consent to psychiatric treatment. A semi-structured interview was used to determine whether they met none, some or all of the four necessary criteria for competence outlined in the Mental Health Act of Ontario. Only 21 of the 60 patients (37%) met all four criteria necessary for a patient to be considered competent to make their own decisions regarding psychiatric treatment. The study outlines the major difficulties in the assessment of competence to consent to psychiatric treatment. Our findings suggest that 74% of patients found incompetent using the current definition in the MHA (Ontario) would fail almost any reasonable test. The implications of these findings are discussed.

Adolescent↗
PubMed1991

The isoproterenol-induced chloride current and cardiac resting potential.

Isoproterenol can induce potentially arrhymthogenic depolarizations of the resting membrane of single guinea-pig ventricular myocytes. This effect on resting potential of single guinea-pig ventricular myocytes differs qualitatively from results obtained by others from intact cardiac muscle preparations and also differs from our experience with single dog ventricular myocytes. We performed experiments on dog and guinea-pig ventricular myocytes in an attempt to clarify the effects of isoproterenol on the resting potential of mammalian ventricular myocytes. Voltage recordings with 40-60 M omega 3 M potassium chloride filled microelectrodes revealed an isoproterenol-induced depolarization of 4.3 +/- 1.0 mV in guinea-pig but no depolarization in dog myocytes. Activation of an outwardly rectifying chloride current is responsible for the isoproterenol-induced depolarization of guinea-pig ventricular myocytes. Our whole cell patch clamp recordings consistently revealed such a current in guinea-pig cells but always failed to demonstrate an isoproterenol-induced chloride current in dog myocytes under identical conditions. In contrast to single cells, isoproterenol did not depolarize intact guinea-pig papillary muscle when potential was recorded with 40-60 M omega 3 M KCl filled electrodes. Furthermore, we saw no depolarization in single guinea-pig myocytes when recording electrodes did not contain chloride. We conclude that: (1) despite activation of a chloride current, isoproterenol does not significantly depolarize guinea-pig ventricular muscle unless the driving force for the current at the resting potential is increased by elevating [Cl]i above physiological levels, and (2) an isoproterenol-induced chloride current, although demonstrable in guinea-pig ventricular cells, is not present in healthy dog ventricular cells.

Animals↗
PubMed1991

Anatomy of the tricuspid annulus. Circumferential myofibers as the structural basis for atrial flutter in a canine model.

BACKGROUND: Little anatomic information is available on the annular myocardium. This study was conducted to determine the anatomic substrate for atrial flutter due to circus movement around the tricuspid annulus in the Y-shaped incision canine model of atrial flutter. METHODS AND RESULTS: We studied photographs of the annular myocardium serial histological sections, made in either of three different planes, and compared these with photographs of the intact and blocked gross heart specimens. We found that the annulus is the most caudal region of the atrial wall. The epicardial aspect of the annulus abuts the ventricular septum or the aortic root in the medial region; in other regions, it is covered by the fat of the coronary sulcus. Its endocardial aspect is delimited by the tricuspid leaflets inferiorly and by the pectinate muscle bundles superiorly, except in the medial region where the pectinate muscle bundles are absent. The annular myocardium is bilaminated. A continuous subepicardial circumferential lamina is the most prominent and is robust in the anterior, lateral, and posterior regions, but it attenuates to a fine muscular connection in the medial region. Myofibers of its superior border merge with the pectinate muscle bundles or are admixed in the medial region with myocardium at the base of the medial atrial wall. Its inferior border makes little contact with the annulus fibrosus about the ring; however, in the medial region, these myofibers insert into fibrous tissue superior to the septal leaflet. A discontinuous, subendocardial perpendicular lamina contains myofibers that descend from the atrium; most of these myofibers insert into the annulus fibrosus about the ring, but the lamina is absent in the anteromedial region. CONCLUSIONS: We conclude that the continuous circumferential lamina provides the anatomic substrate for circus movement of excitation in this model.

Animals↗
PubMed1991

Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil.

