The effects of proteins upon the filtration coefficient of individually perfused frog mesenteric capillaries.

The filtration coefficients (L_p) of the walls of individually perfused frog mesenteric capillaries have been measured using the methods described by Michel et al. (1974). When a vessel was perfused with frog Ringer solution containing no protein, L_p was four to five times greater than its value for the same capillary perfused with frog plasma. The increase of L_p seen on perfusion with protein-free solutions was readily reversible and could be prevented by adding to the Ringer perfusate bovine serum albumin, bovine γ-globulin and human haemoglobin. The addition of whale myoglobin (0.5 g 100 ml^?1) to the Ringer perfusate did not prevent an increase in L_p. Ringer solutions containing 0.1 g of bovine serum albumin 100 ml^?1 were as effective as those containing higher concentrations of albumin in preventing the increase in L_p, but the L_p of capillaries perfused with solutions containing 0.01 g of albumin 100 ml^?1 did not differ from the values for the same capillaries perfused with protein-free solutions. It was shown that in any given capillary, L_p was independent of the direction of fluid flow across the vessel wall and was the same when the capillary was perfused with 9.0 g of bovine albumin 100 ml^?1 and 3 g of bovine γ-globulin 100 ml^?1. Whereas the effects of L_p are seen within 1 min of removing the protein from the perfusate, no changes in L_p were observed during the first 20 min of perfusion and superfusion of capillaries with solutions free of Ca²⁺ and Mg²⁺. L_p also appeared to be unaffected after 20 min perfusion with neuraminidase. It is suggested that plasma proteins are adsorbed onto capillary walls and greatly modify capillary permeability.     

Effect of ventricular premature beats on idioventricular pacemaker activity

The effect of ventricular premature beats on idioventricular pacemaker activity was studied in open-chest dog hearts with a surgically induced block in the His bundle. While the ventricle was paced by basic stimuli at a given rate, the pacing was interrupted for about 2.5 seconds following every twelfth basic beat (V₁) in order to obtain the interval between V₁ and the first escape beat (V_e) or the basic escape interval (V₁V_e). Ventricular premature beats (V₂) were then introduced at various coupling intervals (V₁V₂) and the effect of these premature beats on the postextrasystolic escape interval (V₁V_e) was observed. The plot of V₂V_e against V₁V₂ intervals showed that the V₂V_e interval was shortest at shorter V₁V₂ intervals, and it increased gradually with the increase in V₁V₂ intervals. The V₂V_e intervals at shorter coupling intervals were much shorter than the basic escape interval (V₁V_e), indicating enhanced automaticity after early premature beats. The V₂V_e at longer coupling intervals were much longer than the basic escape intervals, indicating suppressed automaticity after late premature beats. The similar response to ventricular premature beats was noted during spontaneous idioventricular rhythm. The suppression was more pronounced at faster pacing rates and following two successive premature beats, probably due to the phenomenon of overdrive suppression. The same phenomena of altered automaticity after premature beats could be observed under the influence of ouabain, epinephrine, lidocaine, and propranolol, although these agents either decreased or increased the average escape intervals. The results may explain the clinically observed alteration of the idioventricular pacemaker rate following ventricular premature beats.     

A rapid method for the determination of glycosylated hemoglobins using high pressure liquid chromatography

Hemoglobin (Hb) A_Ic is a minor component of Hb found in normal individuals but elevated two or threefold in patients with diabetes mellitus. Limited studies have suggested that the level of Hb A_Ic is proportional to the integrated concentration of glucose over time. Thus it could serve as an index of hyperglycemia. Its measurement may enable a more objective approach to assessing whether or not the control of hyperglycemia can be correlated with the severity of complications of diabetes. Large scale clinical studies of Hb A_Ic have not been undertaken for lack of a rapid assay system. This article describes a method of high pressure liquid chromatography (HPLC) which enables the isolation of Hb A_Ic in 27 min using only 12 μg of Hb (100 μl of blood) and a second method for the isolation of total fast Hb components (also elevated in diabetes) in 11 min. Using the first method, a total of 36 assays were performed on the blood of a single normal volunteer over a one month period. The mean level of Hb A_Ic was 4.95 ± 0.12% (SD) ± 0.02% (SEM), while the coefficient of variation (C.V.) was 2.4%. The mean Hb A_Ia&b level was 1.65 ± 0.06% ± 0.01% (C.V. = 3.6%). Values for Hb A_Ic in 10 normal individuals were 5.06 (mean) ± 0.32% (SD) ± 0.10% (SEM). Hb A_Ic values in 15 patients with diabetes mellitus ranged from 6.8 to 20.0%. The second method was designed to assay Hb A_Ia, Hb A_Ib, and Hb A_Ic as a single peak and yielded results identical to the sum of these components as determined by the first method (r = 0.98; p < 0.001).     

