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Biomedical subjects

B F Hoffman

Publications and source records attributed to B F Hoffman.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1989

Legal principles in the psychiatric assessment of personal injury litigants.

The authors review the legal principles that a psychiatrist must understand in assessing the emotional and psychiatric sequelae of a personal injury leading to a litigation claim. The principles of the establishment of fault or liability, the assessment of pain and suffering, causal connection, the credibility of the plaintiff, the credibility of the expert witness, the determination of prognosis, the award of damages, and the adversarial system are discussed. An appreciation of these principles will enable psychiatrists to provide assessments that will be useful to the legal system in arriving at a fair and accurate determination of the compensation to which a victim is entitled.

Accidents, Traffic↗
PubMed1989

AIDS: clinical and ethical issues on a psychiatric unit.

Using a case illustration, this paper describes how AIDS has affected psychiatric practice on an inpatient unit. The clinical, ethical and administrative issues are discussed from a multi-disciplinary perspective. The issues are discussed as 1. clinical issues (diagnostic and management), 2. effects on ward milieu, 3. staff issues, 4. family counselling and discharge planning and 5. administrative issues. It is important for inpatient staff to discuss these issues and develop clinical guidelines and administrative procedures that will help staff provide the highest level of care possible. Because every patient is potentially an HIV carrier, many of the solutions developed around AIDS related concerns should apply to all patients on a psychiatric ward.

AIDS Dementia Complex↗
PubMed1987

Mechanisms for cardiac arrhythmias.

Possible cellular electrophysiological mechanisms for arrhythmias have been investigated through studies of isolated cardiac tissues. Records through extracellular and intracellular electrodes indicate that arrhythmias may result from either focal or non-focal mechanisms. Focal mechanisms include abnormal impulse initiation (normal or abnormal automaticity), triggering from either early or delayed afterdepolarizations and reflection, whereas the non-focal mechanisms are various forms of reentry due to circus movement. It is reasonable to assume that these mechanisms also occur in vivo. Although it is safe to identify macro-re-entry as the cause of some atrial and ventricular arrhythmias, for the most part direct proof of mechanism usually is lacking for the focal arrhythmias. If 'on line' activation sequence mapping techniques can be developed to quickly and specifically locate arrhythmogenic foci in the in situ heart, it may be possible to use unipolar extracellular recording techniques to identify the exact cellular electrophysiological mechanisms operating within them.

Action Potentials↗