We tested the hypothesis that a selective increase in membrane current, as contrasted with the decreases in currents caused by most antiarrhythmic agents, would be an effective antiarrhythmic intervention. We studied models of early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and abnormal automaticity in single canine ventricular myocytes using intracellular microelectrodes or patch electrodes. EADs were induced by injected current, Bay K 8644 (0.5-1 microM), or ketanserin (1.0 microM); DADs were induced by ouabain intoxication (2 x 10(-7) M); and abnormal automaticity was induced by exposure to barium (0.25 mM). To increase outward K+ current, we used pinacidil and the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate (PDBu). Under control conditions, 10-100 microM pinacidil caused a concentration-dependent and reversible decrease in action potential duration and an increase in steady-state outward current; both effects were blocked by glibenclamide and thus presumably reflected changes in the ATP-regulated potassium current. Pinacidil increased the current required to induce EADs and abolished EADs caused by Bay K 8644 or ketanserin. After exposure of myocytes to ouabain, pinacidil caused a decrease in action potential duration and diminished or abolished DADs. Finally, pinacidil arrested abnormal automaticity caused by Ba2+. PDBu (30 nM) shortened action potential duration without altering plateau amplitude in some of the myocytes. In these cells the depolarizing current needed to produce an EAD was increased by over 70%; outward potassium current tails were also increased, an effect consistent with an increase of the repolarizing potassium current (IK). These findings show that each of the mechanisms for abnormal impulse generation can be effectively antagonized by an increase in outward current and suggest to us that selective augmentation of a repolarizing current, possibly IK, might be a reasonable antiarrhythmic intervention.

Action Potentials↗
PubMed1991

The demographic and psychiatric characteristics of 110 personal injury litigants.

One hundred ten litigants who were suing for emotional damages were assessed by the author for medical-legal reasons. Most of the plaintiffs were involved in motor vehicle accidents and suffered from "whiplash" injuries. Semi-structured interviews were used to reach criteria based on DSM-III-R diagnoses. Requests for consultation, on average, came 25 months after the patient's accident. Approximately 70 percent of patients had evidence for continuing physical injuries to account for the physical and emotional symptoms. The most common DSM-III-R diagnoses were psychiatric condition affecting physical illness (N = 56), major depression (N = 27), and somatoform disorder (N = 12). Alternative diagnoses relating the effect of the accident on the patient's life included: emotional reaction to physical condition (N = 29), difficulty coping with developmental tasks (N = 20), severe depression (N = 20), aggravation of normal premorbid personality (N = 18), aggravation of abnormal premorbid personality (N = 14), phobia (N = 7), no permanent effect (N = 12), and independent illness (N = 2). Severe emotional problems and disability are common among litigants. The causes of their suffering are more complex and less poorly understood than is assumed from the pejorative labels that are sometimes applied. Lawyers and the courts need the help of psychiatrists to understand this suffering. Empirical data such as these may lead to better classification systems and improve our understanding and treatment of these patients.

Accidents, Traffic↗
PubMed1990

Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP.

We studied the effects of pinacidil (3-50 microM) on the membrane currents of canine ventricular myocytes, using the whole-cell variant of the patch-clamp technique, and the modulation of these effects by intracellular environment, using the pipette perfusion technique. The following observations were obtained: (1) pinacidil induced a dose-dependent outward shift in current at voltages positive to -70 mV; (2) the pinacidil-induced current was largely time-independent at voltages positive to -50 mV and displayed an increase in current fluctuations at more positive voltages, resembling the kinetic properties of current through the ATP-regulated K+ channels; (3) elevating the extracellular potassium concentration [( K+]o) caused a positive shift in the voltage where the pinacidil-induced current crossed the voltage axis and increased the slope conductance of this current; (4) the pinacidil-induced current was reduced by Ba2+ (0.5-1.5 mM) and abolished by intracellular Cs+ (125 mM); (5) glibenclamide reversibly reduced or abolished the pinacidil-induced current; (6) the action of pinacidil was decreased by elevating [ATP] in the pipette solution (from 1 to 10 mM); (7) the action of pinacidil was augmented by adding isoproterenol (1 microM) to the superfusate or adding cAMP (0.1 mM) to the pipette solution; (8) elevating temperature augmented, and accelerated the onset of pinacidil's action; (9) pinacidil reversibly decreased the Ca2(+)-independent transient outward current (Ito1) but augmented the Ca2(+)-dependent transient outward current (Ito2). Based on these observations, we reached the following conclusions: (1) the main effect of pinacidil is to increase an outward current through the ATP-regulated K+ channels; (2) pinacidil's action is modulated by an enzymatic reaction.