Effect of prostaglandin A 1 on several vascular beds in man

The effect of PGA₁ on regional blood flow was studied at the time of arterial reconstruction in 19 aortocoronary grafts, five interval carotid arteries, eight aortofemoral grafts, and seven femoropopliteal grafts with the use of an electromagnetic flow probe. Bolus injections of 25 or 50 μg of PGA₁ were given IV or IA as well as papaverine (15 mg. IV or IA) which was used in evaluating the coronary circulation.PGA₁ (25 μg IA) increased flow in the coronary, femoral, and popliteal vascular beds but to a lesser degree than papaverine (15 mg.). When given IV, PGA₁ increased flow in only the femoral bed while papaverine, which was used in evaluating coronary flow only, resulted in a significant increase in coronary flow.     

Third F. Raymond Keating, Jr., Memorial Symposium--parathyroid hormone, calcitonin and vitamin D: clinical considerations. II. Vitamin D--1973

The recent advances in our understanding of the functional metabolism of vitamin D to 25-hydroxyvitamin D (25-(OH)D) and subsequently to 1,25-dihydroxyvitamin D (1,25-(OH)₂D) are presented with a review of current views on the regulation of vitamin D metabolism at the 25-hydroxylation and 1-hydroxylation stages. It seems clear that, physiologically, the latter regulation is governed by parathyroid hormone (PTH) under conditions of hypocalcemia and by serum inorganic phosphorus levels under conditions from normal to hypercalcemia. The molecular mechanism of the regulation of the renal hydroxylations remains unknown.The metabolism of 25-(OH)D₃ to 24,25-(OH)₂D₃ and further to 1,24,25-(OH)₃D₃ has been established. The significance of these reactions is unknown, but 1,24,25-(OH)₃D₃ preferentially stimulates intestinal calcium transport.The mechanism whereby 1,25-(OH)₂D₃ stimulates intestinal calcium transport and the receptors of this metabolite in intestine are discussed. In addition, the application of the metabolites of vitamin D to clinical problems has been considered and 1α-(OH)D₃, an important analog of 1,25-(OH)₂D₃, has been introduced as a potentially important therapeutic compound.     

Effects of intravenous fluorocarbons during and without oxygen enhancement on acute myocardial ischemic injury assessed by measurement of intramyocardial gas tensions

Fluorocarbons (fluorinated organic compounds in which O₂ and CO₂ are highly soluble) have been shown to be effective substitutes for the gas transport functions of blood. In order to investigate the effects of fluorocarbons on acute regional myocardial ischemia, we compared the rise of intramyocardial pCO₂ (ΔPm CO₂) and the decline in intramyocardial pO₂ (nadir PmO₂) produced by paired, temporary coronary artery occlusions (CAO) in anesthetized dogs instrumented with mass spectrometer probes positioned in ischemic myocardium. In protocol A (n = 7) dogs were ventilated with 100% O₂ alone during the first CAO and received fluorocarbons (perfluorochemicals, PFC) 40 ml/kg intravenously in addition to O₂ before a second CAO: ΔPmCO₂ fell from 32.8 ± 4.7 to 23.3 ± 3.9 mm Hg (p < 0.05) and the nadir PmO₂ was higher during the second CAO (21.6 ± 7.4 mm Hg) than during the first (9.4 ± 3.9 mm Hg, p < 0.05). In six dogs in protocol B also ventilated with 100% O₂, 40 ml/kg normal saline was infused before the second occlusion, but this did not alter the response to CAO. Thus the degree of volume expansion produced by PFCs did not reduce ischemia in dogs ventilated with 100% O₂. Subsequent studies were undertaken to determine whether circulating PFCs ameliorated acute ischemic injury in dogs ventilated with ambient air. In eight dogs in protocol C, ΔPmCO₂ was decreased after PFC administration; however, nadir PmO₂s were not altered by PFC; in seven dogs in protocol D receiving only normal saline between CAOs, there were no differences in myocardial gas tension. There were no changes in myocardial blood flow to the central ischemic zone between CAOs in any experimental group. We conclude that circulating PFCs reduce acute regional myocardial ischemia during ventilation with either 100% O₂ or ambient air, and that PFC-O₂ treatment augments myocardial O₂ availability in the central ischemic zone. The mechanisms by which PFC-O₂ and PFC administration reduce ischemic injury are likely multifactorial, combining elements of enhanced O₂ supply and decreased myocardial O₂ demand.     

