Jules Cohen

Reduced Red Cell Glycolysis, 2,3-Diphosphoglycerate and Adenosine Triphosphate Concentration, and Increased Hemoglobin-Oxygen Affinity Caused by Hypophosphatemia

Abstract A marked reduction in red cell glucose utilization, lactate production, and 2,3-diphosphoglycerate and adenosine triphosphate concentration occurred in a patient with intractable diarrhea ...

Determinants of Thyroxine-Induced Cardiac Hypertrophy in Mice

Thyroxine was administered to mice to determine whether the cardiac hypertrophy which accompanies experimental thyrotoxicosis is a result of circulatory changes produced by thyroxine, or the result of a hormonal effect on myocardial growth. When mice were fed both reserpine and thyroxine they developed as much cardiac hypertrophy as those fed thyroxine alone, although the circulatory changes associated with thyrotoxicosis were greatly reduced by reserpine treatment. In addition, when mice were injected with synthetic l-thyroxine, the rate of cardiac protein synthesis was increased before any definite circulatory changes were observed. The results suggest an effect of thyroid hormone on cardiac protein synthesis that is independent of the effects of the hormone on the general circulation.

Reduced Red Cell 2,3-Diphosphoglycerate and Adenosine Triphosphate, Hypophosphatemia, and Increased Hemoglobin-Oxygen Affinity after Cardiac Surgery

Serum inorganic phosphorous was decreased significantly on the third postoperative day following cardiac surgery in 18 patients initially studied. Reduced plasma inorganic phosphate has been shown to cause a reduced concentration of red cell organic phosphates, an important determinant of hemoglobin-oxygen affinity. Therefore, 10 consecutive patients were studied to determine if reduced 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) concentration and increased hemoglobin-oxygen affinity accompanied the fall in serum inorganic phosphate concentration.A significant fall in 2,3-DPG and an increase in hemoglobin-oxygen affinity was present in red cells of patients studied on the first postoperative day. A reduction in red cell ATP was also present and persisted for 5 days during which time red cell 2,3-DPG returned to levels which were in excess of preoperative values. The reduction in serum inorganic phosphorous followed the reduction in red cell 2,3-DPG and correlated with the reduction in ATP. The latter changes may indicate the diversion of glucose and more specifically 1,3-DPG into the Rapoport-Leubering pathway away from ATP generation at the phosphoglycerate kinase step and the utilization of plasma inorganic phosphate for 2,3-DPG resynthesis. Neither the transfusion of stored blood nor the effect of cardiopulmonary bypass fully explained the reduction in red cell 2,3-DPG and the inefficiency of hemoglobin function postoperatively. Further studies in postsurgical patients are needed to clarify the cause of the changes observed since they are potentially deleterious, especially in the subject with compromised cardiovascular and pulmonary function.

Effect of Propranolol on Oxygen Binding to Hemoglobin In Vitro and In Vivo

We have shown that propranolol reduces oxygen binding by hemoglobin in intact red cells by increasing the selective permeability of the red cell membrane resulting in an exodus of potassium, chloride, and water. The latter effects result in a new distribution of hydrogen ion between cell and plasma, and thereby a reduction in red cell pH. The reduction in pH can fully explain the change in hemoglobins affinity for oxygen based on the Bohr effect. Either D- or DL-propranolol can produce the change in red cell pH and oxygen binding by hemoglobin. The drug action on permeability is not prevented by epinephrine, although it is by chlorbutanol. Hence, the membrane action of propranolol does not appear to be related to its activity as a beta-adrenergic receptor blocking agent.Propranolol produced a marked alteration in red cell shape as well as in hydration (hypovolumic stomatocytes). The two effects were separable since dehydration of the cell by the addition of sucrose to plasma did not result in stomatocytes and chlorbutanol blocked the enhancement of permeability of the red cell membrane by propranolol without preventing the shape change (isovolumic stomatocytes). This suggests that propranolol may have two separate sites of membrane interaction.Propranolol (10 to 360 mg) administered to human subjects did not affect hemoglobin-oxygen affinity. This is explained by the fact that the concentration in blood after such doses is nearly 4,000 to 100-fold lower than that required to achieve changes in blood in vitro.

The relationships between arterial oxygen flow rate, oxygen binding by hemoglobin, and oxygen utilization after myocardial infarction.

The interrelationships of arterial oxygen flow rate index, oxygen binding by hemoglobin, and oxygen consumption have been examined in patients with acute myocardial infarction. Proportional extraction of oxygen increased in close association with decreasing oxygen flow rate, and hence, whole body oxygen consumption was constant over nearly a three-fold variation in arterial oxygen flow rate. A reduction in hemoglobin-oxygen affinity at in vivo conditions of pH. Pco(2) and temperature also occurred in proportion to the reduction in arterial oxygen flow rate. Therefore, the increased proportional removal of oxygen from arterial blood at low oxygen flow rates, required to maintain oxygen consumption, may have been facilitated by the reduced affinity of hemoglobin for oxygen at in vivo conditions. However, the decrease in affinity did not appear to explain more than 30-40% of the increased extraction. Respiratory alkalosis was a frequent occurrence in these patients and 2,3-diphosphoglycerate was positively associated with blood pH as well as with the time-averaged proportion of deoxyhemoglobin in arterial and venous blood.Hemoglobin-oxygen affinity measured at standard conditions and the mixed venous oxygen saturation were equally good indicators of reduced arterial oxygen flow rate in patients without shock. However, Svo(2) is more easily measured and is a more useful indicator of reduced oxygen flow rate, since its relationship to oxygen flow appears to be independent of affinity changes and time.

