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Activation of lymphocytes for proliferation is a crucial process in the immune response. Age-related deficiencies in this cellular response strongly correlate with deficiencies in the immune system response, with concomitant increase in disease severity and mortality. Defects associated with the transmission of the initial activation signal and with IL-2 production contribute to the depressed response, but defects in the IL-2 response mechanism also play important roles. A major factor in this area is the inability of the nuclei of these cells to respond to the intracellular factor ADR, which plays a crucial role in the initiation of DNA replication. These cells produce normal levels of ADR; thus, either the nuclei cannot bind ADR in a productive manner or the defect lies beyond the point of ADR binding, perhaps in one of the other proteins of the initiation complex. An interesting contrast to the age-related failure of nuclei to respond to ADR is the failure of neoplastic nuclei to respond to the ADR inhibitor. This inhibitor, found in the cytoplasm of quiescent cells, suppresses both the activation of quiescent nuclei by ADR and the ongoing DNA synthesis in isolated nuclei from activated cells. Nuclei from spontaneous proliferating cell lines were not affected by this inhibitor, which may be an important factor in the uncontrolled growth seen in neoplastic cells. The investigation of ADR has given hints that perhaps two of the fundamental questions in biology, namely why some cells don't proliferate and why some others won't stop proliferating, may be two sides of the same coin.

The effects of intra-arterial administration of alpha-1 and alpha-2 adrenoceptor agonists and antagonists on human digital blood flow were studied before and during reflex sympathetic vasoconstriction in normal subjects. Total finger flow was measured by venous occlusion air plethysmography and capillary flow by the disappearance rate of a radioisotope from a local injection in a fingerpad. Intra-arterial phenylephrine (0·2–1·3 μg min-1) and clonidine (0·12–0·48 μg min-1) produced dose-related decreases in finger blood flow and increases in vascular resistance. Clonidine was the more potent vasoconstrictor. Prazosin (0·48 μg min-1) effectively blocked the vasoconstrictor effect of phenylephrine but not clonidine, while yohimbine (30–70 μg min-1) blocked the effect of clonidine but not phenylephrine. In a 20°C room, prazosin (0·4–13·2 μg min-1) caused no significant changes in finger blood flow (7·7 ± 2·1 to 11·7 ± 3·3 ml min-1) 100 ml-1) or vascular resistance (30·9 ± 8·8 to 28·1 ± 8·7 mmHg ml-1 min-1 100 ml-1). In the 20°C room, yohimbine (30–70 μg min-1) produced a significant increase in finger blood flow (7·8 ± 2·8 to 23·4 ± 6·8 ml, P>0·01) and decrease in vascular resistance (20·5 ± 5·7 to 6·0 ± 2·2 units, P>0·01). No significant changes occurred in finger capillary flow with prazosin or yohimbine infusions. It is concluded that alpha-1 and alpha-2 adrenoceptors are present in human digital vasculature and that alpha-2 adrenoceptors are more important than alpha-1 adrenoceptors in sympathetic neural vasoconstriction. Since capillary blood flow was unaffected by yohimbine infusions during reflex sympathetic vasoconstriction, the alpha-2 adrenoceptors predominantly influence arteriovenous shunts in the finger.

To determine whether thromboxane A2 may be of pathogenetic importance in Raynaud's phenomenon, finger hemodynamic and clinical responses to dazoxiben, a thromboxane synthetase inhibitor, were studied in 25 subjects. Thirteen subjects had idiopathic Raynaud's disease and 12 subjects had secondary Raynaud's disease. A double-blind, 2-week crossover study design was used. Dazoxiben dose was 100 mg four times a day. Total fingertip blood flow (FBF) by venous occlusion plethysmography, fingertip capillary flow (FCF) by radioisotope disappearance rate, and finger systolic blood pressure (FSP) were measured in a 28.3 degree and a 20 degree room at the end of each period. Subjects kept diaries of vasospastic attacks. For the 25 subjects and the two subgroups, dazoxiben did not improve total FBF, FCF, or FSP. Subjects with idiopathic Raynaud's disease had a small decrease in the number of vasospastic attacks and an increase in percentage of attack-free days on dazoxiben, but in an overall evaluation by the subjects in both subgroups, dazoxiben did not improve symptoms. It is concluded that thromboxane is not of pathogenetic importance in Raynaud's phenomenon and that thromboxane synthesis inhibition is not of therapeutic benefit.