The effects of cationised ferritin and native ferritin upon the filtration coefficient of single frog capillaries. Evidence that proteins in the endothelial cell coat influence permeability

To investigate whether certain macromolecules reduce capillary permeability by binding to the surface coat of endothelial cells, the effects of cationised ferritin (CF) upon the filtration coefficient (L_p) of individually perfused frog mesenteric capillaries were compared with those of native ferritin (NF). With perfusate CF concentrations between 0.1 g 100 ml^?1 and 2.5 g 100 ml^?1, L_p was reduced to approximately 30% of its value for the same vessel perfused with protein-free Ringer solution. Electron micrographs of the perfused capillaries revealed that over this range of perfusate concentrations, CF was concentrated uniformly in the endothelial cell coat, occupying 8.5% of its volume. Neither the effect of cationised ferritin upon L_p nor its concentration in the cell coat varied significantly over this range of perfusate concentrations. When perfusate concentration of CF was reduced to 0.01 g 100 ml^?1, CF no longer reduced L_p and its concentration in the cell coat fell below 2%. Native ferritin, which is excluded from the cell coat, did not reduce L_p at a perfusate concentration of 0.1 g 100 ml^?1. At a concentration of 2.5 g 100 ml^?1, NF reduced L_p in a few very permeable vessels (L_p > 60 × 10^?3μm sec^?1 cm H₂O^?1) but had no significant effect on vessels with lower and more normal values of L_p. The effects of CF upon L_p can be described in terms of the Kozeny equation if a major proportion of the hydraulic resistance through the capillary wall is attributed to a fiber protein matrix.     

Studies on obesity. III. Effect of triiodothyronine (T3) on thyroglobulin autoantibodies in euthyroid obese subjects

Effect of T₃ therapy on tanned red cell agglutinating thyroglobulin (TRC-TG) antibodies in 10 obese subjects without apparent thyroid disease was investigated. Six other obese subjects without thyroid dysfunction and of approximately the same mean age who also had circulating TRC-TG antibodies served as control subjects and were untreated. In vitro thyroid tests (TSH, total and free T₄) performed before T₃ therapy, as well as clinical examination, showed thyroid function to be normal in all subjects, and there was no evidence of thyroiditis. TRC-TG antibodies were present in low to moderate titers of 40–1280 in control subjects as well as in subjects selected for T₃ treatment. Therapy with T₃ was started at 50 μg/day and gradually increased to a maximum of 250 μg/day, depending on clinical needs. T₃-treated as well as untreated obese control subjects were all maintained on a high protein, low fat, low carbohydrate diet. Duration of T₃ therapy varied from 2–8 mo, and in all but one T₃-treated subject, TRC-TG antibodies completely disappeared. In the one exceptional case, TRC-TG antibody titer decreased from 1280 to 80 after 7 mo of therapy. In non-T₃-treated obese control subjects, antibody titers remained at the same levels throughout the observation period, thereby indicating a lack of spontaneous regression of circulating immune response. Therapy with T₃, by inhibiting TSH, may have caused regression of inapparent immunologic thyroid lesion, thus leading to the disappearance of circulating TRC antibodies; alternatively, T₃ specifically may have accelerated catabolism of thyroid antibodies. The latter possibility is favored in the absence of clinical and laboratory evidence of thyroiditis in T₃-treated subjects.     