Adenosine Triphosphate↗
PubMed1990

The criminalization of the mentally ill.

This paper presents three patients with manifest psychotic illnesses who were directed into the legal system when they committed criminal acts. All of the patients were ordered to attend a psychiatrist for the year they waited for trial. All three patients pleaded guilty; two were put on probation with continuing psychiatric attendance, a condition of probation, and the other was given an absolute discharge when the court was assured that the patient would remain in treatment. Two of the patients who had previously been noncompliant with psychiatric treatment became very compliant and cooperative as a result of the court process and probation order. The third patient was compliant and cooperative both before and after the legal proceedings. All three patients were embarrassed by the criminal charges and disliked the legal process. Since civil commitment laws have changed, psychiatrists must not abandon the seriously mentally ill but should be willing to treat patients backed up by a probation order. The cooperation of medical and legal professionals is in the patients' interest.

Adult↗
PubMed1989

Future trends in the legal rights of patients in nursing homes.

The author discusses the demographic aging of Canada and outlines how the Canadian Constitution and the Charter of Rights and Freedoms are likely to affect the care and treatment of nursing home residents. Because physical freedom and personal autonomy have been given such a high value in the constitution, civil and legal rights will be protected for all residents in nursing homes, and procedural safeguards will become mandatory in the next few years for patients who refuse treatment and for those who are deemed to be incompetent. Physicians and other caregivers will increasingly be removed from the role of substitute decision-maker for incompetent patients, and patient representatives, court-appointed guardians and courts will assume this responsibility. Judicial safeguards such as impartial hearings, appeals to the court and the principles of natural justice will become commonplace in nursing homes.

Aged↗
PubMed1989

Monophasic action potentials during reentrant atrial flutter in the dog: effects of clofilium and acetylcholine.

Monophasic action potentials (MAP) were recorded from canine atrium during reentrant flutter resulting from circus movement in atrial tissue above the tricuspid ring. A catheter and plaque contact electrodes were developed to record MAP from the epicardium or endocardium during sinus rhythm, paced rhythms, and flutter. The transmembrane action potential duration of tricuspid ring tissue also was studied in vitro. During flutter at cycle lengths of 140-160 ms, MAP showed incomplete repolarization. Pacing at comparable cycle lengths had a similar effect. Acetylcholine (10 micrograms/kg, i.v.) shortened MAP duration during pacing and, during flutter, decreased cycle length and increased MAP amplitude. Clofilium (500 micrograms/kg, i.v.) prolonged flutter cycle length by 18% and terminated the flutter within 30-120 s. During pacing at a cycle length of 300 ms, clofilium increased MAP duration and effective refractory period (ERP) by 30%. Transmembrane action potentials showed that clofilium (0.2 mg/L) modified only action potential duration. Conduction velocity was significantly decreased by clofilium during flutter but not during pacing at a cycle length of 300 ms. These data support the conclusion that in this model of flutter, the circus movement occurs in partially repolarized tissue. The circus movement can be accelerated by agents (acetylcholine) that reduce ADP, and slowed and terminated by agents (clofilium) that increase it.

Acetylcholine↗
PubMed1989

Role of G proteins in the acetylcholine-induced potassium current of canine atrial cells.

The acetylcholine-induced opening of potassium channels depends on GTP-binding proteins in the chick, guinea pig, frog, and rat. In contrast, Bubien and Woods (Biochem. Biophys. Res. Commun. 142: 1039-1045, 1987) have recently postulated that the acetylcholine response in cultured canine atrial cells may be independent of GTP-binding proteins. In whole cell patch-clamp experiments using cultured canine atrial cells, we did not detect an effect of GTP (10(-4) M) in the pipette solution on the acetylcholine-induced potassium current. However, 500 microM guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) in the pipette diminished the response to acetylcholine. Pertussis toxin (30 ng/ml for 24 h) blocked the response to acetylcholine. With guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; 3 microM) in the patch pipette, acetylcholine irreversibly increased membrane conductance. The current-voltage relationship for the persistently activated current was similar to that induced by acetylcholine. We conclude that the acetylcholine-induced potassium current in canine atrial cells behaves like that seen in other species and depends on GTP-binding proteins.

Acetylcholine↗
PubMed1989

Activation mapping of reentry around an anatomic barrier in the canine atrium. Observations during entrainment and termination.