Risk factors for venous thrombosis include conditions leading to venous stasis, hypercoagulable states, and trauma to veins. The most important factor is venous stasis. Both extrinsic and intrinsic coagulation pathways are intimately involved in the thrombotic process. In recent years, the importance in thrombus formation of the endothelium, platelet products, the fibrinolytic system, and inhibitors of clotting mechanisms has been discovered. Deficiencies of proteins that normally protect against venous thrombosis have been found. Heparin therapy with subsequent warfarin therapy is still the primary treatment for deep venous thrombosis or pulmonary emboli. Fibrinolytic agents lyse pulmonary emboli but are not as effective in deep venous thrombosis. The incidence of serious bleeding complications has hampered the use of fibrinolytic agents except in emergency situations. Even the newer agents, which act more specifically on thrombi instead of on plasma factors, are associated with a similar incidence of hemorrhagic events. Dextrans are a suitable alternative for treatment of deep venous thrombosis when heparin cannot be used. In the prophylaxis of deep venous thrombosis, minidose heparin (5,000 U every 8 hours subcutaneously) is effective, safe, and convenient in most situations. Heparin-dihydroergotamine, dextran, or warfarin can also be used. Aspirin has been disappointing. In orthopaedic surgery, minidose heparin is not protective; large pulmonary emboli may be prevented by starting warfarin therapy at the time of surgery or by daily dextran infusions. Finally, recent studies have shown that lower doses of warfarin than previously recommended are protective against recurrent venous thrombosis and have a reduced risk of hemorrhagic complications.

Digital vasospastic phenomena have been reported to result from use of nonselective and cardioselective beta-adrenoreceptor-blocking drugs. The effects of 80 mg/day propranolol and 100 mg/day metoprolol on finger hemodynamics and clinical responses were compared with those of placebo in 16 patients with Raynaud's phenomenon. A double-blind, 2 week crossover study design was used with a 2 week washout placebo period between drugs. Total fingertip blood flow (FBF) as determined by venous occlusion plethysmography, fingertip capillary flow (FCF) as determined by radioisotope disappearance rate, and finger systolic blood pressure (FSP) were measured in a 28.3 degrees and a 20 degrees C room at the end of each period. Subjects kept diaries to record vasospastic attacks. There were no significant changes in FBF, FCF, or FSP in the warm or cool environment during drug treatment as compared with during the placebo period. A decrease in pulse rate occurred with both drugs and there was a decrease in blood pressure with metoprolol. There were no significant changes in the number of vasospastic attacks or in the patients' overall evaluation of their conditions while they were receiving the drugs. It is concluded that the presence of Raynaud's phenomenon is not a contraindication to the use of beta-adrenoreceptor-blocking drugs in the normotensive population.

The effect was determined of changes in heart rate and of intracoronary isoproterenol, levarterenol, and epinephrine on coronary flow in the stopped and beating heart. It was possible by this means to estimate the relative action of these variables on the extravascular and intravascular resistance of the coronary bed in a heart perfused at constant pressure. As heart rate was increased extravascular resistance rose, but intravascular resistance fell to a greater extent indicating a fall in net coronary resistance. Isoproterenol had the greatest and epinephrine the least effect in decreasing the total coronary resistance. The three drugs tested caused only a small fall in extravascular resistance. Since the effect was small, it was concluded that extravascular resistance can be ignored in determining the direct effect of these drugs upon the coronary vasculature.