Effects of prostaglandin H2, prostaglandin E2, and arachidonic acid on parathyroid hormone and antidiuretic hormone activation of rat kidney adenylate cyclase

These experiments examine interactions of arachidonic acid; the substrate for prostaglandin cyclooxygenase, prostaglandin (PG)H₂, a key endoperoxide intermediate in prostaglandin synthesis; and prostaglandin (PG)E₂, an important prostaglandin produced within the kidney; with adenylate cyclase activity in renal cortex, outer medulla, and inner medulla. In addition, the effects of arachidonic acid, PGH₂, and PGE₂ on parathyroid hormone (PTH) activation of adenylate cyclase in cortex, and of antidiuretic hormone (ADH) activation of that enzyme in outer and inner medulla are examined. Arachidonic acid elicited a concentration-dependent inhibition of basal and PTH-stimulated adenylate cyclase activity in renal cortex. Concentration-dependent inhibition by arachidonic acid of basal and ADH-stimulated adenylate cyclase activity was observed in outer and inner medulla. PGH₂ inhibited basal activity in all three areas of the kidney. There was also inhibition by PGH₂ of medullary ADH and cortical PTH stimulation. PGE₂ stimulated adenylate cyclase in all three areas. PGE₂ had no effect upon PTH stimulation in cortex and was additive with ADH in outer and inner medulla. PGE₂ stimulation was inhibited by arachidonic acid, and this inhibition seemed competitive. Inhibition by both arachidonic acid and PGH₂ was not destructive. Experiments with [1-¹⁴C]arachidonic acid and indomethacin suggest that the inhibition by arachidonic acid was actually mediated by arachidonic acid and not a metabolite. Both PGH₂ and arachidonic acid inhibition was independent of phosphodiesterase. This activation by product, PGE₂, and inhibition by its precursors, arachidonic acid and PGH₂, provide a possible mechanism by which the prostaglandin system could modulate adenylate cyclase responsiveness to hormonal activation.     

Observations on the untreated progeny of hypothyroid male rats

The untreated progeny (F₁) of hypothyroid male rats that were either radiothyroidectomized (Tx) or had the neo-T₄ syndrome (an endocrine disorder produced by large doses of thyroxine (T₄) injected during the neonatal period) were studied. The mother rats were all normal. The fathers never had any contact with their progeny.Unexpectedly, the progeny usually showed delayed eye opening, decreased weaning weights, and increased final body weight. The thyroid glands from F₁ offspring of both Tx and neo-T₄ fathers were enlarged significantly in all but F₁ males of Tx fathers. The F₁ of Tx fathers had significantly smaller uteri, both absolutely and relatively. The ovaries were significantly larger, whereas the testes were significantly smaller. Pituitary TSH, stalk-median eminence (SME) TSH, and serum TSH were all normal with the exception of an increase in SME TSH in F₁ males born of neo-T₄ fathers. The response to thyrotropin releasing hormone (TRH) stimulation of the F₁ adult progeny of neo-T₄ fathers was significantly blunted in the males, whereas the response was normal in the offspring of Tx fathers. The mechanisms by which hypothyroid fathers caused changes in their progeny is not known.     

Prevalence of the fourth heart sound by phonocardiography in the absence of cardiac disease

A blinded, prospective study of phonocardiograms revealed a fourth heart sound (S₄) in 181 of 245 consecutively examined ambulatory subjects in sinus rhythm aged 50 to 80 years whose clinical status was unknown until all graphic studies were tabulated. An S₄ was demonstrated in 113 (73.1 per cent) of 152 individuals with and 68 (74.3 per cent) of 93 individuals without evidence of cardiovascular disease, statistically an equal prevalence. S₄ in older persons appears to be “normal” phenomenon.     