We determined total right atrial activation sequences during entrainment and termination of flutter induced in dogs with a surgically induced atrial lesion. This type of atrial flutter is due to circus movement of an impulse around the tricuspid valve orifice. We recorded simultaneously from 96 bipolar intracavity electrodes in the right atrium of the isolated, perfused heart. By constructing isochronal maps, we demonstrated the pattern of atrial activation during atrial pacing protocols that either entrained or entrained and then terminated the reentrant rhythm. We show that during pacing the antidromic wavefront from the paced impulse (An) collides with the orthodromic wavefront from the previous paced impulse (On-1). During entrainment, the site of collision of the orthodromic and antidromic wavefronts was constant during pacing at a fixed rate but shifted in the antidromic direction as the pacing rate increased. Furthermore, the last paced beat was entrained only up to the site of collision of the previous paced beat. During one period of entrainment, termination of the reentrant arrhythmia occurred because On-1 blocked in the reentrant pathway due to refractory tissue left by On-2. However, subsequent An did not collide directly with On as was expected, but rather On blocked by an interaction with tissue left refractory by An. Because On was blocked, no reentry occurred when pacing ended.

Animals↗
PubMed1989

Two components of transient outward current in canine ventricular myocytes.

Repolarization during phase 1 of cardiac action potential is important in that it may influence both impulse conduction in partially depolarized tissue and action potential duration. Thus, it is important to know the properties and regulation of the underlying currents. In about 50% of canine ventricular myocytes, the actin potential displays a phase 1 of fast repolarization and a prominent notch between phase 1 and the plateau. A transient outward current is responsible for both. This current is composed of two components: one (Ito1) blocked by 4-aminopyridine and the other (Ito2) blocked by manganese. In the present study, we characterized each of the components in isolation from the other. Both had an activation threshold between -30 and -20 mV. At the same voltage, Ito1 was larger than Ito2 and had a shorter time to peak. The peak current-voltage relationship for Ito1 was almost linear, but that for Ito2 was bell-shaped. Ito1 decayed during sustained depolarization with a single exponential time course: tau less than 30 msec at all voltages. It recovered from inactivation with a voltage-dependent time course: tau = 70 msec at -90 mV and 720 msec at -40 mV. Ito2 was augmented by elevating [Ca2+]o or by isoproterenol. It was inhibited by caffeine, ryanodine, or a preceding transient inward current, suggesting that it was activated by intracellular calcium released from sarcoplasmic reticulum. We conclude that Ito1 and Ito2 in canine ventricle are similar to those described for many other cardiac tissues, but the kinetics of Ito1 are significantly faster than in other tissues.

4-Aminopyridine↗
PubMed1989

Mechanisms of termination of reentrant atrial arrhythmias by class I and class III antiarrhythmic agents.

We studied atrial flutter due to circus movement in chronically instrumented conscious dogs to identify the mechanism by which class I and class III antiarrhythmic drugs terminate reentrant excitation. We used a crossover experimental design administering five class I agents and one class III agent, by intravenous bolus followed by intravenous infusion. The class I agents other than lidocaine were almost uniformly effective in terminating the arrhythmia (disopyramide in six of seven dogs, propafenone in six of six, flecainide in seven of seven, and SC-40230 in seven of seven). Termination was preceded by a marked increase in cycle length (ranging from +78% with propafenone to +55% with disopyramide), but with the exception of disopyramide, class I agents did not significantly shorten the excitable gap. With disopyramide the gap decreased from 49 +/- 3% to 28 +/- 3% of the cycle length. With no class I agent did the wavelength of effective refractoriness increase to approach the cycle length of the arrhythmia. Lidocaine, used as a negative control, terminated the reentry in one dog with modest prolongation of the cycle length. Terminations with class I agents correlated with depression of conduction rather than prolongation of refractoriness. In contrast with class I agents, D-sotalol prolonged the cycle length minimally (+10%) and terminated the arrhythmia in six of seven dogs. It decreased the excitable gap from 42 +/- 4% to 26 +/- 6% of the cycle, but it still did not cause the wavelength of effective refractoriness to equal the cycle length. Terminations by D-sotalol seemed to result from either failure of the lateral boundaries of the circus path or reflection within the path.

Animals↗