Calf and foot blood flow responses to intravenous epinephrine and norepinephrine were studied by venous occlusion plethysmography. Subjects were studied on two control days and after having ingested 3.6 gms. aspirin daily for two days. Epinephrine-induced vasoconstriction in the foot and vasodilation in the calf were significantly reduced after aspirin as was norepinephrine-induced vasoconstriction in both the foot and the calf. Skin temperatures confirmed the reduction of cutaneous vasoconstrictor responses by aspirin. Pulse and blood pressure responses were unaffected. Le responsas del fluxo de sanguine in sura e pede al administration intravenose de epinephrina e norepinephrina esseva studiate per plethysmographia a occlusion venose. Le subjectos esseva studiate in duo dies de controlo e post haber ingerite aspirina durante duo dies in un dosage de 3,6 g per die. Le vasoconstriction inducite in le pede per epinephrina e le vasodilatation inducite in le sura per ille mesme pharmaco esseva reducite de maniera significative post le uso de aspirina, e le mesmo valeva pro le vasoconstriction inducite per norepinephrina tanto in le pede como etiam in le sura. Le temperaturas cutanee confirmava le effecto reductori de aspirina super le cutanee responsas vasocontrictori. Le responsas del pulso e del tension sanguinee non esseva afficite.

Blood flow and oxygen consumption of the hind limb of the dog were determined before and following short periods of femoral artery occlusions during rest and three levels of exercise. Flow debts were underpaid or barely repaid. Oxygen debts were entirely or partially repaid depending upon the level of muscle performance and the duration of the ischemic period. In resting muscle and during light exercise, both increased blood flow and oxygen extraction were involved in repayment of the oxygen debts while an increased blood flow was most important during medium and strong exercise. Since oxygen debts were often not repaid during strong exercise in the presence of a decreased arteriovenous oxygen difference (and often an oxygen utilization below control levels), oxygen extraction was the limiting factor. Significant excess repayments of oxygen debts occurred in resting muscle and for 30-sec ischemic periods during light and medium exercise. The similarity of these data, especially during medium and strong exercise of skeletal muscles, to the responses of the beating dog heart to ischemic periods is pointed out.

Cota-Robles , E. H. (University of California, Riverside) and M. D. Coffman . Fine structure of the bacteriophage attachment process. J. Bacteriol. 86: 266–273. 1963.—Electron microscopic examination of cells of Escherichia coli infected with coliphage T 2 suggested that the tail spikes of the virus attach to the cell wall. This is followed by a local disorganization of the cell wall and contraction of the virus tail resulting in the approximation of the virus to the cell. Ejection of the viral contents is followed by a retraction of the attached viral ghost from the infected cell. The bacterial cells reveal a fibrillar nuclear structure which in some cases surrounds material that appears to be of cytoplasmic origin.

The clinical and pathologic findings are presented of a patient with pseudoxanthoma elasticum leading to fatal valvular heart disease. The literature concerning the involvement of the heart by this disease is reviewed and reveals that valvular heart disease has not been described as a clinical problem heretofore. The occurrence of the condition in the relatives of the patient is described.

A TEST to demonstrate the deficit in muscle blood flow during exercise in patients with intermittent claudication is necessary for objective diagnosis and evaluation of treatment. In arteriosclerosis obliterans the symptoms and deficit in blood flow are usually present only during exercise. Diagnostic tests in current use either do not indicate the amount of blood flow (arteriography) or cannot be used to measure blood flow during exercise (plethysmography). Therefore, the diagnosis of occlusive vascular disease is most often based on subjective symptoms and physical findings that may sometimes be secondary to other conditions. Dependence on subjective symptoms and tests which . . .

Although digitalis overdosage is known to produce a variety of atrial, junctional, and ventricular arrhythmias, atrial flutter due to digitalis intoxication has been rarely reported. The present paper reviews the literature and reports what appears to be the sixteenth case. The available information on the accepted cases of atrial flutter due to digitalis toxicity has been analyzed for clues as to when digitalis can be considered the cause of the flutter.