Effects of vasodilators on pulmonary hemodynamics and gas exchange in left ventricular failure

Nitroprusside (NP) has been shown to improve left ventricular function in patients with congestive heart failure, but despite an increased cardiac output and decreased pulmonary capillary pressure, arterial oxygen tension (P_aO₂) may fall. In order to determine the mechanism of this hypoxemia, and to determine if similar effects occur with non-parenteral vasodilators, hemodynamic, respiratory, and blood gas responses to NP, hydralazine (H), and hydralazine combined with isiosorbide dinitrate (H+N) were studied in 10 patients with left ventricular failure. At the dosages used, all three drug regimens increased cardiac output equivalently, but pulmonary vascular responses differed. NP and H+N decreased mean pulmonary artery pressure, pulmonary wedge pressure, and pulmonary arteriolar resistance, while H did not. NP decreased P_aO₂ by 10.4 mm. Hg (p < .01) and H+N decreased it by 5.3 mm. Hg (p < .06) while H did not alter P_aO₂. Arteriolar-alveolar oxygen gradient increased with NP (150 ± 39 per cent, p < .01) and with H+N (73 ± 23 per cent, p < .01) but not H alone (51 ± 16 per cent). Similarly, per cent change in venous admixture increased on NP (28.7 ± 3.3 to 38.5 ± 3.1 per cent, p < .01) and H+N (28.1 ± 3.3 to 36.8 ± 3.5 per cent, p < .01) but not H alone (28.1 ± 3.3 to 31.5 ± 4.1 per cent). There was no increase in arterial carbon dioxide tension or change in pulmonary function studies with any of the drugs. Due to the increase in cardiac output, oxygen delivery index (cardiac output times arterial oxygen content) increased with each regimen despite the changes in P_aO₂. Changes in arteriolar-alveolar oxygen gradient correlate with the changes in pulmonary arteriolar resistance. Thus vasodilators which have prominent pulmonary vascular effects can decrease P_aO₂ in patients with congestive heart failure, and this effect is most likely due to increasing ventilation-perfusion inequities.     

Gap phenomenon in “the right and left bundle branch systems” during retrograde conduction in man

Gap phenomenon in right and left bundle branch systems during retrograde conduction is described in two patients with manifest reentry within the His-Purkinje System (V₃ phenomenon). In this form of gap the premature impulse (S₂) initially blocked in the right bundle branch system and conducted retrogradely via the left bundle branch system as manifested by sudden prolongation of S₂H₂ interval and appearance of V₃. At close coupling intervals S₂ impulse encountered retrograde block in the left bundle branch system and resumed retrograde conduction via the right bundle branch system with S₂H₂ intervals shorter than critical value and was not followed by V₃. However, on further shortening the S₁S₂ intervals S₂ impulse blocked again in right bundle branch system and resumed conduction via the left bundle branch system with S₂H₂ intervals longer than critical values and V₃ reappeared. The mechanism of these gaps is not clear but we believe is similar to the one proposed in Types I and II gaps in antegrade bundle branch conduction and involves proximal delay allowing distal recovery. The similarities and differences between the gap phenomenon in bundle branches during antegrade and retrograde conduction are discussed.     

Correlation of the location of coronary arterial spasm with the lead distribution of ST segment elevation during variant angina

The lead distribution of ST segment elevation produced by severe “spasm” of major coronary arteries was correlated with the specific artery involved in a group of 110 cases of variant angina with single vessel coronary arterial spasm made up from eight cases personally observed and 102 cases abstracted from published literature.The most sensitive and specific lead for ST elevation during anterior descending (LAD) coronary arterial spasm was V₃; V₂ was almost as good. For spasm of either the right (RCA) or circumflex coronary artery (CMFX), Leads 3 and aV_F showed ST elevation most frequently; electrocardiographically it was difficult to distinguish between spasm of these two vessels. ST elevation in Leads V₅ and V₆ was not specific, occurring in some cases of spasm of each of the three major coronary arteries. ST elevation in Lead V₁ occurred in either RCA or LAD spas, but never in CMFX spasm. ST elevation in Lead 1 was never seen with isolated RCA spasm.No single lead can detect all cases of transient ST elevation. Simultaneous monitoring of Leads 3 and V₃ would have detected 98.2% of 333 cases of ST elevation reviewed, and addition of Lead aV_L would have detected most of the remainder. These findings should be considered in lead selection for monitoring to detect ST elevation, and in using the ECG to identify spastic coronary arteries.     