Medical education change: a detailed study of six medical schools.

Summary. This article reports a comparative case study of six selected USA medical schools, undertaken to identify factors that facilitate or obstruct innovation in medical education. The findings suggest that the culture of each medical school results from a combination of intra‐institutional and external factors. Together these forces influence substantially the fate of educational innovations. The institutional culture influences critical elements such as educational philosophy, leadership and resources provided in support of innovation. Equally important, the culture shapes the level and type of change a school considers and implements. The findings also suggest that the availability of resources and the creative impetus present in schools giving priority to research can benefit the educational goals and facilitate educational change.

The effects of a beta-adrenergic blocking agent, pronethalol, on digitalis-induced ventricular arrhythmias☆

Abstract The ability of pronethalol, a beta-adrenergic blocking agent, to protect against and to reverse digitalis-induced ventricular arrhythmias has been studied. Pronethalol quickly and permanently reverses arrhythmias due to acetylstrophanthidin. The dose of pronethalol required to restore promptly a sinus mehcanism was far in excess of that which produced acute beta-adrenergic blockade. Pretreatment with pronethalol, in a dose that yielded effective and prolonged beta-adrenergic blockade, failed to protect dogs against acetylstrophanthidin-induced arrhythmias in these experiments. Pretreatment with reserpine or guanethidine did not alter the ability of pronethalol to restore a sinus mechanism. It is concluded that the ability of pronethalol to reverse ventricular arrhythmias due to digitalis is not related to its action as an adrenergic blocking agent, but may be a function of its quinidine-like effect.

Aortic regurgitation first appearing 12 years after successful septal myectomy for hypertrophic obstructive cardiomyopathy

Substantial aortic regurgitation developed in a patient with hypertrophic (obstructive) cardiomyopathy (HCM) who underwent septal myectomy. It was first noted 12 years after surgery. There was no evidence for surgical damage to the valve, subacute bacterial endocarditis, coexisting discrete subaortic stenosis or any other known etiology of aortic incompetence. This experience suggests that aortic regurgitation occasionally may be a late mode of deterioration in surgically treated patients with hypertrophic cardiomyopathy. Possible mechanisms for the development of aortic incompetence in such patients are discussed.

Changes in red blood cell electrolyte concentrations in digitalis intoxication.

The value of red blood cell (RBC) sodium/potassium ratio in diagnosing digitalis toxicity was studied in 60 adult patients. The normal ratio was established in 34 healthy volunteers and in 10 patients with heart disease not receiving digoxin (group I). During chronic digoxin therapy, RBC sodium/potassium (Na/K) ratio and plasma digoxin were measured in 50 nontoxic patients (group II), in 10 toxic patients (group III), and in 9 of these 10 toxic patients after resolution of digoxin toxicity. Red cell sodium and RBC Na/K ratio in nontoxic patients were significantly greater than in the control group. Red cell sodium and the RBC Na/K ratio in toxic patients were significantly greater than in nontoxic patients. Despite significant group differences in these variables, however, there was considerable overlap among the subjects studied. After resolution of toxicity, red cell sodium and the RBC Na/K ratio fell to values indistinguishable from those in the nontoxic group. Although there was a statistically significant positive correlation between RBC Na/K ratio and plasma digoxin level, the RBC Na/K ratio had weak predictive value (33%) in determining digoxin toxicity. Plasma digoxin was a better predictor of digoxin toxicity (60%). The combination of plasma digoxin concentration and of RBC Na/K ratio had a higher calculated predictive value (75%), and may be more useful as an indicator of digoxin intoxication.

Evidence for a histamine-component of the heart rate response to stellate ganglion stimulation.

Histamine exerts a positive chronotropic effect on the myocardium mediated by histamine H 2 -receptors. High concentrations of histamine are present in both myocardial tissue and the stellate ganglia which innervate the heart. Stimulation of the right stellate ganglion produces a positive chronotropic myocardial response. These associations suggest a possible neurotransmitter role for histamine. The present study examines the effect of histamine H 1 - and H 2 -receptor blockers on the myocardial chronotropic response to stellate ganglion stimulation and the coronary sinus histamine concentration following right stellate ganglion stimulation in dogs. Neither metiamide alone nor in combination with diphenhydramine diminished the positive chronotropic response to right stellate ganglion stimulation. However, when the animals were pretreated with propranolol to eliminate the β-adrenergic component of the response, metiamide decreased the positive chronotropic response to right stellate ganglion stimulation by 63% (p 2 -receptors, may mediate a portion of the positive chronotropic response to right stellate ganglion stimulation in the dog.