The return of A-V conduction according to the electrocardiogram, the ability to maintain the blood pressure, the cardiac muscle ATP, the coronary venous pH, lactic acid, and potassium were studied to delineate the effects on the heart of prolonged periods of anoxia in dogs maintained on an extracorporeal circulation. Myocardial anoxia for 100 minutes was the limit for return of A-V conduction in all dogs in these experiments. Only 2 of 5 hearts anoxic for 120 minutes, and 1 of 3 hearts anoxic for 150 minutes regained A-V conduction. One heart subjected to anoxia for 165 minutes did not show A-V conduction on reperfusion of the coronary arteries. The dogs whose hearts were subjected to periods of anoxia longer than 100 minutes could not maintain the blood pressure on removal from the extracorporeal circulation. This was due to the development of an unusual firmness of the left ventricular muscle, usually appearing after 90 minutes of anoxia and progressing to involve the entire heart. This firmness was not reversible on reperfusion of the heart. Since A-V conduction and speed of conduction returned in some of these firm hearts, it was concluded that there was earlier permanent damage to the myocardial muscle than to the conduction system during anoxia. Cardiac muscle ATP values were not definitely changed after 30 minutes of anoxia, but were decreased and regenerated on reperfusion of the heart after 60 minutes of anoxia. The low levels of ATP did not return toward normal on reperfusion of the heart after 90 and 120 minutes of myocardial anoxia. Additional experiments on anoxic hearts of nonperfused dogs also demonstrated the marked decrease in ATP levels. In both types of studies, the earliest onsets of firmness showed some correlation with low ATP levels. The high lactic acid levels and low pH values of the coronary venous blood found after long periods of anoxia may be related to the failure of ATP regeneration and to the onset of firmness in these hearts. Potassium arrest of hearts subjected to anoxia showed no difference in the return of A-V conduction, in the ability to maintain blood pressure on removal from the extracorporeal circulation, in the onset or degree of myocardial firmness, nor in the levels of cardiac muscle ATP, coronary venous pH, and lactic acid, from the anoxic, nonarrested hearts. The variability of the effect of anoxia on A-V conduction and myocardial muscle of different hearts by the parameters measured in this study is stressed.

Coronary blood flow, myocardial oxygen usage, and coronary venous lactate and pyruvate concentrations before and after release of left coronary or left circumflex artery occlusions (10–120 sec) were studied in anesthetized, open-chest dogs. Flow and oxygen theoretical debts were calculated from control blood flow and oxygen usage and compared to the repayments. Flow debts were usually overpaid for all durations of occlusion. Oxygen debts were repaid with an average excess of 1.0 and 3.5 cc after 15 and 30 sec but with a deficit of 0.4 cc for 10-sec left coronary artery occlusions. Excess lactate, as a measure of oxygen debt, was present after 50% of the 30-sec left coronary artery occlusions and after all of the 120-sec circumflex artery clampings. It was demonstrated that ischemia stimulates blood flow and myocardial oxygen consumption and increases oxygen availability. Results indicate that the myocardium can tolerate only brief periods of arterial occlusion but can develop and repay small oxygen debts.

The exercise test as described in this study gives graphic evidence of the deficit in muscle blood flow during exercise in patients with intermittent claudication. It is easy to perform and can be done on an outpatient basis. The equipment cost is reasonable, NaI 131 is available in most hospitals, and the amount of radioactive material received by the patient is very small. Two people can perform the test on both legs of a patient in 45 minutes. Records are easy to interpret; if the isotope disappearance stops, the counts need not even be plotted to determine if the test is abnormal. The exercise test can be used in the diagnosis of leg pain of uncertain etiology, to study the effects of medical or surgical treatment, and in the clinical investigation of the symptoms of intermittent claudication.

Total (plethysmography) and capillary (radioisotope disappearance rate) fingertip flows were measured in 24 patients with Raynaud's phenomenon and compared to 10 normal subjects in a warm room and during reflex sympathetic nerve stimulation by body cooling. Arteriovenous shunt flow was estimated by subtraction of capillary from total flow. Patients with Raynaud's phenomenon had a significantly smaller capillary flow in both warm (6.4 vs. 10 ml per 100 g per minute) and cool (4.0 vs. 7.0 ml) rooms than normal subjects. With body cooling, total and arteriovenous shunt flow, but not capillary flow, decreased significantly in normal controls, whereas all three decreased in Raynaud's phenomenon. During oral reserpine treatment, 11 patients with Raynaud's phenomenon showed a significantly larger capillary flow during warming (8.7 vs. 5.7 ml) and cooling (6.2 vs. 2.8 ml). Patients with Raynaud's phenomenon have a smaller finger nutritional (capillary) flow than normal subjects, and this flow decreases s...