Shell gland responsiveness to prostaglandins F2α and E1 and to arginine vasotocin during the laying cycle of the domestic hen (Gallus domesticus)

Contractile responses of isolated shell gland (SG) strips from laying hens displayed no significant differences 6 hrs before oviposition, at oviposition, and 6 hrs after oviposition when stimulated with arginine vasotocin (AVT), prostaglandin E₁ (PGE₁), or prostaglandin F_2α (PGF_2α). Dose-response curves show that the sensitivity of the SG to these agents, in vitro, is: AVT > PGF₂ > PGE₁. PGF_2α, however, produces the largest contractile response, while PGE₁ appears to be a poor agonist of contractile activity in vitro. These results are discussed in relation to the known hormonal patterns during the ovulatory cycle of the hen and the physiological roles attributed to these oxytocics in the control of oviposition.     

Antioxidant inhibition of prostaglandin production by rat renal medulla.

Antioxidant effects upon renal production of both prostaglandins and cAMP were investigated using slices of rat inner medulla. Synthetic antioxidants were more potent inhibitors of prostaglandin production than were naturally occurring antioxidants. Synthetic compounds 2,7-naphthalenediol, and Santoquin^® (Ethoxyquin) caused a 60% inhibition of prostaglandin E₂(PGE₂) synthesis at a concentration of 0.01 mM. Ascorbic acid caused only a 30% inhibition at a concentration of 10 mM. Antioxidant inhibition of prostaglandin production was also observed following arachidonic acid addition. Antioxidants that reduced PGE₂ synthesis also reduced PGF_2α synthesis. Test agents found to reduce prostaglandin synthesis also lowered cAMP content. 2,7-Naphthalenediol elicited a dose-dependent decrease in both prostaglandin synthesis and cAMP content. While PGE₁ did not increase cAMP in control slices, the low cAMP level produced by Santoquin was increased to control values by PGE₁. Furthermore, Santoquin and 2,7-naphthalenediol did not alter arginine vasopressin-stimulated cAMP content. By contrast, inhibition of the arginine vasopressin stimulation by butylated hydroxyanisole suggested additional effects by this agent. These results are consistent with the hypothesis that endogenously produced PGE₂ can exert a hormonelike action in the inner medulla by increasing cAMP content. Advantages of the inner medullary slice system compared to homogenates for investigation of the actions of antioxidants or other agents thought to alter prostaglandin synthesis are discussed.     

The orthogonal electrocardiogram in normal women. Implications of sex differences in diagnostic electrocariodgraphy.

Normal limits of the orthogonal electrocardiogram and vectorcardiogram in adult women, ranging in age from 18 to 90 years, are presented. A comparison of results is made with those of normal age-matched men, and sex differences are analyzed from a total of 960 normal records (510 men and 450 women). For the majority of scalar and vectorial items, significant sex differences were found which in women included shorter QRS duration, smaller vector loops, and decreased P, Q, R, S, and T deflections. The upper normal limits of R_x, R_y, and R_z amplitudes were 11 per cent, 20 per cent, and 30 per cent less, respectively, in women than in men.The sensitivity and specificity of electrocardiographic criteria, for high and low voltage, were significantly affected by these sex differences in amplitudes. For example, as a discriminator between normals and subjects with left ventricular hypertrophy, the upper normal limit of R_x + R_z amplitude sum was 3.10 millivolts in men but 2.50 millivolts in women. Hence, the use of the limit derived from males in a female population would decrease its sensitivity drasticially. Similar discrepancies existed in the sensitivity and specificity of electrocardiographic criteria for low voltage. Since the lower normal limit of R_x amplitude was 0.51 millivolt in men but only 0.35 millivolt in women, a substantial number of normal women would be misclassified as having right ventricular hypertrophy or chronic obstructive pulmonary disease if the limit derived from males was used as a criterion.The absence of Q waves in Leads x and y was a common finding in each age and sex group and carries no diagnostic significance. While initial anterior QRS forces in Lead z were present in all normal men, they were smaller and even absent in 1 per cent of normal women. Hence, greater difficulties in electrocardiographic diagnosis of anteroseptal myocardial infarction in women may be encountered.Mean vectors at the end of QRS (point J) and early part of the ST segment were more inferiorly and anteriorly directed in men than in women. T waves in Lead z were always negative in men, but flat or positive T waves were observed in some of the normal women. Sex differences in the level of point J and the ST segment may have important bearings on the interpretation of exercise electrocardiograms.The shorter QRS duration in women signified the importance of sex-specific limits for ventricular conduction delays.     