Thirty-three anesthetized dogs of varying weights were subjected to complete asphyxia by tracheal occlusion to produce uniform anoxia of the heart. Eleven showed electrocardiographic evidence of ventricular fibrillation while the other twenty-two demonstrated cardiac arrest. The development of ventricular fibrillation correlated with the heavier body and heart weights and with a lower average right atrial serum potassium level as compared to the dogs not fibrillating. Other serum electrolytes, pH, body temperature and sex showed no correlation with the arrhythmia. The importance of the fact that large dogs have a greater susceptibility to develop ventricular fibrillation during uniform anoxia of the heart is discussed in relation to experimental research on dogs and to a current theory of the cause of ventricular fibrillation.

The effects of intra-arterial and intravenous infusions of epinephrine on total blood flow in the calf and on capillary blood flow in calf muscle were determined in human subjects rising venous occlusion plethysmography and radioisotope disappearance rates respectively. The two technics usually demonstrated similar changes with both intravenous and intraarterial routes of administration. Since intravenous epinephrine affected the radioisotope disappearance rates, the hypothesis that epinephrine acts on arteriovenous shunts alone does not appear to apply in these experiments. Intra-arterial epinephrine often produced a sustained increase in blood flow similar to that produced by intravenous epinephrine, indicating that the initial and sustained actions could be explained by local effects of the agent. These studies also add further support for using the radioisotope disappearance rate as a qualitative measure of skeletal muscle blood flow.

Disturbances in microvascular function were studied by measurement of capillary diffusion capacity (CDC), capillary filtration coefficients (CFC) and resting and hyperemic skeletal muscle blood flows in normal persons and patients with prediabetes and diabetes with and without microangiopathy. Blood flow, CDC and CFC were determined by calf venous-occlusion plethysmography and 133Xe and 131l clearances from hyperemic anterior tibial muscle. Diabetic patients with microangiopathy had significantly larger CDC's and 131l clearances than the normal controls (p less than 0.01) and diabetic patients without microangiopathy (p less than 0.05). Normal persons had hyperemic muscle flows (133Xe) significantly greater than those in the other groups (p less than 0.05). Resting flows and CFC's did not differ significantly among the groups. Three of 11 prediabetic subjects had very abnormal CDC's. The finding of normal CFC and abnormal CDC in diabetic patients with microvascular disease suggests that small ves...

The effects of continuous intra-arterial and intravenous infusion of synthetic bradykinin on plethysmographic calf blood flow and radioisotope disappearance rates from skeletal muscle, and on calf oxygen utilization in man were studied. The plethysmographic findings during intra-arterial infusion of bradykinin demonstrated a large increase in the total calf blood flow. The radioisotope disappearance rates indicated that skeletal muscle capillary blood flow was definitely involved and that bradykinin does not act on arteriovenous shunts alone. The response to continuous infusion may be transient, sustained, or intermittent, depending largely upon the dose. During continuous intra-arterial infusions of bradykinin, the oxygen utilization changes were variable but, after 5–10 min, were not statistically significant compared to control values. The lack of effect of intravenous infusion and the rapid return of flow to control levels when intra-arterial injections are discontinued confirm the rapid destruction of the endogenous polypeptide in the body. Submitted on February 7, 1963

Many physicians do not feel competent in the diagnosis of peripheral obstructive arterial disease. This fact reflects a tendency to omit examination of the peripheral vasculature in patients without complaints in that area or in routine physical examinations. Even in university-hospital settings, peripheral pulses are often not recorded in the detailed physical examinations. If the physician is not skilled in palpating normal pulses, he cannot expect to detect the abnormal. Patients with symptomatic aortoiliac atherosclerosis are frequently treated as orthopedic or neurologic problems, and those with lumbar-disk disease, neurogenic claudication, or arthritis are often referred to vascular specialists. What is . . .