Effects of oral zinc loading on zinc metabolism in humans—I: Experimental studies

The effects of oral zinc on distribution, retention and excretion of orally administered ⁶⁵Zn were studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving 3–18 μCi of ⁶⁵Zn as ZnCl₂ orally after an overnight fast. In the second phase, started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received placebo for ZnSO₄. In the third phase 14 patients continued on placebo while 36 received ZnSO₄ (100mg/day Zn⁺⁺) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of ⁶⁵Zn tracer. Total body retention and activity in plasma and red blood cells were measured for all patients throughout the study. Ten of the 36 patients treated with ZnSO₄ had additional measurements of ⁶⁵Zn activity in liver and thigh made using external detectors. Total body retention during the second phase placebo period was not significantly different (p > 0.25) for the 36 subjects subsequently treated with ZnSO₄ (biological half-time (T_b) 378 ± 12 days) (mean ± SEM) and the 14 who were continued on placebo through the third phase of the study (T_b = 384 ± 8 days). During the third phase patients receiving ZnSO₄ showed an accelerated loss of total body ⁶⁵Zn (T_b = 235 ± 8 days) which was significantly different (p < 0.001) from half-time values during placebo treatment. Accelerated loss of ⁶⁵Zn from the thigh was apparent immediately, while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean ⁶⁵Zn activity from red blood cells.     

Serum thyroxine, free T4, triiodothyronine, and reverse-T3 in diphenylhydantoin-treated patients.

In order to determine the effects of the administration of diphenylhydantoin (DPH) on various parameters of thyroid function, serum samples from 47 male adults receiving therapeutic doses of DPH and 45 euthyroid control subjects were analyzed for total thyroxine (T₄) and an index of free T₄ concentration, using both a competitive protein-binding assay (CPBA) and a solid-phase radioimmunoassay (RIA), total 3,5,3′-triiodothyronine (T₃), 3,3′,5′-triiodothyronine (reverse-T₃, rT₃), and TSH, each measured by specific RIA. Mean total T₄ by both methods was depressed in the DPH group to 0.78 of the control level. Free T₄ Index by RIA was decreased on the average in DPH-patients exactly in proportion to the depression in total T₄. By the CPBA, the difference between two groups in Free T₄ Index was less marked but still significant (DPH/controls = 0.86, p < 0.01). The concentrations of total T₃ were virtually identical in the DPH and the control groups. The average $\text{T}{}_3\text{T}{}_4$ ratio was significantly higher in the DPH patients than in the controls (0.0178 versus 0.0132, p < 0.001). Serum rT₃ was depressed by DPH-treatment in approximately the same proportion to the decrease in total T₄. None of the DPH-patients had an elevated serum TSH. The above findings are interpreted as indirect evidence in support of the view that DPH stimulates T₄ metabolism, particularly the conversion of T₄ to T₃. The normal level of free T₃ may help to maintain a euthyroid state in spite of the decrease in free T₄. The data also define the “euthyroid” ranges for total and free T₄ levels by these methods in patients receiving DPH.     

Significance of P wave terminal force in presumably healthy middle-aged men

In a material comprising 695 males aged 40 to 60 years without cardiovascular disease, the prevalence of abnormal P wave terminal force in V₁ (V₁Ptf) (≤ ? 0.03 mm. second) at rest was 7.1 per cent, whereas the prevalence five minutes after a near-maximal exercise test was 25.4 per cent. Abnormal V₁Ptf was associated with a slightly higher systolic and diastolic blood pressure, maximal rise of systolic blood pressure, and maximal rate-pressure product during the exercise test. The prevalence of abnormal V₁Ptf was not significantly higher in another group of 95 individuals who were angiographied because of strong suspicion of latent coronary heart disease (CHD) according to exercise electrocardiogram.An abnormal V₁Ptf may be considered as a possibly clinically unimportant anomaly in other-wise healthy middle-aged men. V₁Ptf is not suitable as a tool for the diagnosis of latent CHD.